**1. Introduction**

[145] Hoek, K, Rimm, D. L, Williams, K. R, Zhao, H, Ariyan, S, et al. (2004). Expression profiling reveals novel pathways in the transformation of melanocytes to melano‐

[146] Seftor, R. E, Seftor, E. A, Koshikawa, N, Meltzer, P. S, Gardner, L. M, et al. (2001). Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embry‐

[147] Jaeger, J, Koczan, D, Thiesen, H. J, Ibrahim, S. M, Gross, G, et al. (2007). Gene expres‐ sion signatures for tumor progression, tumor subtype, and tumor thickness in laser-

[148] Weeraratna, A. T, Jiang, Y, Hostetter, G, Rosenblatt, K, Duray, P, et al. (2002). Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer

[149] Becker, B, Roesch, A, Hafner, C, Stolz, W, Dugas, M, et al. (2004). Discrimination of melanocytic tumors by cDNA array hybridization of tissues prepared by laser pres‐

[150] Winnepenninckx, V, Lazar, V, Michiels, S, Dessen, P, Stas, M, et al. (2006). Gene ex‐ pression profiling of primary cutaneous melanoma and clinical outcome. J Natl Can‐

[151] Haqq, C, Nosrati, M, Sudilovsky, D, Crothers, J, Khodabakhsh, D, et al. (2005). The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A , 102,

onic vasculogenesis by aggressive melanoma. Cancer Res , 61, 6322-6327.

microdissected melanoma tissues. Clin Cancer Res , 13, 806-815.

sure catapulting. J Invest Dermatol , 122, 361-368.

mas. Cancer Res , 64, 5270-5282.

Cell , 1, 279-288.

66 Highlights in Skin Cancer

cer Inst , 98, 472-482.

6092-6097.

The word "melanoma" was first used by *Rene Laennec*, inventor of the stethoscope, in his manuscript reporting a case of disseminated melanoma in 1812 [1]. Cutaneous malignant melanoma (CMM) arises from the malignant transformation of the pigment producing melanocytes, which are located and evenly distributed in the basal epidermal layer of human skin. These pigment-producing cells (melanocytes) are located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes [2].

The incidence of cutaneous malignant melanoma has increased significantly among all Caucasian populations over the last several decades. The rate of incidence of cutaneous melanoma continues to rise almost inexorably in populations of European origin worldwide. Diagnosis of melanoma at an early stage is almost curable but there is currently no effective treatment for advanced melanoma. Probably a large proportion of melanomas can be ascribed to a single (modifiable) risk factor-sun exposure. It has not been established whether medical intervention of any kind influences the outcome in the case of melanoma. Major initiatives in recent years have concentrated on education about sun avoidance, the importance of skin awareness and skin examination, and the screening of populations at high risk for melanoma. However, it is unclear whether any of the latter measures have had any significant influence on mortality from melanoma. The annual increase in incidence rate varies between popula‐ tions, but in general has been in the order of 3–7% per year for fair-skinned Caucasian populations. CMM represents a significant and growing public health burden because of the increase in incidence and the consequent mortality [3].

© 2013 Kutlubay et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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 ranges between 41% and 59% [5].

95% after treatment by surgical excision alone. Fortunately, the vast majority of CMM (approximately 80%) are diagnosed at this early stage. If the cancer is more advanced, however, survival rates drop substantially to 30% to 60% after five years, depending on the tumor thickness in millimeters (*Breslow*'s depth). Metastatic disease has poor patient outcomes as

Current Management of Malignant Melanoma: State of the Art

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

69

The prognosis for a patient with a newly diagnosed cutaneous melanoma depends mainly on two factors— the thickness of the primary tumour and the presence or absence of metastasis to regional lymph nodes. However, other prognostic factors are very important, including tumour ulceration, mitotic rate, and presence of regression, as well as sex and age of the patient,

For the primary prevention, physical protection from exposure to sunlight is generally accepted as the most important element of melanoma risk reduction. It seems particularly meaningful to prevent multiple erythemas during childhood, convincing parents and care takers not to let children stay too long under the sun. Sun-protective clothing and hats should be worn and peak hours of sun intensity should be avoided. For these purposes, mass media campaigns and widespread public education programmes would be most effective to make changes in attitude and behaviour towards sun protection [8,11]. The wavelength of light that is causal for melanoma is still not known and therefore sunscreens should be broad-spectrum types, providing protection across both UVB and UVA ranges. Advice should be to use sunscreens that are water proof, and sunscreens must be applied regularly and in sufficient quantities [12]. Regular screening of the total population for CMM does not seem useful and is not propagated in any country in the world. However, it seems likely that people with a familial risk of developing melanomas (those with familial or sporadic dysplastic naevus syndrome, xeroderma pigmentosum and large congenital naevi, representing approximately 10% of all melanoma patients) can benefit from regular check-ups. Screening in these popu‐

lations, and regular checks (every 6–12 months) lead to earlier detection [11].

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

treatment options are limited [10].

and tumour site [8].

**2. Etiopathogenesis**

**2.1. Risk factors**

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

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 95% after treatment by surgical excision alone. Fortunately, the vast majority of CMM (approximately 80%) are diagnosed at this early stage. If the cancer is more advanced, however, survival rates drop substantially to 30% to 60% after five years, depending on the tumor thickness in millimeters (*Breslow*'s depth). Metastatic disease has poor patient outcomes as treatment options are limited [10].

The prognosis for a patient with a newly diagnosed cutaneous melanoma depends mainly on two factors— the thickness of the primary tumour and the presence or absence of metastasis to regional lymph nodes. However, other prognostic factors are very important, including tumour ulceration, mitotic rate, and presence of regression, as well as sex and age of the patient, and tumour site [8].

For the primary prevention, physical protection from exposure to sunlight is generally accepted as the most important element of melanoma risk reduction. It seems particularly meaningful to prevent multiple erythemas during childhood, convincing parents and care takers not to let children stay too long under the sun. Sun-protective clothing and hats should be worn and peak hours of sun intensity should be avoided. For these purposes, mass media campaigns and widespread public education programmes would be most effective to make changes in attitude and behaviour towards sun protection [8,11]. The wavelength of light that is causal for melanoma is still not known and therefore sunscreens should be broad-spectrum types, providing protection across both UVB and UVA ranges. Advice should be to use sunscreens that are water proof, and sunscreens must be applied regularly and in sufficient quantities [12]. Regular screening of the total population for CMM does not seem useful and is not propagated in any country in the world. However, it seems likely that people with a familial risk of developing melanomas (those with familial or sporadic dysplastic naevus syndrome, xeroderma pigmentosum and large congenital naevi, representing approximately 10% of all melanoma patients) can benefit from regular check-ups. Screening in these popu‐ lations, and regular checks (every 6–12 months) lead to earlier detection [11].
