Affiliation of authors: Division of Population Studies and Human Genetics, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland, Australia.
Correspondence to: David C. Whiteman, M.B.B.S., Ph.D., Division of Population Studies and Human Genetics, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Queensland 4029 Australia (e-mail: daveW{at}qimr.edu.au).
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ABSTRACT |
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INTRODUCTION |
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Much of the uncertainty in understanding how sunlight causes melanoma appears to stem from the implicit assumption that all cutaneous melanomas arise through the same pathologic pathway. There is no reason a priori why this should be so, given that carcinogenesis is an extraordinarily complex process involving disruption of one or more molecular, cellular, and immunologic control mechanisms.
We have previously suggested a "divergent pathway" model for the development of cutaneous melanoma (9). Under this model, people with an inherently low propensity for melanocyte proliferation require chronic sun exposure to drive clonal expansion of transformed epidermal melanocytes. If we assume that the hypothesis is correct, then melanomas arising in this group of people should occur on habitually sun-exposed body sites such as the face. In contrast, among people with an inherently high propensity for melanocyte proliferation (as characterized by high nevus counts), we predict that exposure to sunlight is required early in the process of carcinogenesis, after which host factors drive melanoma development. This group of patients would be expected to have less solar damage than the former group of melanoma patients and would be expected to develop their tumors on body sites with unstable melanocyte populations such as the trunk. We tested this divergent pathway hypothesis for the development of melanoma according to anatomical site in a population-based epidemiologic study.
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PATIENTS AND METHODS |
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Patients
Patients eligible for inclusion in the study were all residents of the greater Brisbane region (population = 1.5 million; latitude = 27°S) who had their first histologic diagnosis of primary cutaneous melanoma between January 1, 1998, and December 31, 1999. Patients with metastatic disease or a previous diagnosis of melanoma were excluded from this analysis. We randomly selected patients from among three prespecified groups by use of a computer algorithm. The first group was restricted to people with invasive superficial spreading melanoma or nodular melanoma of the trunk (the reference group, n = 154), the second group was restricted to people with invasive superficial spreading melanoma or nodular melanoma of the head and neck (the principal comparison group, n = 77), and the third group was restricted to people with a first diagnosis of primary in situ or invasive lentigo maligna melanoma (LMM) (n = 75). This third group was chosen as a "chronic sun exposure control group" because the LMM subtype is widely accepted as being caused by chronic exposure to sunlight and because of the presence of solar elastosis features in some histologic criteria for LMM (10). Sampling within the three groups of patients was weighted with the aim of achieving similar proportions of participants within strata of sex and age (50 years or younger versus older than 50 years) to maximize statistical efficiency. All participants provided written consent before entering the study.
Data Collection
Participants completed a structured questionnaire and underwent a physical examination. Respondents were asked to report basic demographic details, such as their place of birth (and age at migration to Australia if applicable) and phenotypic characteristics including their hair color as a teenager and the typical reaction of their skin after acute and chronic exposure to the sun (e.g., "tendency to burn" and "ability to tan"). A brief sun exposure history was obtained for the years while attending school, including details such as time spent outdoors after school in summer. Participants were also asked to complete an occupational history (including periods of study and unemployment) since leaving school. For each occupational period, we recorded the number of days per week worked in that job and the typical time spent outdoors on working days. We asked respondents to report both the density of freckles on their face as a teenager and their nevus burden as a teenager from among four categories on a pictorial scale (available at http://jncicancerspectrum.oupjournals.org/jnci/content/vol95/issue11/). A medical history was obtained, in which respondents were asked whether they had ever been treated for solar keratoses ("sunspots") and, if so, to give the number of lesions that had been treated by freezing, creams, excision, or other means. Respondents were also asked to report previous treatments for keratinocyte cancers (basal cell carcinomas and squamous cell carcinomas). Many respondents indicated that they were uncertain whether previously treated skin lesions were solar keratoses or keratinocyte cancers; therefore, we pooled responses to these questions for the analysis and, hereafter, refer to them collectively as "treated solar skin lesions."
