Abstract
Importance
Two pathways have been hypothesized for the development of cutaneous melanoma: one typically affects the head and neck, a site with chronic sun damage, and the other affects the trunk, which is less exposed to the sun. However, the possible cause of limb melanomas is less studied under this hypothesis.
Objective
To investigate the association between phenotypic characteristics, pattern of UV radiation exposure, and risk of melanoma on different body sites.
Design, Setting, and Participants
This study used data on 161 540 women with information on phenotypic characteristics and UV radiation exposure who were part of the Norwegian Women and Cancer study, a population-based prospective study established in 1991 with exposure information collected by questionnaires at baseline and every 4 to 6 years during follow-up through 2015. Data analysis was performed from October 2017 through May 2018.
Exposures
Participants reported hair color, eye color, untanned skin color, number of small symmetric and large asymmetric nevi, and freckling, as well as histories of sunburns, sunbathing vacations, and indoor tanning in childhood, adolescence, and adulthood.
Main Outcomes and Measures
The Norwegian Women and Cancer study was linked to the Cancer Registry of Norway for data on cancer diagnosis and date of death or emigration. Primary melanoma site was categorized as head and neck, trunk, upper limbs, and lower limbs.
Results
During follow-up of the 161 540 women in the study (mean age at study entry, 50 years [range, 34-70 years]; mean age at diagnosis, 60 years [range, 34-87 years]), 1374 incident cases of melanoma were diagnosed. Having large asymmetric nevi was a significant risk factor for all sites and was strongest for the lower limbs (relative risk [RR], 3.38; 95% CI, 2.62-4.38) and weakest for the upper limbs (RR, 1.96; 95% CI, 1.22-3.17; P = .02 for heterogeneity). Mean lifetime number of sunbathing vacations was significantly associated with risk of trunk melanomas (RR, 1.14; 95% CI, 1.07-1.22) and lower limb melanomas (RR, 1.12; 95% CI, 1.05-1.19) but not upper limb melanomas (RR, 0.98; 95% CI, 0.88-1.09) and head and neck melanomas (RR, 0.87; 95% CI, 0.73-1.04; P = .006 for heterogeneity). Indoor tanning was associated only with trunk melanomas (RR for the highest tertile, 1.49; 95% CI, 1.16-1.92) and lower limb melanomas (RR for the highest tertile, 1.33; 95% CI, 1.00-1.76; P = .002 for heterogeneity). Skin color, hair color, small symmetric nevi, and history of sunburns were associated with risk of melanoma on all sites.
Conclusions and Relevance
These results appear to support the hypothesis of divergent pathways to melanoma and that recreational sun exposure and indoor tanning are associated with melanoma on the lower limbs, the most common site of melanoma in women. These findings appear to have important preventive implications.
This population-based cohort study uses data from the Norwegian Women and Cancer study to investigate the association between phenotypic characteristics, pattern of UV radiation exposure, and risk of melanoma on different body sites.
Key Points
Question
Do phenotypic characteristics and pattern of UV radiation exposure differ according to body site of melanoma?
Findings
In this population-based cohort study, associations with large asymmetric nevi, sunbathing vacations, and indoor tanning differed significantly among melanoma sites. Skin color, hair color, small symmetric nevi, residential ambient UV radiation, and sunburns were associated with melanoma risk on all sites.
Meaning
This study adds to the supporting evidence of divergent pathways to melanoma and suggests similar risk profiles for lower limb and trunk melanomas and for upper limb and head and neck melanomas.
Introduction
The incidence of cutaneous melanoma (hereafter, melanoma), has increased markedly in many fair-skinned populations during the past decades.1 Melanoma was responsible for approximately 1.6 million years of healthy life lost globally in 2015, with the greatest burden in New Zealand, Australia, Europe, and North America.2 Excessive sun exposure is the foremost preventable risk factor and is responsible for most melanomas.3 However, the association between sun exposure and melanoma is complex,4,5 and individual risk also depends on pigmentary characteristics, such as hair color, ability to develop a tan, and the type and number of nevi,5,6,7 which in turn are associated with inherited genetic factors, age, and sun exposure.8,9
Two pathways have been hypothesized for the development of melanoma.10,11 One typically affects areas of the skin with long-term sun exposure, such as the head and neck in older individuals (age, >55 years) with few melanocytic nevi. The other pathway arises primarily on areas less exposed to the sun, such as the trunk in younger individuals with multiple melanocytic nevi.12
A number of epidemiologic studies that compared individuals with trunk melanoma vs head and neck melanoma support the existence of divergent pathways in melanoma development,13,14,15 although some studies did not.16,17,18,19 Moreover, the possible cause of limb melanomas is less studied under this hypothesis; because the lower limbs are the most common sites of melanoma among women, clarifying this cause is important for prevention. In addition, even though it is known that artificial UV radiation (UVR) causes melanoma,20,21,22,23 the pathways to melanomagenesis after indoor tanning have not been explored, to our knowledge. We therefore examined the association between phenotypic characteristics, pattern of UVR exposure, and melanoma risk on different body sites using information from the large, population-based, prospective Norwegian Women and Cancer (NOWAC) cohort study.
Methods
The NOWAC Cohort
The NOWAC study was established in 1991. A nationwide random sample of more than 300 000 women aged 30 to 75 years was drawn from the National Population Register; 171 725 women (response rate, 54%) completed and returned the baseline questionnaire from 1991 to 2007 and received follow-up questionnaires every 4 to 6 years. Details on the NOWAC study and the design have been published previously.24 Reproducibility of self-reported melanoma risk factors in the NOWAC study was good or acceptable and was independent of age, educational level, or skin color.25 The Norwegian Data Inspectorate and the Regional Committee for Medical Research Ethics approved the study, and all participants provided written informed consent.
Follow-up and End Points
The unique identity number of Norwegian citizens was used to link individuals from the NOWAC study to the Cancer Registry of Norway for information on cancer (diagnosis date and histopathologic characteristics) and date of death or emigration. Primary tumor site was categorized using International Classification of Diseases, Seventh Revision, codes as head and neck (190.0), trunk (190.1 and 190.7), upper limbs (190.2), lower limbs (190.3 and 190.4), other (190.5, 190.6, and 190.8), and skin unspecified (190.9). Reporting of incident cancers to the Cancer Registry of Norway is compulsory, and 99.9% of melanomas are morphologically verified.26
Phenotypic Characteristics
Participants reported color of hair (dark brown and black, brown, blond and yellow, or red), eyes (brown; green, gray, or mixed; or blue), and untanned skin (recorded from 1 [very fair] to 10 [very dark] and categorized as very dark [9-10], dark [7-8], medium [4-6], and light [1-3]). Participants also reported the number of asymmetric nevi larger than 5 mm on their legs (recorded as 0, 1, 2-3, 4-6, 7-12, 13-24, and ≥25 and categorized as 0, 1, and ≥2; a color brochure with pictures of 3 examples of asymmetric nevi was provided) and freckling after sunbathing (yes or no). Subsamples of the cohort were asked about the number of small symmetric nevi on their legs or arms (categorized together as 0, 1-10, 11-50, and ≥50).
