European Journal of Cancer 152 (2021) 18e25

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Original Research

Epidemiology of cutaneous melanoma and keratinocyte

cancer in white populations 1943e2036

Claus Garbe a,*,1, Ulrike Keim a,1, Sara Gandini b, Teresa Amaral a,c,
Alexander Katalinic d, Bernd Hollezcek e, Peter Martus f, Lukas Flatz a,
Ulrike Leiter a, David Whiteman g,h

a
Center for Dermatooncology, Department of Dermatology, Eberhard Karls University, Tuebingen, Germany
b
Department of Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy
c
Portuguese Air Force Health Care Direction, Lisbon, Portugal
d
Institute for Social Medicine and Epidemiology, Luebeck, Germany
e
Saarland Cancer Registry, Saarbruecken, Germany
f
Institute for Clinical Epidemiology and Applied Biostatistics, Eberhard Karls University, Tuebingen, Germany
g
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia
h
The University of Queensland, School of Public Health, Herston Road, Herston, QLD 4006, Australia

Received 3 February 2021; received in revised form 1 April 2021; accepted 20 April 2021

KEYWORDS Abstract Objectives: Cutaneous melanoma (CM) and keratinocyte cancer (KC) cause
Melanoma; considerable morbidity and mortality. We analysed long-term trends of CM and KC in
Keratinocyte cancer; different white populations.
Incidence; Material and methods: Age-standardised (European Standard Population 2013) incidence and
Mortality; mortality rates (ASIR, ASMR) of CM were extracted from cancer registries in Denmark, New
White-skinned Zealand and the US SEER-Database. ASIRs of KC were sourced from registries of the
population; German federal states Saarland and SchleswigeHolstein, and from Scotland. Age-period-
Denmark; cohort models were used to project melanoma incidence trends.
Germany; Results: In Denmark between 1943 and 2016, melanoma ASIR increased from 1.1 to 46.5 in
New Zealand; males, and from 1.0 to 48.5 in females, estimated to reach 60.0 and 73.1 in males and females
Scotland; by 2036. Melanoma mortality in Denmark (1951e2016) increased from 1.4 to 6.7 (males) and
United States of 1.2 to 3.7 (females). In New Zealand between 1948 and 2016, ASIR increased from 2.7 to 81.0
America (males) and from 3.8 to 54.7 (females), slight declines are estimated by 2036 for both genders.
Melanoma mortality increased six-fold in New Zealand males between 1950 and 2016; smaller
increases were observed in females. We observed three- to four-fold increases in melanoma

* Corresponding author: Division of Dermatooncology, Dept. of Dermatology, Eberhard Karls University of Tuebingen, Liebermeisterstr. 25,
72076 Tuebingen, Germany. Fax: þ49 7071 29 51 87
E-mail address: claus.garbe@med.uni-tuebingen.de (C. Garbe).
1
CG and UK contributed equally.

https://doi.org/10.1016/j.ejca.2021.04.029
0959-8049/ª 2021 Published by Elsevier Ltd.
 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25 19

incidence in US whites, predicted to rise to 56.1 and 36.2 in males and females until 2036. Mel-
anoma mortality also increased among US whites between 1970 and 2017, female melanoma
mortality remained stable. Similar trends are shown for KC.
Conclusions: In white populations, incidence of CM and KC significantly increased. CM inci-
dence continues to rise in the short term but is predicted to decline in future.
ª 2021 Published by Elsevier Ltd.

