**3. Epidemiology**

Generally, an individual's risk for developing melanoma depends on two groups of factors; intrinsic and extrinsic that is environmental. "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the formation of a tumor [26].

Cutaneous malignant melanoma is the most serious form of skin cancer. In general, cutaneous melanoma most commonly affects adult Caucasians and is rarely observed before puberty. Melanoma may occur at any age, although children younger than age 10 years rarely develop a de novo melanoma. It was reported that in 2002 there were 53.600 new cases, and 7.400 deaths from cutaneous malignant melanoma in the United States. The incidence rate of MM has increased 4% per year since 1973 [27]. This epidemic of MM is also evident in other parts of the industrialized world, including Australia and southern Europe. It is predicted that the incidence of MM will continue to increase as a result of the continuing decrease in the concentration of stratospheric ozone and increasing leisure time for sunlight-related recrea‐ tion, including sunbathing, which increases exposure to solar UV radiation [28].

#### **3.1. Environmental factors**

chronic sun-induced damage had frequent mutations in *BRAF* and frequent losses of chro‐ mosome 10, whereas melanomas on skin with chronic sun-induced damage had infrequent mutations in *BRAF* and frequent increases in the number of copies of the *CCND1* gene [21]. *Omholt* et al. demonstrated that *BRAF* mutations occur at an early stage during melanoma pathogenesis rather than being associated with metastasis initiation. Although the *BRAF* mutations do not seem to be important for metastasis initiation, the finding that they are preserved throughout tumor progression suggests that they may still influence tumor maintenance [19]. Although *BRAF* mutations are highly prevalent (59%) in melanomas occurring on skin without chronic sun damage, *BRAF* mutations are significantly less frequent in acral and mucosal melanomas. *BRAF* mutations are more commonly detected in superficial spreading melanomas and melanomas that arise on nonchronically sun-damaged skin [5].

The two recognized major melanoma susceptibility genes, *CDKN2A,* located on chromosome 9p21.3, and *CDK4* both, are involved in controlling cell division. *CDKN2A* mutations are found in approximately 20% of tested melanoma families, while *CDK4* mutations have been found to date in only a few families. *CDKN2A* encodes for two gene products, p14ARF (alternative reading frame) and p16 (also known as INK4A, inhibitor of kinase 4a), which regulate cell cycle entry at the G1 checkpoint and stabilize p53 expression [18, 22, 23]. When defective, p16 is unable to inactivate CDK4 and CDK6, which phosphorylate Rb, releasing the transcription

The *PTEN* gene, located on chromosome 10, encodes a tumor suppressor protein and has also gained considerable attention as the understanding of melanoma pathogenesis has increased [24]. The negative regulation of cell interactions with the extracellular matrix could be the way PTEN phosphatase acts as a tumor suppressor. PTEN gene plays an essential role in human development. Mutations in *PTEN* are found in 10%-20% of primary melanomas and have also been associated with thyroid, breast, and prostate cancer [5,25]. *PTEN* encodes a negative regulator of extracellular growth signals that are transmitted via the phosphatidylinositol-3 kinase (PI3K)-AKT pathway [14]. Inactivation of *PTEN* allows signaling through the AKT

Generally, an individual's risk for developing melanoma depends on two groups of factors; intrinsic and extrinsic that is environmental. "Intrinsic" factors are generally an individual's family history and inherited genotype, while the most relevant environmental factor is sun exposure. Epidemiologic studies suggest that exposure to ultraviolet radiation (UVA and UVB) is one of the major contributors to the development of melanoma. UV radiation causes damage to the DNA of cells, typically thymine dimerization, which when unrepaired can create mutations in the cell's genes. When the cell divides, these mutations are propagated to new generations of cells. If the mutations occur in protooncogenes or tumor suppressor genes, the rate of mitosis in the mutation-bearing cells can become uncontrolled, leading to the

pathway, which contributes to aberrant cell growth and escape from apoptosis [5].

factor E2F and leading to cell cycle progression [8].

**3. Epidemiology**

72 Highlights in Skin Cancer

formation of a tumor [26].

Sunlight and most particularly the ultraviolet spectrum of sunlight is the only environmental factor that has been compellingly implicated as a cause of melanoma [29].

Possible significant elements in determining risk include the intensity and duration of sun exposure, the age at which sun exposure occurs, and the degree of skin pigmentation. Exposure during childhood is a more important risk factor than exposure in adulthood [30, 31].

Individuals with blistering or peeling sunburns (especially in the first twenty years of life) have a significantly greater risk for melanoma. This does not mean that sunburn is the cause of melanoma. Instead it is merely statistically correlated [32].