The same trained research nurse, who was unaware of the study hypotheses, examined each participant. The nurse recorded hair and eye color and counted melanocytic nevi and solar keratoses. Nevi were defined as pigmented macules or papules of any size and were distinguished from freckles and seborrheic keratoses. Numbers of nevi were counted on the head and neck, the upper limbs, and the trunk and were classified according to size as less than 5 mm or greater than or equal to 5 mm in diameter by use of a transparent plastic stencil. Freckles were defined as irregular but sharply demarcated macules, usually small (<4 mm in diameter), uniformly pigmented (tan or light brown), and usually occurring in clusters on exposed body sites. The density of freckling on the face was categorized on a four-point scale. Solar keratoses, defined as superficial, rough scaly areas with erythematous background and ill-defined margins, were counted separately on the dorsal surfaces of the hands, forearms, and face.
Statistical Analysis
Numbers of nevi and solar keratoses were categorized at approximate tertile cut points across the distribution for all patients, and the group with the fewest lesions served as the reference category. We calculated a cumulative occupational sun exposure index for each participant by summing the time spent outdoors for each period of employment, weighted by the duration of employment (in years) and the number of days per week worked in each job. The distribution of the occupational sun exposure index was categorized at tertile cut points. We measured the strength of association between risk factors and each melanoma group by calculating the exposure odds ratio (OR) and 95% confidence interval (95% CI) with polytomous multivariable logistic regression analysis. The reference group in all analyses was patients with melanomas of the trunk, to which the two other groups of melanoma patients were compared. We adjusted for exact age in years and also included a term for age squared in all models to adjust for residual confounding by nonlinear effects of age. To test for trend, categorical data were included in the model as continuous variables, and the corresponding Wald statistic was compared to a 2 statistic with one degree of freedom. Statistical significance was determined at
= .05, and all tests for statistical significance were two-sided. All analyses were performed with SAS software (release 8.2; SAS Institute, Cary, NC).
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RESULTS |
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Overall, 46 participants were born outside Australia; 36 of these were born in countries with a mean latitude greater than 30° (i.e., more distant from the equator than Queensland), and the remainder were born in lower latitude countries (including Zimbabwe, Papua New Guinea, and Malaysia). People with melanomas of the head and neck or LMM were less likely to be born outside Australia than people with truncal melanomas (for head and neck melanomas, OR = 0.55, 95% CI = 0.23 to 1.30 and for LMM, OR = 0.64, 95% CI = 0.27 to 1.52), although these effects were not statistically significant.
There was no difference in the distribution of the various self-reported measures of childhood sun exposure among the three groups of melanoma patients. In contrast, patients with head and neck melanoma were statistically significantly more likely to be in the medium (OR = 2.27, 95% CI = 1.04 to 4.99) or high (OR = 3.70, 95% CI = 1.52 to 8.98) categories of cumulative occupational sun exposure compared with patients with truncal melanoma, after adjusting for exact age, age squared, and sex. Patients with LMM were somewhat more likely to be in the highest category of occupational sun exposure; however, this was not statistically significant (OR = 1.82, 95% CI = 0.80 to 4.13).
Pigmentary Characteristics
We found no evidence that the distribution of variants of hair color, eye color, or reaction of the skin to acute or chronic sun exposure differed among the patients with melanomas of the trunk or the head and neck or with LMM (data not shown). These pigmentary characteristics were not considered further in subsequent analyses.
Numbers of Nevi
Overall, 96% of participants had at least one nevus on the upper limbs, trunk, or head and neck (median = 33 nevi, range = 0444 nevi). Patients with melanomas of the head and neck, compared with patients with melanomas of the trunk, were significantly less likely to have more than 60 nevi (OR = 0.34, 95% CI = 0.15 to 0.79) (Table 2), as were patients with LMM (OR = 0.32, 95% CI = 0.14 to 0.75). Similar patterns were observed in stratified analyses among patients aged 50 years or younger and among patients older than 50 years (data not shown). Patients with melanomas of the head and neck were statistically significantly less likely than patients with truncal melanomas to have five or more large nevi (OR = 0.41, 95% CI = 0.19 to 0.89). Similarly, patients with LMM were less likely to have five or more large nevi than those with melanoma of the trunk (OR = 0.33, 95% CI = 0.15 to 0.73) and were also statistically significantly less likely to report having many nevi as a teenager (Table 2
). However, patients with head and neck melanomas did not differ from the reference group in their self-reported prevalence of nevi as a teenager.