UVR Exposure
Residential ambient UVR was categorized according to region-specific cumulated doses of UV-B as low (northern Norway), medium-low (central Norway), medium (southwestern Norway), and highest (southeastern Norway).27 Participants reported history of severe sunburns (never, 1, 2-3, 4-5, and ≥6 times per year), mean number of weeks spent on sunbathing vacations (never, 1, 2-3, 4-6, and ≥7 weeks per year), and mean use of an indoor tanning device (never; rarely; 1, 2, and 3-4 times per month; and >1 time per week) in childhood (age, ≤9 years), adolescence (age, 10-19 years), and adulthood (age, >19 years).
We summed and categorized the mean number of sunburns before age 20 years and at ages 20 to 49 years as none, 1 or fewer, and more than 1 per year. We further calculated mean annual lifetime number of sunburns by dividing the cumulative number of burns by age. Likewise, we summed and categorized the mean number of weeks spent on sunbathing vacations before age 20 years and at ages 20 to 49 years as none, 1 or fewer, and more than 1 week per year, and calculated mean annual lifetime number of weeks on sunbathing vacations. Indoor tanning history was categorized as never use or ever use, and cumulative number of tanning sessions was calculated and categorized as never and in the following tertiles for users: lowest (≤14 sessions), medium (15-30 sessions), and highest (≥31 sessions) tertile.21 A subsample of women (n = 66 300) was asked if they work outdoors professionally (yes or no). Sunscreen use in Norway or other high latitude countries and low latitude countries was collected by questionnaire as described in detail previously and was categorized as none, sun protection factor less than 15, and sun protection factor of 15 or more.28
Study Sample
Information on phenotypic characteristics and UVR exposure was collected for 162 834 women at baseline (eFigure in the Supplement). We excluded 290 participants with very dark skin (grades 9-10), 915 women with prevalent melanoma or squamous cell carcinoma of the skin, and 89 women who died or emigrated before the date of questionnaire return, resulting in 161 540 women for the analysis.
Statistical Analysis
Poisson regression analysis was used to estimate relative risks (RRs) and 95% CIs for overall and site-specific risk of melanoma, according to phenotypic characteristics and UVR exposure. A standard competing risk framework was used for each site. Person-years were calculated from date of baseline questionnaire to date of diagnosis, emigration, death, or the end of follow-up (December 31, 2015), whichever occurred first. Lifetime number of sunburns, weeks of sunbathing vacations, and cumulative number of indoor tanning sessions were included as time-varying variables in all models. Multinomial logistic regression was used and odds ratios and 95% CIs were calculated to compare age at diagnosis and tumor characteristics by site.
All analyses were adjusted for attained age and birth cohort. In the multivariable analyses of phenotypic characteristics, we adjusted for skin color, hair color, number of large asymmetric nevi, freckling, and residential UVR exposure. Additional adjustments for education and sunscreen use did not change the results. In the analyses of UVR exposures, models included skin and hair color, educational level, and residential UVR exposure. Additional adjustment for large asymmetric nevi, freckling, and sunscreen use did not change the results.
We tested for trend by treating the variable as continuous in the model. Interactions between host factors, number of nevi, and sun exposure are suggested in the literature.12,29 We tested for interactions between hair color, the most important host factor for melanoma in this cohort,30 and small symmetric nevi, large asymmetric nevi, and freckling, as well as between sunbathing and large asymmetric nevi and small symmetric nevi, using a likelihood ratio test. We tested whether exposure-disease associations differed among the sites by a contrast test (test for heterogeneity).31 For covariates with missing information, missing values were treated as a separate category and were included in the models. All P values were 2-sided and results were deemed to be statistically significant at P < .05. Stata, version 14 (Stata Corp), was used in all analyses.
Results
During 2 682 000 person-years of follow-up (median, 18.0 years), 1374 women were diagnosed with a primary invasive melanoma. Mean age at study entry was 50 years (range, 34-70 years) and at diagnosis was 60 years (range, 34-87 years). The lower limb was the most common site of melanoma (n = 520), followed by the trunk (n = 461), upper limb (n = 219), head and neck (n = 110), and other and unspecified (n = 64) (Table 1). Mean age at diagnosis was lowest for the lower limb (59 years [range, 34-85 years]) and highest for head and neck (64 years [range, 42-84 years]). In particular, 27.3% of head and neck melanomas (30 of 110) and 15.5% of upper limb melanomas (34 of 219) were diagnosed in the eighth decade of life; corresponding proportions were 8.7% for the lower limb (45 of 520) and 10.0% for the trunk (46 of 461) (Table 1 and eTable 1 in the Supplement). The proportion of superficial spreading melanoma was higher for trunk and lower limb melanomas compared with head and neck and upper limb melanomas (Table 1 and eTable 1 in the Supplement). Breslow thickness was comparable among the 4 body sites (eTable 1 in the Supplement).
Table 1. Host and Tumor Characteristics Among Women With Incident Melanoma in the Norwegian Women and Cancer Study by Body Site, 1991-2015.
| Characteristic | No. (%) | ||||
|---|---|---|---|---|---|
| Totala (N = 1310) | Trunk (n = 461) | Lower Limb (n = 520) | Upper Limb (n = 219) | Head and Neck (n = 110) | |
| Age at enrollment, y | |||||
