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Department of Dermatology, Erasmus MC University Medical Center, Rotterdam, The NetherlandsDepartment of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Limited data are available on the prevalence and risk factors of actinic keratoses (AKs). Within the Rotterdam Study, full-body skin examinations were performed among participants aged 45 years or older to estimate the age- and sex-standardized prevalence of AK and its associated risk factors. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for associations between risk factors and the presence of 1–3, 4–9, and ≥10 AKs. Of the 2,061 inspected cohort members (mean age 72 years), 21% had 1–3, 9% had 4–9, and 8% had ≥10 AKs. AK prevalence was 49% (95% CI: 46–52%) for men and 28% (26–31%) for women. Male gender, older age, light pigmentation status, severe baldness, skin wrinkling, and high tendency for sunburn were significantly associated with extensive actinic damage (≥10 AKs) in the multivariate analyses. Especially bald males were at an increased risk of severe actinic skin damage (adjusted OR=7.0 (3.8–13.1)). The prevalence of AK is very high, especially among elderly bald males. The prevention and management of AK is a true challenge for patients, physicians, and health-care policymakers.
Abbreviations
AK
actinic keratosis
BCC
basal cell carcinoma
CI
confidence interval
FBSE
full-body skin examination
OR
odds ratio
RS
Rotterdam Study
SCC
squamous cell carcinoma
Introduction
Actinic keratoses (AKs) are a common keratinocytic intra-epidermal neoplasia often occurring on chronically sun-exposed skin of Caucasian individuals (
). AKs are often diagnosed clinically (i.e., rough red scaly patches on chronically sun-exposed skin) without histological confirmation, and are therefore not recorded in pathology databases and cancer registries.
Population-based studies investigating AK prevalence and its associated risk factors (
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
) conclude that elderly subjects with European ancestry and high cumulative UV exposure have the highest risk of developing AKs. However, these studies are few and report prevalences of AK varying from 1.4 to 59.2%. These differences in prevalences could be due to the geographic variability in UV radiation levels (Australia >United States of America >Europe) and the differences between the studied populations (e.g., high-risk patients, pigmentation status and age restrictions). Moreover, skin examinations and AK count were not conducted uniformly in these studies (
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
Most national guidelines or consensus reports recommend the treatment of AK, for which a variety of modalities are available, and follow-up of these patients because of their invasive potential. Implementing these recommendations puts a further burden on general physicians and the dermatological care, which is already strained by the care of cutaneous malignancies (
For the first time in the Netherlands, the prevalence of AK and its associated risk factors were investigated in a population-based cohort study (i.e., Rotterdam Study (RS)) among 2,061 elderly participants.
Results
A total of 2,061 (99.9%) of 2,063 participants visiting the RS research facility between August 2010 and April 2012 agreed to undergo a full-body skin examination (FBSE). Hereof, 208 participants (10.1%) were from Rotterdam Study I (RS-I), 1,542 (74.8%) were from RS-II, and 311 (15.1%) were from RS-III. The majority of the participants were women (55.0%; Table 1). Mean age at the date of FBSE was 71.6 years (SD 7.1; ranging from 51 to 98 years).
Table 1Study characteristics of 2,061 participants of the RS with a full-body skin examination
Characteristic
Total study population (n=2,061)
No AK (%) (n=1,288)
1–3 AKs (%) (n=433)
4–9 AKs (%) (n=177)
≥10 AKs (%) (n=163)
Sex
Women
1,134 (55.0)
815 (63.3)
220 (50.8)
58 (32.8)
41 (25.2)
Men
927 (45.0)
473 (36.7)
213 (49.2)
119 (67.2)
122 (74.8)
Age at FBSE
Mean age in years (SD)
71.6 (7.1)
70.2 (7.2)
73.0 (6.4)
74.1 (6.5)
75.6 (6.2)
<70
874 (42.4)
638 (49.5)
156 (36.0)
50 (28.2)
30 (18.4)
70–79.99
947 (45.9)
532 (41.3)
219 (50.6)
98 (55.4)
98 (60.1)
=80
240 (11.6)
118 (9.2)
58 (13.4)
29 (16.4)
35 (21.5)
Pigmentation status (based on eye, hair, and skin color)
Low (primary education and primary education with a higher not completed education), medium (lower-level secondary education, lower-level vocational education intermediate-level vocational education), and high (general secondary education, higher-level vocational education and university).
