Melanoma—Part 1: epidemiology, risk factors, and prevention

Exposure to sun

Although sun exposure has long been suspected to be a risk factor for melanoma, the relation between sun exposure and melanoma is complex. The evidence that sun exposure may be associated with melanoma is apparent when comparing incidence in Australia and sunny parts of the US with Europe.3 The incidence of melanoma is three to four times higher in Queensland, Australia, than in the UK.2 However, a significant association between sun exposure behaviour and melanoma is less easy to show in a case-control setting.12 13 A meta-analysis of melanoma case-control studies found low relative risks associated with various measures of exposure to ultraviolet radiation, and the relation with sunshine was not dose dependent.14 Sharp, short bursts of acute exposure in childhood, and severe sunburn, were most strongly associated with melanoma. However, cumulative occupational exposure seemed to be protective in some white populations. Odds ratios associated with sun exposure are often no longer significant after adjustment for skin type, which supports a hypothesis that host response to ultraviolet radiation is more important than dose of sun exposure.

Use of sun beds

Melanoma is controversially associated with use of sunbeds. Some epidemiological studies have not found sunbed use to be a significant risk, whereas others have found small increased risks.13 15 16 17

Sunbed use seems to be most detrimental before the age of 20, and current recommendations are that sunbeds should be avoided, especially in relating to premature skin ageing.17 Individuals with red hair and freckles, or multiple atypical naevi, with or without a family history of melanoma, should avoid sunbeds since their risks of developing both melanoma and non-melanoma skin cancer are already significantly increased.18

Skin pigmentation

Having fair skin with a poor ability to tan, or a freckled complexion with or without red hair, doubles a person’s risk of melanoma.18 Polymorphisms in the melanocortin 1 receptor (MC1R) gene have been linked to fair skin and red hair and have been associated with an increased risk of melanoma.19 20

Melanomas present rarely in non-white people, in whom the incidence is 10 to 20 times lower than in white people.3 Body site and histological subtypes differ between white and non-white people. The latter more frequently present with lentiginous and nodular melanoma on the palms and soles and rarely on other parts of the body.3 21

Naevi

Naevi are the most powerful predictor of risk of melanoma. A meta-analysis of observational studies found that an individual who has more than 100 common naevi or more than two atypical naevi has a fivefold to 20-fold increased risk of melanoma.22 Unlike melanoma, atypical naevi (fig 1⇓) are usually symmetrical and do not have a sharp edge with geographical border; asymmetry and sharp edged borders are clear signs of malignant transformation (fig 2⇓).23 Furthermore, naevi remain static whereas melanoma change in size, shape, or colour over weeks or months.

Fig 1 Atypical naevus with diameter of more than 5 mm and hazy border

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Fig 2 Superficial spreading melanoma with a well demarcated edge and irregular pigmentation

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In younger individuals atypical naevi on the trunk and limbs are more predictive of superficial melanoma than of nodular melanoma or lentigo maligna melanoma, which affect older individuals with more sun damage and fewer naevi.24 ^w1 The presence of multiple common naevi and atypical naevi denotes the phenotype for atypical mole syndrome, which may indicate a genetic susceptibility to melanoma (boxes 1 and 2). This phenotype is found in about 2% of a healthy population in the UK.^w2

Two twin studies suggest that naevi are under considerable genetic control, with a 60% concordance in numbers of naevi in identical twins.^{w3 w4} A cross sectional twin study of over 2000 individual twins showed that naevi undergo senescence with age, with a decrease in numbers from the age of 30 to 40 years, but that in patients with the atypical mole syndrome the number of naevi can remain high after middle age.^w3 In patients with the syndrome, naevi are also often found on unusual sites, such as scalp, buttocks, feet, hands, and irises.^w5

Solar keratoses

Solar keratoses carry a relative risk for melanoma of 2 to 4.^{w6 w7} The presence of naevi and solar keratoses is often mutually exclusive, suggesting different pathways to melanoma—via an excess of naevi in younger individuals or via chronic sun damage and cumulative sun exposure in older subjects.24 ^{w6 w7}

Family history of melanoma and genetic factors

Five to ten per cent of individuals with melanoma have a family history of melanoma.^w5 In families with melanoma, affected individuals often have the atypical mole syndrome phenotype (fig 3⇓). About a quarter of all families with melanoma have been linked to mutations in the tumour suppressor gene CDKN2A/p16 on chromosome 9p21, which affects the germline and is therefore transmitted through generations.^w8 Mutation screening outside the research setting is not recommended as the prevalence of germline CDKN2A mutations is very low and does not alter management.23 In some families with melanoma, susceptibility to some other cancers—such as pancreas, brain, and breast cancer—is increased, so taking a thorough family history of cancers in patients with melanoma is important.^w9

Fig 3 Atypical mole syndrome with many atypical naevi on trunk

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Hormonal factors

Mortality studies have shown that women have thinner tumours and survive melanoma better than men even after adjustment for Breslow thickness, ulceration, and body site, which suggests that there may be X linked variable gene expression or hormonal factors affecting melanoma survival.9 ^w10 Anecdote reports melanoma behaving aggressively during pregnancy and metastases manifesting themselves during pregnancy. However, a meta-analysis that examined data on over 5000 female participants showed that risk of melanoma was not affected by pregnancy, oral contraception, or hormone replacement.^w11

Primary prevention—benefits and harms

Health education campaigns aimed at reducing people’s exposure to sun began in Australia in the 1980s and were soon adopted elsewhere in the world. There is, as yet, no direct evidence that reducing sun exposure has had an effect on melanoma incidence. Some commentators have suggested that the slowing down and even downturn in incidence in melanoma in some parts of the world may be due to the health education programmes, but the downturn has been seen in parts of the world where levels of sun exposure and public health campaigns vary.4 Furthermore, the lag time between change in behaviour and the recent downturns in incidence may have been too short for health education to be the sole explanation.

A recent BMJ editorial raised a concern that drastic reduction of sun exposure in temperate climates may have an impact on health because of low vitamin D levels.^w12 Vitamin D is important for bone metabolism but has also been shown to have protective effects against inflammation, cancer, psychiatric diseases, and autoimmune disease. Avoiding sunburn and excessive sun exposure without protection seems to be the most important message in skin cancer prevention without advocating keeping away from the sun altogether.^w13 More research is needed in this field to understand not only the relation between melanoma and sun exposure but also the potential detrimental effects of vitamin D deficiency after sun avoidance.

Secondary prevention—early identification and treatment

Melanoma is amenable to secondary prevention as tumours are highly visible with a good prognosis if detected early. Secondary prevention is a more efficient way to reduce mortality from melanoma than primary prevention as the latter has not yet been proved to reduce incidence or mortality significantly. However, for secondary prevention to be successful, educating the public and health professionals to recognise melanoma early is crucial.