Risk factors of incident melanocytic nevi: A longitudinal study in a cohort of 1,232 young German children
Article first published online: 11 JAN 2005
Copyright © 2004 Wiley-Liss, Inc.
International Journal of Cancer
Volume 115, Issue 1, pages 121–126, 20 May 2005
How to Cite
Bauer, J., Büttner, P., Wiecker, T. S., Luther, H. and Garbe, C. (2005), Risk factors of incident melanocytic nevi: A longitudinal study in a cohort of 1,232 young German children. Int. J. Cancer, 115: 121–126. doi: 10.1002/ijc.20812
- Issue published online: 18 MAR 2005
- Article first published online: 11 JAN 2005
- Manuscript Accepted: 23 SEP 2004
- Manuscript Received: 27 MAY 2004
- melanocytic nevi;
- risk factors;
- prevention and control;
The number of melanocytic nevi is the most important independent risk factor for cutaneous melanoma. Aim of our study was to add information to the controversial discussion on the role of chronic-moderate and intermittent-high sun exposure and sunburns for the development of melanocytic nevi by the use of a large longitudinal study. A longitudinal study with a 3-year follow-up was conducted in 1,232 young children 2–7 years of age attending 78 public nursery schools in Bochum and Stuttgart, Germany. Total body nevus counts, assessment of pigmentary features and nevus counts on arms of parents were carried out. Parents underwent a standardized interview concerning sun exposure, sunburns and sun-protective behavior. Applying multiple linear regression analysis higher numbers of incident nevi were associated with host factors like light skin complexion (skin Type II vs. IV, p = 0.022) and freckling of the face (p < 0.001), with parental factors like nevus counts on mothers' (p < 0.001) and fathers' (p = 0.004) arms and at least one parent being of German descent (p = 0.006), and with environmental factors like intermittent-high sun exposure during holidays (p < 0.001) and chronic-moderate ultraviolet radiation at home (p = 0.007). Sunburns were a significant risk factor for nevus development (p = 0.005). Total cumulative sun exposure seems to be the crucial environmental risk factor for the development of nevi, whether the child is exposed to chronic-moderate or intermittent-high ultraviolet light doses. Public health education should focus primarily on avoiding sun exposure especially in children with fair skin and parents with high nevus counts. © 2004 Wiley-Liss, Inc.
The total number of melanocytic nevi (MN) on the body is known to be the strongest intrinsic risk factor for the development of cutaneous melanoma (CM).1, 2, 3, 4, 5 Moreover, MN were considered to be precursor lesions of a substantial proportion of CM.6, 7 Case control studies on risk factors for CM in adults are influenced by recall bias.8 Childhood is a period of particular susceptibility to the carcinogenic effects of solar radiation.9 Thus, studies on MN in children might give new insights into the pathogenesis of CM.
To date, numerous cross-sectional studies have been published identifying risk factors for MN development in children.10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Studies yielded partly contradicting results to important points like the amount and intensity of sun exposure needed for MN development and the role of sunburns. Few longitudinal studies exist that investigated risk factors for incident MN.20, 21, 22, 23, 24 Such studies might give a better control of the influence of environmental factors and confounders. Our present study longitudinally investigated risk factors for the development of MN in a cohort of 1,232 German kindergarten children, 2–7 years of age, followed-up over a 3-year period.
Material and methods
Our analysis utilized data of children who participated in a randomized controlled trial set up to investigate whether educational intervention and the provision of free sunscreen can reduce the number of newly developing MN over a 3-year follow-up period (unpublished data). Children were recruited from 49 public nursery schools (kindergarten) in Stuttgart (latitude: 48° 46 min), Germany and 29 in Bochum (51° 29 min), Germany, which were randomly selected from a total of 242 public nursery schools in Stuttgart and 169 in Bochum. Most children in Germany from all social classes visit public nursery schools and thus the selection should be representative. Only 3 nursery schools that have been approached refused to participate. In the 78 participating public nursery schools >80% of the parents agreed to enter the study. Children 2–7 years of age with skin Type I–IV according to Fitzpatrick25 and with written parental consent were eligible. Children with skin Type V or VI, with missing age information, with immunosuppression after organ transplantation or due to chemotherapy of cancer, or who did not allow physical examination had to be excluded. At the initial screening from March–October 1998 a cohort of 1,812 children was examined. The results of the baseline cross-sectional study were reported previously.19
Ethical clearance was given by the ethical committees of the Faculty of Medicine, University of Tübingen and Bochum. Parents provided written consent to the study and children gave oral assent.
