**2. Etiopathogenesis**

#### **2.1. Risk factors**

The cancer statistic in the United States was reported to be 6 cases per 100.000 inhabitants at the beginning of the 1970s and 18 cases per 100.000 and year at the beginning of 2000, thus demonstrating a threefold increase in incidence rates. Incidence rates in central Europe increased in the same time period, from 3 to 4 cases to 10 to 15 cases per 100.000 inhabitants and year, which is very similar to the increase in the United States. The highest incidence rates were reported in Australia and New Zealand, with 30 to 60 cases per 100.000 inhabitants and year [4]. Cutaneous melanoma ranks as the sixth most common cancer in American men and women, the second most common cancer in patients between the ages of 20 and 35, and the leading cause of cancer death in women ages 25 to 30 years [5]. Although melanoma accounts for 5% of all skin cancers in the United States, it is responsible for the most common skin cancerrelated deaths (it accounts for 79 percent of all skin cancer deaths) because of its high mortality when identified at an advanced stage [6, 7]. The number of deaths due to CMM has also increased in most fair-skinned populations throughout the world in the past few decades. However, melanoma mortality rates have been rising at a rate of increase lower than that for melanoma incidence. Between 1955 and 1984, mortality from CMM had been rising both in young adults (20–44 years) and in middle-aged populations (45–64 years) in most European countries, North America, Australia and New Zealand, with a rate of increase of 2–4% annually. In Australia in 1985–1999 the mean age-standardized mortality rates were 4.8 and 2.5 per 100.000 in men and women, respectively. In 1990–1994 the rate rose by 3.7% in men to 5.0 per 100.000 and in women it fell by 5.2% to 2.4 per 100.000 [3]. Although mortality rates have increased, 5-year survival has steadily improved over recent decades, and is now greater than 85%, but melanoma causes disproportionate mortality in those of young and middle age, such that an average of 18.6 years of potential life are lost for each melanoma death in the USA, one of the highest rates for adult-onset cancers [8]. Predicted 1-year survival for stage IV disease

The etiology of melanoma is multifactorial that environmental, host, and genetic factors contribute to its development. The most important environmental risk factor is ultraviolet radiation (UVR) exposure [6]. Most melanomas are thought to be caused by periodic, intense sun exposure (particularly during the critical time period of childhood and adolescence), termed the *intermittent exposure* hypothesis, though exposure in adulthood certainly also plays a part. In older people, melanomas appear to be more related to chronic exposure. This is suggested by the body site distribution of melanomas in the elderly, with more melanomas on chronically exposed body sites [7, 9]. The most important host risk factor for CMM in fairskinned people is the presence of both common acquired and atypical (dysplastic) melanocytic naevi. Patients with a family history of melanoma are at increased risk. Around 5–12% of patients with melanoma have a family history of CMM in one or more first-degree relatives. Some of these patients have an inherited mutation in highly penetrant susceptibility genes

Cutaneous malignant melanoma is currently classified into four major clinical subtypes: Superficial spreading, nodular, acral lentiginous, and lentigo maligna, of which superficial spreading melanoma is by far the most common form (approximately 70%) of CMM [10]. CMM that is less invasive and locally defined at diagnosis has a five-year survival rate of more than

which are associated with a significantly increased risk of melanoma [3].

ranges between 41% and 59% [5].

68 Highlights in Skin Cancer

The etiology of melanoma is multifactorial, with environmental, host, and genetic factors contributing to its development. Ultraviolet radiation exposure is the most important envi‐ ronmental risk factor [6]. The precise type of sun exposure that is causal has been controversial but the data are now strong that the dominant cause is intermittent sun exposure [12]. Periodic and intense sun exposure rather than long, heavy sun exposure especially during childhood and adolescence is the feature of intermittent sun exposure. Also, sunburn history particularly blistering and peeling burns are important indicators for intermittent sun exposure [7].

