Lifetime Sunburn Trajectories and Associated Risks of Cutaneous Melanoma and Squamous Cell Carcinoma Among a Cohort of Norwegian Women

Simon Lergenmuller; Corina S Rueegg; Flavie Perrier; Trude E Robsahm; Adele C Green; Eiliv Lund; Reza Ghiasvand; Marit B Veierød

doi:10.1001/jamadermatol.2022.4053

. 2022 Oct 5;158(12):1367–1377. doi: 10.1001/jamadermatol.2022.4053

Lifetime Sunburn Trajectories and Associated Risks of Cutaneous Melanoma and Squamous Cell Carcinoma Among a Cohort of Norwegian Women

Simon Lergenmuller ^1,^2,^✉, Corina S Rueegg ³, Flavie Perrier ¹, Trude E Robsahm ⁴, Adele C Green ^5,⁶, Eiliv Lund ^4,⁷, Reza Ghiasvand ^3,⁴, Marit B Veierød ¹

¹Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway

²Now with Department of Clinical and Registry-Based Research, Institute of Population-Based Cancer Research, Cancer Registry of Norway, Oslo, Norway

³Oslo Centre for Biostatistics and Epidemiology, Oslo University Hospital, Oslo, Norway

⁴Department of Research, Institute of Population-Based Cancer Research, Cancer Registry of Norway, Oslo, Norway

⁵Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

⁶Cancer Research UK Manchester and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, England, United Kingdom

⁷Department of Public Health, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway

Accepted for Publication: July 31, 2022.

Published Online: October 5, 2022. doi:10.1001/jamadermatol.2022.4053

^✉

Corresponding Author: Simon Lergenmuller, PhD, Department of Clinical and Registry-Based Research, Institute of Population-Based Cancer Research, Cancer Registry of Norway, PO Box 5313 Majorstuen, 0304 Oslo, Norway (silr@kreftregisteret.no).

Author Contributions: Dr Lergenmuller had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lergenmuller and Rueegg served as co–first authors and contributed equally to the work.

Concept and design: Rueegg, Lund, Ghiasvand, Veierød.

Acquisition, analysis, or interpretation of data: Lergenmuller, Rueegg, Perrier, Robsahm, Green, Ghiasvand, Veierød.

Drafting of the manuscript: Lergenmuller, Rueegg, Perrier.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lergenmuller, Perrier.

Obtained funding: Veierød.

Administrative, technical, or material support: Veierød.

Supervision: Rueegg, Robsahm, Lund, Ghiasvand, Veierød.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported by the Institute of Basic Medical Sciences, University of Oslo (Dr Lergenmuller), and the Norwegian Cancer Society (Dr Perrier).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank all of the women who participated in the Norwegian Women and Cancer Study, without whom this work would not have been possible.

Additional Information: This work was included in a doctoral thesis that was previously posted in a repository.

^✉

Corresponding author.

PMCID: PMC9535508 PMID: 36197657

This cohort study aims to identify lifetime trajectories of sunburns and compare the association between these trajectories and subsequent risk of cutaneous melanoma and squamous cell carcinoma.

Key Points

Question

What are the lifetime trajectories of sunburns among Norwegian women, and how are these associated with subsequent risk of cutaneous melanoma and squamous cell carcinoma?

Findings

In this cohort study of 168 553 participants from the Norwegian Women and Cancer Study, 5 classes of lifetime sunburn trajectories were identified, in line with health behaviors generally observed in people. Trajectories with high sunburn frequencies in childhood and throughout life were associated with both increased melanoma and cSCC risks.

Meaning

Lifetime trajectories of sunburns were identified, and the findings provide supporting evidence that avoiding sunburns throughout life, in particular in childhood, is crucial.

Abstract

Importance

To our knowledge, no study has prospectively investigated sunburn patterns over age periods from childhood to adulthood and their associations with skin cancer risk.

Objective

To identify lifetime trajectories of sunburns and compare the association between these trajectories and subsequent risk of cutaneous melanoma and squamous cell carcinoma (cSCC).

Design, Setting, and Participants

This population-based cohort study included participants from the Norwegian Women and Cancer Study, established in 1991, with follow-up through 2018. Baseline questionnaires were issued from 1991 to 2007, with follow-up questionnaires every 5 to 7 years. Data analysis was performed from March 16, 2021, to December 4, 2021.

Exposures

Participants reported pigmentation factors, sunbathing vacations, and indoor tanning. Annual frequencies of sunburns were reported for childhood, adolescence, and adulthood.

Main Outcomes and Measures

Information on cancer diagnoses, emigration, and death were obtained through linkage to the Cancer Registry of Norway using the unique personal identification number of Norwegian citizens.

