Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma | Dermatology | JAMA Dermatology | JAMA Network
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Figure 1.  European Standardized Rate (ESR) and Joinpoint Analyses of Cutaneous Squamous Cell Carcinoma (cSCC) in the Netherlands for Male and Female Patients
European Standardized Rate (ESR) and Joinpoint Analyses of Cutaneous Squamous Cell Carcinoma (cSCC) in the Netherlands for Male and Female Patients

A, Main analysis: ESRs per 100 000 person-years for the period from 1989 to 2017 and joinpoint analyses with estimated annual percentage change (APC) for the period from 1989 to 2015, in dark blue for male patients and orange for female patients. The gray background for the period from 2012 to 2015 depicts a spurious flattening owing to nonregistration of patients with cSCC who were increasingly treated in private practices in this period. The light blue background for the years 2016 to 2017 emphasizes the optimized cSCC registration method. The dashed portions of the lines from 2015 to 2017 indicate that no trend analyses were conducted for this period. B, Revised analysis: ESRs per 100 000 person-years and estimated APCs for the period from 1989 to 2017, without the years 2013 to 2015, in dark blue for male patients and orange for female patients. This curve reflects the true burden of cSCC most accurately. aSignificant APC value.

Figure 2.  Distribution of Number of Patients With Single and Multiple Cutaneous Squamous Cell Carcinomas (cSCCs) in 2017
Distribution of Number of Patients With Single and Multiple Cutaneous Squamous Cell Carcinomas (cSCCs) in 2017

A, Patients with 1 or multiple cSCCs in 2017, including their sex and age distribution. B, Distribution of multiple cSCCs (2, 3, or ≥4) per patient in the same year. IQR indicates interquartile range.

Table 1.  Numbers and Age-Standardized Incidence Rates of First Cutaneous Squamous Cell Carcinoma in the Netherlands (1989-2017)
Numbers and Age-Standardized Incidence Rates of First Cutaneous Squamous Cell Carcinoma in the Netherlands (1989-2017)
Table 2.  Absolute Numbers, Crude Rates, and ESRs for First and Multiple cSCCs in 2017
Absolute Numbers, Crude Rates, and ESRs for First and Multiple cSCCs in 2017
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    Original Investigation
    October 28, 2020

    Incidence of Multiple vs First Cutaneous Squamous Cell Carcinoma on a Nationwide Scale and Estimation of Future Incidences of Cutaneous Squamous Cell Carcinoma

    Author Affiliations
    • 1Department of Dermatology, Erasmus Medical Center, Rotterdam, the Netherlands
    • 2Department of Research & Development, Netherlands Comprehensive Cancer Organization, Utrecht, the Netherlands
    JAMA Dermatol. 2020;156(12):1300-1306. doi:10.1001/jamadermatol.2020.3677
    Key Points

    Question  What are the trends in age-standardized incidence rates of cutaneous squamous cell carcinoma (cSCC) from 1989 to 2017 and the estimated trends up to 2027 in the Netherlands and how are these rates associated with the inclusion of multiple cSCCs per patient?

    Findings  This cohort study found that, between 1989 and 2017, age-standardized incidence rates of a first cSCC almost tripled for male patients and increased almost 5-fold for female patients; a further 10-year increase of 23% among male patients and 29% among female patients was estimated. Counting multiple cSCCs per patient additionally increased the cSCC burden by approximately 58% for men and 35% for women.

    Meaning  These findings call for revision of skin cancer health policies to cope with and subsequently halt the high increase in cSCC incidence.

    Abstract

    Importance  Until now, most studies on cutaneous squamous cell carcinoma (cSCC) incidence rates concerned only the first cSCC per patient. Given the increase in incidence rates and the frequent occurrence of subsequent cSCCs per patient, population-based data on the incidence rates of both first and multiple cSCCs are needed.

    Objectives  To calculate annual age-standardized incidence rates for histopathologically confirmed first and multiple cSCCs per patient and to estimate future cSCC incidence rates up to 2027.

    Design, Setting, and Participants  A nationwide population-based epidemiologic cohort study used cancer registry data on 145 618 patients with a first histopathologically confirmed cSCC diagnosed between January 1, 1989, and December 31, 2017, from the Netherlands Cancer Registry and all patients with multiple cSCCs diagnosed in 2017.

