CHAPTER 6

GEOGRAPHIC DISTRIBUTION

The hypothesis that ultraviolet radiation is causally associated with the development of cutaneous malignant melanoma (CMM) has been explored by examining potential exposure to sunlight. Most of the studies are ecological studies which sought to find correlations between incidence or mortality rates of CMM and the potential for sun exposure estimated by proximity to the equator (latitude) or by other surrogates for average exposures to sunlight or UV radiation, such as number of sunlight hours at residence.

This chapter presents results from analyses of the geographic distribution of CMM and includes both incidence and mortality studies. These ecological or geographic correlation studies are subject to many assumptions, and thus the results must be interpreted in light of the many limitations inherent in the study design. For example, the failure to measure individual exposure to sunlight in the study population makes it impossible to establish a causal association between CMM and solar radiation; yet significant associations between surrogate estimates of UV exposure and CMM have provided indications of causal associations which in turn led to studies in which individual exposure has been assessed (these studies are discussed in Chapter 9).

The earliest epidemiologic evidence that solar radiation might play a role in the etiology of CMM resulted from ecological studies which showed a negative correlation between latitude of residence and incidence and mortality rates for CMM in white populations. Using Australian mortality data, Lancaster (1957) showed that the distribution of CMM among "relatively fair-skinned types" was associated with proximity to the equator. Among the states of Australia, he found a north-to-south decreasing gradient in death rates (1951-1953) due to melanoma, with the crude death rates from melanoma in Queensland almost three times higher than those in Tasmania and Victoria, and a decreasing gradient of rates in the intervening states with increasing latitude.

In the same study, Lancaster (1957) examined melanoma mortality rates in other predominantly Caucasian populations and found that rates tended to be higher in populations living closer to the equator. Mortality from melanoma was higher on the northern island of New Zealand than on the southern; rates in the British Isles and Europe were generally lower than those in Australia and New Zealand; and rates in Canada were below those in the United States. Within Europe, however, no latitude gradient was found when CMM mortality rates from the same years were compared. In fact, Norway and Sweden reported higher rates than any other European countries. Lancaster (1956) attributed this absence of a gradient to probable differences in medical certification of death, differences in statistical coding practices between countries, and the fact that melanoma had only recently been separated from carcinomas of the skin. However, studies cited in Chapters 10 and 11 indicate that this lack of gradient may be due to other factors such as differences in ethnicity or pigmentation characteristics. Within the United States (grouped into eight areas), mortality from CMM (1949-1952) was somewhat higher in southern than in northern areas and the coastal areas had higher CMM mortality rates than the mountain or central areas. Lancaster (1956) linked the general latitude association to CMM mortality with the variations in sunlight and UVR, and concluded that the distribution of melanoma among fair-skinned populations was consistent with a hypothesis of excess sunlight as an important predisposing cause of CMM.

Holman et al. (1980a) examined Australian mortality rates from cutaneous malignant melanoma by state in successive 5-year periods from 1931-1934 through 1975-1977 and determined that melanoma mortality rates were highest in Queensland (the northern part of Australia) and diminished on a gradient from north to south, with the lowest rates in Victoria and Tasmania. This relationship of increasing melanoma mortality with decreasing latitude was generally maintained for the six states of Australia over roughly 45 years, even though CMM mortality rates increased steadily over this time period.

An analysis of melanoma incidence rates (1975-1976) in Western Australia (Holman et al. 1980b) showed that the highest rates of CMM occurred in areas which received the fewest hours of bright sunlight per day, although each area received a considerable amount of sunlight each day. Stratifying on the five statistical divisions in the state of Western Australia, the highest rates were found in Perth and the southwestern region, which tend to be coastal and more urbanized. Although tropical, the northern areas are less populated and residents may be more likely to avoid sun exposure in the middle of the day and wear protective clothing than in the more urbanized southwestern coastal areas, where residents are more likely to sunbathe and engage in outdoor recreational activities.

Herron (1969) analyzed data on 1,100 melanoma patients in Queensland, Australia (1963-1969) to investigate the geographical distribution of CMM in this state and found little difference between northern, central, and southern Queensland (rates per 1,000 = 0.63, 0.51, and 0.71, respectively). There were, however, higher rates in residents of coastal areas than in those from inland areas; the author hypothesized that this distribution may be related to sun exposure.

CMM incidence rates in Queensland, Australia, were also examined for geographical differences by Green and Siskind (1983). All incident CMM cases over a 12-month period (July 1979 to June 1980) were analyzed by statistical division, and no association with latitude was found. Like Herron (1969) and Holman et al. (1980b), they found a significantly increased incidence of melanoma in the coastal areas compared to the inland regions. Green and Siskind (1983) stated that a latitudinal relationship with CMM incidence may have been absent due to increased summer cloud cover in North Queensland. In addition, the mapped contours of erythemal UV doses during the summer months deviate substantially from latitude circles, and in summer, the critical recreational portion of the year, there is no association of UV radiation with latitude.