| 30-39 | 168 (12.8) | 58 (12.6) | 73 (14.0) | 30 (13.7) | 7 (6.4) |
| 40-49 | 551 (42.1) | 190 (41.2) | 228 (43.8) | 88 (40.2) | 45 (40.9) |
| 50-59 | 411 (31.4) | 155 (33.6) | 167 (32.1) | 58 (26.5) | 31 (28.2) |
| ≥60 | 180 (13.7) | 58 (12.6) | 52 (10.0) | 43 (19.6) | 27 (24.5) |
| Age at diagnosis, y | |||||
| <50 | 139 (10.6) | 37 (8.0) | 76 (14.6) | 17 (7.8) | 9 (8.2) |
| 50-59 | 448 (34.2) | 175 (38.0) | 181 (34.8) | 64 (29.2) | 28 (25.5) |
| 60-69 | 568 (43.4) | 203 (44.0) | 218 (41.9) | 104 (47.5) | 43 (39.1) |
| ≥70 | 155 (11.8) | 46 (10.0) | 45 (8.7) | 34 (15.5) | 30 (27.3) |
| Educational level, y | |||||
| ≤9 | 240 (18.3) | 81 (17.6) | 95 (18.3) | 39 (17.8) | 25 (22.7) |
| 10-12 | 449 (34.3) | 167 (36.2) | 175 (33.7) | 71 (32.4) | 36 (32.7) |
| ≥13 | 554 (42.3) | 190 (41.2) | 226 (43.5) | 97 (44.3) | 41 (37.3) |
| Missing | 67 (5.1) | 23 (5.0) | 24 (4.6) | 12 (5.5) | 8 (7.3) |
| Skin color | |||||
| Dark | 79 (6.0) | 23 (5.0) | 37 (7.1) | 10 (4.6) | 9 (8.2) |
| Medium | 497 (37.9) | 180 (39.0) | 196 (37.7) | 87 (39.7) | 34 (30.9) |
| Light | 512 (39.1) | 184 (39.9) | 198 (38.1) | 80 (36.5) | 50 (45.5) |
| Missing | 222 (16.9) | 74 (16.1) | 89 (17.1) | 42 (19.2) | 17 (15.5) |
| Eye color | |||||
| Brown | 126 (9.6) | 43 (9.3) | 52 (10.0) | 21 (9.6) | 10 (9.1) |
| Green, gray, or mixed | 488 (37.3) | 153 (33.2) | 199 (38.3) | 88 (40.2) | 48 (43.6) |
| Blue | 661 (50.5) | 253 (54.9) | 256 (49.2) | 102 (46.6) | 50 (45.2) |
| Missing | 35 (2.7) | 12 (2.6) | 13 (2.5) | 8 (3.7) | 2 (1.8) |
| Hair color | |||||
| Black or dark brown | 140 (10.7) | 50 (10.8) | 50 (9.6) | 21 (9.6) | 19 (17.3) |
| Brown | 397 (30.3) | 137 (29.7) | 161 (31.0) | 70 (32.0) | 29 (26.4) |
| Blond or yellow | 646 (49.3) | 236 (51.2) | 258 (49.6) | 100 (45.7) | 52 (47.3) |
| Red | 96 (7.3) | 29 (6.3) | 41 (7.9) | 18 (8.2) | 8 (7.3) |
| Missing | 31 (2.4) | 9 (2.0) | 10 (1.9) | 10 (4.6) | 2 (1.8) |
| Freckling when sunbathing | |||||
| No | 604 (46.1) | 225 (48.8) | 230 (44.2) | 92 (42.0) | 57 (51.8) |
| Yes | 508 (38.8) | 173 (37.5) | 217 (41.7) | 83 (37.9) | 35 (31.8) |
| Missing | 198 (15.1) | 63 (13.7) | 73 (14.0) | 44 (20.1) | 18 (16.2) |
| Large asymmetric nevi on legs, No. | |||||
| 0 | 898 (68.5) | 331 (71.8) | 337 (64.8) | 154 (70.3) | 76 (69.1) |
| 1 | 128 (9.8) | 33 (7.2) | 74 (14.2) | 16 (7.3) | 5 (4.5) |
| ≥2 | 158 (12.1) | 54 (11.7) | 72 (13.8) | 19 (8.7) | 13 (11.8) |
| Missing | 126 (9.6) | 43 (9.3) | 37 (7.1) | 30 (13.7) | 16 (14.5) |
| Small symmetric nevi on arms and legs, No. | |||||
| 0 | 62 (4.7) | 17 (3.7) | 22 (4.2) | 14 (6.4) | 9 (8.2) |
| 1-10 | 206 (15.7) | 61 (13.2) | 85 (16.3) | 39 (17.8) | 21 (19.1) |
| 11-50 | 277 (21.1) | 102 (22.1) | 106 (20.4) | 48 (21.9) | 21 (19.1) |
| ≥51 | 165 (12.6) | 62 (13.4) | 69 (13.3) | 22 (10.0) | 12 (10.9) |
| Missing | 600 (45.8) | 219 (47.5) | 238 (45.8) | 96 (43.8) | 47 (42.7) |
| Melanoma subtype | |||||
| SSM | 816 (62.3) | 308 (66.8) | 347 (66.7) | 118 (53.9) | 43 (39.1) |
| NM | 187 (14.3) | 58 (12.6) | 68 (13.1) | 45 (20.5) | 16 (14.5) |
| LMM | 35 (2.7) | 3 (0.7) | 3 (0.6) | 6 (2.7) | 23 (20.9) |
| Otherb | 268 (20.5) | 91 (19.7) | 102 (19.6) | 48 (21.9) | 27 (24.5) |
| Missing | 4 (0.3) | 1 (0.2) | 0 | 2 (0.9) | 1 (0.9) |
| Breslow thickness, mm | |||||
| <0.80 | 489 (37.3) | 183 (39.7) | 186 (35.8) | 82 (37.4) | 38 (34.5) |
| 0.80-1.00 | 230 (17.6) | 81 (17.6) | 100 (19.2) | 39 (17.8) | 10 (9.1) |
| 1.01-2.00 | 214 (16.3) | 63 (13.7) | 91 (17.5) | 39 (17.8) | 21 (19.1) |
| 2.01-4.00 | 135 (10.3) | 49 (10.6) | 54 (10.4) | 22 (10.0) | 10 (9.1) |
| >4.00 | 46 (3.5) | 19 (4.1) | 15 (2.9) | 7 (3.2) | 5 (4.5) |
| Missing | 196 (15.0) | 66 (14.3) | 74 (14.2) | 30 (13.7) | 26 (23.6) |
Abbreviations: LM, lentigo maligna melanoma; NM, nodular melanoma; SSM, superficial spreading melanoma.
Excluding other and unspecified melanomas (n = 64).
Other subtypes and melanoma not otherwise specified.
Phenotypic Characteristics
Lighter skin color was associated with significantly increased risk of melanoma overall and at all body sites (trunk: RR, 2.32; 95% CI, 1.50-3.58; P < .001 for trend; lower limb: RR, 1.61; 95% CI, 1.14-2.30; P = .002 for trend; upper limb: RR, 2.22; 95% CI, 1.14-4.31; P = .03 for trend; and head and neck: RR, 1.53; 95% CI, 0.75-3.11; P = .04 for trend), with no statistically significant variation by site (P = .84 for heterogeneity) (Table 2). Similarly, red hair was associated with significantly increased melanoma risk across all sites (trunk: RR, 3.30; 95% CI, 2.09-5.21; P < .001 for trend; lower limb: RR, 4.70; 95% CI, 3.11-7.11; P < .001 for trend; upper limb: RR, 4.97; 95% CI, 2.65-9.30; P < .001 for trend; and head and neck: RR, 2.50; 95% CI, 1.09-5.73; P = .05 for trend; P = .62 for heterogeneity). Freckling was significantly associated with melanoma overall (RR, 1.31; 95% CI, 1.15-1.48) and melanoma of upper limbs (RR, 1.43; 95% CI, 1.05-1.96) and lower limbs (RR, 1.42, 1.17-1.43), but with no significant difference by site (P = .35 for heterogeneity). Having large asymmetric nevi was also a significant risk factor for all body sites; association was strongest for lower limbs (RR, 3.38; 95% CI, 2.62-4.38) and weakest for upper limbs (RR, 1.96; 95% CI, 1.22-3.17) (P = .02 for heterogeneity). Small symmetric nevi were associated with melanoma on all body sites alike (trunk: RR, 3.48; 95% CI, 2.42-5.00; P < .001 for trend; lower limb: RR, 2.49; 95% CI, 1.80-3.45; P < .001 for trend; upper limb: RR, 2.19; 95% CI, 1.28-3.74; P < .001 for trend; and head and neck: RR, 2.56; 95% CI, 1.24-5.29; P = .004 for trend; P = .31 for heterogeneity). We found no significant interactions between hair color and number of large asymmetric or small symmetric nevi or freckling (P = .09 and P = .70 for interaction), although indications of joint effects were found for light hair color and both large and small nevi (eTable 2 in the Supplement).