Results

Of the 172 472 women (age range, 31-70 years) who returned questionnaires, 169 768 received questions about sunburns at study inclusion. Five classes (stable low, low-moderate-low, low to high, high to low, and stable high) of individual lifetime sunburn trajectories with similar shapes were estimated in 3 samples up to 39 years (n = 159 773), up to 49 years (n = 153 297), and up to 59 years (n = 119 170). Mean follow-up ranged from 14.3 to 19.5 years in the 3 samples, during which 1252 to 1774 women were diagnosed with incident primary melanoma and 739 to 871 women with incident primary cSCC. With hazard ratios (HRs) and 95% CIs estimated using a Cox proportional hazards model, the stable high and high to low trajectories showed statistically significant increased melanoma and cSCC risks compared with the stable low trajectory across all samples (≤39 years for stable high and high to low trajectories: melanoma: HR, 1.50 [95% CI, 1.28-1.75] and HR, 1.44 [95% CI, 1.20-1.73]; cSCC: HR, 1.51 [95% CI, 1.22-1.87] and HR, 1.47 [95% CI, 1.14-1.91]). Other trajectories showed increased risk, though generally weaker and mainly estimates that were not statistically significant. There was no statistically significant heterogeneity between melanoma and cSCC estimates.

Conclusion and Relevance

This cohort study showed that high sunburn frequency throughout life was associated with increased melanoma and cSCC risk. Furthermore, sunburns in childhood are especially important for subsequent risk of these skin cancers. Avoiding sunburns throughout life, in particular in childhood, is therefore crucial.

Introduction

Cutaneous melanoma (hereafter melanoma) and cutaneous squamous cell carcinoma (cSCC) continue to increase in fair-skinned populations worldwide^1,2,3 and represent a substantial burden for individuals, societies, and health care systems.^4,5,6,7,8 While sun exposure is the main environmental cause of melanoma and cSCC, the relationships between sun exposure and these 2 cancers are complex and likely different. Cutaneous SCC is mainly related to cumulative (chronic, lifetime) sun exposure,^1,9 while both cumulative and intermittent sun exposure play a role in melanoma development depending on anatomic site.^10,11

Sunburn is an inflammatory response of the skin to acute sun exposure. Studies comparing people migrating to low latitudes at different ages found that childhood may be a susceptible phase for the harmful effects of overexposure to the sun.^12,13,14 During childhood, melanocytes may be more susceptible to initiation of UV radiation (UVR)-induced carcinogenesis through sunburns, thus increasing melanoma risk.^{14,15,16,17,18} In their meta-analysis, Gandini et al¹⁹ found higher melanoma risk for people with sunburns in childhood than for people with sunburns in adulthood, though differences between the estimates of the 2 groups were not statistically significant. Later, in the meta-analysis by Dennis et al,²⁰ the effect estimate was highest for people with sunburns in adulthood, but increased melanoma risks were also found for people with sunburns in childhood and adolescence. For cSCC, increased risk has been found after sunburns in childhood^21,22,23,24 but not after sunburns in adulthood.^21,22 Lifetime number of sunburns is associated with both increased risk of melanoma^19,20 and cSCC.^25,26,27,28 To our knowledge, only 1 cohort study has investigated the association between sunburns and both melanoma and cSCC risks, though timing of sunburns was not assessed,²⁷ and no study has investigated sunburn patterns over age periods from childhood to adulthood and their associations with melanoma and cSCC, likely because of the challenges involved.¹⁹ An individual’s behavior in relation to sunburn frequency in early life may affect future behavior,²⁹ including future sunburn frequency, making it difficult to relate sunburns at different ages to skin cancer risk. To overcome these challenges, we used latent class mixed models (LCMMs) in the large population-based Norwegian Women and Cancer (NOWAC) cohort study³⁰ to (1) identify lifetime sunburn trajectories and (2) compare the associations between these trajectories and melanoma and cSCC occurrence.

Methods

The NOWAC Cohort

In the NOWAC cohort, women were selected randomly from the Norwegian Population Register and issued a questionnaire at study inclusion in 1991 to 2007.^30,31 In total, 172 472 women aged 31 to 70 years participated (response rate, 54%). First and second follow-up questionnaires were issued approximately every 5 years (response rate, 80% and 79%, respectively). All women provided informed consent, and data were handled in accordance with the relevant ethical regulations. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines were used.³² The study was approved by the Regional Committees for Medical and Health Research Ethics of North Norway and the Norwegian Centre for Research Data.

Annual Number of Sunburns

Annual number of sunburns that resulted in pain, blistering, and subsequent peeling (never, 1, 2-3, 4-5, ≥6) were recorded at study inclusion for childhood (0-9 years old), adolescence (10-19 years old), and adulthood (≥20 years old). In follow-up questionnaires, information was updated with number of sunburns since the last questionnaire. Depending on the questionnaire (inclusion or follow-ups) and age at inclusion, sunburn frequencies in adulthood were recorded for age periods of varying lengths (range, 1-26 years) and converted into 10-year periods (20-29, 30-39, 40-49 [if applicable], and 50-59 [if applicable] years).

