Version May 2024
INTRODUCTION — Melanoma is the most serious form of skin cancer. The rapid increase in the incidence of melanoma and its associated mortality require a detailed understanding of the risk factors associated with melanoma.
Here we will review epidemiologic changes in the incidence and mortality, specific risk factors, and the management of patients at high risk for the development of melanoma. Primary prevention, screening, and techniques of skin examination are discussed separately.
●(See "Primary prevention of melanoma".)
●(See "Screening for melanoma in adults and adolescents".)
●(See "Melanoma: Clinical features and diagnosis".)
EPIDEMIOLOGY — The incidence of melanoma is rising dramatically worldwide, and mortality rates are beginning to decrease, likely due to increasing early detection efforts and significant breakthroughs in advanced melanoma treatment. Understanding the epidemiology provides information about important causative factors and prevention.
Melanoma is rare in children and adolescents, and approximately 90 percent of these cases are in those ≥10 years of age [1-4]. (See "Melanoma in children", section on 'Epidemiology'.)
Incidence — Melanoma incidence is on the increase worldwide:
●United States – In the United States, melanoma is the fifth leading cancer in males and females [5]. An estimated 97,610 new cases of invasive melanoma and 89,070 cases of in situ melanoma will be diagnosed in the United States in 2023 [6]. In 2019, the annual incidence rate was 27 per 100,000 among non-Hispanic White Americans, 5 per 100,000 among Hispanic Americans, and 1 per 100,000 in Black Americans and Asian/Pacific Islander Americans [7].
Invasive melanoma incidence trends vary by age and sex. Rates among individuals younger than age 50 have stabilized in females and declined by approximately 1 percent per year in males since the early 2000s. However, for adults ages 50 and older, rates continued to increase in females by approximately 1 percent per year from 2015 to 2019 but have stabilized in males [6].
A study performed in Olmsted County, Minnesota, that included patients aged 40 to 60 years with a first lifetime diagnosis of cutaneous melanoma between January 1, 1970, and December 31, 2020, found a nearly 12-fold increase in the age- and sex-adjusted incidence rate of melanoma between 1970 and 2020 (from 8.6 [95% CI 3.9-13.3] per 100,000 person-years in 1970 through 1979 to 99.1 [95% CI 89.5-108.7] per 100,000 person-years in 2011 through 2020) [8]. Of note, there was a 52-fold increase in females and a 6-fold increase in males.
In contrast, trends in melanoma incidence were different for children, adolescents, and young adults. The incidence rates remained low and stable among children (age 0 to 9 years), while for both adolescents (age 10 to 19 years) and young adults (age 20 to 29 years), the incidence peaked at approximately 2004 to 2005 and then began to decrease [9]. Between 2006 and 2015, the incidence rate decreased among adolescent males and females by 4.4 percent (95% CI -1.7 to -7.0) and 5.4 percent (95% CI -3.3 to -7.4), respectively, and by 3.7 percent (95% CI -2.5 to -4.8) and 3.6 percent (95% CI -2.8 to -4.5) among young adult males and females, respectively. Overall, the number of reported cases of melanoma in adolescents and young adults decreased by 23.4 percent from 2006 to 2015 [9]. One hypothesis to explain this decreasing trend in melanoma incidence among persons younger than 30 years is that it may be related to a change in sun-protection behavior. However, as the national registry data do not include information on melanoma risk factors, such as skin pigmentation, ultraviolet (UV) light exposure, sunburn history, and sun-protective behavior, this hypothesis remains to be proven.
●World – In 2020, an estimated 325,000 persons (174,000 males and 151,000 females) worldwide were diagnosed as having melanoma, and approximately 57,000 persons (32,000 males and 25,000 females) died of the disease [10]. Of all newly diagnosed cases in 2020, 259,000 (79.7 percent) were persons older than 50 years of age, and of all deaths in 2020, 50,000 persons (87.7 percent) were older than 50 years of age.
Large geographic variations existed across countries and world regions, with the highest incidence rates among males (42 per 100,000 person-years) and females (31 per 100,000 person-years) observed in Australia/New Zealand, followed by Western Europe (19 per 100,000 person-years for males and females), North America (18 per 100,000 person-years for males and 14 per 100,000 person-years for females), and Northern Europe (17 per 100,000 person-years for males and 18 per 100,000 person-years for females) [10].
●Europe – Between the early 1970s and 2000, the estimated incidence of melanoma in Central Europe increased from 3 to 4 cases/100,000 inhabitants per year to 10 to 15 cases/100,000 inhabitants per year [11]. An analysis of data from 18 European cancer registries showed that between 1995 and 2012 the incidence of both invasive and in situ melanoma increased annually by 4 and 7.7 percent, respectively, in males and by 3 and 6.3 percent, respectively, in females [12]. The overall increase in the incidence of invasive melanoma was predominantly due to an increase in the incidence of thin tumors.
●Australia – Data from the Queensland Cancer Registry for the period 1995 to 2014 confirmed that the incidence of melanoma in Queensland, Australia, is the highest in the world (72 per 100,000 per year) [13]. While the incidence of in situ melanoma increased over the 20-year period across all age groups, the incidence of invasive melanoma decreased among individuals under the age of 40 years, was stable in the age group 40 to 60 years, and increased among individuals older than 60 years. In 2021, it was estimated that the age-standardized incidence rate in Australia was 55 cases per 100,000 persons (67 for males and 45 for females) [14].
Some investigators have suggested that the reported increase in melanoma incidence results at least in part from of an increasing number of skin biopsies and significant variability in the histologic interpretation of early evolving lesions [15]. However, this explanation does not account for the increase in melanoma mortality rates, particularly in older males.
