Malignant Melanoma

Submitted by Dr. Andreas Lambrianides
General Surgeon - Brisbane, Australia

Risk factors - Diagnosis - Prevention

Melanoma is a cancer, which originates in melanocytes. These are the pigment cells in the skin, normally found at the basal layer of the epidermis. The melanoma will initially be located in the skin, but may eventually invade deeper tissues and spread to other organs. The skin has five levels, the first level been the epidermis. The potential to spread to other sites or organs increases as the melanoma grows into deeper layers. Early diagnosis and treatment is thus vital.

Malignant melanoma is a relatively uncommon malignancy, however its incidence is increasing dramatically. It ranges from 0.2 per 100 000 person-years in Asian countries to 40 per 100 000 person-years in Queensland Australia. Melanoma is primarily a diseases of whites with similar incidences for men and women. Despite the similar incidence and stage at diagnosis, women survive longer than men. In the USA the incidence varies from 4 to 26 per 100 000 person-years. Approximately 1 in 123 white persons will have a melanoma develop in their lifetime. The incidence has increased 150% since 1971.

Risk Factors
Family history. 5 to 10% of patients report a relative with the disease. The risk of a second melanoma developing for a patient who already has a melanoma is about 5%. A patient with melanoma has a higher risk of developing a second primary melanoma compared with individuals in the general population.

Complexion. The stereotypical has a fair complexion with a tendency to sunburn rather than tan. Case control studies identified the following relative risks. Red hair, associated with tripling of the relative risk of developing melanoma. Blond hair, associated with 60% risk increase and fair skin associated with the doubling of the risk. Fair or red hair, lighter skin, blue eyes, are all associated with a higher risk of melanoma.

Benign naevi. The presence of large numbers of naevi has been associated with an increased risk of melanoma. In one study a greater than threefold increase in risk existed for patients with more than 20 naevi.

Sunlight Exposure. Studies demonstrate a strong correlation with melanoma incidence. Occasional or recreational exposure to sunlight has been associated with a greater risk of melanoma than lifetime exposure. Major northern hemisphere studies consistently show increases in melanoma in association with recreational and vocational activities.

Several studies suggested an increased risk related to short period of intensive exposure in early adult life. In contrast regular outdoor occupation is associated with a decreased risk. The risk appears to be increased by intermittent exposure to levels of sun, which are higher than normal for that individual, but no increased risk related to long-term chronic exposure. It would be reasonable to suggest that intermittent exposure gives rise to a cyclical process of stimulation of melanocytes, which go through rapid proliferation phases, and then go into a resting phase during the unexposed periods. Such repeated stimulation increases the possibility of malignant transformation. In chronic exposure we have one burst of proliferation of Melanocytes and then maintenance of the chronic exposed condition with the proliferation of the melanocytes, and as such the carcinogenic potential is less. There has been considerable discussion as to where the melanoma arises in sun burnt areas, however there is little evidence to suggest that this occurs. It is more likely to relate to the increase risk of melanoma with those who have a tendency to burn, rather than a direct consequence of the sunburn.

The degree of risk depends on the type of ultra violet rays, the intensity of exposure and the quantity of light absorbing protective mantle in the skin. The UV portion of the spectrum is divided into three wavelength ranges, UVA (320 - 400 nm), UVB (280-320 nm), and UVC (200- 280 nm). Of these, UVB is believed to be responsible for the induction of melanoma. UVC, although a potent mutagen is filtered by the ozone layer. Depletion of the ozone layer will result in a greater risk of melanoma as the amount filtered will diminish. UV rays have a number of effects in cells, including inhibition of cell division, inactivation of enzymes, induction of mutations, and killing of cells in sufficient dosage. UVB causes the formation of pyrimidine dimers in the DNA. This type of damage is repaired by recognition of the DNA lesion, incision of the damaged strand, removal of the damaged segment, and synthesis of a nucleotide patch and finally ligation of the synthesized patch. This process requires the products of at least twenty genes.

With excessive sun exposure the repair process is overwhelmed, hence some DNA damage remains unrepaired, leading to the formation of cancer. The importance of this pathway of repair is demonstrated in a disease called Xeroderma Pigmentosum, this is an autosomal recessive condition characterized by a 2000 fold increase in skin cancer. This is due to an inherited inability to repair UV damaged DNA. As with other carcinogens, UVB causes mutations in oncogenes and tumor supressor genes. Mutant forms of ras and p53 genes have been detected in human skin cancers and UVB induced cancers in mice.

Occupational exposure. Workers exposed to pesticides and ionizing radiation have an increased risk for melanoma. Vinyl chloride has the strongest correlation with melanoma risks.