Fears et al. (1976) plotted U.S. melanoma and non-melanoma skin cancer incidence rates (Third National Cancer Survey 1969-1971) and U.S. CMM mortality rates (1950-1969 by county) for white males and females against latitude and found that incidence, and mortality rates due to melanoma and non-melanoma skin cancers, increased with decreasing latitude. Regression analyses produced strong negative correlation coefficients for each parameter (see Table 6-1).

Haenszel (1963) found a similar increasing north-south gradient in the incidence of malignant melanoma in four northern and four southern U.S. cities based on a 1947 survey of hospitals and physicians' offices. The ratio of north/south incidence rates showed higher risks of CMM in the southern cities than in the northern cities, although the ratio was somewhat lower for CMM of the trunk or lower extremities in males. The north-to-south incidence ratios were generally similar to those presented in a report for basal cell carcinomas and squamous cell carcinomas.

When the 1973-1976 incidence data from the National Cancer Institute's (NCI) Surveillance Epidemiology and End-Results (SEER) program were plotted against the 1977-1978 NCI R-B meter measurements of accumulated dose in eight locations in the United States, a strong positive association was noted (Scotto et al. 1982), as shown in Figure 6-1.

Elwood and Lee (1974) examined age-standardized (1960 U.S. population) mortality rates of CMM and other (non-melanoma) skin tumors separately over the period 1950-1967 for each Canadian province and U.S. state. In both analyses (melanoma and other skin tumors), the mortality rates showed a strong negative correlation with geographic latitude based on the latitude of the largest city in each province or state. Estimates of annual ultraviolet radiation in the erythema-producing wavelengths were made for each province and state. These estimates showed a strong negative association with latitude and with CMM mortality rates. The results were similar for analyses of melanoma mortality and for other skin cancer mortality; in addition, the estimates of UV flux in the erythema-producing wavelengths showed a similar association with CMM mortality as with latitude alone. The authors concluded that the similar relationships of mortality rates due to CMM and other skin cancers to estimates of annual UVR suggest the involvement of ultraviolet radiation as the causal agent in both diseases, and that latitude is a major factor affecting CMM mortality rates.

Baker-Blocker (1980) failed to find a significant correlation between CMM mortality in U.S. white males and females and amount of ultraviolet radiation received in the area. Correlation of average annual UV radiation estimates from 18 counties with CMM mortality rates by county for 1950-1969 (Mason and McKay 1974) showed no association, although the estimates of ultraviolet radiation were significantly correlated with latitude (p=0.01). El Paso County (Texas) had the lowest melanoma mortality rates (1.2 and 1.1. per 100,000 for white males and females, respectively) even though it received the highest amount of ultraviolet radiation. The counties with the highest melanoma mortality rates (Leon County, Florida--2.9/100,000 for females; Tarrant County, Texas--l.9/100,000 for females and 2.5/100,000 for males; and Nassau County, New York--2.3/100,000 for males) received considerably less UV radiation than El Paso County. Bernalillo County (New Mexico) also had low CMM mortality (1.2/100,000 for both sexes) but received more ultraviolet radiation than those counties with the highest melanoma mortality rates. These results were interpreted as evidence that CMM mortality may be due to factors other than ultraviolet radiation, and that the high rates in Nassau and Ulster Counties (New York) and Montgomery County (Maryland) suggest that urbanization may play a role. However, the ethnicity and pigmentation characteristics of the populations were not considered in this analysis. The counties with the lowest rates have high proportions of Hispanics and Indians among their white populations in contrast to counties such as Nassau, Ulster, and Montgomery; in addition, the differences in CMM rates could reflect the varying susceptibility of the populations.

Anaise et al. (1978) found similar results of high CMM incidence in coastal versus inland areas in Israel. An analysis of all incident CMM cases in the total Israeli Jewish population from 1960 to 1972 showed higher age-adjusted rates of melanoma (3.5 and 3.2 per 100,000) for two coastal cities (Haifa and Tel Aviv) than for Jerusalem (2.0 per 100,000), which is situated inland in the mountains. This difference may be consistent with the sunlight exposure hypothesis of etiology, since those in the coastal regions are likely to spend more leisure time in outdoor activities and on the beach, and wear clothes which expose more skin. No analysis of latitude was done in this study.

