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 less than 5% 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. Characteristic images are shown below.
See Can You Recognize Benign Skin Lesions From Cancerous Ones?, a Critical Images slideshow, to help identify various skin lesions.
Also see the Critical Images slideshow, Cutaneous Clues to Diagnosing Metastatic Cancer, to help identify skin lesions that are cause for concern.
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.  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. [2, 3]
Differences in frequency of BRAF or NRAS mutations are also related to patterns of sun exposure, with BRAF mutations more common in intermittently UV-exposed skin compared with chronically sun exposed skin or relatively unexposed skin (eg, acral sites, mucosal sites), which more frequently demonstrate KIT mutations. 
A meta-analysis by Lee et al demonstrated that the prevalence of these mutations may also depend on melanoma histologic subtype. 
Primary cutaneous melanoma may develop in precursor melanocytic nevi (ie, common, congenital, and atypical/dysplastic types), although more than 70% 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/sun sensitivity, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common or atypical/dysplastic nevi (moles), a family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age. [5, 6, 7]
The incidence of melanoma has more than doubled in the white population over the last 30 years, and melanoma currently is the sixth most common cancer in the United States. Approximately 76,380 Americans (46,870 men and 29,510 women) will develop invasive cutaneous melanoma in 2016, with an estimated additional 68,480 or more cases of melanoma in situ.  The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed and managed in the outpatient setting.  The current lifetime risk for developing invasive melanoma is 1 case per 54 Americans, a 2000% increase since 1930. This risk rises to 1 case per 33 Americans if noninvasive melanoma in situ is included.
Encouragingly, a stable-to-reduced melanoma incidence 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; however, the full impact of primary prevention strategies on melanoma incidence and mortality will not be apparent for several decades.
Of recent concern, however, is the rising melanoma incidence in white women younger than 40 years; annual incidence of melanoma more than doubled in this group from 1980-2004. Increased UV radiation exposure through tanning bed use, a World Health Organization (WHO)–classified carcinogen, has been proposed as a potential explanation for this alarming trend.  In addition, a study assessing melanoma incidence among young white girls and women (15-39 y) in California showed significantly higher incidence in those living in higher socioeconomic areas, with the highest UV radiation exposure compared with those from lower socioeconomic neighborhoods, suggesting that affluence (and associated lifestyle behaviors) may have a bigger impact on melanoma risk than UV exposure alone.  Pilots and flight crews demonstrate melanoma risk double that of the general population. 
Melanoma incidence has continued to increase worldwide, with the highest incidence in Australia and New Zealand. The most recent analysis of global cancer statistics for melanoma, from 2012, demonstrated an age-standardized incidence of 34.9 cases per 100,000 men and women in Australia and 35.84 cases per 100,000 men and women in New Zealand, compared with 14.3 cases per 100,000 men and women in the United States. 
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.
In the United States, invasive melanoma has a higher female predilection from birth to age 49 years (1 in 206 women compared with 1 in 297 men). However, from age 50 years and older, melanoma in men predominates, occurring in 1 in 33 men compared with 1 in 52 women over a lifetime. 
Worldwide, of the 232,000 new cases estimated to have occurred in 2012, women were affected slightly more than men. Conversely, of the estimated 55,000 worldwide deaths in 2012, more occurred in men than in women.
The median age at melanoma diagnosis is 63 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. 
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.  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. 
While melanoma accounts for roughly 4% of all skin cancers, it is responsible for nearly 75% of skin cancer deaths. In the United States, one person each hour dies from metastatic disease. Treatment of melanoma in its early stages provides the best opportunity for cure.
An estimated 10,130 deaths will occur in 2016 (6,750 men and 3,380 women).  Analysis of US Surveillance, Epidemiology, and End Results (SEER) data from 1969-1999 has 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).  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. Subsequent analyses continue to demonstrate the highest incidence and mortality rates in older white men in the United States.
Individuals with cutaneous melanoma have higher survival rates in developed countries (92% 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, 232,000 new cases of melanoma were estimated to occur in 2012, with over 55,000 deaths reported. Australia and New Zealand have the highest reported mortality. 
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