Table 2. Risk of Melanoma Overall and Site-Specific Risk of Melanoma According to Phenotypic Characteristics Among 161 540 Women.
| Characteristic | RR (95% CI)a | P Value for Heterogeneityb | ||||
|---|---|---|---|---|---|---|
| Total (N = 1310) | Trunk (n = 461) | Lower Limb (n = 520) | Upper Limb (n = 219) | Head and Neck (n = 110) | ||
| Skin color | ||||||
| Dark | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | .84 |
| Medium | 1.44 (1.26-2.02) | 1.78 (1.16-2.75) | 1.23 (0.87-1.75) | 1.96 (1.02-3.77) | 0.86 (0.41-1.79) | |
| Light | 1.89 (1.49-2.39) | 2.32 (1.50-3.58) | 1.61 (1.14-2.30) | 2.22 (1.14-4.31) | 1.53 (0.75-3.11) | |
| P value for trend | <.001 | <.001 | .002 | .03 | .04 | NA |
| Hair color | ||||||
| Black or dark brown | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | .62 |
| Brown | 1.25 (1.03-1.52) | 1.20 (0.87-1.66) | 1.42 (1.03-1.95) | 1.48 (0.91-2.41) | 0.70 (0.39-1.25) | |
| Blond or yellow | 1.97 (1.64-2.37) | 2.01 (1.48-2.72) | 2.20 (1.63-3.00) | 2.05 (1.29-3.28) | 1.20 (0.71-2.01) | |
| Red | 3.94 (3.03-5.10) | 3.30 (2.09-5.21) | 4.70 (3.11-7.11) | 4.97 (2.65-9.30) | 2.50 (1.09-5.73) | |
| P value for trend | <.001 | <.001 | <.001 | <.001 | .06 | NA |
| Freckling after sunbathing | ||||||
| No | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | .35 |
| Yes | 1.31 (1.15-1.48) | 1.22 (0.99-1.51) | 1.42 (1.17-1.73) | 1.43 (1.05-1.96) | 0.98 (0.63-1.52) | |
| Large asymmetric nevi on legs, No. | ||||||
| 0 | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | .02 |
| 1 | 1.77 (1.47-2.13) | 1.19 (0.81-1.76) | 2.72 (2.11-3.50) | 1.28 (0.77-2.14) | 0.84 (0.34-2.08) | |
| ≥2 | 2.83 (2.38-3.35) | 2.67 (1.96-3.63) | 3.38 (2.62-4.38) | 1.96 (1.22-3.17) | 2.85 (1.57-5.18) | |
| P value for trend | <.001 | <.001 | <.001 | .005 | .008 | NA |
| Small symmetric nevi on arms and legs, No. | ||||||
| 0 | 0.63 (0.48-0.85) | 0.56 (0.33-0.97) | 0.56 (0.35-0.89) | 0.61 (0.33-1.14) | 0.72 (0.33-1.59) | .31 |
| 1-10 | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] | |
| 11-50 | 1.51 (1.26-1.80) | 1.96 (1.43-2.70) | 1.39 (1.04-1.86) | 1.58 (1.03-2.42) | 1.38 (0.75-2.55) | |
| ≥51 | 2.50 (2.04-3.08) | 3.48 (2.42-5.00) | 2.49 (1.80-3.45) | 2.19 (1.28-3.74) | 2.56 (1.24-5.29) | |
| P value for trend | <.001 | <.001 | <.001 | <.001 | .004 | NA |
Abbreviations: NA, not applicable; RR, relative risk.
Poison regression analysis adjusted for attained age, birth cohort, skin color, hair color, large asymmetric nevi on legs, freckling after sunbathing, and residential ambient UV radiation exposure.
Test for difference by body site.
UVR Exposure
Compared with women with trunk or lower limb melanomas, a higher proportion of women diagnosed with upper limb or head and neck melanomas reported no sunbathing vacations or never use of indoor tanning devices during adulthood (Figure). For number of sunburns, proportions were comparable for all women (Figure). Similar patterns were observed for sunburns, sunbathing, and indoor tanning before age 20 years.
Figure. Proportions of Annual Numbers of Sunburns, Weeks of Sunbathing, and Indoor Tanning Sessions in Women Aged 20 to 49 Years.
Living in lower latitudes in Norway was associated with increased melanoma risk on all sites (trunk: RR, 2.45; 95% CI, 1.80-3.35; P < .001 for trend; lower limb: RR, 2.60; 95% CI, 1.92-3.52; P < .001 for trend; upper limb: RR, 1.57; 95% CI, 1.08-2.30; P = .05 for trend; and head and neck: RR, 2.15; 95% CI, 1.18-3.94; P = .02 for trend; P = .22 for heterogeneity) (Table 3). Having outdoor work was significantly associated with increased risk of head and neck melanoma (RR, 2.07; 95% CI, 1.06-4.04; P = .21 for heterogeneity). We found no significant difference by site for history of sunburns before age 20 years, before 20 years and 20 to 49 years combined, and mean lifetime sunburns.
Table 3. Risk of Melanoma Overall and Site-Specific Risk of Melanoma According to UVR Exposure.
| Characteristic | Total (N = 1310) | Trunk (n = 461) | Lower Limb (n = 520) | Upper Limb (n = 219) | Head and Neck (n = 110) | P Value for Heterogeneityb | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Cases, No. | RR (95% CI)a | Cases, No. | RR (95% CI)a | Cases, No. | RR (95% CI)a | Cases, No. | RR (95% CI)a | Cases, No. | RR (95% CI)a | ||
| Residential ambient UVR | |||||||||||
| Low (northern Norway) | 148 | 1 [Reference] | 49 | 1 [Reference] | 50 | 1 [Reference] | 35 | 1 [Reference] | 14 | 1 [Reference] | .22 |
| Medium-low (central Norway) | 154 | 1.51 (1.20-1.90) | 54 | 2.15 (1.46-3.17) | 59 | 2.20 (1.50-3.24) | 26 | 1.58 (0.95-2.62) | 15 | 2.62 (1.25-5.47) | |
| Medium (southwestern Norway) | 282 | 2.06 (1.68-2.52) | 92 | 2.39 (1.68-3.40) | 115 | 2.84 (1.99-4.00) | 46 | 1.81 (1.16-2.82) | 29 | 3.28 (1.72-6.27) | |
| High (southeastern Norway) | 726 | 1.77 (1.48-2.13) | 266 | 2.45 (1.80-3.35) | 296 | 2.60 (1.92-3.52) | 112 | 1.57 (1.08-2.30) | 52 | 2.15 (1.18-3.94) | |
| P value for trend | NA | <.001 | NA | <.001 | NA | <.001 | NA | .05 | NA | .02 | NA |
| Outdoor work | |||||||||||
| No | 515 | 1 [Reference] | 192 | 1 [Reference] | 205 | 1 [Reference] | 81 | 1 [Reference] | 37 | 1 [Reference] | .21 |
| Yes | 92 | 1.25 (1.00-1.56) | 27 | 0.97 (0.65-1.45) | 36 | 1.18 (0.83-1.69) | 18 | 1.53 (0.92-2.56) | 11 | 2.07 (1.06-4.04) | |
| History of sunburns | |||||||||||
| Before age 20 y | |||||||||||
| None | 163 | 1 [Reference] | 54 | 1 [Reference] | 63 | 1 [Reference] | 31 | 1 [Reference] | 15 | 1 [Reference] | .80 |
