UVA, UVB and incidence of cutaneous malignant melanoma in Norway and Sweden

Abstract

Latitudinal dependencies of UVA and UVB were studied together with relevant epidemiological data for squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM) in Norway and Sweden. Our data support the hypothesis that solar UVA radiation may play a role for CMM induction. The etiologies of SCC and CMM are different according to a latitudinal dependency and differences in age curves. Sun exposure patterns, age-related decay rates of repair of UV damage and sex hormones may play different roles for the two skin cancers. Also, UVB induction of vitamin D may be involved. CMM incidence rates among young people have decreased or been constant since about 1990 in Norway and Sweden. All reasons for UVA contributing to CMM will be discussed.

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Introduction

Solar radiation is believed to be the main risk factor for the major forms of skin cancer: squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and cutaneous malignant melanoma (CMM).^1,2 The former two are classified as non-melanoma skin cancers and have much lower death risks per case of incidence than CMM: less than one percent versus 20–30 percent in most countries.^1,2 CMM, SCC and BCC have different etiologies.^3,4 The action spectra for erythema and SCC (Fig. 1) are likely to be strongly UVB weighted, and there seems to be a relationship with the total UV exposure, notably in the case of SCC.⁵

Fig. 1 Action spectra for erythema in human skin according to CIE,⁶ for SCC in mouse skin according SCUP⁵ and for CMM in fish according Setlow et al.⁷

For CMM, the influence of UV radiation has been debated for decades.^1,2,8–14 Some authors even argue that UV plays no major role.¹⁵ The main arguments for and against a relationship between UV and CMM incidence are listed in Tables 1 and 2.

Table 1 Main arguments for a relationship between UV and CMM

	Main arguments for a relationship between UV and CMM	References
1.	Sunburn episodes are risk factors for CMM.	13,16–19
2.	CMMs used to occur mainly on sun-exposed skin.	14,16,20
3.	CMM can be induced in some animals by UV (examples: Angora goats, Sinclair swine, Monodelphis domestica (an opossum) and Xiphophorus (a small swordfish).	21
4.	Patients with CMM have increased risk of BCC and SCC.	22
5.	In Europe, CMM is more frequent in the north than in the south. The whole area is mainly populated by Caucasians.	23,24
6.	Some CMMs contain mutations pointing towards UVB damage (cyclobutane pyrimidine dimers, pyrimidine (6–4) pyrimidone photoproducts).	12,14,20,25,26
7.	Lentigo maligna melanoma is clearly related to UV exposure.	27
8.	CMMs often arise in the borders of pigmented nevi.	17,28
9.	CMM risk decreases with increasing pigmentation. Skin pigments absorb UV.	29–32
10.	CMM risk increases upon migration to more sunny countries.	18,33
11.	CMM patients often have low DNA repair capacity and low minimum erythema doses (MEDs).	8,34–37
12.	Patients with xeroderma pigmentosum (abnormal DNA repair) have at least 1000 times increased CMM risks.	8,36,38
13.	Some reports indicate increased CMM risk for persons frequently using sunbeds.	39–42

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Table 2 Main arguments against a relationship between UV and CMM

	Main arguments against a relationship between UV and CMM	References
1.	CMM is more frequent among people with indoor occupations giving low accumulated UV exposures, (white-collar workers), than among people with large accumulated UV exposures (farmers, fishermen, etc.).	43–45
2.	The localization pattern of CMM on the body is different from that of SCC, which is clearly UV related.	1
3.	CMM is uncommon among albino Africans; opposite to what is found for BCC and SCC.	46
4.	The incidence rate of CMM in sunny Australia is only two times higher than in the high-latitude country Norway, while the incidence rates of BCC and SCC are 10 to 20 times higher.	47
5.	In Europe, CMM is more frequent in the north than in the south. The whole area is mainly populated by Caucasians.	24,47
6.	Around CMM lesions little solar elastosis is found^48 Solar elastosis is related to accumulated UV exposure.	48,49
7.	Sun and artificial sources of UVB are efficient generators of vitamin D which seems to reduce carcinogenesis and tumor progression. It has been demonstrated that higher 25-hydroxyvitamin D3 levels, at CMM diagnosis, were associated with both thinner tumours and better survival from melanoma, independent of Breslow thickness.	48,50–52
8.	CMM may be a disease related to affluence, since the incidence rates increases with increasing gross domestic product (GDP)	13
9.	A number of chemicals seem to be causing CMM. There is a relationship between polycyclic aromatic hydrocarbons (PAH), benzene, and/or polychlorinated biphenyls (PCB) exposure of workers in the petroleum and automobile industry and an increased risk for CMM.	53

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The discussion of whether UVA can generate CMM is of interest from the viewpoints of photobiology and physics, and also health politics. The main argument for and against a causation are listed in Tables 3 and 4.

