Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

DOI 10.1007/s13555-016-0165-y

REVIEW

Skin Cancer: Epidemiology, Disease Burden,

Pathophysiology, Diagnosis, and Therapeutic
Approaches
Zoe Apalla . Dorothée Nashan . Richard B. Weller . Xavier Castellsagué

Received: August 11, 2016

Ó The Author(s) 2017. This article is published with open access at Springerlink.com

ABSTRACT Prevention strategies are also discussed.

Secondly, we discuss the complexities and
Skin cancer, including both melanoma and challenges encountered when diagnosing and
non-melanoma, is the most common type of developing treatment strategies for skin cancer.
malignancy in the Caucasian population. Key case studies are presented that highlight the
Firstly, we review the evidence for the practic challenges of choosing the most
observed increase in the incidence of skin appropriate treatment for patients with skin
cancer over recent decades, and investigate cancer. Thirdly, we consider the potential risks
whether this is a true increase or an artefact and benefits of increased sun exposure.
of greater screening and over-diagnosis. However, this is discussed in terms of the
possibility that the avoidance of sun exposure
Dr Castellsagué very sadly passed away during the in order to reduce the risk of skin cancer may be
development of this article. However, given his less important than the reduction in all-cause
involvement in the preparation and delivery of his mortality as a result of the potential benefits of
presentation at the 9th Skin Academy Symposium, and
his initial guidance on the content of this article, he has increased exposure to the sun. Finally, we
been included as a posthumous author at the request of consider common questions on human
his co-authors and Professor Blume-Peytavi. papillomavirus infection.
Enhanced content To view enhanced content for this
article go to http://www.medengine.com/Redeem/
6C47F0600685C21C. Keywords: Dermatology; Diagnosis; Disease
burden; Epidemiology; Skin cancer; Therapy;
Z. Apalla (&) Treatment
First Department of Dermatology, Aristotle
University of Thessaloniki, Thessaloniki, Greece
e-mail: [email protected]
EVOLVING EPIDEMIOLOGY
D. Nashan AND BURDEN OF SKIN CANCER
Teaching Hospital of the University of Münster,
Münster, Germany
The Increasing Incidence of Skin Cancer
R. B. Weller
University of Edinburgh, Edinburgh, UK
Overall Skin Cancer
X. Castellsagué Skin cancer, including both malignant
Catalan Institute of Oncology (ICO), L’Hospitalet de melanoma (MM) and non-melanoma skin
Llobregat, Catalonia, Spain
S6 Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

cancer (NMSC), represents the most common diagnoses as LL [18]. Furthermore, in a

