Cutaneous malignant melanoma

It originates in the melanocytes, the cells that produce melanin, the pigment that colors the skin and protects it from UV rays. It appears 90% on the skin, although it can also appear in the eyes or, rarely, inside the body. It accounts for only 1% of skin cancers, and although it is associated with the worst prognosis, if detected early it has a high chance of being cured.

Skin cells develop in a controlled and orderly manner. The new cells push the old ones to the skin surface where they die and are eliminated from the body. When some cells acquire DNA damage, uncontrolled growth of new cells can be triggered, resulting in this skin cancer.

Most of the time, the genetic changes associated with melanoma are acquired during life and are not passed on (not inherited). In some cases, they occur randomly in a cell, with no clear cause, and in others, they are likely to occur as a result of an external cause. It is therefore likely that a combination of environmental and genetic factors leads to the development of melanoma.

Ultraviolet (UV) rays, especially type B but also type A, are a major cause of melanoma as they can damage the DNA of skin cells. However, UV light does not cause all melanomas, especially those that occur on parts of the body not exposed to sunlight, so other factors can influence the risk of melanoma.

The following factors can increase a person's risk of developing melanoma:

  • Sun exposure: living at high altitudes or in areas with intense sunlight year-round are at increased risk, as well as staying outdoors during midday extended periods.
  • Indoor tanning in sunbeds, tanning salons, or sunlamps. Their use is strongly discouraged.
  • Moles: people with many moles or unusual, large moles with irregular shape and color (dysplastic nevi or atypical moles) are at increased risk.
  • Fair skin: people with fair complexion, blond or colored hair, blue eyes, and freckles have a higher risk of developing melanoma. This risk is also higher in people who tend to burn their skin rather than tan.
  • Previous skin cancer. People who have already had melanoma or basal cell or squamous cell skin cancer have a higher risk of developing melanoma.
  • Ethnicity: While it can develop in individuals of any ethnicity, people of Caucasian descent are 20 times more at risk than those of African descent.
  • Age: it occurs in young adults more frequently than many other cancers. The median age of diagnosis is around 50 years.
  • Weakened immune system: Both disease and immunosuppressive treatments increase the risk of developing skin cancer, including melanoma.

Additionally, and less frequently, it is possible to inherit genetic changes from parents that increase the risk of melanoma. About 10% of people with melanoma have a family history of the disease, the risk of developing melanoma is 2 to 3 times higher than the average risk if there is a close relative affected. This risk increases if several family members living in different places have been diagnosed with melanoma. In addition, hereditary familial forms of melanoma due to changes in specific genes such as CDKN2A, CDK4, P53, and MITF have been described, although they are rare. Other hereditary conditions (Xeroderma Pigmentosa, Li-Fraumeni syndrome, or hereditary breast and ovarian cancer, among others) are also associated with an increased risk of melanoma.

The etiology of melanoma is complex, involving environmental, phenotypic and genetic factors, and heritability has recently been estimated to be around 58%. Although the biological mechanisms underlying the development of melanoma are not fully understood, a recent meta-analysis of GWAS studies in different populations, including almost 37,000 cases and more than 400,000 controls, has identified 60 susceptibility loci. These results highlight the apparently dominant involvement of nevus formation, pigmentation and telomere maintenance pathways in melanoma susceptibility.

Symptoms

Melanomas can form anywhere on the body, although they most frequently appear in areas that have been exposed to the sun (back, legs, arms or face). They can also occur in areas without sun exposure, such as soles of the feet, palms of the hands or nail beds, although this usually occurs in individuals with darker skin.

Changes in the size, shape, color or texture of a mole are often the first warning signs. These changes can occur on an existing mole, or in the form of a new or unusual looking mole, however, they can also appear on normal looking skin. In 75-80% of cases melanoma appears without a previous mole.

The ABCDE rule summarizes the suspicious features of a pigmented skin lesion:

  • Asymmetry: the lesion is NOT rounded.
  • Borders: The borders are irregular.
  • Color: The lesion has different non-homogeneous colors.
  • Diameter: The size of the lesion is larger than 6mm.
  • Evolution: The previous characteristics have presented changes over time.

Prevention

Although we are still trying to clarify the causes of melanoma and therefore its prevention, and there is no consistent way to avoid its development completely, we can act on the known factors to try to reduce the risk as much as possible. The most important way to reduce the risk of melanoma is to protect yourself from UV exposure:

  • Limit or avoid direct sun exposure during the central hours of the day, when solar radiation is most intense depending on geographic location. Preferably stay in the shade.
  • Wear sun-protective clothing, hats that protect the face, neck, and ears, as well as clothing with UV protection factor and sunglasses with UV protection.
  • Use plenty of broad-spectrum UVA and UVB sunscreen with a sun protection factor (SPF) of at least 30 over the whole body, even if the day is cloudy, every 2 hours or more frequently when perspiring or bathing.
  • Avoid sun lamps or tanning beds and tanning salons.
  • Examine the skin regularly including self-examination to check for new bumps or changes in existing moles, freckles, bumps and birthmarks, and evaluation by a professional.

Including good sources of vitamin D in your diet, or even using supplements, may be necessary in these circumstances.

Number of observed variants

13.5 million variants

Number of risk loci analyzed in the study

60 loci

Bibliography

American Society of Clinical Oncology [April 2022]

American Cancer Society [April 2022]

Mayo Clinic [April 2022]

Landi MT et al. Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility. Nature Genetics. 2020 May;52(5):494-504.

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