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Solar radiation and malignant melanoma of the skin
Special article I
m
Im II
I
I
Solar radiation and malignant melanoma of the skin Alan N. Houghton, M.D., and Michael V. Viola, M.D.
New York, NY, arm Farmington, CT Several observations suggest that a majority of cases of malignant melanoma of the skin are linked to sun exposure. Evidence includes higher occurrence of melanoma on anatomic areas heavily exposed during recreation, development of melanoma more frequently in lightly pigmented persons, and correlation of melanoma incidence and mortality with proximity to the equator. The role of sun exposure in the pathogenesis of melanoma remains unclear, however. Many cases of melanoma may be related to heavy doses of solar radiation received during recreation. Chronic sun exposure is not so clearly linked to the development of melanoma (except in the uncommon lentigo maligna variety). Sunspot cycles have been associated with changes in melanoma incidence; an excess of melanoma cases has been observed every 9 to 12 years after peak sunspot activity. These excess cases may be caused by more intense exposure to solar ultraviolet radiation during sunspot maxima, perhaps related to changes in the stratospheric ozone layer. These epidemiologic and clinical clues suggest that many cases of melanoma are related to sun exposure triggering the appearance of clinically evident melanoma. In this regard, solar radiation behaves as a cocarcinogen or promoter, rather than a dose-dependent carcinogen. These observations also suggest that other factors may be involved in the pathogenesis of melanoma, e.g., nevi, heredity, or exposure to chemical carcinogens. (J AM ACAO DERMATOL5:477-483, 1981.) A number of factors have been implicated in the pathogenesis of malignant melanoma of the skin. These include exposure to solar radiation, heredity, hormones, chemical carcinogens, and trauma. Most factors can be directly implicated in only a small number of cases, for instance, heredity in perhaps 10% of melanoma patients.l However, there is a general impression that solar radiation is associated with the majority of cases of cutaneous melanoma. It remains unclear what role exposure
From she Memorial Sloan-Kettering Cancer Center, New York, and
the University of Connecticut Health Center, Farmington. Reprint requests to: Dr. Alan N. Houghton, Memorial SloanKettering Cancer Center, 1275 York Ave.. New York, NY 10021. 0190-9622/81/100477+07500.70/0 9 1981 Am Acad Dermatol
to solar radiation, and in particular ultraviolet (UV) radiation, may play in the pathogenesis of melanoma, but most evidence suggests that solar radiation acts not as a dose-dependent carcinogen but rather as a cocarcinogen or promoter. This evidence for a role of sun exposure comes from a series of associations made from epidemiologic and clinical observations. The evidence has been reviewed elsewhere 2 and can be summarized as follows. First, the incidence of malignant melanoma in relatively homogeneous white populations in North America, Northern Europe, and Australia is inversely proportional to latitude, that is, as one approaches the equator melanoma rates rise. a'4 In turn, solar radiation, and specifically UV radiation, is more intense at these lower lati477
478
Journal of the American Academy of Dermatology
Houghton and Viola
rl
o 7.0-[ 0
oO 6.0Id.l
zLI.I 5.0 z
4.0-
I.u ~0
3.0J
~
2.0-
1.0 200
L
WZ
_>~_
< 2 100
i..-
.--loO ILl z O0
1935 1940 1945 1950 1955 1960 1965 1970 1975
YEAR Fig. 1. Age-adjusted incidence of malignant melanoma of the skin in Connecticut related to sunspot relative number, 1935-t975. TM ~ , Males and females; ---, males alone. Arrows indicate peaks of sunspot activity.
tudes. Second, melanoma tends to occur on sites more heavily exposed to the sun during recreation, sparing areas which are covered by bathing suits. ~' ~ The highest concentration of melanomas occurs on the trunk, legs, and face, especially the lower legs of women and the trunk of men. TThird, melanoma is more likely to develop in lightly pigmented individuals, s''~ The classic phenotype of a person who develops melanoma is a blond or redhead with blue eyes, freckles, and fair skin, who tans poorly and sunburns easily (however, most persons who develop melanoma do not precisely fit this phenotype). Generally, darker-skinned groups, such as blacks, Hispanics, and Orientals, have mela-
noma incidences which are a fraction of the rates of lightly pigmented groups living in the same area. The general principle is that melanoma is relatively common in fair-skinned persons and is unlikely to occur on sun-exposed surfaces in darkly pigmented persons. Rather, melanoma in darker races tends to occur on the foot and mucous membranes. These epidemiologic and clinical observations are highlighted by the experience in Queensland, Australia, where the highest incidence of melanoma in the world is found. Queensland is a set of worst circumstances--a lightly pigmented population living close to the equator. Furthermore, for dramatic contrast, melanoma is rare among the darker-skinned aboriginal population in the same area. Several other, less compelling, epidemiologic observations are relevant to the association o f melanoma and sun exposure. Susceptible persons who have lived in a sunny climate all of their lives have a higher incidence of melanoma than persons who have recently moved to the same area from less sunny climates. For instance, the incidence of melanoma in native born Israelis of European extractions is greater than in recent European immigrants to Israel, suggesting an effect of more intense sun exposure in the sunnier climate of Israel. to Other geographic factors may affect the occurrence of melanoma. A higher incidence seems to occur in areas with extensive coastlines. ~,7 This may be due to recreational opportunities in these areas, as well as increased sun exposure related to cloud-covering patterns along shorelines. Seasonal differences occur in the diagnosis of melanoma, with diagnosis more likely during summer months when recreational sun exposure and solar UV radiation are most intense, lt-'a However, a skewing of the time of diagnosis may occur; biopsy of suspicious lesions may be done more frequently during summer months, related to the general darkening of pigmented lesions which occurs during tanning. Another epidemiologic observation relevant to melanoma and sun exposure is the distribution of melanoma among various occupational and social groups. Melanoma rates are relatively low for individuals in outdoor occupations, such as construction workers or farmers. Indeed, melanoma
Volume 5 Number 4 October, 1981
Solar radiation and melanoma
479
Table I. Partial correlation coefficients relating annual sunspot number to melanoma incidence Denmark
Finland
N e w York State
Year following sunspots
Connecticut
(1935-1967)
-
(1943-1972)
(1950-1971)
(1943-1972)
0 1 2 3 4
+ O. 190 + 0.459* + 0,695' + 0,378 - 0,005
+ 0.261 + O,390* + 0.376* + 0.273 + 0.072
+ 0.539* + 0.444* + 0.042 + 0.284 + 0,381
+ + + + +
0.232 0.499* 0,534* 0,437* 0,358
*p < 0.05,
occurs most commonly in higher income groups, especially managerial and professional workers. 14, la At first glance, this seems to conflict with a putative association of sun exposure and melanoma. However this suggests that recreational exposure of untanned skin, not chronic sun exposure, is involved in the pathogenesis of many melanomas, especially those arising on the trunk and legs. MELANOMA INCIDENCE AND SUNSPOTS One of the most alarming aspects of the epidemiology of melanoma is the dramatic rise of incidence and mortality rates, a phenomenon occurring in all countries with predominantly white populations.7. 1~-18 The rise in melanoma incidence began for persons born around 1900, a generation which experienced substantial liberalization of recreational dress and behavior as they passed into adulthood. Anatomic areas which had not previously been exposed to the sun, especially the trunk of men and the lower legs of women, were now uncovered during recreation. It is these two sites which have accounted for the largest rise in incidence of melanoma of the skin, while virtually no increase of melanoma of the face has occurred. In this regard, a further observation which relates solar radiation to malignant melanoma is the correlation between sunspot cycles and subsequent increases in melanoma incidence rates. 1.~This association was noticed in a detailed examination of the rising incidence of malignant melanoma. In Connecticut, age-adjusted incidence rates of melanoma have risen from 1.1 cases per 100,000 persons in 1935 to 7.4 cases in 1976. Superimposed on this steady rise in incidence were periods of excessive increases occurring every 8 to 12 years.
