Malignant Melanoma

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Practice Essentials

Malignant melanoma (see the image below) is a neoplasm of melanocytes or of the cells that develop from melanocytes. Although it was once considered uncommon, the annual incidence has increased dramatically over the past few decades. Surgery is the definitive treatment for early-stage melanoma, with medical management generally reserved for adjuvant treatment of high-risk locally advanced melanoma and metastatic disease.



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Malignant melanoma. Image courtesy of Hon Pak, MD.

Signs and symptoms

The history should address the following:

Physical examination includes the following:

Skin examination involves assessing the number of nevi present and distinguishing between typical and atypical lesions. (The images below depict examples of melanomas.) Early melanomas may be differentiated from benign nevi by the ABCDE criteria, as follows:

If a patient is diagnosed with a melanoma, examine all lymph node groups.

See Presentation for more detail.

Diagnosis

The following studies may be helpful in some cases:

The following imaging modalities may be considered in patients with deep melanomas, or when indicated by signs or symptoms:

Procedures to be considered in the workup include the following:

Characteristic histologic findings include the following:

See Workup for more detail.

Management

Surgery (eg, wide local excision with SLNB and regional lymph node dissection if indicated) is the definitive treatment for early-stage melanoma. Preoperative (neoadjuvant) therapy may be appropriate in select cases; adjuvant therapy is used in patients with advanced, metastatic, unresectable, or recurrent melanoma.[1]

Adjuvant therapy for resectable stage III melanoma includes the following agents[2] :

For unresectable stage III, stage IV, and recurrent melanoma, adjuvant therapy may include the following[2] :

Immunotherapy:

Cellular therapies: 

Signal-transduction inhibitors:

Chemotherapy agents:

The following procedures may be used to treat brain metastases:

See Treatment and Medication for more detail.

This article focuses on cutaneous melanoma. For discussion of melanoma arising at other sites, see Oral Malignant Melanoma, Head and Neck Mucosal Melanomas, and Choroidal Melanoma.

Pathophysiology

Melanomas have two growth phases: radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. This is usually indicated by a dermal nest larger than the largest junctional nest, a dermal nest with mitosis, or a dermal nest within reticular dermis. 

Clinically, lesions are classified according to their depth, as follows:

Histologic types of melanoma

There are five different forms, or histologic types, of melanoma, and specific gene mutations determine behavior and response to treatment::

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type. Many SSMs arise from a pigmented dysplastic nevus, often one that has long been stable. Typical changes include ulceration, enlargement, or color changes. An SSM may be found on any body surface, especially the head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas

Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black. The radial growth phase may not be evident in NMs; however, if this phase is evident, it is short-lived, because the tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Approximately 5% of all NMs are amelanotic melanomas.

Lentigo maligna melanomas

Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion. (See the image of lentigo maligna melanoma below.)



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Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo m....

Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal frequency in Blacks and Whites. They occur on the palms, soles, and subungual areas. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Like NM, ALM is extremely aggressive, with rapid progression from the radial to vertical growth phase.

Mucosal lentiginous melanomas

Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines the respiratory, gastrointestinal, and genitourinary tracts. MLMs are rare, accounting for only for 0.8–1.8% of all melanomas in the United States; in Chinese populations, the relative incidence has been reported as high as 23%, likely because of the lower prevalence of cutaneous melanoma in Asian populations. The head and neck  — principally the nasal cavity and paranasal sinuses — is the most common site for MLMs, accounting for approximately half of all cases, but MLMs may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus.[8, 9]

Noncutaneous melanomas commonly are diagnosed in patients of advanced age. MLMs appear to have a more aggressive course than cutaneous melanomas, although this may be in part because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas. In addition, the genetic alterations and oncogenic drivers in mucosal melanomas differ from those in cutaneous melanomas. The BRAF and NRAS mutations that are common drivers in cutaneous melanoma are less often found in mucosal melanoma, whereas SF3B1 and KIT mutations are more often found.[8]

Sites other than the skin

The majority of melanomas are in the skin, but other sites include the eyes, mucosa, gastrointestinal tract, genitourinary tract, and leptomeninges. Metastatic melanoma with an unknown primary site may be found in lymph nodes only.

Etiology

Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis.

Melanomas may develop in or near a previously existing precursor lesion or in healthy-appearing skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of a precursor lesion. Many of these melanomas are induced by solar irradiation, either chronic or intermittent. Melanoma also may occur in unexposed areas of the skin, including the palms, soles, and perineum.

