Cutaneous 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]

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 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]

International

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]

Race

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.

Sex

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] .

Age

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]

Mortality/morbidity

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]

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.)

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 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, on normal-appearing skin and not in association with a precursor nevus), routine sampling or mass removal of stable-appearing melanocytic nevi is not warranted for melanoma prevention. However, individuals with numerous moles (common or atypical/dysplastic) or a family history of melanoma are at increased risk of developing melanoma and should be educated regarding the importance of skin self-examination for early detection.

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. Multiple studies have demonstrated that thinner melanomas are associated with physician detection during routine skin or physical examinations, compared with patient detection of melanoma when a lesion changes or becomes symptomatic.[41]

Clinician 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,[42, 43] which are as follows:

• Asymmetry: Onw 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 be smaller in size; 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 ABCD 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/dysplastic nevi may be difficult to distinguish clinically. The "ugly duckling" warning sign, in which skin examination is focused on recognition of a pigmented or clinically amelanotic “outlier” lesion that looks different from the rest, may assist with detection of lesions that lack the classic ABCDE criteria (eg, nodular, amelanotic, or desmoplastic melanomas).[44, 45]

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

Four major clinicopathologic subtypes of primary cutaneous melanoma have been identified, although newer classifications of melanoma include location on chronically sun-exposed versus intermittently or non‒sun-exposed skin and incorporate the presence of driver mutations in BRAF, NRAS, NF-1, and other oncogenes. 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 pattern of sun exposure varies between the types (chronic in lentigo maligna vs intermittent in superficial spreading and nodular subtypes vs noncontributory in acral lentiginous and mucosal subtypes).

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, NRAS, and KIT mutation frequency among the four main histogenetic types.[46, 47, 48] Differing microRNA signatures between superficial spreading melanoma and nodular melanoma have also been described, which supports the concept of molecular classification of superficial spreading melanoma and nodular melanoma as two distinct phenotypes.[49]

A pooled analysis of more than 30 studies from 1989-2010 concludes that the incidence of BRAF and NRAS mutations differ based on histologic subtype and anatomic site.[8] BRAF mutations are more commonly detected in superficial spreading melanomas and melanomas that arise on nonchronically sun-damaged skin. NRAS mutations are more common in patients with nodular melanomas and melanomas arising on chronically sun-damaged skin. Some, but not all data have shown that NRAS mutations may be associated with thicker tumors (>1 mm) and higher mitotic rate (>1/mm2) compared with mutations in BRAF, and that NRAS mutation status may be associated with worse clinical outcomes, including shorter melanoma specific survival.[50, 51] These studies suggest that further molecular classification of melanoma may assist in the development of more effective targeted therapies.

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 in situ melanomas may not necessarily progress to invasive melanoma, complete removal is recommended to prevent invasion and result in cure.

Superficial spreading melanoma

Superficial spreading melanoma accounts for nearly 70% of cutaneous melanoma and is the most common subtype in individuals aged 30-50 years, as well as those with clinical atypical/dysplastic nevi. It is most common on the trunk in men and women and on the legs in women. See the image below.

Superficial spreading melanoma, left breast, 1.3-mm Breslow depth.

Superficial spreading melanoma commonly displays the ABCD warning signs. It 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

This subtype occurs in 15-30% of patients. It is seen most commonly on the legs and trunk in men and women. Rapid growth occurs over weeks to months; this subtype is responsible for most thick melanomas.[52, 53]

Nodular melanoma may be clinically amelanotic (ie, not pigmented); thus, any rapidly growing flesh-colored lesion that persists after 1 month or ulcerates or bleeds should prompt medical evaluation. Nodular melanoma typically manifests as a dark brown-to-black papule or dome-shaped nodule, which may ulcerate and bleed with minor trauma; however, it may also be clinically amelanotic (ie, not pigmented).

Nodular melanoma 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 is believed to lack a preceding radial or in situ growth phase.

Lentigo maligna melanoma

The incidence of lentigo maligna subtypes (in situ and invasive) appears to be rising in the United States.[54]  It is typically located on the head, neck, and arms (chronically sun-damaged skin) of lighter-skinned older individuals (average age 65 y). See the image below.

Lentigo maligna melanoma, right lower cheek. Centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ).

This subtype grows slowly over 5-20 years. The in situ precursor lesion (termed lentigo maligna) is usually large (>1-3 cm in diameter), present for a minimum of 10-15 years, and demonstrates macular (flat) pigmentation ranging from dark brown to black, although hypopigmented (white) areas are common within lentigo maligna. Progression to dermal invasion (i.e., lentigo maligna melanoma) is believed to be an uncommon event for most melanomas in situ/lentigo maligna type but is clinically characterized by the development of raised blue-black nodules within the in situ lesion.

Histologically, lentigo maligna melanoma  is characterized by a predominantly junctional confluent proliferation of melanocytes and extension along adnexal structures, although dysplastic nevus-like features may be observed.[55] Solar elastosis is typically prominent, and this subtype is now commonly referred to as high cumulative sun damage (CSD) melanoma[56] .

Acral lentiginous melanoma

Acral melanoma is the least common subtype of melanoma in white persons (2-8% of melanoma cases).However, is the most common melanoma subtype in individuals with darker skin tones (ie, African American, Asian, and Hispanic/Latinx persons - who are at lower risk of UVR-related melanomas), representing 29-72% of melanoma cases. Because of delays in diagnosis, acral melanoma may be associated with a worse prognosis.[57, 58, 19]

Acral lentiginous melanoma occurs on the palms, on the soles, or beneath the nail plate of the fingernails or toenails (subungual variant). See the image below.

Acral lentiginous melanoma (1-mm Breslow depth), left sole. Diagnostic punch biopsy site is located superiorly.

Subungual melanoma may manifest as diffuse nail discoloration or a longitudinal pigmented band (melanonychia striata) 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 subungual melanoma. Subungual melanoma may be mistaken for a subungual hematoma, which is usually due to trauma and resolves with time.

Fungal infection of the nail (onychomycosis) can also be confused with subungual melanoma, particularly in the setting of nail dystrophy without suspicious pigmentation. Nonresponsiveness to antifungal agents should prompt more thorough evaluation, including potential biopsy.

Rare variants

Rare melanoma variants (< 5% of melanomas) include (1) desmoplastic/neurotropic melanoma, (2) mucosal (lentiginous) melanoma,[59] (3) blue nevus-like melanoma, (4) melanoma arising in a giant/large congenital nevus, and (5) melanoma of soft parts (clear cell sarcoma).

Desmoplastic melanoma

Desmoplastic melanoma is a less common but important melanoma subtype, given its predilection in older-age individuals, clinical features similar to nonmelanoma (keratinocytic) skin cancer, and potential indication for adjuvant radiation therapy for improved local control following wide excision.

Desmoplastic melanoma may occur in association with macular, lentigo maligna-type pigmentation and show high-CSD features histologically, or it may present de novo as a firm, amelanotic nodule or scar. It occurs most often on sun-exposed areas of the head and neck, with a mean age of 60-65 years.[60]  Lack of pigmentation and clinical features more suggestive of keratinocytic (“nonmelanoma”) skin cancer may result in delay in detection and thicker tumors at diagnosis.

Desmoplastic melanoma frequently exhibits perineural invasion/neurotropism, which confers an increased risk for local recurrence. Wide excision  (based on Breslow thickness) and adjuvant radiation therapy may be necessary for improved local control of this uncommon melanoma subtype.

Amelanotic melanoma

Amelanotic melanoma (< 5% of melanomas) can occur with any subtype. This type is nonpigmented and, clinically appears pink or flesh-colored, often mimicking basal cell or squamous cell carcinoma, dermatofibroma, or a ruptured hair follicle. It occurs most commonly in the setting of the nodular or desmoplastic melanoma subtypes or melanoma metastasis to the skin, presumably because of the inability of these poorly differentiated cancer cells to synthesize melanin pigment.

Metastasis may occur locally (within or around the primary cutaneous site), in the regional lymph node basins, or distally in the following sites:

• Remote skin (away from the melanoma scar)

• Remote lymph node(s)

• Viscera

• Skeletal

• CNS sites

Disease relapse is seen most commonly in the skin, subcutaneous tissue, and lymph nodes.

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 recommended for pathologic staging of the regional nodal basin(s) in 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.