Others have speculated that the increasing incidence of melanoma is related to a rise in screening for melanoma, leading to the detection of thinner, more indolent lesions [16]. However, a study of Surveillance, Epidemiology, and End Results (SEER) data (1992 to 2004) from non-Hispanic White individuals found increasing incidence of melanoma of all thicknesses and among all socioeconomic levels [17]. Individuals of low socioeconomic status, who were believed to be less likely to have access to screening services, exhibited the highest increase in melanoma incidence when compared with subjects with higher socioeconomic status. In a study of a population-based screening program, the incidence of in situ and invasive melanomas in the screened population increased throughout the one-year screening period but returned to baseline levels in the three years after the screening program was discontinued [18]. In the control region, by contrast, a small increase in incidence was observed throughout the study period. These results suggest that screening accounts for some, but not all, of the increase in melanoma incidence.
Ongoing efforts to stratify screening for melanoma are seeking to reduce the burden of indolent disease diagnosis while focusing on the population at higher risk of invasive and advanced disease accounting for current mortality rates [19,20]. (See "Screening for melanoma in adults and adolescents".)
Geographic and ethnic variation — The interplay of genetic and environmental risk factors likely accounts for the wide variation in melanoma incidence in different ethnic groups and geographic areas, as evidenced by the following:
●In an analysis of data from the SEER database from 2014 to 2018, the age-adjusted melanoma incidence rates in the United States in American Indian/Alaska Native, Asian/Pacific Islander, Black, Hispanic, and White individuals were 5.5, 1.3, 0.9, 4.9, and 32.2 per 100,000 individuals per year, respectively [21].
●In another analysis of data from the SEER database from 1975 to 2016, the most common sites for primary melanoma in patients with skin of color, except in patients of American Indian/Alaska Native descent, were the hips and lower limbs, including the soles [22]. For American Indian/Alaska Native and non-Hispanic White patients, the most common site for primary melanomas was the trunk.
●An increased incidence of melanoma is associated with an increased UV index and lower latitude only in non-Hispanic White persons. No evidence to support the association of UV exposure and melanoma incidence in Black or Hispanic populations was observed [23].
Mortality — In Australia, a trend towards a decrease in melanoma mortality rates between the late 1980s and 2002 was demonstrated for both males and females aged 35 to 54 years (-2.4 and -2.9 percent per year, respectively), whereas the rates remained stable for those aged 55 to 79 years [24]. In 2021, it was estimated that the age-standardized mortality rate was 4 deaths per 100,000 persons (5.6 for males and 2.6 for females) compared with the 2019 rate of 4.5 deaths per 100,000 persons (6.6 for males and 2.8 for females) [14]. An analysis of data from the Queensland Cancer Registry for the period 1995 to 2014 showed decreased or stable mortality rates in all age groups except in males aged 60 years or older [13].
In the United States, the overall mortality from melanoma has declined rapidly over the past decade (2011 to 2020) by approximately 5 percent per year in adults younger than age 50 and 3 percent per year in those 50 and older because of advances in treatment. A total of 7990 deaths from the disease are expected in 2023 (5420 males and 2570 females) [6]. From 2007 to 2016, the death rate for melanoma declined by approximately 2 percent per year in adults 50 years of age and older and by approximately 4 percent per year in those younger than 50 [7]. The decline in mortality noted in younger patients may represent the effects of public education on early detection and treatment.
There are no clinical trials demonstrating that screening decreases the mortality from melanoma. However, five years after the completion of a screening program involving approximately 400,000 participants in Germany, the mortality rates from melanoma in the screened area were 50 percent lower than those observed in the nonscreened regions [25]. (See "Screening for melanoma in adults and adolescents".)
ULTRAVIOLET RADIATION
Epidemiologic evidence — Although a direct causal relationship between solar ultraviolet (UV) radiation and melanoma cannot be demonstrated experimentally, the evidence from indirect studies is overwhelming and leaves little doubt that UV exposure is a major risk factor for melanoma:
●Clinical and epidemiologic evidence demonstrates higher rates of melanoma in people with extensive or repeated intense exposure to sunlight. The majority of melanomas develop on sun-exposed skin, particularly in areas that are more susceptible to sunburn. Individuals with naturally dark skin or whose skin darkens easily upon sun exposure have lower rates of melanoma, supporting the concept that greater penetration of UV light into the skin results in a higher risk [26]. (See 'Timing and pattern of sun exposure' below.)
●The major case-control studies assessing sun exposure, sunburn, and melanoma incidence were analyzed in a systematic review [27]. Intermittent exposure and sunburn in adolescence or childhood were strongly associated with an increased risk of melanoma, while occupational exposure did not confer an increased risk. These findings support the hypothesis that melanoma risk is affected primarily by intermittent intense sun exposure. (See 'Timing and pattern of sun exposure' below.)
●Adjusted for skin type, the geographic incidence of melanoma is highest in equatorial areas and decreases proportionately with distance from the equator, with its correspondingly lower level of UV exposure [28]. Geographic variation in melanoma and nonmelanoma skin cancer rates is also documented in African Americans [29].
●Studies strongly indicate that a decrease in recreational sun exposure following the diagnosis of primary melanoma, and thus a change in future individual behavior, can significantly diminish the chance of a second primary melanoma [30,31].
Ultraviolet A versus ultraviolet B irradiation — Ultraviolet B (UVB; wavelengths 290 to 320 nm) radiation appears more closely associated with the development of melanoma than ultraviolet A (UVA; wavelengths 320 to 400 nm). This is supported by the higher incidence of melanoma in equatorial regions than in latitudes farther from the equator, as UVB radiation is most intense at the equator while UVA intensity varies less across latitudes.
Although UVB appears to be more important than UVA as a risk factor, a causal link to UVA exposure is also supported by data from patients using tanning beds and/or treated with psoralen plus ultraviolet A (PUVA) for psoriasis. (See 'Indoor tanning' below and 'Psoralen plus ultraviolet A therapy' below.)
