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Melanoma: Prevention and Early Detection
Melanoma: Prevention and Early Detection Jeremy S. Bordeaux,a,b Kurt Q. Lu,a and Kevin D. Coopera,b,c Exposure to ultraviolet radiation is the main modifiable risk factor for melanoma. Strong epidemiologic and molecular evidence links sun exposure to the development of melanoma. Given the ubiquitous abundance of ultraviolet radiation, prevention aimed at blocking sun exposure is recommended by the American Academy of Dermatology, the Skin Cancer Foundation, the American Cancer Society, the Centers for Disease Control, and the Environmental Protection Agency. However, in contrast to other forms of skin damage, controversial data regarding sunscreen use and increased melanoma risk, possibly secondary to more overall sun exposure in melanoma patients, requires clarification. Primary care physicians may not be as adept at identifying worrisome lesions, but they have more opportunity to make the diagnosis. False positive identification of lesions and biopsy does not lead to extreme morbidity. Counseling patients to perform self skin examinations also contributes to important early detection. Semin Oncol 34:460-466 © 2007 Elsevier Inc. All rights reserved.
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isk factors for developing melanoma include sun exposure, presence of multiple, dysplastic, or congenital nevi, fair skin, freckling, light hair, family history of melanoma, immune suppression, advanced age, male gender, personal history of melanoma, and xeroderma pigmentosum. Reduction of the modifiable risk factor sun exposure should allow primary prevention of new melanomas. Surveillance and education of patients with the aforementioned risk factors should allow early diagnosis of melanoma.1-4 Primary prevention aims to halt disease occurrence and results in a decrease in the incidence of a particular disease. Counseling patients to practice sun protective behaviors such as sunscreen use and midday sun avoidance constitutes melanoma primary preventive practices. Other primary preventive strategies for melanoma that have been proposed include the use of cholesterol-lowering medications and altered diet. Secondary prevention aims to detect disease at an earlier, more treatable stage and results in a decrease in morbidity and/or mortality from a disease. Secondary preventive measures for melanoma include complete body skin examinations performed by physicians and patients to facilitate detection of melanoma in its earlier, more treatable stages. Both aDepartment
of Dermatology, Case Western Reserve University, Cleveland, OH. bMultidisciplinary Melanoma Program, Ireland Cancer Center, University Hospitals Case Medical Center, Cleveland, OH. cVeterans Affairs Medical Center, Cleveland, OH. J.S.B. and K.Q.L. contributed equally to this work. Address correspondence to Kevin D. Cooper, MD, University Hospitals of Cleveland, 11100 Euclid Ave, Lakeside 3516, Cleveland, OH 44106. E-mail: [email protected]
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0093-7754/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2007.09.012
primary and secondary preventive measures are important in the battle against melanoma.
Primary Prevention Exposure to ultraviolet radiation is the main modifiable risk factor for melanoma. Strategies in melanoma primary prevention on the individual and community levels focus on education and policy that promotes protection from sun exposure. After conducting a systematic review, in 2003 the Task Force on Community Preventive Services released recommendations for skin cancer and melanoma prevention intervention based on sun protection, advocating the socalled “covering up” behavior.5 Sun exposure is accepted as the main environmental carcinogen in the development of non-melanoma skin cancers. For melanoma development, sun exposure has been a controversial determinant. However, the increased melanoma incidence in patients affected with xeroderma pigmentosum, a genetic disorder with the inability to repair ultraviolet light (UV)-induced DNA damage, supports a causal role of sun exposure in melanoma development.6,7 Additionally, using a methodology that examined DNA repair capacity (DRC) ex vivo, Wei et al reported a lower DRC in patients who developed melanoma on sun-exposed sites.8 Strong evidence links sun exposure to the development of melanoma from studies of migrant populations and native residents in geographic areas with high ambient solar radiation, especially fairskinned individuals of European origin.6,7,9 Melanomas are observed in higher density in sun-exposed rather than sunprotected areas.10 Studies of individuals and personal sun
Prevention and early detection of melanoma exposure have yielded inconsistent and conflicting relations between sun exposure and melanoma. Data support the hypothesis of increased association of melanoma risk with intermittent/recreational sun exposure. Two reviews of 25 and 29 case-controlled studies calculated observed risks (ORs) of 1.57 (95% confidence interval [CI], 1.29 to 1.91) and 1.87 (95% CI, 1.67 to 2.09), respectively, for intermittent sun exposure and associated melanoma risk.11,12 In the latter study, the authors found a significantly reduced risk with occupational sun exposure with an OR of 0.86 (95% CI, 0.77 to 0.96). Lacking in evidence remains the relationship between total lifetime UV exposures with melanoma. Overall, the evidence suggests that UV exposure is strongly associated with melanoma development. Epidemiologic evidence from decline of mortality from melanoma among generations of Australians benefiting from UV protection programs implicates sun exposure in the development of melanoma.13 While the topic of sunscreen use is controversial, primary prevention strategies remain focused on sun protection. Recommendations include avoidance of excessive sun exposure, especially during midday peak sun intensity, avoidance of artificial UV tanning, guidance on selection and application of sunscreens, and use of sun-protective clothing.14
Role of Sunscreens in Melanoma Acute intense sun exposure leads to sunburn, which is strongly associated with melanoma development. A metaanalysis of 19 studies found a significant association of history of sunburn in adult age and melanoma development (OR 1.91; 95% CI, 1.69 to 2.17).11 The association holds for sunburn history during childhood and adolescence. Hence, given the ubiquitous abundance of UV radiation, prevention aimed at blocking sun exposure has been the recommendation from the American Academy of Dermatology,15 the Skin Cancer Foundation,16 the American Cancer Society,17 the Centers for Disease Control,17 and the Environmental Protection Agency.18 However, several epidemiological studies have repeatedly found an associated increased risk of melanoma development with sunscreen use.19-21 A confounding factor with these studies is that subjects at higher risk for melanoma, fair skin type with a tendency to burn, are the ones more likely to use sunscreens.22 Early studies dealt mainly with sunscreens that had low sun protection factor (SPF) values (⬍10) or that were mainly UVB blockers. Additionally, the recognition of the carcinogenic potential of UVA wavelengths and subsequent development of UVA blockers did not become available until the 1990s. However, despite the use of higher SPF sunscreens, median SPF 17, containing a UVA filter, Autier et al found an increasing number of nevi, a predictor of melanoma, in a study of 631 white European children.19-21 However, in contrast to sunscreens, sun protection from clothing was associated with fewer nevi. Sun protection from clothing also has been associated with decreased melanoma risk.23 The puzzling association of increased melanoma risk and sunscreen use cannot be attributed to a known direct carcinogenic affect of sunscreens.24,25 With the exception of a
461 single sunscreen compound commercially available in Europe before 1995 that contained the photocarcinogen 5methoxypsoralen, no other commercial compounds have been identified as having an increased risk for melanoma.24,25 Furthermore, the speculation that wavelength-specific blockage from UVB or UVA filters afforded protection from melanoma cannot explain the findings that subjects who had never used sunscreens did not appear to have the highest melanoma risk. Evidence reviewed by Autier and Dore supports the hypothesis that sunscreen users tend to have longer durations of sun exposure, particularly from sunbathing activities.26 Two studies found that high SPF users were more likely to sunbathe during midday peak sun.27,28 In one study, high SPF sunscreens were associated with more sunburn episodes. Sunburn experiences did not seem to differ between sunscreen users and non-users. If sunscreens merely afforded longer duration of sun exposure, their use would have little impact because ultimately users and non-users reached similar end points of sunburn development. Additionally, analysis of data regarding sunscreen use and sun exposure may need clarification. Autiers and Dore proposed that a distinction should be made between intentional and non-intentional sun exposure, ISE and NISE, respectively.26 For example, indoor tanning booths and sunbathing would both be considered ISE activities. Gardening and skiing are examples of NISE activities in which the subject’s sun exposure may be limited to uncovered body parts. Traditional classifications would label both sunbathing and skiing as “recreational sun exposure,” not taking into account the exposure risks associated with the activity and behavior. However, the ISE/NISE labels would identify not only anatomic distributions at risk with regards to sun-exposure versus sun-protection but also encompass the nature of the activity with regards to intention for sun exposure.