Standardized interviews of parents
At the time of the first physical examination of the children, standardized interviews were carried out with at least one of the parents (most frequently mothers). Information was asked about the ethnicity and the highest education of the parents. Sun exposure of the child from birth to present was assessed, including usual activities when playing at home outdoors, duration and destination of holidays, sunscreen use, and history and severity of sunburns. Efforts were undertaken to count the number of MN on arms of mothers and fathers.19
Standardized physical examinations were conducted by a dermatologist. Children were examined dressed only in underpants in a well-illuminated room. According to a standard protocol MN were defined as brown to black pigmented macules or papules of any size, darker in the color than the surrounding skin.26 Small MN were distinguished from freckles by their darker color and if present by their elevated appearance. In all cases of doubt pigmented lesions were not counted. Halo nevi, nevi spili, congenital nevi and blue nevi were counted separately and are included in the total count of MN. Hair color and eye color were assessed by means of a range of 10 standard hair samples and 10 iris color prints. The severity and distribution of freckling was estimated semi-quantitatively on the face, both arms and shoulders using drawings developed by Dubin et al.27
Follow-up and final assessment
A total of 1,232 children (68%) of the initial cohort presented for the follow-up examination in Stuttgart in Summer 2001 and in Bochum in Autumn 2001. The average follow-up interval was 3 years. The second and final parental interview and physical examination of the child were conducted in the same way as at the initial assessment.
The number of MN that newly developed between 1998 and 2001 was the target variable.
Potential risk factors
The following potentially influencing characteristics have been considered in the statistical analysis:
- 1Basic characteristics of children, such as age, gender, country of birth, skin type (according to Fitzpatrick25), eye color, hair color, skin pigmentation, freckles in face (assessed in 2001), centre (Stuttgart or Bochum) and intervention group.
- 2Characteristics of parents and family, such as education of parents, ethnicity of parents, reported family history of skin cancer and number of MN on mothers' and fathers' arms.
- 3Sun exposure during 1998–2001 measured by weeks on holidays, weeks on holidays in sunny climates, score of country of holiday (created from the 5 holiday destinations: 0, no holiday; 1, holiday in northern Europe, USA; 2, holiday in northern Mediterranean country; 3, holiday in northern Africa; and 4, holiday in the Tropics; variables were added up for 4 years creating a score ranging from 0–16), hr/day in sun during holidays in sunny climate, and hr/day playing outside at home (assessed in 2001). A home activity score was assessed in 2001. Activities considered were playing ball, sun bathing, swimming outdoors, playing outdoors, walking, riding the bicycle, and being outdoors in general. Each activity scored 0 for less than once or twice per week and 1 for once or twice per week or more often. These scores were added up to gain an overall activity score at home ranging from 0–7.
- 4Sunburn experience between 1998–2001 was measured by the number and an extent and severity score of newly experienced sunburns. The extent of each sunburn was assessed by asking which body parts were affected (face, chest and abdomen, shoulders and back, arms and hands, legs and feet). A summary score measuring extent and severity of sunburns combined, was obtained by weighting the severity of the sunburns (1, erythema without blistering and peeling; 2, erythema with peeling; 3, painful sunburn with blistering and peeling) and adding up the number of body sites affected. This score ranged from 0–30.
Because Germany is located in a temperate zone, ultraviolet radiation exposure while playing outside at home during spring, summer and autumn was referred to as “chronic-moderate.” This was measured by the number hours per day playing outside at home in summer and by the home activity score. In contrast, sun exposure during holidays in sunny climates was classified as “intermittent-high,” measured by weeks on holidays in sunny climates and score of holiday countries.
Depending on the distribution, numerical variables were described by mean values and standard deviations (±SD) or median values and interquartile ranges (IQR). Bivariate comparisons between the number of newly acquired MN and potential risk factors were conducted using non-parametric Wilcoxon tests and Spearman correlation coefficient, as appropriate. In addition, for descriptive purposes the outcome variable “number of incident MN” was categorized into 3 groups using the tertiles of MN per year of age as the cutoff. Bivariate comparisons between children in the tertile categories of incident MN and influencing characteristics were conducted using χ2 tests, analysis of variance and non-parametric Wilcoxon tests as appropriate.