In a meta-analysis by *Dennis* et al., an increased risk of melanoma was seen with an increasing number of sunburns for all time-periods, including childhood, adolescence, adulthood, and lifetime [13]. The relationship between melanoma and exposure to ultraviolet light is complex that lower incidence of melanoma among people who work outdoors is seen compared with those working indoors. The possible explanation for this is that chronically tanned skin is less melanoma-prone than untanned skin exposed to bursts of high intensity sun, in particular sunburns [14].

that determine naevus number are also common melanoma susceptibility genes [12]. Many of the oncogenic mutations initially identified in melanomas have also been detected in benign

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Any family history increases the risk of melanoma. Familial melanoma comprises 10-15% of all patients with melanoma [7,12]. The presence of more than one case of melanoma in a family may occur by chance alone, or may be due to low penetrance alleles and/or sun exposure habits common to affected relatives. However, an estimated 25% of familial melanoma is associated with germline mutations of the CDKN2A gene on chromosome 9 (which codes for the cell cycle inhibitor protein, p16) and often presents with an autosomal dominant pattern of

Melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocyte. These abnormalities promote cell proliferation and prevent normal pathways of apoptosis in response to DNA damage [8]. The driving force behind the initiation and progression of melanoma development is the acquisition of somatic mutations in key regula‐ tory genes. The first gene found to be specifically altered in melanoma was *NRAS*, which harbors mutations in 15–25% of melanoma cell lines and primary tumors [14]. *NRAS* mutations tend to occur in melanomas arising from intermittently sun-exposed skin [5]. *NRAS* mutations are more common in patients with nodular melanomas and melanomas arising on chronically sun-damaged skin. Recent data have shown that *NRAS* mutations may be associated with thicker tumors (>1 mm) and higher mitotic rate (>1/mm2) compared with mutations in *BRAF*. In response to a variety of cellular stimuli, including ligand-mediated activation of receptor tyrosine kinases (RTKs), RAS assumes an activated, GTP-bound state, leading to recruitment of RAF to the plasma membrane and phosphorylation-driven activation of the RAF-MEK-ERK cascade [14]. RAS genes acquire their transforming activity following the acquisition of a single-point mutation that impairs their GTPase activity and leads to constit‐ utive signaling through the mitogen-activated protein kinase (MAPK), PI3K/AKT, and Ral-GDS pathways [18]. *Omholt* et al. demonstrated that *NRAS* mutations are present in the radial growth phase (RGP) of primary melanoma lesions as well as in tumor-associated nevi and that they are preserved in corresponding vertical growth phase (VGP) and metastatic lesions [19].

BRAF is a serine/threonine kinase, which is a major player in the Ras-Raf-Mek-Erk mitogenactivated protein kinase (MAPK) signaling transduction pathway that regulates cell growth, proliferation, and differentiation in response to various stimuli [7]. Mutations in *BRAF* have been found in about 60% of melanoma samples and cell lines. *BRAF* mutations are common in benign and dysplastic nevi pointing to a potential initiating role of *BRAF* in melanocyte transformation [20]. *BRAF* mutations are more common in intermittently UV-exposed skin compared with chronically sun exposed skin or relatively unexposed skin (eg, acral sites, mucosal sites), which more frequently demonstrate *KIT* mutations. Acral and mucosal melanomas have infrequent *BRAF* mutations, and show greater numbers of chromosomal aberrations. There can also be frequent gains in *CCND1* and regions of chromosome 22, and losses from chromosome 4q. *Curtin* et al. demonstrated that melanomas arising on skin without

melanocytic proliferations [5].

transmission [17].

**2.2. Genetics**

The geographic distribution of melanoma supports the importance of UVR exposure in its pathogenesis. Living closer to the equator, where there is the greatest ambient solar radiation, is consistently associated with increased melanoma risk [6]. When the incidence and mortality rates of melanoma compared between Europe and Australia it was reported 5 to 10 times higher incidence rates in Australia [4]. Melanoma incidence and mortality among Caucasians correlate inversely with latitude of residence and dose of UV radiation, termed *latitude gradient.* In the United States, SEER (Surveillance Epidemiology and End Results) data from 1992 to 2001 demonstrate that the latitude gradient applies only to non-Hispanic whites; melanoma incidence was not associated with latitude and UV index in Afro-Americans, Hispanics, Asians and Native Americans [7]. Migration studies also provide evidence for the effect of ambient UVR exposure levels on melanoma risk [6]. Younger migrants to sunny areas have an increased risk for melanoma as compared with adult immigrants [7].