Certain lesions are considered to be precursor lesions of melanoma. These include the following nevi:

Genetics

Many genes are implicated in the development of melanoma, including TERT, CDKN2A (p16), CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras. CDKN2A (p16) appears to be especially important in both sporadic and hereditary melanomas. This tumor suppressor gene is located on band 9p21, and its mutation plays a role in various cancers.

Ultraviolet radiation

Exposure to ultraviolet (UV) radiation is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

UV radiation appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA.

Interestingly, melanoma does not have a direct relationship with the amount of sun exposure, because it is more common in white-collar workers than in those who work outdoors.

Sunburn

Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure–induced melanoma on the trunk and legs, whereas lentigo maligna is associated with chronic sun exposure. This sun-associated risk factor is different from that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

Parkinson disease

Retrospective case-control analyses from the Mayo Clinic concluded that patients with Parkinson disease (PD) have about a 4-fold increased risk of having preexisting melanoma, and patients with melanoma have a similar risk of developing PD. The results support studies by other researchers showing an increased risk for melanoma in patients with PD.[10]

In the Mayo Clinic study, Dalvin et al found 32 cases of melanoma in 974 patients with PD (with 26 of the 32 diagnosed before the onset of PD), versus 63 cases in the control group of 2922 persons without PD; thus, the likelihood of having a history of melanoma was 3.8-fold higher in patients with PD compared with controls (95% confidence interval [CI], 2.1 - 6.8; P< 0.001).

In a second analysis, Dalvin et al found 43 cases of PD in 1544 patients diagnosed with melanoma, compared with 14 cases of PD in a control group of 1544 persons without melanoma. This translated to a 4.2-fold increased risk for PD after being diagnosed with melanoma, compared with controls (95% CI, 2.0 - 8.8; P< 0.001).[10]

Additional risk factors

Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses are etiologic agents that also have been implicated in the development of melanoma.

Greatly elevated risk factors for cutaneous melanoma include the following:

Moderately elevated risk factors for cutaneous melanoma include the following:

Slightly elevated risk factors for cutaneous melanoma include the following:

Epidemiology

Occurrence in the United States

The American Cancer Society estimates that 100,640 cases of invasive cutaneous melanoma will be diagnosed in the United States in 2024 (59,170 in men and 41,470 in women), along with 99,700 cases of in situ melanoma. Since the early 2000s, incidence rates of melanoma in persons younger than age 50 years have stabilized in women and declined by about 1% per year in men; in adults age 50 and older, rates increased in women by about 3% per year but stabilized in men.[11]

Although melanoma accounts for only about 1% of skin cancers, it is responsible for the vast majority of deaths from skin cancers. The American Cancer Society estimates that 8290 people in the US (5430 men and 2860 women) will die of melanoma in 2024.[11]

However, a review of Surveillance, Epidemiology, and End Results (SEER) data from 1975 to 2014 identified discrepancies in incidence and mortality trends that suggest considerable overdiagnosis of melanoma in White persons. During that period, in Blacks, the incidence of melanoma increased by almost 25%, while mortality due to melanoma decreased by approximately 25%. In Whites, melanoma incidence increased approximately 4-fold in women and 6-fold in men, while mortality was stable in women and increased by less than 50% in men. These researchers calculate that had medical care not improved, estimated mortality would have increased 60% in White women and more than doubled in White men. They estimate that 59% of White women and 60% of White men with melanoma were overdiagnosed in 2014.[12]

International statistics

Worldwide, the incidence of malignant melanoma has increased rapidly over the past 50 years, with the highest incidence in fair-skinned populations and in geographic areas closest to the equator. Australia and New Zealand have the highest incidence of melanoma in the world, at an age-standardized rate of 32.5 cases per 100,000 population.[13]

Racial demographics

Melanoma is more common in Whites than in Blacks and Asians. The rate of melanoma in Blacks is estimated to be one twentieth that of Whites. White people with dark skin also have a much lower risk of developing melanoma than do those with light skin. The typical patient with melanoma has fair skin and a tendency to sunburn rather than tan. White people with blond or red hair and profuse freckling appear to be most prone to melanomas. In Hawaii and the southwestern United States, Whites have the highest incidence, approximately 20-30 cases per 100,000 population per year.

Sex- and age-related demographics

Overall, melanoma is the fifth most common malignancy in the US population, accounting for 6% of all new cancer cases in men and 4% of all new cases in women. However, the relative incidence of melanoma in men and women varies by age: in people younger than 50 years of age, incidence rates are higher in women than in men, but thereafter rates are much higher in men. Those differences presumably reflect historical differences in occupational and recreational exposure to UV radiation, as well as higher use of indoor tanning by young women.[11] Women tend to have lesions that are nonulcerated and thinner than those in men.