Melanoma incidence data from 14 health regions in England and Wales (1962-1970) showed a significant negative correlation with latitude for both males (p<0.0001) and females (p<0.05) (Swerdlow 1979). In addition, Swerdlow (1979) analyzed mean daily hours of sunshine (1960-1968) for each region and found a positive correlation between melanoma incidence and mean hours of sunshine, although the correlation was statistically significant (p<0.05) in women only. The author concluded that these findings suggest that exposure to sunshine is an important causal factor for CMM. He also postulated that the higher melanoma incidence rates and stronger correlation with sunshine for females may be due to greater skin exposure to sunlight or sunburn due to sunbathing and style of clothing.

An examination of geographical variation in Norwegian CMM incidence rates from 1955 to 1970 (Magnus 1973) also showed a marked north-south increasing gradient; the age-adjusted incidence in southern Norway was two to three times higher than the rate in the northern part of the country.

An analysis of melanoma incidence from 1953 to 1973 in Finland (Teppo et al. 1978) also showed a distinct north-south increasing gradient, with the age-adjusted (1950 world population) rates being higher in the south. However, when the rates were adjusted for the urban/rural differences in population residence, the north-south gradient almost disappeared because of the high rates of melanoma in the urban areas of southern Finland. While this observation suggests that factors other than latitude may be causally associated with malignant melanoma, this finding does not negate a sunlight hypothesis because people in urban areas in Finland are thought to experience more exposure to the sun through leisure activities and holidays than those living in rural areas, where skin has traditionally been more protected from direct sunlight by clothing (Teppo et al. 1978).

Eklund and Malec (1978) used data from the Swedish Cancer Registry during the period 1959 to 1968 to investigate association of latitude with CMM incidence in Sweden. They found a negative correlation between incidence rates and latitude (R=-0.74) signifying decreasing incidence with increasing latitude. A similar relationship was found when CMM incidence was correlated with annual estimates of ultraviolet radiation (in the erythema-producing wavelengths), supporting the hypothesis that melanoma is influenced by environmental factors such as ultraviolet radiation. These analyses, however, showed considerable variations, with some counties falling well above the regression line. Population density was also associated with melanoma incidence rates, with higher rates in urban areas regardless of latitude. Further analyses tested the hypothesis that these variations were related to frequency of foreign travel to sunny locations (see Chapter 8).

The International Agency for Research on Cancer (IARC 1976) collected and published data on cancer incidence on five continents, including both age-specific and age-standardized incidence rates from 59 population-based cancer registries in 27 countries. Crombie (1979) analyzed the IARC data on malignant melanoma from the 27 cancer registries in Europe and 16 in North America to investigate the relationship between melanoma incidence and latitude in areas with predominantly Caucasian populations. Melanoma incidence in North America showed significantly increasing trends with decreasing latitude for both males (p<0.01) and females (p<0.05). A similar trend of increasing incidence with decreasing latitude was also found for both males (p<0.001) and females (p<0.05) in England. Analyses of data for the European cancer registries showed significant trends in the opposite direction, i.e., increasing melanoma incidence with increasing latitude. The analyses showed particularly high melanoma incidence and mortality rates in Sweden and Norway. These European results contradict findings of ecological studies in North American and England, but are consistent with those of Lee and Issenberg (1972), who found higher incidence and mortality rates due to CMM in Swedish versus English populations, as shown in Table 6-2. IARC (1976) and Armstrong (1984) have attributed the lack of a latitude gradient in Europe to differences in complexion between Mediterranean and Scandinavian populations. Lee and Issenberg (1972) postulated that differences between English and Swedish rates could be due to genetic or occupational factors.

Armstrong (1984) also considered the inconsistencies seen in the relationship between geographic area and melanoma, mainly in Europe, and concluded that in Europe the south-to-north gradient associated with melanoma risk may be explained by a gradient in the opposite direction for skin pigmentation (i.e., more highly pigmented populations reside in southern Europe), and by a more intermittent pattern of sun exposure for populations living in northern Europe.

FINDINGS

From the information reviewed above, the following findings are evident:

6.1 Within nations with predominantly White populations, most ecological studies of melanoma and latitude show increasing melanoma incidence and/or melanoma mortality with decreasing latitude, leading to the hypothesis that melanoma is associated with sunlight, particularly its UV-B component, because of UV's strong correlation with latitude. The ecological studies which failed to show this association may not have accounted adequately for pigmentation differences.

6.2 Although further north, Sweden has higher incidence of and mortality rates due to CMM than England and Wales. As discussed in Chapter 7, pigmentation differences may be responsible, since the Swedish are a more homogeneous fair-skinned population than the English, who are a mixture of several European races.

6.3 In general, CMM incidence and mortality rates tended to be higher in populations living closer to the equator, in coastal compared with inland areas, and in urban versus rural areas within various nations.

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