    Main Outcomes and Measures  Age-standardized incidence rates for cSCC—standardized to the European Standard Population 2013 and United States Standard Population 2000—were calculated per sex, age group, body site, and disease stage. A regression model with positive slope was fitted to estimate cSCC incidence rates up to 2027.

    Results  A total of 145 618 patients in the Dutch population (84 572 male patients [58.1%]; mean [SD] age, 74.5 [11.5] years) received a diagnosis of a first cSCC between 1989 and 2017. Based on incident data, European Standardized Rates (ESRs) increased substantially, with the highest increase found among female patients from 2002 to 2017, at 8.2% (95% CI, 7.6%-8.8%) per year. The ESRs for first cSCC per patient in 2017 were 107.6 per 100 000 person-years (PY) for male patients, an increase from 40.0 per 100 000 PY in 1989, and 68.7 per 100 000 PY for female patients, an increase from 13.9 per 100 000 PY in 1989, which corresponds with a US Standardized Rate of 71.4 per 100 000 PY in 2017 for men and 46.4 per 100 000 PY in 2017 for women. Considering multiple cSCCs per patient, ESRs increased by 58.4% for men (from 107.6 per 100 000 PY to 170.4 per 100 000 PY) and 34.8% for women (from 68.7 per 100 000 PY to 92.6 per 100 000 PY). Estimation of ESRs for the next decade show a further increase of 23.0% for male patients (ESR up to 132.4 per 100 000 PY [95% prediction interval, 125.8-139.0 per 100 000 PY]) and 29.4% for female patients (ESR up to 88.9 per 100 000 PY [95% prediction interval, 84.3-93.5 per 100 000 PY]).

    Conclusions and Relevance  This nationwide epidemiologic cohort study suggests that incidence rates of cSCC keep increasing, especially among female patients, and that the occurrence of multiple cSCCs per patient significantly adds to the current and future burden on dermatologic health care. Revision of skin cancer policies are needed to halt this increasing trend.

    Introduction

    Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer among white-skinned individuals and its incidence is still increasing.1,2 Several population-based studies across the world have illustrated this increasing trend, with the highest numbers reported in Australia3,4 and certain regions of the United States5 and slightly lower numbers in European countries.6-8 Given the high incidence rates of cSCC along with the associated costs and possibility of fatal progression, reliable and up-to-date data on cSCC epidemiologic characteristics are important to optimize patient care and to provide essential information for health care policy makers.9 Nonetheless, national cancer registries in many countries do not routinely record cSCC cases owing to its high incidence, consequently relying on incomplete data sources such as surveys, claims, or treatment data.1 Also, if cSCCs are registered, only the first tumor per patient is usually registered. However, because the occurrence of multiple cSCCs in a single patient is common, it is important to also evaluate the burden of multiple cSCCs per patient.10 Since 1989, the Netherlands Cancer Registry (NCR) records all histopathologically confirmed first cSCCs per patient in the Netherlands. In September 2016, the NCR began recording multiple cSCCs per patient, further approaching the true disease burden. The aims of this study were to investigate annual age-standardized incidence rates of the first primary cSCC in the Netherlands during a period of nearly 30 years (1989-2017), provide recent nationwide incidence data on multiple cSCCs per patient, and estimate future incidence rates of cSCC up to 2027.

    Methods
    Study Design, Setting, and Population

    Data on all patients with histopathologically confirmed cSCC between January 1, 1989, and December 31, 2017, were retrieved from the nationwide NCR.11 The NCR is based on notification of all histopathologically confirmed malignant neoplasms by the nationwide network and registry of histopathology and cytopathology (PALGA).12 Up to September 1, 2016, patients’ demographic characteristics and tumor characteristics were obtained manually from their medical files by trained NCR personnel. Cases of cSCC with only a general practitioner or pathologist as the treating medical specialist were excluded to warrant reliable trend analyses, owing to variation in registration rules over the years and between regional registries. As a result of the high incidence rates of skin cancer, the NCR replaced manual registration with an automatic linkage to PALGA since September 1, 2016. This change in registration method enabled reliable estimations by including cSCCs that were diagnosed by general practitioners, pathologists, or private clinics without further hospital referral. Moreover, multiple cSCCs per patient were registered since September 1, 2016. This study followed the code of conduct of the Foundation Federation of Dutch Medical Scientific Societies,13 which states that informed consent is not needed for studies in which all data are anonymized and not reducible to the patient level.