Published data have shown that baseline laboratory studies (eg, lactate dehydrogenase [LDH] level, liver function tests, chemistry panel, CBC count), chest radiography (CXR), and other imaging studies (eg, CT scanning, positron emission tomography [PET] scanning, bone scanning, MRI) are not useful for asymptomatic stage I/II (cutaneous) melanoma patients, and obtaining these studies is discouraged.[61, 62, 63, 64, 38]

A metastatic workup should be initiated if physical findings or symptoms suggest the presence of metastasis at the time of diagnosis or for concern of metastatic disease recurrence following initial treatment of cutaneous melanoma. Distant metastasis work-up with CT (chest/abdomen/pelvis) or PET-CT may be considered if the patient has documented regional nodal micrometastasis based on results from the SLNB, although the yield is low (0.5-3.7%) and correlates with increasing tumor thickness, ulceration of the primary tumor, and/or large tumor burden in the sentinel lymph node(s).[65]

Practice guidelines developed by the National Comprehensive Cancer Network (NCCN)[38] and American Academy of Dermatology[66] support the concept that most melanoma recurrences are diagnosed clinically. The current guidelines recommend against further workup (ie, baseline laboratory tests and imaging studies) in patients with stage 0 (melanoma in situ) and in asymptomatic patients with any thickness of invasive cutaneous melanoma (stages I and II). Further imaging (CT, PET-CT, MRI) should be obtained only as clinically indicated to evaluate specific signs or symptoms.

Guidelines established by the American Academy of Dermatology in 2019 also do not recommend baseline imaging or laboratory tests in asymptomatic patients with any stage of cutaneous melanoma (IA-IIC).[66]

The key components to melanoma follow-up are careful physical examination (with attention to lymph nodes and skin) and review of systems. Patients should be educated in the performance of monthly skin self-examination for early detection of new primary melanoma as well as self-lymph node examinations (in those with invasive melanoma).

Current NCCN and AAD guidelines do not recommend surveillance (follow-up) laboratory or imaging studies for asymptomatic patients with stage IA, IB, and IIA melanoma (ie, tumors ≤4 mm depth). Imaging studies may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although there is little evidence to suggest that asymptomatic, surveillance-detected recurrence improves patient outcomes.[67]  Routine radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 3-5 years of follow-up.[38, 66]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum LDH levels were first incorporated into AJCC melanoma staging in 2002 for subclassification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in patients with distant disease and have remained a powerful predictor of survival in subsequent AJCC melanoma staging. Serum S-100 protein levels may also be useful as a tumor marker in patients with metastatic disease, but this test is not widely used in the United States.[68]

As discussed previously, studies have confirmed that extensive radiologic studies such as CT, MRI, PET-CT, and bone scans have an extremely low yield in asymptomatic patients with primary cutaneous melanoma (AJCC stages I and II) and are generally not indicated. However, maintaining a low threshold for obtaining symptom-directed tests is important in melanoma surveillance.

Surveillance CXR, CT, or PET-CT may be obtained for asymptomatic melanoma patients with primary tumors greater than 4 mm in depth or ulcerated tumors >2.0-4 mm thickness (i.e. AJCC-8 stage IIB/IIC), although this practice remains optional in the absence of signs or symptoms of metastatic disease.[69]  Melanomas at higher risk for metastasis (stage IIC, III) are generally followed with surveillance imaging, to expedite initiation of therapeutic intervention if disease recurs.

Current NCCN guidelines recommend the use of regional nodal ultrasound in certain clinical settings, including physical examination with equivocal lymph node findings. Regional nodal ultrasound has shown to be superior to palpation alone for assessment of regional lymph node metastasis and surveillance of the regional nodes. A meta-analysis of 74 studies conducted between 1990 and 2009 encompassing 10,528 patients demonstrated the superiority of ultrasonography over CT, PET, and PET-CT for detecting lymph node metastasis.[70] As such, NCCN guidelines recommend consideration of regional nodal ultrasound in patients (1) with an equivocal lymph node examination, (2) who were offered but did not undergo SLNB staging, (3) in whom SLNB was not possible or technically successful, and (4) with apositive SLNB who did not undergo complete lymph node dissection, a practice which is now typical for most SLNB-positive melanomas.[69]

The criterion standard for melanoma diagnosis is histopathologic examination of clinically suggestive skin or mucosal lesions. An excisional biopsy with narrow (1-3 mm) margins is preferred and may consist of a fusiform/elliptical excision, an excisional punch biopsy, or a saucerization/deep shave biopsy (into the deeper reticular dermis), the latter of which is the most common technique used. In the case of melanoma in situ, lentigo maligna type, a broad shave biopsy (into the deeper papillary or superficial reticular dermis to capture potential invasive melanoma) may be the best technique to provide optimal tissue for histopathologic assessment. The biopsy report should generally include the following[66, 71, 72] :

Mandatory histologic features for pathology reporting include:

• Tumor thickness in millimeters (mm), ie, Breslow depth

• Ulceration (present or absent)

• Microsatellitosis (which updates a melanoma to stage III)

• Margin status for biopsies and excisions (to include whether tumor extends to the peripheral and/or deep margin)

Optional (but encouraged) histologic features for reporting include:

• Dermal mitotic rate (measured as number of mitoses/mm2)

• Lymphovascular/angiolymphatic invasion

• Histologic subtype (if desmoplastic, pure vs mixed features should be noted)

• Neurotropism/perineural invasion (particularly in desmoplastic melanoma)

• Regression (if extensive [>75%] or extending below measured Breslow thickness, through regression is generally associated with lower rates of sentinel node positivity and improved disease-free survival)[73]

Immunohistochemical staining for lineage (S-100, homatropine methylbromide 45 [HMB-45], melan-A/Mart-1), nuclear transcription factor (SOX10) , melanoma associated antigen (Preferentially expressed Antigen in Melanoma [PRAME]), and/or proliferation markers (proliferating cell nuclear antigen, Ki67) may be helpful for histologic differentiation from melanoma simulators.

When an excisional biopsy is performed, 1-3 mm of normal skin surrounding the pigmented lesion should be removed to completely remove the lesion and provide accurate diagnosis and histologic microstaging. Wider margins (>1 cm) could theoretically disrupt afferent cutaneous lymphatic flow and affect the ability to identify the sentinel node(s) accurately in patients eligible for this staging procedure. Most data, however, suggest that accurate mapping is possible after wider excision, although an increased number of regional lymph nodes may be removed as a result.

Superficial shave biopsies of suggestive pigmented lesions are discouraged because partial removal of the primary melanoma may not provide an accurate measurement of tumor thickness, which is the most important histologic prognostic factor. As noted above, an important exception to this rule is the lentigo maligna subtype of melanoma in situ, in which the risk of misdiagnosis is higher if small (partial) biopsy is performed. The best diagnostic biopsy technique is often a broad shave biopsy that extends into at least the papillary dermis, which provides the opportunity to exclude microinvasive melanoma and allows for optimal histopathologic interpretation of the tumor.

Superficial spreading melanoma has an in situ (radial growth) phase characterized by increased numbers of intraepithelial melanocytes, which (1) are large and atypical, (2) are arranged haphazardly at the dermoepidermal junction, (3) show upward (pagetoid) migration, and (4) lack the biologic potential to metastasize. Lentigo maligna melanoma and acral lentiginous melanoma demonstrate predominant in situ growth at the dermoepidermal junction and with little tendency for the pagetoid scatter of cells.

Dermal invasion confers metastatic potential, although the greatest risk occurs in the setting of a vertical growth (tumorigenic) phase.[74, 75] Tumorigenicity is characterized by a distinct population of melanoma cells with evidence of proliferation (mitoses, MIB-1 staining) and nuclear pleomorphism within the dermis and, possibly, the subcutaneous fat. Lateral intraepidermal extension of melanoma cells occurs in all subtypes except nodular melanoma. Failure of melanocyte maturation and dispersion as the tumor extends downward into the dermis is characteristic of melanoma. Some investigators have defined a vertical growth phase as (1) any dermal nest larger than the largest junctional nest or (2) invasion into either the reticular dermis or band of solar elastosis.

