**2. Melanoma—Epidemiology and Prevalence**

Melanoma is the most aggressive type of skin cancer, and it arises from melanocytes, which are pigment-producing cells in the skin [18]. This type of cancer involves skin (mostly, but not exclusively, sun-exposed skin), but it can also occur in the eye, in the meninges and on gastrointestinal and genital mucosae [7]. In this section, we focus on cutaneous melanoma.

Melanomas can be characterized deeply from a histological point of view, thus leading to the identification of four major subtypes of melanoma [19]: Superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma. These four subtypes have different patterns of growth and come with different changes in epidermis and dermis [20]. According to a statistic evaluation carried out by the Global Cancer Observatory (GCO), which is part of the International Agency for Research on Cancer (IARC), melanoma incidence is annually increasing worldwide at a very fast rate, which in 2012 was the fastest growing of all types of cancer [21]. In GLOBOCAN 2018, the statistic evaluation of cancer incidence and mortality published by IARC, there were estimated to be approximately 290,000 new cases and 61,000 deaths related to melanoma [22], compared with the 232,000 new cases and 55,000 deaths reported in GLOBOCAN 2012. Melanoma mostly affects young and middle-aged individuals, with a median age at diagnosis of 57 years, while the incidence increases linearly from 25 years until 50 years of age, and then it decreases, especially for females [21]. Overall, the highest incidence is observed in regions with high exposure to solar radiation, such as Australia and New Zealand [23].

There are two types of risk factors for melanoma: (i) Environmental risk factors and (ii) host-related risk factors. Among the environmental risk factors commonly involved in cancer onset, for melanoma there is one particular risk factor which is deeply involved-ultraviolet (UV) light radiation from sunlight [21]. The correlation between sunlight exposure-particularly the UV-B spectrum [24]—and increased risk of melanoma has been deeply investigated, with findings that describe how exposure patterns and timing can contribute to the risk stratification for melanoma [21,25]. Intense and intermittent sun exposure is associated with a higher risk of melanoma, compared with continuous sun exposure, which is more often associated with non-melanoma skin cancers. UV-A exposure from artificial sources, such as sunbeds and devices employed in radiation phototherapy of psoriasis, is associated with a higher risk of melanoma [26]. There are a number of host risk factors related to the patient: (i) The number of congenital and acquired melanocytic nevi, which linearly correlates with melanoma incidence [21]; (ii) pigmentation characteristics of the patient, which are determined by polymorphisms in MC1R gene (melanocortin 1 receptor)—individuals with red hair, light complexion and light eyes exhibit a low pigmentation, and thus an increased risk for melanoma because of their higher sensitivity to UV exposure; (iii) family history of melanoma [21,27]; and (iv) immunosuppression, which is usually caused by comorbidities [28]. Melanoma diagnosis usually comes as an early-stage disease, in which it is possible to proceed with surgical excision and is curable in the majority of cases, while approximately 10% of patients are diagnosed at an advanced stage, which consists of an unresectable and/or metastatic melanoma [21,29]. Furthermore, stage IV melanomas are usually associated with a poor prognosis, lower probability to develop a consistent response to treatments, and, in about 30% of cases, there is brain and visceral involvement [30]. For patients with an advanced-stage melanoma, especially those who cannot undergo excisional surgery or who have metastasis, the wide range of systemic therapies represent the only way to defeat this aggressive type of cancer, which explains their importance and why they are being heavily investigated. This section provides a brief overview of the current available approaches to treat melanoma.