These periods of markedly increased rates peaked at 3 to 5 years, followed by a return toward baseline rates (Fig. 1). In order to examine this phenomenon quantitatively, the effect of increasing incidence of melanoma was represented by a linear regression equation relating melanoma incidence to time, and a cyclical pattern was observed when deviations from this line were calculated. These fluctuations of melanoma incidence correlated with sunspot numbers, and the highest correlation coefficients occurred 2 years after peak sunspot activity. The incidence of other nonmelanoma malignancies registered in Connecticut was not associated with sunspot cycles. Melanoma incidence rates from other tumor registries (including New York State, Finland, and Denmark, but not Norway) have shown similar correlations with sunspot numbers (Table I). In addition, Wigle 2~ confirmed the association between sunspot maxima and rises of melanoma incidence in Alberta and Saskatchewan. SOLAR VARIABILITY AND MELANOMA INCIDENCE The sunspot phenomenon has a complex relationship to geophysical and astrophysical events. We have proposed that sunspot cycles could be related to melanoma incidence through increases in UV radiation emitted by the sun and by solar modulation of the amount of ozone in the Earth's atmosphere, both events affecting the amount of UV radiation reaching the Earth's surface. It is becoming increasingly evident that the sun's activity varies, and sunspot numbers are the clearest indicator of solar activity. Sunspots are dark areas on the visible surface of the sun and are known to be cooler sites of local intense magnetic
Journal of the American Academy of Dermatology
480 Houghton and Viola
activity. Sunspots may vary in size up to fifteen times the Earth's diameter and tend to travel in groups, surviving several rotations of the sun. The number of visible sunspots may vary from day to day, but the mean annual numbers show a distinct periodicity of around I 1 years. At sunspot minimum the average sunspot number approaches zero, but at sunspot maximum up to several 100 sunspots may be sighted. Maximum sunspot numbers coincide with periods of increased solar activity. In particular, the amount of ultraviolet radiation emitted by the sun increases at solar maxima. '-'~ Could periodic increases in the sun's emission of UV radiation be related to rises in melanoma incidence? UV radiation is arbitrarily divided into three regions: UV-A (long wavelength, 320-400 nm), UV-B (280-320 nm), and UV-C (less than 280 nm). UV-B comprises the sunburn spectrum which produces cutaneous erythema, stimulates pigment formation, and is mutagenic and carcinogenic. The longer wavelength UV-A produces mild erythema, immediate pigment darkening, and accentuates the carcinogenic potential of UV-B and other carcinogens. At sunspot maximum, UV-C emitted by the sun may increase by as much as a factor of 1.5 (at 250 nm) and UV-B (at 300 nm) by 18%. '-'1 Ultimately, the amount of UV radiation reaching the Earth's surface is dependent on the Earth's atmosphere, specifically, the ozone layer of the stratosphere. The earth's stratospheric ozone is a tenuous layer of molecular oxygen ( Q ) which, if compressed, would measure only several centimeters thick. Ozone completely absorbs the shorter wavelengths of UV-C, absorbs incompletely the longer U V-B wavelengths, and does not filter UV-A. Some observers suggest that the thickness of the atmospheric ozone layer varies over the 11-year sunspot cycle, and these changes may be modulated by the sun's activity. ''~-'4 Throughout the sunspot cycle there are changes in the shape of the sun's outer atmosphere, or corona. The corona is not a limited envelope like the Earth's atmosphere, but rather expands into the solar system as a solar wind bathing the Earth's atmosphere with ionized particles traveling hundreds of kilometers per second. Increases in the intensity of the solar wind at sunspot max-
ima are associated with numerous terrestrial events, including aurorae and geomagnetic disturbances. It is interesting that these ten'estrial disturbances 9also lag sunspot peaks by about two years. The solar winds of ionized gas may produce changes in the Earth's stratospheric ozone layer (by influencing galactic cosmic rays entering the Earth's atmosphere) such that ozone minimas occur just prior to sunspot maxima...,4..,z (For more detailed discussion, see Viola et al.'-'c~) The overall effect would be an increase in the amount of UV radiation reaching the Earth's surface at sunspot maxima. If this is indeed true, then only small decreases of ozone thickness would be associated with substantial changes in melanoma incidence. Of particular concern in recent years has been the predicted depletion of stratospheric ozone by halocarbons rising from the Earth's surface. It is quite alarming that the National Academy of Sciences has predicted in a recent report an eventual 16.5% depletion of ozone if halocarbons continue to be released from the Earth's surface at the 1977 rate. "7 The melanoma incidence and sunspot data suggest that even a small depletion o f atmospheric ozone may cause a substantial increase in the incidence of melanoma, and therefore these recent estimates of ozone depletion are cause for grave concern. With this background, several comments are relevant to the association of melanoma and sunspots. First, rises in melanoma incidence occur 0 to 3 years after sunspot peaks, suggesting that heavier exposures to U V radiation trigger the clinical appearance of melanoma. Second, one of the highest sunspot maxima of this century may occur around 1979 to 1982: higher sunspot numbers are associated with higher solar activity, and perhaps a greater risk of melanoma of the skin in susceptible populations. '-'8 SOLAR RADIATION AS A DOSE-DEPENDENT
CARCINOGEN Despite the epidemiologic and clinical evidence relating sun exposure and melanoma of the skin, the exact role of solar radiation in the pathogenesis of melanoma remains speculative. For most nonmelanoma skin cancers, specifically basal cell and squamous cell carcinomas of the skin, solar radia-