Early Childhood Sun Exposure In two nationwide cross-sectional surveys of American youths between the ages of 11 and 18, 77% to 83% of respondents report having had one sunburn, 36% with at least three sunburns, and 12% with at least five sunburns.29,30 Evidence to support the role of sun exposure during childhood and the subsequent risk for skin cancer in adulthood is more consistent in non-melanoma skin cancers than in melanoma.31,32 However, in a systematic review of 13 case-control studies reporting risk of melanoma associated with sun exposure during two or more age-periods, Whiteman et al calculated an OR of 1.8 (95% CI, 1.6 to 2.2) for childhood sunburns compared to 1.5 (95% CI, 1.3 to 1.8) sunburns in adulthood.33 In the same report, the authors reviewed four ecological studies and found decreased risk of melanoma in subjects who migrated from areas of low to high ambient UV exposure before ages 10 and 15. These subjects had decreased risk compared to the native-born residents. These findings support the role of high levels of sun exposure in childhood as a strong risk factor for melanoma. National efforts to educate parents and children about sun protection have yielded little improvement in the trends re-
462 garding the practice of sun protection. A comparison of youths between ages 11 to 18 in 1998 and 2004 showed no significant changes in incidence of sunburns, 72% and 69%, respectively.34 In accordance with other surveys, sunscreen use was reported to be in the 30% to 39% range,29,34 and remains the sole method of sun protection with less prevalent use of other protective measures. Therefore, new innovative approaches or adoption of policies may be necessary in the effort to reduce the incidence of childhood sunburns.
Sun Tanning Behaviors Studies of indoor tanning users reported a staggering 8.1-fold increase (95% CI, 1.3 to 49.5) in melanoma risk in individuals younger than age 36 compared to non-users.35 Tanning prevalence estimates in adolescents range from 9.5% to 34%36 and is estimated to be 2.3 million of the North American consumer base.37 Despite educational efforts of the harmful effects of UV exposure and increased public awareness and knowledge of the adverse effects of sun exposure, attitudes regarding tanning remain unaltered. The use of indoor tanning booths has increased, especially among adolescents and young adults.29,38,39 Desired for its cosmetic enhancement, tanning may have other attributes to explain its sustained popularity. The repetitive nature of tanning together with the possibility of UV-induced release of endorphins prompted the consideration of tanning as a substance-related addictive behavior.40,41 Despite the inconsistent evidence of the chemical basis for reinforcement of tanning behavior, 23% and 53%, respectively, of individuals who repetitively tan tested positive for UV substance-related disorder (SRD) when screened by CAGE (cut down, annoyed, guilty, eye-opener) and DSMIV-TR questionnaires.42 In the young adult population, CAGE questionnaires regarding tanning in undergraduates who admitted to purposely tanning their skin revealed that almost one fifth of respondents may have SRD.43 Those respondents were more often indoor tanners than sun-tanners, had experienced a severe burn, and were more likely to purposefully tan their skin 20 or more times a month. Currently, 26 states and four counties have regulations on tanning for minors.44 There is no uniformity in these regulations, with some states establishing a minimum age, ranging from 14 to 18 years, while others permit minors to tan with either a parent’s consent or a doctor’s prescription.
J.S. Bordeaux, K.Q. Lu, and K.D. Cooper less of the biological activity of the melanoma, there is no doubt that the earlier it is detected and treated, the better the chance of survival. Early detection of melanoma can be achieved by complete body skin examinations provided by physicians and self skin examinations performed by patients.
Early Detection/Screening Four conditions must be met for medical screening to be effective. First, a presymptomatic phase of disease must exist during which the patient is unaware disease is present. If symptoms occurred at onset of disease, patients would seek care immediately and screening would be worthless. Medical conditions fulfilling this criteria include cervical cancer, breast cancer, prostate cancer, hypertension, anemia, and melanoma. Second, an accurate screening test that detects the presence of disease in the presymptomatic phase must exist. This test should not cause significant morbidity and should be highly sensitive and specific to decrease the number of false positives and false negatives encountered. Office sphygmomanometry (blood pressure cuff), mammography, and the Papanicolaou smear are all tests that meet these criteria. The blood test for prostate-specific antigen (PSA) is not sufficiently sensitive or specific for it to be effective for screening for prostate cancer. The utility of the complete skin examination to detect melanoma will be discussed at length later. Third, there must be an effective treatment of the disease in question. Without an effective treatment for a disease, screening for that disease would be futile. There are many effective antihypertensive medications and there also are effective treatments for breast cancer, cervical cancer, and melanoma. The last and most important requirement is conceptually the most difficult, and states that treatment of the disease, when detected in the presymptomatic stage, must lead to less morbidity and mortality when compared to treatment of the disease once it becomes clinically apparent. If a disease treatment is equally successful when treating early and late disease, there is no need for early detection. Breast cancer, cervical cancer, and melanoma all have better outcomes when treated earlier. In addition, even when all four of these requirements are satisfied, other variables such as cost of screening must be considered.