malignancy in Caucasians [1–10]. The incidence population-based study correlating the number
of both MM and NMSC is on the rise, with an of skin biopsies and the incidence of MM, the
annual increase in MM of 0.6% among adults investigators noted that there was a parallel
over 50 years [11]. The estimated number of increase during a 15-year period, suggesting
new cases of skin melanoma in 2016 is 76,380, that the MM epidemic may also be related to
which represents 4.5% of all new cancer cases increased scrutiny and number of biopsies [19].
[12]. Deviations in reported incidence rates exist
and are attributed to varying risk factors Non-Melanoma Skin Cancer NMSC includes,
amongst different populations, as well as amongst others, Bowen’s disease, basal cell
discrepancies in national registration systems. carcinoma (BCC), and squamous cell
Furthermore, the incidence of melanoma may carcinoma (SCC). In Caucasians, the incidence
be even higher than indicated, as the National of NMSC is higher (by as much as 18–20 times)
Cancer Registries has reported an than that of MM [20–22]. However, there are
underestimation of its incidence in certain significant limitations to NMSC epidemiology,
countries [13]. mainly attributed to marked geographic
variations in incidence rates, as well as to
Melanoma The increased incidence of exclusion of NMSC by large cancer registries
melanoma has not been accompanied by a due to low mortality rates. Even secondary
corresponding increase in mortality rates [12]. analyses, whereby incidence data are extracted
This has led to the question of whether there is from administrative healthcare databases, are
a true melanoma epidemic, or if the increased comparatively limited [23].
incidence represents an epiphenomenon NMSC carries a substantial economic burden
attributable to over-diagnosis resulting from [24, 25]. In Australia, it is the most costly
intense screening and more biopsies. cancer, accounting for expenditure of
The increased incidence of melanoma in the AUS$511 million in 2010 [24]. In the USA, it
USA involves all thickness groups (American has been estimated that total annual
Joint Committee on Cancer tumor categories) NMSC-related expenditure is US$650 million,
and is independent of socio-economic status with Medicare costs 6–7 times greater than
(a surrogate marker for access to care and those for treating melanoma [26].
screening), suggesting that increased
screening and biopsy alone cannot account Reasons for Increased Incidence
for the dramatic change observed [14, 15]. This of Skin Cancer
finding is in agreement with the results
reported by Shaikh et al., who showed that The observed increases in skin cancer rates
thickness increased in T3/T4 tumors and are associated with several factors, including
nodular melanoma [16]. These observations the transition toward significantly older
together ‘‘suggest that the melanoma epidemic populations that are associated with a higher
is real and not simply an artefact of increased risk of NMSC [27]. However, research has also
detection pressure of earlier-stage T1/T2 revealed the important role of increased
lesions’’ [16]. occupational and recreational UV light
Conversely, there is evidence that exposure [22, 28]. For example, women
over-diagnosis may have a part to play. Recent \40 years exhibited a constant linear increase
epidemiologic studies indicate that melanoma in BCC incidence rates of 6.3% between
in situ, with an annual incidence of 9.5% [12], 1973 and 2009 [29], and studies have shown
occupies a disproportionately high percentage that indoor tanning is associated with a
of the overall increase in MM incidence [17]. significantly increased risk of BCC and SCC,
From the dermatopathologic point of view, with a higher risk with use in early life
there are studies suggesting a current trend (\25 years) [30].
towards reclassification of prior non-malignant
Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19 S7

DIAGNOSTIC AND THERAPEUTIC may be helpful to improve diagnostic accuracy

in some skin cancers [33–37] (the case presented
APPROACHES TO SKIN CANCER:
in Fig. 5 may have benefitted from such
CHALLENGING CLINICAL CASES technologies, for example). Photodynamic
visualization (fluorescent visualization of skin
Skin Cancer Diagnosis cancerization extension after preparation with
5-aminolaevulinic acid and subjection to
A diagnosis of skin cancer needs consideration photodynamic therapy [light exposure]) might
of alternative diagnoses. Concerning actinic also be beneficial for identification of actinic
keratosis, benign conditions include seborrheic keratosis, with histologic confirmation also
keratosis, verruca vulgaris, actinic being necessary in cases in which invasive skin
porokeratosis, O’Brien’s actinic granuloma, cancer is suspected [38].
eczema, lentigo solaris, lichen planus, or
psoriasis (Figs. 1, 2, 3), whereas malignant Treatment Challenges
conditions include SCC, Bowen’s disease,
BCC, lentigo maligna, keratoacanthoma, or
Treatment strategies for skin cancers require
extramammary Paget’s disease.
careful consideration, and there are many
Clinicians should ideally perform total body
challenges to overcome. However, with
skin examination (see Fig. 4 as an example case
increasing treatment choices, in terms of both
of actinic keratosis appearing on the back of the
therapy combinations and sequences, we can
hand, as is often overlooked), at least for
achieve better outcomes for patients with fewer
high-risk individuals [31, 32]. The use of
recurrences and longer treatment-free periods.
non-invasive optical technologies, such as
optical coherence tomography (non-invasive
imaging test of the retina using light waves) or Field Cancerization and Non-Melanoma
dermatoscopy (imaging of the skin, allowing Skin Cancer
statements concerning thickening of layers,
epidermal organization, and borders of a Field cancerization of the skin, by which large
lesion—in the case of actinic keratosis, the areas are affected by carcinogenic alternations,
typical honeycomb pattern may be observed), presents various therapeutic challenges (Fig. 6).