Pathogenetic mechanisms — Two independent pathogenetic pathways for UV-induced melanomagenesis have been postulated: a melanin-independent pathway associated with direct UVB-induced deoxyribonucleic acid (DNA) damage and a UVA-initiated, pigment-dependent pathway associated with indirect oxidative DNA damage in melanocytes [32]. UVB-induced mutations are typically cytosine-to-thymine transitions arising from cyclobutane pyrimidine dimers (CPDs) that are rapidly formed in the DNA as an effect of UVB irradiation. In contrast, UVA radiation generates CPDs in melanocytes for over three hours after exposure ("dark CPDs") by a mechanism that involves melanin, in particular pheomelanin, and reactive oxygen species as cofactors [33]. Furthermore, in experimental studies, both UVA and UVB radiation have been shown to accelerate BRAF-mediated melanomagenesis through TP53 mutation [34]. Epigenetic modulators of melanogenesis and melanoma progression represent an active area of research, with microribonucleic acids (microRNAs), such as miR-21, identified to play a role in this process [35].
Timing and pattern of sun exposure — The pattern and timing of sun exposure appear to be important for skin cancer. Nonmelanoma cancers are associated with cumulative sun exposure and occur most frequently in areas maximally exposed to the sun (eg, face, dorsal hands, forearms).
In contrast, melanomas tend to be associated with intense, intermittent sun exposure and sunburns, and they frequently occur in areas exposed to the sun only sporadically (eg, the back in males, the legs in females) [36-39]. This association with intermittent sun exposure may not be true for all body sites. For example, melanomas of the head and neck are more frequent in patients with high occupational sun exposure [40,41].
Exposure early in life seems particularly important. Individuals who have had five or more severe sunburns in childhood or adolescence have an estimated twofold greater risk of developing melanoma [36,42]. Moreover, the incidence of melanoma is higher among people who migrate from northern to more equatorial latitudes; this effect is seen predominantly among those who were children at the time of migration [43,44].
It is not clear why intermittent extreme sun exposure appears to increase the risk of melanoma, whereas chronic suberythemogenic exposure is associated more with nonmelanoma skin cancer. After severe UV radiation-induced DNA damage, keratinocytes (from which squamous and basal cell carcinomas arise) undergo apoptosis or programmed cell death. In contrast, melanocytes are resistant to this level of radiation, and their survival results in the propagation of mutated genes, especially if damaged DNA is not fully repaired [26,45].
This may be an evolutionarily selected advantage for the organism, as the melanocytes survive a sunburn and can protect regenerating keratinocytes. However, on a cellular level, melanocytes that have suffered mutation of growth-regulating genes may have an unwanted growth advantage, resulting in disordered control of cell cycling and replication. Despite the high mortality associated with melanoma, the mechanisms that diminish melanocyte apoptosis may paradoxically be evolutionarily selected, as melanomas most often arise after the age of childbearing.
Indoor tanning — In the 1920s, "sun therapy" gained popularity as a cure for multiple maladies. The French fashion designer Gabrielle "Coco" Chanel further glamorized the deep tan as a status symbol. Fifty years later, commercial tanning beds, which emit UVA light, became widespread.
Results from the United States 2010 National Health Interview Survey and 2011 Youth Risk Behavior Survey reveal that nearly one-third of White females aged 18 to 25 years reported indoor tanning in the past year, with approximately 15 percent engaging in frequent indoor tanning (≥10 sessions in the previous year) [46,47]. The analysis of data from the Health Information National Trends Survey, a mailed survey from the years 2007, 2011, 2013, 2014, 2017, and 2018, showed a substantial decrease of indoor tanning prevalence among adults (from 10 to 4 percent) and among young adults aged 18 to 34 years (14 to 4 percent) [48]. Indoor tanning decreased in states that enacted youth access legislation by 2018 but did not decrease for other states.
The reasons for the decline in the use of indoor tanning among high school students in the United States is incompletely understood. It is possible that multiple factors, including the acknowledgment of the role of UV-emitting tanning devices as a carcinogen to human skin by the World Health Organization [49], increased taxation on indoor tanning implemented in 2010, and restriction of minors from accessing indoor tanning in most states, may have increased the awareness of the health risks associated with indoor tanning in the general population.
A systematic review of 88 observational studies with nearly 500,000 participants from 16 Western countries found a summary prevalence of ever exposure to indoor tanning of 36 percent among adults, 55 percent among university students, and 19 percent among adolescents [50]. Regulations restricting the access to indoor tanning facilities to young individuals have been implemented worldwide; they are reviewed in detail elsewhere. (See "Primary prevention of melanoma", section on 'Tanning bed use'.)
Based upon evidence from multiple studies suggesting that tanning beds increase the risk of melanoma, in 2009 the World Health Organization International Agency for Research on Cancer (IARC) classified ultraviolet light emitted from tanning beds as a human carcinogen [49,51]. Subsequent observational studies and meta-analyses have confirmed the association between indoor tanning and melanoma [52-55]. Case-control studies have also found an association between tanning devices and ocular melanoma [56-58]:
●A 2021 meta-analysis of 36 observational studies with 14,583 melanoma cases showed a significant association between indoor tanning and risk of melanoma (relative risk [RR] 1.27, 95% CI 1.16-1.39) [59]. Moreover, the risk was higher for first exposure at an early age (≤20 years) and higher exposure (annual frequency ≥10 times) (RR 1.47, 95% CI 1.16-1.85 and RR 1.52, 95% CI 1.22-1.89, respectively).
●A population-based, case-control study including 681 patients with melanoma and 654 matched controls younger than 50 years found that females who had ever tanned indoors had a two- to sixfold increased risk of melanoma compared with females who had never tanned indoors [60]. Of note, among females aged 30 to 39 years and 40 to 49 years, indoor tanning was strongly associated with the risk of melanoma after controlling for known phenotypic and lifestyle risk factors for melanoma (OR 3.5, 95% CI 1.2-9.7 and OR 2.3, 95% CI 1.4-3.6, respectively). In all age groups, the risk was consistently increased for females who started tanning indoors before age 25 years and for those who reported >10 lifetime tanning sessions.
The possibility that the association between tanning bed use and melanoma in fair-skinned individuals is overestimated due to residual confounding cannot be excluded. Tanning bed use may be a marker of populations more exposed to the sun. Studies have shown that tanning bed users are more likely to be regular sunbathers and to have poorer sun protection behavior than nonusers [61,62].
