Epidemiology and Risk

F a c t o r s o f Me l a n o m a
Stephanie Carr, DO, Christy Smith, MD, Jessica Wernberg, MD*

KEYWORDS
 Melanoma  Carcinogen  Ultraviolet radiation  Indoor tanning  Prevention

KEY POINTS
 The worldwide incidence of melanoma continues to increase.
 Ultraviolet light, especially indoor tanning, is a known carcinogen and exposure is clearly
correlated with an increased incidence of melanoma.
 The average cost of diagnosis and treatment of melanoma is 10 times greater than a non-
melanotic skin cancer.
 Clinicians should educate patients about risk factors for melanoma as well as the ABCDEs
of melanoma to facilitate early detection and diagnosis.
 Multiple public initiatives are now underway to reduce the prevalence of indoor tanning,
with 17 states now banning indoor tanning for minors.

INTRODUCTION

Melanoma is a potentially fatal skin malignancy that continues to increase in incidence

worldwide . The current lifetime risk of developing melanoma is 1 in 63 in the United
States, and similar ratios are noted in other Western nations.1 Although melanoma
is less common than other skin cancers, it is more lethal, accounting for nearly 73%
of skin cancer–related deaths.2 Melanoma is treatable with surgery at the localized
stage and has a high 5-year relative survival rate of 98%. However, this percentage
drops substantially when patients are diagnosed with advanced or metastatic mela-
noma (64% for regional to 23% for distant melanoma lesions) where treatment options
are limited.3
Because of the high metastatic potential of melanoma, research is ongoing to iden-
tify the risk factors associated with melanoma and develop improved methods to
diagnose and treat this aggressive skin cancer. Lifestyle and genetic risk factors are
the major contributing factors to melanoma development (Box 1).1 The following
chapter discusses these risk factors in detail and focus on the growing health crisis
involving indoor tanning.

General Surgery, Marshfield Medical Center, 1000 North Oak Avenue, Marshfield, WI
54449, USA
* Corresponding author.
E-mail address: [email protected]

Surg Clin N Am - (2019) -–-

https://doi.org/10.1016/j.suc.2019.09.005 surgical.theclinics.com
0039-6109/19/ª 2019 Elsevier Inc. All rights reserved.
2 Carr et al

Box 1
Risk factors of melanoma

Modifiable Risk Factors

 Indoor tanning
 Ultraviolet exposure
 Medications
Nonmodifiable Risk Factors
 Genetics
 Family history
 Socioeconomic status
 Nevi
 Race
 Age
 Gender

EPIDEMIOLOGY
Types of Melanoma
Melanoma is a cancer that originates in the melanocytes and is broadly classified by
site of presentation specifically cutaneous or noncutaneous. There are 4 major sub-
types of cutaneous melanoma4:
 Superficial spreading melanoma (70%): the most common type of melanoma. It
undergoes lateral (radial) growth before vertical (invasive) growth occurs.
 Nodular melanomas (15%–30%): rapidly enlarging elevated or polypoid lesions
that are often blue or black and exhibit an early vertical growth phase.
 Lentigo maligna melanoma (4%–10%): occurs more commonly in older patients
with chronically sun-exposed skin. It typically begins as a small freckle-like
macule. Over time it grows, becomes darker, asymmetric, and exhibits a vertical
growth phase.
 Acral lentiginous (<5%): lesions arise most commonly on palms, soles, subun-
gual, and occasionally, mucosal surfaces.
Melanoma may also develop at any noncutaneous site where melanocytes normally
occur, including ocular, gastrointestinal, genitourinary, and nasopharyngeal locations.
These are much less common than cutaneous melanoma according to a review in the
National Cancer Data Base, which contains records of 84,836 patients with cutaneous
and noncutaneous melanoma. Cutaneous melanomas comprised 91.2% of all diag-
nosed melanoma. Occular melanoma represents 5.2%, with 1.3% of melanoma of
mucosal primary origin, and the remaining 2.2% of cases were classified as melanoma
of unknown primary site.5 The prognosis of melanoma is based on lesion thickness
with thicker lesions corresponding to a higher rate of mortality.6 Therefore, early
detection and resection of melanoma lesions is necessary to prevent metastasis.
Global Distribution
The overall incidence of melanoma has been increasing worldwide, particularly in the
United States, European countries, and other countries with a predominantly Cauca-
sian population (Figs. 1 and 2). Queensland, Australia, has the highest incidence of
 Epidemiology and Risk Factors of Melanoma 3

