Diagnosis and Immunotherapy Strategies for Melanoma: A Review

Melanoma is a type of skin cancer. Melanoma skin cancer is made up of abnormal pigment cells (melanocytes). Melanocytes are located at the bottom of the epidermis. These cells make melanin, which spreads to the top of the epidermis and gives skin its colour. Melanoma is usually brown or black in colour because the cell still makes melanin. Melanoma is more dangerous than other skin cancers because it more likely to spread if it is not found early. However, most melanomas about 84 out of 100 are found early before they have spread and so are likely to be cured with treatments. Melanoma can occur on any skin surface. In men, it’s often found on the skin on the head, on the neck, or between the shoulders and the hips. In women, it’s often found on the skin on the lower legs or between the shoulders and the hips. Melanoma is rare in people with dark skin. When it does develop in people with dark skin, it’s usually found under the fingernails, under the toenails, on the palms of the hands, or on the soles of the feet. Although one of the less common types of skin cancer, melanoma is considered the most serious type of skin cancer because it is more likely to spread to other parts of the body, especially if not detected early. The earlier melanoma is found, the more successful treatment is likely to be. Despite the many investigations in this field and a rapidly growing knowledge base, classification according to specific mutational profiles is not yet validated. Further investigations are required for validation and refinement, and to possibly identify additional factors.


Introduction
Cancer is a disease of the cells, which are the body's basic building blocks. The body constantly makes new cells to help us grow, replace worn-out tissue and heal injuries. Normally, cells multiply and die in an orderly way. Sometimes cells don't grow, divide and die in the usual way. This may cause blood or lymph fluid in the body to become abnormal, or form a lump called a tumour. A tumour can be benign or malignant.

Benign tumour
Cells are confined to one area and are not able to spread to other parts of the body. This is not cancer.

Malignant tumour
This is made up of cancerous cells, which sometimes also have the ability to spread by travelling through the bloodstream or lymphatic system (lymph fluid) (Figure 1). The cancer that first develops in a tissue or organ is called the primary cancer. A malignant tumour is usually named after the organ or type of cell affected. A malignant tumour that has not spread to other parts of the body is called localized cancer. A tumour may invade deeper into surrounding tissue and can grow its own blood vessels in a process called angiogenesis. If cancerous cells grow and form another tumour at a new site, it is called a secondary cancer or metastasis. A metastasis keeps the name of the original cancer. For example, melanoma that has spread to the bones is called metastatic melanoma, even though the person may be experiencing symptoms caused by problems in the bones (Figure 2).

The skin
The skin is the largest organ in the body. It acts as a barrier to protect the body from injury, control body temperature and Basal cells: These block-like cells make up the lower layer of the epidermis and multiply constantly. As they age, they move upwards in the epidermis and flatten out to form squamous cells.
Melanocytes: These cells sit between the basal cells of the skin and produce a dark pigment called melanin, the substance that gives skin its colour. When skin is exposed to ultraviolet (UV) radiation, melanocytes make extra melanin to try to protect the skin from getting burnt. This is what causes skin to tan. Melanocytes are also

Epidemiology and Aetiology
Exposure to the sun is the most commonly associated factor [3,4]. Predisposing factors that have been found to increase the risk of melanoma include skin that sunburns easily, poor tanning response, light-colored skin, history of severe sunburns, numerous nevi (more than 50), atypical nevi (that is, dysplastic nevi), a tendency toward freckling, a history of skin cancer, a family history of melanoma, the use of tanning salon, previous melanoma, and a weakened immune system (due to other cancers, transplant drugs, or HIV infection). Oral methoxsalen (psoralen) and ultraviolet A radiation is an effective treatment for psoriasis, but it is carcinogenic and increases the risk for melanoma. Individuals with recreational and vacation sun exposure may be at greater risk than those whose occupation exposes them to the sun constantly. In fact, continuous sun exposure appears to be a protective factor where melanoma is concerned.
Melanoma is a common cancer. In early 2005, the American Cancer Society estimated that approximately 59,500 individuals would be diagnosed with melanoma, the projected number of deaths was 7,770. The prevalence of melanoma is 13:1,000 Caucasian Americans. During the 1970s, the incidence rate of melanoma showed a marked increase of approximately 6.0% per year, although this rate slowed to approximately 3.0% a year beginning in 1981. There is some data to suggest that superficial spreading melanoma has been found more frequently during the last 30 years. Five-year survival rates for melanoma of the skin have increased from 80% in 1976 to 85% in 1985 to 91% in 2000 [5].