The anatomic distribution of melanoma also offers insight into the pathogenesis of the disease and the role of UVR. The most common sites for melanoma are the trunk in men and the lower legs in women which are areas of high levels of acute, intermittent sun exposure. In older people, there is a greater incidence of melanomas located on chronically sun exposed areas with maximal cumulative sun exposure that the face is the most common location [6,7].

*Cust* et al. reported that UV radiation exposure from sunbeds is a risk factor for early-onset melanoma, particularly melanoma diagnosed between ages 18 and 29 years [15]. Artificial lights (psoralen and ultraviolet A light (PUVA), UVB and tanning booths) have been associated with the development melanoma [7].

Weaker phenotypic risk factors are related to; the presence of skin that burns easily in the sun such as: skin phototype I-II, high density of freckles, fair complexion/sun sensitivity, an increased number of common or atypical/dysplastic nevi (moles), blue eye colour and red hair colour [12]. *Loria* et al. reported that the crude relative risk increased significantly for individ‐ uals with red hair, but hair color was no longer significant in multivariate analysis and lightcolored eyes were an independent risk factor even after controlling for the number of nevi, skin type, and other relevant factors [16].

The strongest phenotypic risk factor for melanoma is the presence of increased numbers of melanocytic naevi [12]. With growing numbers of melanocytic nevi, the melanoma risk increases nearly linearly. In addition, the presence of atypical melanocytic nevi was found to be an independent risk factor [4]. Adults with more than 100 clinically typical-appearing nevi, children with more than 50 typical-appearing, and any patient with atypical nevi are at risk. Large congenital nevi are recognized potential precursors of melanoma, although the degree of risk varies depending on the size of the lesion [7]. Twin studies have provided strong evidence that naevus number is predominantly genetically determined with a smaller effect of environmental factors, particularly sun exposure. It is theorized, therefore, that the genes that determine naevus number are also common melanoma susceptibility genes [12]. Many of the oncogenic mutations initially identified in melanomas have also been detected in benign melanocytic proliferations [5].

Any family history increases the risk of melanoma. Familial melanoma comprises 10-15% of all patients with melanoma [7,12]. The presence of more than one case of melanoma in a family may occur by chance alone, or may be due to low penetrance alleles and/or sun exposure habits common to affected relatives. However, an estimated 25% of familial melanoma is associated with germline mutations of the CDKN2A gene on chromosome 9 (which codes for the cell cycle inhibitor protein, p16) and often presents with an autosomal dominant pattern of transmission [17].

#### **2.2. Genetics**

that lower incidence of melanoma among people who work outdoors is seen compared with those working indoors. The possible explanation for this is that chronically tanned skin is less melanoma-prone than untanned skin exposed to bursts of high intensity sun, in particular

The geographic distribution of melanoma supports the importance of UVR exposure in its pathogenesis. Living closer to the equator, where there is the greatest ambient solar radiation, is consistently associated with increased melanoma risk [6]. When the incidence and mortality rates of melanoma compared between Europe and Australia it was reported 5 to 10 times higher incidence rates in Australia [4]. Melanoma incidence and mortality among Caucasians correlate inversely with latitude of residence and dose of UV radiation, termed *latitude gradient.* In the United States, SEER (Surveillance Epidemiology and End Results) data from 1992 to 2001 demonstrate that the latitude gradient applies only to non-Hispanic whites; melanoma incidence was not associated with latitude and UV index in Afro-Americans, Hispanics, Asians and Native Americans [7]. Migration studies also provide evidence for the effect of ambient UVR exposure levels on melanoma risk [6]. Younger migrants to sunny areas

The anatomic distribution of melanoma also offers insight into the pathogenesis of the disease and the role of UVR. The most common sites for melanoma are the trunk in men and the lower legs in women which are areas of high levels of acute, intermittent sun exposure. In older people, there is a greater incidence of melanomas located on chronically sun exposed areas with maximal cumulative sun exposure that the face is the most common location [6,7].

