IV.1 Epidemiology of Melanoma

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IV.1.1 Epidemiology of Melanoma Melanoma is a common cancer of humans.

Global incidence varies significantly based on a number of risk factors. To a large extent these risk factors have been determined from hypoth- eses arising from the global distribution, including risk factors such as skin colour and ultraviolet radiation.

This chapter discusses the distribution of melanoma, risk factors and preventive mea- sures.

Epidemiology of Melanoma

Scott Kitchener

IV.1

Contents

IV.1.1 Epidemiology of Melanoma . . . .185

IV.1.2 Global Epidemiology . . . .185

IV.1.3 Real or Apparent Trends in Incidence and Mortality . . . .186

IV.1.4 Risk Factors . . . .186

IV.1.4.1 Skin Colour . . . .186

IV.4.2 Genetic Factors . . . .187

IV.4.3 Naevi . . . .187

IV.1.4.4 Latitude . . . .188

IV.1.4.5 Sun Exposure . . . .188

IV.1.4.6 Migration . . . .189

IV.1.4.7 Artificial Light Sources . . . .189

IV.1.4.8 Occupation . . . .189

IV.1.5 Prevention of Melanoma . . . .190

IV.1.5.1 Primary Prevention . . . .190

IV.1.5.2 Secondary Prevention . . . .190

References . . . .191

IV.1.2 Global Epidemiology

The incidence of melanoma varies by region and is apparently rising in several regions of the world (Table IV.1, IV.2) [1]. Australia has the highest incidence of melanoma, recording 8900 new cases between 1990 and 2000 in a population of nearly 20 million people, making it the fourth most common cancer registered (man- datory reporting of non-melanomatous cancer is not nationwide) [2]. In North America it is now the fifth most common cancer among males and the sixth most common cancer among females in the United States [3]. Several countries in Europe have noted a rising trend and recent stabilization in melanoma incidence and mortality [3]. Mortality rates are variable, with continuing increases in France, Italy and Czechoslovakia, which seem to be behind a general trend across Europe to decreasing mortality led by the U.K., Scandinavian countries and Spain [5–7]. Notably in the UK both stabilization then reductions have been observed in mortality and incidence rates [8, 9].

Table IV.1. Approximate incidences of melanoma by region

Region Incidence

Mediterranean <10/100,000 [127]

Northern Europe 11/100,000 [128]

South Africa

(fair-skinned people) 20/100,000 [129]

Australia 30/100,000 [130]

Australia (Queensland) 50/100,000 [131]

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The first observed flattening in the rise of mortality and then a reduction in mortality rates was observed in Australia [10]. Mortality from melanoma probably peaked in 1985 at approximately 5/100,000, has remained relatively steady for males and has begun to reduce for females. This is believed to be related to early detection, although the full effect of such programs are yet to be seen [11].

IV.1.3 Real or Apparent Trends in Incidence and Mortality While there appears to have been a steady epidemic of melanoma globally followed by early stages of stabilisation of this epidemic, there is some question as to whether these are true variations in the incidence or only apparent variations [12, 13]. An apparent increase in melanoma incidence, rather than a true increase, may be associated with more and closer detection methods in clinics, resulting in more melanoma found [14–16]. The trend in diagnosis of melanoma has been closely shadowed by an increase in biopsy rates [17]. This has led to diagnosis of earlier-stage melanoma and a trend towards thinner, less invasive tumours and perhaps un- masked a form of melanoma that is biologically benign despite appearing malignant on histopathology [18, 19]. As earlier stages of melanoma appear in biopsy and excision specimens pre- sented to histopathologists, the reliability of the histopathology diagnostic process (and incidence data) decreases [20–22], particularly the distinction between severe dysplasia and melanoma in situ [23].

Greater effort and improved sensitivity in detection has resulted in early diagnosis of melanoma, which has probably translated into an apparent stabilization of melanoma mortality [19, 24]. The incidence of melanoma is influ- enced by several factors and is intimately associated with mortality rates associated with melanoma, not only in the obvious manner, but also through the shifting nature of melanoma being detected and treated. Regions clearly pass through an evolution of incidence and mortality changes. Interpreting these changes must be conducted with caution recognizing multiple and interrelated factors.