Covariates

Annual number of weeks spent on sunbathing vacations in high and/or lower latitudes (never, 1, 2-3, 4-6, ≥7), and history of use of indoor tanning devices (never, rarely, 1, 2, 3-4 times/mo, >1 time/wk) were recorded for the same age periods as sunburns. We calculated the cumulative number of weeks spent on sunbathing vacations^33,34 and categorized it as none, lowest, middle, or highest tertile. Use of indoor tanning devices was categorized as never or ever. Residential ambient UVR exposure was categorized based on mean ambient UVR hours of the region of residence³⁵ (latitudes 70°-58°) as low (northern Norway), medium-low (central Norway), medium (southwestern Norway), and highest (southeastern Norway).^31,33 Participants reported the number of years of education (categorized as ≤10, 11-13, ≥14 years), smoking status (never, former, current), hair color (black/dark brown, brown, blond/yellow, red), untanned skin color (color scale from 1 [very fair] to 10 [very dark]; categorized as light [1-3], medium [4-5], dark [6-8], very dark [9-10]), freckling when sunbathing (no, yes), and number of asymmetrical nevi larger than 5 mm in diameter on the legs (0, 1, 2-3, 4-6, 7-12, 13-24, ≥25; categorized as 0, 1, >1). Skin reactions to acute sun exposure (brown without being red first, red, red with burning, red with burning and blistering) and chronic sun exposure (deep brown, brown, light brown, never brown) were recorded for a subsample of the cohort.

Follow-up

The cohort was linked to the Cancer Registry of Norway using the unique personal identification number of Norwegian residents, ensuring complete information on cancer diagnoses and vital status (alive, emigrated, dead; before and after receiving the questionnaires), with dates of diagnosis, emigration, or death until December 31, 2018. Melanoma and cSCC cases were identified by the International Classification of Diseases, Seventh Revision (ICD-7), codes 190.0 to 190.9 for melanoma and 191.0 to 191.9 for cSCC (including the International Classification of Diseases for Oncology, Third Edition, morphology codes 80703, 80713, 80763, 80953, 80513, 80723, and 80743). We excluded cases with code 190.5/191.4 (perineum, perianal) because they are unrelated to UVR exposure. The Cancer Registry of Norway does not routinely record information on basal cell carcinoma.

Study Sample

Of the 172 472 women who returned questionnaires, 169 768 received questions about sunburns at study inclusion (Figure 1). We excluded women with very dark skin (grades 9-10; n = 290), prevalent melanoma (n = 803) or cSCC (n = 86), and who emigrated or died before date of questionnaire return (n = 36), resulting in 168 553 women born from 1927 through 1965. Owing to the wide age range at inclusion (31-71 years)—and to use the maximum number of women with sunburn information available for 4-, 5-, and 6-age decades—3 samples were created: (1) those with fewer than 40 years of exposure, (2) those with fewer than 50 years of exposure, (3) and those with fewer than 60 years of exposure. For the sample of fewer than 40 years of exposure (used for analyses of sunburn trajectories 0-39 years), we excluded women with missing sunburn information in all age decades less than 40 years (n = 8780), resulting in 159 773 women. For the sample of fewer than 50 years of exposure (used for analyses of sunburn trajectories 0-49 years), we further excluded women with missing sunburn information in all age decades less than 50 years (n = 6476), resulting in 153 297 women. For the sample of fewer than 60 years of exposure (used for analyses of sunburn trajectories 0-59 years), we further excluded women with missing sunburn information in all age decades less than 60 years (n = 34 127), resulting in 119 170 women.

Statistical Analysis

We calculated the average number of annual sunburns in each age decade by converting the recorded numbers into 0, 1, 2.5, 4.5, or 7 sunburns/y and averaging over each decade. Classes of individual lifetime sunburn trajectories were then identified in each sample using an LCMM.^36,37,38 The model assumes that the population consists of k latent classes (underlying, unobserved groups of individuals) that follow class-specific sunburn trajectories. The average lifetime sunburn trajectory in each class was modeled using a class-specific mixed model, with median age in each decade as timescale and average annual number of sunburns in each decade as longitudinal outcome. Median age in each decade was included as a second order polynomial, and a random intercept was included allowing observations to be correlated in time (eMethods 1 in the Supplement).

The optimal number of classes of sunburn trajectories was identified based on quality-of-model fit (Akaike/Bayesian information criterion, residual plots), classification power (model entropy, posterior probabilities), and relevance of the trajectories (eMethods 1 in the Supplement). Sankey diagrams illustrate similarities of participants’ classifications across the 3 samples (eFigures 1-3 in the Supplement). The association between class membership and melanoma/cSCC risk was estimated separately for melanoma and cSCC in each of the 3 samples with hazard ratios (HRs) and 95% CIs (robust variances) using Cox proportional hazards models. We used age as timescale and stratified by year at inclusion. We used proportional assignment to account for the classification uncertainty, allowing each participant to contribute to each class, weighted according to its posterior probability of belonging to each class^39,40,41 (eMethods 2 in the Supplement). Adjustments were chosen based on a directed acyclic graph^42,43 (eFigure 4 in the Supplement) and included residential ambient UVR exposure, hair color, freckling when sunbathing, and cumulative number of sunbathing vacations.