Melanoma may occur at any age, although children younger than age 10 years rarely develop a de novo melanoma. The median age at diagnosis is 66 years, and 80% of patients are 45 to 84 years old.[14]  As a percentage of cancers, the incidence rates of melanoma in US adolescents and young adults from 1973-2015 were as follows[15] :

Prognosis

Malignant melanomas usually present at two extremes: at one end of the spectrum are patients with small skin lesions that are easily curable by surgical resection, and at the other are patients with widely metastatic disease, in whom the therapeutic options are limited and the prognosis is dismal, with a median survival of only 6-9 months. For this reason, physicians must be aware of the clinical characteristics of melanoma to make an early diagnosis.

Prognosis also is related to the type of melanoma. Superficial spreading and nodular types of melanoma are the 2 most common fatal melanomas, based on a review of data from the original 9 registries of the Surveillance, Epidemiology, and End Results (SEER) program from 1978-2007.[16] This confirms prior studies.

The most important prognostic factors include the following[2] :

In general, positive prognostic factors include the following[2] :

In a review of 3,872 cases of lymph node–positive melanoma, the proportion of examined lymph nodes found to be positive (the lymph node ratio) independently predicted disease-specific survival. These researchers concluded that the lymph node ratio consistently improved the prognostic accuracy of the TNM system.[17]

Prognosis is also worse in patients with immune compromise (eg, organ transplant recipients, persons with HIV infection).[18] A study of patients who developed melanoma after solid organ transplantation found that their overall survival was worse than the rate reported in a national sample of patients with melanoma. In transplant recipients with thicker melanomas, disease-specific survival was significantly poorer than in patients without a prior history of transplantation.[19]

In patients with mucosal melanoma, a multivariable analysis determined that anatomic primary site was an independent predictor of overall survival and disease-specific survival. Tumors in the nasal cavity and oral cavity were associated with survival superior compared with tumors in the nasopharynx and paranasal sinuses. Age older than 70 years, tumor size, nodal status, and distant metastasis status were also predictive of outcome.[20]

Stage and prognosis

Prognosis depends on the disease stage at diagnosis. According to SEER data from 2013-2019, 5-year relative survival rates are as follows[18] :

For stage IV melanoma, prognosis varies according to the site of metastasis. Sandru et al reported that median overall survival by metastasis site was as follows[21] :

Also see Malignant Melanoma Staging.

 

History

Family history

Carefully obtain any family history of melanoma or skin cancer. Also, a family history of irregular, prominent moles is important. Approximately 10% of all patients with melanoma have a family history of melanoma. These patients typically develop melanoma at an earlier age and tend to have multiple dysplastic nevi. These patients also are more likely to have multiple primaries.

Presence of a familial melanoma syndrome should be considered in patients with a family history of pancreatic cancer or astrocytoma. Mutations in the CDKN2A tumor suppressor gene (also known as p16) are the most common genetic abnormalities found in these families.

Patient history

Any previous history of melanoma must be elicited from patients, because those patients are at increased risk of developing a second melanoma. Patients have reported as many as eight or more primary melanomas. Multiple primaries especially are prevalent in patients with multiple dysplastic nevi. The term familial atypical mole or melanoma (FAMM) syndrome is used to describe this hereditary tendency to develop multiple dysplastic nevi and melanomas.

Sun exposure

Question the patient extensively about previous sun exposure, including severe sunburns in childhood. The capacity to tan is also important, because individuals who tan easily are less likely to develop a melanoma than those who burn easily.

Moles

Question the patient about any changes noted in moles. Any history of change in size, color, or symmetry, as well as knowledge of bleeding or ulceration of the lesion must be obtained. Also elicit any history or family history of multiple nevus syndrome.

Physical Examination

Total body examination

A total-body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The skin examination should be performed on initial evaluation of the patient and during all subsequent visits. A study from a general dermatology practice found that most melanomas diagnosed during a 3-year period were not the presenting complaint but were discovered only because a dermatologist performed a total-body skin examination; moreover, these incidentally discovered melanomas were more likely to be thinner or in-situ lesions, and thus more amenable to cure.[22]

Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

Serial photography and new techniques, such as epiluminescence microscopy and computerized image analysis, are useful adjuncts. Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied. Computerized image analysis stores images of the lesions and makes them available for comparison over time.

Skin examination

During a skin examination, assess the total number of nevi present on the patient's skin. Attempt to differentiate between typical and atypical lesions. (The images below depict examples of melanomas.) The ABCDE criteria for differentiating early melanomas from benign nevi include the following:



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Malignant melanoma. Image courtesy of Hon Pak, MD.