Volume 5 Number 4 October, 1981 tion behaves as a dose-dependent carcinogen. These tumors occur most commonly on chronically exposed sites of the body in areas of actinically damaged skin. The incidence is strongly agedependent, with most cases occurring in old age. On the other hand, the evidence is meager that solar radiation is a dose-dependent carcinogen in the etiology of melanoma of the skin. However, there are two circumstances in which this may be the case. First, lentigo maligna melanoma, which comprises 10% of melanomas of the skin, most commonly develops on exposed and actinically damaged areas of the body in elderly persons. Second, malignant melanoma and other skin cancers occur at a very high rate in patients with the inherited autosomal recessive disorder, xeroderma pigmentosum. The cells of these patients have defects in their ability to repair UV damage to deoxyribonucleic acid (DNA). At an early age, these patients develop telangiectasias, dermal atrophy, solar keratoses, and multiple skin cancers, including melanoma. This association of solar damage to skin and melanoma is reminiscent of lentigo maligna melanoma. The occun'ence of multiple melanomas in patients with xeroderma pigmentosum suggests an acceleration of damage to skin by repeated, low-dose UV exposure, with increased sensitivity to the carcinogenic potential of UV radiation. SOLAR RADIATION AS A COCARCINOGEN OR PROMOTER
In contrast to lentigo maligna melanoma, solar radiation does not act as a dose-dependent carcinogen in most cases of melanoma, particularly the common types of superficial spreading and nodular melanoma. Rather than behaving as a chronic carcinogen, sun exposure appears to be a later or more proximal event in the pathogenesis of melanoma, as suggested by several observations. The rapid rise in melanoma incidence shortly after sunspot peaks suggests that increases in UV radiation precede the appearance of clinically apparent melanoma by only several years. Also, other epidemiologic observations mentioned previously suggest that relatively brief exposures of untanned skin to sun may trigger the majority of melanomas of the skin. Melanoma favors sites
Solar radiation and melanoma
481
exposed intermittently and intensively to the sun during recreation, particularly the male trunk and the female lower extremity. A lower incidence of melanoma in persons who work outdoors, with a relatively greater incidence in persons with high incomes (and more recreation opportunities) suggest that UV radiation is not a dose-dependent carcinogen. The higher incidence of melanoma in light-complexioned persons who sunburn easily but tan poorly also supports this hypothesis. In addition, although most animal models of melanoma rely on genetic factors or chronic (or rarely single) exposure to chemical carcinogens, in a relevant animal model Epstein et al produced blue nevi on hairless mice by treatment with a single application of the hydrocarbon, dimethylbenzanthracene.2r~ After exposure of these chemically induced nevi to UV radiation, metastatic melanomas developed in some animals. Again, exposure to UV radiation was a later event in the pathogenesis of these murine melanomas. These observations suggest that solar radiation, and in particular UV radiation, may behave as a cocarcinogen or promoter in the pathogenesis of melanoma of the skin. Tumor promoters are factors that can influence the development of cancer; in animals previously exposed to carcinogens, promoters can shorten the latent period and increase the incidence of tumors. The hypothesis that solar radiation is a promoter in the development of melanoma requires briefly reviewing the multistage theory of cancer development. Foulds a~ and others suggested that most cancers in humans develop in multiple steps. Thus, as normal cells evolve into cancer ceils, there are stages of development from initiated cells to preneoplastic cells to metastatic malignant cells, al These sequential steps are illustrated in a simple manner by the two-stage model of skin carcinogenesis in mice. 3'-' A single low dose of a hydrocarbon can induce, or initiate, a latent change in epidermal cells, but the skin itself still appears normal. If a promoter, such as a phorbol ester, is later applied, then metastasizing carcinomas may appear in the treated areas. Promoters are able to induce frank neoplasia in previously initiated cells and therefore are related to later steps in the development of cancer. The properties of initiating
Journal of the American Academy of Demmtology
482 Hottghton and Viola
agents and promoters appear to be different. While initiating agents are usually mutagenic, acting on DNA, promoters may have nonmutagenic properties which favor the growth of previously initiated cells, perhaps through changes in properties of cell differentiation or specific immunosuppression. Taking all of these observations together, UV radiation may behave both as an initiator and a promoter in human skin cancers. It acts as a dose-dependent carcinogen in the pathogenesis of basal cell and squamous cell carcinoma of the skin and lentigo maligna melanoma, but behaves as a promoter in most other types of cutaneous melanoma. In the development of malignant melanoma, there are most likely early and late events in the transformation of normal melanocytes to invasive melanoma cells. UV radiation as a promoter would be related to the later events. Many unanswered questions remain concerning the possible role of UV radiation in the pathogenesis of melanoma. What spectrum of UV radiation is related to the development of melanoma? Is it the mutagenic UV-B spectrum, or perhaps the potentially cocarcinogenic, longer wavelengths of UV-A? The occurrence of squamous cell carcinomas of the skin within several years after exposure to UV-A and psoralen, or within a month after UV-A treatment of patients with xeroderma pigmentosum, suggests a promoter role for UV-A in the pathogenesis of these cutaneous tumors. :~, :~-L A related question is how UV could act as a promoter. Could UV-A or UV-B promote tumors by producing hyperplasia of initiated melanocytes or by specific suppression of immunologic surveillance in the skin? Are other factors involved in earlier steps of the pathogenesis of melanoma (e.g., hereditary factors, premalignant melanocytic nevi, exposure to chemical carcinogens, immunologic suppression, hormones, oncogenic viruses, or even earlier exposure to mutagenic UV radiation during childhood or adolescence)? Despite epidemiologic and clinical clues, the putative relationship of solar radiation, and specifically UV radiation, to the pathogenesis of malignant melanoma of the skin is still tentative and complex. Factors such as genetic susceptibility, recreational behavior, and other cultural and socioeconomic factors may affect melanoma inci-