Start of follow-up (hereafter baseline) was age at receipt of the last questionnaire used to create sunburn trajectories. All trajectories were estimated before baseline, and all exposure and covariate information was collected prior to cancer diagnosis. Participants contributed with person-years of follow-up from baseline to first primary melanoma diagnosis, cSCC diagnosis, emigration, death, or end of follow-up, whichever occurred first. We censored incident cSCCs and incident melanomas in analyses of melanoma risk and cSCC risk, respectively. Two pathways have been proposed for melanoma: melanomas that arise primarily on intermittently or chronically sun-exposed anatomic sites.¹⁰ Thus, we analyzed the association between class-membership and site-specific risk of melanoma: head/neck/upper limbs (ICD-7 codes 190.0, 190.2) and trunk/lower limbs (ICD-7 codes 190.1, 190.3, 190.4, 190.7).⁴⁴ We censored incident trunk/lower limbs melanomas in analyses of head/neck/upper limbs melanoma risk and vice versa. Heterogeneity of the HRs between melanoma and cSCC, and between melanoma sites, were tested using the contrast test statistic.⁴⁵

The LCMM handles missing sunburn information when estimating trajectories.³⁷ When combining the other covariates, we had up to 27% missing data (≤17% for individual covariates; Table 1) and used multiple imputation with chained equations⁴⁶ to impute 40 data sets.

Table 1. Participant Characteristics in the 3 Samples Used to Estimate Classes of Individual Lifetime Sunburn Trajectories.

Characteristic	Samples, No. (%)^a
Characteristic	<40 y^b	<50 y^c	<60 y^d
No. of women	159 773	153 297	119 170
Age at baseline, mean (SD), y	49.0 (8.4)	51.3 (6.1)	56.1 (3.9)
Total person-years of follow-up	3 112 435	2 689 943	1 698 739
Person-years of follow-up, mean (SD)	19.5 (6.5)	17.5 (5.5)	14.3 (4.2)
Incident melanoma cases	1774	1678	1252
Age at melanoma diagnosis, mean (SD), y	61.9 (9.0)	62.7 (8.3)	65.4 (7.0)
Incident cSCC cases	871	854	739
Age at cSCC diagnosis, mean (SD), y	68.0 (9.1)	68.2 (9.0)	69.7 (8.2)
Recruitment year to the NOWAC study
1991-1994	55 633 (34.8)	50 835 (33.2)	32 157 (27.0)
1995-1999	38 000 (23.8)	36 322 (23.7)	30 129 (25.3)
2000-2008	66 140 (41.4)	66 140 (43.1)	56 884 (47.7)
Residential ambient UVR exposure
Low (northern Norway)	17 862 (11.2)	16 921 (11.0)	12 469 (10.5)
Medium low (central Norway)	33 981 (21.3)	33 296 (21.7)	27 554 (23.1)
Medium (southwestern Norway)	78 085 (48.9)	74 495 (48.6)	56 925 (47.8)
Highest (southeastern Norway)	29 845 (18.7)	28 585 (18.6)	22 222 (18.6)
Education, y
≤10	51 927 (34.2)	49 760 (34.2)	39 536 (35.1)
11-13	45 512 (29.9)	43 457 (29.8)	32 889 (29.2)
≥14	54 571 (35.9)	52 428 (36.0)	40 099 (35.6)
Missing	7763	7652	6646
Smoking status at baseline
Never	53 929 (34.2)	52 162 (34.4)	42 085 (35.7)
Former	54 959 (34.8)	53 351 (35.2)	42 647 (36.2)
Current	48 915 (31.0)	45 949 (30.3)	33 088 (28.1)
Missing	1970	1835	1350
Hair color
Black/dark brown	25 611 (17.1)	24 723 (17.0)	19 852 (17.1)
Brown	60 411 (40.3)	58 638 (40.3)	46 795 (40.2)
Blond/yellow/red	64 065 (42.7)	62 123 (42.7)	49 703 (42.7)
Missing	9686	7813	2820
Untanned skin color
Dark	27 842 (21.6)	27 834 (21.6)	22 304 (20.8)
Medium	48 814 (37.9)	48 805 (37.9)	40 554 (37.8)
Light	52 072 (40.5)	52 054 (40.4)	44 350 (41.4)
Missing	31 045	24 604	11 962
Freckling when sunbathing
No	85 697 (64.8)	85 680 (64.8)	72 367 (65.8)
Yes	46 556 (35.2)	46 535 (35.2)	37 673 (34.2)
Missing	27 520	21 082	9130
No. of asymmetric nevi >5 mm on legs
0	127 893 (88.2)	122 491 (88.2)	94 252 (88.1)
1	9825 (6.8)	9403 (6.8)	7279 (6.8)
>1	7230 (5.0)	6940 (5.0)	5430 (5.1)
Missing	14 825	14 463	12 209
Skin reaction to acute sun exposure^e
Brown without being red first	25 456 (27.7)	23 795 (27.8)	17 320 (28.4)
Red	46 027 (50.0)	42 926 (50.2)	30 985 (50.8)
Red with burning	16 296 (17.7)	14 977 (17.5)	10 062 (16.5)
Red with burning and blistering	4195 (4.6)	3861 (4.5)	2588 (4.2)
Missing	67 799	67 738	58 215
Skin reaction to chronic sun exposure^e
Deep brown	12 410 (15.0)	11 621 (14.9)	8373 (14.3)
Brown	47 390 (57.3)	44 757 (57.3)	33 647 (57.5)
Light brown	21 403 (25.9)	20 305 (26.0)	15 432 (26.4)
Never brown	1500 (1.8)	1420 (1.8)	1086 (1.9)
Missing	77 070	75 194	60 632
Cumulative No. of weeks on sunbathing vacations
None	16 976 (12.3)	12 145 (9.3)	6656 (6.4)
Lowest tertile	40 659 (29.4)	40 401 (30.9)	32 283 (31.1)
Middle tertile	40 198 (29.1)	38 687 (29.6)	32 470 (31.3)
Highest tertile	40 407 (29.2)	39 674 (30.3)	32 494 (31.3)
Missing	21 533	22 390	15 267
Indoor tanning
Never	46 258 (33.4)	41 968 (32.0)	32 864 (31.7)
Ever	92 392 (66.6)	89 044 (68.0)	70 755 (68.3)
Missing	21 123	22 285	15 551

