Melanoma epidemiology and trends

Clinics in Dermatology (2009) 27, 3–9

Melanoma epidemiology and trends Claus Garbe, MD ⁎, Ulrike Leiter, MD Division of Dermato-oncology, Eberhard Karls-University, 72076 Tuebingen, Germany

Abstract Rising incidence rates of cutaneous melanoma have been observed during the last four decades in white populations worldwide. The cancer statistics in the United States have revealed 6 cases per 100,000 and year at the beginning of the 1970s and 18 cases per 100,000 inhabitants and year at the beginning of 2000, demonstrating a threefold increase in incidence rates. Incidence rates in central Europe increased in the same time period from 3 to 4 cases to 10 to 15 cases per 100,000 inhabitants and year, which is very similar to the increase in the United States. Cohort studies from several countries indicate that the trend of increasing incidence rates will continue in the future for at least the next 2 decades; thus, an additional doubling of incidence rates is expected. The highest incidence rates have been reported from Australia and New Zealand, from 40 to 60 cases per 100,000 inhabitants and year. Mortality rates likewise slightly increased in the United States and in Europe during the 1970s and 1980s. In the 1990s, however, a leveling off of mortality rates was observed in many countries. Simultaneously, a clear decrease of Breslow tumor thickness was reported in the United States and European countries. This development indicates improved early recognition of cutaneous melanoma, which is presently the main factor for a more favorable prognosis. © 2009 Elsevier Inc. All rights reserved.

Introduction During the last decades, cutaneous melanoma (CM) has shown increasing incidence rates and has developed from a very rare disease entity into a cancer with growing importance medically.1 Cutaneous melanoma is a skin cancer nearly exclusively occurring in white populations, whereas its incidence remains very in low populations of African or Asian origin with darker pigmentation. Increasing incidences were mainly reported from industrial countries with white populations, with the highest incidence rates in Australia and the southern states of the United States.2 ⁎ Corresponding author. Tel.: +49 7071 29 83768; fax: +49 7071 29 5187. E-mail address: [email protected] (C. Garbe). 0738-081X/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2008.09.001

Incidence rates in the European countries are still lower but likewise showed threefold to fivefold increases during the last decades.3 This increase of melanoma incidence is related to changing attitudes of leisure time behavior and of sun exposure. This contribution focuses on recent developments of melanoma epidemiology in white populations worldwide.

Increase of melanoma incidence in white populations A continuous increase of CM incidence rates has been observed during the last 4 decades in many countries with white populations.4 The annual increase of CM incidence varies between populations but has been estimated at between 3% and 7%.5-9 These estimates suggest a doubling

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C. Garbe, U. Leiter

Fig. 1 Age-standardized (European standard population) incidence and mortality rates in the Federal Republic of Germany during 25 years. Estimates of incidence rates are based on data from several cancer registries in different Federal States.11

of rates every 10 to 20 years. Cutaneous malignant melanoma is the most rapidly increasing cancer in white populations. The cancer statistic in the United States was reported to be 6 cases per 100,000 inhabitants at the beginning of the 1970s and 18 cases per 100,000 and year at the beginning of 2000, thus demonstrating a threefold increase in incidence rates.5,10 Incidence rates in central Europe increased in the same time period, from 3 to 4 cases to 10 to 15 cases per 100,000 inhabitants and year, which is very similar to the increase in the United States.2 The Federal Health Authority in Germany used several regional population-based cancer registries to estimate the trend of incidence

of CM, and a threefold increase resulted during a 3-decade period (Fig. 1).11 The frequency of CM occurrence is closely associated with the constitutive color of the skin and depends on the geographic zone. From the 1990s onwards, studies from Europe, Canada, the United States, and Australia reported that the increase of incidence rates was slowing or stabilizing.5,9,12-15 In 2003 in the United States, 54,200 new diagnoses of CM and 7600 deaths from melanoma were reported.1,10 Incidence rates in central Europe are in the middle between the high-incidence countries and low-incidence countries (Fig. 2).11 The highest incidence rates in Europe

Fig. 2 Age-standardized (world standard population) incidence rates from 17 countries worldwide for the year 2002. USA, United States of America.11