Tumor thickness, as defined by the Breslow depth, is the most important histologic determinant of prognosis and is measured vertically in millimeters from the top of the granular layer (or base of superficial ulceration) to the deepest point of tumor involvement. Increased tumor thickness confers a higher metastatic potential and a poorer prognosis.[76, 77] Analysis of worldwide data has shown that the presence of ulceration microscopically, defined as a full-thickness epidermal defect overlying the melanoma, is the next most important histologic determinant of patient prognosis and, when present, should be used to up-stage patients with both primary and nodal melanoma.[78] Data have suggested that both the presence and extent of histologic ulceration predict survival, with extent of ulceration (measured either as diameter or percentage of tumor width) providing more accurate prognostic information than the presence of ulceration alone. Specifically, in an analysis of 4661 patients,those with minimally/moderately ulcerated tumors (defined as less than or equal to 70% or less than or equal to 5 mm) had a significantly higher risk of death (HR=1.53 and HR=1.39, respectively), compared with nonulcerated melanoma, and the risk of death was even higher for patients with extensively ulcerated tumors (>70%: HR=2.20 and >5 mm: HR=2.03).[79]

The Clark level was used for more than 40 years to provide a measurement of tumor invasion anatomically, though its relevance diminished with greater understanding of histologic prognostic factors. In the 2002 AJCC melanoma staging system, Clark level was included only in thin primary tumors (≤1 mm depth) because its prognostic value was minimal in thicker primary melanomas. However, analysis of the worldwide AJCC 2008 melanoma staging database demonstrated lower statistical correlation with melanoma survival when level of invasion was compared with thickness, mitotic rate, ulceration, age, sex, and site. As such, the 7th edition of the AJCC Cancer Staging Manual (effective January 2010) excluded Clark level in T1 melanomas (≤1 mm depth), replacing it with dermal mitotic rate (greater than or equal to 1/mm2) to upstage a T1a melanoma to a T1b melanoma.[80]

While dermal mitotic rate is no longer incorporated into AJCC 8th edition melanoma staging for T1 melanoma, it remains a key prognostic factor and should be measured for all invasive melanomas. Higher mitotic rate (as a continuous variable) across all tumor thicknesses confers a greater risk for metastasis, including SLNB metastasis, and is an independent predictor of worse survival.

The melanoma staging system initially developed in 1983 by the AJCC and the International Union Against Cancer (UICC) divided melanoma into 4 stages and incorporated tumor thickness and anatomic level of invasionlevel of invasion (Clark level) for stages I and II (localized cutaneous disease), with the later recommendation to follow Breslow depth over Clark level when any discordance arose. Stage III disease involved the regional lymph nodes; stage IV disease included distant skin, subcutaneous, nodal, visceral, skeletal, or CNS metastasis.

Following publication of the AJCC melanoma guidelines in 2002, an international multidisciplinary Melanoma Staging Committee established a new clinicopathologic database of more than 17,000 patients worldwide to test the validity of the proposed staging changes.[81, 82, 83]  Several important modifications to prior AJCC staging included the incorporation of histologic ulceration of the primary tumor and number of lymph nodes involved (instead of size) to better stratify metastatic risk and patient prognosis.[39] Furthermore, microscopic regional lymph node metastasis detected largely by SLNB was differentiated from macroscopic (palpable) nodal metastasis. Further changes in AJCC melanoma  staging for the 7th edition were made based on an improved understanding of prognostic factors that relate to melanoma-specific survival.

The 8th edition of the AJCC Cancer Staging manual (effective January 2018) used a newly created international AJCC Collaborative database that included over 49,0000 patients with staged I-III melanoma from 1998 on (meaning that most were pathologically staged with SLNB) from the US, Australia, and Europe (Italy, Greece, Spain) to provide the best available prognostic information.[84] The estimated 5-year overall survival (OS) in the Table below is based on analysis of these worldwide data. Patients with T2 to T4 melanoma were included only if they had negative sentinel lymph nodes, whereas those with T1N0 melanoma were included regardless of whether they underwent SLNB. Survival estimates for stage IV melanoma (distant disease) were not included due to the rapidly changing treatment landscape.[37]

The 8th edition of the AJCC Cancer Staging manual[84]  had several important changes, including reporting of Breslow thickness to the nearest 0.1 mm, rather than the nearest 0.01 mm, owing to the lack of precision in measurement beyond the 1/10th decimal point.[84] Thin melanoma less than or equal to 1 mm (T1), was subdivided into T1a (for tumors < 0.8 mm without ulceration) and T1b (for tumors < 0.8 mm with ulceration or 0.8-1.0 mm with or without ulceration). Tumor mitotic rate was removed as a staging criterion in T1 melanoma, although histopathologic measurement of mitotic rate (in #/mm2) is recommended across all tumor thicknesses given its impact on prognosis. The 8th edition excluded Clark level from staging, again noting its lack of predictive value for survival compared with other prognostic variables.

For stage III melanoma, tumor thickness and presence or absence of lymphatic metastasis (microsatellite, satellite or in-transit) were incorporated, and stage IIID was added to reflect worse prognosis for T4b primaries with nodal and/or lymphatic metastasis. For stage IV disease, the subcategory of M1d was added to include distant metastasis to the central nervous system (CNS).

Table. AJCC Eighth Edition Melanoma Staging (2018) (Open Table in a new window)

Numerous adjuvant therapies have been investigated for the treatment of localized cutaneous melanoma following complete surgical removal. No overall survival (OS) benefit was demonstrated for adjuvant chemotherapy, nonspecific immunotherapy, radiation therapy, retinoid therapy, vitamin therapy, or biologic therapy.[85]  High-dose IFN alfa-2b was the first US Food and Drug Administration (FDA)‒approved adjuvant therapy for high-risk cutaneous melanoma (currently defined as stages IIB, IIC, and III) to prevent relapse and death but has been supplanted by newer immune approaches. The landscape has changed dramaticially for adjuvant, neoadjuvant and systemic therapeutic approaches for stage III and IV melanoma, with the advent of modern immunotherapies via immune checkpoint blockade and targeted therapies against specific oncogenic mutations.

Current adjuvant immunotherapies/targeted therapies for resected stage III melanoma

Ipilimumab (Yervoy) is an immune checkpoint inhibitor of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and was approved in 2015 for the adjuvant treatment of stage III melanoma, including pathologic involvement of regional lymph nodes larger than 1 mm, followed by complete lymph node resection. Approval for adjuvant therapy was based on results from the EORTC 18071 study that was conducted in 951 high-risk patients with stage III melanoma who had undergone a complete lymph node dissection.[86] Recurrence-free survival (RFS) was significantly higher in the ipilimumab group compared with the placebo group at 1 year (63.5% vs 56.1%), at 2 years (51.5% vs 43.8%), and at 3 years (46.5% vs 34.8%), as was median RFS was in the ipilimumab group (26.1 vs 17.1 months). However, the initial FDA-approved regimen for adjuvant ipilimumab (10 mg/kg q3wk for 4 doses then every 3 months for up to 3 y) was significantly higher in dose and duration than that approved for patients with unresectable stage III and IV melanoma (3mg/kg q3week for 4 doses), making toxicity and tolerability problematic. High dose ipiliumumab was demonstrated to not only improve recurrence-free survival, but also overall survival (11% at 5 years) in resected stage III melanoma patients[87] , though with significant risk of immune-related adverse events; it is thus seldom used in the adjuvant setting.

The phase 3 ECOG (E1609) trial assessed the use of low (3 mg/kg) versus high-dose ipilimumab compared with high-dose IFN in 1,670 patients with resected stage IIIB and IV melanoma randomized (1:1:1) between 2011 and 2014.[88] Treatment related adverse events grade ≥ 3 were higher in the high-dose ipilimumab arm (58%) vs low-dose arm (37%), leading to treatment discontinuation in over 50% of patients on the higher-dose. In comparison to high dose IFN, low-dose ipilimumab showed improved OS (hazard ratio [HR], 0.78; 95.6% repeated CI, 0.61 to 0.99; P = .044), while high-dose ipilimumab did not achieve statistical significance in this regard. In situations where adjuvant ipilimumab may be considered, the low dose regimen (3 mg/kg) is thus recommended over the high-dose regimen.[38]

Two adjuvant trials showed increased RFS for resected stage III melanoma with combination MAP kinase inhibitor therapy (dabrafenib/trametinib)[89]  and for resected stage III and IV melanoma with nivolumab (Opdivo) therapy (over low-dose ipilimumab)[90] , resulting in FDA approval in 2017 for anti-PD1 monotherapy and for dabrafenib/trametenib in 2018. In the Checkmate 238 trial, significantly lower immune-related adverse events (14.4% vs 45.9%) were noted on adjuvant nivolumab compared with adjuvant ipilimumab, making it the preferred treatment immunotherapy option over ipilimumab. However, overall survival at 4-years of follow-up on the study was similar in both groups (77.9% with nivolumab and 76.6% with ipilimumab), with fewer deaths than anticipated.[91]

Adjuvant pembrolizumab (Keytruda) was approved for resected stage III melanoma in 2019 based on results of the EORTC trial showing increased RFS compared to placebo (75.4% vs 61.0% at median follow-up of 15 months) in patients with resected stage III melanoma who were treated with 200 mg of pembrolizumab (514 patients) or placebo (505 patients) intravenously every 3 weeks for a total of 18 doses (approximately 1 year), with similar favorable toxicity and efficacy profile to nivolumab.[92] The impact of adjuvant pembrolizumab on OS has not yet been reported.