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Facial freckling at the time of interview was relatively uncommon, with approximately 60% of these adult participants having none, and was similarly prevalent among the three groups of melanoma patients (data not shown). However, patients with melanomas of the head or neck were more than twice as likely to report moderate or heavy freckling of the face as a teenager as patients with melanomas of the trunk (OR = 2.32, 95% CI = 1.11 to 4.87). Patients with LMM were also more likely than patients with truncal melanomas to report the presence of freckles as a teenager, although this association was statistically significant only for intermediate categories of freckling (Table 2).
Solar Skin Lesions
The prevalence of solar keratoses was high among this sample of melanoma patients residing in subtropical Queensland, with 64% of participants having at least one such lesion identified at interview (median = 4 lesions, range = 0262 lesions). A similar proportion (70%) of participants reported having had prior treatment for solar skin lesions, and the self-reported number of treated lesions was positively associated with the nurses counts of solar keratoses (P<.001).
Patients with head and neck melanomas were more than three times as likely as patients with trunk melanomas to have any solar keratoses (Table 3), and this strong association was clearly observed among both younger (
50 years) and older (>50 years) patients (data not shown). Similarly, patients with head and neck melanomas were almost twice as likely as patients with melanomas of the trunk to report a past history of treatment for solar skin lesions (OR = 1.87, 95% CI = 0.89 to 3.92), although this result was not statistically significant. We restricted the analysis to include only those reported lesions that had been treated by excision as a means of identifying lesions most likely to have been skin cancers. We found a statistically significant trend of increasing odds of melanoma of the head and neck versus melanoma of the trunk with greater numbers of previously excised skin lesions (Ptrend = .017; Table 3
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Finally, we fitted models simultaneously including terms for both melanocytic nevi and solar keratoses to adjust for possible confounding (Table 4). The patterns of association were essentially unchanged by mutual adjustment among patients with melanomas of the head and neck; however, including nevi in the model attenuated the association between numbers of solar keratoses and LMM.
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DISCUSSION |
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We believe that our study is a critical test of the divergent pathway hypothesis (9) and that our results support the existence of at least two different pathologic pathways to melanoma. Our schematic representation of the divergent pathway model is presented in Fig. 1. The model builds upon evidence from epidemiologic (11) and animal (12) studies that epidermal melanocytes are predominantly initiated and transformed by exposure to sunlight early in life. We propose that the factors that then drive melanoma development vary according to phenotypic and environmental conditions experienced by the host. After initiation by sunlight, melanocytes of nevus-prone individuals are induced to proliferate and become neoplastic with little (if any) further requirement for sun exposure. Among this group of people, melanomas are more likely to arise among the numerically large and ontogenetically "unstable" populations of melanocytes on the trunk (13,14), as we have found in this study.
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Our model thus suggests that the proliferative response of an individuals melanocytes to sun exposure is a key phenotypic marker for determining how melanoma develops in any given individual. We found that the "classical" measures of sun responsivenessnamely, propensity to sunburn and ability to tanwere similarly prevalent among different subgroups of melanoma patients. Thus, burning and tanning are markers of sun sensitivity that appear to be common to the development of all cutaneous melanomas, most likely facilitating initiation of melanocytes early in the pathway. This interpretation is consistent with the common observation from casecontrol studies that both of these measures distinguish melanoma patients from people without this disease.
