Cutaneous Melanoma

Updated: May 09, 2017
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

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 less than 5% of all skin cancers; however, it causes the greatest number of skin cancer–related deaths worldwide. [1] Early detection of thin cutaneous melanoma is the best means of reducing mortality. Characteristic images are shown below.

Malignant melanoma. Courtesy of Hon Pak, MD. Malignant melanoma. Courtesy of Hon Pak, MD.
Cutaneous melanoma with characteristic asymmetry, Cutaneous melanoma with characteristic asymmetry, irregular borders, and color variation. Courtesy of Wendy Brick, MD.

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.

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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. [2] 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. [3, 4]

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. [4, 5]

A meta-analysis by Lee et al demonstrated that the prevalence of these mutations may also depend on melanoma histologic subtype. [6]

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. [7, 8, 9]

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Epidemiology

Frequency

United States

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 87,110 Americans (52,1709 men and 34,940 women) will develop invasive cutaneous melanoma in 2017, with an estimated additional 74,680 or more cases of melanoma in situ. [10] The incidence may be higher due to melanoma underreporting to cancer registries, particularly for tumors that are diagnosed and managed in the outpatient setting. [11] 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. [12] 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. [13] Pilots and flight crews demonstrate melanoma risk double that of the general population. [14]

International

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. [15]

Race

Melanoma is primarily a malignancy of white individuals, with an annual incidence of 26 cases per 100,000 population in 2017. [10] African American persons develop melanoma approximately one twentieth as frequently as white persons (annual incidence rate of 1 case per 100,000 population in 2017), and the prevalence in Hispanic persons is approximately one fifth of that in white persons (annual incidence 5 cases per 100,000 population in 2017). 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 higher female predilection from birth to age 49 years (1 in 155 women compared with 1 in 220 men in 2017). However, from age 50 years and older, melanoma in men predominates, occurring in 1 in 28 men compared with 1 in 44 women over a lifetime. [10]

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.

Age

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. [16]

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. [17] 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. [17]

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Etiology

Melanoma shows an increased worldwide incidence in fair-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation. Most data support the hypothesis that melanoma development is related to intermittent, intense sun exposure, particularly in childhood or adolescence. [18, 19] In contrast, chronic sun exposure does not appear to confer increased risk, except for the more UV-related melanoma subtypes (lentigo maligna and lentigo maligna melanoma). The use of tanning beds has also increased the risk of melanoma in young patients. [20]

Primary risk factors and clinical warning signs for melanoma include the following:

  • Changing mole (most important clinical warning sign)
  • Presence of xeroderma pigmentosum or familial atypical mole melanoma syndrome: These genodermatoses confer a 500- to 1000-fold greater relative risk of developing melanoma.
  • Clinical atypical/dysplastic nevi in familial melanoma
  • Sporadic (nonfamilial) clinical atypical/dysplastic nevi (particularly >5-10)
  • Melanoma in first-degree relative(s) (especially multiple)
  • Large numbers of common nevi (>100)
  • Previous melanoma
  • Male sex
  • Age older than 50 years
  • Sun sensitivity/history of excessive sun exposure or sunburns
  • Large (giant) congenital nevi (>20 cm diameter in an adult)
  • Prior nonmelanoma skin cancer (basal cell and squamous cell carcinoma) [20]
  • Immunosuppression

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. [21, 22, 23, 24, 25]

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Prognosis

Prognosis is multifactorial and primarily depends on (1) tumor thickness, (2) the presence or absence of histologic ulceration, and (3) lymph node involvement (most important). Despite remarkable advances in the treatment of metastatic disease, detection and treatment of cutaneous melanoma in its thin, early phase remains the best chance for cure.

Cutaneous melanoma (stages I and II) prognosis

Thin primaries (≤1 mm) are associated with a 5-year survival rate of 94-97%, depending on the presence or absence of histologic ulceration and mitotic rate of greater than or equal to 1/mm2 versus less than 1/mm2.

Intermediate-thickness melanoma (1.01-4 mm) is associated with a 5-year survival rate of 68-91%, depending on ulceration, thickness (1.01-2 mm, 2.01-4 mm) of the primary tumor, and sentinel lymph node biopsy status.

Patients with high-risk tumors (>4 mm) have a 5-year survival rate of 71% without ulceration, compared with 53% with an ulcerated primary, although higher rates have been reported in the absence of sentinel lymph node involvement.

Ulceration significantly reduces survival at each tumor stage, even when regional lymph nodes are involved.

Stage III disease prognosis

Regional lymph node metastasis is associated with a 5-year survival rate of 38-78%, depending on the number of nodes involved, microscopic or macroscopic (matted nodes/gross extracapsular extension) disease, and ulceration of the primary melanoma. In-transit metastasis/satellite lesions are associated with a 69% 5-year survival rate, with a significantly worse prognosis in the setting of concomitant regional nodal metastasis (40%).

Stage IV disease prognosis

Prior to the advent of checkpoint inhibitors and targeted therapy for melanoma, prognosis for distant metastatic disease was extremely poor, with median survival of only 6-9 months and 5-year survival rates of less than 20%, depending on the site(s) of metastasis. In general, patients with soft tissue, nodal, and isolated lung metastases have had slightly better prognoses than those with other visceral metastases and/or elevated LDH levels. With immune checkpoint blockade or targeted therapy, high overall response rates and disease control has become the norm in patients with unresectable stage III and IV melanoma. Durable complete responses have been observed, particularly with novel immunotherapies.

Systemic chemotherapy is no longer the mainstay of treatment for metastatic melanoma; it is associated with low response rates (< 20%), which also tend to be of short duration.

Biochemotherapy, using standard chemotherapeutic agents with biologic response modifiers such as IL-2, IFN alfa, or granulocyte macrophage colony-stimulating factor, has shown limited success in the management of unresectable stage IV melanoma and no OS benefit or durable responses in patients with metastatic disease. [26] High-dose IL-2 alone, or combined with histamine dihydrochloride, has resulted in durable remission in a very small subset of patients with advanced disease, but is characterized by significant toxicity and need for hospitalization and careful monitoring during drug administration. [27]

Mortality/morbidity

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.

US mortality/morbidity

An estimated 9,730 deaths will occur in 2017 (6,380 men and 3,350 women). [10] 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). [16] 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.

Worldwide mortality/morbidity

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. [15]

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Patient Education

Educate patients with a history of melanoma regarding the following:

  • Sun-protective measures (including sun-protective clothing and sunscreens)
  • Skin self-examinations for new primary melanoma, particularly important in individuals with numerous moles (common or atypical) or a strong family history of melanoma
  • Possible recurrence within the melanoma scar
  • Screening of first-degree relatives, particularly if they have a history of atypical moles
  • Potential referral to a cancer genetics clinic for individuals with 3 or more invasive melanomas (personal or in the same side of the family) or families with 3 or more “cancer events,” including 2 invasive melanomas and 1 pancreatic cancer (or vice versa) for discussion of genetic testing for the CDKN2A ( P16) mutation. [28] (However, a negative result would not affect the need for ongoing dermatologic surveillance in patients at increased risk or history of multiple primary melanomas.)

For patient education resources, visit the Cancer and Tumors Center and Procedures Center, as well as Skin Cancer, Skin Biopsy, and Mole Removal.

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