Malignant Melanoma in the 21St Century, Part 1: Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis

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SYMPOSIUMMALIGNANT MELANOMA ON IN SOLID THE 21ST CENTURYTUMORS

Malignant Melanoma in the 21st Century, Part 1: Epidemiology, Risk Factors, Screening, Prevention, and Diagnosis

SVETOMIR N. MARKOVIC, MD, PHD; LORI A. ERICKSON, MD; RAVI D. RAO, MBBS; ROGER H. WEENIG, MD; BARBARA A. POCKAJ, MD; ADITYA BARDIA, MD; CELINE M. VACHON, PHD; STEVEN E. SCHILD, MD; ROBERT R. MCWILLIAMS, MD; JENNIFER L. HAND, MD; SUSAN D. LAMAN, MD; LISA A. KOTTSCHADE, RN; WILLIAM J. MAPLES, MD; MARK R. PITTELKOW, MD; JOSE S. PULIDO, MD, MS, MPH, MBA; J. DOUGLAS CAMERON, MD; AND EDWARD T. CREAGAN, MD, FOR THE MELANOMA STUDY GROUP OF THE MAYO CLINIC CANCER CENTER

Malignant melanoma is an aggressive, therapy-resistant malig- decades, a heightened awareness of melanoma has led to an nancy of melanocytes. The incidence of melanoma has been steadily increasing worldwide, resulting in an increasing public increased rate of diagnosis of early-stage disease. Notwith- health problem. Exposure to solar UV radiation, fair skin, dysplas- standing the fact that treatment of advanced melanoma still tic nevi syndrome, and a family history of melanoma are major risk remains in the realm of experimental and early-phase clini- factors for melanoma development. The interactions between genetic and environmental risk factors that promote melanoma- cal trials, tremendous research efforts in melanocyte biol- genesis are currently the subject of ongoing research. Avoidance ogy, melanoma genetics, and tumor immunology are pro- of UV radiation and surveillance of high-risk patients have the viding hope for a cure. potential to reduce the population burden of melanoma. Biopsies of the primary tumor and sampling of draining lymph nodes are Although more than 95% of tumors are found in the required for optimal diagnosis and staging. Several clinically rel- skin, melanoma is not exclusively a skin cancer. Sites of evant pathologic subtypes have been identified and need to be primary extracutaneous melanoma include ocular, mu- recognized. Therapy for early disease is predominantly surgical, with a minor benefit noted with the use of adjuvant therapy. cosal, gastrointestinal, genitourinary, leptomeninges, and Management of systemic melanoma is a challenge because of a lymph nodes (melanoma of unknown primary cancer). paucity of active treatment modalities. In the first part of this 2- With the exception of neuroectodermally derived melano- part review, we discuss epidemiology, risk factors, screening, prevention, and diagnosis of malignant melanoma. Part 2 (which will cytes that give rise to the retinal pigment epithelium, mel- appear in the April 2007 issue) will review melanoma staging, anocytes originate from neural crest cells. During the early prognosis, and treatment. weeks of gestation, melanocyte precursors differentiate Mayo Clin Proc. 2007;82(3):364-380 and migrate from the neural crest to numerous tissues (including the skin). he current spectrum of malignant melanoma includes The function of melanocytes is best studied and defined T2 clinical extremes. At one end of the spectrum, thin in the skin. Within the basal layer of the epidermis, each primary cutaneous melanoma is characterized by a rela- melanocyte develops an intimate relationship with many tively uniform treatment and a high cure rate. At the oppo- keratinocytes, sending out slender dendritic processes that site end, metastatic melanoma is characterized by no transfer packets of melanin pigment (melanosomes) to proven effective therapy and poor outcomes. In recent keratinocytes. The melanin granules orient in an umbrella- like fashion over the keratinocyte nucleus parallel to the skin surface. Melanin absorbs ultraviolet radiation (UVR) From the Division of Hematology (S.N.M.), Department of Oncology (S.N.M., and possesses potent antioxidant properties capable of neu- R.D.R., R.R.M., L.A.K., E.T.C.), Department of Immunology (S.N.M.), Depart- ment of Laboratory Medicine and Pathology (L.A.E.), Department of Dermatol- tralizing UVR-generated free radicals. Paradoxically, mel- ogy (R.H.W., J.L.H., M.R.P.), Department of Internal Medicine (A.B.), Depart- anocytes are injured and transformed by the same agent ment of Health Sciences Research (C.M.V.), and Department of Ophthalmology (J.S.P., J.D.C.), Mayo Clinic College of Medicine, Rochester, Minn; Department that melanocytes are programmed to defend against, UVR. of Surgery (B.A.P.), Department of Radiation Oncology (S.E.S.), and Depart- Moreover, the cancers that melanocytes help prevent ment of Dermatology (S.D.L.), Mayo Clinic College of Medicine, Scottsdale, Ariz; and Division of Hematology/Oncology (W.J.M.), Mayo Clinic College of (squamous cell and basal cell carcinoma) are less lethal Medicine, Jacksonville, Fla. A complete list of the current members of the than the cancer that melanocytes become (melanoma). Melanoma Study Group of the Mayo Clinic Cancer Center appears at the end of this article. Melanoma is rare among deeply pigmented ethnic Address correspondence to Svetomir N. Markovic, MD, PhD, Division of groups relative to individuals of Northern European decent. Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN The type of melanin pigment (eumelanin vs pheomelanin), 55905. Individual reprints of this article and a bound reprint of the entire Symposium on Solid Tumors will be available for purchase from our Web site as well as the number, size, and density of melanosomes, www.mayoclinicproceedings.com. determines skin pigmentation. Anthropological and ge- © 2007 Mayo Foundation for Medical Education and Research netic studies trace human pigment dilution to the migra-