Melanoma epidemiology and trends were in Scandinavian countries, 8,10,16 but significant increases of melanoma incidences were also found in central and southern Europe. The Mediterranean countries had the lowest incidence rates.3,17,18 The reason for this north–south gradient is a darker skin type (type III–IV according to Fitzpatrick) in the Mediterranean populations and different attitudes to recreational activities. The highest incidence rates were reported in Australia and New Zealand, with 30 to 60 cases per 100,000 inhabitants and year.4,15,19,20 In these countries, CM is one of the most frequent cancer types. The highest incidence rates were found in the northern equatorial areas of Australia such as in Queensland, where incidence rates up to 60 per 100,000 inhabitants and year were registered.19

Leveling off of mortality rates Mortality rates from CM were increasing until the 1980s in the populations of most European countries21,22 as well as in the populations of North America, Australia, and New Zealand.10,23-25 Mortality rates peaked in 1988 to 1990 and thereafter have been less uniform. Mortality rates are still rising in several European countries for middle-aged adults but with more favorable trends among women; some levelingoff in rates has occurred for young adults and have remained roughly constant among men.26 The favorable mortality trends have been related to changing patterns of sunshine exposure and sunburn in younger generations as well as better and earlier diagnosis of CM. A trend towards thinner and less invasive melanomas in both central Europe and Australia has also been observed during recent decades.27-29

Clinical epidemiology Analyses for the clinical aspects of melanoma epidemiology are mainly based on large clinical databases that contain

5 follow-up information of melanoma patients and are appropriate for survival analysis.30-33 In Germany, the Central Malignant Melanoma Registry (CMMR) is such a database, which has registered more than 70,000 cases with CM.34-36 This article presents some of the data to illustrate the clinical epidemiology of melanoma.

Sex and age The male/female ratio varies in melanoma databases in different countries. In countries with a high CM incidence, such as Australia and the United States, a preponderance of men is observed.4,5,15,37 In countries with a lower incidence, such as Great Britain, a higher ratio of women patients with melanoma can be found.38 In Germany in the time of low incidence rates in the 1970s, almost two-thirds of CM patients were women; whereas in the 1990s, the ratio of both sexes equalized.34 In contrast to nonmelanoma skin cancer, CM is diagnosed at an earlier age. The median age is about 55 years, which means that 50% of all CMs are already diagnosed before this age. Nevertheless, the age-specific incidence is slightly increasing with older age and reaches the highest agespecific incidence rates in individuals aged older than 65 years (Fig. 3).11

Anatomic site The anatomic site varies according to sex. In men, 55% of the tumors are localized on the trunk, with 39% on the back; in women, 42% are localized on the lower extremity, with 24% on the lower leg, followed by 25% on the trunk (Table 1). CM localized on the head and neck region and the upper extremity follow and are nearly equivalent in both sexes.34,36 A very similar site distribution was found in most industrial nations

Fig. 3 Age-specific incidence rates in the Federal Republic of Germany. Estimates of incidence rates in men (dark bars) and women (light bars) are based on data from several cancer registries in different Federal States.11

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C. Garbe, U. Leiter Table 1 to sex a

Anatomic sites of cutaneous melanoma according

Anatomic Site

Face Scalp Neck Anterior trunk Posterior trunk Genital region Upper extremity Lower extremity

Men

Women

Percent

Median age, y b

Percent

Median age, y b

8.2 5.1 2.2 16.3 39.3 0.2 12.2 16.5

66 64 57 55 55 59 58 52

10.1 2.0 1.6 7.7 17.1 0.8 18.4 42.3

70 61 56 45 48 65 59 56

a The analysis is based on 78,809 cases of the database of the German Central Malignant Melanoma Registry (updated March 2008). b The median age is given at the time point of diagnosis.

thickness is the most important criterion for analyzing the development of early detection of melanoma.46,47 An ongoing trend for diagnosis of melanoma with thinner tumor thickness has been shown for a number of countries.27,29,48,49 In Germany a trend towards diagnosing thin melanoma has been reported since the 1980s.34,50,51 The median tumor thickness decreased from 1.81 mm to 0.53 mm in 2000. The percentages of in situ and level II CM increased.34 The tumor thickness at the time of primary diagnosis is also age dependent. Generally, there is a significant decrease of melanomas with a tumor thickness of 1.0 mm or less in higher ages and is less than 50% at the age of 70. In contrast, the fraction of thick melanoma increases significantly and reaches 20% at the age of 80 years in both sexes.52