Multiple linear regression analysis was utilized to assess the effects of potential risk factors on the number of incident MN. For multivariate linear regression analysis the target variable was log-transformed to acquire an approximately normally distributed variable. All categorical variables were dummy-coded. After a final stable model was developed based on stepwise selection procedures, all remaining variables were considered as potential confounders. In addition, all possible two-way interactions of factors in the model were assessed for significance. Results of multivariate linear regression analysis were given as regression coefficients and 95% confidence intervals (CI). The 3 study arms of the intervention study (control vs. education vs. education and sunscreen) have also been included into the model and showed no significant differences (unpublished data). Statistical analysis was conducted using SPSS for Windows (release 6.3.1). Throughout the analysis a significance level of 0.05 was assumed.
Description of participating children and bivariate associations with newly acquired MN
Overall, 1,232 children (51.4% boys) 2–7 years of age at first visit completed follow-up. The majority of these children (98.5%) were born in Germany and 83.6% had parents who were both of German descent. During the follow-up period between 1998–2001, the children acquired overall a median number of 26 MN (IQR = [17, 40], range = 1–186). The median number of incident MN was 25 (IQR = [16, 38]) for girls and 28 (IQR = [18, 42]) for boys (p = 0.003). The number of newly acquired MN was increasing with age (p < 0.001) (Fig. 1). Pigmentary characteristics such as skin type, hair color and freckling were related significantly to the occurrence of incident MN (p < 0.001, respectively) (Table I). Parental characteristics such as ethnicity of parents and number of MN on mothers' arms were also significantly related to the number of incident MN (p < 0.001, respectively), as were measurements of history of sun exposure (Table I).
|Characteristic1||Overall (n = 1232)||First tertile of MN (n = 433)||Second tertile of MN (n = 400)||Third tertile of MN (n = 399)||p-value2|
|Basic characteristics of children (%)|
|Mean age (±SD)||4.3 (± 1.1)||4.3 (± 1.1)||4.3 (± 1.1)||4.3 (± 1.1)||0.873|
|Born in Germany||98.5||97.7||98.8||99.2||0.159|
|Skin Type I||11.6||9.7||10.5||14.8||<0.001|
|Blue eye colour||51.1||45.5||52.3||55.9||0.002|
|Blonde-fair hair colour||56.3||45.5||61.3||63.2||<0.001|
|No freckles in face||75.9||82.7||77.8||66.7||<0.001|
|From the town of Stuttgart||56.3||51.3||56.5||61.7||0.011|
|Characteristics of parents and family (%)|
|At least one parent with university degree||42.3%||44.0%||41.2%||41.5%||0.327|
|Both parents of German decent||83.6%||78.3%||86.5%||86.5%||<0.001|
|Family history of skin cancer||4.9%||3.8%||5.2%||5.8%||0.384|
|Median number of nevi on mothers' arms, (IQR)||30 (14, 52)||24 (9, 45)||31 (15, 56)||32 (17, 57)||<0.001|
|Median number of nevi on fathers' arms, (IQR)||21 (7, 46)||20 (5, 38)||20 (8, 42)||29 (10, 52)||<0.001|
|Sun exposure of children between 1998 and 2001 or as assessed in 2001|
|Median weeks on holidays, (IQR)||6 (4, 9)||6 (4, 9)||6 (4, 8)||7 (4, 9)||0.007|
|Median score of holiday countries, (IQR),||4 (3, 6)||4 (3, 5.5)||4 (3, 6)||5 (3, 6)||<0.001|
|% with score > 6||13.5%||9.1%||12.1%||19.7%|
|Median weeks on holidays in sunny climates, (IQR),||5 (2, 8)||4 (2, 8)||4 (2, 7)||6 (2, 8)||<0.001|
|% no holidays||18.5%||22.2%||18.4%||14.5%|
|Median hours spent in the sun per day during holidays in sunny climates, (IQR),||4 (3, 6)||4 (3, 5)||4 (3, 6)||4 (3, 6)||0.002|
|% with > 5 hours||25.4%||21.4%||25.1%||30.1%|
|Median score of outdoor activities at home during summer, (IQR),||5 (4, 6)||5 (4, 6)||5 (4, 6)||5 (4, 6)||0.143|
|% maximal score||9.8%||7.9%||9.8%||12.1%|
|% playing more than 4 hours per day outside at home in summer||20.0%||21.7%||22.0%||16.0%||0.312|
|Median number of sunburns, (IQR),||0 (0, 1)||0 (0, 1)||0 (0, 1)||0 (0, 1)||<0.001|
|% with no sunburn||63.6%||69.1%||65.2%||56.0%|
|Median score of extent and severity of sunburns, (IQR)||0 (0, 2)||0 (0, 1)||0 (0, 2)||0 (0, 3)||<0.001|
Results of multivariate linear regression analysis
Increasing age (p < 0.001), male gender (p = 0.044), and increasing numbers of freckles in the face (p < 0.001) were significantly related to an increased number of newly acquired MN (Table II). There was a significant interaction between the predictors skin type and hair color, showing that children with skin Type II and fair hair color were even more likely to have acquired more MN than children with skin Types I, III or IV and with non-fair hair color (p = 0.0178). No other significant interactions were found. Children with at least one parent of German descent (p = 0.006) and children with high numbers of MN on their mothers' (p < 0.001) or fathers' (p = 0.004) arms were more likely to develop more MN during the follow-up period. Children with a history of sunburns (p < 0.001) and children with a high score concerning the extent and severity of experienced sunburns (p = 0.005) were more likely to acquire more MN.