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Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo m....

Lymph node examination

If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate through the lymphatics, leading to the involvement of regional lymph nodes; and hematogenously, leading to the involvement of any node basin in the body.

Mucosal melanoma

Although mucosal melanomas can occur on any mucosal surface, approximately half arise in the head and neck — mainly in the nasal cavity and paranasal sinuses, followed by the oral cavity, and rarely in the nasopharynx, oropharynx, hypopharynx, and larynx. Head and neck mucosal melanomas are typically asymptomatic in their early stages. Typical presentations include the following[9] :

Approach Considerations

The diagnosis of melanoma is confirmed by excisional biopsy. Sentinel lymph node biopsy or gene profile assay may be appropriate as prognostic studies in selected patients, but there is little evidence that they affect longevity.

In early-stage disease, laboratory and imaging studies are rarely indicated. In all stages, they are generally appropriate when prompted by signs or symptoms. Routine testing can lead to frequent false-positive results and a cascade of unnecessary tests.

Preoperative imaging studies have significant costs and offer minimal benefit in most patients with melanoma.[23] One meta-analysis of diagnostic tests used in staging melanoma has shown that ultrasonography is the best imaging study to diagnose lymph node involvement and that positron emission tomography computed tomography scanning (PET/CT) is the best imaging study to look for other sites of metastasis.[24]  In general, these studies are appropriate in high-risk patients or when localizing signs or symptoms are present.

Biopsy of a Suggestive Lesion

A complete excisional biopsy is preferred when possible, and for many lesions on the trunk this takes the form of a saucerized shave removal. The sample should have a 1-3 mm margin of healthy skin when possible, but partial sampling may be appropriate for larger lesions.

If the suggestive lesion is large or situated in a cosmetically sensitive area, a tangential, incisional, or punch biopsy may be appropriate, depending on the thickness of the lesion. Care should be taken to sample every morphology within the lesion, as skip areas and collision with other lesions is common in lentigo maligna.

The National Comprehensive Cancer Network acknowledges that superficial tangential biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness in thicker lesions, but considers shave biopsy acceptable in some lesions, and advises that a broad shave biopsy may be optimal for histologic assessment of melanoma in situ, lentigo maligna type (ie, melanoma on skin with high cumulative sun damage).[1] In cases where a tangential biopsy doesn’t allow for assessment of tumor depth, a complete excisional biopsy of the lesion should be performed, if possible, to determine the depth and extent of the lesion.

Surgical Excision or Reexcision After Biopsy

Because failure to perform a reexcision after biopsy of a melanoma is associated with a local recurrence rate of as high as 40%, a reexcision must usually be performed. Recommendations are evolving, but a vital structure should never be sacrificed for an arbitrary margin.

Current recommendations for surgical margins of excision are as follows[1] :

A study by Gillgren et al determined that a 2-cm excision provided a safe and reliable resection margin to treat lesions thicker than 2 mm.[25]

Histologic Findings

Although no single histologic feature is pathognomonic for melanoma, many characteristic features exist. Cytologic atypia virtually always is noted, with enlarged cells containing large, pleomorphic, hyperchromic nuclei with prominent nucleoli. Numerous mitotic figures often are noted.

Immunohistochemical stains usually are not necessary for diagnosis; they may be necessary in cases with indeterminate findings on routine histology. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanocytes and the latter shows a gradient in most benign nevi other than blue nevi. S-100 and SOX-10 are highly sensitive, although not specific, for melanocytes. They are particularly helpful in poorly differentiated or spindled tumors. 

PRAME (preferentially expressed antigen in melanoma) can stain the junctional component of benign nevi but dermal staining is suggestive of melanoma. It is not completely specific and stains other tumors, including testicular tumors and cellular neurothekeoma. It is particularly helpful in distinguishing preexisting nevus remnants from melanoma.[26, 27, 28, 29]  PRAME is preferentially expressed in melanoma, but suffers from false positives and false negatives, as with any other assay.

Mart-1/MelanA as well as MITF are sometimes used to establish the pattern of melanocytes, but all 3 may stain pseudonests in lichenoid tissue reactions. S100 is often poorly expressed in the nail matrix; HMB-45 and Mart-1 may be superior in that location. Next-generation gene sequencing and microarray genomic hybridization are becoming commonplace for the diagnosis of unique types of nevi and difficult melanocytic lesions.  Fluorescent in situ hybridization (FISH) assays also have evolving applications and molecular predictors of biologic response to targeted immunotherapy are in common use, with BRAF testing being the most frequent.[30, 31, 32, 33]

Elective Lymph Node Dissection

Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a lymph node biopsy. For years, patients without clinically enlarged nodes underwent lymph node dissection (LND). However, studies show that in patients with melanomas that are 1-4 mm thick, LND may not yield a significant survival advantage.