    All pathology reports with topography “skin” (C44) from the International Classification of Diseases for Oncology, third edition (ICD-O-3)14 with the following morphology codes were considered invasive cSCC: 8010/3, 8051/3, 8070/3-8076/3, 8078/3, 8081/3, 8083/3, and 8084/3. Anatomical subsite of the ICD-O-3 was categorized as follows: lips (code C44.0), eyelid (code C44.1), ear (code C44.2), face (code C44.3), scalp and neck (code C44.4), trunk (code C44.5), arms (code C44.6), legs (code C44.7), and unknown or overlapping (codes C44.8 and C44.9).

    Starting September 1, 2016, pathology reports with the following characteristics were considered a report of a new cSCC per patient: a different ICD-O-3 anatomical subsite than in the previous report, the same ICD-O-3 anatomical subsite as in the previous report but another lateralization than in the previous report, the same ICD-O-3 anatomical subsite and lateralization as in the previous report at least 3 months after the previous report. Pathology reports with the same ICD-O-3 anatomical subsite and lateralization as in the previous report within 3 months were counted as 1 cSCC.

    To study trends, the study period was divided into 6 periods (1989-1993, 1994-1998, 1999-2003, 2004-2008, 2009-2013, and 2014-2015). Given the change in registration method, the years 2016 and 2017 were evaluated separately. Age at cSCC diagnosis was divided into 3 categories (<70, 70-79, and ≥80 years) and stage (the TNM staging system) was evaluated postoperatively according to the then-current edition.15 When postoperative stage was unknown or surgery was not performed, the clinical TNM stage was used. Information on the historical Dutch population size was retrieved from Statistics Netherlands.16

    Statistical Analysis

    Annual crude and age-standardized incidence rates per 100 000 person-years (PY) were calculated using the population size (determined on January 1 each year) obtained from Statistics Netherlands. To calculate age-standardized incidence rates, the European Standard Population (ESP) 201317 and United States Standard Population (USSP) 200018 were used. The ESP and USSP are theoretical population structures resembling the European and US population structure, totaling 100 000, which is used in the weighting of incidence data to produce European Standardized Rates (ESRs) and US Standardized Rates (USSRs). Although crude rates could show biased values because of the population’s age distribution, the use of age-standardized incidence rates prevents this bias from occurring. For our main analyses, we used ESRs because the ESP resembles the Dutch population data best. European Standardized Rates were calculated according to sex, age group, body site, and disease stage. Age standardization to other standard populations than ESP and USSP was performed as well.

    To evaluate trends in incidence rates for cSCC over time, we calculated the estimated annual percentage change (EAPC) with corresponding 95% CIs using joinpoint regression analyses that identify periods with a statistically significant change in incidence rates.19 To prevent a spurious increasing trend as a result of the automatic linkage to PALGA since mid-2016, the joinpoint regression analyses were restricted to the years up to 2015 in our main analysis. For the years 2013 to 2015, a flawed trend was expected because skin cancers were increasingly treated in private practices during this period but no NCR registration of these tumors took place.20 Therefore, in a revised analysis, we omitted the years 2013 to 2015 and included the years 2016 and 2017 to perform a trend analysis most likely representing the true incidence rates.

    To estimate incidence rates of cSCC up to 2027, 2 models were fitted with a positive slope and 95% prediction intervals (PIs) were calculated.21,22 The fitted models were Ecit = niti + βit) and Ecit = nitαi(1 + βt), where nit is the number of PY in age group i and year t; αi, βi, and β are the model parameters; and Ecit is the expected number of cases in the corresponding stratum. The first model assumes linear changes for the incidence cit/nit over time t. The second model assumes proportionality of the slope (αiβ) to the intercept (αi) in the linear trend, hereby preserving the age-dependent pattern of incidence rates within the period of estimation. Consequently, age-specific estimations can be made with greater precision. The second model showed the best fit and was used for our cSCC estimations.