1. Introduction SchleswigeHolstein, and from Scotland. No KC regis-

try data were available from America or Oceania.
High incidence rates of cutaneous melanoma (CM) and
keratinocyte cancer (KC) are reported predominately 2. Material and Methods
from white populations, susceptible to damaging effect
of UV radiation, the main cause of skin cancer [1]. They 2.1. Cancer registry and population data
rarely occur in dark-skinned populations, e. g. Africans
or Asian, who are protected against UV radiation by
Data on incident cases and deaths of CM (ICD-10: C43)
their pigment [2]. In the period after the Second World
and KC (ICD-10: C44) were retrieved from population-
War, white populations, especially in Western countries,
based cancers registries in the United States, New Zea-
experienced a sharp increase in the incidence rates of
land and from the European countries, Denmark, Ger-
CM and KC [3,4]. First cancer registration, including
many and Scotland. Historical and forecast population
melanoma began in Connecticut, Denmark and New
sizes and age structure were obtained from the statistics
Zealand, where incidence data were reported since 1935,
agencies of each nation.
1943 and 1948, respectively. This allows analysis of
Melanoma incidence (1943e2016) and mortality
incidence trends over more than seven decades [5,6].
(1951e2016) data for Denmark were sourced from the
Before 1950, melanoma incidence rates were also very
NORDCAN database, which records cancer data for
low (<5 cases per 100,000 person-years) in white pop-
each of the Nordic countries for more than five decades
ulations [5,6] and showed a tremendous increase after
[12]. Historical (1980e2016) and projected (2017e2036)
the Second World War. In some high-risk countries,
population data were obtained from the Statistics
such as Scandinavia or New Zealand, the incidence rates
Denmark [13].
have increased by a factor of 30e40 over a period of 70
For New Zealand, melanoma incidence (1948e2016)
years. The annual increase varied between different
and mortality data (1950e2016) were obtained from the
populations but has been estimated to be 3e7% [7,8].
New Zealand Cancer Registry [14]. Population estimates
Incidence data for KC are scarce. Studies, that have
and projections were retrieved from Statistics New
attempted to estimate the burden of KC, have observed
Zealand [15].
similar trends to melanoma with steeply increasing
Melanoma data for US whites were sourced from the
incidence rates [9]. In cancer registries, KC is recorded
SEER Program. Incidence data (1975e2016) were
as non-melanoma skin cancer (NMSC), and this defi-
extracted from the SEER 9 database, comprising 9
nition includes rare adnexal tumours, Merkel cell car-
registries, which together represent about 9.4% of the
cinomas, cutaneous sarcomas, and lymphomas in
total US population [16]. The population structure for
addition to basal cell carcinomas and squamous cell
the SEER 9 white population largely resembles that of
carcinomas [10]. However, the proportion of these rare
all US whites. Thus, 9.4% of each age and sex category
tumours besides KC is less than one percent and is
of the total population, sourced from the US Census
insignificant to the increase in incidence of this cancer
Bureau, was used as estimates for the population pro-
entity [11]. Unlike for incidence, however, rare tumours
jections [17]. CM mortality data (1970e2017) were
such as Merkel cell carcinoma play a greater role for
available for the total US Population [16].
mortality. Throughout the manuscript, the term KC is
Incidence data on KC for Germany were obtained
used instead of NMSC.
from two epidemiological cancer registries. The Saar-
The aim of the present study was to analyse long-
land Cancer Registry records KC incidence data be-
term trends in incidence and mortality rates of CM and
tween 1970 and 2017, the Cancer Registry in
KC using data from long-standing cancer registries with
SchleswigeHolstein covers the period 1999e2016
historical data. For CM, we examined data from regis-
[18,19]. Data on KC for Scotland (1992e2017) were
tries covering the populations of Denmark, New Zea-
extracted from the Scottish Cancer Registry, which
land and the US. For KC, we used registry data from
provides separate data for basal cell carcinoma (BCC)
the German federal states Saarland and
and squamous cell carcinoma (SCC) [20].
20 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25
Incidence rates and mortality rates were age stand-
ardised using the New European Standard Population
from 2013 and are expressed as number per 100,000
person-years (p.a.), stratified by sex [21].
2.2. Analyses of incidence trends
The average annual percentage of change (AAPC) in