The only patients who seem to benefit from LND are those with lesions 1.1–2 mm thick and who are younger than 60 years. Patients with lesions greater than 4 mm in thickness are widely considered not to benefit from removal of clinically negative nodes.

Sentinel Lymph Node Biopsy

Lymphatics from any given region on the skin drain to a single lymph node. This node is called the sentinel lymph node and almost always is the first site of nodal involvement when melanoma spreads to regional nodes.

To determine which node is the sentinel node, the following two techniques, often in combination, are used. The combination of the two techniques allows detection of the sentinel node in as many as 98% of cases.

The first technique involves injecting a blue dye at the site of the primary melanoma and, through a small incision over the nodal basin, determining the location of the sentinel node. The second technique involves a radiolabeled solution injected into the site of the primary and the use of a hand-held gamma detector to determine the location of the sentinel node. The node is then removed for pathologic evaluation. Removal of the node should precede wide excision of the primary.[2]

Sentinel lymph node biopsy (SLNB) is now known to offer important prognostic, diagnostic, and therapeutic information.[34]

Guidelines from the National Comprehensive Cancer Network (NCCN) recommend discussing and offering SLNB to patients with stage IB or stage II melanoma that is 0.76-1 mm thick with ulceration or with a mitotic rate ≥1/mm2, or > 1 mm thick with any characteristic adverse features. The NCCN recommends discussing and considering SLNB in patients with stage IA melanoma that is 0.76-1 mm thick, with no ulceration and a mitotic rate of 0/mm3.[1] SLNB may be offered either as standard care or in the context of a clinical trial.

The NCCN does not recommend SLNB for patients whose melanoma is 0.75 mm or less in thickness. The NCCN advises that SLNB may be considered if conventional risk factors such as ulceration, high mitotic rate, or lymphovascular invasion are present, but notes that those are very uncommonly found with melanomas that thin.[1]

Joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) recommend SLNB for patients with intermediate-thickness melanomas (Breslow thickness 1–4 mm) of any anatomic site. There is less evidence for patients with thick melanomas (T4; Breslow thickness >4 mm), but sentinel lymph node biopsy is recommended for staging and facilitating regional disease control. Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking, but it may be an option in selected patients with high-risk features in whom the benefits of staging outweigh the risks of the procedure.

Cadili et al reported that the likelihood of non–sentinel lymph node metastasis can be predicted on the basis of total metastasis within the sentinel lymph node. Their data showed that patients with ≥5 mm of metastasis have a 30% risk of metastasis. In contrast, those with less than 2 mm of total sentinel lymph node metastasis are unlikely (< 3.67% likelihood) to harbor metastasis in non-sentinel nodes, and those patients may not benefit from additional nodal dissection.[35]

Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.

Complete Chemistry Panel

The chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase level may signal metastasis to the bone or liver, while elevated levels on liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastasis to the liver.

Total protein and albumin provide information concerning the overall health and nutritional status of the patient and may afford prognostic information.

Many chemotherapy regimens may be toxic to the kidneys; therefore, a creatinine level is necessary prior to initiation of any treatment.

Lactate Dehydrogenase Assay

The lactate dehydrogenase (LDH) level is elevated in many conditions, including many malignancies. Although LDH elevation is not specific for melanoma, it may be useful in the follow-up care of some patients with melanoma. A markedly elevated LDH at diagnosis or at a follow-up visit may indicate distant metastases, especially in the lung and liver.

Although the specificity and sensitivity of this test are low, multiple studies show an elevated LDH level to be an independent predictive factor for poor prognosis. LDH level is currently considered part of the staging system for melanoma.

Chest Radiography

To date, no studies support obtaining a routine radiograph in patients with melanoma. However, a normal chest radiograph finding at diagnosis provides a baseline for future comparison.

Patients with stage III disease, in-transit disease, or local recurrence should have a chest radiograph or computed tomography (CT) scan of the chest, because the lungs often are the first site of metastatic disease.

Magnetic Resonance Imaging

MRI of the brain should be obtained during the workup of a patient with known distant metastases to detect additional asymptomatic metastatic disease. This is especially true for patients being considered for high-dose interleukin-2 treatment. MRI of the brain in patients without known metastatic disease should be done only in those who have neurologic symptoms. 