| ≤1 per year | 292 | 1.65 (1.39-1.96) | 261 | 1.73 (1.29-2.33) | 292 | 1.62 (1.21-2.14) | 118 | 1.47 (0.98-2.19) | 66 | 1.74 (0.99-1.07) | |
| >1 per year | 125 | 2.06 (1.69-2.50) | 118 | 2.29 (1.65-3.18) | 125 | 1.97 (1.42-2.73) | 54 | 1.99 (1.26-3.15) | 20 | 1.57 (0.79-3.11) | |
| P value for trend | NA | <.001 | NA | <.001 | NA | <.001 | NA | .003 | NA | .11 | NA |
| Combined age <20 y and 20-49 y | |||||||||||
| None, none | 81 | 1 [Reference] | 27 | 1 [Reference] | 32 | 1 [Reference] | 15 | 1 [Reference] | 7 | 1 [Reference] | .88 |
| None, ever | 66 | 0.91 (0.66-1.26) | 22 | 0.89 (0.51-1.56) | 24 | 0.81 (0.48-1.39) | 15 | 1.21 (0.59-2.50) | 5 | 0.92 (0.29-2.92) | |
| ≤1 per year, none | 109 | 1.69 (1.26-2.25) | 44 | 2.00 (1.24-3.24) | 40 | 1.51 (0.95-2.43) | 15 | 1.30 (0.63-2.65) | 10 | 2.02 (0.78-5.27) | |
| ≤1 per year, ever | 556 | 1.58 (1.24-2.01) | 193 | 1.59 (1.06-2.40) | 221 | 1.49 (1.01-2.20) | 90 | 1.51 (0.87-2.63) | 52 | 2.11 (0.94-4.67) | |
| >1 per year, ever | 279 | 2.00 (1.54-2.59) | 100 | 2.08 (1.34-3.22) | 116 | 1.95 (1.29-2.97) | 44 | 1.86 (1.02-3.40) | 19 | 2.07 (0.86-4.97) | |
| P value for trend | NA | <.001 | NA | <.001 | NA | <.001 | NA | .04 | NA | .01 | NA |
| Mean No. of sunburns per y | 1181 | 1.20 (1.13-1.28) | 409 | 1.21 (1.09-1.33) | 466 | 1.23 (1.11-1.36) | 205 | 1.19 (1.04-1.37) | 101 | 1.09 (0.87-1.37) | .76 |
| History of sunbathing vacation | |||||||||||
| Before age 20 y | .007 | ||||||||||
| None | 469 | 1 [Reference] | 161 | 1 [Reference] | 170 | 1 [Reference] | 86 | 1 [Reference] | 52 | 1 [Reference] | |
| ≤1 wk/y | 428 | 1.21 (1.05-1.38) | 154 | 1.20 (0.94-1.52) | 166 | 1.30 (1.03-1.64) | 72 | 1.24 (0.88-1.77) | 36 | 1.01 (0.65-1.57) | |
| >1 wk/y | 275 | 1.31 (1.12-1.52) | 94 | 1.24 (0.95-1.62) | 134 | 1.72 (1.35-2.18) | 35 | 1.01 (0.66-1.54) | 12 | 0.58 (0.30-1.11) | |
| P value for trend | NA | <.001 | NA | .08 | NA | <.001 | NA | .73 | NA | .14 | NA |
| Combined age <20 y and 20-49 y | |||||||||||
| None, none | 89 | 1 [Reference] | 23 | 1 [Reference] | 33 | 1 [Reference] | 18 | 1 [Reference] | 15 | 1 [Reference] | .002 |
| None, ≤1 wk/y | 197 | 1.04 (0.81-1.35) | 70 | 1.39 (0.86-1.56) | 66 | 0.87 (0.57-1.32) | 40 | 1.25 (0.70-2.21) | 21 | 0.76 (0.38-1.50) | |
| None, >1 wk/y | 177 | 1.08 (0.83-1.40) | 67 | 1.54 (0.94-2.50) | 69 | 1.05 (0.69-1.60) | 26 | 0.92 (0.49-1.71) | 15 | 0.61 (0.30-1.26) | |
| ≤1 wk/y, ≤1 wk/y | 67 | 0.89 (0.65-1.24) | 26 | 1.28 (0.72-2.28) | 20 | 0.67 (0.38-1.17) | 12 | 0.95 (0.45-2.01) | 9 | 0.85 (0.36-1.99) | |
| ≤1 wk/y, >1 wk/y | 343 | 1.40 (1.10-1.78) | 122 | 1.83 (1.15-2.92) | 138 | 1.43 (0.97-2.12) | 59 | 1.40 (0.81-2.43) | 24 | 0.66 (0.34-1.29) | |
| >1 wk/y, ever | 267 | 1.38 (1.07-1.77) | 90 | 1.71 (1.06-2.76) | 131 | 1.67 (1.13-2.47) | 35 | 1.09 (0.59-1.99) | 11 | 0.41 (0.18-0.93) | |
| P value for trend | NA | <.001 | NA | .007 | NA | <.001 | NA | .54 | NA | .09 | NA |
| Sunbathing vacation, mean No. of wk/y | 1240 | 1.08 (1.04-1.13) | 436 | 1.14 (1.07-1.22) | 493 | 1.12 (1.05-1.19) | 208 | 0.98 (0.88-1.09) | 103 | 0.87 (0.73-1.04) | .006 |
| History of indoor tanningc | |||||||||||
| Never | 179 | 1 [Reference] | 107 | 1 [Reference] | 131 | 1 [Reference] | 33 | 1 [Reference] | 41 | 1 [Reference] | .12 |
| Ever | 397 | 1.18 (1.02-1.29) | 274 | 1.21 (0.97-1.52) | 326 | 1.18 (0.96-1.46) | 122 | 0.98 (0.71-1.33) | 54 | 0.72 (0.54-1.06) | |
| Cumulative No. of indoor tanning sessions | |||||||||||
| None | 345 | 1 [Reference] | 107 | 1 [Reference] | 131 | 1 [Reference] | 66 | 1 [Reference] | 41 | 1 [Reference] | .002 |
| Lowest tertile | 193 | 1.12 (0.95-1.29) | 67 | 0.98 (0.75-1.29) | 77 | 0.90 (0.70-1.16) | 32 | 0.54 (0.35-0.81) | 17 | 0.51 (0.29-0.90) | |
| Middle tertile | 146 | 1.21 (1.01-1.35) | 98 | 1.86 (1.39-2.48) | 106 | 1.74 (1.33-2.28) | 41 | 1.44 (0.97-2.15) | 19 | 0.91 (0.49-1.67) | |
| Highest tertile | 319 | 1.29 (1.10-1.45) | 109 | 1.33 (1.00-1.76) | 143 | 1.49 (1.16-1.92) | 49 | 1.00 (0.67-1.47) | 18 | 0.70 (0.39-1.26) | |
| P value for trend | NA | <.001 | NA | .005 | NA | <.001 | NA | .35 | NA | .17 | NA |
Abbreviations: NA, not applicable; RR, relative risk; UVR, UV radiation.
Poison regression analysis adjusted for attained age, birth cohort, skin color, hair color, education, and residential ambient UVR exposure.
Test for difference by body site.
Additionally adjusted for cumulative number of sunburns and cumulative number of weeks on sunbathing vacations.
History of sunbathing vacations before age 20 years was significantly associated with lower limb melanoma (RR, 1.72; 95% CI, 1.35-2.18; P < .001 for trend) but not other sites (trunk: RR, 1.24; 95% CI, 0.95-1.62; upper limb: RR, 1.01, 95% CI, 0.66-1.54; and head and neck: RR, 0.58; 95% CI, 0.30-1.11; P = .007 for heterogeneity). Moreover, when combining histories of sunbathing before age 20 years and 20 to 49 years, the highest category of exposure was associated with increased risk of trunk (RR, 1.71; 95% CI, 1.06-2.76) and lower limb melanomas (RR, 1.67; 95% CI, 1.13-2.47) and decreased risk of head and neck melanoma (RR, 0.41; 95% CI, 0.18-0.93; P = .002 for interaction). Mean lifetime number of weeks of sunbathing vacation was also associated with significantly increased risk of trunk (RR, 1.14; 95% CI, 1.07-1.22) and lower limb melanomas (RR, 1.12; 95% CI, 1.05-1.19), but not with upper limb melanomas (RR, 0.98; 95% CI, 0.88-1.09) and head and neck melanomas (RR, 0.87; 95% CI, 0.73-1.04); (P = .006 for heterogeneity). We found no significant interaction between sunbathing and large asymmetric or small symmetric nevi (P > .10 and P < .89 for interaction).