Fig. 1 Case studies: 80-year-old woman presenting with field cancerization, and 45-year-old woman presenting with lupus
erythematodes (forehead and cheek shown)
S8 Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

Fig. 2 Case study: lichen planus complicating diagnosis in a 78-year-old man with actinic keratosis on his hand

Fig. 3 Case study: psoriasis complicating diagnosis in a 47-year-old man with actinic keratosis on his hand

Fig. 4 Case study: cheilitis actinica versus actinic keratosis (mouth and cheek shown)

Owing to the difficulty in determining which treated [39]. For a patient with actinic
actinic keratosis lesions may progress to keratosis, there are three evolutionary
invasive SCC, European guidelines recommend possibilities: spontaneous clearing; persistence;
that all lesions, or the affected field, are or progression to invasive SCC [40].
Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19 S9

Fig. 5 Case study: 89-year-old woman presenting with multiple comorbidities (leg shown)

Fig. 6 Case study: field cancerization in an 80-year-old patient (head and shoulder/neck shown)

Approximately 60–65% of primary SCCs are treat all actinic keratosis lesions and field
believed to have arisen from lesions previously cancerization [44] (see ‘‘Cyclooxygenase in
diagnosed clinically as actinic keratosis [41, 42], Cancer Prevention and Treatments for Actinic
and the rate at which a specific lesion may Keratosis’’, by Gareth Thomas and Colin
become SCC is estimated to be a fraction of a Morton, published in this Supplement, for
percent over the course of a year [43]. Even further details on actinic keratosis treatment).
when actinic keratosis lesions are classified While long-term efficacy and tolerance of
according to their clinical appearance, there is treatments are key considerations for
little correlation with their histologic clinicians, comorbidities may impact
classification, thereby reinforcing the need to treatment success.
S10 Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

The broad actinic keratosis spectrum approaches are restricted). Figure 7 shows an
characterized by age, localization, medication, example of a transplant patient in whom there
co-dermatoses, and exogenous factors (Figs. 1, 5) was a suspicion of actinic keratoses in an
requires an individualized treatment approach extended field, with treatment choices being
for each patient. Figures 1, 2, 3, 4, 5, 6, 7 and 8 operative or destructive.
show examples of clinical cases. Patients who Many more therapeutic options are available
have received a kidney transplant represent a for non-immunosuppressed patients. However,
particularly challenging population. Skin there is still limited availability of some
tumors are a major problem in these patients, medications as they are not approved for
and key challenges for the clinician include all NMSC types and localizations (Table 1).
treatment of the whole integument, sequential Furthermore, when extensive field
therapies, and achievement of long-term success cancerization encompassing the whole
when the patient is immunosuppressed integument is evident, treatment must occur
(where inflammatory and immunomodulatory over a very large area of affected skin.

Fig. 7 Case study: Treatment of a patient who had received a kidney transplant (leg shown)

Fig. 8 Case study: 85-year-old woman with multiple basal cell carcinomas (forehead shown)
Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19 S11

Table 1 Recommended topical treatments for actinic keratosis

Drug EMA approval date Approved for localization Area
5% 5-FUa [92] 1998 All localizations 500 cm2
5-FU 0.5% with 10% salicylic 2011 All localizations 25 cm2 (maximum of 10 lesions)
acidb [93]
3% diclofenac with 2.5% hyaluronic 2000 All localizations Maximum of 8 g/day
acidb [94]
5% imiquimoda [95] 1998 Head 25 cm2
3.75% imiquimoda [96] 2012 Head 25 cm2
0.05% ingenol mebutatec [97] 2012 Body, extremities 25 cm2
0.015% ingenol mebutatec [98] 2012 Head 25 cm2
Please refer to your local prescribing information
a
MEDA (http://www.meda.co.za/)
b
Almirall (http://www.almirall.com/en/)
c
LEO (http://www.leo-pharma.co.uk/)