The use of adjuvant BRAF inhibitor dabrafenib (150 mg twice daily) and MEK inhibitor trametinib (150 mg twice daily) for 12 months was studied in 870 patients with completely resected, stage III melanoma with BRAF V600E or V600K mutations. Improved 3-year RFS (58%) was noted in the combination MAP kinase group (58%) compared with the placebo group (39%), with similar safety/toxicity profile to that observed in unresected stage III and IV studies.[89] Other BRAF/MEK inhibitor combinations may be used (i.e. vemurafenib/cobimetinib or encorafenib/binimetinib) for unacceptable side effects on dabrafenib/trametinib.

Ongoing close clinical observation with periodic surveillance imaging is also an option for resected stage III melanoma, though anti-PD1 monotherapy and dual BRAF/MEK inhibitors are associated with fewer side effects and much greater efficacy than prior adjuvant therapies. These studies highlight the importance of accurate pathologic staging of cutaneous melanoma with SLNB in appropriate patients, since upstaging disease to stage III would result in eligibility for potentially life-saving adjuvant therapy.

Melanoma vaccines

Melanoma vaccines are a type of specific active immunotherapy based on melanoma cell expression of certain HLA- and tumor-associated antigens. Vaccines remain a theoretically attractive therapeutic option due to low associated toxicity (eg, fatigue, myalgias, local inflammatory skin reactions). Numerous melanoma-associated antigens have been identified, and which of these are the most important in eliciting the necessary cytotoxic and humoral responses to kill melanoma cells remains unclear. In addition, HLA haplotype restriction (mainly to the A2 allele) limits the use of peptide vaccines in many patients. Vaccine trials have been conducted in the setting of advanced disease (stages III and IV) and not for melanoma prevention.

Vaccine types include whole cell preparations, cell lysates, gangliosides, peptides/proteins, dendritic cell vaccines, and DNA vaccines. Melanoma vaccines may be autologous (killed cell and recombinant types), allogeneic, shed from tumor, defined antigen-directed or genetically engineered, and either polyvalent or univalent in nature. Enhanced delivery systems, such as dendritic cell preparations, DNA-plasmid vectors, and intranodal infusion, have been studied to enhance immunogenicity and host response. Biologic response modifiers such as granulocyte macrophage colony-stimulating factor, IL-2, IL-12, and IFN gamma are often integrated into vaccine strategies.

As yet, no large, phase III randomized trial has demonstrated an OS advantage for vaccine-treated melanoma patients. However, a phase III trial of gp100:209-217(210M) peptide vaccine in combination with high-dose IL-2 showed significant improvement in response rate and progression-free survival compared with IL-2 alone and provided the first evidence of clinical benefit for vaccine strategies in patients with melanoma.[93, 94, 95] Vaccine strategies remain challenging in melanoma but continue to be investigated.

BRAF and MEK inhibitors for advanced melanoma (unresectable stage III and IV)

The mitogen-activated protein kinase (MAPK) signaling pathway (RAS/RAF/MEK/ERK) has been found to be constitutively activated in up to 80-90% of melanomas, with the most common mutations in either NRAS (15-30% of melanomas) or BRAF (50-70% of melanomas). Drugs that target this pathway, including multikinase inhibitors, which decrease BRAF activity, are highly effective in treating metastatic melanoma.[96, 97, 98]

Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF(V600E). The drug is indicated for the treatment of unresectable or metastatic melanoma with BRAF(V600) mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib and other BRAF inhibitors are contraindicated in patients with wild-type BRAF melanoma.

The BRAF Inhibitor in Melanoma (BRIM)–3 study results showed vemurafenib improved progression-free and overall survival compared with standard chemotherapy in patients with advanced melanoma with no previous treatment. Results found vemurafenib had a 74% reduction in the risk for progression (or death) compared with patients receiving dacarbazine chemotherapy (hazard ratio, 0.26; P< .001). Mean progression-free survival was 5.3 months in the vemurafenib group, compared with 1.6 months in the dacarbazine group. At 6 months, the estimated OS rate was 84% (95% CI, 78-89) in the vemurafenib group and 64% (95% CI, 56-73) in the dacarbazine group.[97] Vemurafenib continued to be associated with improved median OS in the BRIM-3 trial after extended follow-up through August 2015, although convergence of survival curves after about 3 years was attributabed to crossover from dabrafenib to vemurafenib and receipt of other cancer therapies.[99]

Adverse effects from vemurafenib monotherapy are largely cutaneous and include photosensitivity, which appears to be driven by UV-A light,[100] alopecia, xerosis, follicular hyperkeratosis (keratosis pilaris‒like), rash, and potential development of cutaneous squamous cell carcinoma (SCC), particularly the keratoacanthoma type. The keratinocyte proliferations observed with BRAF inhibition, ranging from benign papillomas to SCC, tend to appear early in the course of treatment and are likely driven by paradoxical activation of the MAPK pathway. Reports of atypical melanocytic proliferations in patients on selective BRAF inhibitors, including new primary melanomas and dysplastic nevi, highlighted the need for routine skin examination in all treated individuals.[101]

Dabrafenib (Taflinar) is a BRAF inhibitor that inhibits the mutant BRAF protein in melanomas with either the V600E or V600K genotype. A phase III study demonstrated high clinical response rates and improved progression-free survival in BRAF(V600E) metastatic melanoma patients who received dabrafenib compared with dacarbazine.[102] Efficacy has also been demonstrated in BRAF(V600K) patients and in those with brain metastasis. Dabrafenib appears similar to vemurafenib in terms of efficacy but may be associated with less photosensitivity, although it is associated with increased pyrexia; it was FDA approved in 2013.[103]

A subsequent phase III open-label trial assessing the use of an oral selective MEK inhibitor, trametinib (Mekinist), versus dacarbazine in 322 patients with metastatic melanoma (unresectable stage IIIC or IV) demonstrated improved rates of progression-free and OS in patients with the BRAF(V600E) or BRAF(V600K) mutation.[104] At 6 months, OS was 81% in the trametinib group and 67% in the chemotherapy group, despite allowances for cross-over from the chemotherapy group to the trametinib group following disease progression (hazard ratio for death, 0.54; 95% CI, 0.32-0.92, P = .01). Rash, diarrhea, and peripheral edema were the most common toxic effects in the trametinib group, although secondary skin neoplasms, including cutaneous SCCs, were not noted.

Trametinib was FDA approved in May 2013 as a single agent, though it is seldom used as monotherapy. The combination of BRAF and MEK inhibitors (dabrafenib/trametinib) showed higher response rates and more durable clinical benefit than monotherapy with either agent[105, 106] and was FDA approved in  2014. Combination BRAF/MEK inhibition is considered first-line therapy over BRAF monotherapy.