IV.1.4 Risk Factors IV.1.4.1 Skin Colour

Melanoma incidence is inversely proportional to darkness of skin. Fairer-skinned Singapor- eans of Chinese origin have a higher incidence of melanoma (0.5/100,000) than darker-skinned Indian Singaporeans (0.2/100,000) [25], and white South Africans have a greater incidence of melanoma than those with mixed ancestry and then black South Africans [26, 27, 129]; however, the relationship of darkness of skin, ultraviolet light penetration and melanoma incidence is probably complex. Both latitude and the ultraviolet index were associated with significantly greater incidence of melanoma for black men as for white people in the United States, but this was not significant for Hispanic people [28, 29], and unlike Caucasians, the incidence of melanoma among African-Americans, Asians, Indi- ans and Hawaiians has not changed notably over the past three decades [30].

Melanoma in darker-skinned people presents in different anatomic locations than in lighter- coloured people with a greater proportion of acral melanoma and melanoma presenting in non-sun-exposed areas [31, 32]. Diagnosis is at a more advanced stage in these groups, and 5-year survival for melanoma is less than for whites in the U.S. (72.2–81.1 vs 89.6% for whites) [33, 132].

This may be an effect of socio-economic status;

however, in this study, African-Americans were also found to have a 1.48-fold greater mortality

Table IV.2. Incidence of melanoma in several collocated ethnic groups from surveillance data (U.S.) between 1992 and 2001

Ethnic group (in the U.S.) Incidence [132]

Whites 18.4/100,000

Hispanics 2.3/100,000

American Indians 1.6/100,000 Asian/Pacific Islanders 1.0/100,000 African-Americans 0.8/100,000

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risk after adjustment for stage of melanoma at diagnosis, suggesting possible distinct tumour characteristics among this population.

IV.4.2 Genetic Factors

Xeroderma pigmentosa is a genetic disorder with a mutation of the XPD gene leading to nucleotide excision repair defects [34]. Patients experience 1000-fold greater risk of melanoma as they are unable to repair UV-induced DNA [35].

This understanding has led to consideration of whether DNA repair capacity may also be a factor in melanoma in the general population. Mel- anoma cases have been found to have a statisti- cally lesser ability to repair DNA compared with matched controls, and melanoma cases with primary tumours in sun-exposed skin locations have a lower repair capacity than those with primary melanoma on unexposed skin [36]. The relative ability to repair DNA modifies the risk in the presence of other host factors such as age, poor tanning ability and dysplastic naevi [37].

Two pleomorphisms of the XPD gene are associ- ated with a decreased risk of melanoma among women with five or more severe sunburns or high cumulative sun exposure [38].

Mutations of the melanocortin-1 receptor gene variants are more common among fair- skinned and red-haired people. Polymorphism of this gene is associated with melanoma (OR=2.43) and, though common, is present in approximately one-third of controls (37.5%) and two-thirds of cases (59.4%) [39]. The risk is ad- ditional to the phenotype of pigmentation of the individual atypical naevi, >50 melanocytic naevi, high recreational and occupational sun exposures [39, 40].

The relative risk of melanoma in light of a family history of one or more family members previously with melanoma is approximately two- to threefold based on results from multiple studies across various sun-exposed populations of fair-skinned people [41, 42]. More than three family members with melanoma raises this to over 35, unrelated to other familial traits such as hair and eye colour, naevus count and freckling [41]; nor are sun exposure in childhood and adulthood important determinants of melano-

ma risk in families with a strong history of melanoma [43].

The first familial melanoma-related genetic mutation (in CDKN2A on chromosome 9p21), explaining transmission from one generation to the next, was discovered in 1994 in 13 of 18 kin- dreds of familial melanoma, followed by anoth- er shortly afterwards [44, 45]. A clear association with cell-cycle regulation, cell senescence and apoptosis was demonstrated. Penetrance of the CDKN2A mutation seems to increase with age and vary with population melanoma incidence rates, being greater in Australia (0.91 by 80 years of age) than the U.S. (0.76) and Europe (0.58), leading to the conclusion that the same factors affect melanoma incidence as mediate CDKN2A penetrance [46]. Mutations CDKN2A may account for up to 25% of familial melanoma cases worldwide [47], but the incidence of this mutation, even in Australia, is low (2%) so that only 1 of 200 melanoma cases in Australia probably carry a CDKN2A mutation [48]. As screening has poor predictive value, even in cases of atypical mole syndrome, it is not recommended outside of the research setting at this time [49, 50].