364 Mayo Clin Proc. • March 2007;82(3):364-380 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. MALIGNANT MELANOMA IN THE 21ST CENTURY tion of early human groups to northern latitudes. Mutations 1500 in 1935 and 1 in 250 in 1980.3,5,6 Parallel with this of genes that govern skin pigmentation and/or are associ- increasing incidence is an increase in melanoma-related ated with increased melanoma risk were likely propagated mortality, albeit to a lower degree. In the United States, the by selective pressures (sexual selection) and/or a founder mortality rate from malignant melanoma increased by effect. 1.4% every year between 1977 and 1990. Since 1990, the The causal relationship of UV exposure to melanoma is mortality rate has shown a small downward trend and complex, and acute, intense, intermittent sun exposure in decreased by 0.3% per year from 1990 to 2002. Currently, youth equates to higher risk of melanoma. The risk of 1 person dies each hour from metastatic melanoma.3 The melanoma also increases with proximity to the equator. annual direct cost of treating newly diagnosed melanoma in The intensity of UVR increases considerably at midday, the United States was estimated to be $563 million in around which time (10 AM to 3 PM) sun avoidance is 1997.7,8 strongly encouraged. Fueled in part by public education Melanoma is notorious for affecting young and middle- campaigns, stories of melanoma diagnoses among celebri- aged people, unlike most other solid tumors, which mainly ties, and marketing efforts by the manufacturers of sun- affect older adults. The median age at diagnosis of mela- screen and photoprotective clothing, melanoma awareness noma is 57 years, and the median age at death is 67 years.3 and sun avoidance behaviors have substantially increased. The incidence of melanoma increases linearly after the age However, sunbed use, low sun protection factor sun- of 15 years until the age of 50 years and then slows, screens, and sun-seeking behaviors remain popular among especially in females.3 Approximately half the incidence is young people. in people between the ages of 35 and 65 years, with ap- Every clinician encounters patients at risk for mela- proximately 80% occurring in those in the age range of 20 noma. Additionally, depending on the tumor location and to 74 years.3 The age distribution is likely to show a left- stage, melanoma is a disease that requires the unique exper- ward shift with a trend toward an increase in the incidence tise and collaboration of medical, surgical, and pathology of melanoma among children, as well as due to an increase specialists. This review is intended to provide clinicians with in skin biopsy rates.9,10 Males are approximately 1.5 times a comprehensive, multispecialty overview of melanoma. more likely to develop melanoma than females.3 The distribution of favored sites of occurrence of melanoma is sex dependent: the most common areas are the back for men EPIDEMIOLOGY and the arms and legs for women.11,12 Melanoma is the fifth most common cancer in men and the White populations have an approximately 10-fold sixth most common cancer in women1,2 in the United greater risk of developing cutaneous melanoma than black, States. An estimated 62,190 new cases of melanoma were Asian, or Hispanic populations.3 This presumably relates to diagnosed in the United States during 2006.1,2 According to the higher sensitivity of white skin to sun exposure. How- data from Surveillance, Epidemiology, and End Results ever, both white and African American populations have a (National Cancer Institute), in 2000 approximately 629,822 similar risk of developing plantar melanoma.13 Noncutane- people (304,097 men and 325,725 women) alive had a ous melanomas (eg, mucosal) are more common in non- history of melanoma.3 The annual age-adjusted incidence white populations. of and mortality from melanoma in the United States is 18.3 per 100,000 persons per year and 2.7 per 100,000 RISK FACTORS persons per year, respectively.3 Internationally, the incidence rates vary 100-fold among different populations, Several factors have been hypothesized to be responsible with Australia having the highest rates worldwide; in for the worldwide increase in the incidence of melanoma. Queensland, Australia, the cumulative incidence in the Of these, the major factors that are responsible for most of population older than 50 years is 1 in 19 for men and 1 in 25 this increase are increased exposure to UVR, predomi- for women.4 nantly due to the depletion of the ozone layer, allowing The incidence of malignant melanoma is increasing rap- penetration of UV rays into the atmosphere but possibly idly worldwide, including in countries with historically low also due to behavioral change (such as increased use of sun incidence rates. This increase is occurring at a faster rate or tanning beds), and increased surveillance.10,14 These fac- than for any other neoplasm, with the exception of lung tors are summarized in Table 1 and reviewed subsequently. cancer in women.3 In the United States, the incidence of malignant melanoma from 1973 to 2002 increased by ENVIRONMENTAL FACTORS 270%.3 Currently, 1 in 63 Americans will develop mela- Sunlight. A large body of evidence supports the role of noma during their lifetime; historically, the risk was 1 in solar UVR exposure as the most important environmental

