Trend Shifts in Age-Specific Incidence for In Situ and Invasive Cutaneous Melanoma in Sweden

Simple Summary The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM by analysing data obtained from the Swedish Melanoma Register and the Swedish Cancer registry for 35,350 in situ tumours and 59,932 CM. Trend shifts in age-specific incidence for in situ and invasive CM reflect a rise among both sexes since the 2000s and could be a result of more effective secondary prevention efforts and a higher awareness of CM. Abstract Background: The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden. The aim was to present age- and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM. Methods: Joinpoint regression models were used to analyse data from the Swedish Cancer Register and the Swedish Melanoma Registry 1997–2018 (N = 35,350 in situ CM; 59,932 CM). Results: The AAPC of CM for women was 4.5 (4.1–5.0; p < 0.001) for the period 1997–2018. For men, the APCC was 4.2 (3.0–5.4; p < 0.001), with a significantly higher annual percentage change (APC) for the period 2000–2018 (5.0; 4.6–5.4; p < 0.001) compared to 1997–1999. An increasing annual incidence of CM ≤ 0.6 mm and 0.7 mm Breslow tumour thickness was found for men with a significant incidence shift for the period 2006–2015, respectively. Similarly for women, with a significantly higher APC for CM ≤ 0.6 mm from 2005. The incidence of intermediate thick CM (2.1–4.0 mm) has not increased since 2011. The incidence of CM > 4.0 mm has been increasing among both sexes, with a significantly lower APC among women from 2005. Conclusions: The incidence of in situ and low-risk CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s.


Introduction
The incidence of invasive cutaneous melanoma (CM) is increasing in Sweden as in the majority of the Western countries with fair-skinned populations, e.g., North America, Northern Europe, Australia and New Zealand [1,2]. The highest incidence rates world-wide have been reported from Australia and New Zealand [3,4]. In Australia, the age-standardised incidence rates in 2018 were 40.4/100,000 cases per year for men and 27.5/100,000 cases per year for women [1]. In all European countries, the incidence rates of CM have increased since the 1950s, with an estimated annual increase of 3-7% over the past decades [5,6]. The incidence rates within Europe vary between countries, with the highest incidence rates found in the western parts of Northern Europe, with incidence rates of 15.0-29.6/100,000 per year [1,[5][6][7]. Sweden, Norway and Denmark are the countries with the highest incidence for women in Europe, ranging from 26.2 to 33.1/100,000 per year; these rates are now in the same order of magnitude as those for women in Australia and New Zealand. The incidence rates for men in the same countries are not far behind, with incidence rates of 22.4 to 29.0/100,000 per year. The CM incidence is also increasing in the US population, with an age-standardised incidence rate of 14.9/100,000 per year for men and 11.0/100,000 per year for women [1].
Ultraviolet (UV) radiation is the main risk factor for CM, and an increased UV exposure has mainly contributed to the observed increase in CM incidence world-wide [8][9][10][11]. Different population-based prevention approaches have therefore been implemented to reduce skin cancer incidence. In Australia, the public education to increase the awareness of early CM began in Queensland as early as the 1960s, and these efforts were eventually expanded to include primary prevention through sun protection [10,[12][13][14]. In Australia, a recent stabilisation in invasive CM incidence has been observed, which is probably attributed to a decline in younger birth cohorts (4). However, in Europe, no declining incidence shift has been observed [7,[15][16][17][18]. Instead, the increase in incidence of both in situ and invasive CM is a considerable burden to public health, and the annual costs of CM management within health care are substantial [19][20][21]. These challenges of CM prevention and care emphasise the continued need for population-based epidemiologic surveillance.
In this report, we present age-and sex-specific trends of the age-standardised incidence and the average annual percentage change (AAPC) for in situ and invasive CM between 1997 and 2018 by using population-based registries: the Swedish Cancer Register (SCR) for in situ CM, and the Swedish Melanoma Registry (SweMR) for information on invasive CM.
The median age at diagnosis for in situ CM was 67 years (interquartile range (IQR): 55-76 years). This corresponded to 65 years for women and 69 years for men. The total number of cases for invasive CM registered between 1997 and 2018 was 59,932 (Table 1). Of these, the number of women and men were comparable (49.2% and 50.8%, respectively). The median age was 65 years at diagnosis (IQR 51-75 years). The median age for women was 62 years, and 67 years for men. The majority of the cases (n = 21,352; 35.6%) were T1a CM. T1b corresponded to 9450 (15.8%) cases. The overall median tumour thickness was 0.9 mm (IQR: 0.5-2.0 mm). The median tumour thickness for women was 0.8 mm (IQR: 0.5-1.7 mm), and 1.0 mm (IQR: 0.5-2.2 mm) for men.

Invasive Cutaneous Melanomas
For all patients, the average annual age-standardised incidence of invasive CM was 28.0/100,000 per year between 1997 and 2018, which corresponds to 26.5/100,000 per year among women and 30.7/100,000 per year among men (standardised by the Swedish population in the year 2000). In particular, the increase in CM incidence is higher in women >70 years compared to women <50 years ( Figure 1).