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Abbreviations: cSCC, cutaneous squamous cell carcinoma; NOWAC, Norwegian Women and Cancer; UVR, UV radiation.

^{^a}

Because of rounding, percentages may not sum to 100%.

^{^b}

Sample used to estimate classes of individual lifetime trajectories up to 39 years and includes all women with information on sunburns in at least 1 age decade within 40 years of exposure.

^{^c}

Sample used to estimate classes of individual lifetime trajectories up to 49 years and includes all women from the sample of fewer than 40 years of exposure who had information on sunburns in at least 1 age decade within 50 years of exposure.

^{^d}

Sample used to estimate classes of individual lifetime trajectories up to 59 years and includes all women from the sample of fewer than 50 years of exposure who had information on sunburns in at least 1 age decade within 60 years of exposure.

^{^e}

Recorded in subsamples of the cohort.

We conducted several complete-case sensitivity analyses. To investigate potential selection bias, we conducted analyses including prevalent melanomas and cSCCs. We used alternative methods for class allocation to account for class-membership uncertainty^39,40,47 (eMethods 2 in the Supplement). Finally, we also conducted all analyses based on an alternative LCMM. For further details and additional sensitivity analyses, see eMethods 3 in the Supplement.

All tests were 2-sided and deemed to be significant at P < .05. Statistical analyses were conducted using R, version 3.6.1, and the lcmm package, version 1.9.2 (R Foundation).

Results

Participant Characteristics

Mean (SD) age at baseline was 49 (8.4) years for the 159 773 women in the sample of fewer than 40 years of exposure, 51 (6.1) years for the 153 297 women in the sample of fewer than 50 years of exposure, and 56 (3.9) years for the 119 170 women in the sample of fewer than 60 years of exposure (Table 1). Respectively, in the samples of fewer than 40, 50, and 60 years of exposure, 1774, 1678, and 1252 women were diagnosed with incident primary melanoma and 871, 854, and 739 women with incident primary cSCC during a mean (SD) follow-up of 19.5 (6.5) years, 17.5 (5.5) years, and 14.3 (4.2) years. Participants in the sample of fewer than 60 years of exposure were recruited later and less likely to never have been on sunbathing vacations; all other characteristics were similar among the 3 samples.

Lifetime Sunburn Trajectories

The best model identified 5 classes of sunburn trajectories from 0 to 39 years (<40 years of exposure sample): stable low (16.6%), low-moderate-low (8.3%), low to high (16.6%), high to low (13.8%), and stable high (44.7%) (Figure 2). Women in the stable low trajectory were more likely to be from northern Norway, less educated, and current smokers; have darker hair and skin color and no freckles; and sunbathe less (eTable 1 in the Supplement). In contrast, women in the stable high trajectory were more likely to have lighter hair color and more severe skin reactions to acute sun exposure.

Figure 2. — A, The estimated average trajectories of sunburn up to 39 years of exposure in the 5 latent classes (n = 159 773). B-F, The estimated average trajectory for each class separately (bold line), with a sample of 500 observed individual trajectories displayed in the background, picked at random among participants with the highest probabilities of belonging to each class. A random jitter was added to the observed trajectories to distinguish common trajectories.

The best model identified 5 classes of sunburn trajectories from 0 to 49 years (<50 years of exposure sample; eFigure 5 in the Supplement) and 0 to 59 years (<60 years of exposure sample; Figure 3), labeled as in the sample of fewer than 40 years of exposure (Figure 2). Trajectories in the sample of fewer than 60 years of exposure were somewhat different from those in the samples of fewer than 40 and 50 years of exposure, in particular the low-moderate-low trajectory, which started at a higher level and included a higher proportion of participants. Participant characteristics in the samples of fewer than 50 and 60 years of exposure were distributed similarly as in the sample of fewer than 40 years of exposure (eTables 2 and 3 in the Supplement).

Figure 3. — A, The estimated average trajectories of sunburn up to 59 years of exposure in the 5 latent classes (n = 119 170). B-F, The estimated average trajectory for each class separately (bold line), with a sample of 500 observed individual trajectories displayed in the background, picked at random among participants with the highest probabilities of belonging to each class. A random jitter was added to the observed trajectories to distinguish common trajectories.