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TABLE 1. Summary of Risk Factors for Malignant Melanoma by Evidence Inconclusive or Strong evidence Weak evidence no increased risk Environmental and lifestyle factors Exposure to sunlight Tanning beds, sunlamps Exogenous hormones Geographical location Obesity Alcohol, smoking Industrial occupation Coffee Vitamins A and E Host factors Number of nevi Personal history of skin cancer Pregnancy Dysplastic nevi Higher socioeconomic status Family history of melanoma Brown hair Immunosuppression Male sex Sun sensitivity or inability to tan Endogenous hormones Blue or green eyes; blond or red hair (age at menarche, parity) risk factor for developing malignant melanoma. Multiple Protection From UVR Exposure. The relationship es- studies have shown that intermittent sun exposure, assessed tablished between UVR exposure and melanoma risk has indirectly by history of sunburns, appears to be a major prompted researchers to hypothesize that sunscreen use determinant of risk for melanoma (in contrast to non- may reduce the risk of melanoma developing. However, melanomatous skin cancers, which are linked more to cu- studies to prove this hypothesis have been inconclusive.28-30 mulative sun exposure).15 This etiological link is further Proper use of sunscreens with broad-spectrum sun protec- supported by the finding of higher melanoma incidence in tion factor 30 has been shown to reduce the number of populations that live in lower latitudes, higher incidences acquired nevi that develop in children by 30% to 40%.31 in white populations, lower incidences among dark- Because acquired nevi are markers for sun exposure (and skinned populations, and data from genetic and migration thereby for increased risk of developing melanoma), sun- studies.16-21 The risk of melanoma developing in people screen use may have a role in melanoma prevention. How- who have had sunburns is double that in people who have ever, other studies found that by protecting against sun- never had a sunburn. Moreover, the age at which sunburns burns, sunscreen use results in an increase in the actual occur appears to be important; sunburns in childhood are duration of intentional (ie, recreational) sunlight exposure associated with the highest risk.15,22 Further evidence for and may increase the total exposure to UVR.32-36 Therefore, the role of UVR comes from studies of immigrant popula- reliance on sunscreen as a sole method of sun protection is tions in Australia, which have shown that the risk of mela- not recommended, and other methods (eg, long-sleeved noma is proportional to the length of stay and inversely clothing) should be used in conjunction with sunscreen. to age at arrival.4 Likewise, further support for the role Occupation. Because exposure to sunlight is a major of UVR as a risk factor for melanoma comes from clin- risk factor for melanoma, a concern has been that people ical evidence. Patients with xeroderma pigmentosum (a occupationally exposed to sun, such as farmers, would genetic disorder characterized by deficient DNA repair have a higher risk of developing melanoma. However, mechanisms and a corresponding hypersensitivity to although farmers are indeed at a higher risk of developing UVR damage) have a substantially higher risk of develop- skin cancers such as squamous cell carcinoma, they appear ing melanoma, particularly in sun-exposed skin.18-20,23,24 to have no increased risk for melanoma.37,38 Swedish airline The use of psoralen–UV-A radiation photochemotherapy pilots, compared with the general male Swedish popula- for psoriasis has also been associated with an increased tion, have been identified to have an increased incidence of risk of melanoma.25 melanoma. The same study reported that Swedish military Other Sources of UVR. A relationship between in- pilots did not have an increased risk of melanoma but only creased risk of melanoma from nonsolar sources of UVR of nonmelanoma skin cancer.39 These findings support the (eg, fluorescent light, sunlamps, sunbeds and tanning beds) hypothesis that intermittent (rather than cumulative) sun has been postulated, but data have been inconclusive.11,26,27 exposure increases the risk of melanoma. Occupational A recent meta-analysis of 12 case-control studies and 1 exposure to ionizing radiation, vinyl chloride, polychlori- cohort study suggested that sunbed and sunlamp exposure nated biphenyls, and petrochemicals has been linked to a might lead to a slightly higher risk of melanoma (odds possible increase in the risk of melanoma; however, the ratio, 1.25; 95% confidence interval, 1.05-1.49).27 The risk risk attributable to these factors appears to be small. More- was higher with longer duration of exposure and earlier age over, this link has not been shown consistently in different at exposure. studies.