Secondary Prevention
Screening for Melanoma—Physicians
Secondary prevention (early detection) is crucial in reducing melanoma morbidity and mortality. As discussed previously, melanoma survival relates directly to the depth of invasion of the primary tumor at the time of diagnosis. Fortunately, most melanomas are detected early, with greater than 50% being stage I and less than 1% being stage IV at the time of diagnosis.4 Although some melanomas may be more biologically aggressive than others, with some thin tumors metastasizing while some thick tumors do not, there is currently no way to differentiate these more aggressive tumors. However, regard-
The presence of a presymptomatic phase occurs in melanoma. Symptoms patients might experience, including pain, bleeding, and pruritus, frequently do not occur until later in the disease process. More often, subtle changes in size, shape, or color are first noted. If patients routinely notice and report these subtle changes to physicians, they would be decreasing the length of the “presymptomatic phase.” As patients become better at noticing these changes on their own and seeking medical attention when symptoms are noted, the utility of screening will actually decrease. However, the majority of
Prevention and early detection of melanoma patients will have their melanoma for quite sometime before they notice obvious or subtle symptoms. Screening tests available that may be used to detect the presence of melanoma include complete skin examinations performed by physicians and complete skin examinations performed by patients. Low sensitivity and specificity lead to false positives with resultant unneeded biopsies and personal angst, and false negatives, which lead to false reassurance. Variables that alter the sensitivity and specificity of complete skin examinations include physician type and presence or absence of additional techniques such as dermoscopy and digital photography. Complete surgical removal of early melanoma with appropriate margins is often curative. Thus, the third condition of screening, presence of a successful treatment of the condition, is met. Melanoma fulfills the last condition of screening, treatment rendered during the presymptomatic phase of disease must be more effective than treatment rendered at time of clinical presentation, perfectly. Once a melanoma becomes symptomatic, it is very likely that it has grown deeper into the skin than when it was asymptomatic. Thinner melanomas have a much better prognosis than thick melanomas. Thus it is imperative that melanoma be detected during its asymptomatic phase so that surgery can be curative. Epstein et al showed that melanomas detected by physicians had a median depth of 0.23 mm and melanomas detected by patients had a median depth of 0.9 mm.45 Similar results were found in an Australian study that reported the odds of a melanoma being thin were 2.56 times greater if detected by a physician as opposed to the patient.46
Screening Tests The major screening test for detecting melanoma is the complete body skin examination performed by a physician. It consists of a physician examining a patient from head to toe in an environment with good lighting. The accuracy of this examination depends on the training of the practitioner and the presence of any additional techniques such as dermoscopy, digital photography, or computer mole-map programs. The examination has low morbidity and is quick and easy to perform. The sensitivity and specificity of a complete body skin examination for detecting melanoma have been estimated to be 84.5% and 99.2%, respectively.47 As expected, dermatologists are better at diagnosing melanoma than primary care physicians.48 False positives do not lead to extreme morbidity. Patients undergo a skin biopsy, which is very low risk. False negatives will hopefully be detected at a subsequent visit. Primary care physicians may not be as adept at identifying worrisome lesions, but they have more opportunity to make the diagnosis. A study of patients diagnosed with melanoma showed that 87% of these patients had a primary care physician, and 63% of these patients had seen their primary care physician within 1 year of diagnosis of their melanoma. Only 20% of the patients had seen a dermatologist in the previous year.49 There are many more primary care physicians in the
463 world than there are dermatologists. However, primary care physicians may not have the training to diagnose melanoma. Unfortunately only 12% of primary care physicians were able to diagnose five of six melanomas and only 38% of primary care physicians correctly diagnosed four of six melanomas.50 In addition, only 17% of primary care physicians categorized their relevant training as excellent or good.50 Raising awareness of the significance of melanoma and bettering physician’s ability to confidently diagnose melanoma will be an important advance. Other tools that may be used to aid the physician in performing a complete skin examination include dermoscopy, digital photography, and mole-mapping devices. Dermoscopy entails the use of a handheld device similar in size to an otoscope that features a 10⫻ magnification capability and illumination. Dermoscopy has been shown to increase the sensitivity and specificity of the diagnostic accuracy of dermatologists for melanoma in a large meta-analysis.51 It has been shown to reduce the number of pigmented lesions removed for diagnostic verification in a randomized controlled trial by dermatologists.52 Dermoscopy also has been shown to increase the accuracy of primary care physicians in diagnosing melanoma in Spain, Italy, and Australia.53,54 However, only 23% of dermatologists in the United States are currently using dermoscopy.55 Digital photography can be used as a reference for referral by the physician to establish a baseline. Care must be taken to compare the old pictures to the current patient. These pictures can be used with or without the aid of dermoscopy. Early reports suggest that full-body photography may aid in early diagnosis of melanoma.56,57 Unanswered questions with regard to the use of full-body photography include cost and legal liability. Additionally, “mole-map machines,” which allow computer programs to compare old and new pictures of moles, can calculate degrees of change that can go unnoticed by the human eye. The time required and cost of these machines have not been determined, nor has their effectiveness.
Who Should Be Screened? Risk Stratification and Cost-Effectiveness Health care resources are limited, and several questions remain to be answered: Should screening for melanoma be performed? If so, which patients should be screened and how often? The gold standard to answer the screening question is a large, prospective, randomized controlled trial comparing mortality in a screened and nonscreened group. Such a trial was developed and implemented and early results looked promising. However, secondary to a lack of funding, this trial was stopped early.58 Multiple cost-effective analyses have been performed. The common threshold in the United States for cost-effectiveness is $50,000 to $100,000 per qualityadjusted life-year (QALY) gained, although these numbers have been challenged.59 Freedberg et al estimated a $29,170 per year of life (YLS) saved for a one-time screening of a high-risk population by a dermatologist. High risk was de-
464 fined as adults greater than 20 years of age who were lightskinned and burned easily, or who had a family history of skin cancer, extensive sun exposure, and higher than average number of nevi.60 In Australia, cost-effectiveness for screening every 2 years by primary care physicians has been calculated to be $15,000/YLS in 50-year-old men and $25,800/ YLS in women aged 50.61 A recent study by Losina et al reported an incremental cost-effectiveness ratio of $10,100/ QALY for one-time screening by dermatologists of patients over 50 years of age and $80,700/QALY for screening every 2 years in the same group.62 They also reported a cost-effectiveness ratio of $35,500/QALY for screening siblings of patients with melanoma every 2 years. These data support routine screening in high-risk populations. However, the United States Preventive Services Task Force has given screening for skin cancer an “I” recommendation, concluding that there is insufficient evidence to recommend for or against routine screening. The same group has given an “A” recommendation, strongly recommends for clinicians to provide this service yearly, for Papanicolaou tests for life ($24,100/QALY) and fecal occult blood test plus sigmoidoscopy every 5 years after the age of 50 ($47,400/YLS).63-65 However, this last analysis for skin cancer screening was performed in April 2001 and a current update is in progress. The American Cancer Society does recommend regular skin examinations as part of the periodic health exam. The Canadian Task force on Preventive Health Care, The American College of Preventive Medicine, and the American College of Obstetricians and Gynecologists recommend total skin examinations for high-risk patients.66
Screening for Melanoma—Patients Counseling patients to perform self skin examinations also can help with early detection. Self skin examinations are deliberate exams looking for new or changing lesions performed at a specific interval (usually monthly). In a casecontrol study, Berwick et al suggested that routine self skin examination could reduce mortality from melanoma by 63%.67 Additionally, patients with a history of melanoma who were taught self skin examinations and had a second melanoma were diagnosed significantly earlier than with the first.68 Care should be taken to explain how to perform the complete self skin examination and how often it should be done. A recent randomized controlled trial evaluating performance of self skin examinations by patients who were taught alone and patients who were taught with a partner found that those taught with a partner were more likely to perform the examination.69 Proper instruction on the importance of performing and how to perform the self skin examination is an important aspect of melanoma education.
Public Education Regardless of all our hard work, there are not enough physicians to screen all patients. Public education campaigns such
J.S. Bordeaux, K.Q. Lu, and K.D. Cooper as the Slip, Slop, Slap program in Australia are important public educational campaigns. This campaign was introduced in 1981 in Australia to raise public awareness of the dangers of skin cancer. Sid the Seagull and his son Sam taught children and adults alike the importance of sun protection. Sunburn rates in Australia have decreased, attitudes about sunlight and suntans have changed, and melanoma mortality rates in younger patients are decreasing.70 Care must be taken in developing, implementing, and testing future global public awareness messages to ensure their efficacy.