Sun exposure and melanoma with inhabitants of white origin such as in Europe, the United States, and Australia.12,23,39,40 The site-specific incidence of melanoma varies according to age. The incidence of melanoma localized on the trunk and on the lower extremity decreases with advancing age, whereas a significant increase of melanoma localized on head and neck areas can be found in older patients.41,42 Nearly 80% of melanomas in patients aged 80 years and older were found on head and neck areas. Melanomas developing at different body sites are associated with distinct patterns of sun exposure. Melanomas of the head and neck are associated with on-going patterns of sun exposure, whereas trunk melanomas are associated with intermittent patterns of sun exposure, supporting the hypothesis that melanomas may arise through divergent causal pathways.42,43

Histopathologic subtype Superficial spreading melanoma is the most frequent histopathologic CM subtype, composing nearly 59% of all CM, followed by nodular melanoma at 21%, lentigo-maligna melanoma at 11%, and acrolentiginous melanoma at 4% (Table 2). A similar distribution is found in the analyses of incidence rates in the United States and Canada.5,12 Different age distributions are found for the respective histopathologic subtypes. The peak age is 54 years old for superficial spreading melanomas, 59 years old for nodular melanomas, 65 years old for acral lentiginous melanoma, and 69 years old for lentigo-maligna melanoma (Table 2).

Tumor thickness The tumor thickness is the most important prognostic factor in primary melanoma.30,35,44,45 In this respect tumor

To date, it is widely accepted that a person's total risk of melanoma is determined through the interplay between genetic factors and exposure to sunlight.53 Eighty percent of melanomas develop in regions that receive intermittent sun exposure. Intermittent sun exposure and sunburn history have been identified as risk factors for melanoma in epidemiologic studies.54,55 The role of sunlight in melanoma development has been a matter of debate for decades because the effect of sunlight in the etiology of CM is far less clear compared with nonmelanoma skin cancer.56 The following clinical and epidemiologic features have raised doubts about an etiologic effect of sunlight in CM development: • The anatomic distribution of CM does not closely match body areas of greatest sun exposure; unlike epithelial skin cancer, 80% to 90% of which is located on the head and neck, only 10% to 15% of CMs are located in in this anatomic area. • Cutaneous melanoma is most common during the middle decades of life (except the subtype of lentigomaligna melanoma, which counts for 10% of all

Table 2

Histopathologic subtypes of cutaneous melanoma a

Melanoma subtype

No.

Percentage

Median age, y b

Superficial spreading Nodular Lentigo-maligna Acral lentiginous Others Total

41,013 14,398 7511 2897 4143 69,962

58.6 20.6 10.7 4.2 5.9 100.0

54 59 69 65 54

a

The analysis is based on 69,962 cases of the German Central Malignant Melanoma Registry database with valid information on melanoma subtype (updated March 2008). b The median age is given at the time point of diagnosis.

Melanoma epidemiology and trends CMs) and not in older age, which is the time of highest cumulative sun exposure. • An elevated CM risk after higher cumulative sun exposure in adulthood and after sunburns during the years before melanoma diagnosis was not detected in most of the case–control studies performed. The first hints on the etiologic role of sunlight came from the observation that the CM incidence increased in white populations who lived close to the equator and thus with the intensity of ultraviolet radiation (UVR). This was most striking when a comparison of melanoma incidence and mortality rates between Europe and Australia reported five to 10 times higher incidence rates in Australia.57 Differences in CM incidence and mortality rates were observed between natives and immigrants to areas with sunny climates such as Australia, Israel, and Hawaii.58-61 Interestingly, melanoma incidence rates equalized to the higher native rates when immigrants came in early childhood, and the lowest rates were observed when the immigrants were older than 20 years when they arrived (the lower European risk). This was the first finding hinting on the development of melanoma risk in childhood. Finally, case–control studies on the risk for melanoma development revealed that CM risk was closely associated with the number of melanocytic nevi the individuals had on their integument and, additionally, to the occurrence of sunburns in childhood.62-64 Sunburns in childhood and adolescence were shown to elevate significantly the risk for melanoma development, but additional sunburns during adulthood did not contribute to any further risk elevation. This was in agreement with the previous finding that melanoma risk is mainly acquired in childhood. The number of melanocytic nevi on the entire integument has been identified as the most important risk factor for CM. With growing numbers of melanocytic nevi, the melanoma risk increases nearly linearly.65,66 In addition, the presence of atypical melanocytic nevi was found in these studies to be an independent risk factor. The risk for the development of melanocytic nevi in childhood seemed to be associated with sunburns during this period of life.67,68 To achieve more insight into the relationship between sun exposure and nevus development, epidemiologic studies have been performed in young children. With exposure to intense UVR, children in Australia developed melanocytic nevi early in life and in large numbers.69 Duration of sun exposure was a stronger risk factor than the occurrence of sunburns. In a study of 1812 German nursery children, high numbers of nevi were preferentially associated with the number of weeks on sunny holidays and with outdoor activities at home linked with moderate sun exposure.70,71 These findings show that sunburns are not required and that moderate sun exposure seemed to be sufficient for induction of melanocytic nevi.72 The epidemiologic evidence implicating sun exposure in the causation of melanocytic nevi and melanoma is supported