Table 3 Main arguments for a relationship of UVA and CMM

	Main arguments for a relationship of UVA and CMM.	References
1.	In populations with similar skin type there is a clear latitudinal gradient, which is larger for BCC and SCC than for CMM. The UVB gradient is also larger than the UVA gradient. The incidence rate of CMM in sunny Australia is only two times higher than in the high-latitude country Norway, while the incidence rates of BCC and SCC are 20 to 40 times higher.	24
2.	CMM risk decreases with increasing skin pigmentation. Melanin absorbs UVA.	32
3.	CMMs contain some DNA damage pointing towards UVA damage (8-oxo-7,8-dihydroguanine).	8–10,26,54
4.	Some reports indicate increased CMM risk for persons frequently using sunbeds. Most sunbeds emit relatively more UVA than the sun does.	39–42,55,56
5.	Albino Africans lacking melanin have very high rates of BCC and SCC but low rates of CMM. This seems to suggest that melanin, which absorbs UVA, is a chromophore for CMM.	46
6.	There seems to be little CMM protective effect of only UVB absorbing sunscreens. However, a broad-spectrum (UVB and UVA) sunscreen reduces risk of CMM.	57–60
7.	Around CMM lesions little solar elastosis is found, indicating low UVB exposure. Solar elastosis is related to accumulated UVB exposure.	48,49,61

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Table 4 Main arguments against a relationship of UVA and CMM

	Main arguments against a relationship of UVA and CMM	References
1.	UVA induces CMM neither in Monodelphis domestica nor in transgenic mice.	62–65
2.	Recently, the original Xiphophorus experiments of Setlow et al. were attempted to be reproduced, but did not show any CMM-generating effect of UVA.	7,66

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The arguments for melanomagenic effects of UV, notably of UVA, are, in our opinion, stronger than the arguments against, and it seems that intermittent exposures, resulting in sunburns, are particularly dangerous as judged from the pattern of body distribution of SCC and CMM.¹ The distribution of SCC and BCC on different parts of the body is different and changing with time.^1,67 The density of SCC and BCC per unit skin area is, and has always been, largest on the face, as might be expected if the total sun exposure is important.^1,68,69 The same was true for CMM until the 1980s when the density became larger on the trunk in some populations (Norway, Canada, Switzerland) for young persons (<50 years).^70–72 This was attributed to intermittent sun exposure and sunburns.

The relative role of UVB and UVA in the etiology of CMM is of crucial importance for health authorities formulating rules for legal sunbeds. At present sunbeds emit similar UVB fluence rates as those in Mediterranean noon sun but six to ten times higher UVA fluence rates.^55,56

We will try to elucidate the relative role of UVA and UVB for CMM and SCC by studying the north–south gradient of CMM and SCC in Norway and Sweden. As earlier stated, the north–south gradient is larger for the annual fluences of UVB than for that of UVA.^1,67

Materials and methods

Incidence rates of CMM and SCC in Norway and Sweden

We have analyzed epidemiological data from the Cancer Registries of Norway and Sweden for overall CMMs and SCCs in different counties.

The age-standardized incidence rates for the world standard population (ASIR (W)) per 100 000 persons for CMM by age (0–49 and older than 50 years of age) in Sweden and in Norway are retrieved from the online data base of International Agency for Research on Cancer (IARC).^73–77

Ultraviolet doses in Norwegian and Swedish counties

Relevant UVA doses are determined under the assumption that the action spectrum (Fig. 1) of CMM is similar to the action spectrum for melanoma in Xiphophorus fish⁷⁸ and that UVB doses are represented by CIE action spectrum for erythema.⁶ Calculations are based on daily satellite measurements (Total Ozone Mapping Spectrometer (TOMS) on Nimbus-7 satellite). The calculations include daily cloud cover and total ozone. The annual doses are averages over a ten-year period (1980–1990). A cylinder representation of the human skin surface was used as described and argued for earlier.⁷⁹ Further arguments for this model are based on latitudinal dependencies of CMM rates on different body localizations and will be presented later (manuscript in preparation). The conclusions arrived in the present work would be essentially the same if a planar, horizontal surface were used, although the north–south gradients would be different.

ASIR was used to compare time trends between CMM at different age groups (0–49 and older than 50 years of age) for the north, mid/west and south regions of Norway. Assignment of the Norwegian counties into three regions, north, mid/west and south, was based on ambient annual UV doses, calculated and measured as earlier described.^80,81 The south region of Norway (mean latitude 60°) has high annual ambient UV exposure (37 × 10⁴ J m⁻²). The mid/west region (mean latitude 64°) has middle annual ambient UV exposure (30.5 × 10⁴ J m⁻²) and the north region (mean latitude 70°) has low annual ambient UV exposure (26 × 10⁴ J m⁻²).^80,81

The data were analyzed using SigmaPlot 11.0 software from Systat Software, Inc. (Richmond, CA, USA). Significant P-value was considered < 0.05.