The Sankey diagrams (eFigures 1-3 in the Supplement) showed that the low-moderate-low trajectory was the class with the most dissimilarities across the samples. Posterior probabilities of belonging to this class were generally lower than for the other classes (eMethods 1 in the Supplement).

Sunburn Trajectories and Skin Cancer Risk

Complete-case and multiple imputation analyses showed similar results; thus, results from multiple imputation analyses are presented. Compared with the stable low trajectory, there were statistically significant increased melanoma and cSCC risks for stable high and high to low trajectories. The HRs were similar across samples but strongest for the sample of fewer than 40 years of exposure (stable high vs stable low trajectories: melanoma: HR, 1.50 [95% CI, 1.28-1.75] and cSCC: HR, 1.51 [95% CI, 1.22-1.87]; high to low vs stable low trajectories: melanoma: HR, 1.44 [95% CI, 1.20-1.73] and cSCC: HR, 1.47 [95% CI, 1.14-1.91]). In general, compared with the stable low trajectory, no statistically significant increased skin cancer risk was found for low to high or low-moderate-low trajectories, except for the low-moderate-low trajectory in the sample of fewer than 60 years of exposure (melanoma: HR, 1.29 [95%, CI, 1.07-1.54] and cSCC: HR, 1.46 [95% CI, 1.17-1.83]). In all samples, and for all trajectories, effect estimates were not statistically significantly different between melanoma and cSCC (Table 2).

Table 2. Hazard Ratios (HRs) for Classes of Lifetime Sunburn Trajectories and Risk of Melanoma and Cutaneous Squamous Cell Carcinoma.

Sample	Women, No. (%)^a	Complete-case analyses^b					Multiple imputation analyses^c
		Melanoma		cSCC		P value for heterogeneity^d	HR (95% CI)		P value or heterogeneity^d
		No. of cases	HR (95% CI)	No. of cases	HR (95% CI)	P value for heterogeneity^d	Melanoma	cSCC	P value or heterogeneity^d
Class of lifetime sunburn trajectory^e
<40 y^f	117 352	1293	NA	613	NA	NA	NA	NA	NA
Stable low	18 191 (15.5)	134	1 [Reference]	68	1 [Reference]	NA	1 [Reference]	1 [Reference]	NA
Low-moderate-low	10 509 (9.0)	76	0.98 (0.75-1.28)	32	1.06 (0.72-1.57)	.74	1.09 (0.87-1.36)	1.21 (0.89-1.66)	.58
Low to high	20 104 (17.1)	192	1.15 (0.93-1.42)	100	1.29 (0.96-1.73)	.52	1.20 (1.00-1.43)	1.24 (0.98-1.58)	.80
High to low	17 108 (14.6)	206	1.39 (1.12-1.72)	82	1.36 (0.99-1.87)	.91	1.44 (1.20-1.73)	1.47 (1.14-1.91)	.88
Stable high	51 440 (43.8)	685	1.44 (1.20-1.73)	331	1.55 (1.19-2.02)	.66	1.50 (1.28-1.75)	1.51 (1.22-1.87)	.95
<50 y^g	117 101	1260	NA	610	NA	NA	NA	NA	NA
Stable low	22 583 (19.3)	166	1 [Reference]	88	1 [Reference]	NA	1 [Reference]	1 [Reference]	NA
Low-moderate-low	12 116 (10.3)	112	1.13 (0.90-1.41)	61	1.14 (0.84-1.55)	.95	1.12 (0.92-1.36)	1.15 (0.89-1.49)	.85
Low to high	15 601 (13.2)	135	1.07 (0.86-1.33)	70	1.19 (0.89-1.60)	.56	1.11 (0.92-1.33)	1.14 (0.90-1.46)	.84
High to low	24 924 (21.3)	304	1.39 (1.15-1.67)	150	1.45 (1.12-1.88)	.78	1.40 (1.19-1.64)	1.48 (1.19-1.83)	.70
Stable high	41 877 (35.8)	543	1.41 (1.19-1.68)	241	1.36 (1.06-1.74)	.80	1.44 (1.24-1.67)	1.37 (1.12-1.69)	.73
<60 y^h	96 407	992	NA	551	NA	NA	NA	NA	NA
Stable low	18 735 (19.4)	135	1 [Reference]	73	1 [Reference]	NA	1 [Reference]	1 [Reference]	NA
Low-moderate-low	19 601 (20.3)	198	1.21 (0.98-1.49)	136	1.60 (1.22-2.08)	.11	1.29 (1.07-1.54)	1.46 (1.17-1.83)	.39
Low to high	12 721 (13.2)	102	1.06 (0.84-1.34)	67	1.24 (0.92-1.68)	.42	1.12 (0.91-1.37)	1.17 (0.91-1.51)	.77
High to low	13 837 (14.4)	150	1.32 (1.07-1.64)	80	1.44 (1.08-1.91)	.65	1.34 (1.10-1.62)	1.43 (1.13-1.82)	.66
Stable high	31 513 (32.7)	407	1.48 (1.22-1.79)	195	1.34 (1.04-1.74)	.55	1.50 (1.27-1.78)	1.35 (1.09-1.68)	.46

Open in a new tab

Abbreviation: cSCC, cutaneous squamous cell carcinoma.