Two phase III trials (COMBI-v and coBRIM) demonstrated that combination therapy with a BRAF inhibitor and a MEK inhibitor is more efficacious than therapy with a BRAF inhibitor alone, with longer progression-free survival, resulting in FDA approval in 2014 for vemurafenib/dabrafenib as first-line therapy over BRAF inhibitor monotherapy, and for vemurafenib/cobimetinib in 2015. Extended follow-up of the phase Ib BRIM7 trial showed median OS in BRAFi-naive pts on combination therapy of 31.8 months, with landmark OS rate plateauing at 39.2% at years 4 and 5 of follow-up.[107] Similar favorable long-term (5-year) results were noted in the coBRIM study.[108]

Encorafenib (BRAFTOVI) and binimetinib (MEKTOVI) were FDA approved in 2018 as combination therapy based on the results of phase 3 COLUMBUS trial showing improved PFS (14.9 months) in 577 treatment naive patients or those who had progressed on or after previous first-line immunotherapy, compared to vemurafenib monotherapy (7.3 months) at medial follow-up of 16.6 months, with improved tolerability on the combined regimen.[109] Subsequent interim OS analysis at median follow-up of 36.8 months showed median OS of 33.6 months with encorafenib plus binimetinib vs 16.9 months with vemurafenib (hazard ratio 0·61 [95% CI 0·47–0·79]; two-sided p< 0·0001), demonstrating clinical meaningful efficacy and improved tolerability.[110] Combination BRAF/MEK inhibition is the standard of care for BRAF mutant advanced melanoma, particularly in the setting of rapidly progressing and/or high-volume metastasis.[111]

Immunotherapies for advanced melanoma (unresectable stage III and IV)

The fixed dose combination of nivolumab/relatlimab (Opdualag) is indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody.  The combination results in increased T-cell activation compared to activity of either antibody alone. 

Approval in March 2022 was based on the RELATIVITY-047 phase 2/3 global trial  which found a median progression-free survival (PFS) of 10.1 months among 355 patients randomly assigned to the combination therapy compared with 4.6 months among 359 patients who received nivolumab alone (HR, 0.75; P = .0055).[178]  

Ipilimumab (Yervoy) is a monoclonal antibody against CTLA-4, which inhibits T-cell inactivation, allowing expansion of melanoma-specific cytotoxic T cells. Ipilimumab, a CTLA-4 blocker, was the first drug to demonstrate an OS in stage IV melanoma and was FDA approved in 2011 for patients with unresectable stage III and IV melanoma.

In the pivotal phase III trial, ipilimumab (3 mg/kg q3wk for 4 treatments) was shown to enhance T-cell response in HLA-A2–positive patients and prolong OS in patients with metastatic melanoma compared with a glycoprotein 100 (gp 100) peptide vaccine (median OS, 10.1 vs 6.4 months, respectively; hazard ratio for death 0.66; P = .003). Durable responses were observed for over 2 years in 9 (60%) of 15 of ipilimumab responders, suggesting a durable response benefit that has been demonstrated to be independent of HLA status.[112] Results of a phase III trial comparing dacarbazine plus ipilimumab (administered at 10 mg/kg ) versus dacarbazine alone also demonstrated improved median OS in the ipilimumab-treated group (11.2 vs 9.1 months), with a consistent survival benefit noted at years 1, 2, and 3 of follow-up.[113]

As noted, the use of both low- and high-dose ipilimumab is tempered by potential severe immune-related adverse events, primarily enterocolitis and hypophysitis, which require prompt initiation of high-dose corticosteroids and/or other immune response modifiers, as well as hormone replacement for hypophysitis (including hypopituitarism and adrenal insufficiency) alteration. Dermatitis, pruritus, and potential vitiligo may also be seen with ipilimumab therapy, emphasizing the importance of dermatologic consultation for management of associated skin conditions.

Enhanced antitumor activity was also demonstrated with human monoclonal antibodies against the programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, or its ligand, PD-L1. Objective responses, durable tumor regression, and prolonged stabilization of disease were demonstrated in patients with a variety of advanced cancers, including non–small-cell lung cancer, renal cell cancer, and melanoma following treatment with the anti–PD-L1 antibody BMS-936559, with reduced toxicity in comparison to ipilimumab. Objective responses (complete or partial) were observed in 9 (17%) of 52 of melanoma patients, generating enthusiasm for these agents in patients with metastatic disease.[114, 115]

Accelerated FDA approval of the PD1 inhibitor pembrolizumab (Keytruda) was granted in 2014 for patients with advanced or unresectable melanoma following progression on prior therapies, including ipilimumab and BRAF inhibitors.[116] , and later approved as first-line therapy in 2015, based on demonstration of superior survival and lower toxicity compared with ipilimumab in the phase 3 KEYNOTE-006 trial.[117] Concurrent studies of the PD1 inhibitor nivolumab (Opdivo) showed similar durable tumor remission and long-term safety, with median OS of 16.8 months and 1- and 2-year survival rates of 62% and 43%, respectively, in patients with advanced, treatment-refractory melanoma.[118] The use of nivolumab in previously untreated BRAF wild-type melanoma patients showed significantly improved OS at 1 year compared with dacarbazine (72.9% vs 42.1%, respectively), with objective response rates of 40% versus 13.9%, respectively, resulting in FDA approval of nivolumab in March 2015.[119] Subsequent documented superior progression-free survival over ipilimumab in the CheckMate 067 trial resulted in similar FDA approval as a first-line agent for metastatic melanoma. Both anti-PD-1 agents are considered first-line monotherapy in patients with advanced (unresectable stage III and IV) melanoma and now for adjuvant therapy in resected, stage II melanoma, as noted above.[120] Known adverse effects include induction of immunobullous disease, especially pemphigoid, as well as eruptive keratoacanthomas similar to those seen with BRAF therapy.[121, 122, 123, 124] .

The combination of ipilimumab and PD1 inhibitors (has shown even greater efficacy for PFS and OS in patients with advanced melanoma and more rapid response rates (akin to targeted therapy) than single agent immune checkpoint inhibitors, but it is associated with increased toxicity.[125] In 2015, the FDA approved the combination regimen of nivolumab 1 mg/kg plus ipilimumab mg/kg for 4 doses q3 weeks followed by nivolumab 3 mg/kg q2 weeks in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma based on results from the Checkmate 067 trial.[126, 127]  Long-term follow-up (6.5 years) has shown a compelling benefit of dual immune checkpoint inhibition with ipilimumab and nivolumab, with median OS  of 72 months for the combination regimen compared with 36.9 months for nivolumab monotherapy and 19.9 months for ipilimumab monotherapy.[128] However, since increased immune-related adverse events occur on the combined regimen, appropriate patient selection, careful monitoring during treatment, and prompt initiation of appropriate therapy are warranted.

In October 2015, the FDA approved talimogene laherparepvec, commonly known as T-VEC (Imlygic), a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and produce the immune stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF).[129] It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery. It is administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound guidance.

Approval was based on results from the OPTiM study, a randomized, controlled trial conducted in adults with unresectable regionally or distantly metastatic melanoma.[130] The study enrolled 436 patients, of which 295 patients treated with talimogene laherparepvec were compared with 141 patients treated with GM-CSF. The primary endpoint was the durable response rate, defined as the rate of complete response plus partial response continuously lasting at least 6 months and beginning within the first 12 months. Secondary endpoints included OS and the overall response rate.

The durable response rate was significantly higher among patients who received talimogene laherparepvec compared with those given GM-CSF (16.3% vs 2.1%; odds ratio, 8.9; P< .001). Of the patients who experienced a durable response, 29.1% had a durable complete response and 70.8% had a durable partial response. The median time to response was 4.1 months (range, 1.2-16.7 months) in the arm receiving talimogene laherparepvec.

The overall response rate was also higher with talimogene laherparepvec (26.4% vs 5.7%; P< .001). In all, 32 (10.8%) patients receiving talimogene laherparepvec experienced a complete response, compared with just one (< 1%) patient receiving GM-CSF. The median time to treatment failure was 8.2 months with talimogene laherparepvec and 2.9 months with GM-CSF (hazard ratio, 0.42). Median OS was 23.3 months and 18.9 months, respectively (hazard ration, 0.79; P = .051), which just missed being statistically significant.

Additional immunotherapy and targeted therapy regimens are being actively investigated, including the combination of nivolumab and relatlimab, which inhibits lymphocyte-activation gene 3 (LAG-3)[131] . The combination of targeted therapy and immunotherapy (in BRAF-mutated melanoma) with vemurafenib/cobimetinib plus the PD-L1 inhibitor atezolizumab[132]  was FDA approved in 2020, although the triple regimen is associated with more toxicity compared with dual BRAF/MEK inhibition. For melanomas with a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, targeted therapy with larotrectinib[133]  or entrectinib[134] were FDA approved in 2018 and 2019, respectively, although NTRK fusions are uncommon in cutaneous melanoma (< 1%), including acral melanoma (2.5%), compared to the spitzoid melanoma subtype (21-29%).[135]

Surgery is the primary mode of therapy for localized cutaneous melanoma.