1 Based on the Norwood–Hamilton scale for men and Ludwig scale for women.
2 Wearing sunglasses and/or a rimmed hat in the sunshine.
3 Low (primary education and primary education with a higher not completed education), medium (lower-level secondary education, lower-level vocational education intermediate-level vocational education), and high (general secondary education, higher-level vocational education and university).
Of 2,061 participants, 773 (37.5%) had at least one or more AK, of which 56.0% had 1–3 AK, followed by 4–9 (22.9%) and 10 or more (21.1%). Overall, the prevalence of one AK or more was 49.0% (95% confidence interval (CI): 45.8–52.2%) for men and 28.1% (25.5–30.7%) for women (Supplementary Table S1 online). AK prevalence increased with age in both men and women, but there was a small dip in the age category of 80–84 years compared with younger age groups in men and women (Supplementary Table S1 online and Figure 1).
Extrapolation to the Netherlands showed that 1,408,641 of the 5,985,164 Dutch citizens aged 50 years or older were affected by AK in 2011, of which 817,823 (58%) were men and 596,487 (42%) were women. This corresponds to an AK prevalence of 23.5% (95% CI: 21.7–25.3%) in the Dutch population aged 50 years or older; 28.8% (25.9–31.7%) for men; and 19.0% (16.7–21.2%) for women.
Location of AKs
The face was the location most commonly affected by 1–3 (42.5%) and 4–9 (33.4%) AK, whereas ≥10 (36.2%) AKs were more frequently located on the scalp (Supplementary Table S2 online). Stratification by sex showed that extensive actinic damage (≥10 AKs) was most often found on the scalp (47.5%) in bald men, whereas this was 0.0% in women (Supplementary Table S2 online).
Risk factors of AKs
In Supplementary Table S3 online, the results of the univariate multinomial logistic regression were shown. Medium baldness was associated with 4–9 (odds ratio (OR) 1.8 (95% CI: 1.2–2.8)) and ≥10 AKs (OR 2.1 (95% CI: 1.3–3.4)), whereas severe baldness was associated with all three outcome groups in a linear manner up to an OR of 13.9 (9.3–20.7) for ≥10 AKs compared with no or minimal hairloss. Nevi, outdoor work history, and educational level were not significantly associated with AK, whereas ever smoking was associated with 4–9 and ≥10 AKs (OR 2.0 (95% CI: 1.4–3.0) and OR 1.6 (95% CI: 1.1–2.4), respectively). All significant variables in the univariate, except smoking, remained significantly associated with AK in the multivariate multinomial model (Table 2). Severe baldness remained the strongest risk factor for ≥10 AKs (adjusted OR 6.3 (95% CI: 3.6–1.0); P-value for trend <0.001). After stratification by sex (data not shown), severe baldness remained significantly associated with ≥10 AKs in men (adjusted OR 7.0 (3.8–13.1)), but not in women (no OR could be calculated, as only 8 women had severe baldness). Male sex, the age of 70 years or older, Glogau 3 and 4, and the tendency to develop sunburn remained significantly associated with all three outcome groups. Light pigmentation status was associated with 1–3 (OR 2.3 (95% CI: 1.3–3.8)) and ≥10 AKs (OR 2.5 (95% CI: 1.1–5.7)), but not with 4–9 AKs. Use of sun-protective measurement was associated with ≥10 AKs (adjusted OR 2.0 (95% CI: 1.2–3.4)).
Table 2Multivariate multinomial logistic regression: risk factors associated with AKs among 2,061 participants of the RS
Low (primary education and primary education with a higher not completed education), medium (lower-level secondary education, lower-level vocational education intermediate-level vocational education), and high (general secondary education, higher-level vocational education, and university).
