Background: Melanoma is a malignancy of pigment-producing cells (melanocytes) located predominantly in the skin, but also found in the eyes, ears, GI tract, leptomeninges, and oral and genital mucous membranes. Melanoma accounts for only 4% of all skin cancers; however, it causes the greatest number of skin cancer–related deaths worldwide. Early detection of thin cutaneous melanoma is the best means of reducing mortality.

Pathophysiology: The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, is poorly understood. It likely involves a multistep process of progressive genetic mutations that (1) alter cell proliferation, differentiation, and death and (2) impact susceptibility to the carcinogenic effects of ultraviolet radiation (Demierre, 2003). Recent data suggest multiple pathways of melanoma pathogenesis, with melanomas in sun-protected skin (trunk) developing in association with a high nevus count and intermittent ultraviolet radiation as opposed to those developing on sun-exposed skin in patients with low nevus counts and chronic sun exposure (Whiteman, 2003; Maldonado, 2003). Primary cutaneous melanoma may develop in precursor melanocytic nevi (ie, common, congenital, and atypical/dysplastic types), although more than 60% of cases are believed to arise de novo (ie, not from a preexisting pigmented lesion).

The development of melanoma is multifactorial and appears to be related to multiple risk factors, including fair complexion, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common and dysplastic moles, a family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age (Sober, 1979; Rhodes, 1987; Williams, 1994).

Frequency:

—      In the US: The incidence of melanoma has more than tripled in the white population during the last 20 years, and melanoma currently is the seventh most common cancer in the United States. Approximately 62,190 Americans will develop invasive cutaneous melanoma in 2006, with an estimated additional 49,710 or more cases of melanoma in situ (Jemal, 2006). The current lifetime risk for developing invasive melanoma is 1 case per 60 Americans, a 2000% increase since 1930. This risk rises to 1 case per 32 Americans if noninvasive melanoma in situ is included.

—      Internationally: Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics, from 2002, demonstrated a prevalence of 37.7 cases per 100,000 men and 29.4 cases per 100,000 women in Australia and New Zealand, compared with 6.4 cases per 100,000 men and 11.7 cases per 100,000 women in North America (Parkin, 2005).

Mortality/Morbidity: While melanoma accounts for roughly 4% of all skin cancers, it is responsible for more than 77% of skin cancer deaths. In the United States, one person each hour dies from metastatic melanoma. Treatment of melanoma in its early stages provides the best opportunity for cure.

—      United States: An estimated 7910 deaths will occur in 2006 (5020 men, 2890 women). Analysis of US Surveillance, Epidemiology, and End Results (SEER) data from 1969-1999 demonstrated a disproportionate burden of melanoma deaths among middle-aged and older white men. While melanoma mortality rates have fallen 39% in women and 29% in men aged 20-44 years over this period, they have increased 66% in men aged 45-64 years and 157% in older men (>65 y) (Geller, 2002). Incidence data generally parallel mortality data and have shown a 3-fold increase in middle-aged men and a 5-fold increase in older men over a similar period. Encouragingly, a stable-to-reduced melanoma rate has been noted in younger age groups in the United States, which may be a result of primary prevention campaigns aimed at reducing excessive sun exposure over the past 30 or more years, although the full impact of primary prevention strategies on melanoma incidence and mortality will not be apparent for several decades.

—      Worldwide: Individuals with cutaneous melanoma have higher survival rates in developed countries (91% in US SEER registries and 81% in Europe) than in developing countries (approximately 40%). Increased educational efforts in developed areas result in earlier diagnosis, treatment, and potential cure of thinner lesions. Worldwide, 160,000 new cases of melanoma were estimated to occur in 2002, with 41,000 deaths reported (Parkin, 2005).

Race: Melanoma is primarily a malignancy of white individuals. African American persons develop melanoma approximately one twentieth as frequently as white persons, and the prevalence in Hispanic persons is approximately one sixth of that in white persons. However, mortality rates are higher in African Americans and Hispanics, who are more likely to have acral melanoma and advanced disease at presentation.

Sex: In the United States, invasive melanoma has a slight male predilection, occurring in 1 in 52 males, compared with 1 in 77 females (Jemal, 2006). Worldwide, of the 160,000 new cases estimated to have occurred in 2002, women were affected slightly more than men (male-to-female ratio, 0.97:1). Conversely, of the estimated 41,000 worldwide deaths in 2002, more occurred in men than in women (male-to-female ratio 1.2:1).

Age: The median age at melanoma diagnosis is 53 years; however, it is the most common cancer in women aged 25-29 years and is second only to breast cancer in women aged 30-34 years. The most striking differences in melanoma incidence and mortality occur in individuals older than 65 years, although modest differences in age-specific incidence and mortality are notable in persons older than 50 years (Geller, 2002).