A common misconception about indoor tanning is that it may be helpful to prevent sunburn, a recognized risk factor for melanoma [63] (see "Sunburn", section on 'Prevention'). A reanalysis of data from a population-based, case-control study including more than 1800 participants examined the risk of melanoma associated with indoor tanning among individuals with and without history of sunburn [64]. In this analysis, among individuals who reported no lifetime sunburns, melanoma patients were almost four times more likely to have used tanning beds than controls, after adjusting for potential confounders (OR 3.87, 95% CI 1.68-8.91).
Psoralen plus ultraviolet A therapy — Exposure to oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) used in the treatment of psoriasis and other skin conditions is associated with a late increase in the risk of melanoma. In a multicenter series of 1380 patients with severe psoriasis who were first treated with PUVA in 1975 and 1976, the incidence of invasive or in situ cutaneous melanomas was not elevated above that expected in the general population in the first 15 years following treatment. However, the incidence rate for all melanomas was increased fivefold between 16 and 20 years, and more than 12 times than expected beyond 20 years of follow-up [65]. The amount of PUVA treatment was also a factor; patients who received high doses of PUVA had a greater risk for melanoma.
PHENOTYPIC TRAITS
Skin pigmentation and tanning ability — Light skin pigmentation, red or blond hair, blue or green eyes, freckling tendency, and poor tanning ability (table 1), which reflect the skin sensitivity to sunlight, are well-known risk factors for melanoma. In a meta-analysis of observational studies, light skin phototype, blue eye color, red hair, and high freckle density were associated with a two- to fourfold increase in melanoma risk (table 2) [66].
Common (typical) nevi — Although some nevi are precursors to cutaneous melanoma, they are more often markers of increased risk [67], as only approximately one-third of melanomas arise from pre-existing nevi [68]. Common nevi are usually ≤5 mm in diameter and can be raised or flat with a round shape and uniform color (picture 1). Most of these nevi occur in photo-exposed areas.
Number of nevi — Studies have supported a strong association of high total body nevus counts with melanoma (table 2) [69-72]. The relative risk (RR) of melanoma that is associated with high total nevus counts ranges from 1.6 to 64 with a dose-response effect based upon the number of nevi present (including routine junctional, compound, and dermal nevi) [73-76]. The number most often cited as the cut-off for increased melanoma risk is 50 to 100 nevi, which is associated with an RR of 5 to 17 [77,78]. However, a meta-analysis of observational studies found that increased risk may be present in individuals with more than 25 nevi [79]. In this study, 42 percent of melanoma cases were attributable to having ≥25 typical nevi (population attributable fraction [PAF] = 0.15). Lower nevus counts were less strongly associated with melanoma (PAF for 0 to 10 nevi = 0.04, PAF for 11 to 24 nevi = 0.07).
The number of nevi on one arm appears to be predictive of the total body nevus. In a United Kingdom study involving 3694 female twins with a median age of 47 years, females with >11 nevi on the right arm were approximately nine times more likely to have a total body count of >100 nevi (odds ratio [OR] 9.4, 95% CI 6.7-13.1) [80].
"Divergent pathway" model — The "divergent pathway" model describes the theory that individuals with the propensity to develop fewer melanocytic nevi require greater sun exposure to promote the development of melanoma, and tend to develop melanoma on chronically sun-exposed sites (eg, head or neck) [69,70,81,82]. Conversely, individuals with large numbers of nevi may require less solar stimulation to drive the development of melanoma and are prone to develop melanoma in sites where large numbers of nevi are found, such as the back. This "divergent pathway" model suggests that melanomas on different sites of the body may occur via different mechanisms.
A meta-analysis of 24 observational studies found that high nevus counts were more strongly associated with the development of melanoma on the legs or trunk (RR 1.79, 95% CI 1.56-2.06 and RR 1.67, 95% CI 1.45-1.92, respectively) when compared with anatomical sites associated with chronic sun exposure, such as the head or arms (RR 1.42, 95% CI 1.23-1.64 and RR 1.60, 95% CI 1.39-1.83, respectively) [72]. In addition, a pooled analysis of ten case-control studies (2406 female melanoma patients and 3119 female controls) identified a statistically significant trend indicating an association of increasing numbers of nevi with melanoma on the trunk and limbs, but not with melanoma of the head and neck [70]. The RRs for melanoma in females with high numbers of nevi compared with females with no nevi were reported as highest for melanoma on the trunk (OR 4.6, 95% CI 2.7-7.6) and limbs (OR 3.4, 95% CI 1.5-7.9), followed by the head and neck (OR 2.0, 95% CI 0.9-4.5).
Although advances have shed much light on the mechanisms linking nevi and melanoma, many questions remain. In particular, imaging, genetics, and cognitive computing have enormous potential to stratify risk categories, but protocols for integrating them into regular clinical care are still in the developmental stage [83].
Congenital nevi — Congenital melanocytic nevi (CMN) are classically defined as melanocytic nevi present at birth or within the first few months of life. These occur in 1 to 2 percent of newborn infants, and large or giant CMN occur in approximately 1 of 20,000 births. For patients with large CMN, the risk of developing melanoma (cutaneous or extracutaneous) is estimated to be approximately 2 to 5 percent over a lifetime, with most melanomas occurring in the first five years of life [84].
The clinical features, complications, and management of CMN are discussed separately. (See "Congenital melanocytic nevi".)
Atypical nevi — Atypical nevi are benign, acquired melanocytic neoplasms that share some of the clinical features of melanoma, such as asymmetry, irregular borders, multiple colors, and diameter >5 mm. The terms "atypical nevi" and "dysplastic nevi" are clinically used interchangeably, although in theory a dysplastic nevus refers to a histologic diagnosis. Although atypical nevi are benign lesions, they are strong phenotypic markers of an increased risk of melanoma, especially in individuals with numerous nevi and/or a family history of melanoma (table 2). In a meta-analysis of observational studies, the RR of melanoma associated with atypical nevi was 1.5 (95% CI 1.3-1.6) for the presence of a single atypical nevus and 6.36 (95% CI 3.80-10.33) for five atypical nevi versus none [85].