observed incidence and mortality rates was calculated
using the Joinpoint Regression Program (version
4.8.0.1, National Cancer Institute, Bethesda, MD, USA)
[22]. Modified age-period-cohort models with a power-
link function were used to predict melanoma incidence
rates for four 5-year periods (2017e2021 to 2032e2036).
Details of the regression model have previously been
described [23]. Briefly, the calculations were based on
observed melanoma cases (last year of observation
2016), on population data covering the same period, and
on population forecasts for 2017e2036. Incident cancer
cases were aggregated into 5-year periods and 5-year age
groups (0e4, to 85þ), and stratified by sex. The number
of observation periods used in the prediction base was
determined by a goodness-of-fit test (5% level). The
linear trend parameter was gradually reduced by 25%,
50% and 75% in the second (2022e2026), third
(2027e20/31) and fourth (2032e2036) prediction
period, accounting for the attenuating impact of current
trends in future times. Analyses were carried out with
NORDPRED, a statistical software package in R [24].
3. Results
3.1. Melanoma incidence trends
In Denmark, ASIRs for men rose from 1.1 in 1943 to
46.5 in 2016 and from 1.0 to 48.5 for women, corre-
sponding to an average annual percentage change of
4.8% for both sexes (Fig. 1A). For men, projected inci-
dence rates peaked between 2027 and 2031 (60.4), and
then stabilised. Incidence rates for women are expected
to rise to 73.1 by 2032e2036 (Fig. 1B).
In New Zealand, ASIRs increased at around 4.2%
p.a. for women, climbing from 3.8 in 1948 to 54.7 in
2016 and at around 5.2% p.a. for men, climbing from 2.7
to 81.0 (Fig. 1C). In 1995, the incidence curve shows a
sharp increase with a subsequent decrease in 1996 and
1997. Then, for both women and men, the curve shows a
flattening. Since 1994 new regulations codified the
manner in which reports were made to the NZ Cancer
Registry. Many historic diagnoses were reported to the
newly organised registry, which had the effect of
showing large increases in all cancers for a couple of
years (1995e1996). These are widely regarded as arte-
facts following implementation of the new legislation.
By 2032e2036 rates are projected to fall to 60.4 for men
and to 42.7 for women (Fig. 1D).
In the US, we observed three- to four-fold increases
in melanoma incidence rates. The SEER data showed an
increase in the ASIRs from 11.3 in 1975 to 54.7 in 2016
for men (AAPC Z 4.0%) and from 9.5 to 32.8 for
women (AAPC Z 3.1%) (Fig. 1E). For the next 10e15
years, ASIRs will rise for males to 59.1 and for females
to 36.6. Signs of stabilisation (females: 36.2) or a decline
(males: 56.1) is to be expected in later years for both
sexes (Fig. 1F).
3.2. Melanoma mortality trends
Melanoma mortality rates increased by 1e3% p.a. in all
populations. In Denmark, ASMRs rose from 1.4 in 1951
to 6.7 in 2016 for men and from 1.2 to 3.7 for women
(Fig. 2A). In New Zealand, ASMRs increased from 2.2
in 1950 to 15.1 in 2016 for men and from 1.4 to 6.0 for
women (Fig. 2B). In the US, ASMRs for men increased
from 3.1 in 1970 to 6.7 in 2009; and then declined to 5.1
cases in 2017. ASMRs for women remained largely the
same (around 2.1 cases) (Fig. 2C).
3.3. KC incidence trends
Stronger increases (2e6% p.a.) were found for KC. In
the German federal state of Saarland ASIRs rose from
18.6 in 1970 to 174.1 in 2017 (AAPC Z 5.5%) for men
and from 17.0 to 147.8 for women
(AAPC Z 5.7%) (Fig. 3A). In SchleswigeHolstein,
ASIRs increased from 204.2 in 1999 to 391.4 in 2016 for
men (AAPC Z 2.6%) and from 137.2 to 262.9 for
women (AAPC Z 3.8%) (Fig. 3B). In 2015 and 2016,
there was a sharp increase in the incidence of KC,
resulting in the highest values of 391 for men and of 262
for women. The possible reason for this development
might be the implementation of a new cancer registry
law in 2015.
In Scotland, both entities have shown rising incidence
rates, with stronger increases for SCC
(AAPC Z 3.1e4.0%) than for BCC
(AAPC Z 1.8e2.4%). For the period 1992 to 2017, the
ASIRs of SCC increased from 44.5 to 107.2 in men and
from 17.2 to 34.8 in women. The ASIRs of BCC
increased from 103.2 to 178.3 in men and from 78.1 to
122.7 in women (Fig. 3C).
3.4. KC mortality trends
In Germany, ASMRs for KC first decreased and then
stabilised in the last two decades. In the German federal
state of Saarland, ASMRs dropped from 2.4 in
1972e1976 to 1.3 in 2012e2016 for men and from 1.1 to
0.5 for women. In SchleswigeHolstein, ASMRs
remained nearly stable with 0.53 for 1999e2003 and
0.62 for 2012e2016 for men and with 0.15 and 0.4 for
women.
 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25 21