dence in different areas. Other environmental variables may be involved, affecting the amount of solar radiation reaching the Earth's surtace, including altitude during exposure, cloud-covering patterns, and time of day during exposure. The carcinogenic and promoting action spectra of UV radiation (i.e., the dose a n d wavelength required for specific biologic effects) still need to be defined for melanocytes, particularly nevus cells. Finally, nonsolar factors involved in the pathogenesis of melanoma must be investigated. REFERENCES 1. Anderson DE: Clinical characteristics of the genetic variety of cutaneous melanoma in man. Cancer 21:721725, 1971. 2. Climatic Impact Committee: Environmental impact of stratospheric flight. Washington, DC, 1975, National Academy of Sciences, USA. 3. Elwood JM, Lee JAH, Walter SD, Mo T, Green AES: Relationship of melanoma and other skin cancer mortality to latitude and ultraviolet radiation in the United States and Canada. lnt J Epidemiol 3:325-332, 1974. 4. Crombie IK: Variation o f melanoma incidence with latitude in North America and Europe. Br J Cancer 40:774-781, 1979. 5. Davis NC, Herron JJ, McLeod GR: Malignant melanoma in Queensland. Lancet 2:407-410, 1966. 6. Fitzpatrick TB, Sober AJ, Pearson B, Lew R: Cutaneous carcinogenic effects of sunlight in humans, in Urbach F, editor: Research in photobiology. Oxford, 1969, Pergamon Press, pp. 635-650. 7. Houghton AN, Flannery JT, Viola MV: Malignant melanoma in Connecticut a n d Denmark. Int J Cancer 25:95-104, 1980. 8. Gellin GA, Kopf AW, Garfinkel L: Malignant melanoma: A controlled study o f possibly associated factors. Arch Dermatol 99:43-48, 1969. 9. Klepp O, Magnus K: Some environmental and bodily characteristics of melanoma patients. A case control study. Int J Cancer 23:482-486, 1979. 10. Movshovitz M, Modan B: Role of sun exposure in the etiology of malignant melanoma. Epidemiologic inference. J Natl Cancer hast 51:777-779, 1977. 11. Lee JAH: Letter to the Editor. Br Med J 1:623, 1969. 12. Malec E, Eklund G: The changing incidence of malignant melanoma of the skin in Sweden: 1959-1968. Scand J Plast Reconstr Surg 12: 19-27, 1978. 13. Scotto J, Nam JM: Skin melanoma and seasonal patterns. Am J Epidemiol 111:309-3 14, 1980. 14. Lee JAH: Current evidence about the causes of malignant melanoma. Prog Clin Cancer 6:151-161, 1975. 15. Williams PR, Stegens NL, Goldsmith JR: Associations of cancer site and type with occupation and industry from the Third National Cancer Survey Interview. J Natl Cancer Inst 59:1147-1185, 1977. 16. Lee JAH, Carter AP: Secular trends in mortality from malignant melanoma. J Natl Cancer Inst 45:91-97, 1970.
Volume 5 Number 4 October, 1981
17. Lee JAH: The trend of mortality from primary malignant tumor of the skin. J Invest Dermatol 59:445-448, 1973. 18. Magnus K: Incidence of malignant melanoma in the five Nordic countries: Significance of solar radiation. Int J Cancer 20:477-485, 1977. 19. Houghton AN, Munster E, Viola MV: Increased incidence of malignant melanomas after peaks of sunspot activity. Lancet 1:259-260, 1978. 20. Wigle DT: Malignant melanoma of the skin and sunspot activity. Lancet 2:38, 1978. 21. Heath EF, Thekaekara MP: The solar spectrum between 1200 and 3000A, ilt White OR, editor: The solar output and its variation. Boulder, CO, 1977, Colorado Associated University Press, pp. 193-212. 22. Willet HD: The relationship of total atmospheric ozone to the sunspot cycle. J Geophys Res 67:661-670, 1962. 23. Paetzold HK, Piscolor F, Zschorner T: Secular variation of the stratospheric ozone layer over middle Europe during the solar cycles from 1951 to 1972. Nature (Phys Sci) 240:106-107, 1972. 24. Ruderman MA, Chamberlain JW: Origin of sunspot modulation of ozone: Its implications for stratospheric ion chemistry. Planet Space Sci 23:247-268, 1975. 25. Ruderman MA, Foley HM, Chamberlain JW: Eleven year variation in polar ozone and stratospheric ion chemistry. Science 192:555-557, 1976.
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26. Viola MV, Houghton AN, Monster EW: Solar cycles and malignant melanoma. Med Hypotheses 5:153-160, 1979. 27. Stratospheric ozone depletion by halocarbons: Chemistry and transport. Washington, DC, 1975, National Academy of Sciences USA. 28. Kane RP: Predicted intensity of the solar maximum. Nature 275:139-/40, 1978. 29. Epstein JH, Epstein WL, Nakai T: Production of melanomas from DMBA-induced "blue nevi" in hairless mice with ultraviolet radiation. J Natl Cancer lnst 38:19-30, 1967. 30. ffoulds L: Neoplastic development. London, 1975, Academic Press, Inc., pp. 1-108. 3 I. Farber E: The sequential analysis of liver cancer induction. Biochim Biophys Acta 605:149-166, 1980. 32. Berenblum I: Cocarcinogenic action of croton resin. Cancer Res 1:44-48, 1941. 33. Spellman CW: Skin cancer after PUVA treatment for psoriasis. N Engl J Med 301:554, 1979. 34. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick T: Risk of cutaneous carcinoma in patients treated with oral methoxsalen photoehemotherapy for psoriasis. N Engl J Med 300:809-813, 1979.
m
Im II
I
I
Solar radiation and malignant melanoma of the skin Alan N. Houghton, M.D., and Michael V. Viola, M.D.