The clinical features, diagnosis, and management of atypical nevi are discussed in detail elsewhere. (See "Atypical (dysplastic) nevi".)
FAMMM syndrome and atypical mole syndrome — Some familial cases of melanoma occur in the setting of the familial atypical multiple mole and melanoma (FAMMM) syndrome and the atypical mole syndrome. The FAMMM syndrome was originally described in families showing concordance for malignant melanoma and a cutaneous phenotype characterized by multiple large moles of variable size and color (reddish-brown to bright red) with pigmentary leakage [86,87]. Their lifetime cumulative incidence of melanoma approached 100 percent.
The atypical mole syndrome (sometimes also called the dysplastic nevus syndrome) refers to patients who have 50 to 100 or more nevi, at least one of which is ≥8 mm in diameter, and at least one with atypical features, without personal or family history of melanoma [88]. (See "Atypical (dysplastic) nevi".)
PERSONAL HISTORY OF MELANOMA — A personal history of melanoma is associated with a higher risk of developing a second primary cutaneous and noncutaneous melanoma (table 2) [89-94]. A population-based study using data from the Swedish Cancer Registry from 1958 to 2010 found that patients with either familial or sporadic melanoma have a two- to threefold increased risk of a subsequent melanoma and that the risk remains stable for patients with two or more previous melanomas [95]. An additional population-based study in the United States has shown that individuals with prior cutaneous melanoma were more likely to develop a second cutaneous melanoma (standardized incidence ratio [SIR] 8.17, 95% CI 8.01-8.33), ocular melanoma (SIR 1.99, 95% CI 1.54-2.53), oral melanoma (SIR 6.87, 95% CI 2.23-16.04), and vaginal/exocervical melanoma (SIR 10.17, 95% CI 4.65-19.30) [93].
Although the risk is highest in the first year after the initial diagnosis, it persists over time, and estimates of the risk of developing a second melanoma have ranged from 2 to 11 percent at five years [90,94,96]. In a study of 2253 patients with primary melanoma from the German Central Malignant Melanoma Registry, 146 patients (6.5 percent) developed a second primary melanoma during a median follow-up time of 73 months; in 70 patients (3 percent), a second primary tumor was detected in the first year of follow-up, and in 39 patients (1.7 percent) in the first 30 days [97]. The risk is similar for patients whose first primary cancer was either in situ or invasive melanoma [96].
Patient characteristics may influence the probability of developing additional lesions. For individuals with a history of both dysplastic nevi and cutaneous melanoma, the risk of a second primary lesion is greater than for those with a sporadic cutaneous melanoma [98].
Age and lesion site also may be markers for increased risk. In one population-based study, patients who were less than 30 years of age at the time of the initial diagnosis or who had a history of melanoma on the head or neck had a greater risk for developing a second primary lesion than other melanoma survivors [89]. An analysis of data from the Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 2006 on 551 adolescents and young adults with an invasive first primary melanoma and subsequent primary melanoma and 38,110 adolescents and young adults with only a first primary melanoma found that non-Hispanic White ethnicity, younger age at first diagnosis of melanoma, and female sex were associated with an increased risk of developing a subsequent melanoma [99].
High nevus counts, strong family history of melanoma (melanoma in more than one first-degree relative), and melanoma type also affect the risk of developing additional primary melanoma [100]. In a cohort of 1083 melanoma patients who were followed for more than 16 years, the hazard ratios (HR) for developing a second primary melanoma were highest for patients with high nevus counts (HR 2.91, 95% CI 1.94-4.35), strong family history of melanoma (HR 2.12, 95% CI 1.34-3.36), and for patients having lentigo maligna melanoma (HR 1.80, 95% CI 1.05-3.07) or nodular melanoma (HR 2.13, 95% CI 1.21-3.74) as the first primary melanoma [100].
Data obtained from the SEER registry from 1973 to 2006 indicate that compared with first melanomas, second melanomas tend to be thinner at the time of diagnosis (78 versus 70 percent <1 mm in depth) [89]. The authors of this study speculated that increased clinical surveillance and/or patient awareness following the initial diagnosis may have contributed to this finding. A general trend towards earlier detection of melanoma also may have been a factor [101]. (See "Screening for melanoma in adults and adolescents".)
GENETIC BACKGROUND — Approximately 10 percent of melanomas are familial [102]. (See "Inherited susceptibility to melanoma".)
Among subjects from melanoma families, defined as kindreds in which melanoma occurred in two or more blood relatives, the likelihood of developing melanoma is even greater among those family members who have dysplastic nevi [103,104]. In a subset of these kindreds, the apparent familial pattern of inheritance may be attributable to clustering of sporadic cases in families who share common heavy sun exposure and susceptible skin type, making genetic analysis and risk stratification more challenging. This concept is substantiated by studies in which CDKN2A mutation status, sun exposure, and prevalence of dysplastic/benign nevi influence melanoma risk in families unselected for family history as well as melanoma-prone families [76].
There appears to be considerable genetic heterogeneity among different families, suggesting that multiple genes contribute to melanoma predisposition [105]. Molecular defects in both tumor suppressor genes and oncogenes have been linked to familial melanoma:
●The major gene resides on chromosome 9p and encodes the tumor suppressor gene CDKN2A, also called p16INK4A or MTS1 (multiple tumor suppressor-1). Increased frequency of CDKN2A mutations is associated with multiple cases of melanoma in a family, early age at diagnosis, and family members with multiple primary melanomas or pancreatic cancer [106,107].