Results

The incidence rates of CMM and SCC for both sexes are increasing in Norway and Sweden (Fig. 2). The slopes are very similar for the two countries and are significantly (P < 0.05) larger for SCC than for CMM (Fig. 2). The slopes for CMM are similar for men and women (Fig. 2A, B). For SCC, the overall incidence rates in Sweden are about two times larger for men than for women (Fig. 2D). Unfortunately, we do not have separate incidence rates of SCC in Norway for men and women.

Fig. 2 The age-standardized incidence rates (according to the world standard population (ASIR (W)) per 100 000 women and men for CMM (A, B) and SCC (C, D) in Norway (A, C) and in Sweden (B, D).

We have calculated, on the basis of measurements as described in materials and methods, the UVA and the UVB annual fluences for the different regions of Norway and Sweden (Fig. 3A). The UVA/UVB ratio decreases with decreasing latitude (Fig. 3B), and so do the ratios of CMM/SCC incidence rates (Fig. 3C). These ratios are smaller for men than for women (Fig. 3C), in agreement with Fig. 2B and 2D.

Fig. 3 UVA and UVB annual fluences at different latitudes (A), ratios of UVA/UVB annual fluences at different latitudes (B), and ratios of incidence rates of CMM and SCC for men and women (C).

SCC comes later in life than CMM (Fig. 4). For CMM the age curves (in both countries) are different for men and women: For persons younger than 50 years the rates are highest for women, while for persons older than 50 years the rates are highest for men (Fig. 4A). Thus, the overall ASIR of CMM are similar for the two sexes (Fig. 2A, B).

Fig. 4 Age distributions of the age-standardized incidence rates (according to the world standard population (ASIR (W)) per 100 000 of CMM (A) and SCC (B) for men and women in Norway and Sweden. For SCC we have data for men and women only for Sweden.

The incidence rates of CMM for both sexes increase with decreasing latitude (Fig. 5A). The increase is larger for the oldest persons (Fig. 5). Thus, the ratio of rates for >50 and <50 years is largest for old people living in the south parts of Norway (Fig. 5B).

Fig. 5 Latitudinal dependencies of the age-standardized incidence rates of CMM in Norway (according to the world standard population (ASIR (W)) per 100 000 (A) for both sexes younger and older than 50 years of age, and for the corresponding ratios (B).

The incidence rates for the younger generations (<50 years) have decreased or stayed constant after about 1990, notably in the south region of Norway (Fig. 6A–C). In view of this and of the age curves shown in Fig. 4, we calculated the time gradients (on the basis of Fig. 6) for the periods before and after 1990 and for younger (<50 years age) and older (>50 years age) persons (Fig. 7). Except for younger men (<50 years age) in the north region (for whom the data are scattered due to few cases) all gradients before 1990 are positive and almost similar (Fig. 7). All gradients are smaller after 1990 than before 1990. For younger men (<50 years age) they are even negative, showing decreasing incidence rates. The same is true for younger women (<50 years age) living in the south region (Fig. 6 and 7).

Fig. 6 Time development of the age-standardized incidence rates of CMM (according to the world standard population (ASIR (W)) per 100 000 for persons at two age groups (0–49 (A–C) and >50 years (E–F)) in the north (A,D), the mid/west (B, E) and the south (C, F) regions of Norway.

Fig. 7 Time gradients (slopes from Fig. 6) of the CMM incidence rates in Norway for two age groups (younger and older than 50 years). The values are given for the periods 1966–1990 and 1990–2005 using approximate regression lines.

Discussion

The present data (Fig. 2 and 3) are more detailed than our earlier findings,²⁴ but agree with these where we compared the CMM, SCC and BCC rates in Scandinavia with those in Australia, and suggest that UVA might be melanomagenic. In the period 1983–1987 the SCC and BCC rates were 20–40 times higher in Australia than in Norway, but the CMM rates were only a factor of 2–3 larger.²⁴ We also found that the annual fluences of UVA were around 1.3 times larger in Australia than in Scandinavia, and those of UVB were around 2 times larger.²⁴ We conclude that all our epidemiological data for latitudinal dependencies of CMM and SCC rates indicate that UVA may play a role for human CMM carcinogenesis.²⁴ If this is true and can be confirmed in future studies, the findings suggest to reduce the legal UVA fluence rates in sunbeds and not to recommend sunscreens that absorb mainly UVB and transmit UVA. However, sun-like sunbeds, with less UVA than those used now, would act as summer sun and might, carefully used, improve the winter levels of vitamin D. Keeping a constant vitamin D level throughout the year might be optimal. This has been argued for from a physiological and from a biochemical point of view.⁸² Most of the human evolution occurred in Africa, where vitamin D is produced in skin with a constant rate throughout the year. The relationship between vitamin D and CMM has recently been reviewed.^51,52,83 A preventive role of vitamin D cannot be ruled out. Thus, it was recently found that weekend and holiday sun exposure (which are likely to be of intermittent character) were strongly associated with increased vitamin D level but did not increase the CMM risk.⁸⁴