New York, NY, arm Farmington, CT Several observations suggest that a majority of cases of malignant melanoma of the skin are linked to sun exposure. Evidence includes higher occurrence of melanoma on anatomic areas heavily exposed during recreation, development of melanoma more frequently in lightly pigmented persons, and correlation of melanoma incidence and mortality with proximity to the equator. The role of sun exposure in the pathogenesis of melanoma remains unclear, however. Many cases of melanoma may be related to heavy doses of solar radiation received during recreation. Chronic sun exposure is not so clearly linked to the development of melanoma (except in the uncommon lentigo maligna variety). Sunspot cycles have been associated with changes in melanoma incidence; an excess of melanoma cases has been observed every 9 to 12 years after peak sunspot activity. These excess cases may be caused by more intense exposure to solar ultraviolet radiation during sunspot maxima, perhaps related to changes in the stratospheric ozone layer. These epidemiologic and clinical clues suggest that many cases of melanoma are related to sun exposure triggering the appearance of clinically evident melanoma. In this regard, solar radiation behaves as a cocarcinogen or promoter, rather than a dose-dependent carcinogen. These observations also suggest that other factors may be involved in the pathogenesis of melanoma, e.g., nevi, heredity, or exposure to chemical carcinogens. (J AM ACAO DERMATOL5:477-483, 1981.) A number of factors have been implicated in the pathogenesis of malignant melanoma of the skin. These include exposure to solar radiation, heredity, hormones, chemical carcinogens, and trauma. Most factors can be directly implicated in only a small number of cases, for instance, heredity in perhaps 10% of melanoma patients.l However, there is a general impression that solar radiation is associated with the majority of cases of cutaneous melanoma. It remains unclear what role exposure
From she Memorial Sloan-Kettering Cancer Center, New York, and
the University of Connecticut Health Center, Farmington. Reprint requests to: Dr. Alan N. Houghton, Memorial SloanKettering Cancer Center, 1275 York Ave.. New York, NY 10021. 0190-9622/81/100477+07500.70/0 9 1981 Am Acad Dermatol
to solar radiation, and in particular ultraviolet (UV) radiation, may play in the pathogenesis of melanoma, but most evidence suggests that solar radiation acts not as a dose-dependent carcinogen but rather as a cocarcinogen or promoter. This evidence for a role of sun exposure comes from a series of associations made from epidemiologic and clinical observations. The evidence has been reviewed elsewhere 2 and can be summarized as follows. First, the incidence of malignant melanoma in relatively homogeneous white populations in North America, Northern Europe, and Australia is inversely proportional to latitude, that is, as one approaches the equator melanoma rates rise. a'4 In turn, solar radiation, and specifically UV radiation, is more intense at these lower lati477
478
Journal of the American Academy of Dermatology
Houghton and Viola
rl
o 7.0-[ 0
oO 6.0Id.l
zLI.I 5.0 z
4.0-
I.u ~0
3.0J
~
2.0-
1.0 200
L
WZ
_>~_
< 2 100
i..-
.--loO ILl z O0
1935 1940 1945 1950 1955 1960 1965 1970 1975
YEAR Fig. 1. Age-adjusted incidence of malignant melanoma of the skin in Connecticut related to sunspot relative number, 1935-t975. TM ~ , Males and females; ---, males alone. Arrows indicate peaks of sunspot activity.
tudes. Second, melanoma tends to occur on sites more heavily exposed to the sun during recreation, sparing areas which are covered by bathing suits. ~' ~ The highest concentration of melanomas occurs on the trunk, legs, and face, especially the lower legs of women and the trunk of men. TThird, melanoma is more likely to develop in lightly pigmented individuals, s''~ The classic phenotype of a person who develops melanoma is a blond or redhead with blue eyes, freckles, and fair skin, who tans poorly and sunburns easily (however, most persons who develop melanoma do not precisely fit this phenotype). Generally, darker-skinned groups, such as blacks, Hispanics, and Orientals, have mela-
noma incidences which are a fraction of the rates of lightly pigmented groups living in the same area. The general principle is that melanoma is relatively common in fair-skinned persons and is unlikely to occur on sun-exposed surfaces in darkly pigmented persons. Rather, melanoma in darker races tends to occur on the foot and mucous membranes. These epidemiologic and clinical observations are highlighted by the experience in Queensland, Australia, where the highest incidence of melanoma in the world is found. Queensland is a set of worst circumstances--a lightly pigmented population living close to the equator. Furthermore, for dramatic contrast, melanoma is rare among the darker-skinned aboriginal population in the same area. Several other, less compelling, epidemiologic observations are relevant to the association o f melanoma and sun exposure. Susceptible persons who have lived in a sunny climate all of their lives have a higher incidence of melanoma than persons who have recently moved to the same area from less sunny climates. For instance, the incidence of melanoma in native born Israelis of European extractions is greater than in recent European immigrants to Israel, suggesting an effect of more intense sun exposure in the sunnier climate of Israel. to Other geographic factors may affect the occurrence of melanoma. A higher incidence seems to occur in areas with extensive coastlines. ~,7 This may be due to recreational opportunities in these areas, as well as increased sun exposure related to cloud-covering patterns along shorelines. Seasonal differences occur in the diagnosis of melanoma, with diagnosis more likely during summer months when recreational sun exposure and solar UV radiation are most intense, lt-'a However, a skewing of the time of diagnosis may occur; biopsy of suspicious lesions may be done more frequently during summer months, related to the general darkening of pigmented lesions which occurs during tanning. Another epidemiologic observation relevant to melanoma and sun exposure is the distribution of melanoma among various occupational and social groups. Melanoma rates are relatively low for individuals in outdoor occupations, such as construction workers or farmers. Indeed, melanoma
Volume 5 Number 4 October, 1981
Solar radiation and melanoma
479
Table I. Partial correlation coefficients relating annual sunspot number to melanoma incidence Denmark
Finland
N e w York State
Year following sunspots
Connecticut
(1935-1967)
-
(1943-1972)
(1950-1971)
(1943-1972)
0 1 2 3 4
+ O. 190 + 0.459* + 0,695' + 0,378 - 0,005
+ 0.261 + O,390* + 0.376* + 0.273 + 0.072
+ 0.539* + 0.444* + 0.042 + 0.284 + 0,381
+ + + + +
0.232 0.499* 0,534* 0,437* 0,358
*p < 0.05,
occurs most commonly in higher income groups, especially managerial and professional workers. 14, la At first glance, this seems to conflict with a putative association of sun exposure and melanoma. However this suggests that recreational exposure of untanned skin, not chronic sun exposure, is involved in the pathogenesis of many melanomas, especially those arising on the trunk and legs. MELANOMA INCIDENCE AND SUNSPOTS One of the most alarming aspects of the epidemiology of melanoma is the dramatic rise of incidence and mortality rates, a phenomenon occurring in all countries with predominantly white populations.7. 1~-18 The rise in melanoma incidence began for persons born around 1900, a generation which experienced substantial liberalization of recreational dress and behavior as they passed into adulthood. Anatomic areas which had not previously been exposed to the sun, especially the trunk of men and the lower legs of women, were now uncovered during recreation. It is these two sites which have accounted for the largest rise in incidence of melanoma of the skin, while virtually no increase of melanoma of the face has occurred. In this regard, a further observation which relates solar radiation to malignant melanoma is the correlation between sunspot cycles and subsequent increases in melanoma incidence rates. 1.~This association was noticed in a detailed examination of the rising incidence of malignant melanoma. In Connecticut, age-adjusted incidence rates of melanoma have risen from 1.1 cases per 100,000 persons in 1935 to 7.4 cases in 1976. Superimposed on this steady rise in incidence were periods of excessive increases occurring every 8 to 12 years.