Women reporting ever engaging in indoor tanning had significantly increased melanoma risk overall (RR, 1.18; 95% CI, 1.02-1.29) (Table 3). We found significant dose-response associations between cumulative number of indoor tanning sessions and risk of trunk (RR for highest tertile, 1.33; 95% CI, 1.00-1.76) and lower limb melanomas (RR for highest tertile, 1.49; 95% CI, 1.16-1.92) but not upper limb (RR for highest tertile, 1.00; 95% CI, 0.67-1.47) and head and neck melanomas (RR for highest tertile, 0.70; 95% CI, 0.39-1.26; P = .002 for heterogeneity).
Discussion
In this large population-based cohort study, associations with number of large asymmetric nevi, history of sunbathing vacations, and history of indoor tanning differed significantly among melanoma sites. Site-specific associations were also found for outdoor work and freckling but with no significant heterogeneity among sites. Skin color, hair color, number of small symmetric nevi, residential ambient UVR exposure, and history of sunburns were associated with increased melanoma risk on all sites.
Lower limb and trunk melanomas were significantly associated with younger age at diagnosis and were more likely to be superficial spreading melanoma (less likely to be nodular or lentigo maligna melanoma), in contrast with head and neck and upper limb melanomas; this finding agreed with the divergent pathways hypothesis and previous reports.32 Unlike other reports of head and neck melanoma being thickest,13 we found no significant difference in thickness among sites.
The melanocortin-1 receptor is one of the pigmentation genes responsible for pigment variation in humans.33 The melanocortin-1 receptor is highly polymorphic in white individuals, and the variants determine phenotypic characteristics, such as fair skin, freckling, red hair, and tanning response to UVR exposure.34 Melanocortin-1 receptor variants are associated with BRAF mutations and melanomas on the trunk and limbs.34,35,36 In our study, light skin color, blond and yellow hair, and freckling were associated with increased risk of trunk and limb melanomas but not head and neck melanoma, in line with the molecular findings. Red hair was significantly associated with increased risk of melanoma over all sites, although associations were strongest for the trunk and limbs. In a meta-analysis of 24 epidemiologic studies, light hair color and freckling were more strongly associated with melanoma on the trunk and limbs, and light skin color was more strongly associated with melanomas on the head and arms.18
Our finding of a dose-response association between the number of large asymmetric nevi and melanoma in all sites, with a greater dose-response association for trunk and lower limb melanomas compared with upper limb and head and neck melanomas, is consistent with the literature,13,16,18 as is the significant association found between the number of small nevi with melanoma risk on all sites.13,18 According to the divergent pathway hypothesis, people with an inherently high propensity for melanocytic proliferation (indicated by a high nevus count) require only a modest level of sun exposure to initiate melanoma on body sites with many nevi,12 such as the back in men and legs in women.37 Lack of distinctive heterogeneity of association between the number of nevi and site of melanoma in epidemiologic studies18 might reflect the complexity of the association between sun exposure, age, number of nevi, and melanoma. The number of nevi reflects both inherent genetic factors and sun exposure38,39 and is inversely associated with long-term sun exposure and increasing age.40,41
The risk of head and neck melanoma was doubled with outdoor work, with no significant association for the other sites, supporting previous reports.13,15 Conversely, mean lifetime number of sunburns was associated with risk of trunk and limb melanomas but not head and neck melanomas. However, we found no heterogeneity of association between the number of sunburns before age 20 years or sunburns up to age 49 years and melanoma by site, again consistent with previous reports,15,17 and the likelihood that sunburn is a component of both pathways.17 The number of sunburns has been associated with actinic keratosis42 and solar elastosis,13 which are indicators of long-term sun exposure, reflecting the large total doses of UVR that multiple sunburns represent.13,17 The importance of sunburn before age 20 years was notable in our results.
The heterogeneity of association between history of sunbathing vacations and site-specific melanoma risk is in agreement with the literature and the nevus-associated pathway.15 However, the heterogeneity of association between upper and lower limb melanomas suggests that the risk profile of lower limb melanomas resembles that of trunk melanomas, arising through the nevus-associated pathway, and the risk profile of upper limb melanomas resembles that of head and neck melanomas. Moreover, our finding that history of sunbathing vacations before age 20 years is associated with increased risk of lower limb melanomas is worth attention in prevention strategies, considering that lower limbs are the most frequent melanoma sites in women. Unexpectedly, a history of sunbathing vacations tended to be inversely associated with risk of head and neck melanoma in our study. A pooled analysis of 13 studies reported no association between intermittent sun exposure and head and neck melanomas.15 One likely explanation for the apparent inverse association is that intermittent sun exposure might be inversely associated with long-term sun exposure. We found that working outdoors was significantly associated with lower mean weeks of sunbathing vacation; also, women diagnosed with head and neck melanoma reported fewer weeks of sunbathing vacation compared with others. Thus, the lower risk of head and neck melanoma might have been negatively confounded by chronic sun exposure. However, we had no detailed information on chronic sun exposure, and only a subsample of the cohort was asked about outdoor work. Another possible explanation is false protectivity, which can arise with lack of independence among competing outcomes43,44 (in our study, melanoma in different sites). If an unmeasured factor, such as a genetic or environmental factor, increases the risk of one outcome or initiates it earlier in time, it increases the probability that the individual is censored with respect to the other outcome and can induce a false association.
A previous study reported a dose-response association between indoor tanning and risk of melanoma in this cohort21; however, the study lacked power to perform a proper site-specific analysis owing to shorter follow-up time. Our current results suggest that, similar to sunbathing, indoor tanning is associated with melanoma on the trunk and lower limbs. To our knowledge, 2 other studies reported an association between indoor tanning and site-specific risk of melanoma,45,46 but one study lacked power to estimate for the association with head and neck melanoma and both studies combined upper and lower limb melanomas. Thus, these are novel findings.
Limitations
Several limitations must be noted. Lack of information on site-specific sunburns and site-specific use of sunscreen is a limitation. Moreover, we do not know if melanomas occurred on distal or proximal parts of the limbs. It is suggested that nevus-associated melanomas typically affect proximal limbs that are usually intermittently exposed to the sun, whereas other melanomas affect distal limbs that are usually exposed to the sun long term32,36; thus, combining distal and proximal melanomas might dilute a true difference. Our results may not be generalizable to men because their site-specific pattern of sun exposure may differ from that in women. We have tested many risk factors for multiple sites; thus, the P values must be interpreted bearing this in mind.