We are not aware of any other analytical studies that have been specifically designed to test the hypothesis that cutaneous melanomas arise through different pathways. Although several earlier studies (1519) have undertaken post hoc analyses of risk factors by anatomical site, there were invariably insufficient numbers of people with melanomas from less commonly affected sites to adequately test the hypothesis. Nevertheless, the few existing reports have been reasonably consistent. Weinstock et al. (15) reported that melanomas of the trunk and legs were statistically significantly associated with high nevus counts, but no such association was observed for melanomas of the upper extremities. They concluded that some degree of etiologic heterogeneity by anatomical site might explain these differences. Similarly, two German casecontrol studies (16,17) reported that high nevus counts conferred substantially increased risks for melanoma of the trunk and legs but were much less strongly associated with melanomas of the head and neck or arms. From a study in Connecticut comparing people with and without melanoma (18), researchers found that 10 or more nevi on the arms were associated with substantially lower relative risks of melanoma of the head and neck (OR = 3.2) than melanomas of the trunk (OR = 5.6), upper limb (OR = 5.6), and lower limb (OR = 5.9), although these differences were not statistically significant. Bataille et al. (19) took a different approach that examined the distribution of nevi and solar keratoses in a casecontrol study of cutaneous melanoma conducted in New South Wales, Australia, and found that patients with melanomas of the head and neck had substantially fewer nevi and more solar keratoses than patients with melanoma of the trunk or legs.
Sources of Error
We considered the possibility that our findings might be explained by various sources of error. Our sample size was constrained by the number of patients presenting with melanoma during the study period, and this limitation was exacerbated by our stratified sampling scheme. Consequently, some analyses were statistically underpowered, and the role of chance cannot be excluded as an explanation for individual risk estimates.
The effects of confounding by age deserve particular attention, because the prevalence of nevi and solar keratoses are both strongly influenced by age. We addressed this issue in three ways. First, we deliberately oversampled younger patients with melanoma to increase the statistical power of the study to examine age effects. This approach was moderately successful, although we did not achieve parity across the strata of age and sex because of the low incidence of LMM and head and neck melanomas among young people. Second, to account for this imbalance, we adjusted for linear and nonlinear effects of age, respectively, by including terms for exact year of age and age squared in all regression models. Third, we separately examined risk estimates for the principal exposure measures among older and younger participants and found risks of similar magnitude within both age strata.
Recall bias would be unlikely to explain our observations, because all of the participants in this study had been recently diagnosed with melanoma (i.e., they were case patients with disease) and had no knowledge of the aims of the study. Moreover, the principal exposure measures contributing to this analysis were measured objectively by a single trained nurse who was also unaware of the study hypotheses. Any errors in measuring these factors were likely to have occurred independently of melanoma subgroup and hence on average would bias risk estimates toward the null. This conclusion is supported by our observation that associations for self-reported numbers of nevi and solar keratoses were generally weaker than the associations for similar measures obtained by the nurse interviewer.
Testing the Hypothesis
The divergent pathway model raises interesting new questions about the development of melanoma that can be tested across several disciplines of biomedical research. At the level of descriptive epidemiology, several registries have already published associations between squamous cell skin cancers and melanoma (20,21), and it would be a relatively straightforward matter to conduct analyses separately testing for associations with head and neck melanoma and trunk melanomas. We would predict that the squamous cell cancers of the skin would be more strongly associated with melanomas of the head and neck than with melanomas of the trunk. There is already some histologic evidence that melanomas of the trunk are more likely than those of the head and neck to arise in conjunction with a preexisting nevus (22,23), although this finding needs to be confirmed in a well-designed prospective study. Finally, although there is experimental evidence that UV radiation induces melanocytic proliferation in humans (24,25), it remains to be established whether the magnitude of this effect is modified by nevus phenotype, as we have assumed. Because the number of nevi is almost certainly influenced by genetic factors (26,27), these loci, once confirmed, would make promising candidates for studies of melanocytic proliferation in response to sunlight.
Implications
Confirmation of the divergent pathway model for melanoma by future research would raise serious issues about appropriate public health strategies for control of this disease. For example, health education campaigns aimed at reducing population-wide exposure to the sun may actually be less effective than targeted messages delivered to particular subgroups in reducing the burden of melanoma. Similarly, reducing sun exposure in later life may confer less benefit in terms of melanoma risk than reducing sun exposure in childhood, at least for nevus-prone individuals. Resolving these issues should be the aim of future epidemiologic research.
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NOTES |
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We are grateful for the helpful insights given by Dr. Margaret McCredie during the preparation of this manuscript.
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Manuscript received October 5, 2002; revised March 18, 2003; accepted April 1, 2003.
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