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Reproductive Factors and Oral Contraceptive Use. cases.65 In a person with a family or a personal history of Estrogen and progesterone have been postulated to in- melanoma, the presence of dysplastic nevi is a marker for a crease the risk of melanoma by stimulating melanocyte significantly increased risk of melanoma.72 Moreover, the proliferation.40,41 Furthermore, patients with breast cancer presence of dysplastic nevi is a risk factor for the develop- have a slightly higher risk (odds ratio, 1.4) of developing ment of multiple primary melanomas. Dysplastic nevi often melanoma,42 which has led to speculation that the develop- cluster in families, particularly in families with melanoma.73-81 ment to melanoma is influenced by the hormonal milieu. A A familial syndrome variously referred to as dysplastic ne- few early studies indicated that oral contraceptive pill or vus syndrome, atypical mole syndrome, or familial atypical hormone replacement therapy use increased the risk of multiple mole and melanoma syndrome81 has been recog- melanoma.43 However, more recent studies and a pooled nized. Patients with this syndrome have almost a 100-times analysis failed to validate these findings.44,45 A link be- higher risk of developing melanoma, and approximately tween an increased risk of melanoma and several reproduc- 50% of these patients develop melanoma by the age of 50 tive factors (eg, age at menarche, menopausal status, age at years.75 menopause, number of live births) has been noted, again Melanomas that develop in the setting of previous nevi suggesting the influence of estrogen on melanogenesis. A are more likely to be on the trunk, occur in younger pa- recent pooled analysis of 10 case-control studies suggested tients, and belong to the superficial spreading variety.59,82 that women with both earlier age at first birth (<20 years) Family History. A family history of melanoma is a and higher parity (≥5 live births) had a lower risk than strong risk factor for melanoma. Patients with a history of women with later age at first birth and lower parity (odds melanoma in a first-degree relative have approximately a 2- ratio, 0.33).44,46 Presumably, endogenous rather than exog- times higher risk of developing melanoma than those with- enous hormones act as risk factors. Of note, pregnancy out a family history; the risk increases in the presence of does not seem to significantly affect the risk of malignant other risk factors.83,84 Familial melanoma is thought to ac- melanoma.47 count for 10% of all melanoma cases.85 Presence of a familial Anthropometric, Dietary, and Lifestyle Factors. melanoma syndrome should be considered in patients with a Obesity has been postulated to increase the risk of mela- family history of pancreatic cancer or astrocytoma. Some noma, plausibly because of a larger body surface area families with inherited melanoma demonstrate a clear pat- exposed to sun or differential hormonal profiles.45,48 Epide- tern of autosomal dominant inheritance with multiple family miological studies evaluating the role of dietary vitamins members affected in more than 1 generation. Mutations in have been inconclusive.48-50 Similarly, the relationship with CDKN2A (or p16) are the most common genetic abnormali- other dietary factors, including intake of fat, vitamin E, ties found in these families. A second mutation, CDK4, has alcohol, coffee, and smoking, has been inconsistent.48-58 been found much more rarely.86,87 Features in a patient with melanoma that indicate an underlying genetic predisposition HOST FACTORS include occurrence at a younger age (<40 years),88-92 multiple Melanocytic Nevi. Melanocytic nevi are benign accu- primary melanomas, or a history of precursor lesions such as mulations of melanocytes or nevus cells and may be con- dysplastic nevi. Patients with a genetic predisposition to genital or acquired. The risk of melanoma varies on the melanoma are more likely to have tumors that are superfi- basis of type, size, number, and location of nevi. In ap- cially invasive and have a better prognosis.93,94 Additionally, proximately 25% of cases, melanoma occurs in conjunc- melanoma is known to cluster in families with family cancer tion with a preexisting nevus.59 syndromes such as familial retinoblastoma, Li-Fraumeni The risk of melanoma has been directly correlated to the cancer syndrome, and Lynch syndrome type II. total number of benign nevi (both dysplastic and non- A genetic predisposition to melanoma may also occur in dysplastic) on the body. The risk is approximately 1.5- a patient without a suggestive family history. Such patients times higher in people with 11 to 25 nevi (compared with may have a new mutation, including an alteration in the ≤10 nevi) and appears to be doubled with every increase of CDKN2A gene or CDK4 gene. Once acquired, this predis- 25 nevi.4,11,16,60-65 Similarly, larger nevi (particularly >5 mm) position can be passed on to offspring in an autosomal are associated with a higher risk of melanoma.66-68 Giant nevi dominant fashion. (>20 cm) are associated with a significantly higher risk of Immunosuppression. Immunosuppression has been melanoma.69,70 associated with a higher risk of melanoma. This has been Dysplastic nevi (ie, melanocytic nevi with cytological noted in patients with acquired immunodeficiency syn- atypia) are associated with an increased risk of mela- drome, those with hematological malignancies, and those noma.61,62,71 Nonfamilial melanoma may occur in the setting receiving immunosuppressive agents after solid organ of a preexisting dysplastic nevus in up to 29% to 49% of transplantation.95-100

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Phenotypic Characteristics and Variations in Mel- tion and especially parents about sun protection, risk fac- anocortin-1 Receptor. Certain phenotypic characteristics, tors for skin cancer, and the skin self-examination (ABCD such as eye color (blue or green), hair color (red > blond > of melanoma) is essential.116,117 Photoprotective measures brown compared with black), presence of freckles, sun sensi- (sun-safe behavior) should also be emphasized for all indi- tivity, and an inability to tan, have been associated with viduals, especially those with a personal or family history approximately a doubling of the risk of developing mela- of melanoma. The most successful example of such popu- noma.22,45,71,101,102 One possible mechanism for the increased lation-based cancer education programs is the effort of risk relates to variation in melanocortin-1 receptor. Variation the Anti-Cancer Council of Victoria in Australia. The in melanocortin-1 receptor alleles has been found to result in council has been organizing sun protection programs the development of both sporadic cutaneous melanomas and (Slip! Slap! Slop! and SunSmart) for more than 20 years. an increased risk of melanoma among those predisposed to These programs have resulted in marked reductions in sun familial melanoma. Studies have found that red hair, pres- exposure and have helped change society’s approach to ence of freckles, and sun sensitivity are associated with the sun.118 Also noteworthy are primary chemoprevention specific genetic variations in melanocortin-1 receptor and efforts using statins and fibrates in patients at risk for possibly account to some extent for the increased risk seen melanoma. As yet, there does not appear to be conclusive with the phenotype. evidence of the benefit of such interventions.119-121 Other Factors. Higher socioeconomic status has been Secondary prevention of melanoma is accomplished by associated with a higher risk of melanoma. A personal his- diagnosis and treatment of early-stage (highly curable) tory of melanoma (and other skin cancers) can increase the melanoma. People at high risk for development of mela- risk of subsequent melanoma developing. However, both of noma should be identified and evaluated. Screening of these associations appear to be confounded by an increased high-risk patients is cost-effective and likely to be associ- exposure to sunlight and better surveillance.15,93,94,103-112 ated with an improved survival.122 Individuals with xeroderma pigmentosum, giant congenital nevi, immunosup- RISK PREDICTION MODELS pression, familial atypical multiple mole and melanoma Risk prediction models have been developed to estimate an syndrome, unusual-appearing nevi, numerous (>50) nevi, individual’s lifetime risk of melanoma.83,84,113 Risk factors changing nevi, and a family history of melanoma and men that have been consistently demonstrated to increase the risk older than 50 years should receive complete baseline and of melanoma include family history of melanoma, higher periodic follow-up skin examinations by a physician.123-125 number of nevi, history of severe sunburn (>3 before the age Additionally, such people should be encouraged to conduct of 20 years), marked freckling on the upper back, and light skin self-examinations. Patients with a history of mela- hair color. When compared with the risk in the general pop- noma should be educated on the need for continued surveil- ulation, the presence of 1 or 2 of these risk factors is associ- lance for subsequent additional primary melanomas and for ated with a 2- to 4-times higher risk, and occurrence of 3 or recurrence and metastasis.126 Melanoma screening includes more factors results in approximately a 20-fold risk.83,84,113 complete skin examination as part of a general medical examination by primary care physicians, during evalua- tions for other skin problems by a dermatologist, and com- SCREENING AND PREVENTION munity-based screening programs. Each of the foregoing Prevention and public health measures are essential to de- screening methods has afforded increased rates of melanoma crease the risk of melanoma. Melanoma prevention is well detection.127-129 Both the value and the need for sustained divided into primary, secondary, and tertiary prevention. melanoma education were demonstrated by a nationwide Primary prevention (prevention of occurrence) of mela- melanoma awareness campaign in Australia, resulting in noma entails reduction of known risk factors in high-risk reduction of the median melanoma thickness overall and a populations. Reducing UV exposure, especially intense, higher percentage of thin (<0.75 mm) melanomas diagnosed intermittent sun exposure, is the most important modifiable during the campaign year. After the campaign, both mea- behavior for melanoma prevention. Reducing UV exposure surements rebounded to precampaign year values. Tertiary would include avoiding excessive sun exposure (midday prevention of melanoma involves limiting morbidity and sun), covering skin with clothing, wearing broad-brimmed extending survival in patients with advanced disease. hats, using detergent that increases the photoprotective ability of one’s clothing, and applying sunscreen.114 These DIAGNOSIS OF MELANOMA measures should also be emphasized in individuals with a personal or family history of melanoma. Sunburn avoid- The diagnostic clinical features of melanoma range from ance in childhood is paramount.115 Educating the popula- subtle to obvious characteristics. A well-established guide