Optimizing Patient Care: Where Are We Headed? Primary melanoma prevention requires more precise identification of patients at risk, so that cost-effective efforts can be focused on the susceptible populations. Although some familial melanoma genes have been described, they identify only a small subset of primary melanoma patients, and work on identifying complex interactive genetic traits, such as vitamin D receptor polymorphisms,71 are critical for determining a genetic risk profile that can be managed during the critical childhood years, where a great deal of environmental melanoma risk is acquired. Primary prevention also would be benefited by a better understanding of the process of melanomagenesis. What are the critical gene modifications that lead to transformation of melanocytes? Is protection against UVB sufficient to prevent melanoma, or does the action spectrum for melanoma induction reach into the visible wavelengths, as suggested by Setlow.72 Are there dietary or chemoprevention interventions that may be effective, such as vitamin D supplementation or use of statins and fibrates (although a systematic review and meta-analysis of these agents do not validate their role in melanoma prevention73). In any case, a better understanding of the progressively increasing risk of melanoma in the population by the general public, educators, coaches, and physicians is critical for changing sun exposure behaviors that are associated with increased melanoma risk. Continual development of public awareness campaigns can help educate the public about the importance of melanoma and how they may best prevent it (sun protective behaviors) and detect it early (self skin examinations). Further education of primary care physicians and allied healthcare providers should be employed to increase their awareness of the morbidity and mortality related to melanoma and tools for education of their patients and families need to be widely available and easy to use. Wide dissemination of a focus on avoidance of midday sun, emphasis on protective clothing/hats and shade, and secondary supplementation of protection with broad-spectrum sunscreens are key messages that are a cornerstone of primary prevention. Secondary prevention is a critical component of reducing death from melanoma, because of the curable potential at early stages. Better education of all healthcare providers, as well as hairdressers, cosmeticians, and others with wide ex-
Prevention and early detection of melanoma posure to the public can aid in the recognition of suspicious pigmented lesions that need closer evaluation. Development of tools that can be used by primary care physicians to allow easy risk stratification to determine which patients will benefit most from melanoma screening will obviously benefit these efforts. Secondary prevention will be aided by advances in the development of early detection methodologies. Dermatologists and primary care physicians who become better educated in the use of dermoscopy will increase the sensitivity and specificity of melanoma screening. In process are complex algorithms for analyzing dermoscopic optical data that can calculate risk of melanoma of a given pigmented lesion, and wide dissemination of such methodologies may further enhance our secondary prevention capabilities by better identification of at risk lesions. Whole-body digital photography with digital analysis offers promise into objectively and accurately identifying which pigmented lesions represent new and enlarging lesions, which are known in adults to be at higher risk for representing melanomas. Once a lesion is identified at significant risk for melanoma and is subjected to biopsy, there remains a critical role for additional secondary prevention. In addition to disparity among dermatopathologists regarding the threshold for diagnosing melanoma, there also is an inability to determine by histopathology the full risk of an emerging pigmented lesion. Thus, “genetic finger printing” by which genes or proteins expressed by melanomas may reveal the likelihood of progression of a melanocytic nevus into melanoma, whether a melanocytic lesion has begun to express signature genes for melanoma, or whether the lesion is at risk of metastasis regardless of depth at diagnosis, offers great promise in determining which early lesions require more extensive resection at the outset. Thus, both standard public health intervention and technical innovations will benefit the prevention and early detection of melanoma, and when combined, offer the potential for reduction of risk from death from melanoma.
References 1. Lens MB, Dawes M: Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150:179185, 2004 2. Cancer Facts and Figures. American Cancer Society, 2007 3. Melanoma Fact Sheet. American Academy of Dermatology, 2007 4. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600 melanoma patients: Validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol 19:36223634, 2001 5. Saraiya M, Glanz K, Briss P, et al: Preventing skin cancer: Findings of the Task Force on Community Preventive Services on Reducing Exposure to Ultraviolet Light. MMWR 52:1-12, 2003 6. Armstrong BK, Kricker A: How much melanoma is caused by sun exposure? Melanoma Res 3:395-401, 1993 7. Khlat M, Vail A, Parkin M, et al: Mortality from melanoma in migrants to Australia: Variation by age at arrival and duration of stay. Am J Epidemiol 135:1103-1113, 1992 8. Wei Q, Lee JE, Gershenwald JE, et al: Repair of UV light-induced DNA damage and risk of cutaneous malignant melanoma. J Natl Cancer Inst 95:308-315, 2003
465 9. Kricker A, Armstrong BK, Goumas C, et al: Ambient UV, personal sun exposure and risk of multiple primary melanomas. Cancer Causes Control 18:295-304, 2007 10. Elwood JM, Gallagher RP: Body site distribution of cutaneous malignant melanoma in relationship to patterns of sun exposure. Int J Cancer 78:276-280, 1998 11. Elwood JM, Jopson J: Melanoma and sun exposure: An overview of published studies. Int J Cancer 73:198-203, 1997 12. Nelemans PJ, Rampen FH, Ruiter DJ, et al: An addition to the controversy on sunlight exposure and melanoma risk: A meta-analytical approach. J Clin Epidemiol 48:1331-1342, 1995 13. Giles GG, Armstrong BK, Burton RC, et al: Has mortality from melanoma stopped rising in Australia? Analysis of trends between 1931 and 1994. BMJ 312:1121-1125, 1996 14. Glanz K, Saraiya M, Wechsler H: Guidelines for school programs to prevent skin cancer. MMWR 51:1-18, 2002 15. Lim HW, Cooper K: The health impact of solar radiation and prevention strategies: Report of the Environment Council, American Academy of Dermatology. J Am Acad Dermatol 41:81-99, 1999 16. Year-Round Sun Protection. Skin Cancer Foundation, 2007 17. Skin Cancer Prevention and Early Detection. American Cancer Society, 2007 18. Geller AC, Cantor M, Miller DR, et al: The Environmental Protection Agency’s National SunWise School Program: Sun protection education in US schools (1999-2000). J Am Acad Dermatol 46:683-689, 2002 19. Westerdahl J, Olsson H, Masback A, et al: Is the use of sunscreens a risk factor for malignant melanoma? Melanoma Res 5:59-65, 1995 20. Elwood JM, Gallagher RP: More about: Sunscreen use, wearing clothes, and number of nevi in 6- to 7-year-old European children. J Natl Cancer Inst 91:1164-1166, 1999 21. Autier P, Dore JF, Schifflers E, et al: Melanoma and use of sunscreens: An EORTC case-control study in Germany, Belgium and France. The EORTC Melanoma Cooperative Group. Int J Cancer 61:749-755, 1995 22. Weinstock MA: Do sunscreens increase or decrease melanoma risk: An epidemiologic evaluation. J Invest Dermatol Symp Proc 4:97-100, 1999 23. Holman CD, Armstrong BK, Heenan PJ: Relationship of cutaneous malignant melanoma to individual sunlight-exposure habits. J Natl Cancer Inst 76:403-414, 1986 24. Cartwright LE, Walter JF: Psoralen-containing sunscreen is tumorigenic in hairless mice. J Am Acad Dermatol 8:830-836, 1983 25. Ashwood-Smith MJ, Poulton GA, Barker M, et al: 5-Methoxypsoralen, an ingredient in several suntan preparations, has lethal, mutagenic and clastogenic properties. Nature 285:407-409, 1980 26. Autier PaD, JF: The role of sunscreens in melanoma prevention, in Thompson JF, Kroon B (eds): Textbook of Melanoma, vol 1. London, Martin Dunitz, 2004, p 90 27. Autier P, Dore JF, Negrier S, et al: Sunscreen use and duration of sun exposure: A double-blind, randomized trial. J Natl Cancer Inst 91: 1304-1309, 1999 28. Autier P, Dore JF, Reis AC, et al: Sunscreen use and intentional exposure to ultraviolet A and B radiation: A double blind randomized trial using personal dosimeters. Br J Cancer 83:1243-1248, 2000 29. Geller AC, Colditz G, Oliveria S, et al: Use of sunscreen, sunburning rates, and tanning bed use among more than 10 000 US children and adolescents. Pediatrics 109:1009-1014, 2002 30. Davis KJ, Cokkinides VE, Weinstock MA, et al: Summer sunburn and sun exposure among US youths ages 11 to 18: National prevalence and associated factors. Pediatrics 110:27-35, 2002 31. Gallagher RP, Hill GB, Bajdik CD, et al: Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma. Arch Dermatol 131:164-169, 1995 32. Gallagher RP, Hill GB, Bajdik CD, et al: Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma. Arch Dermatol 131:157-163, 1995 33. Whiteman DC, Whiteman CA, Green AC: Childhood sun exposure as a risk factor for melanoma: A systematic review of epidemiologic studies. Cancer Causes Control 12:69-82, 2001