●The melanocortin-1 receptor (MC1R) gene, located on chromosome 16q24, is a key regulator of skin pigmentation. Variants of MC1R are associated with the red hair/fair skin phenotype, a known risk factor for melanoma [108]. However, some MC1R variants may carry an increased risk of melanoma independently from phenotypic characteristics and sun exposure [109,110]. In a case-control study including 991 patients with melanoma and 800 controls, carriers of two or more MC1R variants had an approximately twofold increased risk of melanoma, compared with wild type carriers, after adjusting for age, sex, number of sunburns before age 20, and signs of actinic skin damage [111].
●BAP1 mutations with a propensity for uveal (in 25 percent of carriers) and cutaneous melanomas (in 17 percent of carriers) and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome. Patients in this cohort might present with benign and/or atypical nevi phenotypes. Histologic assessment of cutaneous melanomas in this group has demonstrated spitzoid and nevoid features [112-115]. (See "BAP1-inactivated melanocytoma".)
A comprehensive review of the melanoma susceptibility genes is presented separately. (See "Inherited susceptibility to melanoma".)
HISTORY OF NONMELANOMA SKIN CANCER — Individuals who have had basal cell or squamous cell skin carcinomas appear to have not only an increased risk of developing melanoma, but also an increased risk of dying from it [116,117].
IMMUNOSUPPRESSION — De novo melanoma occurs with increased frequency in immunosuppressed patients, including organ transplant recipients, patients with lymphoma, and patients with human immunodeficiency virus (HIV) infection, and is associated with a poorer prognosis [118,119]. A population-based study of approximately 90,000 renal transplant recipients in the United States followed over a 10-year period, identified 246 patients with melanoma and a 3.6 times greater likelihood for the development of melanoma in organ transplant recipients compared with the general population [120]. This finding has been confirmed in an analysis of data from a cohort of over 105,000 renal transplant recipients from the United States Renal Data System database (years 2004 through 2012) [121]. The prevalence of melanoma in this cohort was 0.5 percent, with a standardized incidence ratio of 4.9 compared with the Surveillance, Epidemiology, and End Results population.
Among patients with melanoma treated before transplantation, recurrences are frequent (19 percent in one series), and usually occur within five years [122]. (See "Malignancy after solid organ transplantation".)
OTHER PROPOSED RISK FACTORS — A number of other factors, including occupational exposures and lifestyle factors, have been evaluated as possible risk factors for melanoma [123].
Occupational — Occupational exposure to chemicals has been examined in a number of studies focusing on polychlorinated biphenyls (PCBs), petroleum products, ionizing radiation, and selenium [124]. Although initial analyses showed patterns of increased incidence, no statistically significant occupational risk factors were found after adjustment for known risk factors such as nevus count and sun exposure.
Dietary — Studies addressing the role of dietary factors (eg, antioxidants, retinoids, vitamin C, and vitamin E) have not shown a consistent impact of diet on the incidence of melanoma [125,126]:
●Vitamin D – The role of vitamin D in the development of melanoma is controversial. A case-control study has suggested that diets rich in vitamin D and carotenoids and low in alcohol may be associated with a reduced risk for melanoma [127]. Another small, case-control study found an association between low blood levels of vitamin D (≤20 ng/ml) and melanoma risk [128]. However, a large, Mendelian, randomization study using data from a large, genome-wide association study meta-analysis of melanoma risk (12,874 cases and 23,203 controls of European ancestry) on five single nucleotide polymorphisms associated with plasma levels 25(OH)D found no association between genetically determined low levels of vitamin D and melanoma risk [129]. (See "Mendelian randomization" and "Primary prevention of melanoma", section on 'Dietary vitamin D'.)
●Alcohol – A meta-analysis of 16 case-control and cohort studies including over 6000 patients found a modest increase in melanoma risk associated with moderate to high alcohol drinking compared with no or occasional drinking (relative risk [RR] 1.20, 95% CI 1.06-1.37). The risk was 55 percent higher for individuals drinking 50 g of alcohol per day. However, these results should be interpreted with caution, since residual confounding by sun exposure cannot be excluded [130].
●Coffee – The association between coffee and tea intake and melanoma is controversial. Of note, in multiple meta-analyses of large observational studies, a protective association has been found for caffeinated coffee but not for decaffeinated coffee [131-134]. Proposed mechanisms of action of caffeine and other bioactive compounds present in regular coffee in preventing melanoma are based upon in vitro and animal studies but remain unproven in humans [135,136].
A 2016 meta-analysis including two case-control and five cohort studies including nearly 850,000 participants found a modest inverse association between coffee intake and melanoma, with a pooled RR of 0.81 (95% CI 0.68-0.97) for highest versus lowest consumption of caffeinated coffee [131]. The study found a linear dose-response relationship between melanoma risk and level of coffee intake; the risk was reduced by 4.5 percent for one cup per day increment of caffeinated coffee intake compared with no consumption. In a stratified analysis, the protective effects of caffeinated coffee were significant in females (RR 0.76, 95% CI 0.61-0.95) but not in males (RR 1.11, 95% CI 0.91-1.36). No effect was found for decaffeinated coffee.
A subsequent analysis of data from a large cohort from 10 European countries including nearly 500,000 individuals aged 25 to 70 years participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study confirmed an inverse association between caffeinated coffee and melanoma [137]. In this analysis, the consumption of caffeinated coffee or tea was associated with a decrease in melanoma risk among males but not among females (hazard ratio [HR] 0.31, 95% CI 0.14-0.69 and HR 0.96, 95% CI 0.62-1.47, respectively), after adjusting for education, smoking habit, alcohol intake, diet, body mass index, reproductive history, and use of exogenous hormones. No association was found for decaffeinated coffee or tea. However, the significance of these results remains uncertain because data on known risk factors for melanoma, including light phenotype, number of nevi, family history of melanoma, and ultraviolet radiation exposure, were not available for the participants in this study.