IV.4.3 Naevi

Naevi are considered to be harbingers of melanoma, but the number and nature of naevi related to melanoma is complex. Histopatho- logically dysplastic naevi do not confer an independent risk of melanoma; however, dysplasia is not reliably assessed [51].

Atypical mole syndrome (AMS) is a phenotype characterized by a large number of naevi, both common and atypical. It is more common in families with predisposition to melanoma and more common (OR=10.4) among melanoma cases (16%) than controls (2%) [52]. People with more than 100 common moles (compared with <5; OR=7.7) or more than four atypical naevi (OR=28.7) are also at greater risk of melanoma. The phenotype is more relevant when present in younger people (OR=16.1 if

<40 years).

The total number of naevi is strongly related to risk of melanoma in Australia – a 12-fold risk

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with more than 100 naevi compared with less than 10 – and the effect is stronger in younger (<40 years) people [53]. Multiple atypical naevi in either sun-exposed or non-exposed areas carried a fivefold risk in this study. Atypical naevus count is less relevant in higher sun-exposed areas, so that in Australia three or more atypical moles carries less risk of melanoma than in the U.K. (OR=4.6 vs 51.7), as the prevalence of atypical naevi and AMS (6% among control subjects) is greater in Australia [54].

The relationship of naevi count may not be consistent for all melanomas. Cutaneous melanoma may develop along two different paths:

associated with naevi in naevi-prone skin on naevi-prone people; and on chronically sun-exposed skin. Those cases of melanoma on the trunk are more likely to have a high naevus count (>60) than cases of melanoma occurring on the head and neck or lentigo maligna melanoma which are more likely to be associated with dermal elastosis or solar keratoses from chronic sun exposure [55, 56]. Not only is naevus count probably related to melanoma arising with melanocyte proliferation, these melanomas are more likely to be identified with histological evidence of having arisen from a naevus [56, 57].

IV.1.4.4 Latitude

The negative association of mortality from melanoma with latitude is a long-standing factor in melanoma identified early in Australia associated with Caucasians, particularly living in northern, tropical parts of the continent [58, 59]. The relationship also exists for incidence of melanoma among fair-skinned people on other continents [60, 61], and has been demonstrated in some darker-skinned people [28]. The study of populations living closer to the equator has served as a foundation of the argument for sun exposure in the aetiology of melanoma [62, 63].

IV.1.4.5 Sun Exposure

While initial clinical investigations suggested a direct association of sunlight in aetiology of melanoma [62], the effect was soon recognized as much less clear than for other skin cancers [64]. Over the past four decades knowledge of this complex relationship still only suggests that the role of sun exposure is possibly primary and probably supportive [62].

As discussed above, lighter-skinned people have a higher risk of melanoma than darker skinned people, those with genetic sensitivity to ultraviolet damage, and proximity to the equator are associated with higher incidence of melanoma, all suggesting the sun exposure is a major risk factor. A purely linear dose response relationship is unlikely to exist between sun exposure and melanoma aetiology. Intermittent sun exposure has been supported as a pattern of exposure more closely related to melanoma incidence, although the retrospective assessment of such an exposure is inaccurate. Nevertheless, recollections of high recreational sun exposure has been associated with an odds ratio for melanoma of 1.71 in a meta-analysis of 23 studies [65].

The nature and measurement of sun exposure varies significantly in these studies. Sun- burn is perhaps more objective than quantifica- tion of sun exposure; however, it also suffers from recall and measurement bias being vari- ably defined as peeling, blistering or simply ery- thema. History of sunburn does suggest intermittent very high and damaging sun exposure, and incurs a twofold higher risk of melanoma, approaching a fourfold increased risk following numerous episodes of severe sunburn [65, 66].

More than five severe sunburns recalled before the age of 15 years carried a relative risk of 2.7 for subsequent melanoma [67].