Fig. 1. Age-standardized rate of melanoma incidence worldwide for 2018. (Reproduced

with permission from Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A,
Soerjomataram I, Bray F (2018). Global Cancer Observatory: Cancer Today. Lyon, France: In-
ternational Agency for Research on Cancer. Available from: https://gco.iarc.fr/today, ac-
cessed 9/13/2019; Data source: GLOBOCAN 2018. Graph production: IARC (http://gco.iarc.
fr/today). World Health Organization.)

malignant melanoma in the world where melanoma is the leading malignancy and
cause of cancer-related death in Australians aged 15 to 44 years.1,7 Melanoma is
the sixth most common cancer in women and the fifth most common in men in the
United States.2 Although populations with darker pigmented skin are still considered
to be low risk for developing melanoma, they are not exempt from the disease and
tend to develop more noncutaneous melanomas than fair-skinned individuals.1 The

Fig. 2. Age-standardized rate of melanoma mortality worldwide for 2018. The age-
standardized rate adjusts the age structure of populations to allow for comparisons that ac-
counts for the different age structure of the populations. (Reproduced with permission from
Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Piñeros M, Znaor A, Soerjomataram I, Bray F
(2018). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for
Research on Cancer. Available from: https://gco.iarc.fr/today, accessed 9/13/2019; and Data
source: GLOBOCAN 2018. Graph production: IARC (http://gco.iarc.fr/today). World Health
Organization.)
4 Carr et al

incidence of melanoma has increased by 270% over the past 30 years in the United
States, attributed to a variety of factors including increased exposure to ultraviolet
(UV) radiation and increased surveillance.1 Sun exposure patterns and exposure to
artificial UV light can influence melanoma development.1 A nested case-control anal-
ysis of 130 cases and 300 controls from the Nurses’ Health Study cohort by Oliveria
and colleagues8 observed an increased risk of melanoma in women whose residence
during the ages of 15 to 20 years was closer to the equator compared with the women
living at higher latitudes during the same time periods. This risk did not continue past
the age of 30 years.
Race
The incidence of melanoma varies based on race, with a lifetime risk of 2.6% for Cau-
casians, 0.1% for African Americans, and 0.58% for Hispanics.9 Caucasians are at a
10-fold increased risk of developing cutaneous melanoma compared with those with
dark skin pigmentation.1 However, noncutaneous melanomas are more common in
the non-Caucasian population.1 In the United States, non-Caucasian patients have
a worse outcome overall and present with a more advanced stage of melanoma
compared with Caucasian patients.10
Age and Gender
Melanoma tends to be diagnosed in young to middle-aged adults with an average age
at diagnosis of 57 years.1 Between 25 to 50 years of age, the incidence of melanoma
increases linearly; however, incidence of melanoma differs by gender as well as age.
From age 25 to 40 years, women are more likely to develop melanoma than men, but
after 75 years, men are 3 times more likely to develop melanoma compared with
women.1 Overall, men are 1.5 times more likely to develop melanoma.11

RISK FACTORS
Location
Melanoma is notorious for a wide variety of presentations depending on body site. Any
melanoma at a noncutaneous location or in a location that is difficult to visualize is
more likely to be diagnosed at a more advanced stage than cutaneous lesions.1 Su-
perficial spreading and nodular cutaneous melanomas tend to have a more classic
presentation including irregular borders, asymmetry, and enlarged diameter. Lentigo
maligna melanomas are more common on the face while acral lentiginous melanomas
are most commonly found at the palms of the hands, soles of the feet, and nail beds.
Some patterns of melanoma distribution are related to sun exposure patterns, his-
tory of sunburns, and gender. For this reason, men are more likely to develop lesions
on the back, whereas women are more likely to develop melanoma on the arms and
legs.1 Melanomas on the trunk have been associated with a history of severe sunburn,
and patients with a family history of melanoma were more likely to develop lesions on
the limbs, 57% versus 42%, compared with those with no family history.7,12 Watts and
colleagues7 found that patients who self-report having “many nevi” developed truncal
melanoma 41% of the time versus patients with “few” nevi who developed truncal
melanoma 29% of the time.
Ultraviolet Radiation
UV radiation exposure is a clear risk factor for the development of melanoma. In 1992,
solar UV radiation was classified as a carcinogen by the International Agency of
Research on Cancer and in 2009 was updated to include UV radiation from indoor tan-
ning.13,14 In 2012, UV radiation from arc welding was also classified as carcinogenic to
 Epidemiology and Risk Factors of Melanoma 5