●Citrus fruit – An analysis of data from over 100,000 individuals participating in the Nurse's Health Study found a modest increase in melanoma risk associated with high dietary intake of citrus fruit or juice (HR 1.36, 95% CI 1.14-1.63), after adjusting for recognized risk factors for melanoma, such as family history of melanoma-phenotypic characteristics, number of nevi, and lifetime number of blistering sunburns [138]. A potential explanation for the association between melanoma and citrus fruit consumption is that citrus fruits are a source of psoralens, chemical compounds present in plants known to be photosensitizers [139]. However, the results of this study need further confirmation, because, given the small increase in risk, residual confounding cannot be excluded. In the meantime, changes in dietary advice to the public are not warranted.
Smoking — Although skin changes may be related to smoking, smoking has not been found to be an independent risk factor for melanoma [140]. One study suggested an inverse relationship between smoking and melanoma in males [141].
Oral contraceptives and postmenopausal hormone therapy — Multiple studies have assessed the risk of melanoma associated with oral contraceptive pills, with some finding an elevated risk, particularly with prolonged use. However, two meta-analyses of observational studies showed no evidence for an increased risk of melanoma with the use of oral contraceptive pills [142,143]. Posthoc analysis of the Women's Health Initiative trials on postmenopausal hormone therapy found no increased risk of melanoma with hormone therapy [144]. An EPIC cohort study found a weak, statistically nonsignificant association between oral contraceptive pill or hormone therapy use and melanoma risk [145].
Drugs — Several drugs have been associated with increased risk of melanoma:
●Tumor necrosis factor inhibitors – A connection between tumor necrosis factor (TNF)-alpha inhibitors and melanoma was initially suggested by a few case reports [146-149]. A 2011 systematic review and meta-analysis of two studies from cancer registries found an increased risk of melanoma associated with TNF (RR 1.79, 95% CI 0.92-2.67) [150].
●BRAF inhibitors – Case reports have been published describing secondary cutaneous melanoma in patients treated with BRAF inhibitors alone or in combination with MEK inhibitors. It is unclear if this association is based on a direct BRAF inhibition effect or due to the identification of synchronous melanomas that might have already been present at the time treatment was initiated [151].
●Sildenafil – A study of nearly 26,000 males participating in the Health Professionals Follow-Up Study, followed up from 2000 to 2010, found an association between sildenafil (a phosphodiesterase-5 [PDE5] inhibitor used to treat erectile dysfunction) and invasive melanoma after controlling for potential melanoma risk factors, such as age, number of moles, and severe sunburns (HR 1.84, 95% CI 1.04-3.22) [152]. However, this finding must be interpreted with caution because of the lack of control for other confounders (eg, health status, lifestyle practices) and lack of information about the dose, frequency, and duration of sildenafil use or the use of other PDE5 inhibitors.
A modest 14 to 30 percent increase in risk of melanoma for males who had at least one prescription of a PDE5 inhibitor was also found in a nested case-control study in the Swedish Prescribed Drug Register and the Swedish Melanoma Register including over 4000 males with a diagnosis of melanoma and 20,000 cancer-free male controls [153]. However, the absence of a dose-response effect for PDE5 inhibitors and the lack of information on important personal and lifestyle-related melanoma risk factors raise the question on whether this association is causal.
Finally, a large population-based matched cohort study using the United Kingdom Clinical Practice Research Datalink and including over 145,000 males with ≥1 PDE5 inhibitor prescription and 560,000 unexposed matched controls found only a weak association between PDE5 inhibitor use and incidence of melanoma (HR 1.14, 95% CI 1.01-1.29) [154]. However, the study found a similar weak association of PDE5 inhibitors with basal cell carcinoma and actinic keratosis but not colorectal cancer. These findings, in addition to the absence of a dose-response effect between PDE5 inhibitors and melanoma and the lack of information on personal sun exposure habits, suggest that the association between PDE5 inhibitors and melanoma is likely explained by the confounding effect of sun exposure.
●Voriconazole – Melanoma in situ has been reported in two patients during long-term therapy with voriconazole, an antifungal drug that has been associated with cutaneous photosensitivity and squamous cell carcinoma [155]. Additional studies are necessary to determine whether there is an association between melanoma and this drug.
Parkinson disease — Parkinson disease (PD) has been associated with an increased risk for melanoma [156-159].
An epidemiologic study involving more than 14,000 patients with PD found a statistically significant increase in the incidence of melanoma in this population compared with the general population (standardized incidence ratio 1.95, 95% CI 2.4-2.6) [156].
A Swedish, population-based, register study assessed the risk of melanoma in a cohort of approximately 12,000 patients with PD and in a matched cohort of approximately 60,000 PD-free individuals [160]. The risk of melanoma was also evaluated in approximately 17,000 siblings of PD patients and 84,000 siblings of PD-free individuals. PD patients had a 60 percent higher risk of melanoma than PD-free individuals (HR 1.61, 95% CI 1.35-1.92). In contrast, the risk of melanoma was similar in siblings of PD patients and in those of PD-free individuals.
A retrospective, United States study using data from the Rochester Epidemiology Project (REP) medical records from 1976 to 2013 identified a cohort of 974 PD patients, of whom 26 had a diagnosis of melanoma preceding the diagnosis of PD, whereas 6 had a melanoma following the diagnosis of PD [161]. Compared with controls, PD patients had a 3.8-fold increased likelihood of having a history of melanoma. Patients with melanoma identified from the same database had a 4.2-fold increased risk of developing PD after the diagnosis of melanoma compared with controls. While these findings suggest that melanoma and PD may share environmental or genetic risk factors, the underlying cause of this association remains to be clarified.
Although early case reports mentioned levodopa (a common therapy for PD) as a potential etiologic factor [162], an increased risk for melanoma precedes the diagnosis and treatment of the neurologic disorder [157]. In addition, a systematic review and a subsequent case-control study found no association between melanoma and this drug [162,163].
Other disease association — There are reports of increased melanoma risk associated with other conditions, including endometriosis and prostate cancer:
●Endometriosis – A prospective, epidemiologic study has shown a statistically significant increase of melanoma in females with endometriosis (RR 1.6) [164]. Smaller, retrospective studies have observed a similar relationship [165].