466 34. Cokkinides V, Weinstock M, Glanz K, et al: Trends in sunburns, sun protection practices, and attitudes toward sun exposure protection and tanning among US adolescents, 1998-2004. Pediatrics 118:853-864, 2006 35. Westerdahl J, Ingvar C, Masback A, et al: Risk of cutaneous malignant melanoma in relation to use of sunbeds: Further evidence for UV-A carcinogenicity. Br J Cancer 82:1593-1599, 2000 36. Magee KH, Poorsattar S, Seidel KD, et al: Tanning device usage: What are parents thinking? Pediatr Dermatol 24:216-221, 2007 37. Dellavalle RP, Parker ER, Cersonsky N, et al: Youth access laws: In the dark at the tanning parlor? Arch Dermatol 139:443-448, 2003 38. Knight JM, Kirincich AN, Farmer ER, et al: Awareness of the risks of tanning lamps does not influence behavior among college students. Arch Dermatol 138:1311-1315, 2002 39. Robinson JK, Rigel DS, Amonette RA: Trends in sun exposure knowledge, attitudes, and behaviors: 1986 to 1996. J Am Acad Dermatol 37:179-186, 1997 40. Levins PC, Carr DB, Fisher JE, et al: Plasma beta-endorphin and betalipoprotein response to ultraviolet radiation. Lancet 2:166, 1983 41. Kaur M, Liguori A, Lang W, et al: Induction of withdrawal-like symptoms in a small randomized, controlled trial of opioid blockade in frequent tanners. J Am Acad Dermatol 54:709-711, 2006 42. Warthan MM, Uchida T, Wagner RF Jr: UV light tanning as a type of substance-related disorder. Arch Dermatol 141:963-966, 2005 43. Poorsattar SP, Hornung RL: UV light abuse and high-risk tanning behavior among undergraduate college students. J Am Acad Dermatol 56:375-379, 2007 44. Tanning Restrictions for Minors, A State-by-State Comparison. National Conference of State Legislatures, August 22, 2007 45. Epstein DS, Lange JR, Gruber SB, et al: Is physician detection associated with thinner melanomas? JAMA 281:640-643, 1999 46. McPherson M, Elwood M, English DR, et al: Presentation and detection of invasive melanoma in a high-risk population. J Am Acad Dermatol 54:783-792, 2006 47. Grin CM, Kopf AW, Welkovich B, et al: Accuracy in the clinical diagnosis of malignant melanoma. Arch Dermatol 126:763-766, 1990 48. Chen SC, Pennie ML, Kolm P, et al: Diagnosing and managing cutaneous pigmented lesions: Primary care physicians versus dermatologists. J Gen Intern Med 21:678-682, 2006 49. Geller AC, Koh HK, Miller DR, et al: Use of health services before the diagnosis of melanoma: Implications for early detection and screening. J Gen Intern Med 7:154-157, 1992 50. Cassileth BR, Clark WH Jr, Lusk EJ, et al: How well do physicians recognize melanoma and other problem lesions? J Am Acad Dermatol 14:555-560, 1986 51. Kittler H, Pehamberger H, Wolff K, et al: Diagnostic accuracy of dermoscopy. Lancet Oncol 3:159-65, 2002 52. Carli P, de Giorgi V, Chiarugi A, et al: Addition of dermoscopy to conventional naked-eye examination in melanoma screening: A randomized study. J Am Acad Dermatol 50:683-689, 2004
J.S. Bordeaux, K.Q. Lu, and K.D. Cooper 53. Argenziano G, Puig S, Zalaudek I, et al: Dermoscopy improves accuracy of primary care physicians to triage lesions suggestive of skin cancer. J Clin Oncol 24:1877-1882, 2006 54. Westerhoff K, McCarthy WH, Menzies SW: Increase in the sensitivity for melanoma diagnosis by primary care physicians using skin surface microscopy. Br J Dermatol 143:1016-1020, 2000 55. Tripp JM, Kopf AW, Marghoob AA, et al: Management of dysplastic nevi: A survey of fellows of the American Academy of Dermatology. J Am Acad Dermatol 46:674-682, 2002 56. Lucas CR, Sanders LL, Murray JC, et al: Early melanoma detection: Nonuniform dermoscopic features and growth. J Am Acad Dermatol 48:663-671, 2003 57. Feit NE, Dusza SW, Marghoob AA: Melanomas detected with the aid of total cutaneous photography. Br J Dermatol 150:706-714, 2004 58. Aitken JF, Janda M, Elwood M, et al: Clinical outcomes from skin screening clinics within a community-based melanoma screening program. J Am Acad Dermatol 54:105-114, 2006 59. Ubel PA, Hirth RA, Chernew ME, et al: What is the price of life and why doesn’t it increase at the rate of inflation? Arch Intern Med 163:16371641, 2003 60. Freedberg KA, Geller AC, Miller DR, et al: Screening for malignant melanoma: A cost-effectiveness analysis. J Am Acad Dermatol 41:738745, 1999 61. Girgis A, Clarke P, Burton RC, et al: Screening for melanoma by primary health care physicians: A cost-effectiveness analysis. J Med Screen 3:47-53, 1996 62. Losina E, Walensky RP, Geller A, et al: Visual screening for malignant melanoma: A cost-effectiveness analysis. Arch Dermatol 143:21-28, 2007 63. Screening for Skin Cancer. US Preventive Services Task Force, 2007 64. Screening for Cervical Cancer. US Preventive Services Task Force, 2007 65. Screening for Colorectal Cancer. US Preventive Services Task Force, 2007 66. Koh HK: Melanoma screening: Focusing the public health journey. Arch Dermatol 143:101-103, 2007 67. Berwick M, Begg CB, Fine JA, et al: Screening for cutaneous melanoma by skin self-examination. J Natl Cancer Inst 88:17-23, 1996 68. DiFronzo LA, Wanek LA, Morton DL: Earlier diagnosis of second primary melanoma confirms the benefits of patient education and routine postoperative follow-up. Cancer 91:1520-1524, 2001 69. Robinson JK, Turrisi R, Stapleton J: Efficacy of a partner assistance intervention designed to increase skin self-examination performance. Arch Dermatol 143:37-41, 2007 70. Marks R: Campaigning for melanoma prevention: A model for a health education program. J Eur Acad Dermatol Venereol 18:44-47, 2004 71. Li C, Liu Z, Zhang Z, et al: Genetic variants of the vitamin D receptor gene alter risk of cutaneous melanoma. J Invest Dermatol 127:276-280, 2007 72. Setlow RB: Spectral regions contributing to melanoma: A personal view. J Invest Dermatol Symp Proc 4:46-49, 1999 73. Freeman SR, Drake AL, Heilig LF, et al: Statins, fibrates, and melanoma risk: A systematic review and meta-analysis. J Natl Cancer Inst 98: 1538-1546, 2006
R
isk factors for developing melanoma include sun exposure, presence of multiple, dysplastic, or congenital nevi, fair skin, freckling, light hair, family history of melanoma, immune suppression, advanced age, male gender, personal history of melanoma, and xeroderma pigmentosum. Reduction of the modifiable risk factor sun exposure should allow primary prevention of new melanomas. Surveillance and education of patients with the aforementioned risk factors should allow early diagnosis of melanoma.1-4 Primary prevention aims to halt disease occurrence and results in a decrease in the incidence of a particular disease. Counseling patients to practice sun protective behaviors such as sunscreen use and midday sun avoidance constitutes melanoma primary preventive practices. Other primary preventive strategies for melanoma that have been proposed include the use of cholesterol-lowering medications and altered diet. Secondary prevention aims to detect disease at an earlier, more treatable stage and results in a decrease in morbidity and/or mortality from a disease. Secondary preventive measures for melanoma include complete body skin examinations performed by physicians and patients to facilitate detection of melanoma in its earlier, more treatable stages. Both aDepartment
of Dermatology, Case Western Reserve University, Cleveland, OH. bMultidisciplinary Melanoma Program, Ireland Cancer Center, University Hospitals Case Medical Center, Cleveland, OH. cVeterans Affairs Medical Center, Cleveland, OH. J.S.B. and K.Q.L. contributed equally to this work. Address correspondence to Kevin D. Cooper, MD, University Hospitals of Cleveland, 11100 Euclid Ave, Lakeside 3516, Cleveland, OH 44106. E-mail: [email protected]
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0093-7754/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2007.09.012
primary and secondary preventive measures are important in the battle against melanoma.