1 P-value based on multivariate ordinal logistic regression.
2 Based on the Norwood–Hamilton scale for men and Ludwig scale for women.
3 Wearing sunglasses and/or a rimmed hat in the sunshine.
4 Low (primary education and primary education with a higher not completed education), medium (lower-level secondary education, lower-level vocational education intermediate-level vocational education), and high (general secondary education, higher-level vocational education, and university).
The multivariate binary logistic regression was in line with the results of the multinomial model (Supplementary Table S4 online).
Skin cancer history and detection during FBSE
In total, 238 (11.5%) participants had a history of basal cell carcinoma (BCC), 51 (2.5%) had a history of SCC, and 20 (0.5%) had a history of melanoma. The risk of a history of one of these cutaneous malignancies increased across the AK severity strata (i.e., from none to ≥10 AKs). For BCC, SCC, and melanoma, these risks increased, respectively, from 7.2 to 26.5%, 1.2 to 13.6%, and 0.7 to 1.9% (Supplementary Figure S1 online). Although these risks increased gradually for BCC and melanoma, a sharper increase was seen for SCC. Participants with ≥10 AKs (13.6%) had a three-fold higher risk for having a SCC history compared with participants with 4–9 AKs (4.0%). Of the 2,061 participants who received a FBSE during our study period, it was histologically confirmed that 59 (2.9%) had a BCC, 11 (0.5%) had a SCC, and 9 (0.4%) had melanoma (including 5 invasive and 4 in situ). Overall, the detection rate of these cutaneous malignancies in our study population was 4.0% (82 out of 2,061 participants).
Discussion
In this Dutch population-based study, including more than 2,000 individuals with a mean age of 72 years who were examined by trained physicians, almost 38% had one or more AK and 8% had 10 or more (age- and sex-adjusted 23% and 5%, respectively). This AK prevalence is the highest in individuals aged 50 years or older when compared with previous European population-based studies and comparable to or less than studies from the USA and Australia (
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
In Europe, the South Wales Skin Cancer Study observed an AK prevalence of 23% (95% CI: 19.5–26.5), unadjusted for age and sex, among 1,034 persons aged 60 years or older. The lower prevalence may be explained by the fact that skin examinations were limited to the head and neck, lower arms (until shoulders), lower legs, and feet, and were performed by research registrars in dermatology. Recently, in the PRAKTIS study, a representative sample of 12,483 individuals of the Italian population aged >45 years were selected by a stratified random sampling design in which 1.4% of the individuals were affected by AK (
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
). In addition, the distribution of phenotypic characteristics of the Dutch (i.e., light skin, hair, and eyes) increase the risk for AK development when compared with the distribution in the Italian population with slightly darker skin, hair, and eyes. German studies using claims data estimated AK prevalences ranging from 2 to 31%, but these data were not population based and included dermatology patients (
), patients without history of skin cancer who were invited to undergo skin examination when visiting their practice-based physician, or healthy workers who could undergo a voluntary FBSE at their workplace (
), in which 101 dermatologists performed FBSE in more than 8,000 white participants aged between 25 and 74 years, observed a crude AK prevalence of around 17% (
). Two Australian studies from the eighties who screened 2,095 and 1,040 individuals randomly selected from sample state electoral roll demonstrated that 40–60% of the participants had at least one AK (
). In men, baldness was found to be the strongest risk factor for the presence of AK and severe actinic skin damage, probably because it continuously exposes the scalp in a horizontal plane to UV radiation, resulting in high cumulative UV doses. In clinical practice, these patients with large cutaneous fields affected by AK on the scalp are numerous and difficult to manage.