●History of prostate cancer – The United States Health Professionals' Follow-Up Study, including over 40,000 participants, found that a personal history of prostate cancer was associated with an increased risk of melanoma (HR 1.83, 95% CI 1.32-2.54, adjusted for age, body mass index, smoking, use of sildenafil, skin phototype, nevus count, family history of melanoma, and history of sun exposure) [166]. The underlying mechanism of this association is unknown. Further studies are needed to confirm the hypothesis of a potential role for androgens in the etiology of melanoma.
RISK PREDICTION MODELS — Risk prediction models provide a single personalized assessment of an individual's risk based on a combination of melanoma risk factors (rather than relying on multiple individual risk factors) and may assist clinicians in matching preventive interventions to risk levels. With increasing computational capability to process a large amount of data, one approach has been to generate melanoma risk prediction models in melanoma risk assessment to aid in management decisions. Optimally, these models can be integrated into the clinical workflow and eventually into reliable artificial intelligence algorithms and electronic medical records to maximize risk-appropriate management and patient education.
●A prediction model developed based on the "Australian Study" data identified total number of nevi ≥2 mm, solar lentigines on the upper back, hair color at age 18 years, and personal history of keratinocyte cancer as the lead criteria to include in the model [167]. The area under the curve (AUC) was 0.79 (95% CI 0.76-0.83) on internal validation in the "Australian Study" and 0.73 (95% CI 0.70-0.75) on subsequent external validation in the "Leeds Study." The authors concluded that the model may be useful for offering tailored preventive interventions, such as sun protection advice and skin screening based on personal risk level, in primary care and other clinical settings where dermatologic risk factors can be assessed. Prospective evaluation of the clinical risk prediction model will be needed.
●A prediction model to assess the risk of developing subsequent melanomas was developed based on the New South Wales Genes, Environment, and Melanoma case-control study database in which controls had single primary melanomas and cases had multiple primary melanomas [168]. A total of 1266 participants with 2613 melanomas were included in the analysis. The final model comprises 12 of the 21 initially considered risk factors, resulting in good discrimination for predicting a second melanoma (Harrell's C-statistic 0.73) and moderate discrimination (0.65) for predicting a third or fourth melanoma. The model showed a strong upward linear trend in the risk of subsequent melanoma across risk-score quintiles. The risk of a subsequent primary melanoma was substantially higher for people with two or more melanomas than for people with one (mean absolute risk 47 versus 8 percent).
●An attempt to perform a systematic review of prediction models for melanoma based on study characteristics, differences in risk factor selection and assessment, evaluation, and validation methods identified 40 studies comprising 46 different risk prediction models eligible for the review [169]. However, due to the substantial heterogeneity in risk factor selection and assessment (as well as methodologic aspects of model development) among the included studies, direct comparison was not feasible. The authors identified a total of 35 different risk factors across models, with nevi being the most common one in 35 studies (87 percent); minimal consistency in other risk factors was observed. Results of an internal validation were reported for less than one-half of the studies (n = 18, 45 percent), and only six performed external validation. In terms of model performance, 29 studies assessed the discriminative ability of their models. The authors stated that uniform methodologic standards for the development and validation of risk prediction models for melanoma and reporting standards for the accompanying publications are necessary and should be required.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Melanoma screening, prevention, diagnosis, and management".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Sunburn (The Basics)" and "Patient education: Melanoma skin cancer (The Basics)")
●Beyond the Basics topics (see "Patient education: Sunburn (Beyond the Basics)" and "Patient education: Melanoma treatment; localized melanoma (Beyond the Basics)" and "Patient education: Melanoma treatment; advanced or metastatic melanoma (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Incidence and mortality – The incidence of melanoma has increased rapidly over the years. The estimated age-standardized incidence rates of melanoma in males and females worldwide increased from 2.3 and 2.2/100,000 people, respectively, in 1990 to 3.1 and 2.8/100,000 people, respectively, in 2008. In the United States, melanoma is the fifth most common cancer in males and females. In Australia, the estimated age-standardized mortality rate in 2021 was 4 deaths per 100,000 persons. (See 'Epidemiology' above.)
●Risk factors:
•Ultraviolet radiation and patterns of exposure – Evidence suggests that ultraviolet radiation is a major risk factor for melanoma. Although ultraviolet B (UVB) radiation plays a greater role in the development of melanoma, exposure to ultraviolet A radiation (including tanning beds and psoralen plus ultraviolet A radiation [PUVA] therapy) also appears to be a risk factor. (See 'Ultraviolet radiation' above.)
Melanoma tends to be associated with a history of intense, intermittent sun exposure and most frequently occurs on areas that are exposed to the sun sporadically, such as the back in males and legs in females. However, chronic sun exposure may contribute to the development of melanoma on other sites, such as the head and neck. A history of multiple severe sunburns in childhood is also associated with increased melanoma risk. (See 'Timing and pattern of sun exposure' above.)
•Indoor tanning – The results of several studies have implicated tanning beds as a risk factor for melanoma. In 2009, the World Health Organization classified ultraviolet light emitted from tanning beds as a human carcinogen. Ultraviolet A therapy with high doses of psoralens (PUVA) has also been identified as a risk factor for melanoma. (See 'Indoor tanning' above and 'Psoralen plus ultraviolet A therapy' above.)
•Phenotypic traits and genetic background – Patient-specific factors influence the risk for melanoma. High numbers of typical nevi, the presence of atypical nevi, a personal history of melanoma, and genetic factors can increase risk. Patients with the familial atypical multiple mole and melanoma (FAMMM) syndrome have a risk of melanoma much greater than that of the general population. (See 'Common (typical) nevi' above and 'Atypical nevi' above and 'Personal history of melanoma' above and 'Genetic background' above.)
●Counseling for high-risk patients – Patients at high risk for melanoma should be counseled about sun protection and skin self-examination and should be followed with periodic dermatologic evaluation, including dermoscopy and digital imaging where available, according to melanoma risk stratification protocols. (See "Primary prevention of melanoma".)
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