Cutaneous Melanoma

Updated: Mar 22, 2022
  • Author: Susan M Swetter, MD; Chief Editor: Dirk M Elston, MD  more...
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Practice Essentials

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, although mortality rates have dropped over the past decade due to the advent of more effective targeted and immune therapies for patients with advanced disease. [2] Characteristic images of cutaneous melanoma are shown below. 

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

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 the majority of patients with melanoma. 

A total-body skin examination is critical when evaluating a patient at risk for melanoma, particularly those with increased mole count, presence of clinical atypical nevi, prior nonmelanoma skin cancer (i.e., keratinocyte carcinoma), and/or strong family history of melanoma. 

Classic histopathologic melanoma subtypes include superficial spreading, nodular, lentigo maligna, and acral lentiginous. Distinction among these subtypes is based on histologic growth pattern (predominantly junctional in lentiginous types vs pagetoid in superficial spreading and predominantly dermal in nodular), anatomic site, and degree of sun damage. 

The most important aspects of the initial workup for patients with cutaneous melanoma are a careful history, review of systems, and physical examination. Sentinel lymph node biopsy (SLNB) is generally indicated for pathologic staging of the regional nodal basin(s) for primary tumors greater than 1 mm depth and when certain adverse histologic features (eg, ulceration, high mitotic rate, lymphovascular invasion) are present in thinner melanomas.

Surgery is the primary mode of therapy for localized cutaneous melanoma. In December 2021, the FDA approved the immune checkpoint inhibitor pembrolizumab for the adjuvant treatment of stage IIB or IIC melanoma following complete resection in adult and pediatric patients aged 12 years and older. Additionally, adjuvant treatment for stage III melanoma following complete resection expanded to include pediatric patients aged 12 years and older.

The fixed dose combination of nivolumab/relatlimab (Opdualag) was approved in March 2022. It is indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. 



The sequence of events in which normal melanocytes transform into melanoma cells, referred to as melanomagenesis, is believed to involve 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 (UVR) [3] . Genome-wide analysis of these genetic aberrations has elucidated the complex interplay of signaling pathways that lead to melanoma pathogenesis [4] , as well as the contributions of phenotypic and environmental factors. For instance, melanomas on sun-protected skin (trunk) tend to develop in association with a high nevus count and intermittent UVR, as opposed to those developing on sun-exposed skin, which are associated with low nevus count and chronic UVR  exposure. [5, 6]

Differences in frequency of BRAF or NRAS oncogenic 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. [6, 7]  A meta-analysis by Lee et al demonstrated that the prevalence of these mutations may also depend on melanoma histologic subtype. [8]

Primary cutaneous melanoma may develop in association with 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). Some data suggest that de novo melanomas have a more aggressive biology (i.e., likely to be thicker, ulcerated, and later stage) than those that are nevus associated. [9]

The development of melanoma is multifactorial and appears to be related to multiple risk factors, including lighter skin complexion/sun sensitivity, excessive childhood sun exposure and blistering childhood sunburns, an increased number of common or atypical/dysplastic nevi (moles), family history of melanoma, the presence of a changing mole or evolving lesion on the skin, and, importantly, older age. [10, 11, 12]



Melanoma shows an increased incidence worldwide in lighter-complexioned individuals living in sunny climates and nearer the equator, suggesting a causative role for ultraviolet radiation (UVR). Most data support the hypothesis that melanoma development is related to intermittent, intense sun exposure, particularly in childhood or adolescence. [13, 14] In contrast, chronic sun exposure does not appear to confer increased risk, except for the more UVR-related melanoma subtypes (lentigo maligna and invasive lentigo maligna melanoma). The use of tanning beds (artificial UVR) has also increased the incidence of melanoma, most notably in younger patients. [15]

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/typical 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 (i.e., keratinocyte carcinomas: basal cell and squamous cell carcinoma) [15]

  • Immunosuppression

Lighter-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, although a growing burden of melanoma has been observed in individuals with darker skin. [16, 17, 18, 19]

Pregnancy or hormonal therapy with oral contraceptives or hormone replacement does not appear to be a risk factor for melanoma development. [20, 21, 22, 23, 24]




United States

The incidence of melanoma has more than doubled in the white population over the last 30 years, and melanoma currently is the fifth most common cancer in the United States in both men and women. Approximately 106,111 Americans (62,260 men and 43,850 women) developed invasive cutaneous melanoma in 2021, with an estimated additional 101,280 or more cases of melanoma in situ. [1]  The actual incidence of melanoma may be higher due to melanoma underreporting to cancer registries, particularly for in situ and thinner tumors that are diagnosed and managed in the outpatient setting. [25]