Sunburn at any time in life has often been demonstrated to be associated with increased incidence of melanoma later in life [68, 69]. The effect is most strongly observed in studies of childhood and adolescent exposure; however, adult exposure cannot be excluded in relevance [70]. Chronic high level of sun exposure in adulthood is more associated with melanoma of the head and neck and with lentigo maligna

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melanoma than recreational exposures, whereas intermittent patterns of exposure are more linked to truncal melanoma [71]. A lifelong history of sunburn carries a lesser risk (OR=1.7) than the specific history of sunburn in childhood (OR=5.9) [72], but childhood sunburn is related to the tendency to burn, to skin type and to hair colour which, when controlled, mitigates the association with melanoma development later in life [73, 74]. Thus, sunburns during each of adulthood and childhood are probably interdependent and those people at highest risk are adults who have had intense childhood sun exposure and continue to have burns as adults [75].

IV.1.4.6 Migration

Migration studies are often used to investigate the influence of exposures to sun at differing ages. The mortality of native born Australians from melanoma is higher than those coming to Australia [76–79]. As noted above, sun exposure during childhood and adolescence is relevant for later risk of melanoma. When migration towards sunny climates occurs, there is an inverse link between mortality from melanoma and age of migration to the sunnier location [80, 81]. Mi- gration to Australia before the age of 10 years confers a risk similar to locals; however, migrating after 10 and certainly after 15 years of age, is associated with one-third to one-quarter of the local risk [82, 83]. Findings were comparable for European children migrating to the Mediterra- nean or tropical areas from Belgium, France and Germany before the age of 10 years experi- encing a fourfold (OR=4.3; 95% CI: 1.7–11.1) increased risk for melanoma later in life [69]. Peo- ple migrating to California from more northern areas of North America are also found to be spared risk of melanoma compared with locally born Californians [84].

Duration of residence following emigration from more temperate zones to more sun-exposed areas is probably less relevant than age of migration, but risk for melanoma increases with longer duration in the high sun-exposed climate [69, 80, 82].

IV.1.4.7 Artificial Light Sources

Sun beds and sun lamps are an artificial light source used for tanning of skin and treatment of various skin conditions; reduction of UV-B light emission in these occurred during the 1980s. Earlier European studies demonstrated comparable risks for sun bed use beginning before 1980 (OR=2.71) and much higher risk for recreational use for greater than 10 h (OR=8.97) [74, 85]. A later European case-control study did not support an association with sun beds (OR=0.90; 95% CI: 0.71–1.14) despite finding a greater use with more northern locations [86].

A recent systematic review of sun bed use concluded that a history of ever using sun beds was associated with a very mild increased risk of melanoma (summary relative risk=1.15), which increased when first exposure was before the age of 35 years (SRR=1.75) [87]. The known risk factors of number of naevi and skin type were still the strongest indicators for melanoma risk.

IV.1.4.8 Occupation

Fritschi and Driscoll recently estimated that in Australia only a small percentage of melanoma (4.3% in males and 0.4% in females) are able to be attributed to occupational exposures [88].

Studies of melanoma in occupations have suggested that occupational sun exposure may be protective [67, 89], or that no association exists between occupation and melanoma incidence, though this is potentially due to inadequate power or misclassification [90]. Considering the more specific classification of melanoma of the head and neck, strong association with high occupational exposure to sun is found [71]. Other studies have found increased incidence assocat- ed with specific occupations including those associated with artificial light exposure, solvent exposure (including polychlorinated biphenyls and polyvinyl chlorides), intermittent high solar ultraviolet light and magnetic fields (arising from electricity transmission) [91–94]. Notably, farmers and other workers in occupations with high ultraviolet light exposure have only a slightly higher incidence of melanoma (odds ratio: 1.07–1.25) independent of other exposures such as solvents and pesticides [95–97].

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IV.1.5 Prevention of Melanoma IV.1.5.1 Primary Prevention

Environmental alterations, social changes and behavioural modification to reduce ultraviolet exposure have been used for primary prevention of melanoma. The Slip, Slop, Slap program devel- oped and first introduced in Australia to encour- age people to slip on a shirt, slop on sunscreen and slap on a hat. Awareness of skin cancer was raised with Skin Cancer Awareness Week [98].

Later the SunSmart program continued these messages with expansion of the program towards environmental interventions. These programs have extended across the country, across social groups and through workplaces, recreation ac- tivities and schools. Messages and delivery modes were tailored to focus on children and then ado- lescents recognizing ultraviolet exposures at these ages as factors in melanoma risk [99, 100].