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FIGURE 1. Primary cutaneous melanoma demonstrating pigmented FIGURE 2. Primary cutaneous melanoma demonstrating irregularly variation. shaped lesion. to examine and interpret pigmented lesions for both health review of the specimen. An established diagnosis of malig- care professionals and patients has been the ABCDE acro- nant melanoma can be made only after histopathologic nym. This list of features, which is easy to memorize and analysis. Even then, the diagnosis can be challenging. Ma- use, stands for Asymmetry, Border irregularity, Color lignant melanoma must be distinguished from conventional variation, Diameter (>6 mm), and the recently added E, for melanocytic nevi, proliferation nodules in congenital nevi, Evolving (or changing), has been widely popularized dur- atypical or dysplastic nevi, and unusual nevus variants such ing the past 2 decades. Evolving encompasses any signifi- as Spitz nevi, pigmented spindle cell nevi, deep penetrating cant change in size, shape, surface (raised, bleeding, crust- nevi, plexiform spindle cell nevi, clonal nevi, genital nevi, ing), shades of color, or symptoms (itching, tenderness) acral nevi, flexural nevi, cellular blue nevi, and recurrent and was only recently added to the list since most patients melanocytic nevi, among many others. Unusual morpho- with melanoma have been found to observe these com- logic variants of malignant melanoma must be recognized ponent changes occurring within suspicious pigmented to prevent misdiagnosis as an epithelial or mesenchymal lesions.130 neoplasm. The histologic evaluation of the tumor also pro- Various assistive optical devices for a more detailed vides prognostic information needed by the clinician and examination of the skin and, in particular, pigmented le- surgeon to formulate the treatment plan. sions are becoming part of routine clinical practice. These Criteria for the histologic diagnosis of cutaneous malig- devices include high-resolution optical handheld devices nant melanoma are based on architectural and cytologic that have been designated dermoscopes (or dermatoscopes features and need to be interpreted in the context of the or epiluminescent microscopes). In addition, portable scan- ning units using visible, infrared, and UV sources create images or spectroscopic outputs that can be electronically captured, archived, retrieved, and analyzed. A number of these devices are continually being developed, refined, and tested in clinical studies aimed at improving the diagnostic accuracy and sensitivity of melanoma detection. Several excellent reviews are recommended for further reading.131-134 During evaluation of suspicious pigmented lesions, clinicians must heed the observation of the patient or the patient’s family member of a changing or new pigmented skin lesion. Pigment variation (Figure 1), an irregular or ill- defined border, asymmetry in color or shape, ulceration, development of a nodule within a preexisting lesion (Fig- ure 2), and pigment loss (Figure 3) are clinical clues for melanoma. However, a definitive diagnosis or an exclusion FIGURE 3. Primary cutaneous melanoma demonstrating focal pig- of melanoma requires biopsy and experienced pathological ment loss.