|Predictor||Regression coefficient||95% CI||p-value|
|Characteristics of children|
|Age in 1998||0.168||0.133–0.203||<0.001|
|I versus IV||0.191||−0.020–0.402||0.075|
|II versus IV||0.194||0.028–0.360||0.022|
|III versus IV||0.177||0.021–0.332||0.026|
|Fair versus dark||0.016||−0.197–0.229||0.883|
|Blonde versus dark||0.220||0.050–0.391||0.011|
|Red-blonde versus dark||0.025||−0.150–0.201||0.777|
|Brown versus dark||0.183||0.010–0.356||0.038|
|Skin Type II and fair hair||0.238||0.041–0.434||0.0178|
|Freckles in face in 2001||0.006||0.004–0.008||<0.001|
|Education: at least one parent with university degree||−0.100||−0.179–−0.022||0.012|
|Ethnicity: at least one parent of German descent||0.245||0.069–0.420||0.006|
|Number of moles on mothers' arms||0.002||0.001–0.003||<0.001|
|Number of moles on fathers' arms||0.001||0.0005–0.002||0.004|
|Sun exposure between 1998 and 2001 or as assessed in 2001|
|Score of holiday countries visited between 1998 and 2001||0.040||0.022–0.059||<0.001|
|Activity score at home||0.043||0.012–0.075||0.007|
|History of sunburns (yes/no)||0.181||0.087–0.275||<0.001|
|Score for extent and severity of experienced sunburns||0.012||0.004–0.021||0.005|
Pigmentary factors indicate children at high risk for MN development. These children should be particularly protected. In our present study children with skin Type II and III developed significantly more nevi than Type IV, whereas children with Type I did not. The interaction showed that children with skin Type II and fair hair color were most prone to develop many MN. Thus, children with lighter skin but with the ability to slightly tan and with fair hair are at higher risk of incident MN. These results are in agreement with previous cross-sectional studies.14, 16, 17, 19, 28, 29, 30, 31 As demonstrated in a previous cross-sectional analysis of our study, skin Type I had lower nevus counts,19 which might be due to better protection of these sun-sensitive children by their parents. Freckling was found to be associated with higher prevalence17, 21, 28, 29, 31, 32, 33 and with higher incidence of MN20, 23 in children. Our data also showed freckling to be associated significantly with a higher incidence of MN. All above mentioned studies concordantly reported that the prevalence of MN in children increased continuously with age and our present study demonstrated that the incidence of nevi was also correlated significantly with age.
Studies on parental pigmentary factors have shown MN counts of children to be correlated significantly with MN counts of mothers34 and the arms of both parents.19 The present longitudinal data support this association. Moreover the susceptibility to develop MN depends on skin complexion and populations with pigmentary traits that protect the skin more effectively against solar radiation develop fewer nevi.14, 35, 36 In our study, there was a clear association of ethnicity of parents with MN counts in children in the cross-sectional19 and longitudinal analysis. Most non-German parents were immigrants from southern European countries with darker complexions. These findings support the hypothesis of a hereditary disposition that determines the risk of MN development in children. The impact of genetic factors on MN counts was investigated previously by twin studies and environmental factors seem to influence the expression of these genes.37 The associations demonstrated by the present analysis might in part be also explained by lifestyle features being shared by parents and their children.