Primary Prevention Exposure to ultraviolet radiation is the main modifiable risk factor for melanoma. Strategies in melanoma primary prevention on the individual and community levels focus on education and policy that promotes protection from sun exposure. After conducting a systematic review, in 2003 the Task Force on Community Preventive Services released recommendations for skin cancer and melanoma prevention intervention based on sun protection, advocating the socalled “covering up” behavior.5 Sun exposure is accepted as the main environmental carcinogen in the development of non-melanoma skin cancers. For melanoma development, sun exposure has been a controversial determinant. However, the increased melanoma incidence in patients affected with xeroderma pigmentosum, a genetic disorder with the inability to repair ultraviolet light (UV)-induced DNA damage, supports a causal role of sun exposure in melanoma development.6,7 Additionally, using a methodology that examined DNA repair capacity (DRC) ex vivo, Wei et al reported a lower DRC in patients who developed melanoma on sun-exposed sites.8 Strong evidence links sun exposure to the development of melanoma from studies of migrant populations and native residents in geographic areas with high ambient solar radiation, especially fairskinned individuals of European origin.6,7,9 Melanomas are observed in higher density in sun-exposed rather than sunprotected areas.10 Studies of individuals and personal sun
Prevention and early detection of melanoma exposure have yielded inconsistent and conflicting relations between sun exposure and melanoma. Data support the hypothesis of increased association of melanoma risk with intermittent/recreational sun exposure. Two reviews of 25 and 29 case-controlled studies calculated observed risks (ORs) of 1.57 (95% confidence interval [CI], 1.29 to 1.91) and 1.87 (95% CI, 1.67 to 2.09), respectively, for intermittent sun exposure and associated melanoma risk.11,12 In the latter study, the authors found a significantly reduced risk with occupational sun exposure with an OR of 0.86 (95% CI, 0.77 to 0.96). Lacking in evidence remains the relationship between total lifetime UV exposures with melanoma. Overall, the evidence suggests that UV exposure is strongly associated with melanoma development. Epidemiologic evidence from decline of mortality from melanoma among generations of Australians benefiting from UV protection programs implicates sun exposure in the development of melanoma.13 While the topic of sunscreen use is controversial, primary prevention strategies remain focused on sun protection. Recommendations include avoidance of excessive sun exposure, especially during midday peak sun intensity, avoidance of artificial UV tanning, guidance on selection and application of sunscreens, and use of sun-protective clothing.14
Role of Sunscreens in Melanoma Acute intense sun exposure leads to sunburn, which is strongly associated with melanoma development. A metaanalysis of 19 studies found a significant association of history of sunburn in adult age and melanoma development (OR 1.91; 95% CI, 1.69 to 2.17).11 The association holds for sunburn history during childhood and adolescence. Hence, given the ubiquitous abundance of UV radiation, prevention aimed at blocking sun exposure has been the recommendation from the American Academy of Dermatology,15 the Skin Cancer Foundation,16 the American Cancer Society,17 the Centers for Disease Control,17 and the Environmental Protection Agency.18 However, several epidemiological studies have repeatedly found an associated increased risk of melanoma development with sunscreen use.19-21 A confounding factor with these studies is that subjects at higher risk for melanoma, fair skin type with a tendency to burn, are the ones more likely to use sunscreens.22 Early studies dealt mainly with sunscreens that had low sun protection factor (SPF) values (⬍10) or that were mainly UVB blockers. Additionally, the recognition of the carcinogenic potential of UVA wavelengths and subsequent development of UVA blockers did not become available until the 1990s. However, despite the use of higher SPF sunscreens, median SPF 17, containing a UVA filter, Autier et al found an increasing number of nevi, a predictor of melanoma, in a study of 631 white European children.19-21 However, in contrast to sunscreens, sun protection from clothing was associated with fewer nevi. Sun protection from clothing also has been associated with decreased melanoma risk.23 The puzzling association of increased melanoma risk and sunscreen use cannot be attributed to a known direct carcinogenic affect of sunscreens.24,25 With the exception of a
461 single sunscreen compound commercially available in Europe before 1995 that contained the photocarcinogen 5methoxypsoralen, no other commercial compounds have been identified as having an increased risk for melanoma.24,25 Furthermore, the speculation that wavelength-specific blockage from UVB or UVA filters afforded protection from melanoma cannot explain the findings that subjects who had never used sunscreens did not appear to have the highest melanoma risk. Evidence reviewed by Autier and Dore supports the hypothesis that sunscreen users tend to have longer durations of sun exposure, particularly from sunbathing activities.26 Two studies found that high SPF users were more likely to sunbathe during midday peak sun.27,28 In one study, high SPF sunscreens were associated with more sunburn episodes. Sunburn experiences did not seem to differ between sunscreen users and non-users. If sunscreens merely afforded longer duration of sun exposure, their use would have little impact because ultimately users and non-users reached similar end points of sunburn development. Additionally, analysis of data regarding sunscreen use and sun exposure may need clarification. Autiers and Dore proposed that a distinction should be made between intentional and non-intentional sun exposure, ISE and NISE, respectively.26 For example, indoor tanning booths and sunbathing would both be considered ISE activities. Gardening and skiing are examples of NISE activities in which the subject’s sun exposure may be limited to uncovered body parts. Traditional classifications would label both sunbathing and skiing as “recreational sun exposure,” not taking into account the exposure risks associated with the activity and behavior. However, the ISE/NISE labels would identify not only anatomic distributions at risk with regards to sun-exposure versus sun-protection but also encompass the nature of the activity with regards to intention for sun exposure.
Early Childhood Sun Exposure In two nationwide cross-sectional surveys of American youths between the ages of 11 and 18, 77% to 83% of respondents report having had one sunburn, 36% with at least three sunburns, and 12% with at least five sunburns.29,30 Evidence to support the role of sun exposure during childhood and the subsequent risk for skin cancer in adulthood is more consistent in non-melanoma skin cancers than in melanoma.31,32 However, in a systematic review of 13 case-control studies reporting risk of melanoma associated with sun exposure during two or more age-periods, Whiteman et al calculated an OR of 1.8 (95% CI, 1.6 to 2.2) for childhood sunburns compared to 1.5 (95% CI, 1.3 to 1.8) sunburns in adulthood.33 In the same report, the authors reviewed four ecological studies and found decreased risk of melanoma in subjects who migrated from areas of low to high ambient UV exposure before ages 10 and 15. These subjects had decreased risk compared to the native-born residents. These findings support the role of high levels of sun exposure in childhood as a strong risk factor for melanoma. National efforts to educate parents and children about sun protection have yielded little improvement in the trends re-
462 garding the practice of sun protection. A comparison of youths between ages 11 to 18 in 1998 and 2004 showed no significant changes in incidence of sunburns, 72% and 69%, respectively.34 In accordance with other surveys, sunscreen use was reported to be in the 30% to 39% range,29,34 and remains the sole method of sun protection with less prevalent use of other protective measures. Therefore, new innovative approaches or adoption of policies may be necessary in the effort to reduce the incidence of childhood sunburns.