Melanoma incidence varies across birth cohorts and by anatomic site and sex. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) registry between 1975 and 2017 showed continued increases in melanoma incidence at all anatomic sites, except for head and neck melanomas in men, although much of this increase was driven melanoma by detection of thin tumors (< 1.5 mm). Rates of melanoma in situ (intraepithelial) have also steadily risen to equal those of invasive melanoma, raising concerns regarding overdiagnosis of melanocytic neoplasms that would otherwise prove harmless [26] . In the United States, the current lifetime risk of developing melanoma is about 2.6% (1 in 38) for whites, 0.1% (1 in 1,000) for Blacks, and 0.6% (1 in 167) for Hispanics [27] .

Encouragingly, decreasing melanoma incidence rates have been noted in younger age groups (< age 30 years) in the United States [28] , 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 public health strategies on melanoma incidence will not be apparent for some time to come.

Melanoma incidence more than doubled from 1980-2004 in white women younger than 40 years, a trend attributed at least in part to increased UVR exposure through tanning bed use, which is a World Health Organization (WHO)–classified carcinogen. [29] A study assessing melanoma incidence among younger white girls and women (15-39 y) in California showed significantly higher incidence in those living in higher socioeconomic areas with the highest UVR exposure compared with those from lower socioeconomic neighborhoods with the highest UVR exposure, suggesting that affluence (and associated lifestyle behaviors) could have a greater impact on melanoma risk than outdoor UVR exposure alone. [30] These trends prompted public health and legislative efforts to prohibit indoor tanning bed use in minors and to ban indoor tanning entirely in the US, as has been done in several other countries. In terms of occupational risk pilots and flight crews demonstrate melanoma risk double that of the general population. [31]


Melanoma incidence has continued to increase worldwide, with the highest rates persisting in Australia and New Zealand. However, melanoma incidence in Australia has decreased since 2005 by -0.7% per year, likely reflecting the role of successful primary prevention campaigns [1]  over the past 40 years. The most recent analysis of global cancer statistics for melanoma from 2020 demonstrated an age-standardized incidence rate of 36.6 in cases per 100,000 men and women in Australia and 31.6 cases per 100,000 men and women in New Zealand, compared with 16.6 cases per 100,000 men and women in the United States. [32]


Melanoma is primarily a malignancy of white individuals. However, mortality rates are higher in African Americans and Hispanics, who are more likely to have acral melanoma and later-stage disease at presentation.


In the United States, invasive melanoma has a higher female predilection from birth to age 49 years (1 in 156 women compared with 1 in 230 men in 2021). However, from age 50 years and older, melanoma in men predominates, occurring in 1 in 27 men compared with 1 in 40 women over a  lifetime. [1, 33]

Worldwide, of the 324,625 new cases estimated to have occurred in 2020, men  were affected slightly more than women 173,844 vs 150,791, respectively. However, of the estimated 57,043 worldwide deaths in 2020, significantly more occurred in men than in women (32,385 vs 24,658, respectively) [32] .


The median age at melanoma diagnosis is 65 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. From 2010 through 2014, melanoma incidence decreased slightly in younger non-Hispanic white men and women but continued to increase significantly in men >54 years and women >44 years [34] . 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. [35]

Older individuals are both more likely to acquire and to die from melanoma (particularly white men aged 65 years and older), marking them a primary target for early detection and screening. [36] 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, although newer immune and targeted therapies are often well tolerated patients of advance age. [36]



Prognosis is multifactorial and primarily depends on (1) tumor thickness, (2) the presence or absence of histologic ulceration, and (3) regional lymph node involvement, which are used to determine melanoma stage following diagnosis. However, dermal mitotic rate in the primary tumor, which is not included in AJCC 8th edition melanoma staging, remains an important prognostic factor across all tumor thicknesses [37] . Histologic ulceration significantly reduces survival at each tumor stage, even when regional lymph nodes are involved. Despite remarkable advances in the treatment of metastatic disease, detection and treatment of cutaneous melanoma in its thinner, early phase remains the best chance for cure.

Cutaneous melanoma (stages I and II) prognosis

Overall survival for patient with metastatic melanoma improved dramatically since the first immune checkpoint inhibitor and targeted therapies were FDA approved in the US in 2011. Melanoma-specific survival data from the international collaborative database for the AJCC 8th edition (AJCC-8) does not incorporate contemporary melanoma outcomes data and so is likely underestimated.

Thin primaries (≤1 mm) are associated with a 5-year survival rate of 99% and 10-year survival rate of 96-98% depending on the presence or absence of histologic ulceration and/or thickness < 0.8 mm vs ≥0.8 mm, per AJCC-8 melanoma staging.