Basal Cell Carcinoma The combination of BRAF- and

MEK-inhibitors is well established in patients
Though the majority of patients with BCC have with tumors harboring the BRAF mutation,
a good prognosis, some patients develop a more primarily owing to the development of tumor
complex, advanced disease with relatively few resistance with BRAF-inhibitor monotherapy
treatment options; indeed, no formal treatment [46]. Although this combination represents an
algorithms are available. However, the recent effective option with an acceptable toxicity
development of hedgehog signaling pathway profile [47], questions still remain as to
inhibitors, such as vismodegib, has been whether sequential or cyclic application of
significant, providing an effective treatment BRAF- and MEK-inhibitors would be more
option for some patients. In particular, beneficial, and whether immunotherapies may
vismodegib treatment may be appropriate if represent equally useful alternatives [48].
the tumor is considered inoperable and With regard to immunotherapies, anti-PD-1
radiation therapy is declined; complete monotherapy may be preferable to anti-CLTA-4
remission is achieved in 21% of locally monotherapy [49]: combining anti-PD-1 and
advanced BCC [45], even in those infiltrating anti-CTLA-4 therapies may increase response and
adjacent muscle and bone structures. Many remission rates. However, this may be at the risk of
more cases with partial remission and higher toxicity (with predominantly
shrinking tumors may be considered for gastrointestinal, hepatic, and cutaneous adverse
operation (Fig. 8). events) [50] and therefore would be most
appropriate in patients with progressive disease
or lower PD-L1 expression. Further studies on
Malignant Melanoma Stage IV sequential/cyclic combinations of these
immunotherapies with consideration of
Treatment approaches for melanoma immunologically relevant parameters (e.g., PD-L1
encompass two main strategies: targeted expression levels, BRAF/NRAS/cKIT mutation
therapies (e.g., BRAF- and MEK-inhibitors); analysis), tumor typing and staging, and patient
and immunotherapies (e.g., anti-CTLA-4 characteristics (e.g., age, comorbidities, treatment
and anti-PD-1). history) are ongoing [48].
S12 Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

THE SUN: FRIEND OR FOE? supplementation has no effect on blood

pressure, ischemic heart disease, or stroke
The Impact of Sunlight Exposure [58, 61], although vitamin D3 supplementation
on Health may reduce all-cause mortality [60]. Although
vitamin D may account for some of the
beneficial effects observed with sunlight
The impact of sunlight exposure on health is
exposure, it may be considered a marker of the
subject to debate—here, we present our views
person’s occupational or recreational sun
on the available evidence. Several
exposure.
epidemiologic studies have provided evidence
for the beneficial effect of sun exposure on
overall health status. All-cause mortality (death Nitric Oxide and the Skin as a Mechanism
due to any cause) was inversely correlated with Behind the Positive Effects of Sunlight
increased sun exposure in several studies, with a It has been proposed that many of the
particular reduction in cardiovascular mortality. documented beneficial effects of exposure
A nationwide Danish case–control study to sunlight, particularly those related to
showed that having a diagnosis of skin cancer, cardiovascular health, involve mechanisms
a marker for sun exposure, was associated with a unrelated to melatonin, vitamin D, and
lower incidence of myocardial infarction, fewer exposure to UVB [62]. Recent studies suggest
hip fractures in those below the age of 90 years, that stores of nitric oxide (NO)-related species in
and fewer deaths from any cause [51]. Similarly, the skin may be particularly important in this
among Swedish women, habits indicating respect. Both the skin and the dermal
avoidance of sun exposure were a risk factor vasculature contain biologically significant
for all-cause mortality; the mortality rate among stores of bound NO species [63]. Upon
such ‘avoiders’ was approximately two-fold exposure of the skin to UVA,
higher compared with the highest sun photodecomposition of these NO stores takes
exposure group [52]. It is possible that severely place and NO species are released into the
restricting sun exposure, particularly at circulation, resulting in arterial vasodilation,
locations with low solar intensity, might in with cardioprotective and antihypertensive
fact have a negative effect on health [52]. effects [62, 64]. This mechanism has also been
In addition, studies have shown that blood shown to suppress the development of diabetes
pressure and the incidence of ischemic heart and metabolic syndrome in a mouse model [65].
disease correlate with the latitude of a person’s Long-term suberythemal and erythemal UV
country of residence [53, 54]. It is also known light significantly suppressed weight gain,
that blood pressure is lower during summer glucose intolerance, and insulin resistance in
compared with winter [55]. This is of great mice fed a high-fat diet, an effect that was not
significance as high blood pressure is the reproduced by vitamin D supplementation.
leading cause of disease and premature death Importantly, skin induction of NO reproduced
in the world [56, 57]. many of the effects of UV radiation [65].
Meta-analyses of several studies indicate
that serum vitamin D levels are inversely
correlated with blood pressure and the
WHAT SHOULD
incidence of cardiovascular disease, diabetes, A DERMATOLOGIST KNOW
and hypertension [58, 59]. Furthermore, ABOUT HPV?
observational studies indicate that the risk of
death from any cause is correlated with There are several key areas in which knowledge
circulating 25-hydroxyvitamin D [60]. of HPV natural history and vaccination status is
However, extensive studies, comprising important for dermatologists. Table 2 provides
meta-analyses of several clinical trials, have examples of common questions, along with
conclusively shown that oral vitamin D evidence-based responses for each question.
Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19 S13