Sun Tanning Behaviors Studies of indoor tanning users reported a staggering 8.1-fold increase (95% CI, 1.3 to 49.5) in melanoma risk in individuals younger than age 36 compared to non-users.35 Tanning prevalence estimates in adolescents range from 9.5% to 34%36 and is estimated to be 2.3 million of the North American consumer base.37 Despite educational efforts of the harmful effects of UV exposure and increased public awareness and knowledge of the adverse effects of sun exposure, attitudes regarding tanning remain unaltered. The use of indoor tanning booths has increased, especially among adolescents and young adults.29,38,39 Desired for its cosmetic enhancement, tanning may have other attributes to explain its sustained popularity. The repetitive nature of tanning together with the possibility of UV-induced release of endorphins prompted the consideration of tanning as a substance-related addictive behavior.40,41 Despite the inconsistent evidence of the chemical basis for reinforcement of tanning behavior, 23% and 53%, respectively, of individuals who repetitively tan tested positive for UV substance-related disorder (SRD) when screened by CAGE (cut down, annoyed, guilty, eye-opener) and DSMIV-TR questionnaires.42 In the young adult population, CAGE questionnaires regarding tanning in undergraduates who admitted to purposely tanning their skin revealed that almost one fifth of respondents may have SRD.43 Those respondents were more often indoor tanners than sun-tanners, had experienced a severe burn, and were more likely to purposefully tan their skin 20 or more times a month. Currently, 26 states and four counties have regulations on tanning for minors.44 There is no uniformity in these regulations, with some states establishing a minimum age, ranging from 14 to 18 years, while others permit minors to tan with either a parent’s consent or a doctor’s prescription.
J.S. Bordeaux, K.Q. Lu, and K.D. Cooper less of the biological activity of the melanoma, there is no doubt that the earlier it is detected and treated, the better the chance of survival. Early detection of melanoma can be achieved by complete body skin examinations provided by physicians and self skin examinations performed by patients.
Early Detection/Screening Four conditions must be met for medical screening to be effective. First, a presymptomatic phase of disease must exist during which the patient is unaware disease is present. If symptoms occurred at onset of disease, patients would seek care immediately and screening would be worthless. Medical conditions fulfilling this criteria include cervical cancer, breast cancer, prostate cancer, hypertension, anemia, and melanoma. Second, an accurate screening test that detects the presence of disease in the presymptomatic phase must exist. This test should not cause significant morbidity and should be highly sensitive and specific to decrease the number of false positives and false negatives encountered. Office sphygmomanometry (blood pressure cuff), mammography, and the Papanicolaou smear are all tests that meet these criteria. The blood test for prostate-specific antigen (PSA) is not sufficiently sensitive or specific for it to be effective for screening for prostate cancer. The utility of the complete skin examination to detect melanoma will be discussed at length later. Third, there must be an effective treatment of the disease in question. Without an effective treatment for a disease, screening for that disease would be futile. There are many effective antihypertensive medications and there also are effective treatments for breast cancer, cervical cancer, and melanoma. The last and most important requirement is conceptually the most difficult, and states that treatment of the disease, when detected in the presymptomatic stage, must lead to less morbidity and mortality when compared to treatment of the disease once it becomes clinically apparent. If a disease treatment is equally successful when treating early and late disease, there is no need for early detection. Breast cancer, cervical cancer, and melanoma all have better outcomes when treated earlier. In addition, even when all four of these requirements are satisfied, other variables such as cost of screening must be considered.
Secondary Prevention
Screening for Melanoma—Physicians
Secondary prevention (early detection) is crucial in reducing melanoma morbidity and mortality. As discussed previously, melanoma survival relates directly to the depth of invasion of the primary tumor at the time of diagnosis. Fortunately, most melanomas are detected early, with greater than 50% being stage I and less than 1% being stage IV at the time of diagnosis.4 Although some melanomas may be more biologically aggressive than others, with some thin tumors metastasizing while some thick tumors do not, there is currently no way to differentiate these more aggressive tumors. However, regard-
The presence of a presymptomatic phase occurs in melanoma. Symptoms patients might experience, including pain, bleeding, and pruritus, frequently do not occur until later in the disease process. More often, subtle changes in size, shape, or color are first noted. If patients routinely notice and report these subtle changes to physicians, they would be decreasing the length of the “presymptomatic phase.” As patients become better at noticing these changes on their own and seeking medical attention when symptoms are noted, the utility of screening will actually decrease. However, the majority of
Prevention and early detection of melanoma patients will have their melanoma for quite sometime before they notice obvious or subtle symptoms. Screening tests available that may be used to detect the presence of melanoma include complete skin examinations performed by physicians and complete skin examinations performed by patients. Low sensitivity and specificity lead to false positives with resultant unneeded biopsies and personal angst, and false negatives, which lead to false reassurance. Variables that alter the sensitivity and specificity of complete skin examinations include physician type and presence or absence of additional techniques such as dermoscopy and digital photography. Complete surgical removal of early melanoma with appropriate margins is often curative. Thus, the third condition of screening, presence of a successful treatment of the condition, is met. Melanoma fulfills the last condition of screening, treatment rendered during the presymptomatic phase of disease must be more effective than treatment rendered at time of clinical presentation, perfectly. Once a melanoma becomes symptomatic, it is very likely that it has grown deeper into the skin than when it was asymptomatic. Thinner melanomas have a much better prognosis than thick melanomas. Thus it is imperative that melanoma be detected during its asymptomatic phase so that surgery can be curative. Epstein et al showed that melanomas detected by physicians had a median depth of 0.23 mm and melanomas detected by patients had a median depth of 0.9 mm.45 Similar results were found in an Australian study that reported the odds of a melanoma being thin were 2.56 times greater if detected by a physician as opposed to the patient.46
Screening Tests The major screening test for detecting melanoma is the complete body skin examination performed by a physician. It consists of a physician examining a patient from head to toe in an environment with good lighting. The accuracy of this examination depends on the training of the practitioner and the presence of any additional techniques such as dermoscopy, digital photography, or computer mole-map programs. The examination has low morbidity and is quick and easy to perform. The sensitivity and specificity of a complete body skin examination for detecting melanoma have been estimated to be 84.5% and 99.2%, respectively.47 As expected, dermatologists are better at diagnosing melanoma than primary care physicians.48 False positives do not lead to extreme morbidity. Patients undergo a skin biopsy, which is very low risk. False negatives will hopefully be detected at a subsequent visit. Primary care physicians may not be as adept at identifying worrisome lesions, but they have more opportunity to make the diagnosis. A study of patients diagnosed with melanoma showed that 87% of these patients had a primary care physician, and 63% of these patients had seen their primary care physician within 1 year of diagnosis of their melanoma. Only 20% of the patients had seen a dermatologist in the previous year.49 There are many more primary care physicians in the
463 world than there are dermatologists. However, primary care physicians may not have the training to diagnose melanoma. Unfortunately only 12% of primary care physicians were able to diagnose five of six melanomas and only 38% of primary care physicians correctly diagnosed four of six melanomas.50 In addition, only 17% of primary care physicians categorized their relevant training as excellent or good.50 Raising awareness of the significance of melanoma and bettering physician’s ability to confidently diagnose melanoma will be an important advance. Other tools that may be used to aid the physician in performing a complete skin examination include dermoscopy, digital photography, and mole-mapping devices. Dermoscopy entails the use of a handheld device similar in size to an otoscope that features a 10⫻ magnification capability and illumination. Dermoscopy has been shown to increase the sensitivity and specificity of the diagnostic accuracy of dermatologists for melanoma in a large meta-analysis.51 It has been shown to reduce the number of pigmented lesions removed for diagnostic verification in a randomized controlled trial by dermatologists.52 Dermoscopy also has been shown to increase the accuracy of primary care physicians in diagnosing melanoma in Spain, Italy, and Australia.53,54 However, only 23% of dermatologists in the United States are currently using dermoscopy.55 Digital photography can be used as a reference for referral by the physician to establish a baseline. Care must be taken to compare the old pictures to the current patient. These pictures can be used with or without the aid of dermoscopy. Early reports suggest that full-body photography may aid in early diagnosis of melanoma.56,57 Unanswered questions with regard to the use of full-body photography include cost and legal liability. Additionally, “mole-map machines,” which allow computer programs to compare old and new pictures of moles, can calculate degrees of change that can go unnoticed by the human eye. The time required and cost of these machines have not been determined, nor has their effectiveness.