Sun exposure is one of the major determinants of MN development and studies comparing different populations have clearly shown higher MN counts in children living at lower latitudes.30, 32, 33 The role of intermittent exposure to high doses of ultraviolet light in holidays vs. continuous mild to moderate sun exposure at home have been discussed controversially in the literature. The apparent contradiction might be explained by study populations from different latitudes. Publications from tropical countries stressed the predominant role of continuous habitual exposure to ambient sunlight for the development of MN and that sun exposure during holidays plays a minor role.14, 17, 18, 23, 33, 38 Only one study from tropical Australia found that both acute and chronic exposure to sun were associated with MN development.17 In contrast in regions with less intense solar radiation like Europe and Canada, number and distribution of MN in children was found to be related to exposure to high ultraviolet light doses in holidays.13, 15, 21, 31, 39 In our current study, the incidence of MN was significantly associated with duration of sun exposure at home with mild to moderate levels of ultraviolet radiation as well as with high levels of sun exposure during holidays in sunny climates.
In tropical countries children are exposed to high doses of ambient ultraviolet light throughout the year.40, 41, 42, 43 Habitual sun exposure there is much more intense than in more temperate zones such as Central Europe or Canada. The effect of additional holidays with more intense sun exposure might be much more evident in children from higher latitudes and might be covered by the impact of the ubiquitous solar radiation in the tropics. In conclusion, MN development seems to be closely related to the cumulative ultraviolet light exposure, whether it is mild or intense.
Sunburn is the most undesirable acute effect of intermittent-high dose ultraviolet light exposure. History of sunburns in childhood has been regarded as a significant risk factor for CM development in case-control studies with adults,44, 45, 46, 47, 48, 49 which might be due to the fact that these are best memorized indicators of sun exposure. The role of sunburns as risk factors for MN has been discussed controversially in literature. Sunburns were found to be associated significantly with the number of MN in children,10, 12, 13, 17, 29, 31, 39, 50 yet some studies could not demonstrate such an association.19, 28
In contrast to an earlier cross-sectional analysis,19 the present longitudinal multivariate analysis identified history and the extent and severity of sunburns as significant risk factors for the development of new MN. This might be explained by better control of confounders, better awareness of parents concerning sunburn and sun exposure, and hence more reliable data. The role of sunburns still remains somewhat unclear and contradictory results might be explained by different study populations, study designs and confounding. There is an evident and strong association of intermittent sun exposure and sunburn and both parameters might measure the same effect. In the light of our findings, sunburns seem to contribute to nevus development but seem not to be an obligatory precondition. Suberythemal doses of ultraviolet radiation seem to be capable for induction of nevus growth.
Comparison of children who were available for final assessment and children lost to follow-up showed that children prone to develop more MN were more likely to complete follow-up (unpublished data), i.e., children with fair skin, more nevi at baseline assessment and with parents with higher nevus counts on their arms. Children lost to follow-up had a tendency to be in the low risk group to develop many incident MN. This selection bias implies that the group of children included in our present analysis were more homogenous with respect to the risk factors mentioned above. It was less likely for risk factors to be significant in multiple linear regression analysis because the low risk group was less prominent. It is likely, therefore, that the study is underestimating the effect of some risk factors on the development of MN. We believe that the sample size of our present study allowed us to identify the major risk factors for MN. There might, however, be additional minor risk factors that did not reach the level of significance. Our present study is based on the difference of MN counts between 1998–2001 referred to as incidence of MN. Our study did not track individual MN and occurrence of complete regression of MN might have slightly influenced MN counts. During a digital dermoscopic follow-up study of almost 2,000 MN in 173 children from the same cohort only 18 MN showed complete regression (unpublished data). We suggest that this effect might play a minor role within our present study.
In conclusion, host factors, and parental as well as environmental risk factors associated with an increased risk of high numbers of MN have been confirmed by this large longitudinal study. Based on these risk factors, children at high risk for MN and potential subsequent CM development can be identified early and specific preventive measures can be provided. Cumulative sun exposure seems to be the crucial environmental risk factor whether the child is exposed to chronic-moderate or intermittent-high ultraviolet light doses. Public health education should focus on the message to avoid sun exposure in young children.
- 7Epidemiologic evidence for the role of melanocytic nevi as risk markers and direct precursors of cutaneous malignant melanoma. Results of a case control study in melanoma patients and nonmelanoma control subjects. J Am Acad Dermatol 1992; 26: 920–6., , , , , .
- 26Epidemiological studies of melanocytic naevi: protocol for identifying and recording naevi. IARC Internal Report 90/002. Lyon: IARC, 1990., , , , , .
- 45Associated 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: 700–5., , , , , , , , , .