Conclusions
This large prospective study appears to provide evidence on divergent pathways to melanoma. Our results suggest similar associations for lower limb and trunk melanomas arising through the nevus-associated pathway, whereas upper limb and head and neck melanomas arise through the long-term sun exposure pathway. Our results suggest that, similar to sunbathing, indoor tanning is associated with trunk and lower limb melanomas. Moreover, our finding that sunbathing vacations before the age of 20 years is associated with significantly increased risk of lower limb melanomas highlights the importance of starting sun protection early in life.
eFigure. Flow Diagram of Study Sample From the Norwegian Women and Cancer (NOWAC) Study
eTable 1. Odds Ratios (ORs) and 95% CIs for Age at Diagnosis, Subtype and Breslow Thickness by Body Sites of Melanoma
eTable 2. Relative Risks (RRs) and 95% CIs for Joint Effects of Hair Color, Number of Large Asymmetric Nevi on Legs, Number of Small Symmetric Nevi on Arms/Legs, and Freckling When Sunbathing, for Risk of Melanoma Overall and Site Specific
References
- 1.Whiteman DC, Green AC, Olsen CM. The growing burden of invasive melanoma: projections of incidence rates and numbers of new cases in six susceptible populations through 2031. J Invest Dermatol. 2016;136(6):1161-1171. doi: 10.1016/j.jid.2016.01.035 [DOI] [PubMed] [Google Scholar]
- 2.Karimkhani C, Green AC, Nijsten T, et al. . The global burden of melanoma: results from the Global Burden of Disease Study 2015. Br J Dermatol. 2017;177(1):134-140. doi: 10.1111/bjd.15510 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Lucas R, McMichael T, Smith W, Armstrong BK, Prüss-Üstün A. Solar ultraviolet radiation: global burden of disease from solar ultraviolet radiation. World Health Organization IV Series: environmental burden of disease series; no 13. Geneva, Switzerland: World Health Organization; 2006. [Google Scholar]
- 4.Gandini S, Autier P, Boniol M. Reviews on sun exposure and artificial light and melanoma. Prog Biophys Mol Biol. 2011;107(3):362-366. doi: 10.1016/j.pbiomolbio.2011.09.011 [DOI] [PubMed] [Google Scholar]
- 5.Berwick M, Buller D, Cust A, et al. . Melanoma epidemiology and prevention In: Kaufman HL, Mehnert JM, eds. Melanoma. Vol 167 Basel, Switzerland: Springer International Publishing; 2016:17-49. doi: 10.1007/978-3-319-22539-5_2 [DOI] [PubMed] [Google Scholar]
- 6.Vuong K, Armstrong BK, Weiderpass E, et al. ; Australian Melanoma Family Study Investigators . Development and external validation of a melanoma risk prediction model based on self-assessed risk factors. JAMA Dermatol. 2016;152(8):889-896. doi: 10.1001/jamadermatol.2016.0939 [DOI] [PubMed] [Google Scholar]
- 7.Gandini S, Sera F, Cattaruzza MS, et al. . Meta-analysis of risk factors for cutaneous melanoma, I: common and atypical naevi. Eur J Cancer. 2005;41(1):28-44. doi: 10.1016/j.ejca.2004.10.015 [DOI] [PubMed] [Google Scholar]
- 8.Bataille V, Snieder H, MacGregor AJ, Sasieni P, Spector TD. Genetics of risk factors for melanoma: an adult twin study of nevi and freckles. J Natl Cancer Inst. 2000;92(6):457-463. doi: 10.1093/jnci/92.6.457 [DOI] [PubMed] [Google Scholar]
- 9.Garbe C, Büttner P, Weiss J, et al. . Associated factors in the prevalence of more than 50 common melanocytic nevi, atypical melanocytic nevi, and actinic lentigines: multicenter case-control study of the Central Malignant Melanoma Registry of the German Dermatological Society. J Invest Dermatol. 1994;102(5):700-705. doi: 10.1111/1523-1747.ep12374298 [DOI] [PubMed] [Google Scholar]
- 10.Whiteman DC, Watt P, Purdie DM, Hughes MC, Hayward NK, Green AC. Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma. J Natl Cancer Inst. 2003;95(11):806-812. doi: 10.1093/jnci/95.11.806 [DOI] [PubMed] [Google Scholar]
- 11.Green A. A theory of site distribution of melanomas: Queensland, Australia. Cancer Causes Control. 1992;3(6):513-516. doi: 10.1007/BF00052747 [DOI] [PubMed] [Google Scholar]
- 12.Whiteman DC. Testing the divergent pathway hypothesis for melanoma: recent findings and future challenges. Expert Rev Anticancer Ther. 2010;10(5):615-618. doi: 10.1586/era.10.42 [DOI] [PubMed] [Google Scholar]
- 13.Kvaskoff M, Pandeya N, Green AC, et al. . Solar elastosis and cutaneous melanoma: a site-specific analysis. Int J Cancer. 2015;136(12):2900-2911. doi: 10.1002/ijc.29335 [DOI] [PubMed] [Google Scholar]
- 14.Kvaskoff M, Pandeya N, Green AC, et al. . Site-specific determinants of cutaneous melanoma: a case-case comparison of patients with tumors arising on the head or trunk. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2222-2231. doi: 10.1158/1055-9965.EPI-13-0475 [DOI] [PubMed] [Google Scholar]
- 15.Chang YM, Barrett JH, Bishop DT, et al. . Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009;38(3):814-830. doi: 10.1093/ije/dyp166 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Olsen CM, Zens MS, Stukel TA, et al. . Nevus density and melanoma risk in women: a pooled analysis to test the divergent pathway hypothesis. Int J Cancer. 2009;124(4):937-944. doi: 10.1002/ijc.24011 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Olsen CM, Zens MS, Green AC, et al. . Biologic markers of sun exposure and melanoma risk in women: pooled case-control analysis. Int J Cancer. 2011;129(3):713-723. doi: 10.1002/ijc.25691 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Caini S, Gandini S, Sera F, et al. . Meta-analysis of risk factors for cutaneous melanoma according to anatomical site and clinico-pathological variant. Eur J Cancer. 2009;45(17):3054-3063. doi: 10.1016/j.ejca.2009.05.009 [DOI] [PubMed] [Google Scholar]
- 19.Randi G, Naldi L, Gallus S, Di Landro A, La Vecchia C; Oncology Study Group of the Italian Group for Epidemiologic Research in Dermatology (GISED) . Number of nevi at a specific anatomical site and its relation to cutaneous malignant melanoma. J Invest Dermatol. 2006;126(9):2106-2110. doi: 10.1038/sj.jid.5700334 [DOI] [PubMed] [Google Scholar]
- 20.Ghiasvand R, Rueegg CS, Weiderpass E, Green AC, Lund E, Veierød MB. Ghiasvand et al respond to ‘indoor tanning—a melanoma accelerator?’. Am J Epidemiol. 2017;185(3):160-161. [DOI] [PubMed] [Google Scholar]
- 21.Ghiasvand R, Rueegg CS, Weiderpass E, Green AC, Lund E, Veierød MB. Indoor tanning and melanoma risk: long-term evidence from a prospective population-based cohort study. Am J Epidemiol. 2017;185(3):147-156. [DOI] [PubMed] [Google Scholar]