Who Should Be Screened? Risk Stratification and Cost-Effectiveness Health care resources are limited, and several questions remain to be answered: Should screening for melanoma be performed? If so, which patients should be screened and how often? The gold standard to answer the screening question is a large, prospective, randomized controlled trial comparing mortality in a screened and nonscreened group. Such a trial was developed and implemented and early results looked promising. However, secondary to a lack of funding, this trial was stopped early.58 Multiple cost-effective analyses have been performed. The common threshold in the United States for cost-effectiveness is $50,000 to $100,000 per qualityadjusted life-year (QALY) gained, although these numbers have been challenged.59 Freedberg et al estimated a $29,170 per year of life (YLS) saved for a one-time screening of a high-risk population by a dermatologist. High risk was de-
464 fined as adults greater than 20 years of age who were lightskinned and burned easily, or who had a family history of skin cancer, extensive sun exposure, and higher than average number of nevi.60 In Australia, cost-effectiveness for screening every 2 years by primary care physicians has been calculated to be $15,000/YLS in 50-year-old men and $25,800/ YLS in women aged 50.61 A recent study by Losina et al reported an incremental cost-effectiveness ratio of $10,100/ QALY for one-time screening by dermatologists of patients over 50 years of age and $80,700/QALY for screening every 2 years in the same group.62 They also reported a cost-effectiveness ratio of $35,500/QALY for screening siblings of patients with melanoma every 2 years. These data support routine screening in high-risk populations. However, the United States Preventive Services Task Force has given screening for skin cancer an “I” recommendation, concluding that there is insufficient evidence to recommend for or against routine screening. The same group has given an “A” recommendation, strongly recommends for clinicians to provide this service yearly, for Papanicolaou tests for life ($24,100/QALY) and fecal occult blood test plus sigmoidoscopy every 5 years after the age of 50 ($47,400/YLS).63-65 However, this last analysis for skin cancer screening was performed in April 2001 and a current update is in progress. The American Cancer Society does recommend regular skin examinations as part of the periodic health exam. The Canadian Task force on Preventive Health Care, The American College of Preventive Medicine, and the American College of Obstetricians and Gynecologists recommend total skin examinations for high-risk patients.66
Screening for Melanoma—Patients Counseling patients to perform self skin examinations also can help with early detection. Self skin examinations are deliberate exams looking for new or changing lesions performed at a specific interval (usually monthly). In a casecontrol study, Berwick et al suggested that routine self skin examination could reduce mortality from melanoma by 63%.67 Additionally, patients with a history of melanoma who were taught self skin examinations and had a second melanoma were diagnosed significantly earlier than with the first.68 Care should be taken to explain how to perform the complete self skin examination and how often it should be done. A recent randomized controlled trial evaluating performance of self skin examinations by patients who were taught alone and patients who were taught with a partner found that those taught with a partner were more likely to perform the examination.69 Proper instruction on the importance of performing and how to perform the self skin examination is an important aspect of melanoma education.
Public Education Regardless of all our hard work, there are not enough physicians to screen all patients. Public education campaigns such
J.S. Bordeaux, K.Q. Lu, and K.D. Cooper as the Slip, Slop, Slap program in Australia are important public educational campaigns. This campaign was introduced in 1981 in Australia to raise public awareness of the dangers of skin cancer. Sid the Seagull and his son Sam taught children and adults alike the importance of sun protection. Sunburn rates in Australia have decreased, attitudes about sunlight and suntans have changed, and melanoma mortality rates in younger patients are decreasing.70 Care must be taken in developing, implementing, and testing future global public awareness messages to ensure their efficacy.
Optimizing Patient Care: Where Are We Headed? Primary melanoma prevention requires more precise identification of patients at risk, so that cost-effective efforts can be focused on the susceptible populations. Although some familial melanoma genes have been described, they identify only a small subset of primary melanoma patients, and work on identifying complex interactive genetic traits, such as vitamin D receptor polymorphisms,71 are critical for determining a genetic risk profile that can be managed during the critical childhood years, where a great deal of environmental melanoma risk is acquired. Primary prevention also would be benefited by a better understanding of the process of melanomagenesis. What are the critical gene modifications that lead to transformation of melanocytes? Is protection against UVB sufficient to prevent melanoma, or does the action spectrum for melanoma induction reach into the visible wavelengths, as suggested by Setlow.72 Are there dietary or chemoprevention interventions that may be effective, such as vitamin D supplementation or use of statins and fibrates (although a systematic review and meta-analysis of these agents do not validate their role in melanoma prevention73). In any case, a better understanding of the progressively increasing risk of melanoma in the population by the general public, educators, coaches, and physicians is critical for changing sun exposure behaviors that are associated with increased melanoma risk. Continual development of public awareness campaigns can help educate the public about the importance of melanoma and how they may best prevent it (sun protective behaviors) and detect it early (self skin examinations). Further education of primary care physicians and allied healthcare providers should be employed to increase their awareness of the morbidity and mortality related to melanoma and tools for education of their patients and families need to be widely available and easy to use. Wide dissemination of a focus on avoidance of midday sun, emphasis on protective clothing/hats and shade, and secondary supplementation of protection with broad-spectrum sunscreens are key messages that are a cornerstone of primary prevention. Secondary prevention is a critical component of reducing death from melanoma, because of the curable potential at early stages. Better education of all healthcare providers, as well as hairdressers, cosmeticians, and others with wide ex-
Prevention and early detection of melanoma posure to the public can aid in the recognition of suspicious pigmented lesions that need closer evaluation. Development of tools that can be used by primary care physicians to allow easy risk stratification to determine which patients will benefit most from melanoma screening will obviously benefit these efforts. Secondary prevention will be aided by advances in the development of early detection methodologies. Dermatologists and primary care physicians who become better educated in the use of dermoscopy will increase the sensitivity and specificity of melanoma screening. In process are complex algorithms for analyzing dermoscopic optical data that can calculate risk of melanoma of a given pigmented lesion, and wide dissemination of such methodologies may further enhance our secondary prevention capabilities by better identification of at risk lesions. Whole-body digital photography with digital analysis offers promise into objectively and accurately identifying which pigmented lesions represent new and enlarging lesions, which are known in adults to be at higher risk for representing melanomas. Once a lesion is identified at significant risk for melanoma and is subjected to biopsy, there remains a critical role for additional secondary prevention. In addition to disparity among dermatopathologists regarding the threshold for diagnosing melanoma, there also is an inability to determine by histopathology the full risk of an emerging pigmented lesion. Thus, “genetic finger printing” by which genes or proteins expressed by melanomas may reveal the likelihood of progression of a melanocytic nevus into melanoma, whether a melanocytic lesion has begun to express signature genes for melanoma, or whether the lesion is at risk of metastasis regardless of depth at diagnosis, offers great promise in determining which early lesions require more extensive resection at the outset. Thus, both standard public health intervention and technical innovations will benefit the prevention and early detection of melanoma, and when combined, offer the potential for reduction of risk from death from melanoma.
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