    All analyses were stratified by sex. All tests were 2-sided with P < .05 considered statistically significant. Statistical analyses were performed using SPSS, version 25.0 statistical software (SPSS Inc); STATA, version 14 with the predaaap macro (StataCorp); and Joinpoint Regression Program, version 4.7.0.0 (IMS Inc).19

    Results
    Incidence of First cSCC per Patient

    From 1989 through 2017, 145 618 patients in the Dutch population received a diagnosis of a first cSCC. Of these, 84 572 were male (58.1%), with an overall mean (SD) age of 74.5 [11.5] years. The age-standardized incidence rates of male patients with a first cSCC almost tripled during the 29-year study period (ESR, 40.0 per 100 000 PY in 1989 and 107.6 per 100 000 PY in 2017; USSR, 26.5 per 100 000 PY in 1989 and 71.4 per 100 000 PY in 2017). For female patients, the age-standardized incidence rates increased almost 5-fold (ESR, 13.9 per 100 000 PY in 1989 and 68.7 per 100 000 PY in 2017; USSR, 9.3 per 100 000 PY in 1989 and 46.4 per 100 000 PY in 2017).

    The ESRs and USSRs for cSCC per period of diagnosis and age group are shown in Table 1. The ESRs stratified per body site and stage are shown in eTable 1 in the Supplement and the age-standardized incidence rates for each year separately, including age standardizations to other standard populations, are included in eTable 2 in the Supplement.

    Stratified per age group, patients 80 years or older showed the highest age-standardized incidence rates for both sexes with an ESR as high as 974.9 per 100 000 PY for male patients (USSR, 951.6 per 100 000 PY) and 492.9 per 100 000 PY for female patients (USSR, 486.2 per 100 000 PY) in 2017 (Table 1). The face was the site with the most cSCCs in both male (30 473 of 84 572 [36.0%]) and female patients (27 357 of 61 046 [44.8%]), and two-thirds of all cSCCs were diagnosed in stage I (male patients, 56 450 of 84 572 [66.7%]; female patients, 40 821 of 61 046 [66.9%]) (eTable 1 in the Supplement).

    Prominent sex-specific differences were found regarding body site of cSCCs. Although the face showed the highest ESRs for both male and female patients, the ears and scalp and neck were much less affected in female patients than in male patients (eTable 1 in the Supplement). The ESR of cSCCs located on the ears was the second-highest affected location up to 2006 for male patients; after 2006, the scalp and neck region was the second-highest affected location (eFigure 1 in the Supplement). For female patients, the arms showed the second-highest ESRs instead.

    Time Trends for cSCC Incidence

    Joinpoint regression analyses with EAPCs for the years preceding the change in registration method (1989-2015) are shown in Figure 1A. Significant increases in cSCC incidence were found in the first 2 time periods for both sexes: the ESR of cSCC for male patients increased by 1.3% (95% CI, 1.0%-1.7%) between 1989 and 2003 and increased by 6.5% (95% CI, 5.4%-7.6%) between 2003 and 2011. Incidence rates in males were higher than incidence rates in females, but the EAPCs in females showed slightly greater slopes: 2.9% (95% CI, 2.3%-3.5%) between 1989 and 2002 and 8.2% (95% CI, 7.0%-9.5%) between 2002 and 2011. Although the years 2013 to 2015 showed a flattening inclination in ESRs, this observed trend did not reach significance. Our revised analysis showed almost equal EAPC values as in our main analysis. However, the increasing trend now prolonged from 2002 to 2017, with an EAPC of 5.7% (95% CI, 5.2%-6.1%) for male patients and 8.2% (95% CI, 7.6%-8.8%) for female patients, was revealed (Figure 1B).

    Multiple cSCCs per Patient in 2017

    Analysis of the total number of cSCCs in 2017 resulted in 19 359 cSCCs in 17 512 patients. Two-thirds of all patients had a single cSCC in 2017 (11 943 [68.2%]), and one-third of all patients (5569 [31.8%]) had multiple cSCCs in 2017. Most patients with multiple cSCCs (n = 5089) already had 1 or more cSCCs diagnosed before 2017, and 8.6% (n = 480) developed both their first and subsequent tumors in 2017 (Figure 2A). Figure 2B shows the distribution of the number of cSCCs (2, 3, and ≥4) among patients in 2017 with multiple cSCCs. This is the distribution of cSCCs in 1 calendar year in the NCR and not the total distribution of multiple cSCCs per patient. Location-specific distributions of cSCCs between the first and subsequent cSCCs were comparable (eFigure 2 in the Supplement).