Fig. 1. Observed and predicted incidence rates and annual percentage change of melanoma in Denmark, New Zealand and the US (SEER 9).
(A) Age-standardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in Denmark 1943e2016. (B) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in Denmark, projected until 2036. (C) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in New Zealand 1948e2016. (D) Age-stand-
ardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in New Zealand, projected until 2036. (E) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in the US (SEER 9) 1975e2016. (F) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) incidence rates of melanoma in the US (SEER 9), projected until 2036.

4. Discussion in CM in all three populations over time, ranging be-

This study examined incidence trends for CM in the
Danish cancer registry over 73 years, in the New Zea-
land cancer registry over 68 years and in the US SEER
database over 41 years. We found substantial increases
tween 3 and 5% p.a. for both sexes. In Denmark and
New Zealand with data from the middle decades of the
20th century CM incidence was very low (<5/100,000
p.a.). By the 1970s, CM incidence had climbed to about
10/100,000 p.a. in Denmark and the US, and in New
22 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25
Fig. 2. Observed mortality rates and annual percentage change of
melanoma in Denmark, New Zealand and the US (SEER 9). (A)
Age-standardised (EU-27 þ EFTA Standard Population, 2013)
mortality rates of melanoma in Denmark 1951e2016. (B) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) mor-
tality rates of melanoma in New Zealand 1950e2016. (C) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) mor-
tality rates of melanoma in the US 1970e2017.
Zealand to about 20/100,000 p.a. By the start of the new
millennium, in all three populations, CM incidence had
basically doubled (women) or even tripled (men). In
subsequent decades rates have continued to rise. It is
striking that in the USA and New Zealand significantly
higher incidence rates are found in males than in fe-
males, whereas in Europe rather a reverse trend is
evident. Olsen et al. describe in a comparative analysis
that total melanoma incidence in Caucasians was higher
in men than women in US individuals, Canada,
Australia, and New Zealand, but not in Denmark, the
Fig. 3. Observed incidence rates and annual percentage change of
keratinocyte skin cancer in the Federal States of Saarland/Ger-
many, SchleswigeHolstein/Germany and Scotland. (A) Age-
standardised (EU-27 þ EFTA Standard Population, 2013) inci-
dence rates of keratinocyte skin cancer in the Federal State of
Saarland (Germany) 1970e2017. (B) Age-standardised (EU-
27 þ EFTA Standard Population, 2013) incidence rates of kera-
tinocyte skin cancer in the Federal State of SchleswigeHolstein
(Germany) 1999e2016. (C) Age-standardised (EU-27 þ EFTA
Standard Population, 2013) incidence rates of keratinocyte skin
cancer (separated for BCC and SCC) in Scotland 1992e2017.
UK, Norway and Sweden [25]. This suggests different
UV exposure habits.
However, based on underlying trends by age, birth
cohort and time period, we project that rates will likely
plateau in the coming decades.
For KC, much less data are available, as KC is not
registered by most cancer registries worldwide. In
particular, there are no registry data for KC from North
America and Oceania. Therefore, the true disease
burden of skin cancer remains unclear and is often
 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25
underestimated [26]. A number of studies that have
attempted to estimate the burden of KC have reported
exceptionally high incidence rates of KC for sub-
populations within those countries. Five time higher
incidence rates of KC have been reported from
Queensland, Australia [27].
We analysed population-based data from two regis-
tries in Germany and one in Scotland. In Germany, the
Saarland Cancer Registry records KC data since 1970.
In the five decades between 1970 and 2017, KC inci-
dence increased about 9-fold for both men and women
It is striking that the registered incidence rates for KC in
SchleswigeHolstein and Saarland differ greatly with
slightly 100 cases more in SchleswigeHolstein than in
Saarland. The most likely explanation for this is the
degree of pigmentation of the respective populations.
While in Northern Germany a Scandinavian skin type
(blond and skin types IeII) is more predominant, in
Southern Germany many people are brown to black
haired and pigmented with skin types III and IV.
The data from Scotland, which only date back to
1992, show a similar picture of markedly rising incidence
of KC over recent decades. In 2017, the ratio of SCC to
BCC was about 2:3 in men and 1:4 in women.
For melanoma, mortality has also continued to rise
over time in all populations, although at a slower pace
than incidence, suggesting an increase in thicker mela-
nomas, in addition to thinner, good prognosis tumours.
Skin cancer is mainly caused by UV radiation
(UVR) [28]. Historically, rates of sunlight-induced skin
cancers were low among populations residing in high-
latitude locations, due to the ambient conditions, and
the attitudes of modesty that prevailed. At the begin-
ning of the 20th century, the ideal of pallor still existed
and people protected themselves from UV radiation to
the greatest extent possible. Rising incidence rates
suggest that a fundamental change in behaviour took
place worldwide around the middle of the 20th century.
It was not until after the Second World War that there