*Cust* et al. reported that UV radiation exposure from sunbeds is a risk factor for early-onset melanoma, particularly melanoma diagnosed between ages 18 and 29 years [15]. Artificial lights (psoralen and ultraviolet A light (PUVA), UVB and tanning booths) have been associated

Weaker phenotypic risk factors are related to; the presence of skin that burns easily in the sun such as: skin phototype I-II, high density of freckles, fair complexion/sun sensitivity, an increased number of common or atypical/dysplastic nevi (moles), blue eye colour and red hair colour [12]. *Loria* et al. reported that the crude relative risk increased significantly for individ‐ uals with red hair, but hair color was no longer significant in multivariate analysis and lightcolored eyes were an independent risk factor even after controlling for the number of nevi,

The strongest phenotypic risk factor for melanoma is the presence of increased numbers of melanocytic naevi [12]. With growing numbers of melanocytic nevi, the melanoma risk increases nearly linearly. In addition, the presence of atypical melanocytic nevi was found to be an independent risk factor [4]. Adults with more than 100 clinically typical-appearing nevi, children with more than 50 typical-appearing, and any patient with atypical nevi are at risk. Large congenital nevi are recognized potential precursors of melanoma, although the degree of risk varies depending on the size of the lesion [7]. Twin studies have provided strong evidence that naevus number is predominantly genetically determined with a smaller effect of environmental factors, particularly sun exposure. It is theorized, therefore, that the genes

have an increased risk for melanoma as compared with adult immigrants [7].

sunburns [14].

70 Highlights in Skin Cancer

with the development melanoma [7].

skin type, and other relevant factors [16].

Melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocyte. These abnormalities promote cell proliferation and prevent normal pathways of apoptosis in response to DNA damage [8]. The driving force behind the initiation and progression of melanoma development is the acquisition of somatic mutations in key regula‐ tory genes. The first gene found to be specifically altered in melanoma was *NRAS*, which harbors mutations in 15–25% of melanoma cell lines and primary tumors [14]. *NRAS* mutations tend to occur in melanomas arising from intermittently sun-exposed skin [5]. *NRAS* mutations are more common in patients with nodular melanomas and melanomas arising on chronically sun-damaged skin. Recent data have shown that *NRAS* mutations may be associated with thicker tumors (>1 mm) and higher mitotic rate (>1/mm2) compared with mutations in *BRAF*. In response to a variety of cellular stimuli, including ligand-mediated activation of receptor tyrosine kinases (RTKs), RAS assumes an activated, GTP-bound state, leading to recruitment of RAF to the plasma membrane and phosphorylation-driven activation of the RAF-MEK-ERK cascade [14]. RAS genes acquire their transforming activity following the acquisition of a single-point mutation that impairs their GTPase activity and leads to constit‐ utive signaling through the mitogen-activated protein kinase (MAPK), PI3K/AKT, and Ral-GDS pathways [18]. *Omholt* et al. demonstrated that *NRAS* mutations are present in the radial growth phase (RGP) of primary melanoma lesions as well as in tumor-associated nevi and that they are preserved in corresponding vertical growth phase (VGP) and metastatic lesions [19].

BRAF is a serine/threonine kinase, which is a major player in the Ras-Raf-Mek-Erk mitogenactivated protein kinase (MAPK) signaling transduction pathway that regulates cell growth, proliferation, and differentiation in response to various stimuli [7]. Mutations in *BRAF* have been found in about 60% of melanoma samples and cell lines. *BRAF* mutations are common in benign and dysplastic nevi pointing to a potential initiating role of *BRAF* in melanocyte transformation [20]. *BRAF* mutations are more common in intermittently UV-exposed skin compared with chronically sun exposed skin or relatively unexposed skin (eg, acral sites, mucosal sites), which more frequently demonstrate *KIT* mutations. Acral and mucosal melanomas have infrequent *BRAF* mutations, and show greater numbers of chromosomal aberrations. There can also be frequent gains in *CCND1* and regions of chromosome 22, and losses from chromosome 4q. *Curtin* et al. demonstrated that melanomas arising on skin without 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].

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‐

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Sunlight and most particularly the ultraviolet spectrum of sunlight is the only environmental

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

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

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

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

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 high-

during childhood is a more important risk factor than exposure in adulthood [30, 31].

tion, including sunbathing, which increases exposure to solar UV radiation [28].

factor that has been compellingly implicated as a cause of melanoma [29].

melanoma. Instead it is merely statistically correlated [32].

melanoma are at risk of developing a second primary tumor [34, 35].

have been identified as the highest and lowest [36].

**3.1. Environmental factors**

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

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