Surgical margins for primary melanoma

The narrowest efficacious margins for cutaneous melanoma have yet to be determined. Surgical margins of 5 mm are currently recommended for melanoma in situ, although wider (1 cm) margins may be needed to achieve clear histologic margins in certain subtypes (lentigo maligna and acral lentiginous) that are characterized by subclinical extension.[136] Margins of 1 cm are recommended for melanomas less than or equal to 1 mm in depth and are now being studied for thicker melanomas T2b-T4.[137] For melanoma in situ (LM and ALM subtypes) and thin (T1) on anatomically constrained sites (i.e., head and acral sites), tissue sparing may be critical, and surgical techniques that provide complete margin assessment via Mohs micrographic surgery or staged excision with permanent sections may be appropriate. However, Mohs surgery is not recommended in either the NCCN or AAD melanoma guidelines for surgical resection of invasive cutaneous melanoma when standard clinical margins can be obtained.

Randomized prospective studies showed that 2-cm margins are generally appropriate for tumors of intermediate thickness (1-4 mm Breslow depth), although 1-cm margins have been proven effective for tumors of 1- to 2-mm thickness.[138, 139] Margins of 2 cm are recommended for cutaneous melanomas greater than 4 mm in thickness (high-risk primaries) to prevent potential local recurrence in or around the scar site.

A 2004 prospective study of melanoma greater than or equal to 2 mm thickness (median depth 3 mm) from the United Kingdom suggested that narrower margins (1 cm) result in higher locoregional recurrence compared with wider margins (3 cm), although no difference was noted in melanoma-specific survival between the two groups.[140] However, this study was criticized for combining satellite, in-transit, and regional nodal recurrences as the primary endpoint and by excluding SLNB (which would have demonstrated existing occult regional nodal metastasis at the time of wide local excision). Likewise, because a 2-cm margin is as efficacious as a 4-cm margin for melanomas of 1-4 mm depth, a 3-cm margin has been deemed unlikely to prove more beneficial than a 2-cm margin.

A retrospective study of high-risk primary melanomas (>4 mm thickness, median depth 6 mm) showed that excisional margins greater than 2 cm have no effect on local recurrence, disease-free relapse, or OS rates; therefore, a 2-cm margin is likely appropriate in this subgroup.[141]

In a multicenter randomized controlled trial in 9 European countries from 1992 to 2004, 936 patients with clinical stage IIA–IIC cutaneous melanoma >2.0 mm were treated with 2- vs 4-cm resection margins. At a median overall follow-up of 19·6 years, 621 deaths were reported, 304 (49%) in the 2-cm group and 317 (51%) in the 4-cm group; 397 deaths were attributed to cutaneous melanoma, 192 (48%) in the 2-cm excision margin group and 205 (52%) in the 4-cm excision margin group (unadjusted HR 0·95, 95% CI 0·78–1·16, p=0·61). This large study with nearly 2 decades of follow-up support the use of a maximum of 2 cm surgical margins for thicker (T3-T4) melanoma.[142, 143]  As noted, a randomized trial is in progress to determine differences in disease-free survival using a 1 vs 2 cm for patients with primary cutaneous melanoma with Breslow thickness > 2.0 mm or 1.0-2.0 mm with ulceration (T2b-pT4b).

Mohs micrographic surgery has also been proposed for cutaneous melanoma and has the advantage of providing visualization of 100% of peripheral and deep margins microscopically (i.e., complete circumferential peripheral and deep margin assessment). While studies have shown no increased local recurrence for Mohs micrographic surgery compared with historical controls, much of the data stem from thinner tumors that have a lower risk of locoregional recurrence and distant metastasis.[144] A recent review of published data regarding Mohs micrographic surgery and staged excision for cutaneous melanoma demonstrated serious or critical bias in 1 or more ROBINS-I criteria, specifically noting that definitions of local recurrence rate were generally poorly or not defined and that longer follow-up, clear tumor classifications, and prospective, randomized study designs are necessary in future research.[145]

Dissection

Sentinel lymph node biopsy (SLNB)

Lymphatic mapping and sentinel node biopsy serve as the most effective and accurate means of staging the regional lymph node basin(s) in patients with melanoma greater than 1 mm in depth and in those less than or equal to 1 mm in depth with adverse features (eg, ulceration, lymphovascular invasion, high mitotic rate—particularly for tumors 0.8-1.0 mm in thickness).

SLNB for cutaneous melanoma was developed in the early 1990s to allow a selective approach to identifying individuals with occult regional nodal metastasis through localization of the first-draining, or sentinel, node. The success of the technique is based on the concept that cutaneous lymphatic flow is well-delineated in melanoma and that the histology of the sentinel node is characteristic of the entire lymph node basin (ie, a negative sentinel node obviates the need for further lymph node dissection). Both of these concepts were borne out in initial and subsequent studies of the staging technique.[146]

Preoperative radiographic mapping (lymphoscintigraphy) and vital blue dye injection around the primary melanoma or biopsy scar (at the time of wide local excision/reexcision) is performed to identify and remove the initial draining regional node(s).

The sentinel node is examined for the presence of micrometastasis using both routine histology and immunohistochemistry; if present, a therapeutic or completion lymph node dissection (CLND) has traditionally been performed, although recent data have shown no evidence of improved OS in patients who underwent CLND versus clinical observation following SLNB. A negative sentinel node biopsy result prevents the morbidity associated with an unnecessary lymphadenectomy.

Sentinel node status (positive or negative) is widely regarded as the most important prognostic factor for recurrence and the most powerful predictor of survival in melanoma patients. In a study of 612 patients with cutaneous melanoma (stage I/II), negative results from SLNB were associated with a nearly 60% increase in 3-year disease-free survival compared with positive SLNB results.[147]

Current AJCC melanoma staging and National Comprehensive Cancer Network clinical practice guidelines advocate pathologic staging of the regional lymph nodes for cutaneous melanoma of greater than 1 mm depth along with microstaging of the primary melanoma as the most complete means of staging.[69, 83]

SLNB provides the most reliable and accurate means of detecting occult regional nodal micrometastasis in clinically appropriate patients with primary melanomas and provides a more accurate determination of patient prognosis compared to clinical staging. However, it has not demonstrated an impact on overall survival in various RCTs.[148] The results of the Multicenter Selective Lymphadenectomy Trial (MSLT), the Florida Melanoma Trial, and the Sunbelt Melanoma Trial have not demonstrated that SLNB provides a therapeutic benefit in patients with cutaneous melanoma, although low rates of sentinel lymph node positivity in all studies limit their power to detect an overall survival difference.

The final analyses of the MSLT-1 was published in 2014.[149] This analysis of the subset of 1270 patients with intermediate-thickness melanoma (1.2-3.5 mm) demonstrated no overall (melanoma-specific) survival differences in the group that underwent SLNB at the time of primary excision of the melanoma versus the group that underwent wide local excision alone. However, immediate lymphadenectomy in the setting of a positive sentinel lymph node was associated with improved 10-year survival compared with delayed lymph node dissection in patients who developed macroscopic nodal metastasis following primary excision alone (62.1% vs 41.5%, respectively). The risk of death was reduced by nearly one half in this subset (hazard ratio, 0.56; 95% CI, 0.37-0.84; P = .0006) in the node-positive subset of patients who underwent immediate versus delayed lymph node dissection for regional nodal metastasis. The treatment-related difference persisted when patients with false-negative SLNB results were included in the final analysis (10-year melanoma-specific survival 56% vs 41.5%, respectively, hazard ratio, 0.67; 95% CI, 0.46-97; P = .04), However, OS rates did not differ in the subset of patients with thick melanoma (>3.5 mm).

The potential therapeutic benefit of early removal of micrometastasis in the regional nodal basin as well as the merits of CLND following a positive SLNB continue to be analyzed in various studies worldwide. Two prospective randomized trials showed that immediate CLND following a positive SLNB increases rate of regional disease control but does not impact melanoma specific survival.[38] to forego CLND in most cases of a positive SLNB and incorporate the use of nodal basin ultrasound surveillance as an alternative. However, these studies had few cases of head and neck melanomas, and there may be an advantage of improved nodal basin control for primary melanomas with high risk features and/or large tumor burden within the sentinel lymph node(s), Incorporation of newer molecular techniques, such as gene expression profiling, may aid in determining the therapeutic benefit and selection of the most appropriate patients for both SLNB and CLND. See the Medscape article The Role of Sentinel Node Biopsy in Skin Cancer for further information.