Computed Tomography

A chest CT scan should be included in the staging workup of a patient with stage IV disease (ie, the patient with known distant metastases) to detect asymptomatic metastatic lesions. In patients with stage I, II, or III disease, a chest CT scan should be performed only if clinically indicated.

A CT scan of the abdomen often is obtained when evaluating a patient with stage III, locally recurrent, or in transit disease. Although the yield is low, a negative CT scan provides a baseline study for future comparison.

CT scan of the pelvis is indicated only if a patient has local regional recurrence below the waist, is symptomatic, or has known metastatic disease with a history of primary tumors below the waist.

Positron Emission Tomography

PET/CT is currently the most sensitive tool for the diagnosis of metastatic disease. PET scans are not indicated in early-stage disease (stage I or II), but a PET scan may aid in staging patients with known node involvement or in-transit or satellite lesions. Many studies report that PET scans have greater sensitivity than conventional radiographic studies for the detection of metastatic disease.

One meta-analysis found PET/CT scanning to be the best imaging study for finding other sites of metastasis.[24] In particular, fluorodeoxyglucose (FDG) PET/CT scans are a valuable tool for detecting additional metastasis as part of the preoperative evaluation of patients with advanced and metastatic melanoma.[36] Finally, PET scans often are useful in evaluating the response of metastatic disease to therapy.

Staging

The American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging systems for cutaneous melanoma are provided below.[37]  The TNM system has incorporated the older Breslow classification of melanoma thickness, whose four classes of lesion depth correspond with levels T1-4. Clark levels, another older classification of melanoma, are now largely used for historical reference.

T classification (thickness) is as follows:

N classification (regional lymph node and/or lymphatic metastasis) is as follows:

Note that micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

M classification is as follows:

Cases (beyond M0)  in which the lactate dehydrogenase (LDH) level is known are given the suffix (0), for normal LDH level, or (1), for elevated LDH level.

AJCC prognostic staging is as follows:

Also see Malignant Melanoma Staging.

Approach Considerations

Surgery is the definitive treatment for early-stage melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management or treatments such as gamma knife radiation may alleviate symptoms and provide local control of disease.[38]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (> 4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.

By stage, standard treatment options for melanoma are as follows[2]

Multiple options for adjuvant treatment of node-positive melanoma have become available. A critical question for guiding the choice of regimens is whether the tumor contains a BRAF V600 mutation. BRAF and BRAF/MEK inhibitor combinations are useful in some patients to slow the progression of disease.

In patients with no BRAF mutation (ie, wild-type BRAF), current guidelines from the National Comprehensive Cancer Network (NCCN) recommend single-agent immunotherapy with the programmed cell death–1 (PD-1) inhibitor pembrolizumab or nivolumab.[1]  

For patients with a BRAF mutation, the NCCN recommends targeted combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib.[1] ​ Targeted therapy is preferred if clinically needed for early response. Current targeted therapies can slow tumor growth (eg, BRAF inhibition) or release the brakes on the immune response, resulting in tumor lysis (eg, PD-1 inhibition).

For metastatic or unresectable disease, NCCN preferred regimens are as follows[1] :

For BRAF V600 mutation–positive disease, recommended regimens are as follows[1]

Interferon alfa-2b was approved in 1995 for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. However, while high-dose interferon alfa-2b and pegylated interferon have been shown to improve relapse-free survival, neither improves overall survival.[2] This is not currently offered to patients unless there are contraindications to giving PD-1 inhibitors or BRAF/MEK inhibitor combinations.

Neoadjuvant therapy for high-risk resectable melanoma has demonstrated significant efficacy in early clinical trials.[39, 40] Current NCCN guidelines recommend consideration of neoadjuvant therapy, preferably in the context of a clinical trial, in patients with any of the following:[1]

Neoadjuvant therapy most often consists of pembrolizumab or nivolumab/ipilimumab.[1]

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

Regional Lymph Node Dissection

A joint practice guideline from the American Society of Clinical Oncology and the Society of Surgical Oncology recommends completion lymph node dissection (CLND) for patients with a positive sentinel lymph node biopsy (SLNB), but the risk of morbidity must be weighed for each patient. CLND has not been shown to affect overall survival, but does help with regional disease control. Careful observation with removal of enlarged nodes is an option.