Have these primary prevention approaches worked? In summary, with regard to international skin cancer primary prevention programs, women are more knowledgeable about sun protection than men, although they are more likely to intentionally sunbathe; children reflect their parent’s behaviours; sunscreen is the most commonly used primary (as opposed to adjunct) method of sun protection; and all age groups could improve their use of sun protection [101]. These issues are not addressed in detail here as the most relevant end point for assessment of these programs is incidence and mortality from melanoma in the population.

The incidence of melanoma in Australia has been suggested as evidence that programs have not worked [102]. This does not necessarily rec- ognize the complexities of health outcome data in evaluating success of such programs. In fact, as discussed previously, incidence rates have stabilized in Australia, and have even reduced in some age groups, particularly women, support- ing efficacy of primary prevention programs which have been running for two decades [103].

In Queensland, with the highest incidence of melanoma recorded in Australia, reduction in incidence attributed to primary prevention has occurred with an age cohort effect (in those less than 35 years of age) [19]. A further generation

will be necessary to realize the full benefit possible. Long-term consistency and continuity of effort at all social levels is necessary for primary prevention programs to be effective [98, 104].

Sunscreens have been a contentious primary prevention approach. Use has been associated with spending longer in the sun with the percep- tion of protection by the sunscreen resulting in more ultraviolet skin damage [105]. The sun protection factor (SPF) of sunscreens has been di- rectly related to increased duration of exposure to the sun by users [106]. An increased risk of melanoma by approximately twofold is related to use, depending upon the nature of the sunscreen [107]. Higher SPF does provide more protection against sunburn, but this may lead to use as a tanning aid rather than protection against exposure [108, 109]. Nevertheless, used correctly as an adjunct to an overall regimen of sun protection including clothing, hats, sun avoidance and shade provision, sunscreens are associated with reduc- ing melanoma incidence on a population level, but the specific contribution can only be determined with a prospective study [101, 110, 111].

IV.1.5.2 Secondary Prevention

Screening programs are effective for conditions of high incidence and high mortality for which effective treatment may be initiated. In Australia, incidence is high; however, a national campaign for screening was not instigated following an health economic evaluation finding of AUD5103 as the cost per life saved [112]. Screening for melanoma in selected high-risk groups by dermatol- ogists and plastic surgeons in Western Australia has had disappointing results with a low 1-year sensitivity (63.6%) [113]. Community-based programs of melanoma screening in Queensland are able to attract Queenslanders for skin screening by primary care physicians [114, 115], and these detect melanoma with a reasonable specificity (86.1%) [116] at a rate (1 of 500 patients screened) comparable with other screening programs in Europe and North America [117–119].

The reluctance of Australian Governments to invest in sustained screening campaigns is partly as the private health market has begun to address the need. Australian primary care phy-

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sicians are familiar with screening and detection of melanoma [120]. Since the start of the randomized community-based trial discussed above, private skin cancer clinics by primary care physicians have begun to expand in number, assuming a significant load of melanoma detection [121]. Evolving technology of dermoscopy and sequential imaging has improved melanoma detection including among primary care physicians [122, 123]. Many primary care skin cancer clinics utilize dermoscopy for detection of melanoma. Further research is required;

however, early data from these clinics indicate a rate of melanoma detected comparable to that of screening campaigns employing specialist physicians, with high specificity and moderate to high sensitivity [124–126].

C Core Messages

■ For the latter half of the twentieth century, the incidence of melanoma has been recorded and rising. In some countries, incidence and mortality have stabilized and even reduced in some groups.

■ Risk factors known for melanoma are high numbers of (especially atypical) naevi and sun exposure, particularly in childhood and adolescence.

■ Adult and occupational exposures are also important particularly for superfi- cial melanoma of the head and neck.

■ Phenotypic characteristics of fair skin, red hair and the tendency to sunburn are major risk factors, which have been linked to genetic markers. Other genetic markers of DNA repair ability are also relevant.

■ Primary prevention programs have had preliminary success in utilizing knowledge of risk factors.

■ Secondary prevention through early detection has tended to diagnose earlier stages of melanoma, pushing the accuracy of histological diagnosis and consequentially epidemiological data.

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