Although it remains controversial whether or not to actively treat AK (as not all will progress to SCC), individuals with multiple lesions (in this study defined as ≥10) are most likely to benefit from treatment and require a closer follow-up over time to prevent or detect the early development of SCC. Even this conservative approach is a health-care challenge, because it involves 5% of the Dutch 50-plus citizens (∼300,000 individuals), and this proportion is likely to increase over time. This is confirmed by a quick review of the claims data demonstrating that dermatologists reported twice as many AK-related visits and treatment between 2007 and 2011 (from 42,115 to 76,395), emphasizing the strain cutaneous (pre-)malignancies put on the health-care system (
The fact that FBSE was performed by a few trained physicians in more than 2,000 participants from a population-based study makes the Dutch point prevalence highly accurate. In general, AK have a typical presentation and are therefore clinically diagnosed by dermatologists and general practitioners. However, AK can resemble keratinocyte carcinoma (including BCC and SCC), possibly leading to misclassification and an underestimation or overestimation of AK in this study (
). Nevertheless, this possible non-differential misclassification is considered small, as trained physicians performed FBSE and previous studies observed a positive predictive value for AK diagnosis ranging from 74 to 94% (
). In this study, AK prevalence was determined cross-sectionally, and it was unknown whether participants were previously treated for AK, which also could have resulted in an underestimation of the Dutch AK prevalence. Unfortunately, the design of the study does not allow a longitudinal follow-up of individual AK to study its natural course. The individual number of AK lesions within a participant was not counted; instead, AK presence was divided into three categories (i.e., 1–3, 4–9,≥10). Although categorical data are less precise than continuous data, previous studies showed that the inter-observer variation between dermatologists was large when counting the individual number of AK lesions within a participant, and using categorized data greatly reduced this variation (
). The population of the RS is 45 years and older and almost exclusively Caucasian, possibly limiting the generalizibility of the findings. However, none of the participants aged below 55 years (n=50) had AK, and AKs are rare in individuals with darker skin, suggesting that the extent of this limitation is rather small. At the time of FBSE, only feet and areas covered by underwear were not examined, because of practical and psychological reasons. It is unlikely that this restriction resulted in an underestimation of the AK prevalence, because these areas are not chronically UV exposed.
Conclusions
Cutaneous (pre)maligancies are an enormous burden for health-care providers. Preventive measures including promoting sun-protective behavior and raising awareness on cutaneous keratinocyte carcinoma and persistent AK should focus in particular on elderly, bald men and those with photodamaged facial skin to reduce the number of SCC.
Materials and Methods
Study population
The RS is an ongoing prospective population-based cohort study that follows inhabitants of the Ommoord district of Rotterdam, the Netherlands since 1990. The study design and objectives of the RS have been described elsewhere (
In January 1990, the first cohort (RS-I) of 7,983 participants (78% of invitees) aged 55 years or older was established (Figure 2). In 2000, a second cohort (RS-II) was added to the RS, including 3,011 participants (67% of invitees) who had turned 55 years of age or had moved into the study district. The third cohort (RS-III) was established in 2006, in which 3,932 participants (65% of invitees) aged 45–54 years were added to the cohort. Participants of the present study were all above 50 years of age. The RS is approved by the Medical Ethics Committee of the Erasmus MC University Medical Center and The Netherlands Ministry of Health, Welfare and Sports. Our study was conducted in accordance with the Helsinki guidelines. All patients participating in the RS gave written informed consent.
Figure 2Flowchart of the Rotterdam Study (RS). FBSE, full-body skin examination.
In August 2010, dermatology was introduced in the RS (Figure 2). Since then, FBSE (with the exception of the feet and the skin covered by socks and underwear, respectively) are being conducted by four trained physicians focussing on the most common skin diseases such as skin (pre-)malignancies, atopic dermatitis, hand eczema, psoriasis, and varicose veins.
Actinic keratoses
An AK was diagnosed clinically and was defined as a rough (keratotic) lesion with adherent scaling and erythema, not fitting another diagnosis (
). As AK lesions are often confluent and located on sun-damaged skin, it is difficult to count the total number of individual lesions within a participant (
We counted the overall number of AK per participant and subdivided this into the number of AK per localization using the same categories: no presence of AK, 1–3, 4–9, or ≥10 AKs. The subdivision per anatomical localization consisted of the most important sun-exposed areas including scalp, face (excluding ears), ears, neck, back of hands, forearms, chest, or other localizations.