Genetics. Approximately 10% of melanomas tend to occur in families. These melanomas are often associated with multiple dysplastic naevi. Some of the suspected melanoma associated genes include

1. CMM1 gene on Chromosome 1 p 36

2. The tumor suppressor gene p16, mapped to chromosome to 9 p 21

3. The cyclin-dependent kinase gene CDK4 on chromosome   12 q 14

Dysplastic naevus syndrome. The association between naevi and melanoma was made more than 180 years ago although it was not until 1978 that the true precursor of malignant melanoma was described in detail. Dysplastic naevi are larger than most acquired naevi, often greater than 5 mm across, and may occur as hundreds of lesions on the body surface. They are flat, slightly raised or target like lesions with a darker raised center and regular flat periphery; they usually show variation in pigmentation and irregular boarders. They have a tendency to occur on non-sun-exposed as well as sun-exposed surfaces. Dysplastic naevi have been documented in members of families prone to the development of malignant melanoma. In these cases the genetic analysis has demonstrated an autosomal dominant inheritance possibly involving the genes on 1p36, 9p21 and 12q14 chromosomes. Dysplastic naevi may also occur as isolated lesions not associated with the heritable melanoma syndrome in which case the risk of malignancy is low. Dysplastic naevi occur in 2 - 7 % of all white persons and 30 - 50% of patients with melanomas. Affected individuals have between 10 and 100 of these pigmented lesions. The risk of melanoma developing in the heritable appears to be 3% per year in patients who have two or more family members with dysplastic naevus syndrome and melanoma. After the diagnosis of the condition, family members should be screened and patients observed closely.

 

Prognosis
For localized primary melanoma, thickness is the single most significant factor. Data published shows that patients with melanomas thinner than 0.85 mm had a 99% eight year survival. Those between 0.85 and 1.69 mm had a 93% eight year survival rate. Patients with lesions between 1.7 and 3.64 had a 69% eight year survival rate and patients with a lesion greater than 3.65 mm had a 38% eight year survival. There is a direct correlation of metastatic nodes and survival. Patients with one metastatic node had a better survival than with two or more nodes. Three-year survival rates in patients with positive lymph nodes range from

40 % to 15% for those with one positive node and those with five or more nodes respectively. The number of organs or tissues containing metastatic disease is the most significant factor in prognosis for patients with distant metastasis. The median survival period is 7 months for patients with metastasis to one side, four months at two sites and two months for patients with two or more sites.

          Prevention
Exposure to sunlight is strongly associated with the development of melanoma, and two thirds of all melanomas can be specifically attributed to solar exposure. All people exposed to solar radiation should adopt the following recommendations.
Physical Protection
Physical protection should be a primary preventive measure. This involves avoidance of direct sunlight exposure, the utilization of shade structures, the wearing of sun protective clothing such as hats and long sleeved shirts. Dark clothing offers adequate protection, as dark, closely woven fabrics are more protective than light loosely woven clothing. A system of rating fabrics should be introduced to help consumers select clothing with high protection factors.
 
Sunscreens
Only sunscreens with a minimum SPF 15+ are recommended. Sunscreens should be regarded as filters and not as sun blocks, and as such damage to the skin occurs despite the use of sunscreens. They should be reapplied at regular intervals as the screen may be rubbed off by water, clothing, physical activity and toweling. All sunscreens should be broad spectrum extending into the UVA range and when used for swimming a water resistant screen should be selected. Avoidance of sun beds, tanning booths and tanning lamps should be advised, as there is a potential risk of UV damage from such equipment. Childhood exposure to sun is closely related to the development of naevi. The presence of naevi is a strong risk factor for melanoma. Studies indicate that sun exposure during child hood is very important in causing melanoma; therefore, a strong emphasis should be placed on protection from excessive sunlight exposure in childhood. Sun damage is cumulative and substantially irreversible. It is cumulative in people of all ages, and thus protective measures apply to all people.

Family Surveillance. As 10% of malignant melanoma cases will have at least one melanoma - affected first degree relative, families with strong history of melanoma or families with excessive number of naevi, should be offered referral to a specialized melanoma unit for inclusion in genetic studies.

Congenital Lesions. Large congenital lesions, greater than 20cm in diameter or 2 - 5 % of total body surface area have a highly significant increase risk of developing melanoma and this should be closely monitored for the lifetime of the person. Excisions should be considered if cosmetically acceptable. Baseline photographs of skin surface are useful to monitor patients with large numbers of melanocytic or dysplastic naevi. Regular follow up can then be undertaken comparing the patient’s pigmented lesions with the baseline photographs to detect any changes.

Education and self-examination. A melanoma may arise from clear skin or from a pre-existing mole. A history of change is usually over two to six months, the change noted may be minor and it is sometimes associated with an itch, which does not necessarily have to be constant. Itch in a naevus in isolation, is not significant, but in association with other suspicious clinical features may be helpful. Bleeding is rare in early melanomas and pain is not a feature of primary melanoma. Important key factors include

1. Irregularity of color
2. Irregularity of outline
3. Irregularity of surface

Amelanotic melanoma is difficult to diagnose usually appearing as a smooth red nodule or patch. The presence of hairs does not exclude melanoma. More advance melanomas however destroy hair follicles as they invade.

Many deaths from melanoma will occur at a younger age than for other solid tumors. The number of person years of life lost due to melanoma exceeds that of other cancers. It is imperative thus to maximize effective prevention measures as protection is much than easier than cure sometimes.

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