These periods of markedly increased rates peaked at 3 to 5 years, followed by a return toward baseline rates (Fig. 1). In order to examine this phenomenon quantitatively, the effect of increasing incidence of melanoma was represented by a linear regression equation relating melanoma incidence to time, and a cyclical pattern was observed when deviations from this line were calculated. These fluctuations of melanoma incidence correlated with sunspot numbers, and the highest correlation coefficients occurred 2 years after peak sunspot activity. The incidence of other nonmelanoma malignancies registered in Connecticut was not associated with sunspot cycles. Melanoma incidence rates from other tumor registries (including New York State, Finland, and Denmark, but not Norway) have shown similar correlations with sunspot numbers (Table I). In addition, Wigle 2~ confirmed the association between sunspot maxima and rises of melanoma incidence in Alberta and Saskatchewan. SOLAR VARIABILITY AND MELANOMA INCIDENCE The sunspot phenomenon has a complex relationship to geophysical and astrophysical events. We have proposed that sunspot cycles could be related to melanoma incidence through increases in UV radiation emitted by the sun and by solar modulation of the amount of ozone in the Earth's atmosphere, both events affecting the amount of UV radiation reaching the Earth's surface. It is becoming increasingly evident that the sun's activity varies, and sunspot numbers are the clearest indicator of solar activity. Sunspots are dark areas on the visible surface of the sun and are known to be cooler sites of local intense magnetic
Journal of the American Academy of Dermatology
480 Houghton and Viola
activity. Sunspots may vary in size up to fifteen times the Earth's diameter and tend to travel in groups, surviving several rotations of the sun. The number of visible sunspots may vary from day to day, but the mean annual numbers show a distinct periodicity of around I 1 years. At sunspot minimum the average sunspot number approaches zero, but at sunspot maximum up to several 100 sunspots may be sighted. Maximum sunspot numbers coincide with periods of increased solar activity. In particular, the amount of ultraviolet radiation emitted by the sun increases at solar maxima. '-'~ Could periodic increases in the sun's emission of UV radiation be related to rises in melanoma incidence? UV radiation is arbitrarily divided into three regions: UV-A (long wavelength, 320-400 nm), UV-B (280-320 nm), and UV-C (less than 280 nm). UV-B comprises the sunburn spectrum which produces cutaneous erythema, stimulates pigment formation, and is mutagenic and carcinogenic. The longer wavelength UV-A produces mild erythema, immediate pigment darkening, and accentuates the carcinogenic potential of UV-B and other carcinogens. At sunspot maximum, UV-C emitted by the sun may increase by as much as a factor of 1.5 (at 250 nm) and UV-B (at 300 nm) by 18%. '-'1 Ultimately, the amount of UV radiation reaching the Earth's surface is dependent on the Earth's atmosphere, specifically, the ozone layer of the stratosphere. The earth's stratospheric ozone is a tenuous layer of molecular oxygen ( Q ) which, if compressed, would measure only several centimeters thick. Ozone completely absorbs the shorter wavelengths of UV-C, absorbs incompletely the longer U V-B wavelengths, and does not filter UV-A. Some observers suggest that the thickness of the atmospheric ozone layer varies over the 11-year sunspot cycle, and these changes may be modulated by the sun's activity. ''~-'4 Throughout the sunspot cycle there are changes in the shape of the sun's outer atmosphere, or corona. The corona is not a limited envelope like the Earth's atmosphere, but rather expands into the solar system as a solar wind bathing the Earth's atmosphere with ionized particles traveling hundreds of kilometers per second. Increases in the intensity of the solar wind at sunspot max-
ima are associated with numerous terrestrial events, including aurorae and geomagnetic disturbances. It is interesting that these ten'estrial disturbances 9also lag sunspot peaks by about two years. The solar winds of ionized gas may produce changes in the Earth's stratospheric ozone layer (by influencing galactic cosmic rays entering the Earth's atmosphere) such that ozone minimas occur just prior to sunspot maxima...,4..,z (For more detailed discussion, see Viola et al.'-'c~) The overall effect would be an increase in the amount of UV radiation reaching the Earth's surface at sunspot maxima. If this is indeed true, then only small decreases of ozone thickness would be associated with substantial changes in melanoma incidence. Of particular concern in recent years has been the predicted depletion of stratospheric ozone by halocarbons rising from the Earth's surface. It is quite alarming that the National Academy of Sciences has predicted in a recent report an eventual 16.5% depletion of ozone if halocarbons continue to be released from the Earth's surface at the 1977 rate. "7 The melanoma incidence and sunspot data suggest that even a small depletion o f atmospheric ozone may cause a substantial increase in the incidence of melanoma, and therefore these recent estimates of ozone depletion are cause for grave concern. With this background, several comments are relevant to the association of melanoma and sunspots. First, rises in melanoma incidence occur 0 to 3 years after sunspot peaks, suggesting that heavier exposures to U V radiation trigger the clinical appearance of melanoma. Second, one of the highest sunspot maxima of this century may occur around 1979 to 1982: higher sunspot numbers are associated with higher solar activity, and perhaps a greater risk of melanoma of the skin in susceptible populations. '-'8 SOLAR RADIATION AS A DOSE-DEPENDENT
CARCINOGEN Despite the epidemiologic and clinical evidence relating sun exposure and melanoma of the skin, the exact role of solar radiation in the pathogenesis of melanoma remains speculative. For most nonmelanoma skin cancers, specifically basal cell and squamous cell carcinomas of the skin, solar radia-