Dermatologist, as follows:

• For clinical/dermoscopic evaluation and surveillance of individuals at increased risk of developing melanoma based on mole phenotype, family history, sun sensitivity, and other factors
• For clinical assessment and biopsy of suspicious skin lesions to diagnose melanoma
• For surgical or topical treatment of cutaneous melanoma
• For long-term follow-up of patients with cutaneous melanoma to assess for disease recurrence
• For lifelong skin surveillance to detect possible new primary melanoma
• For early detection of melanoma, including use of total body photography in patients with atypical mole patterns

Surgical oncologist, as follows:

• For sentinel node biopsy, typically performed at the time of wide local excision and following preoperative lymphoscintigraphy
• For surgical and/or intralesional treatment of regional lymph node disease and soft tissue and/or in-transit recurrence (stage III disease)
• For palliative surgical treatment of visceral and CNS metastasis

Medical oncologist, as follows:

• To discuss adjuvant systemic therapy with approved agents or clinical trials: Patients with high-risk resected melanoma who are eligible for adjuvant therapy (usually stage III melanoma) should be referred to a medical oncologist or melanoma specialist soon after surgery in order to optimize the chances for appropriate adjuvant therapy or clinical trial entry. Patients with unresectable stage III or IV melanoma should be referred primarily to medical oncologists for initiation of first-line therapy with targeted agents, immune checkpoint inhibitors, or clinical trial consideration.
• To discuss and initiate treatment of metastatic melanoma (stage IV) with systemic therapy

Nuclear medicine specialist, as follows:

• For preoperative lymphoscintigraphy if SLNB is performed
• For PET-CT scan interpretation

Pathologist/dermatopathologist, as follows:

• For accurate histologic microstaging of primary melanoma and atypical melanocytic neoplasms that may mimick melanoma
• For proper processing and evaluation of nodal tissue from SLNB for micrometastasis
• For confirmation of the diagnosis of recurrent/metastatic disease

Radiation oncologist, as follows:

• For consideration of local adjuvant therapy for high-risk desmoplastic melanoma for improved local control, as detailed in current NCCN guidelines
• For consideration of adjuvant treatment of selected patients with resected bulky regional nodal metastasis per current NCCN guideline recommendations
• For palliative treatment of distant metastatic disease, particularly bony metastasis or brain involvement (whole brain radiotherapy or stereotactic radiosurgery)

Neurosurgeon, as follows:

• For evaluation and treatment of resectable brain metastasis

Patients should be monitored regularly after a diagnosis of cutaneous melanoma, particularly in the setting of thicker tumors, because most metastases occur in the first 1-3 years after treatment of the primary tumor. Annual skin examinations are recommended for life because an estimated 4-8% of patients with a history of melanoma develop new primary melanoma, generally within the first 3-5 years following diagnosis.[150] The risk of new primary melanoma increases in the setting of increased nevus count; multiple clinical atypical/dysplastic nevi and/or germline mutation in CDKN2A/p16; family history of melanoma; lighter skin/sun sensitivity; and male sex.[151] Individual patient risk factors should be taken into account in the determining the frequency of dermatologic surveillance.

The diagnosis of recurrent/metastatic disease depends on a routine evaluation schedule that varies according to the AJCC melanoma stage (based on tumor thickness, presence or absence of histologic ulceration, and regional lymph node status determined by SLNB), and the following additional factors:

• Mitotic rate in the primary tumor
• Results of the examination of the melanoma scar site – for local recurrence (persistent disease type with in situ component vs satellite (lymphatic) metastatic recurrence
• Results of the examination of regional and distant lymph node basins
• Mole pattern and examination findings from the entire cutaneous surface for new primaries

American Academy of Dermatology clinical practice guidelines

Guidelines have been published by the American Academy of Dermatology (last in 2019) regarding biopsy, pathology reporting, and management of primary cutaneous melanoma.[66]

Evidence strongly indicates that Breslow thickness, ulceration, and dermal mitotic rate are important predictors of patient outcome in primary cutaneous melanoma.

The recommended first-line treatment for any-thickness primary cutaneous melanoma, as well as for melanoma in situ, is surgical excision with histologically negative margins; tumor thickness should dictate the margins.

Surgical margins for invasive cutaneous melanoma, as measured clinically around the primary tumor, should be a minimum of 1 cm and a maximum of 2 cm, although narrower margins can be used to accommodate function and/or anatomic location. It is recommended that the excision be as deep as, but not inclusive of, the fascia.

It is not recommended that asymptomatic patients with newly diagnosed stage 0-II primary cutaneous melanoma undergo baseline radiologic imaging and laboratory studies. Routine testing of the primary tumor with available gene expression profiling tests is not recommended.

For cutaneous melanoma at baseline, radiologic imaging and laboratory studies should be conducted only to assess the specific signs or symptoms of synchronous metastasis (regional nodal or distant).

At baseline or when physical examination of lymph nodes is equivocal and requires surveillance, the use of lymph node ultrasonography is encouraged. Surveillance with such imaging is also encouraged in the following patients:

• Those who meet criteria for sentinel lymph node biopsy (SLNB) but do not undergo the procedure
• Patients in whom SLNB is not possible or is technically unsuccessful (eg, when lymphoscintigraphic dye migration has failed and a draining sentinel lymph node cannot be identified)
• Those with a positive SLNB who do not undergo complete lymph node dissection

Regular clinical follow-up represents the most important strategy for detecting cutaneous melanoma recurrence. The need for further radiologic or laboratory studies to detect local, regional, or distant metastatic disease should be determined via history (review of systems) and physical examination findings.

Patients should be taught self-examination of the skin and lymph nodes in order to detect recurrent disease or new primary cutaneous melanoma.

For the first 3 months of BRAF inhibitor monotherapy, patients with numerous squamoproliferative neoplasms should undergo dermatologic evaluation every 2-4 weeks, although less skin toxicity is associated with the standard treatment, combination BRAF/MEK inhibition.

Patients being treated with immune checkpoint inhibitors should undergo dermatologic evaluation within the first month of therapy, with such assessment being continued as needed to manage dermatologic adverse effects, which can have delayed onset and develop or persist off therapy.

National Comprehensive Cancer Network clinical practice guidelines

Guidelines on cutaneous melanoma management and systemic therapy for metastatic or unresectable cutaneous melanoma and recommendations for adjuvant systemic therapies were revised in December 2021 (v1.2022) by the National Comprehensive Cancer Network (NCCN). The NCCN clinical practice guidelines are continually updated based on new evidence and FDA approval for therapeutics.[38]

Systemic therapy for metastatic or unresectable disease

Recommended first-line therapy (metastatic or unresectable disease):

• Anti–programmed cell death protein 1 (PD1) monotherapy: pembrolizumab, nivolumab
• Combination nivolumab/ipilimumab
• Combination targeted therapy for BRAF V600–activating mutation: dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib
• Other recommended regimens: pembrolizumab/low-dose ipilimumab
• Combination targeted therapy and immunotherapy if BRAF V600-activiting mutation present: vemurafenib/cobimetinib + atezolizumab

Recommended second-line or subsequent therapy

• Preferred regimens: Anti-PD1 monotherapy (pembrolizumab, nivolumab); nivolumab/ipilimumab; pembrolizumab/low-dose ipiliumab for tumors that progressed following prior anti-PD1 therapy); combination targeted therapy for BRAF V600–activating mutation (dabrafenib/trametinib, vemurafenib/cobimetinib, encorafenib/binimetinib)
• Other regimens: ipilimumab; high-dose interleukin 2 (IL-2)
• Useful in certain circumstances: imatinib for tumors with KIT-activating mutations; larotrectinib or entrectinib for NTRK gene fusion-positive tumors; binimetinib for NRAS-mutated tumors that progressed following prior immune checkpoint inhibitor therapy; cytotoxic agents (mainly for palliative therapy); ipilimumab/intralesional talimogene laherparepvec (T-VEC); pembrolizumab/levatinib