Mayo Clin Proc. • March 2007;82(3):364-380 • www.mayoclinicproceedings.com 369 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. MALIGNANT MELANOMA IN THE 21ST CENTURY clinical situation. A junctional melanocytic proliferation have a different prognosis,142-145 but the importance of the that shows areas of pagetoid spread from an acral site of a histologic type of melanoma may decrease with multivari- pediatric patient would likely be interpreted differently ate analysis.146,147 This classification is not included in the than a similar proliferation on sun-damaged skin of the face American Joint Committee on Cancer staging system but is of an elderly patient. Additionally, partial or incisional generally included on pathology reports. biopsies of larger lesions are well-known pitfalls in the Superficial spreading is the most common type of ma- diagnosis of malignant melanoma. There is no absolute lignant melanoma, accounting for approximately 70% of criterion for the diagnosis of malignant melanoma. A con- cases. Superficial spreading melanomas most often occur stellation of architectural and cytologic features is evalu- on the back of the legs of women and on the backs of ated along with clinical information. men.148 These tumors are commonly found on sun-exposed Architectural features of malignancy include large size, skin, particularly areas of intermittent sun exposure. Such asymmetry, poor circumscription, pagetoid spread, con- tumors usually show prominent pagetoid spread and are fluence of growth, effacement of the rete ridges, scalloping composed of epithelioid melanoma cells.149 By convention, of the dermal-epidermal junction, marked cellularity, sheet- superficial spreading melanomas extend 3 rete ridges be- like growth pattern, effacement of underlying dermal archi- yond the dermal component.150 Superficial spreading mela- tecture, lack of architectural and cytologic maturation with nomas may arise de novo or in association with a nevus. depth, and perineural invasion, among many others. Cyto- Nodular melanoma accounts for 5% of melanomas and logic features of malignancy include enlarged nuclei, most often occurs on the trunk and limbs of patients in the prominent nucleoli, thick and irregular nuclear membranes, fifth or sixth decade of life, with males more commonly abnormal cytoplasmic melanization, dermal mitotic activ- affected than females.146,151 Nodular melanomas are often ity, and atypical mitotic figures. ulcerated and when amelanotic may be mistaken for a Complicating the diagnosis of melanoma is the under- vascular neoplasm.152 Nodular melanomas do not have a standing that many of these histologic features can be seen radial growth phase; they have only a vertical growth in benign melanocytic nevi. Generally, the larger the size of phase. Nodular melanomas are not frequently associated a lesion the more suspicious for melanoma; however, con- with regression or an associated nevus.149 Polypoid mela- genital melanocytic nevi can be large and melanomas can nomas are considered a variant of nodular melanoma.153 be small. Small melanomas, measuring only 2 to 3 mm in Acral lentiginous melanoma is uncommon, accounting diameter, are well documented.135,136 Pagetoid spread is for 5% of melanomas among white people. Although acral thought to be one of the most important features for the lentiginous melanoma is uncommon in all ethnic groups, it diagnosis of malignant melanoma; however, pagetoid is the most common type of melanoma among Asian pa- spread is seen in most nevi of palms and soles, recurrent tients, Hispanic patients, and patients of African de- nevi, and genital nevi and is seen in a proportion of Spitz scent.141,154-157 The overall incidence of melanoma in these nevi, pigmented spindle cell nevi, and nevi of infancy and ethnic groups is low compared with that in white patients. childhood.137 Confluence of growth along the dermal-epi- Acral lentiginous melanoma occurs on glabrous skin and dermal junction is often seen in malignant melanoma, but a adjacent skin of the digits, palms, and soles.143,151,158-165 On confluence of junctional theques (aggregations of nevus the soles, acral lentiginous melanomas often involve cells) can also be seen in genital nevi.138 Mitotic figures, heels.141,159 Digit melanomas usually involve the nail bed of particularly deep and atypical mitotic figures, are often the great toe or thumb and more commonly affect elderly seen in malignant melanoma, but mitotic figures can also people, with a female predominance.154,157,159,166-173 Superfi- be seen in benign melanocytic nevi. Nevoid melanomas cial spreading and nodular melanomas may also involve “mimic ordinary compound or intradermal melanocytic acral sites, including the nail bed.167,172 In a study of 100 nevi when the melanoma cells are small, or Spitz’s nevi subungual melanomas, approximately half were acral when the cells are large.”139 Thus, the diagnosis of malig- lentiginous type. nant melanoma requires careful evaluation of numerous Lentigo maligna accounts for 4% to 15% of cutaneous histologic features in each patient. melanoma and correlates with long-term sun exposure and Conventional melanomas are classified as superficial increasing age.146,149,174-177 Additionally, lentigo maligna is spreading, nodular, lentigo maligna, and acral lentiginous. known as Hutchinson melanotic freckle178 and precancer- However, this classification may be difficult to apply in ous melanosis of Dubreuilh.179 Lentigo maligna melano- small incisional biopsy specimens. Malignant melanomas mas are composed of single melanocytic cells and can show such heterogeneity that they may not always be dyshesive nests along an atrophic dermal-epidermal junc- classifiable.140,141 A number of studies suggest that different tion. The tumor cells often show extension down into hair types of melanoma (eg, nodular, acral lentiginous) may follicles. These tumors usually arise in the skin, showing

370 Mayo Clin Proc. • March 2007;82(3):364-380 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. MALIGNANT MELANOMA IN THE 21ST CENTURY marked solar elastosis and other features of long-term sun TABLE 2. Unusual Variants of Melanoma damage. Among the types of in situ melanoma, lentigo Melanoma variant References maligna can be difficult to distinguish from melanocytic Desmoplastic melanoma 161, 162, 183-213 hyperplasia in sun-damaged skin.180,181 This lesion may Mucosal melanoma 214-219 evolve for decades before invading into the papillary der- Malignant melanoma arising in 174 blue nevus (malignant blue nevus) 220-228 mis. To distinguish between lentigo maligna and malig- Nevoid melanoma 139, 162, 229-233 nant melanoma in situ, the term lentigo maligna has been Minimal deviation melanoma 162, 210, 234-257 proposed.175,182 In the precursor lesion lentigo maligna, Small cell melanoma 141, 234, 258-261 Spitzoid melanoma 151, 162, 237, 238, 245 there is an increase in atypical melanocytic cells singly Dermal melanoma 262, 263 disposed along the dermal-epidermal junction, whereas in Amelanotic melanoma 264-268 malignant melanoma in situ, the lentigo maligna type Myxoid melanoma 234, 269-277 Signet ring cell melanoma 234, 258, 264, 278-288 shows nesting along the junction, confluence, and pagetoid Balloon cell melanoma 151, 161, 234, 258, 289-292 spread. Progression to invasive melanoma from malignant Rhabdoid melanoma 234, 258, 293-297 melanoma in situ of the lentigo maligna type is thought to Pigment-synthesizing animal or equine melanoma 234, 298 be similar to other forms of melanoma in situ, whereas Osteoid melanoma 169, 299-303 progression from lentigo maligna, as a precursor lesion, is Chondroid and cartilaginous melanoma 169, 304-309 hypothesized to occur over a much longer time.175,182 Basomelanocytic tumor 310, 311