Types of melanoma
Superficial spreading melanoma: It begins with an intraepidermal horizontal or radial growth phase, appearing first as a macule that slowly evolves into a plaque, often with multiple colours and pale areas of regression. Secondary nodular areas may also develop. This is the most common type of melanoma, making up 55-60% of all cases. It is more common in younger people and is often related to a pattern of irregular high sun exposure, including episodes of sunburn. It can start as a new brown or black spot that spreads within the outer layer of the skin (epidermis), or an existing spot, freckle or mole that changes size, colour or shape. It can develop on any part of the body. This type of melanoma often grows slowly and becomes more dangerous when it invades the lower layer of the skin (dermis) [6].

Nodular melanoma
Is a primarily nodular, exophytic brown-black, often eroded or bleeding tumour, which is characterized by an aggressive vertical phase, with a short or absent horizontal growth phase. This type makes up about 10-15% of melanomas. It usually appears as a round, raised lump on the surface of the skin that is often red, pink, brown or black and feels firm to touch. It may develop a crusty surface that bleeds easily. It is most commonly found in older people on severely sun-damaged skin on the head and neck. It is a fast growing and aggressive form of melanoma, spreading quickly into the lower layer of the skin (dermis) [7]. Lentigo maligna melanoma: Arises often after many years from a lentigo maligna (melanoma in situ) located predominantly on the sun-damaged faces of older individuals. This type of melanoma is most common in older people. It makes up about 10-15% of melanomas and begins as a large freckle (lentigo maligna) in an area of sun-damaged skin, such as the face, ears, neck and head. It may grow slowly and superficially over many years before it penetrates more deeply into the skin. Acral lentiginous melanoma: is typically palmoplantar or subungual. In its initial intraepidermal phase (which may be protracted), there is irregular, poorly circumscribed pigmentation; later a nodular region reflects the invasive growth pattern. This is an uncommon type of melanoma (around 1-2% of all cases). It is most commonly found on the hairless skin on the soles of the feet or palms of the hands, or under the fingernails or toenails. It commonly appears as a colourless or lightly pigmented area, which can be mistaken for a stain or bruise. In the nails, it most often presents as a long streak of pigment in the nail or discoloration in the skin around the nail. It may grow slowly before it becomes invasive.

Symptoms of Melanoma
Often the first sign of melanoma is a change in the shape, color,

c)
Color that is uneven: Shades of black, brown, and tan may be present. Areas of white, gray, red, pink, or blue may also be seen d) Diameter: There is a change in size, usually an increase.
Melanomas can be tiny, but most are larger than the size of a pea (larger than 6 millimeters or about 1/4 inch).

Diagnostic approach Clinical and Dermoscopic diagnosis
In

Molecular diagnosis
Molecular analysis of distant or regional metastasis or, if sampling of the metastatic tissue is not feasible, of the primary tumour is required for patients with distant metastasis or nonrespectable regional metastasis, who are candidates for systemic medical treatment [13]. Currently, the main test performed involves the BRAF V600 mutational status, in order to identify patients eligible for treatment with BRAF inhibitors and MEK inhibitors.  (Table 1).

Immunotherapy
Cytokines such as IFN-alpha and IL-2 were examined in several clinical trials in melanoma and achieved moderate response rates in non-controlled trials. Improvement of survival has never been shown in randomized clinical trials. Vaccination strategies have raised a lot of interest, but so far, no efficacious vaccines have been developed. In some trials, results may suggest even deleterious effects [15]. antibody ipilimumab was the first immunotherapy that showed a benefit for OS in two controlled trials in metastatic melanoma [16][17][18]. Ipilimumab is approved for melanoma therapy in the USA and in the EU. It is presently administered as four intravenous infusions at a dose of 3 mg/kg/infusion separated by 3 weeks (Table 2). 110 benefit with prolonged survival. Meanwhile, the introduction of PD-1 antibodies changed the role of ipilimumab, which, in the future, will no longer be considered as the treatment of choice for first-line therapy, but ipilimumab will likely be used in combination with PD-1 antibodies ( Table 3). The PD-1 antibodies nivolumab and pembrolizumab are approved for therapy of unresectable metastatic melanoma in the USA and Europe. Nivolumab was shown to improve progression-free and OS as compared to dacarbazine (CheckMate-066 trial) and as compared to ipilimumab (CheckMate-067 trial). Pembrolizumab showed improved progression-free and OS in comparison to ipilimumab (KEYNOTE-006 trial). Objective response rates of w50% were achieved with PD-1 blockade. However, longterm survival data are not yet widely available, but in some studies a 2 yearsurvival rate of 50% seems to be achieved by PD1-blokers.
PD-1 blockade will be the first-line treatment of patients with BRAF wild-type tumours in future and may be considered for first-line treatment also in patients with BRAF mutation. The combination of nivolumab with ipilimumab was shown to be superior in progression-free survival to ipilimumab and to nivolumab as single drugs (Check-Mate-067 trial) leading to a FDA approval before OS data are available. However, there is clearly an increased toxicity as compared to the treatment with the single substances.

Conclusion
The frequency and extent of follow-up examinations depends on the primary tumour characteristics. The first 5 years following