Volume 5 Number 4 October, 1981 tion behaves as a dose-dependent carcinogen. These tumors occur most commonly on chronically exposed sites of the body in areas of actinically damaged skin. The incidence is strongly agedependent, with most cases occurring in old age. On the other hand, the evidence is meager that solar radiation is a dose-dependent carcinogen in the etiology of melanoma of the skin. However, there are two circumstances in which this may be the case. First, lentigo maligna melanoma, which comprises 10% of melanomas of the skin, most commonly develops on exposed and actinically damaged areas of the body in elderly persons. Second, malignant melanoma and other skin cancers occur at a very high rate in patients with the inherited autosomal recessive disorder, xeroderma pigmentosum. The cells of these patients have defects in their ability to repair UV damage to deoxyribonucleic acid (DNA). At an early age, these patients develop telangiectasias, dermal atrophy, solar keratoses, and multiple skin cancers, including melanoma. This association of solar damage to skin and melanoma is reminiscent of lentigo maligna melanoma. The occun'ence of multiple melanomas in patients with xeroderma pigmentosum suggests an acceleration of damage to skin by repeated, low-dose UV exposure, with increased sensitivity to the carcinogenic potential of UV radiation. SOLAR RADIATION AS A COCARCINOGEN OR PROMOTER
In contrast to lentigo maligna melanoma, solar radiation does not act as a dose-dependent carcinogen in most cases of melanoma, particularly the common types of superficial spreading and nodular melanoma. Rather than behaving as a chronic carcinogen, sun exposure appears to be a later or more proximal event in the pathogenesis of melanoma, as suggested by several observations. The rapid rise in melanoma incidence shortly after sunspot peaks suggests that increases in UV radiation precede the appearance of clinically apparent melanoma by only several years. Also, other epidemiologic observations mentioned previously suggest that relatively brief exposures of untanned skin to sun may trigger the majority of melanomas of the skin. Melanoma favors sites
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exposed intermittently and intensively to the sun during recreation, particularly the male trunk and the female lower extremity. A lower incidence of melanoma in persons who work outdoors, with a relatively greater incidence in persons with high incomes (and more recreation opportunities) suggest that UV radiation is not a dose-dependent carcinogen. The higher incidence of melanoma in light-complexioned persons who sunburn easily but tan poorly also supports this hypothesis. In addition, although most animal models of melanoma rely on genetic factors or chronic (or rarely single) exposure to chemical carcinogens, in a relevant animal model Epstein et al produced blue nevi on hairless mice by treatment with a single application of the hydrocarbon, dimethylbenzanthracene.2r~ After exposure of these chemically induced nevi to UV radiation, metastatic melanomas developed in some animals. Again, exposure to UV radiation was a later event in the pathogenesis of these murine melanomas. These observations suggest that solar radiation, and in particular UV radiation, may behave as a cocarcinogen or promoter in the pathogenesis of melanoma of the skin. Tumor promoters are factors that can influence the development of cancer; in animals previously exposed to carcinogens, promoters can shorten the latent period and increase the incidence of tumors. The hypothesis that solar radiation is a promoter in the development of melanoma requires briefly reviewing the multistage theory of cancer development. Foulds a~ and others suggested that most cancers in humans develop in multiple steps. Thus, as normal cells evolve into cancer ceils, there are stages of development from initiated cells to preneoplastic cells to metastatic malignant cells, al These sequential steps are illustrated in a simple manner by the two-stage model of skin carcinogenesis in mice. 3'-' A single low dose of a hydrocarbon can induce, or initiate, a latent change in epidermal cells, but the skin itself still appears normal. If a promoter, such as a phorbol ester, is later applied, then metastasizing carcinomas may appear in the treated areas. Promoters are able to induce frank neoplasia in previously initiated cells and therefore are related to later steps in the development of cancer. The properties of initiating
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agents and promoters appear to be different. While initiating agents are usually mutagenic, acting on DNA, promoters may have nonmutagenic properties which favor the growth of previously initiated cells, perhaps through changes in properties of cell differentiation or specific immunosuppression. Taking all of these observations together, UV radiation may behave both as an initiator and a promoter in human skin cancers. It acts as a dose-dependent carcinogen in the pathogenesis of basal cell and squamous cell carcinoma of the skin and lentigo maligna melanoma, but behaves as a promoter in most other types of cutaneous melanoma. In the development of malignant melanoma, there are most likely early and late events in the transformation of normal melanocytes to invasive melanoma cells. UV radiation as a promoter would be related to the later events. Many unanswered questions remain concerning the possible role of UV radiation in the pathogenesis of melanoma. What spectrum of UV radiation is related to the development of melanoma? Is it the mutagenic UV-B spectrum, or perhaps the potentially cocarcinogenic, longer wavelengths of UV-A? The occurrence of squamous cell carcinomas of the skin within several years after exposure to UV-A and psoralen, or within a month after UV-A treatment of patients with xeroderma pigmentosum, suggests