The Mysteries of Geographic Variability in Nonmelanoma Skin Cancer Incidence

IN THE second half of this millennium, efforts to document the incidence of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have greatly expanded. The article in this month's ARCHIVES¹ presents new data on this subject showing that incidence in Finland is similar to that in other northern European nations. It is clear that among people of European ancestry whose ancestors migrated to either the United States or Australia, BCC is by far the most common cancer. Although only about one fifth as frequent as BCC in the United States and Australia, SCC of the skin is among the most frequent cancers in the United States and, after BCC, the most frequent cancer in Australia. The substantial differences in the risk of these tumors among Europeans, Asians, and Africans is well documented. Some studies suggest that the incidence of these tumors has increased over recent decades.² A brief look at the available incidence data reveals how much more there is to be learned about both the epidemiology and the natural history of nonmelanoma skin cancer.

As summarized in Table 1, nearly 50-fold differences in the incidence of BCC and 100-fold differences in SCC have been noted between white populations in northern Europe and Australia. Although these incidence estimates might vary because of differences in methodologies among the studies, the degree of difference in age-adjusted incidence estimates of BCC and SCC are extraordinary compared with differences in incidence of virtually any other common cancer among genetically similar populations studied in various geographic locales.

Differences in sun exposure may account for the higher risk of these cancers in residents of the United States and Australia. Unfortunately, our limited knowledge of risk factors for nonmelanoma skin cancer, particularly for BCC, leaves great uncertainty about whether sun exposure alone accounts for these tremendous differences. Australia is far sunnier than Finland or the Netherlands. But why are the rates observed in the Hawaiian white population substantially lower than those for Australian whites?¹¹ Few areas have more sunlight or a climate more conducive to sun exposure and more likely to attract a sun-loving population than Hawaii.

The lower incidence of nonmelanoma skin cancer, especially of BCC, in Hawaii may be a result of the large number of immigrants there who had less sun exposure earlier in life. Childhood sun exposure seems to be a more important risk factor for BCC than sun exposure during adulthood.^{12 - 13} Moreover, intermittent sun exposure has been postulated as a greater risk factor for BCC than cumulative sun exposure.¹⁴ However, evidence for this hypothesis is not persuasive. The Finnish study of a genetically homogeneous population indicates that outdoor occupations with presumably more sun exposure in childhood and adolescence (ie, farming, fishing, and forestry) are associated with a trend toward lower risks of nonmelanoma skin cancer than occupations and/or environments that offer less and more intermittent childhood sun exposure.¹

Models relating SCC risk to increases in UV exposure suggest that a 1% increase in UV exposure increases the risk by about 2%.¹⁵ For BCC, this "multiplier" is probably even lower. If this multiplier applies to the Finnish vs Australian differences, it would mean that Australians receive up to 50 times more UV radiation than Finns, an extraordinary difference. Given the urban and industrialized nature of both countries as well as the frequent vacations to sunny locales taken by many northern Europeans and the increasing practice of sun protection among Australians, differences in lifetime UV exposure of such magnitudes seem unlikely. Other possible, but unsatisfactory, explanations for the much higher risks of nonmelanoma skin cancer in the United States and Australia compared with Europe include a threshold effect (ie, exposure levels that, when exceeded, greatly increase risk) or genetic differences. Neither of these explanations is well supported by data.

Genetics and sun exposure (as well as other carcinogens) affect skin cancer risk. Epidemiologic studies, however, describe only modest differences in risk among persons of European ancestry residing in a single country. For example, the age-adjusted incidence of BCC for whites is only 50% higher in the sunny southern state of New Mexico than in rainy Seattle, which is much further north.⁸ Among native Australians of northern European ancestry, the number of grandparents born in the British Isles is not a strong risk factor for SCC. The strength of relation of time since immigration to Australia and risk of nonmelanoma cancer varies among studies.^{16 - 17} Across countries, various indicators of sun sensitivity, including burning and not tanning, are generally associated with only modest increases in risk (usually with relative risk in the range of 1.5-3) as compared with the risk in persons who do not tan easily and who are not susceptible to the acute (erythema) effects of UV radiation.^{18 - 19} A history of prolonged or excessive sun exposure resulting in sunburns is associated with similar modest increases in nonmelanoma skin cancer risk. Therefore, differences in risk associated with genotypic and phenotypic factors, and to some extent exposure patterns, seem insufficient to account for the very great differences in incidence observed between the United States/Australia and Europe.

Another puzzle concerning nonmelanoma skin cancer is the differences in the change in incidence over the past decades. As shown in Table 2, the change in incidence varies according to type of skin cancer (BCC vs SCC) and country. No consistent pattern of temporal change in incidence is apparent: BCC incidence is increasing more quickly than SCC incidence in some countries, while the reverse holds true in other countries. The variability in rates of change in incidence among countries, between sexes, and according to type of tumor suggests that factors other than changing sun exposure patterns (especially ascertainment bias and probably other factors) may be important explanations for the differences observed.

Although nonmelanoma skin cancer is by far the most frequent tumor in the United States, support for research of the epidemiology, natural history, and optimal therapy of BCC and SCC is, at best, limited. No recent rigorous population-based studies assessing risk factors, natural history, optimal therapy, or (with the exception of some chemoprevention trials) preventive strategies have been undertaken in the United States. The apparent acceptance of a high incidence of these tumors, with only recommendations for sun avoidance at all ages in virtually all persons, seems to be the predominant but uncritical response to this common and increasing problem. Efforts to assess risk factors for skin cancer, the efficacy of preventive strategies, and cost-effectiveness of alternative treatments are needed if we are to provide optimal treatment of nonmelanoma skin cancer. These tumors have substantial economic, cosmetic, and medical consequences. A million cases per year should be important enough to warrant supporting efforts to unlock the puzzles of nonmelanoma skin cancer.