    Table 2 shows the outcome of including multiple cSCCs per patient in 2017 compared with including only the first cSCC. When only the first cSCC per patient is considered, 31.1% of all cSCCs in that year (6013 of 19 359) are being disregarded. This means that almost one-third of the overall burden of cSCCs in 2017 was caused by subsequent cSCCs per patient. In terms of ESRs, this corresponds with an increase of 58.4% for male patients (from 107.6 to 170.4 per 100 000 PY) and an increase of 34.8% for female patients (from 68.7 to 92.6 per 100 000 PY).

    Estimation of Future cSCC Incidence Rates

    Based on the incidence rates of a first cSCC between 2008 and 2017, analyses resulted in an expected number of 12 273 newly diagnosed male patients with cSCC (95% PI, 11 682-12 864) and 9780 newly diagnosed female patients with cSCC (95% PI, 9269-10 289) in 2027. Compared with the incidence of a first cSCC in 2017 (male patients, 7261; and female patients, 6085 [Table 2]), this estimate corresponds with a 69.0% increase in the number of male patients and 60.7% increase in the number of female patients. The estimated ESRs for 2027 are 132.4 per 100 000 PY (95% PI, 125.8-139.0 per 100 000 PY) for male patients and 88.9 per 100 000 PY (95% PI, 84.3-93.5 per 100 000 PY) for female patients, equivalent to an increase of 23.0% in ESRs among male patients and a 29.4% increase in ESRs among female patients between 2017 and 2027.

    Discussion

    In this nationwide population-based study with nearly 150 000 patients with cSCC, the incidence rates of cSCC increased for both sexes and in all age groups, with the highest increase during the period from 2002 to 2017. Although male patients showed the highest overall incidence rates of cSCC, the mean annual increase in incidence was markedly higher for female patients of all age groups, irrespective of body site. Data on multiple cSCCs in 2017 showed that incidence rates increased by approximately 58% for men and 35% for women when subsequent tumors per patient were included, which has been an underexposed group until now in most cSCC studies worldwide. Given the even higher estimated incidence rates for 2027 and presence of multiple tumors per patient, a better understanding of epidemiologic characteristics of cSCC is important for all stakeholders (eg, physicians and health care policy makers) to cope with the high volume of patients with cSCC.

    We found the highest ESRs for cSCCs located on the face and scalp and neck of male patients and on the face and arms of female patients, which is in line with findings of previous studies.7,8,23,24 The male-specific locations mainly reflect the UV light–damaged skin owing to a history of outdoor work and a short haircut or baldness. Patients with a cSCC on one of these most common locations were also the patients with more subsequent cSCCs, again suggesting the relevance of high cumulative UV light exposure. The fact that body sites that are generally covered, such as the trunk and legs, showed the highest location-specific increases in ESR over time in both sexes is most likely associated with changed tanning habits.7,25 Because male patients already had the highest cSCC incidence rates, the relative association of augmentened outdoor recreational activities with cSCC incidence might have been larger for female patients, explaining the steeper increase in cSCC incidence for female patients as found for the recent years.

    The age-standardized incidence rates in our population are among the highest in Europe1,7,8 except for the United Kingdom.23 Higher age-standardized incidence rates of cSCC have been found in Australia,3,4,26 New Zealand,27 Scotland,28 and the United States.5 Besides variances in exposure to risk factors (eg, differences in latitude and climate, skin type and genetic predisposition, sunbed usage, outdoor activities, and clothing style), dissimilarities in keratinocyte carcinoma registration procedures, accustomed health-seeking behavior, and access to health care might explain the differences in cSCC incidence across countries. Regarding trends over time, the EAPCs found in the Netherlands were almost equal to the EAPCs in Belgium29 and higher compared with Denmark,30 Sweden,31 and Norway8 in the same study periods.