Recommended adjuvant systemic therapies

For stage III (sentinel lymph node positive) disease:

• Primary treatment: Wide local excision of primary lesion with positive sentinel lymph node biopsy, followed by nodal basin ultrasound (generally preferred) or complete lymph node dissection
• Recommended adjuvant options: systemic therapy based on risk of recurrence: nivolumab, pembrolizumab, dabrafenib/trametinib for BRAF-activating mutation, or observation

For stage III (clinically positive nodes [no in-transit or satellite metastases]) disease, including recurrence:

• Primary treatment: Wide local excision of primary lesion and therapeutic lymph node dissection or consideration of neoadjuvant therapy, preferably in the context of a clinical trial
• Recommended adjuvant options: Preferred: nivolumab, pembrolizumab, dabrafenib/trametinib for BRAF-activating mutation and/or locoregional therapy with radiation therapy to the nodal basin in selected high risk patients, or observation

For stage III (clinical or microscopic satellite/in-transit) disease, including recurrence:

• Primary treatment for limited resectable disease: complete surgical excision to clear margins, talimogene laherparepvec (T-VEC)/intralesional therapy, or systemic therapy
• Recommended adjuvant options: nivolumab, pembrolizumab, dabrafenib/trametinib BRAF-activating mutation, observation
• Primary treatment of unresectable disease: Preferred: systemic therapy with above agents
• Local therapy options: intralesional injection (T-VEC, IL-2), topical imiquimod for superficial dermal lesions, radiation therapy, palliation of symptomatic disease (limited excision, ablation), regional therapy with isolated limb infusion/perfusion with melphalan

For stage IV oligometastatic disease:

• Primary treatment: metastasis-directed therapy with resection or stereotactic ablative therapy or systemic therapy
• Recommended options: Preferred: nivolumab, pembrolizumab; Other recommended regimens: nivolumab/ipilimumab, combination BRAF/MEK inhibitors for BRAF-activating mutation; Useful in certain circumstances: ipilimumab if prior exposure to anti-PD1 agents

For stage IV widely disseminated disease:

• Without brain metastasis: Preferred: systemic therapy; For extracranial lesions: intralesional T-VEC, consider palliative resection and/or radiation therapy for symptomatic extracranial disease, best supportive care; multidisciplinary consultation for brain metastasis, with above options

Ipilimumab, a CTLA-4 blocker, was FDA approved in 2015 for resected stage III melanoma, although the risk of immune-related adverse events tempered enthusiasm for the high-dose regimen in the adjuvant setting.[152, 113]  The high-dose regimen is not recommended in current NCCN melanoma clinical practice guidelines.

Talimogene laherparepvec (Imlygic) was approved in 2015. It is a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and produce the immune-stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Considering new developments in adjuvant immunotherapy (checkpoint inhibitors) and and targeted agents (BRAF/MEK inhibitors), adjuvant IFNα is no longer used in the adjuvant setting. Immune checkpoint inhibition with the PD-1 inhibitor pembrolizumab was FDA approved in December 2021 for adjuvant therapy in resected stage IIB and IIC patients, following pathologic staging with SLNB (as in the KEYNOTE-716 trial).

Checkpoint inhibitors such as nivolumab and pembrolizumab are PD-1 inhibitors and are often used a monotherapy for patients with metastatic/unresectable stage III/IV disease and for those who lack the BRAF V600 mutation and are not eligible for targeted therapy with BRAF/MEK inhibitors. Ipilimumab is a different checkpoint inhibitor, a CTLA-4 blocker, and was approved by the FDA in 2015 for resected stage III melanoma, although the risk of immune-related adverse events have tempered enthusiasm for the high-dose regimen in the adjuvant setting.[152, 114] . Ipilimumab may be used as a second line agent for individuals who have progression on PD-1 inhibition, but is more commonly used with the PD-1 inhibitor nivolumab for dual checkpoint blockade in patients with unresectable stage III/IV melanoma.

Talimogene laherparepvec (Imlygic) was approved in 2015. It is a genetically modified, live-attenuated herpes simplexvirus programmed to replicate within tumors and produce the immune-stimulatory protein granulocyte macrophage colony-stimulating factor (GM-CSF). It is indicated for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.

Targeted therapy with BRAF/MEK inhibitors is used in patients with advanced melanoma and have a BRAF V600 mutation; however, immunotherapy with immune checkpoint blockade is the preferred initial option in terms of efficacy and durable responses. Dabrafenib/trametinib is an adjuvant treatment option for patients with resected stage III or recurrent disease and who have a BRAF V600-activating mutation.

Class Summary

Immunomodulatory agents enhance host immunity for cancer surveillance and eradication.

Interferon alfa-2b (Intron A)

Interferon alfa-2b is a protein product manufactured by recombinant DNA technology. It is produced naturally by cells in the body to combat infections and tumors. Its mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles.

Interferon alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists. However, its use has been supplanted by superior adjuvant therapy options (immune checkpoint inhibitors and BRAF/MEK inhibitors).

Class Summary

Monoclonal antibodies may be considered for unresectable or metastatic melanoma. Examples include inhibitors of programmed death-1 (PD1) protein, a T-cell co-inhibitory receptor, and a lymphocyte activation gene-3 (LAG-3) blocking antibody. 

Ipilimumab (Yervoy)

Ipilimumab is a targeted T-cell antibody. It is a recombinant, human cytotoxic T-lymphocyte antigen 4 (CTLA-4)–blocking antibody indicated for unresectable or metastatic melanoma. CTLA-4 is a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The proposed mechanism of action is indirect, possibly through T-cell–mediated antitumor immune responses. Ipilimumab is an IgG1 kappa immunoglobulin with an approximate molecular weight of 148 kd. It is produced in mammalian (Chinese hamster ovary) cell culture.

It is indicated for the treatment of unresectable or metastatic melanoma. Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also indicated in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab.

Pembrolizumab (Keytruda)

Pembrolizumab binds PD-1 ligands to PD-1 receptor found on T-cells, which inhibits T-cell proliferation and cytokine production. It is indicated as monotherapy in the adjuvant setting for unresectable or metastatic melanoma. It is also indicated for adjuvant treatment of Stage IIB, IIC, or III melanoma following complete resection in adult and pediatric patients aged 12 years and older.

Nivolumab (Opdivo)

Nivolumab is indicated for as monotherapy in the adjuvant setting for resected stage III and stage IV melanoma or for treatment of unresectable or metastatic melanoma. Dual checkpoint blockade is FDA-approved for the combination of ipilimumab and nivolumab.

Nivolumab/relatlimab (Opdualag)

Fixed dose combination indicated for treatment of adults and pediatric patients aged 12 years and older with unresectable or metastatic melanoma. Nivolumab is a programmed death receptor-1 (PD-1) blocking antibody and relatlimab is a lymphocyte activation gene-3 (LAG-3) blocking antibody. The combination results in increased T-cell activation compared to activity of either antibody alone. 

Class Summary

Some mutations in the BRAF gene including V600E result in constitutively activated BRAF proteins, which can cause cell proliferation in the absence of growth factors that would normally be required for proliferation. Mitogen-activated extracellular signal regulated kinase (MEK) inhibitors are used in combination with BRAF inhibitors or in single-agent therapy.

Vemurafenib (Zelboraf)

Vemurafenib is a BRAF inhibitor indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by an FDA-approved test. It is not recommended for use with wild-type BRAF melanoma. BRAF inhibitors are not generally used as monotherapy, but rather in combination with MEK inhibitors. The approved regimens are vemurafenib/cobimetinib, dabrafenib/trametinib, and encorafenib/cobemetinib.

Trametinib (Mekinist)

Trametinib is a MEK inhibitor used in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Dabrafenib (Taflinar)

Dabrafenib is a BRAF protein kinase inhibitor used in combination with trametinib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations. The combination of dabrafenib/trametinib is FDA approved in the adjuvant setting for resected stage III melanoma.

Class Summary

These agents are used adjunctively following the resection of lesions.

Talimogene laherparepvec (Imlygic)

Talimogene laherparepvec is an oncolytic herpes simplex virus. It  is a genetically modified, live-attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. It causes lysis of tumors, followed by the release of tumor-derived antigens, which together with virally derived GM-CSF may promote an antitumor immune response. It is a solution for intralesional injection that may be considered for local treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrence after initial surgery.