a promoter role for UV-A in the pathogenesis of these cutaneous tumors. :~, :~-L A related question is how UV could act as a promoter. Could UV-A or UV-B promote tumors by producing hyperplasia of initiated melanocytes or by specific suppression of immunologic surveillance in the skin? Are other factors involved in earlier steps of the pathogenesis of melanoma (e.g., hereditary factors, premalignant melanocytic nevi, exposure to chemical carcinogens, immunologic suppression, hormones, oncogenic viruses, or even earlier exposure to mutagenic UV radiation during childhood or adolescence)? Despite epidemiologic and clinical clues, the putative relationship of solar radiation, and specifically UV radiation, to the pathogenesis of malignant melanoma of the skin is still tentative and complex. Factors such as genetic susceptibility, recreational behavior, and other cultural and socioeconomic factors may affect melanoma inci-
dence in different areas. Other environmental variables may be involved, affecting the amount of solar radiation reaching the Earth's surtace, including altitude during exposure, cloud-covering patterns, and time of day during exposure. The carcinogenic and promoting action spectra of UV radiation (i.e., the dose a n d wavelength required for specific biologic effects) still need to be defined for melanocytes, particularly nevus cells. Finally, nonsolar factors involved in the pathogenesis of melanoma must be investigated. REFERENCES 1. Anderson DE: Clinical characteristics of the genetic variety of cutaneous melanoma in man. Cancer 21:721725, 1971. 2. Climatic Impact Committee: Environmental impact of stratospheric flight. Washington, DC, 1975, National Academy of Sciences, USA. 3. Elwood JM, Lee JAH, Walter SD, Mo T, Green AES: Relationship of melanoma and other skin cancer mortality to latitude and ultraviolet radiation in the United States and Canada. lnt J Epidemiol 3:325-332, 1974. 4. Crombie IK: Variation o f melanoma incidence with latitude in North America and Europe. Br J Cancer 40:774-781, 1979. 5. Davis NC, Herron JJ, McLeod GR: Malignant melanoma in Queensland. Lancet 2:407-410, 1966. 6. Fitzpatrick TB, Sober AJ, Pearson B, Lew R: Cutaneous carcinogenic effects of sunlight in humans, in Urbach F, editor: Research in photobiology. Oxford, 1969, Pergamon Press, pp. 635-650. 7. Houghton AN, Flannery JT, Viola MV: Malignant melanoma in Connecticut a n d Denmark. Int J Cancer 25:95-104, 1980. 8. Gellin GA, Kopf AW, Garfinkel L: Malignant melanoma: A controlled study o f possibly associated factors. Arch Dermatol 99:43-48, 1969. 9. Klepp O, Magnus K: Some environmental and bodily characteristics of melanoma patients. A case control study. Int J Cancer 23:482-486, 1979. 10. Movshovitz M, Modan B: Role of sun exposure in the etiology of malignant melanoma. Epidemiologic inference. J Natl Cancer hast 51:777-779, 1977. 11. Lee JAH: Letter to the Editor. Br Med J 1:623, 1969. 12. Malec E, Eklund G: The changing incidence of malignant melanoma of the skin in Sweden: 1959-1968. Scand J Plast Reconstr Surg 12: 19-27, 1978. 13. Scotto J, Nam JM: Skin melanoma and seasonal patterns. Am J Epidemiol 111:309-3 14, 1980. 14. Lee JAH: Current evidence about the causes of malignant melanoma. Prog Clin Cancer 6:151-161, 1975. 15. Williams PR, Stegens NL, Goldsmith JR: Associations of cancer site and type with occupation and industry from the Third National Cancer Survey Interview. J Natl Cancer Inst 59:1147-1185, 1977. 16. Lee JAH, Carter AP: Secular trends in mortality from malignant melanoma. J Natl Cancer Inst 45:91-97, 1970.
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17. Lee JAH: The trend of mortality from primary malignant tumor of the skin. J Invest Dermatol 59:445-448, 1973. 18. Magnus K: Incidence of malignant melanoma in the five Nordic countries: Significance of solar radiation. Int J Cancer 20:477-485, 1977. 19. Houghton AN, Munster E, Viola MV: Increased incidence of malignant melanomas after peaks of sunspot activity. Lancet 1:259-260, 1978. 20. Wigle DT: Malignant melanoma of the skin and sunspot activity. Lancet 2:38, 1978. 21. Heath EF, Thekaekara MP: The solar spectrum between 1200 and 3000A, ilt White OR, editor: The solar output and its variation. Boulder, CO, 1977, Colorado Associated University Press, pp. 193-212. 22. Willet HD: The relationship of total atmospheric ozone to the sunspot cycle. J Geophys Res 67:661-670, 1962. 23. Paetzold HK, Piscolor F, Zschorner T: Secular variation of the stratospheric ozone layer over middle Europe during the solar cycles from 1951 to 1972. Nature (Phys Sci) 240:106-107, 1972. 24. Ruderman MA, Chamberlain JW: Origin of sunspot modulation of ozone: Its implications for stratospheric ion chemistry. Planet Space Sci 23:247-268, 1975. 25. Ruderman MA, Foley HM, Chamberlain JW: Eleven year variation in polar ozone and stratospheric ion chemistry. Science 192:555-557, 1976.
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26. Viola MV, Houghton AN, Monster EW: Solar cycles and malignant melanoma. Med Hypotheses 5:153-160, 1979. 27. Stratospheric ozone depletion by halocarbons: Chemistry and transport. Washington, DC, 1975, National Academy of Sciences USA. 28. Kane RP: Predicted intensity of the solar maximum. Nature 275:139-/40, 1978. 29. Epstein JH, Epstein WL, Nakai T: Production of melanomas from DMBA-induced "blue nevi" in hairless mice with ultraviolet radiation. J Natl Cancer lnst 38:19-30, 1967. 30. ffoulds L: Neoplastic development. London, 1975, Academic Press, Inc., pp. 1-108. 3 I. Farber E: The sequential analysis of liver cancer induction. Biochim Biophys Acta 605:149-166, 1980. 32. Berenblum I: Cocarcinogenic action of croton resin. Cancer Res 1:44-48, 1941. 33. Spellman CW: Skin cancer after PUVA treatment for psoriasis. N Engl J Med 301:554, 1979. 34. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick T: Risk of cutaneous carcinoma in patients treated with oral methoxsalen photoehemotherapy for psoriasis. N Engl J Med 300:809-813, 1979.