    Our analyses showed that the age-standardized incidence rates of cSCC will continue to increase, which will have major implications on health care planning and cost management and hopefully stimulate further prevention strategies. We also showed that 30% of all cSCCs in a year are missed when only the first cSCC per patient is registered and all subsequent cSCCs are disregarded. This finding corresponds with the underrepresentation of 30% to 50% as found in studies from Australia26 and New Zealand,27 emphasizing that the true burden caused by cSCCs is much higher than shown in most studies considering only the incidence of first cSCC per patient.

    Limitations

    This study has some limitations. Despite the nationwide population-based setting of our study, as well as the highly advanced registration system of the NCR, we may still have underestimated the cSCC incidence rates, as patients treated by general practitioners or private practices without further hospital referral were not registered until 2016. Furthermore, cSCCs diagnosed on the same body site within 3 months’ time were considered recurrences and therefore were not counted as new tumors, which may have caused an underestimation of the true number of cSCCs per patient as shown for 2017. However, recurrences could have occurred after the 3-month window as well, meaning that the reported number of subsequent primary cSCCs for 2017 could have comprised recurrent cSCCs. Also, while recurrences were not counted as new tumors, in reality they add to the burden of skin cancer care, which is therefore even higher than we presented. Another downside of the automatic linkage system was that the recording of tumor stages decreased significantly because no manual check of medical records was being performed since September 2016, leading to high proportions of unknown tumor stages since 2016. Hence, we obtained more truthful incidence rates but could not assess an association with each tumor stage. Moreover, only histopathologically confirmed cSCCs were registered, missing a proportion of patients who were treated without histologic confirmation or who did not seek any medical care. However, because the cSCC guideline from the Dutch Society for Dermatology and Venereology states that all removed cSCCs should follow histopathologic examination, we expect the proportion of nonhistologically confirmed cSCCs to be rather small.32 Last, the underestimation of ESRs was mainly apparent from 2013 to 2015, when skin cancers were increasingly treated in private practices with no NCR registration thereof.20 To account for this spurious fluctuation, we performed a revised regression analysis that reflected the real incidence trend in the population as close to reality as possible.

    Conclusions

    Both the current and estimated incidence rates up to 2027 show a high and still increasing trend for cSCC incidence. Compared with all other cancers, the cSCC incidence rates are highest and keep increasing, while the incidence rates of almost all other malignant neoplasms in the Netherlands have flattened.33 We therefore emphasize the importance and value of complete nationwide cSCC registries with the same quality as for other invasive malignant neoplasms. Considering the even higher burden on dermatologic care when multiple cSCC data are included, our results call for revision of skin cancer health policies to be able to cope with the rising burden of keratinocyte carcinoma management. Full attention is needed to identify high-risk cSCCs or patients at risk for multiple cSCCs to establish efficient follow-up regimens.34 Ultimately, primary prevention will remain the key strategy to halt the increasing trend in cSCC incidence and the occurrence of multiple cSCCs per patient.

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    Article Information

    Accepted for Publication: July 30, 2020.

    Corresponding Author: Marlies Wakkee, MD, PhD, Department of Dermatology, Erasmus Medical Center, PO Box 2040, 3000 CA, the Netherlands (m.wakkee@erasmusmc.nl).

    Published Online: October 28, 2020. doi:10.1001/jamadermatol.2020.3677

    Author Contributions: Ms Tokez 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.

    Concept and design: Tokez, Hollestein, Nijsten, Wakkee.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Tokez, Wakkee.

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

    Statistical analysis: Tokez, Hollestein, Louwman.

    Obtained funding: Nijsten.

    Supervision: Hollestein, Louwman, Nijsten, Wakkee.

    Conflict of Interest Disclosures: Dr Wakkee reported receiving personal fees for consulting from Sanofi-Aventis. No other disclosures were reported.

    Additional Contributions: We thank the registration and analysis team of the Netherlands Comprehensive Cancer Organization (IKNL) for the collection of data and support with analyses of data for the Netherlands Cancer Registry. Jeffrey Damman, MD, Department of Pathology, Erasmus MC and PALGA, selected the morphology codes and provided additional information on tumor localization. Marianne van der Mark, PhD, Department of Research & Development, IKNL, performed the prediction analyses for cSCC incidence rates due to her vast experience in prediction analyses using data from IKNL. These analyses were performed in consultation with Ms Tokez. Damman and van der Mark were not compensated for their contributions.

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