was a change in perceptions. “Tanning” became a
symbol of beauty and health and has become a domi-
nant goal in holidays [29,30]. Sun holidays, preferably
by the sea, have become a part of the normal life of
broad social strata. One reason for the increase in in-
cidences may also be the earlier diagnosis of CM and
KC, since many of these tumours were not diagnosed
early in the past. In addition, there is also speculation
about possible overdiagnosis, although this cannot be
quantified [31].
For both CM and KC, the main intracellular target
for UVR is DNA [32]. Ultraviolet B radiation is
responsible for the formation of the principal DNA le-
sions, cyclobutane pyrimidine dimers and pyrimidine (6-
4) pyrimidine photoproducts, whose incorrect repair
23
leads to base mutations of cytidine to thymidine (C > T
or CC > TT), which are considered as ‘UV signature
mutations’ [33,34]. Both CM and KC are caused by
UVR, but keratinocytes can go into apoptosis upon UV
damage and KC only develop at older ages. Melano-
cytes, on the other hand, have an apoptosis-protective
mechanism and melanomas can occur as early as
adolescence because of cumulative mutations [32].
A measure of the number of mutations is the tumour
mutation burden (TMB). The highest TMB among all
cancers is found in basal cell carcinomas, followed by
cutaneous squamous cell carcinomas, cutaneous
melanomas and bronchial carcinomas [35,36]. These are
tumours triggered by exogenous carcinogens, skin tu-
mours by UVR and bronchial carcinomas by smoking.
Beginning in the early 1980s, numerous prevention
campaigns have been introduced in high-risk populations
to combat skin cancer. Nevertheless, still rising incidence
rates of CM and KC, particularly in Europe and the US,
suggest that previous prevention campaigns have not
been effective so far. An exception is apparently
Australia, where a flattening of the incidence with plateau
formation is reported from about 2005 [3]. High incidence
rates of skin cancer, especially of melanoma, prompted
Australia to start first prevention campaigns in the early
1980s. The prevention campaigns were accompanied by
sustainable measures such as the introduction of sun
protective clothing for schoolchildren (school uniforms),
the installation of sun sails in public places and school-
yards, etc. This could explain the stabilisation of incidence
rates in Australia in recent years [37].
Incidence projections for Denmark and the US sug-
gest a further increase in incidence at least until 2025.
Thus, melanoma will probably be one of the most
common types of cancer in white susceptible pop-
ulations in future [3,38]. People who will develop skin
cancer during this period have already accumulated
sufficient amounts of UVR to develop skin cancer. Due
to the long latency period of 20e30 years, it is not ex-
pected that behavioural changes will lead to a significant
decrease in melanoma incidence in the coming years.
The present work has some limitations. There are only
a few registries worldwide that have continuously regis-
tered CM for more than five decades. Therefore, the
trends in incidence rates of CM are exemplary rather than
representative. The overall data on KC is very sparse and
only a few registries worldwide document KC.
In conclusion, this study confirms the overall observed
sharp increase in the incidence rates of CM and KC in
white populations in recent decades. Although consider-
able efforts have been undertaken in many susceptible
populations to combat skin cancer, a further increase in
melanoma, and most likely also in keratinocyte skin
cancer, are to be expected in the near future. In New
24 C. Garbe et al. / European Journal of Cancer 152 (2021) 18e25
Zealand and Australia, however, skin cancer prevention
campaigns appear to be showing initial successes in
decreasing incidence rate of melanoma.
Funding
This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-
profit sectors. DW is funded by a Research Fellowship
from the National Health and Medical Research
Council of Australia [APP1155413]
Author contributions
CG, UK, SG, TA, AK, BH, PM, LF, UL, DW:
conceived, designed, and planned the study. CG, UK,
AK, BH: acquired the data. CG, UK, SG, TA, AK, BH,
PM, LF, UL, DW: analysed the data. CG, UK, SG, TA,
AK, BH, PM, LF, UL, DW: interpreted the data. CG,
UK, TA, LF, UL, DW: drafted the manuscript. CG,
UK, SG, TA, AK, BH, PM, LF, UL, DW: reviewed the
manuscript for important intellectual content. All au-
thors reviewed the interim drafts and the final version of
the manuscript and agreed with its content and
submission.
Conflict of interest statement
Dr. Garbe reports personal fees from Amgen, grants
and personal fees from BMS, personal fees from MSD,
grants and personal fees from Neracare, grants and
personal fees from Novartis, personal fees from Philo-
gen, grants and personal fees from Roche, grants and
personal fees from Sanofi, outside the submitted work.
Dr. Amaral reports grants from Neracare, grants from
Novartis, grants from SkylineDx, personal fees and
travel support from BMS, travel support from Novartis,
personal fees from CeCaVa, outside the submitted work.
Dr. Leiter reports personal fees from Roche, Novartis
and Sanofi, grants and personal fees from MSD, outside
the submitted work. Dr. Whiteman reports grants from
National Health and Medical Research Council of
Australia, personal fees from Pierre-Fabre, outside the
submitted work. All remaining authors have declared no
conflicts of interest.
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