Invasive Cutaneous Melanomas
For all patients, the average annual age-standardised incidence of invasive CM was 28.0/100,000 per year between 1997 and 2018, which corresponds to 26.5/100,000 per year among women and 30.7/100,000 per year among men (standardised by the Swedish population in the year 2000). In particular, the increase in CM incidence is higher in women >70 years compared to women <50 years ( Figure 1).

In Situ Cutaneous Melanomas
Among men, in situ CM significantly increased during the whole study period, but was more prominent (an average annual percentage (APC) 2 of 12.8, 95% CI 11.9-13.7, p < 0.001) from the year 2002 (Table 2a).

Invasive Cutaneous Melanomas
The modelled data showed that the overall sex-specific annual age-standardised incidence of invasive CM fluctuated depending on the thickness group. The AAPC of the incidence of invasive CM for women was 4.5 (4.1-5.0; p < 0.001) for the total study period, 1997-2018 (Table 2a). For men, the APCC was 4.2 (3.0-5.4; p < 0.001), with a significantly higher annual percentage change for the period 2000-2018 (APC2) (5.0; 4.6-5.4; p < 0.001) compared to 1997-1999 (APC1) (Table 2a). An increasing annual incidence of CM with tumour thicknesses ≤0.6 mm and 0.7 mm was found for men, with a significant shift of incidence from 2006 and 2015, respectively (Table 2a, Figure 1b). A similar trend was shown for women, where CM with a thickness of ≤0.6 mm increased for the entire study period, but with a significantly higher APC from 2005. The incidence of 0.7 mm thick CM decreased between 1997 and 2003, but with a significant shift of an increasing incidence from 2003 in females (Table 2a, Figure 1b).         (Table 2a; Figure 1a). The incidence of CM > 4.0 mm increased among both sexes during the study period, but with a significant trend of a lower APC among women from the year 2005 (Table 2a, Figure S1).

Discussion
By using the population-based, high-coverage SweMR, we have pointed out specific age-and sex-specific trends in CM incidence in the Swedish population which may contribute to the implementation of new CM prevention strategies. The incidence of in situ and low-risk invasive CM ≤ 1.0 mm in tumour thickness has been rising among both sexes since the 2000s. Interestingly, this has appeared later among males compared to females, with a trend of an increased incidence of thinner CM towards men > 70 years. CM > 4.0 mm in tumour thickness with a high risk of recurrences and CM-related death still continue to increase among both sexes, but with a slightly lower increase among females. The results may indicate sex-specific differences of CM awareness and health care-seeking behaviour.
We show that the annual age-standardised incidence of both in situ and invasive CM continues to increase among both men and women in Sweden, which is in line with the incidence trends in almost all Caucasian populations world-wide [1,2,5,22,23]. For example, the highest age-standardised CM incidence rates within Europe for 2018 ranged from 15.3 to 33.1/100,000 per year [1,5,6,15]. Behavioural changes in lifestyle factors associated with an increased exposure to UV radiation during the decades from 1950 and later have probably contributed to the increase in CM incidence [5,8,9]. The sun protection campaigns have generally been less coordinated in Europe and in the US compared to the early national efforts in Australia and New Zealand [4,14,24]. The trend of increasing CM incidence world-wide evokes the question of whether there are additional risk factors other than UV radiation. An association between commonly used drugs and risk for CM has been reported [25][26][27]. Some medications have secondary immuno-modulating effects in mouse models and human cell lines, but the clinical impact has to be validated [28][29][30][31]. However, the incidence rates seem to stabilise or decrease among younger individuals in New Zealand and Australia, as well as in some parts of Europe, Canada and the US [3][4][5]32,33]. We found a similar trend for men aged below 50 years in Sweden. A possible explanation may be reduced sun exposure in younger individuals due to sun protection information, less outdoor work and reduced outdoor leisure activities [14,34,35].
Ongoing trends towards thinner (≤1.0 mm in tumour thickness) CM have been described in several countries with fair-skinned populations [3,16,17,33,36]. The increase in the annual incidence of in situ CM seems to follow the same pattern as for invasive tumours. Some of these reports have even shown that the annual incidence rate of in situ CM has been increasing more rapidly than that of invasive CM in Queensland, Australia; Denmark, the Netherlands; and the US [3,17,33].
Moreover, the increase in CM incidence in Sweden corresponds to the CM incidence among women in Australia, but the increase corresponds to thin low-risk CM with a good prognosis [1,37]. However, we also found that thick CM > 4.0 mm are still increasing among men and women, which shows that the increase in age-standardised CM incidence in Sweden is not only attributed to improved detection of low-risk tumours.
In a recent publication by H. Gilbert Welch et al. with the title The Rapid Rise in Cutaneous Melanoma Diagnoses [38], the authors pointed out that considerable disagreement still exists as to whether this increased incidence represents a true epidemic, or rather, an "epidemic of diagnosis". The authors stated that "The most important step to break the cycle of melanoma overdiagnosis is to stop population-wide screening for skin cancer". In Sweden, melanomas are mostly diagnosed in primary care by general practitioners. For dermatologic specialist care, a referral is mandatory, and screening is not reimbursed in the tax funded Swedish health care system. Screening for melanoma is basically absent in Sweden, besides targeted screening in high risk persons, e.g., members of melanoma-prone families and patients with a history of multiple melanomas. The recent trend of an increasing proportion of pre-invasive and early invasive CM could be explained by the more widespread use of dermatoscopy since the early 2000s in Sweden [39]. Dermatoscopy, with better diagnostic accuracy for CM than naked eye assessment, could have a populationwide impact by improving early detection and diagnosing thinner CM. The features of early melanomas can be very subtle clinically, therefore escaping detection until dermatoscopy is applied [40,41]. Pre-invasive and early invasive CM also tend to be histopathologically ambiguous and therefore more prone to both over and underdiagnosis, to an extent that is still not settled [42,43].
The main strengths of the present study include prospectively collected populationbased data from the high-coverage, national SweMR, with detailed clinico-pathological information on all invasive CM diagnosed in Sweden, making the results generalizable to other populations. The weaknesses include less detailed clinical information on in situ CM.
In conclusion, although we show an alarming increase in the annual age-standardised incidence of in situ and invasive CM in Sweden, we found that this largely corresponds to a trend of in situ and low-risk CM ≤ 1.0 mm in tumour thickness in both sexes since the 2000s.