7 by biologic evidence that damage caused by UVR, particularly damage to DNA, plays a central part in the pathogenesis of these tumors.53,55 Childhood exposure to UVR seems to be the main factor to induce mutations in the melanocytic system associated with an increased induction of melanocytic nevi and later on an increased risk for the development of melanoma. Most melanocytic nevi display mutational activations of the BRAF gene.73-75 Mutational activation of the Ras/Raf/mitogen activated protein kinase pathway in nevi seems to be a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis. Thus, the presence and number of melanocytic nevi indicate the mutational status of the pigment system, and melanocytic nevi are a marker of later melanoma risk. A possible explanation for the marked differences in the epidemiology of CM compared with nonmelanoma skin cancer76 is that after exposure to UVR, the most severely damaged keratinocytes undergo apoptosis, leaving the less damaged keratinocytes to up-regulate their DNA-repair capacity and to undergo nearly perfect repair. The development of nonmelanoma skin cancer therefore remains an event in older age. In contrast, melanocytes do not undergo apoptosis so fast. Their function is to provide protective melanin to the surviving cells, and they are retained within the epidermis, even if damaged. Thus, a high dose of UVR in melanocytes will cause substantial damage but not apoptosis; the melanocytes will survive to mutate and divide. Some mutations induced by UVR are thought to enable melanocytes to cross the epidermal basement membrane into the dermis, where subsequent proliferation gives rise to junctional nevi. Melanoma can then arise in body regions with intermittent sun exposure. Interestingly, the body distribution of melanoma closely matches with the distribution of melanocytic nevi.44,77 This hypothesis likewise explains why melanoma can develop in young adults.

Trends in melanoma epidemiology In most countries with white populations, an ongoing trend of increasing incidence for CM still continues. Cohort studies in Europe do not yet indicate a leveling of incidence rates, and expectations are that this trend will continue for at least the next 2 or 3 decades and that the melanoma incidence will further double during this period.78,79 Similarly, agecohort analyses of CM incidence revealed that incidence rates may well continue to rise in the United States.1 In contrast to the development in Europe, rates of melanoma in younger people in Australia seem to have stabilized, which might be explained by long-lasting primary prevention campaigns aimed at reducing solar exposure.80 Mortality of melanoma has leveled in many countries despite the rising incidence rates.26 Some investigations have already described a trend toward decreasing mortality rates.81 This seems to be mainly due to improved early detection,

8 indicated by the decrease in Breslow tumor thickness at the time of the first diagnosis of CM.29 It can be expected that despite the increasing incidence rates, a further decrease in melanoma mortality may develop as a result of more screening activities and improvement of early diagnosis. The increasing life expectancy will shift the median age of melanoma patients to higher age groups. This will also contribute to a further increase in the incidence of melanoma.52 Thus, melanoma in the elderly will become a more noteworthy topic. Finally, epidemiologic melanoma research will also be influenced by the recent findings that melanoma is a heterogeneous disease and that different melanoma types should be distinguished at the molecular level.43 These new findings will, hopefully, lead to new insights in pathogenesis and treatment options.

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