Table 2 What should the dermatologist know about HPV? Key questions and answers
Question Answer
Does every patient develop genital warts after HPV Even though HPV infection is very common, very few
infection? patients will develop genital warts after infection
How long can HPV infections last? Up to 90% of HPV infections will clear within 2 years
Is a patient with subclinical infection contagious? Yes, but we should distinguish between subclinical and latent
infections (we know very little about latent infections).
subclinical infections do exist and can last for years, but
they are probably only contagious when there is viral
replication and shedding
Is the patient no longer infectious once genital warts have Patients can be infectious even after removal/treatment of
been treated? genital warts
Is there a rationale for treating subclinical HPV infections? No, what is important is the lesions, not the infection itself
What should be the advice for patients who have been The important thing to focus on is the lesions; screening for
treated for genital warts, but who may still have subclinical early lesions, and subsequent treatment
infection? Although there is no formal recommendation, HPV
vaccination is advised among patients with a history of
HPV-related lesions
What advice should patients receive for their sexual partners The important thing to focus on is the lesions; screening for
concerning infection? early lesions, and subsequent treatment
Although there is no formal recommendation, HPV
vaccination is advised among patients with a history of
HPV-related lesions
Is there any risk of HPV-related cancer in male patients? Only patients who do not resolve HPV infections are at a
higher risk of HPV persistence and subsequent
HPV-related diseases, including pre-cancer and cancer
Do HPV vaccines protect against other HPV genotypes that Yes, they protect against HPV types 6 and 11 that cause 90%
may cause genital warts? of genital warts and recurrent respiratory papillomatosis
Considering the cost of the vaccine, is there enough evidence The current cost of HPV vaccines in national immunization
for vaccination of already infected patients? And for their programs has been reduced threefold
sexual partners? Yes, the vaccine will not cure current active infections but
will block new infections as well as auto-inoculated virions
Is there a rationale for HPV vaccination in young males? Yes, very strong, and threefold:
1. To reduce transmission and circulation in the population
2. To protect themselves (male burden is now considerable)
3. For gender equality
S14 Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19