Risk factors
Sex and age (in years) at date of skin examination were registered. Educational level (classified into three categories: low (primary education and primary education with a higher not completed education), medium (lower-level secondary education, lower-level vocational education intermediate-level vocational education), and high (general secondary education, higher-level vocational education, and university)), smoking (never versus ever), hair color at young age (red, fair/blond, dark blond/brown, and black), and four questions assessing UV exposure were available from interview data. The questions on UV exposure included the tendency for sunburns, history of more than 25 years of outdoor work, having lived more than 1 year in a sunny country, and sun-protective behavior (i.e., wearing sunglasses and/or a rimmed hat in the sunshine). The first three UV items had binary responses, and the latter was categorized into never/almost never, often/not always, and always. Eye color (blue, intermediate, brown) was available from and scored by the ophthalmology department within the RS.
During FBSE, the following potential phenotypic risk factors for AK were scored: skin color (very white (3.4%), white (79.1%), white to olive (14.5%), light brown (1.7%), brown (1.1%), dark brown/ black (0.2%)), Glogau score (type 1 “no wrinkles”, type 2 “wrinkles in motion”, type 3 “wrinkles at rest”, and type 4 “only wrinkles”) (
) for women. In the analyses, baldness of the scalp was divided into none or minimal (Norwood–Hamilton score A, B, C, I, J, and Ludwig scale score 1), mild (Norwood–Hamilton score D,E,F,K, and Ludwig scale score 2), and extensive baldness (Norwood–Hamilton score G, H, L, and Ludwig scale score 3).
Because of significant correlation (phi-test for correlation, P<0.001) between the phenotypic characteristics, hair color at young age, eye color, and skin color, these three variables were combined into one variable “pigmentation status” and classified by light, medium, or dark pigmentation status.
Skin cancer history
All RS participants were linked to PALGA, the Dutch nationwide network and registry of histo- and cytopathology in the Netherlands, which contains excerpts of all pathology reports with nationwide coverage from 1991 onward (
Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive.
). An excerpt encloses encrypted patient data, a summary of the pathology report, and a diagnosis line based upon standard pathology terminology similar to the Systematized Nomenclamenture of Medicine issues by the College of American Pathologists. Individuals in the database have an encrypted patient identification code that enables linkage with all available pathology data within PALGA. The search in PALGA was based on codes corresponding to all types of BCC (
). Participants were counted only once per cutaneous malignancy (Figure 2).
Statistical analyses
The prevalence of AK within the 2,061 studied participants of the RS was standardized by age (5-year bands) and sex, and 95% CIs for proportion were calculated. The sex- and age-specific prevalences were multiplied by the sex- and age-specific population size in the Netherlands (5-year bands). Population size was obtained from Statistics Netherlands and estimated on the first of January 2011 (
). Extrapolated AK prevalence was calculated for the Dutch population aged 50 years or older.
To investigate risk factors associated with the development of AK, univariate and multivariate multinomial logistic regression analyses were performed and OR with 95% CI were calculated for each of the three outcome groups: 1–3, 4–9, and ≥10 AKs.
In addition, considering the ordinal structure of the latter outcome groups, an ordinal logistic regression was used to provide a cumulative OR. A significant cumulative OR corresponds to a statistically significant trend of increase in risk across the AK strata (
). A corresponding P-value for trend (based on the ordinal logistic regression) was calculated (Table 2). However, not all variables met the proportional odds assumption for this test and fitted therefore better in the multinomial logistic regression model.
To compare participants with extensive actinic damage (≥10 AKs) with those with no or less actinic damage (0–9 AKs), univariate and multivariate binary logistic regression analyses were used to calculate (adjusted) OR with 95% CI. All variables included in the univariate analyses were included in the multivariate analyses as possible confounders for AK risk. No significant interaction terms were observed. All statistical analyses were performed using SPSS for Windows version 17.0 (SPSS, Chicago, IL). P-values were two-sided and considered statistically significant if P-value was <0.05.
ACKNOWLEDGMENTS
The authors thank the participants of the Rotterdam Study for their participation, and the research physicians and assistants for the data collection. We thank Loes Hollestein for statistical assistance and Robert Stern for critically reviewing the manuscript. This work was supported by The Netherlands Organization for Health Research and Development (ZonMw), project number 152001013/ VIDI 91711315.
Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive.
Prevalence of actinic keratoses and associated factors in a representative sample of the Italian adult population: results from the prevalence of Actinic Keratoses Italian Study, 2003–2004.
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