^{^a}

Because of rounding, percentages may not sum to 100%.

^{^b}

Cox proportional hazards model with age as the timescale, stratified by calendar year at study inclusion and adjusted for residential ambient UV radiation exposure, hair color, freckling when sunbathing, and cumulative number of sunbathing vacations. Participants were assigned to classes using proportional assignment.

^{^c}

Analyses with multiple imputation of missing data conducted using chained equations and a total of 40 imputed data sets, using the same models as in the complete-case analyses (sample of <40 years of exposure: n = 159 773 [1774 melanoma cases, 871 cSCC cases]; sample of <50 years of exposure: n = 153 297 [1678 melanoma cases, 854 cSCC cases]; sample of <60 years of exposure: n = 119 179 [1252 melanoma cases, 739 cSCC cases]).

^{^d}

Heterogeneity test conducted using the contrast test statistic.

^{^e}

Classes of individual lifetime trajectories estimated from a latent class mixed model. Mean annual number of sunburns was modeled using I-splines with 4 equidistant knots. Mixed model with random intercept only.

^{^f}

Trajectories estimated using sunburn information up to 39 years of exposure.

^{^g}

Trajectories estimated using sunburn information up to 49 years of exposure.

^{^h}

Trajectories estimated using sunburn information up to 59 years of exposure.

Melanoma site-specific analyses yielded similar results as the overall analysis, and effect estimates were not statistically significantly different between sites (eTable 4 in the Supplement). Sensitivity analyses including prevalent melanomas and cSCCs, and analyses using alternative methods for class allocation (eTables 5-7 in the Supplement) yielded similar results. Analyses using the alternative LCMM identified somewhat different trajectories but with similar results for the associations between these trajectories and skin cancer risk (eFigure 6 and eTable 8 in the Supplement).

Discussion

In this large, prospective cohort study of Norwegian women, we identified 5 classes of lifetime sunburn trajectories, with similar shapes when estimated over 4 (0-39 years), 5 (0-49 years), or 6 (0-59 years) decades of exposure. Women with a high number of sunburns throughout life (stable high trajectory) and high numbers in childhood but low in adulthood (high to low trajectory) showed statistically significant increased melanoma and cSCC risks compared with women with low numbers throughout life (stable low trajectory). A low number of sunburns in childhood and high in adulthood (low to high trajectory) was associated with increased melanoma and cSCC risk, although not significantly. Finally, women with low-moderate-low sunburn trajectory showed increased melanoma and cSCC risk that was not statistically significant when estimated over 4 and 5 decades and statistically significant when estimated over 6 decades.

Lifetime Sunburn Trajectories

To our knowledge, no previous study has yet described lifetime sunburn trajectories. The identified trajectories are in line with latent clusters of health behaviors expected in a population.^48,49,50,51 There are people who live consistently healthy or unhealthy lifestyles represented in the stable low and stable high trajectories. However, in the present study, sunburn frequencies not only depend on people’s behavior, but also on their phenotype and place of living.⁵² This was confirmed by a larger proportion of women with fair complexion and sun-sensitive skin in the stable high trajectory and with women of darker complexion and from northern Norway in the stable low trajectory. Women with many sunburns in childhood might learn from their painful experience and protect themselves more in adulthood, resulting in high to low trajectories. Conversely, parents might protect their children from sunburns in childhood but not in adolescence, a phase with lower health-seeking behaviors.⁵³ People then become more health conscious with age, leading to the low-moderate-low trajectory⁵⁴ and the decreasing trajectories observed when estimated over 6 decades.

Sunburn Trajectories and Skin Cancer Risk

Similar to other studies,^24,26,27 we found no differences in the estimates between melanoma and cSCC, nor between melanoma occurring on chronically sun-exposed sites (head/neck/upper limbs) and intermittently sun-exposed sites (trunk/lower limbs). Lifetime number of sunburns was associated with both skin cancers, and previous studies reported effect estimates similar to the ones reported herein for stable high trajectories (range: melanoma, 1.52-2.27; cSCC, 1.40-2.40).^{19,20,25,26,27,28} Interestingly, women with high to low and stable high trajectories had similar risks of developing these skin cancers, despite a higher cumulative number of sunburns in the stable high trajectory. These 2 trajectories combined correspond to higher number of sunburns in childhood, and studies investigating childhood sunburns also found increased skin cancer risks with similar effect estimates (range: melanoma, 1.63-3.20; cSCC, 1.55-2.32),^{19,20,22,23,24} though less precision. Women with low to high trajectories had no statistically significantly increased risk compared with stable low trajectories even though the cumulative number of sunburns was more or less the same than for high to low trajectories. Those findings support that childhood is a susceptible phase for harms from overexposure to the sun^{12,13,14,15,16,17,18} and may be a driving factor for melanoma and cSCC risk in the present analysis.