Human Papillomavirus and Cancer studied. However, the association of b HPV

infection with NMSC in patients with a very
More than 150 human papillomavirus (HPV) rare, genetically determined condition,
types have so far been identified. HPV falls into epidermodysplasia verruciformis, has been well
five genera, with the Alpha and Beta/Gamma established [81]. In stark contrast to
genera representing the largest groups [66]. a HPV-associated cancers (such as cervical
Mucosal HPV types from the Alpha genus are cancer, as discussed above), the presence of
the ones associated with neoplastic disease and b-HPV DNA does not appear to be essential
the most common viral infections of the for the maintenance of the malignant
reproductive tract; the World Health phenotype [82].
Organization acknowledges that most sexually
active men and women will be infected at some Prevention Through Vaccination
point in their lives [67]. Twelve Alpha HPVs Strategies
are classified as carcinogenic to humans and
fifteen as probably/possibly carcinogenic [68]. Three HPV vaccines are commercially
Two HPVs, HPV 16 and 18, stand out for available including a bivalent form against
their carcinogenicity and contribute to HPV types 16 and 18, a quadrivalent form
approximately 70% of all HPV-related cancers against HPV types 6, 11, 16 and 18, and a
worldwide [69–74]. Although most infections 9-valent form against types 6, 11, 16, 18, 31,
resolve spontaneously and the majority of 33, 45, 52 and 58 [83]. Persistent infection
women with infection do not develop cancer, with high-risk HPV types 16 and 18 is
a small proportion of HPV infections will persist responsible for the majority of cervical
and progress to pre-cancer and cancer [75]. cancer worldwide, whereas low-risk types 6
Protective risk factors that reduce the risk of and 11 are responsible for most genital warts
HPV infection and subsequent cancer include [84]. The vaccines are highly efficacious,
consistent condom use [76], male circumcision immunogenic and safe in the prevention of
[77], and use of an intrauterine device [78]. pre- and neoplastic cervical-, vulvar-, vaginal-
The impact of the estimated contribution of or anal-related disease in women [85–87]. The
HPV to cancer from an epidemiologic point of quadrivalent HPV vaccine has been shown to
view is larger than previously thought. Indeed, be effective against genital warts [88, 89] and
HPV infection can be considered a pandemic anal precancerous lesions [90]. As well as
disease for several reasons [79]. Firstly, it is being associated with wart formation,
universal and widespread, occurring on all cutaneous papillomaviruses can lead to the
continents, in both women and men, among development of NMSC, but further research
young people and adults, and across most races with HPV vaccines is needed to assess their
and socioeconomic groups. Secondly, it is efficacy in preventing NMSC.
extensive, as it causes a variety of related Data from multiple countries have shown a
diseases, both pre-cancerous and cancerous, clear impact in the reduction of HPV infections
involving a wide range of anatomic sites. and related conditions within a few years of
Finally, the epidemiology of HPV is dynamic, vaccine introduction [91], and pediatricians,
as opposed to stable, with increasing rates of gynecologists, primary healthcare professionals,
infection and disease. clinicians, and public health officials, as well as
dermatologists, have all played a key role in
The Role of HPV in Skin Cancer achieving this wide vaccination coverage.
This article is based on previously conducted
Some studies suggest that a particular genus, the studies, and does not involve any new studies of
b HPVs, may play a role in the pathogenesis of human or animal subjects performed by any of
NMSC [80], though this role has not been well the authors.
Dermatol Ther (Heidelb) (2017) 7 (Suppl 1):S5–S19 S15

ACKNOWLEDGEMENTS Open Access. This article is distributed

under the terms of the Creative Commons
Sponsorship and article processing charges for Attribution-NonCommercial 4.0 International
this supplement were funded by Almirall S.A. License (http://creativecommons.org/licenses/
This article is based on presentations from the by-nc/4.0/), which permits any noncommercial
9th Skin Academy Symposium, April 9–10, use, distribution, and reproduction in any
2016, Barcelona, Spain, sponsored by medium, provided you give appropriate credit
Almirall S.A. All named authors meet the to the original author(s) and the source, provide
International Committee of Medical Journal a link to the Creative Commons license, and
Editors (ICMJE) criteria for authorship for this indicate if changes were made.
manuscript, take responsibility for the integrity
of the work as a whole, and have given final
approval to the version to be published. We REFERENCES
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