UNUSUAL VARIANTS OF MALIGNANT MELANOMA show nerve infiltration. When this occurs, they have been Unusual variants of melanoma (Table 2 and Figure 4) are referred to as desmoplastic neurotropic melanomas. When rare and can be confused with epithelial or mesenchymal matched for depth of invasion, desmoplastic melanomas neoplasms. These unusual variants of malignant melanoma have a lower risk of metastases than conventional melano- generally behave similarly to conventional types of mela- mas of similar depth.187,189,315-317 Desmoplastic melanomas noma when prognostic factors such as depth of invasion are may show immunopositivity for actin and can be confused taken into account. The most important aspect of these with smooth muscle tumors. Thus, immunoperoxidase variants is knowledge of their existence to avoid misdiag- studies need to be interpreted with caution in cases of nosis as another tumor or as a scar in the case of desmoplas- desmoplastic melanoma. tic melanoma. Desmoplastic melanomas have high recurrence rates due to their highly infiltrative growth and frequent peri- DESMOPLASTIC MELANOMA neural invasion and are usually deeply invasive at diagno- Desmoplastic malignant melanoma often arises on the head sis.195 A large retrospective study from the Mayo Clinic and neck183-186 but can occur on a variety of cutaneous and demonstrated that desmoplastic melanomas have a high mucosal areas, including the conjunctiva, gingiva, genitalia, incidence of local recurrence, rarely metastasize to the and perianal areas.183,187,304,312-314 Desmoplastic melanoma oc- lymph nodes, and have a propensity to metastasize to the curs in older individuals from the sixth to eighth decades of lungs. The same clinical behavior has been confirmed by life and is slightly more common in men.161,162,183,184,188-193 other groups, with the incidence of lymph node me- Clinically, desmoplastic melanoma may be amelanotic and tastases ranging from 0% to 8%. A distinction must be present as an erythematous or pale or flesh-colored nodule made between pure desmoplastic melanomas and mela- or plaque arising in sun-damaged skin or with pigmentation nomas with a desmoplastic component. The pure des- overlying a dermal nodule. Some desmoplastic melanomas moplastic melanomas have unique clinical behaviors, arise in association with a lentigo maligna melanoma, but whereas melanomas with desmoplastic components be- they may also arise in association with superficial spread- have as other cutaneous melanomas; this may explain the ing melanoma, mucosal melanoma, or acral lentiginous conflicting reports of older clinical studies that found melanoma. a higher rate of lymph node metastases. The differ- Desmoplastic melanomas are positive for S100, but ence between pure desmoplastic melanomas and cutane- many commonly used markers of melanocytic differentia- ous melanomas has been further distinguished by gene tion, including HMB45, Mart 1, and Melan A, are usually profiling in which desmoplastic melanomas have down- negative.185,193,315 Differentiating desmoplastic malignant regulation of melanocyte differentiation and up-regula- melanoma from scar tissue in reexcised specimens can be tion of neurotropic factors. On the basis of the predilec- particularly difficult because S100-positive cells can also tion for local recurrence, the North Central Treatment be seen in dermal scars. Desmoplastic melanomas often Group has embarked on a phase 2 study evaluating the

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FIGURE 4. Unusual variants of melanoma. A, Desmoplastic melanoma showing prominent perineural invasion. B, Balloon cell melanoma metastatic to a lymph node. C, Myxoid melanoma with marked cytologic atypia and mitotic activity. D, Osteogenic melanoma from the foot. E, Rhabdoid melanoma. F, Basomelanocytic melanoma. utility of adjuvant radiation for the treatment of desmo- BALLOON CELL MELANOMA plastic melanoma. Balloon cell melanoma is a rare histologic variant of malig- When matched for depth of invasion, desmoplastic nant melanoma that resembles balloon cell nevus but ef- melanomas have a lower risk of metastases than conven- faces the dermal architecture with sheets of tumor cells and tional melanomas of similar depth.195 Comparing desmo- shows cytologic atypia, nuclear pleomorphism, and mito- plastic melanomas with conventional types with a depth ses.290,291 Balloon cell melanomas must be differentiated of invasion more than 4 mm, the 5-year survival for des- from cutaneous clear cell tumor and metastases. The clear moplastic melanoma is 72% compared with 37% to 48% cytoplasm has been thought to represent degenerating mel- for conventional melanoma.189 Overall survival for both anosomes, lipid, or glycogen.292 Immunohistochemical and groups was similar to that for patients with other cutaneous electron microscopic findings suggest that the tumor cells melanomas. Factors associated with higher rates of local are likely metabolically active melanocytic cells.291 The recurrence were surgical margin clearance less than 1 cm prognosis of these rare histologic variants usually correlates and neurotropism. However, desmoplastic melanomas with tumor thickness and is similar to that in other types of showed a lower rate of regional lymph node metastasis at melanoma. These melanomas are often deeply invasive at presentation than conventional melanomas.189 diagnosis, which reflects in the overall poor survival.291