—      Older individuals are both more likely to acquire and to die from melanoma; thus, elderly persons should be a primary target for secondary melanoma prevention, including early detection and screening (Swetter, 2004).

—      Treatment options in elderly persons may also be limited because of comorbid medical conditions, an inability to tolerate adverse medication effects or toxicity, the increased likelihood of drug interactions, and potential exclusion from clinical trials based on age criteria (Swetter, 2004).

History: A new or changing mole or blemish is the most common warning sign for melanoma. Variation in color and/or an increase in diameter, height, or asymmetry of borders of a pigmented lesion are noted by more than 80% of patients with melanoma at the time of diagnosis. Symptoms such as bleeding, itching, ulceration, and pain in a pigmented lesion are less common but warrant an evaluation. Again, because the majority of cutaneous melanoma arises de novo (ie, not in association with a precursor nevus), the wholesale removal of melanocytic nevi is not warranted for melanoma prevention. However, individuals with numerous moles (common or dysplastic) or a family history of melanoma should be educated regarding the importance of skin self-examination for early detection of skin cancer.

—      Information regarding the changes noted in any of the following is relevant to the patient’s history. Physician and patient education regarding the warning signs of early melanoma (particularly the superficial spreading subtype) has been achieved successfully through the use of the ABCDE criteria for a changing mole (Friedman, 1985; Abassi, 2004), which are as follows:

—      Asymmetry: Half the lesion does not match the other half.

—      Border irregularity: The edges are ragged, notched, or blurred.

—      Color variegation: Pigmentation is not uniform and may display shades of tan, brown, or black; white, reddish, or blue discoloration is of particular concern.

—      Diameter: A diameter greater than 6 mm is characteristic, although some melanomas may have smaller diameters; any growth in a nevus warrants an evaluation.

—      Evolving: Changes in the lesion over time are characteristic; this factor is critical for nodular or amelanotic (nonpigmented) melanoma, which may not exhibit the classic criteria above.

—      The ABCDEs have the greatest diagnostic accuracy when used in combination. Lesions exhibiting these features should be considered potential melanoma, although severely atypical nevi may be difficult to distinguish clinically.

—      More recent use of the “ugly duckling” warning sign, wherein skin examination is focused on recognition of a pigmented or clinically amelanotic lesion that simply looks different from the rest, may assist with detection of lesions that lack the classic ABCDE criteria (eg, nodular, amelanotic, or desmoplastic melanomas) (Grob, 1998; Gachon, 2005).

Physical: Four major clinicopathologic (or histogenetic) subtypes of primary cutaneous melanoma have been identified. These include superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and acral lentiginous melanoma. Distinction among the subtypes is based on histologic growth pattern (predominantly junctional in lentiginous types vs buckshot scatter in superficial spreading vs nodular), anatomic site, and degree of sun damage. The pattern of sun exposure varies between the types (sustained in lentigo maligna vs intermittent in superficial spreading). Whether the melanoma subtype affects the overall prognosis remains controversial. However, molecular analysis has demonstrated different patterns of cell death, oncogene expression, gene amplification, and BRAF mutation frequency among the 4 main histogenetic types (Miracco, 1998; Bastian 2000; Sasaki, 2004).

—      With the exception of nodular melanoma, the growth patterns of the other subtypes are characterized by a preceding in situ (radial growth) phase that lacks the biologic potential to metastasize and may last from months to years before dermal invasion occurs. While all in situ melanoma may not necessarily progress to invasive melanoma, complete excision is recommended to prevent invasion and effect cure.

—      Superficial spreading melanoma characteristics are as follows:

—      It is most common on the trunk in men and women and on the legs in women; this subtype is most commonly seen in individuals aged 30-50 years. See Image 1.

—      Superficial spreading melanoma manifests as a flat or slightly elevated brown lesion with variegate pigmentation (ie, black, blue, pink, or white discoloration).

—      It is generally greater than 6 mm in diameter.

—      Irregular asymmetric borders are characteristic.

—      Histologically, it is characterized by buckshot (pagetoid) scatter of atypical melanocytes within the epidermis.

—      Nodular melanoma characteristics are as follows:

—      This subtype occurs in 15-30% of patients.

—      It is seen most commonly on the legs and trunk.

—      Rapid growth occurs over weeks to months; this subtype is responsible for most thick melanomas (Richard, 1999; Demierre, Arch Dermatol, 2005).

—      It manifests as a dark brown-to-black papule or dome-shaped nodule, which may ulcerate and bleed with minor trauma; it may be clinically amelanotic (ie, not pigmented).