Intermediate-thickness melanomas (1.01-4 mm) are associated with 5-year survival rate of 86-95%, depending on thickness (>1.0-2 mm, >2.0-4 mm) and presence or absence of ulceration of the primary tumor, and negative sentinel lymph node biopsy status.

Patients with the thickest  tumors (>4 mm) have a 5-year survival rate of 90% without ulceration, compared with 82% with an ulcerated primary, in the absence of sentinel lymph node involvement. As noted, dermal mitotic rate (number of mitosis per mm2) may significantly impact prognosis, with mitotic rate 11/mm2 reducing 5-year survival to 84% (regardless of tumor thickness) [37] .

Stage III disease prognosis

Regional lymph node metastasis is heterogenous, with 5-year survival rates ranging from 32-93% [37] , depending on the number of nodes involved, microscopic or macroscopic (matted nodes/gross extracapsular extension) disease, and tumor thickness/ulceration status of the primary melanoma. Lymphatic metastasis that are histologically evident within the primary tumor specimen (microsatellites) or clinically evident (satellite/in-transit metastasis) within or around the melanoma scar site are considered stage III melanoma. Lymphatic metastasis are associated with a 68-75% 5-year survival rates, depending on whether microscopic or macroscopic disease is evident (or both). Survival rates are worse in the setting of concomitant regional nodal metastasis.

Stage IV disease prognosis

Prior to the advent of checkpoint inhibitors (i.e., ipilimumab, nivolumab, pembrolizumab) and targeted therapy (i.e., BRAF/MEK inhibitors) 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 demonstrated slightly better prognoses than those with other visceral metastases and/or elevated LDH levels. However, with immune checkpoint blockade or targeted therapy against somatic mutations in the tumor, high overall response rates and disease-free survival has become the norm in patients with unresectable stage III and IV melanoma. Durable complete responses have been observed, particularly with immune checkpoint blockade, which is now commonly used in the adjuvant setting for resected stage III and IV melanoma [38] . Neoadjuvant approaches to bulky, resectable stage III disease are gaining traction worldwide, with initial systemic therapy to reduce the extent of subsequent surgery and promote cure rates.

Novel targeted and immunotherapy agents have supplanted the use of cytotoxic chemotherapy, which usually provides only temporary tumor regression and is mainly used in the palliative setting, as well as older immunomodulators such as interferon alfa and high-dose IL2.  As a second-line therapy in patients who have progressed on immune checkpoint inhibitors and/or targeted therapy, high-dose IL-2 alone, or combined with histamine dihydrochloride, may be considered. High-dose IL-2 has resulted in durable remission in a small subset of patients with advanced disease but is characterized by significant toxicity and need for hospitalization and careful monitoring during drug administration. [39]


While melanoma accounts for roughly 4% of all skin cancers, it is responsible for over 62% of skin cancer deaths [1] . Despite favorable trends in mortality for patients with advanced disease, treatment of melanoma in its early stages provides the best opportunity for cure.

US mortality/morbidity

An estimated 7,180 melanoma-related deaths occurred in 2021 (4600 men and 2580 women) [1] . From 2013 to 2016, overall mortality decreased by 17.9% (annual percent change [APC] = -6.2%) with the most notable declines among men 50 years and older (APC = -8.3%) observed since 2014 [2] , following the advent of the modern therapeutic era. However, there remains a disproportionate burden of melanoma deaths among older white men and individuals of lower socioeconomic status – across all racial-ethnic groups.

Worldwide mortality/morbidity

Individuals with cutaneous melanoma have higher survival rates in developed countries (i.e,, 93% 5-year relative survival in the US)  compared with countries with lower national levels of socioeconomic economic development. Increased educational efforts in developed areas result in earlier diagnosis, treatment, and potential cure of thinner lesions and improved access to life-saving therapies for individuals with advanced disease. Worldwide, 324,625 new cases of melanoma were estimated to occur in 2020, with 57,043 deaths reported. Australia and New Zealand have the highest reported mortality. [32]


Patient Education

Educate patients with a history of melanoma regarding the following:

  • Sun-protective measures (including sun-protective clothing and use of sunscreens)

  • Skin self-examinations for new primary melanoma, particularly important in individuals with numerous moles (common or atypical) and/or a strong family history of melanoma

  • Possible recurrence within the melanoma scar (visible pigmentation and/or nodularity in and around the excision 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. [40] (However, a negative result does not affect the need for ongoing dermatologic surveillance in patients at increased risk or history of multiple primary melanomas.)