humans, and in 2017, this was updated to include welding fumes.13,15 UV exposure
occurs during sun exposure, indoor tanning, and welding. Sun exposure has long
been associated with increased development of skin cancer. Multiple studies have
demonstrated that increased exposure to ultraviolet light and many years of occupa-
tional sun exposure (>20 years) lead to increased development of melanoma.16
Chronic sustained sun exposure is also linked to squamous and basal cell carci-
nomas,17,18 whereas intermittent sun exposure and sunburns are more closely asso-
ciated with melanoma.12 A definitive link between welding and skin cancer
development has not been shown; however, the full spectrum of UV radiation expo-
sure in welding has been linked to ocular melanoma.13,15,19,20 A French population–
based case-control study showed elevated risk of ocular melanoma among welders
compared with the general population (odds ratio 7.3).19 Therefore, protection from
UV radiation is paramount for preventing melanoma and nonmelanoma skin cancers.
Indoor tanning is a leisure activity with high UV exposure that is particularly popular
with teenagers and young adults in affluent European and North American countries.
In a 2014 survey of university students, 55% of students had tanned at least once and
43% reported having tanned in the year before the study survey.21 Indoor tanning is a
risk factor of melanoma development, and any previous indoor tanning experience is
associated with a 16% to 20% increased risk of melanoma development compared
with those never exposed to indoor tanning.22
More than 6,000 melanomas each year are thought to be caused by indoor tanning
in the United States and an increased duration and earlier age at initiation of indoor
tanning is associated with an even higher risk of melanoma development compared
with individuals who do not engage in indoor tanning.21,22 In women with a history
of indoor tanning, melanomas were most likely to develop on the trunk, but men
with the same history were more likely to develop head or neck melanomas.23
Exposure to UV radiation can also occur during medical treatment. Psoralen and ul-
traviolet A (PUVA) is used for treatment of psoriasis, eczema, and vitiligo and is asso-
ciated with development of melanoma and nonmelanoma skin cancers. Patel and
colleagues24 noted that the risk of squamous cell carcinoma is increased by 100-
fold in patients undergoing greater than 330 treatments, and the risk of developing ma-
lignant melanomas post-PUVA is even greater, as patients were at increased risk after
250 treatments.

Genetics
Certain skin, hair, and eye color phenotypes are associated with increased
sun sensitivity and risk of skin cancer development. Freckles, light-colored
eyes, red hair, fair skin, and inability to tan increase an individual’s risk for mela-
noma by nearly 50%.1 The red hair/fair skin phenotypes are associated with vari-
ants in melanocortin-1 receptor (MC1R), which regulates the production of
pheomelanin and eumelanin.25 Individuals with light-colored skin are more likely
to develop amelanotic lesions, which often go unnoticed until the lesion becomes
more advanced.1
In other cases, the genetic component of increased skin cancer risk is less obvious
although family history of melanoma and genetic variants that alter the efficacy of UV-
induced DNA repair mechanisms, cell damage–induced signaling pathways, and so
forth are known to influence melanoma development. In a combined analysis from 8
case-control studies in Caucasian populations, individuals with a positive family his-
tory of melanoma have a relative risk of 2.24 for melanoma compared with individuals
without a positive family history.26 This risk was independent of age, nevus count, hair
and eye color, and freckling.
6 Carr et al

The most common germline mutation identified in familial forms of melanoma is

CDKN2A. Mutations in CDKN2A result in changes that alter the function of p16, which
is a negative regulator of cell cycle progression.27 A germline mutation in CDK4 has
also been identified in familial melanoma and has a similar phenotype to the CDKN2A
mutation.28
Other genetic mutation syndromes that increase cancer risk overall also confer
increased risk of melanoma although melanoma is not the primary tumor type. For
example, whereas BRCA1 and BRCA2 genes are associated with increased risk of
breast, ovarian, and prostate cancers, there is also an increased risk of melanoma.29
Variants in other tumor suppressor genes such as p53 and RB1 are also associated
with increased risk for melanoma.30,31
Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder of DNA repair
characterized by increased sensitivity to ultraviolet radiation. In a 40-year National In-
stitutes of Health follow-up study of 106 XP patients, the risks of nonmelanoma skin
cancer and melanoma were found to be 10,000-fold and 2000-fold higher, respec-
tively, in these patients compared to the general population.32