—      It tends to lack the typical ABCDE melanoma warning signs and, thus, may elude early detection. More commonly, it exhibits elevation, ulceration with bleeding, or both at presentation.

—      Histologically, it lacks a radial growth phase.

—      Lentigo maligna melanoma characteristics are as follows:

—      The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States (Swetter, 2005).

—      It is typically located on the head, neck, and arms (chronically sun-damaged skin) of fair-skinned older individuals (average age 65 y). See Image 2.

—      It grows slowly over 5-20 years.

—      The in situ precursor lesion is usually large (>1-3 cm in diameter), present for a minimum of 10-15 years, and demonstrates macular pigmentation ranging from dark brown to black, although hypopigmented (white) areas are common within lentigo maligna. Dermal invasion (progression to lentigo maligna melanoma) is characterized by the development of raised blue-black nodules within the in situ lesion.

—      Histologically, it is characterized by a predominantly junctional confluent proliferation of melanocytes and extension along adnexal structures. Solar elastosis is typically prominent.

—      Acral lentiginous melanoma characteristics are as follows:

—      This is the least common subtype of melanoma (2-8% of melanoma cases in white persons).

—      It accounts for 29-72% of melanoma cases in dark-skinned individuals (ie, African American, Asian, and Hispanic persons) and, because of delays in diagnosis, may be associated with a worse prognosis (Cress, 1997; Byrd, 2004).

—      Acral lentiginous melanoma occurs on the palms, on the soles, or beneath the nail plate (subungual variant). See Image 3.

—      Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band within the nail plate.

—      It must be differentiated from a benign junctional melanocytic nevus of the nail bed, which has a similar appearance.

—      Pigment spread to the proximal or lateral nail folds is termed the Hutchinson sign, which is a hallmark for acral lentiginous melanoma.

—      Rare melanoma variants (<5% of melanomas) include (1) desmoplastic/neurotropic melanoma, (2) mucosal (lentiginous) melanoma (Rogers, 1997), (3) malignant blue nevus, (4) melanoma arising in a giant congenital nevus, and (5) melanoma of soft parts (clear cell sarcoma).

—      Amelanotic melanoma (<5% of melanomas) characteristics are as follows:

—      This type is nonpigmented and, clinically, appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma or a ruptured hair follicle.

—      It occurs most commonly in the setting of the nodular melanoma subtype or melanoma metastasis to the skin, presumably because of the inability of these poorly differentiated cancer cells to synthesize melanin pigment.

—      Melanoma can occur on any skin or mucosal surface, although a history of cutaneous melanoma does not appear to increase the risk of developing primary intraocular or mucosal melanoma.

—      Melanoma occurs most commonly on the trunk in white males and the lower legs and back in white females. In African American, Hispanic, and Asian persons, the most common site is the plantar foot, followed by subungual, palmar, and mucosal sites.

—      Desmoplastic melanoma typically occurs in conjunction with (or in sites typical for) lentiginous types of melanoma (lentigo maligna and acral lentiginous melanoma).

Causes:

—      Superficial spreading melanoma tends to occur at sites of intermittent, intense sun exposure (ie, on trunk in males and legs and back in females). Lentigo maligna melanoma is more prevalent on chronically sun-damaged skin of the head, neck, and arms. The disease shows an increased worldwide incidence in fair-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation.

—      Primary risk factors for or clinical warning signs of melanoma include the following:

—      Changing mole (most important clinical warning sign)

—      Clinical atypical/dysplastic nevi (particularly >5-10)

—      Large numbers of common nevi (>100)

—      Large (giant) congenital nevi (>20 cm diameter in an adult)

—      Previous melanoma

—      Sun sensitivity/history of excessive sun exposure

—      Melanoma in first-degree relative(s)

—      Prior nonmelanoma skin cancer (basal cell and squamous cell carcinoma) (Friedman, 2000)

—      Male sex

—      Age older than 50 years

—      Presence of xeroderma pigmentosum or familial atypical mole melanoma syndrome: These 2 genodermatoses confer a 500- to 1000-fold greater relative risk of developing melanoma.

—      A fair-skin phenotype (blue/green eyes, blond or red hair, light complexion, sun sensitivity) and the occurrence of blistering sunburn(s) in childhood and adolescence are universal risk factors for melanoma. Individuals with these traits have been the focus of preventive efforts worldwide.

—      Pregnancy or hormonal therapy with oral contraceptives or hormone replacement does not appear to be a risk factor for melanoma development (Lederman 1985; Hannaford, 1991, Driscoll, 1993; Smith, 1998; Schwartz, 2003).

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