Fair and red-headed people, individuals with multiple atypical nevi or dysplastic nevi and people born with giant congenital melanocytic nevi are at increased risk [33]. Melanoma incidence is 10–20-fold higher among the fair-skinned than the dark-skinned people. Among fair-skinned people, melanoma incidence generally increases with proximity to the equator (some exceptions occur, particularly in continental Europe, where the association is confound‐ ed by pigmentation). Fair-skinned migrants from high- (e.g. the UK) to low-latitude countries (e.g. Australia) have lower melanoma rates than native-born residents, and vice versa [29].

History of melanoma in melanoma-prone families due to mutations in some genes were found to greatly increase the risk of a person. (e.g. CDKN2A and CDK4). Patients with a history of melanoma are at risk of developing a second primary tumor [34, 35].

Looking at the geographical distribution of the incidence of malignant melanoma in Europe has increased in Northern Europe, especially Scandinavian countries (20.7 per 100.000 personyear). Incidence rates were lowest in Southern and Eastern Europe for both males and females, with rates between 5-10 per 100.000 person-year. mortality rates in studies conducted in Europe (5.1 per 100 000 person-years ranging from 2.5) was found to be different in a lot less. Death rates lower in women than men had been established. In the 1990s compared the incidence and mortality rates in southern and eastern Europe, northern and western Europes have been identified as the highest and lowest [36].

Between the years 1970-2009, a study conducted among young adults in the United States the incidence of cutaneous melanoma is increasing rapidly, especially among women. This highrisk population should be closely monitored constantly [37]. The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed and managed in the outpatient setting [38].

tory changes in *Europe* regarding the range of pesticides available for domestic use. However, data from these studies indicate that questions regarding the type and frequency of pesticide

Current Management of Malignant Melanoma: State of the Art

http://dx.doi.org/10.5772/55304

75

Xeroderma pigmentosum (XPD) is a genetic disorder with a mutation of the XPD gene leading to nucleotide excision repair defects. Patients experience 1000-fold greater risk of melanoma as they are unable to repair UV-induced DNA damage. The relative ability to repair DNA modifies the risk in the presence of other host factors such as age, poor tanning ability and dysplastic naevi. Two polymorphisms of the XPD gene are associated with a decreased risk of melanoma among women with five or more severe sunburns or high cumulative sun exposure. Mutations of the melanocortin-1 receptor gene variants are more common among fair-skinned and red-haired people. Polymorphism of this gene is associated with melanoma. The risky factors are the phenotype of pigmentation of the individual, the presence of atypical naevi, >50 melanocytic naevi, high recreational and occupational sun exposures [45]. People with a past history of other types of skin cancer (basal cell carcinomas and squamous cell carcinomas) caused by high doses of solar UV radiation have threefold higher risks of melanoma than the

Several forms of artificial light have been associated with the development of melanoma in some studies: fluorescent lighting and suntan beds and parlors. Although exposure to fluorescent lighting was hypothesized to increase risk for developing melanoma, there have been no studies to support this idea. On the other hand, the use of tanning lamps and tanning

Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation like pregnancy, have led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has already been diagnosed [41, 49, 50].

The most common sites that melanomas are found include the trunk (back) followed by the upper extremities, and head and neck for men; and the lower extremities followed by the back,

use should be added to future case–control studies [43, 44].

**3.4. Genetic factors**

average population [46].

parlors may increase risk for melanoma [47, 48].

**3.6. Female sex hormones and melanoma**

**4. Clinical presentation**

**3.5. Artificial light**

While melanoma accounts for roughly 4% of all skin cancers, it causes more than 75% of skin cancer deaths. Treatment of melanoma in its early stages provides the best opportunity for cure. In the United States, an estimated approximately 9.000 deaths will occur in 2012. Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics for melanoma, from 2002, demonstrated a prevalence of 37.7 cases per 100.000 men and 29.4 cases per 100.000 women in Australia and New Zealand, compared with 6.4 cases per 100,000 men and 11.7 cases per 100.000 women in North America [39].

Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation such as pregnancy, has led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has already been diagnosed [40, 41].

### **3.2. Occupation and melanoma**

Airline crews, particularly pilots, have been recorded in a number of studies as having a higherthan-expected incidence of melanoma. It is suggested that this may be due to greater oppor‐ tunities for recreational sun exposure during regulation breaks between flights in areas of the world with a high solar exposure [42].

A number of publications show conflicting results concerning the risk of melanoma developing after renal transplantation and the necessary immunosuppression. Studies from Sweden and the Netherlands show no increase in melanoma incidence over that expected in these countries [43], while studies from the USA and UK show a significantly increased risk, 3.6- and 8-fold higher for USA and UK patients, respectively. While some of these differences may relate to time frames of studies and changes in immunosuppressive regimes over time, further large long-term contemporary studies are required to determine the degree of increased cutaneous surveillance required for transplant patients [44].