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MYXOID MELANOMA OSTEOGENIC MELANOMA Myxoid melanoma can easily be confused with other myx- Osteogenic melanomas usually occur on the digits (particu- oid and mucinous neoplasms. Prominent myxoid change larly subungual) and in the nose and sinuses and are often can be seen in primary melanomas,234,258,269-273,318-320 recur- deeply invasive at the time of diagnosis.169,299-303 Melano- rences, and metastases.274,319,321-323 Benign melanocytic neo- mas may also show cartilaginous differentiation in these plasms can also show myxoid and mucinous change.324-327 sites.169,304-309 Men and women appear to be equally af- In primary cutaneous tumors, the presence of a junctional fected, and the tumor is most common in middle-aged component helps to confirm a diagnosis of myxoid mela- and elderly patients. Osteogenic melanomas mimic osteo- noma. Melanomas with only foci of myxoid change are sarcomas, chondrosarcomas, and metaplastic carcinomas. also less difficult to diagnose than those that are predomi- Osteogenic melanomas must be differentiated from osteo- nantly myxoid. Myxoid melanomas often show a vaguely sarcomas because their treatment is different.301 Strong im- lobular architecture with pushing margins and paraseptal munoreactivity for S100 protein, HMB45, and Melan A is and perivascular accentuation of cells. The tumor cells helpful in differentiating osteogenic melanomas from os- may be small, stellate, spindled, or large and epithelioid teosarcomas and tumors with osteoid metaplasia. and are arranged singly, in cords, or rarely as pseudo- glandular structures.258 Myxoid change can be seen in RHABDOID MELANOMA metastases even when not present in the primary tumor.321 Malignant melanoma with rhabdoid cytomorphologic fea- Thus, a high index of suspicion is needed to diagnose tures has been described in both primary and metastatic melanoma in a metastasis that shows myxoid change. lesions.234,258,293-296 Primary rhabdoid melanomas usually Cutaneous tumors in the differential diagnosis include show junctional activity or a background of more conven- myxoma, nerve sheath myxoma, malignant chondroid sy- tional cells, which are helpful in recognizing the differen- ringoma, myxoid dermatofibrosarcoma protuberans, tiation of the tumor. Although rhabdoid melanomas are myxoid atypical fibrous histiocytoma, mucinous eccrine positive for S100, they often lose HMB45 expression.295,296 carcinoma, and metastases.321-323,327-336 Immunohis- Additionally, focal aberrant expression of both keratin and tochemical studies can be helpful for diagnosis because smooth muscle actin has been noted in these tumors.295 The myxoid melanomas are positive for S100, NKIC3, vimen- rhabdoid phenotype may represent further evolution to a tin, and HMB45.271,273,321 Keratin immunopositivity and more primitive dedifferentiated form.295 The prognosis for negative staining for S100 are helpful in ruling out a patients with melanoma metastases with rhabdoid features myxoid melanoma. is similar to that of conventional melanoma metastases. Not enough data are available to evaluate whether rhabdoid SIGNET RING CELL MELANOMA morphologic findings have prognostic significance in the Signet ring cell melanoma is a rare but well-recognized primary tumor. variant of malignant melanoma.234,258,264,278-288,337 Signet ring cell features are more common in metastases than in pri- BASOMELANOCYTIC TUMORS mary melanomas. The presence of signet ring cells in a Biphasic tumors with epithelial and melanocytic compo- melanocytic neoplasm is not diagnostic of malignancy nents are rare.310,311 Four squamomelanocytic tumors have because signet ring cells have been described in melano- been described, but none of the patients were reported to cytic nevi.284 The importance of a signet ring cell pheno- die of metastatic melanoma or squamous cell carcinoma.338 type is unknown, but it is important to consider this vari- In a recent report, a patient with a basomelanocytic tumor ant in the differential diagnosis of a primary cutaneous died of metastatic malignant melanoma, suggesting that at tumor or a metastasis with signet ring cell features. Signet least a subset of biphasic tumors may have a more aggres- ring cells are most common in mucin-secreting adenocar- sive biologic potential than previously known.311 Biphasic cinomas but may be seen in lymphomas, liposarcomas, tumors show an intimate admixture of melanocytic cells basal and squamous cell carcinomas, ovarian stromal tu- and basaloid cells or squamous cells, in contrast to collision mors, epithelioid smooth muscle tumors, hidradenomas, tumors in which there are usually distinctly separate com- and cylindromas, among others.234,258,278,279,284,287 Metas- ponents of melanocytic and epithelial cells.339 However, a tases of malignant melanoma with signet ring cell cyto- recent report of a malignant melanoma metastatic to a basal morphologic features have been described in lymph nodes, cell carcinoma showed an intimate association of the mela- in the lungs, and as peritoneal effusions.258,278,279,280,284,287 The noma cells within the basal cell carcinoma.340 Another case immunohistochemical profile can clarify the diagnosis, but of a malignant melanoma colonizing a basal cell carcinoma a high index of suspicion, particularly in a metastasis, is has been reported, but the malignant melanoma was limited necessary. to the epidermis.341 The cells in basomelanocytic tumors

Mayo Clin Proc. • March 2007;82(3):364-380 • www.mayoclinicproceedings.com 373 For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. MALIGNANT MELANOMA IN THE 21ST CENTURY may arise from a common precursor and show biphasic 5. Rigel DS, Naylor M, Robinson J. What is the evidence for a sunscreen and melanoma controversy? Arch Dermatol. 2000;136:1447-1449. immunophenotypic differentiation. Overall, these are rare 6. Rigel DS, Carucci JA. Malignant melanoma: prevention, early detection, tumors in which a subset appears to have a more aggressive and treatment in the 21st century. CA Cancer J Clin. 2000;50:215-236. 7. Tsao H, Sober AJ. Ultraviolet radiation and malignant melanoma. Clin biologic potential than previously known. Dermatol. 1998;16:67-73. 8. Tsao H, Rogers GS, Sober AJ. An estimate of the annual direct cost of treating cutaneous melanoma. J Am Acad Dermatol. 1998;38(5, pt 1):669-680. CONCLUSION 9. Strouse JJ, Fears TR, Tucker MA, Wayne AS. 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The Symposium on Solid Tumors will continue in the April issue.

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