The second Multicenter Selective Lymphadenectomy Trial (MSLT-II) confirmed that immediate CLND in patients with metastases found on SLNB increases the rate of regional disease control and provides prognostic information. However, immediate CLND did not increase melanoma-specific survival.[41]

In MSLT-II, patients who had sentinel node metastases detected via standard pathologic assessment or a multimarker molecular assay were randomized to receive either immediate CLND (n = 971) or nodal observation with ultrasonography (n = 968). At a median follow-up of 43 months, the mean 3-year rate of melanoma-specific survival (the primary endpoint for the study) was similar in the dissection group and the observation group (86 ± 1.3% and 86 ± 1.2%, respectively; P = 0.42).[41]  

Secondary endpoints slightly favored CLND over observation, with 3-year rates of disease control of 92 ± 1.0% versus 77 ± 1.5%, respectively (P < 0.001) and 3-year disease-free survival of 68 ± 1.7% versus 63 ± 1.7%, respectively (P = 0.05). However, lymphedema developed in 24.1% of the dissection group versus 6.3% of the observation group (P< 0.001). Lymphedema was mild in 64% of cases, moderate in 33%, and severe in 3%.[41]

In patients whose SLNB reveals micrometastases, a randomized phase 3 trial by Steiner et al found no survival benefit with CLND. No statistically significant differences (ie, 10% or higher) in 5-year recurrence-free survival, distant metastases–free survival, or melanoma-specific survival were evident between 242 patients who underwent CLND and 241 patients who received observation only. At a median follow-up of 35 months, however, regional lymph node metastases developed in 14.6% of patients in the observation group versus 8.3% of those in the CLND group.[42]

Neoadjuvant Immunotherapy

Investigational studies suggest that neoadjuvant therapy with checkpoint inhibitors may be superior to adjuvant therapy. Blank et al randomized 20 patients with palpable stage III melanoma to receive ipilimumab/nivolumab in either four courses after surgery (adjuvant arm) or two courses before surgery and two courses after surgery (neoadjuvant arm). Neoadjuvant therapy proved feasible, with all patients undergoing surgery at the preplanned time point; 78% of patients achieving pathological response; and on median follow-up of 25.6 months, no patient experiencing relapse.[43]

However, in both the adjuvant and neoadjuvant arms, 9 of the 10 patients experienced one or more grade 3/4 adverse events. These authors concluded that neoadjuvant therapy appears promising, but further investigation is needed into reducing toxicity while preserving efficacy.[43]

OpACIN-neo, a multicenter phase 2 trial by Rozeman et al in 86 patients with macroscopic stage III melanoma, identified an effective and tolerable dosing schedule for neoadjuvant therapy. In this randomized comparison of three neoadjuvant dosing schedules, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously was associated with the lowest rate of grade 3-4 immune-related adverse events (20%). Of patients receiving this schedule, 57% achieved a radiologic objective response and 77% achieved a pathological response. Rozeman et al suggest that this schedule might be suitable for broader clinical use.[44]

Adjuvant Therapy

Adjuvant therapy is used for locally advanced melanoma (stage III) melanoma, and most recently, resected advanced-stage disease. Although observation rather than adjuvant therapy is standard for stage II melanoma at this time, those patients are encouraged to enroll in clinical trials. Gould Rothberg et al developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.[45]

Immune therapy and targeted therapy (eg, in cases with BRAF mutations) are preferred for treatment of unresectable or distant metastatic disease.[46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57]  Isolated limb perfusion and intralesional therapy with talimogene laherparepvec (T-VEC) therapy may be appropriate for some patients with localized metastases.[58, 59, 60, 61]

Dabrafenib plus trametinib

In 2018, the US Food and Drug Administration (FDA) approved dabrafenib in combination with trametinib for adjuvant treatment, following complete resection, of patients with melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s).

Approval was based on COMBI-AD, an international, multicenter, randomized, double-blind, placebo-controlled trial in 870 patients with stage III melanoma with BRAF V600E or V600K mutations and regional lymph node involvement. Patients in the treatment arm (dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily) had significantly longer relapse-free survival (RFS) compared with those in the placebo arm. The estimated median RFS was not reached for patients who received the combination therapy, compared with 16.6 months (95% confidence interval [CI]: 12.7, 22.1) for those receiving placebo. Patients in the treatment arm also had experienced fewer recurrences/deaths by the time of data cutoff: 38% (n=166), compared with 57% (n=248) in the placebo arm (hazard ratio [HR] 0.47; 95% CI 0.39, 0.58; P < 0.0001).[62]

Five-year follow-up of COMBI-AD confirmed the long-term benefit of dabrafeinb plus trametinib in this setting. RFS was 53% in the treatment arm versus 36% in the placebo arm. Distant metastasis-free survival rates were 65% versus 54%, respectively.[63]