Nevi
Dysplastic nevi are a relatively common occurrence in populations of Northern Euro-
pean descent with a frequency of about 10%.33 The presence of dysplastic nevi is
associated with a 1.5- to 10-fold increased risk of melanoma and depends on the
number of dysplastic nevi present.34 The risk for melanoma development is approxi-
mately 1.5 times higher in people with 11 to 25 nevi and seems to be doubled with
every increase of 25 nevi.11

Personal History of Cancer

A personal history of melanoma is associated with an increased risk for a second mel-
anoma and is greatest within the first year of index diagnosis.35 There is also an
increased risk of a second primary malignancy. Spanogle and colleagues35 used
the SEER database to analyze disease outcomes in 16,591 cutaneous melanoma sur-
vivors and found a 32% higher risk of developing any second primary malignancy, with
the standardized incidence ratio being greatest for development of a second
melanoma.

Smoking
A validated association between smoking and melanoma has not been established
although numerous studies have reported an inverse relationship between smoking
and cutaneous melanoma.36–39 However, a direct positive correlation between current
smoking and sentinel lymph node metastasis, ulceration, and increased Breslow
thickness in smokers who developed melanoma was noted by Jones and
colleagues.36

Socioeconomic Status
Lower socioeconomic status correlates with more advanced disease at diagnosis and
overall worse outcomes.40 A National Cancer Database study found that patients
without insurance had a 67% greater risk of death from melanoma than those with pri-
vate insurance, and Medicare and Medicaid patients had worse outcomes than those
with private insurance. Furthermore, patients living in an area with a lower average in-
come and those without a high school diploma were more likely to die of melanoma.40
A similar study performed in California highlighted that men with a lower
 Epidemiology and Risk Factors of Melanoma 7

socioeconomic status tended to be diagnosed with more advanced melanoma

including ulcerated primaries and metastases.41

Immunosuppression/Transplant
Patients with weakened immune systems are at increased risk for developing
skin cancers. Solid organ transplant patients requiring immunosuppression have a
well-known increased risk for developing skin cancers, particularly squamous cell
carcinoma.42 Patients with a history of solid organ transplant are documented to
have a 2- to 4-fold increase in developing melanoma compared with the nontransplant
population. Certain immunosuppressants, including cyclosporine and sirolimus, have
been associated with an increased incidence of melanoma.42,43 Individuals with hu-
man immunodeficiency virus infection are also known to have an increased risk of
squamous cell carcinoma and basal cell carcinoma although multiple studies have
not demonstrated an increased risk with malignant melanoma in this population.44,45
Similar to the general population, the incidence of melanoma is increasing in trans-
plant recipients. Two groups of solid organ transplant patients from the years 1991 to
2000 and 2001 to 2015 were studied. The latter group had a 4 times greater risk of
developing melanoma.46 All transplant and immunosuppressed patients should un-
dergo yearly skin examinations to ensure early identification of skin cancer.

PUBLIC AWARENESS
Early Detection
Early detection is essential to decrease mortality. Incidence of melanoma detection
has increased over time due in part to increased awareness and surveillance for
abnormal skin lesions. However, increased surveillance is unlikely to be the only factor
for increased melanoma rate as evidenced by increased incidence in both thin and
thick lesions and increase in sun bathing and sun seeking behavior over time.2,47
Increased public awareness of self-skin assessments and recognition of the Asymme-
try, irregular Borders, variation of Color, Diameter >6 mm, and Evolution (ABCDEs) of
melanoma have increased the sensitivity of self-examinations to nearly 90%.1 The
ABCDE criteria for melanoma were created in 1985 to increase public awareness of
the importance of early detection of skin cancer (Fig. 3). Any skin lesion that has
one or more of these characteristics should be evaluated by a dermatologist.