#### **3.3. Pesticide exposure**

A case–control study comparing melanoma on the palms and soles in both the UK and Australia observed that melanoma patients reported greater exposure to pesticides than that reported by controls, and recently, an Italian case–control study has confirmed higher use of pesticides in a residential setting in melanoma patients compared with that in controls. Interpretation of these data is complex, as over the past decade there have been many regula‐ tory changes in *Europe* regarding the range of pesticides available for domestic use. However, data from these studies indicate that questions regarding the type and frequency of pesticide use should be added to future case–control studies [43, 44].

#### **3.4. Genetic factors**

risk population should be closely monitored constantly [37]. The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed

While melanoma accounts for roughly 4% of all skin cancers, it causes more than 75% of skin cancer deaths. Treatment of melanoma in its early stages provides the best opportunity for cure. In the United States, an estimated approximately 9.000 deaths will occur in 2012. Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics for melanoma, from 2002, demonstrated a prevalence of 37.7 cases per 100.000 men and 29.4 cases per 100.000 women in Australia and New Zealand, compared with 6.4 cases per 100,000 men and 11.7 cases

Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation such as pregnancy, has led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has

Airline crews, particularly pilots, have been recorded in a number of studies as having a higherthan-expected incidence of melanoma. It is suggested that this may be due to greater oppor‐ tunities for recreational sun exposure during regulation breaks between flights in areas of the

A number of publications show conflicting results concerning the risk of melanoma developing after renal transplantation and the necessary immunosuppression. Studies from Sweden and the Netherlands show no increase in melanoma incidence over that expected in these countries [43], while studies from the USA and UK show a significantly increased risk, 3.6- and 8-fold higher for USA and UK patients, respectively. While some of these differences may relate to time frames of studies and changes in immunosuppressive regimes over time, further large long-term contemporary studies are required to determine the degree of increased cutaneous

A case–control study comparing melanoma on the palms and soles in both the UK and Australia observed that melanoma patients reported greater exposure to pesticides than that reported by controls, and recently, an Italian case–control study has confirmed higher use of pesticides in a residential setting in melanoma patients compared with that in controls. Interpretation of these data is complex, as over the past decade there have been many regula‐

and managed in the outpatient setting [38].

74 Highlights in Skin Cancer

per 100.000 women in North America [39].

already been diagnosed [40, 41].

**3.2. Occupation and melanoma**

**3.3. Pesticide exposure**

world with a high solar exposure [42].

surveillance required for transplant patients [44].

Xeroderma pigmentosum (XPD) is a genetic disorder with a mutation of the XPD gene leading to nucleotide excision repair defects. Patients experience 1000-fold greater risk of melanoma as they are unable to repair UV-induced DNA damage. The relative ability to repair DNA modifies the risk in the presence of other host factors such as age, poor tanning ability and dysplastic naevi. Two polymorphisms of the XPD gene are associated with a decreased risk of melanoma among women with five or more severe sunburns or high cumulative sun exposure.

Mutations of the melanocortin-1 receptor gene variants are more common among fair-skinned and red-haired people. Polymorphism of this gene is associated with melanoma. The risky factors are the phenotype of pigmentation of the individual, the presence of atypical naevi, >50 melanocytic naevi, high recreational and occupational sun exposures [45]. People with a past history of other types of skin cancer (basal cell carcinomas and squamous cell carcinomas) caused by high doses of solar UV radiation have threefold higher risks of melanoma than the average population [46].

#### **3.5. Artificial light**

Several forms of artificial light have been associated with the development of melanoma in some studies: fluorescent lighting and suntan beds and parlors. Although exposure to fluorescent lighting was hypothesized to increase risk for developing melanoma, there have been no studies to support this idea. On the other hand, the use of tanning lamps and tanning parlors may increase risk for melanoma [47, 48].

#### **3.6. Female sex hormones and melanoma**

Differing melanoma incidence between males and females, and the tendency for females to develop excess melanin pigmentation during periods of hormonal stimulation like pregnancy, have led to a number of studies investigating the role of pregnancy, oral contraceptives and hormone replacement therapy both as risk factors for melanoma and also as events that may affect prognosis. Cumulative data from publications on these topics provide no evidence that prior pregnancy is a risk factor for melanoma. Similarly, there is no evidence to indicate that oral contraceptive or hormone replacement use contributes to melanoma risk, nor that either factor alters the prognosis for those in whom melanoma has already been diagnosed [41, 49, 50].