Patients and Methods
The nationwide, population-based SweMR includes prospectively collected clinicopathological data on invasive CM in Sweden since 1990. The register was initiated by the multidisciplinary Swedish Melanoma Study Group, and has had a high coverage (99%) since 1996, as compared to the reference register, the SCR [44,45]. The SCR is maintained by the National Board of Health and Welfare, and reporting to this register is mandatory both for clinicians and for the diagnosing pathologists. The SCR includes invasive as well as in situ CM.
Initially, reporting to the SweMR was lower in some parts of Sweden between 1990 and 1996 [44]. This study therefore includes CM patients diagnosed from 1997 and onwards, to obtain high coverage national data. Between 1997 and 2018, 59,932 invasive CM were recorded in the SweMR. The corresponding number of in situ CM was 35,350 cases.
Data on in situ (Tis) CM were obtained from the SCR and included sex and age (<50, 50-70, >70 years).
The patients were classified according to the 8th edition of the American Joint Committee on Cancer (AJCC) 8 staging for invasive CM [46]. Information on clinico-pathological variables was assessed from the SweMR and included: sex, age (<50, 50-70, >70 years), Breslow tumour thickness (continuous), ulceration status (absent, present, missing infor-

Statistical Analysis
The statistical analysis was performed for men and women separately. All incidence rates per 100,000 inhabitants were calculated for each year of diagnosis and standardised by the Swedish population in the year 2000. Joinpoint regression models were used to evaluate whether temporal trends had statistically significant points of change, and to estimate the average annual percentage change (AAPC) with subdivisions of sex, age-groups and tumour thickness [47]. The time periods (tp) were autogenerated by the joinpoint analyses, and for each time period, the annual percentage change (APC(tp)) was calculated. For this purpose, we used the Joinpoint Regression Software developed by the Surveillance Research Program of the US National Cancer Institute [48,49]. The Joinpoint Regression Program used a permutation test to find the optimal number of joinpoints. The Program ran 4499 permutations to select the model with an overall significance level of 0.05. The analyses allowed a maximum of one joinpoint, and the maximum number of estimated APCs was consequently two. The statistical analyses were performed using SPSS version 27 software (IBM, Armonk, NY, USA) or R version 4.0.0. (R Core Team, Vienna, Austria). Missing data were handled by pairwise deletion.

Conclusions
In conclusion, although we show an alarming increase in the annual age-standardised incidence of in situ and invasive CM in Sweden, we found that this largely corresponds to a trend of in situ and low-risk CM ≤ 1.0 mm in tumour thickness in both sexes since the 2000s. These trends may be a result of more effective secondary prevention efforts, including an improved understanding and awareness of the disease both among clinicians and the public. Still, the incidence of high-risk CM continues to rise among both sexes. Prevention efforts such as coordinated and repeated national primary prevention campaigns are needed, including an improved understanding of putative novel risk factors and biomarkers in high-risk populations, and targeted towards specific subgroups (e.g., children/young adults) and high-risk individuals (e.g., older men).

Supplementary Materials:
The following are available online at https://www.mdpi.com/article/10 .3390/cancers13112838/s1, Figure S1. Trends in annual percentage change (APC) in age-standardized incidence rates for in situ and invasive cutaneous melanoma by tumour thickness and sex, in Sweden 1997-2018.