Economic Impact
The medical costs associated with a diagnosis of melanoma are substantial compared
with other skin cancers. The average cost per melanoma diagnosed in the United
States is $32,594, whereas the average cost per nonmelanoma skin cancer is
$2496. This difference is easily attributable to the more substantial cost for surgical
resection and staging, imaging, and immunotherapies in advanced melanoma.48
Total-body skin examination (TBSE) is used to identify and diagnose melanoma at
an early stage, although there are no definitive recommendations on the timing or
even effectiveness of TBSE. In 2017, Matsumoto and colleagues48 analyzed 33,647
TBSEs over a 5-year period and found a 30% biopsy rate but only a 0.46% rate of mel-
anoma diagnosis.
Since there is a strong association between indoor tanning and melanoma develop-
ment, limiting indoor tanning in minors may reduce the incidence of melanoma in teen-
agers and young adults. Using a cohort of 61 million individuals aged 14 years or
younger, Guy and colleagues49 estimated that 61,839 cases of melanoma and 6753
deaths attributed to melanoma could be avoided if minors were banned from indoor
8 Carr et al

Fig. 3. ABCDEs of melanoma. These characteristics may be used by health care providers and
patients to identify skin lesions of concerns that may necessitate a biopsy due to concerning
features. ([A–D] Courtesy of E. Stratman, Marshfield, WI; E: From National Cancer Instiute
Visuals Online. Available at: https://visualsonline.cancer.gov/.)

tanning, with an estimated treatment savings of more than $340 million in the United
States alone.
Prevention
Large public initiatives to decrease sun exposure, increase sunscreen utilization, and
reduce indoor tanning have been present for many years. In addition, the US Surgeon
General announced a Call to Action to Prevent Skin Cancer in 2014. This initiative set
forth multiple goals to increase prevention of skin cancer, including increasing aware-
ness of the effects of UV radiation, reducing indoor tanning, and promoting research in
the treatment of skin cancers. Although there is no evidence to support annual skin
examinations for the general population, the United States Preventative Services
Task Force does recommend patient education to reduce UV radiation and indoor tan-
ning in patients aged 10 to 24 years.2 In the 2018 Call to Prevention Progress Report
released by the Centers for Disease Control, there is a new emphasis on sun safety
and sunscreen application in schools. The report also highlights the progress made
to enact legislation limiting or banning indoor tanning for minors, reporting that 17
states have banned indoor tanning for minors, whereas many other states have
some type of restriction for minors (Fig. 4). Only 6 states have no restrictions on indoor
tanning for minors.50
Tanning Restrictions
In 2015, Guy and colleagues51 reported that approximately 11.3 million individuals,
including 1.9 million high school students, in the United States participate in indoor
tanning. In a meta-analysis of multiple international databases from 2007 to 2012,
Wehner and colleagues21 determined that nearly half of university students have
tanned in the previous year. Although the association between tanning and the
 Epidemiology and Risk Factors of Melanoma 9

Fig. 4. Map of the United States of America demonstrating the states with restrictions on
indoor tanning for minors (<18 years of age) as of June 2018. a“prohibits some minors
from tanning” is defined as restrictions for any other age group, including for minors
younger than 17,16,15,or14. b As of june 25,2018,in both New York and Rhode Island,a
bill prohibiting all minors under 18 from indoor tanning was awating the stste governor’s
signature. (From Skin Cancer Prevention Progress Report 2018. Atlanta, GA: Centers for Dis-
ease Control and Prevention, US Dept of Health and Human Services; 2018. Available at:
https://www.cdc.gov/cancer/skin/pdf/SkinCancerPreventionProgressReport-2018-508.pdf.)

increased risk of skin cancer is well known, studies have demonstrated that knowl-
edge of this associated risk has no effect on the frequency of indoor tanning in young
adults.52 The Food and Drug Administration has proposed steps to ban indoor tanning
for minors, but this legislation is not yet in place nationwide. As of June 2018, seven-
teen states have banned indoor tanning for minors. A 2017 study evaluating the effec-
tiveness of state legislation found that one-third of tanning salons did not comply with
their state’s regulations. Tanning salons that were independently owned and those
located in rural or Southern states were least likely to comply with state regulations
for minors.53

SUMMARY

Melanoma continues to be a substantial cause of morbidity and mortality in the United

States and worldwide. The increase in melanoma incidence has been attributed to
increased UV radiation exposure and increased surveillance. Despite increasing pub-
lic awareness of the dangers of excessive UV exposure in relation to melanoma devel-
opment there has been no change in the behavior of young adults using indoor tanning
beds. Current public health initiatives to reduce melanoma incidence include
decreasing sun exposure, increasing sunscreen utilization, and reducing indoor tan-
ning, especially for minors. Decreasing the morbidity and mortality associated with
melanoma will require a unified effort from the public as well as health care
professionals.
10 Carr et al

ACKNOWLEDGMENTS

The authors acknowledge Emily Andreae, PhD, for content editing.

DISCLOSURE STATEMENT

The authors have no conflicts of interest or financial disclosures.

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