Previous studies could not confirm whether early-life sunburns increased melanoma risk more than later-life sunburns.^19,20 This might be because unlike the present study, melanoma risk was compared with exposure in different periods of life separately. Early-life behavior may affect later behavior, making it difficult to disentangle the direct effects on disease risk of exposure in different age periods.²⁹

For cSCC, the literature suggests increased risk associated with sunburns in childhood^21,22,23,24 but not in adulthood,^21,22 in line with the present findings for trajectories estimated over 4 and 5 decades. However, when estimated over 6 decades, almost all trajectories had higher cSCC risk compared with the stable low trajectory, indicating that repeated sunburns over a long period of life represent high amounts of cumulative exposure, an important cSCC risk factor.^1,9

Limitations

We have a well-characterized cohort with no major selection bias,⁵⁵ complete follow-up, and more than 99% of melanomas and cSCCs were morphologically verified.⁵⁶ Nonetheless, this study has limitations. Measuring sunburn is challenging, and reproducibility studies found generally lower reliability coefficients for sunburn than for other skin cancer risk factors.⁵⁷ Poor measurement can result in exposure misclassification, especially for younger age decades. All exposure information was collected before cancer diagnosis; thus, misclassification is likely nondifferential, limiting the potential for recall bias. Residual confounding is inevitable in observational studies. Using all information available in NOWAC, we identified potential confounders based on a directed acyclic graph, and sensitivity analyses using alternative adjustments yielded similar results.

Conclusions

In this cohort study, we identified 5 latent classes of sunburn trajectories, in line with health behaviors generally observed in people. By studying lifetime sunburn trajectories, to our knowledge for the first time, we found that high sunburn frequencies throughout life were associated with both increased melanoma and cSCC risks in Norwegian women. Importantly, the present results suggest that childhood is a more susceptible phase with regard to sunburns and subsequent risk of these skin cancers. It is therefore crucial to emphasize the importance of avoiding sunburns throughout life, and in particular in childhood.

Supplement.

eMethods 1. Identification of classes of individual lifetime sunburn trajectories

eMethods 2. Estimation of the association between class-membership and the two skin cancers

eMethods 3. Summary of sensitivity analyses

eFigure 1. Sankey diagram illustrating the similarities and dissimilarities of participants’ classifications when identified 0-39 (sample <40) and 0-49 years (sample <50)

eFigure 2. Sankey diagram illustrating the similarities and dissimilarities of participants’ classifications when identified 0-39 (sample <40) and 0-59 years (sample <60)

eFigure 3. Sankey diagram illustrating the similarities and dissimilarities of participants’ classifications when identified 0-49 (sample <50) and 0-59 years (sample <60)

eFigure 4. Directed acyclic graph of the assumed causal pathways for sunburn trajectories and risk of cutaneous squamous cell carcinoma (cSCC)

eFigure 5. Estimated average lifetime trajectories of sunburns up to 49 years (sample <50, n=153,297) Norwegian Women and Cancer Study, 1991-2018

eFigure 6. Estimated average lifetime trajectories of sunburns up to 39 years (sample <40, n=159,773, left), 49 years (sample <40, n=153,297, middle) and 59 years (sample <40, n=119170, right), using a threshold model for the number of sunburns, Norwegian Women and Cancer Study, 1991-2018

eTable 1. Characteristics of Participants Stratified by Classes of Individual Lifetime Sunburn Trajectories Estimated up to 39 years, Norwegian Women and Cancer Study, 1991-2018

eTable 2. Characteristics of Participants Stratified by Classes of Individual Lifetime Sunburn Trajectories Estimated up to 49 years, Norwegian Women and Cancer Study, 1991-2018

eTable 3. Characteristics of Participants Stratified by Classes of Individual Lifetime Sunburn Trajectories Estimated up to 59 years, Norwegian Women and Cancer Study, 1991-2018

eTable 4. Hazard Ratios and 95% Confidence Intervals for Classes of Individual Lifetime Sunburn Trajectories and Risk of Site-Specific Melanoma. Norwegian Women and Cancer Study, 1991-2018

eTable 5. Hazard Ratios and 95% Confidence Intervals for Classes of Individual Lifetime Sunburn Trajectories and Risk of Melanoma and Cutaneous Squamous Cell Carcinoma, Without Exclusion of Prevalent Melanomas and Cutaneous Squamous Cell Carcinomas. Norwegian Women and Cancer Study, 1991-2018

eTable 6. Hazard Ratios and 95% Confidence Intervals for Classes of Individual Lifetime Sunburn Trajectories and Risk of Melanoma and Cutaneous Squamous Cell Carcinoma Using Modal Assignment to Assign Classes, Norwegian Women and Cancer Study, 1991-2018

eTable 7. Hazard Ratios and 95% Confidence Intervals for Classes of Individual Lifetime Sunburn Trajectories and Risk of Melanoma and Cutaneous Squamous Cell Carcinoma, Using Multiple Pseudo-class Draws to Assign Classes, Norwegian Women and Cancer Study, 1991-2018

eTable 8. Hazard Ratios and 95% Confidence Intervals for Classes of Lifetime Sunburn Trajectories and Risk of Melanoma and Cutaneous Squamous Cell Carcinoma, Using an Alternative Model for Class Identification, Norwegian Women and Cancer Study, 1991-2018

eReferences

Click here for additional data file.^{(1.7MB, pdf)}

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