BCC and SCC, like most internal cancers, increase in incidence with age, as shown here for SCC (Fig. 4). This is also true for CMM incidence on the face in Norway, but not for CMM on the trunk, where CMM is most frequent among middle-aged people.⁷⁰ The incidence rates of CMM increased with doubling times of the order of 12–15 years over many decades until about 1990.⁸⁵ The rate of increase in that early period was almost the same in all regions and for young and old persons (Fig. 6 and 7), i.e. 12–15 years. In Australia, in the United States, Sweden and Canada the CMM rates have stabilized or decreased after 1990, notably for young people.^74–77 The decrease is statistically significant (P < 0.05) for the southern part of Norway (Fig. 6). In all cases the gradient of the incidence rate has decreased with time (Fig. 6 and 7). This decrease has taken place in a period with a steep increase in use of sunbeds and the relationship needs further studies.

Recent epidemiological investigations indicate that those who use sunbeds have increased CMM risks.^{41,42,86–88} This may be related to the high fluence rate of UVA in sunbeds.^55,56 Some older investigations show no increased risk, which might be related to different UVA/UVB ratios at earlier times.³⁹ However, even a very recent study showed no increased CMM risk associated with sunbed use.⁸⁹

Sun exposure may have a dual role in melanomagenesis. Thus, in time periods of increasing rates of CMM on sun exposed body localizations (face, trunk, etc.), the rates of CMM on non-UVB exposed localizations (the uveal part of the eye, the vulva and the perianal region) seem to decrease and vice versa.^90,91 Sometimes there is even an opposite latitudinal gradient for exposed and non-exposed localizations.⁹¹ Also, the prognosis of CMM is best for CMMs arising on skin with elastosis and signs of high UVB exposure.^48,49 All these observations indicate that UVB-induced vitamin D may play a protective role.

Can the age distribution of CMM (Fig. 4) give any information about the role of UVA? Age-related differences in exposure patterns (more intermittent exposures and more use of UVB absorbing sunscreens among young persons) may explain the early onset of CMM compared with that of SCC. However, even before extensive use of UVB-absorbing sunscreens there was a difference between the age of onset for CMM and SCC in Norway.⁹² Most likely, the differences between the age curves for CMM and SCC (Fig. 4) indicate that the etiologies of these two cancer forms are different. Recent studies demonstrate that melanoma cells contain not only mutations related to past exposure to UV radiation, but also mutations unrelated to UV exposure.^93,94 The difference between the curves for CMM in men and those in women may suggest that estrogens play a role for the high incidence among younger women (<50 years age) (Fig. 4), as indicated in other investigations.^95–97

The latitudinal dependencies of the age standardized CMM incidence rates for persons younger and older than 50 years of age (Fig. 5) and of the corresponding ratios (Fig. 5) are not easy to explain. Why should relatively more old people get CMM in the south than in the north (Fig. 5B)? It would be speculative to relate this to any role of UVA. Possibly, sunburning among old persons is more frequent in the south than in the north? Or, maybe, accumulation of solar damage is more prominent in the south than in the north, as related to higher life-time exposures? These hypothesis should be tested in the future.

In conclusion the present work supports the hypothesis that UVA radiation from the sun may play a role for CMM induction. The etiologies of SCC and CMM are different as indicated by differences in age curves and latitudinal gradients. Sun exposure patterns, age related repair of different types of UV damage, and sex hormones may play different roles for the two cancers. CMM incidence rates among young people have decreased or been constant since about 1990, while use of sunbeds has increased strongly over the same period. UVB-generation of vitamin D may contribute to the differences in latitudinal gradients of SCC and CMM rates, and should be paid attention to in future investigations and discussions of the etiologies of SCC and CMM.

Acknowledgements

The present work was supported by the Norwegian Cancer Society (Kreftforeningen). We thank the NASA/GSFC TOMS Ozone Processing Team for the use of their Numbus 7 TOMS data.

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Footnotes

† This article is dedicated to the memory of Dr Egil Kvam for his important work in photobiology and for his contributions to our scientific communities through scientific discussions and through friendship. Egil Kvam pioneered investigations on the relationship between UVA and skin cancer.

‡ Contribution to the themed issue on the biology of UVA.

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