- 22.Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. J Am Acad Dermatol. 2014;70(5):847-857. doi: 10.1016/j.jaad.2013.11.050 [DOI] [PubMed] [Google Scholar]
- 23.El Ghissassi F, Baan R, Straif K, et al. ; WHO International Agency for Research on Cancer Monograph Working Group . A review of human carcinogens—part D: radiation. Lancet Oncol. 2009;10(8):751-752. doi: 10.1016/S1470-2045(09)70213-X [DOI] [PubMed] [Google Scholar]
- 24.Lund E, Dumeaux V, Braaten T, et al. . Cohort profile: the Norwegian Women and Cancer Study—NOWAC—Kvinner og kreft. Int J Epidemiol. 2008;37(1):36-41. doi: 10.1093/ije/dym137 [DOI] [PubMed] [Google Scholar]
- 25.Veierød MB, Parr CL, Lund E, Hjartåker A. Reproducibility of self-reported melanoma risk factors in a large cohort study of Norwegian women. Melanoma Res. 2008;18(1):1-9. doi: 10.1097/CMR.0b013e3282f120d2 [DOI] [PubMed] [Google Scholar]
- 26.Cancer in Norway 2016: Cancer Incidence, Mortality, Survival and Prevalence in Norway. Oslo, Norway: Cancer Registry of Norway; 2017. [Google Scholar]
- 27.Ghiasvand R, Lund E, Edvardsen K, Weiderpass E, Veierød MB. Prevalence and trends of sunscreen use and sunburn among Norwegian women. Br J Dermatol. 2015;172(2):475-483. doi: 10.1111/bjd.13434 [DOI] [PubMed] [Google Scholar]
- 28.Ghiasvand R, Weiderpass E, Green AC, Lund E, Veierød MB. Sunscreen use and subsequent melanoma risk: a population-based cohort study. J Clin Oncol. 2016;34(33):3976-3983. doi: 10.1200/JCO.2016.67.5934 [DOI] [PubMed] [Google Scholar]
- 29.Veierød MB, Adami HO, Lund E, Armstrong BK, Weiderpass E. Sun and solarium exposure and melanoma risk: effects of age, pigmentary characteristics, and nevi. Cancer Epidemiol Biomarkers Prev. 2010;19(1):111-120. doi: 10.1158/1055-9965.EPI-09-0567 [DOI] [PubMed] [Google Scholar]
- 30.Veierød MB, Weiderpass E, Thörn M, et al. . A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95(20):1530-1538. doi: 10.1093/jnci/djg075 [DOI] [PubMed] [Google Scholar]
- 31.Wang M, Spiegelman D, Kuchiba A, et al. . Statistical methods for studying disease subtype heterogeneity. Stat Med. 2016;35(5):782-800. doi: 10.1002/sim.6793 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Whiteman DC, Pavan WJ, Bastian BC. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin. Pigment Cell Melanoma Res. 2011;24(5):879-897. doi: 10.1111/j.1755-148X.2011.00880.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Pasquali E, García-Borrón JC, Fargnoli MC, et al. ; M-SKIP Study Group . MC1R variants increased the risk of sporadic cutaneous melanoma in darker-pigmented Caucasians: a pooled-analysis from the M-SKIP project. Int J Cancer. 2015;136(3):618-631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Landi MT, Bauer J, Pfeiffer RM, et al. . MC1R germline variants confer risk for BRAF-mutant melanoma. Science. 2006;313(5786):521-522. doi: 10.1126/science.1127515 [DOI] [PubMed] [Google Scholar]
- 35.Fargnoli MC, Pike K, Pfeiffer RM, et al. . MC1R variants increase risk of melanomas harboring BRAF mutations [published correction appears in J Invest Dermatol. 2008;128(10):2546]. J Invest Dermatol. 2008;128(10):2485-2490. doi: 10.1038/jid.2008.67 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Shain AH, Bastian BC. From melanocytes to melanomas. Nat Rev Cancer. 2016;16(6):345-358. doi: 10.1038/nrc.2016.37 [DOI] [PubMed] [Google Scholar]
- 37.Nicholls EM. Development and elimination of pigmented moles, and the anatomical distribution of primary malignant melanoma. Cancer. 1973;32(1):191-195. doi: [DOI] [PubMed] [Google Scholar]
- 38.Wachsmuth RC, Gaut RM, Barrett JH, et al. . Heritability and gene-environment interactions for melanocytic nevus density examined in a UK adolescent twin study. J Invest Dermatol. 2001;117(2):348-352. doi: 10.1046/j.0022-202x.2001.01415.x [DOI] [PubMed] [Google Scholar]
- 39.Wachsmuth RC, Turner F, Barrett JH, et al. . The effect of sun exposure in determining nevus density in UK adolescent twins. J Invest Dermatol. 2005;124(1):56-62. doi: 10.1111/j.0022-202X.2004.23548.x [DOI] [PubMed] [Google Scholar]
- 40.Harth Y, Friedman-Birnbaum R, Linn S. Influence of cumulative sun exposure on the prevalence of common acquired nevi. J Am Acad Dermatol. 1992;27(1):21-24. doi: 10.1016/0190-9622(92)70149-A [DOI] [PubMed] [Google Scholar]
- 41.Armstrong BK, Cust AE. Sun exposure and skin cancer, and the puzzle of cutaneous melanoma: a perspective on Fears et al: mathematical models of age and ultraviolet effects on the incidence of skin cancer among whites in the United States: American Journal of Epidemiology 1977;105:420-427. Cancer Epidemiol. 2017;48:147-156. doi: 10.1016/j.canep.2017.04.004 [DOI] [PubMed] [Google Scholar]
- 42.Kennedy C, Bajdik CD, Willemze R, De Gruijl FR, Bouwes Bavinck JN; Leiden Skin Cancer Study . The influence of painful sunburns and lifetime sun exposure on the risk of actinic keratoses, seborrheic warts, melanocytic nevi, atypical nevi, and skin cancer. J Invest Dermatol. 2003;120(6):1087-1093. doi: 10.1046/j.1523-1747.2003.12246.x [DOI] [PubMed] [Google Scholar]
- 43.Di Serio C. The protective impact of a covariate on competing failures with an example from a bone marrow transplantation study. Lifetime Data Anal. 1997;3(2):99-122. doi: 10.1023/A:1009672300875 [DOI] [PubMed] [Google Scholar]
- 44.Stensrud MJ, Valberg M, Røysland K, Aalen OO. Exploring selection bias by causal frailty models: the magnitude matters. Epidemiology. 2017;28(3):379-386. doi: 10.1097/EDE.0000000000000621 [DOI] [PubMed] [Google Scholar]
- 45.Nielsen K, Måsbäck A, Olsson H, Ingvar C. A prospective, population-based study of 40,000 women regarding host factors, UV exposure and sunbed use in relation to risk and anatomic site of cutaneous melanoma. Int J Cancer. 2012;131(3):706-715. doi: 10.1002/ijc.26408 [DOI] [PubMed] [Google Scholar]
- 46.Cust AE, Armstrong BK, Goumas C, et al. . Sunbed use during adolescence and early adulthood is associated with increased risk of early-onset melanoma. Int J Cancer. 2011;128(10):2425-2435. doi: 10.1002/ijc.25576 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eFigure. Flow Diagram of Study Sample From the Norwegian Women and Cancer (NOWAC) Study
eTable 1. Odds Ratios (ORs) and 95% CIs for Age at Diagnosis, Subtype and Breslow Thickness by Body Sites of Melanoma
eTable 2. Relative Risks (RRs) and 95% CIs for Joint Effects of Hair Color, Number of Large Asymmetric Nevi on Legs, Number of Small Symmetric Nevi on Arms/Legs, and Freckling When Sunbathing, for Risk of Melanoma Overall and Site Specific