Pembrolizumab

Pembrolizumab, a monoclonal antibody to programmed cell death-1 protein (PD-1), has FDA approval for adjuvant treatment of resected, high-risk stage III melanoma. Approval was based on data from the EORTC1325/KEYNOTE-054 trial (n=1019) showing a significantly prolonged 1-year RFS compared with placebo (75.4% vs 61%; P < 0.001).[64]

On 3-year median follow-up of KEYNOTE-054, pembrolizumab continued to produce a sustained, clinically meaningful improvement in RFS across subgroups. In the overall population, the 3-year cumulative incidence of distant metastasis as the first recurrence was 22.3% with pembrolizumab  versus 37.3% with placebo group (HR 0.55, 95% CI 0.44-0.69). In the pembrolizumab arm, 3-year RFS was superior in PD-L1 positive patients, at 65%, versus 57% for PD-L1 negative patients.[65]

In 2021, the FDA expanded the approval of pembrolizumab to the adjuvant treatment of stage IIB or IIC melanoma following complete resection, in patients age 12 years and older. Approval was based on data from the KEYNOTE-716 trial, which demonstrated a statistically significant improvement in RFS at the time of the first interim analysis for patients randomized to the pembrolizumab arm compared with placebo, with an HR of 0.65 (95% CI 0.46-0.92; P=0.0132). The median RFS was not reached in either arm.[66]

Pembrolizumab is also indicated for first-line treatment of unresectable or metastatic melanoma.

Nivolumab

The PD-1 inhibitor nivolumab (Opdivo) is approved for adjuvant treatment in patients with lymph node involvement or metastatic melanoma who have undergone complete resection. Approval was based on findings from the phase 3 CheckMate-238 trial, in which 906 patients with completely resected stage IIIB/C or stage IV melanoma received either nivolumab or ipilimumab for up to 1 year. The 12-month RFS rate was 70.5% in the nivolumab arm compared with 60.8% in the ipilimumab arm (HR for disease recurrence or death, 0.65; 97.56% CI, 0.51-0.83; P < 0.001).[67] Based on this study, nivolumab is the current drug of choice in the adjuvant setting.

A study by Weber et al in patients with advanced melanoma that had progressed after treatment with ipilimumab or ipilimumab and a BRAF inhibitor reported a higher objective response rate and fewer toxic effects in patients treated with nivolumab (n=272) than in those treated with dacarbazine, or with paclitaxel plus carboplatin (objective response rates 31.7% versus 10.6%, respectively).[4]

Ipilimumab

In a phase 3 trial in patients with high-risk stage III melanoma, adjuvant therapy with the checkpoint inhibitor ipilimumab resulted in significantly higher rates of RFS, overall survival, and distant metastasis–free survival compared with placebo.[68] The study included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes and were randomized to receive ipilimumab at 10 mg/kg (IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years, or until disease recurrence or unacceptable toxicity.

Median RFS—the primary endpoint—was 26.1 months with ipilimumab versus 17.1 months with placebo. However, 52% of patients (245 of 475) who started ipilimumab discontinued treatment due to adverse events, and 38.6% did so within 12 weeks. Grade 3-4 immune-related adverse events occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. Five patient deaths were linked to immune-related adverse events in the ipilimumab arm.[68]

Encorafenib plus binimetinib

The BRAF kinase inhibitor encorafenib is indicated in combination with the MEK1/2 inhibitor binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. In 7-year analysis of the COLUMBUS trial in 577 patients who were treatment-naive or progressed after first-line immunotherapy, progression-free survival rates were 21.2% with encorafinib plus binimetanib, versus 6.4% with vemurafenib, while overall survival rates were 27.4% versus 18.2 %, respectively.[69]

Intralesional therapy

In 2015, the FDA approved the oncolytic immunotherapeutic vaccine talimogene laherparepvec (Imlygic) 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.[70]

Talimogene laherparapvec is a live-attenuated herpes simplex type I virus that has been genetically modified by deleting the gene that encodes infected cell protein 34.5(ICP 34.5) and replacing it with the coding sequence for the immune stimulatory protein granulocyte-macrophage colony-stimulating factor (GM-CSF). Once injected into a tumor, the modified virus replicates and produces GM-CSF.

A phase 3 clinical trial by Andtbacka et al demonstrated therapeutic benefit of talimogene laherparepvec against melanoma. The study compared 295 patients treated with talimogene laherparepvec and141 patients treated with GM-CSF. The primary endpoint was the durable response rate (DRR), defined as the rate of complete response plus partial response continuously lasting ≥6 months and beginning within the first 12 months. Secondary endpoints included overall survival (OR) and the overall response rate (ORR).[71]

The DRR 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 < 0.001). 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 (range: 1.2 to 16.7) months in the arm receiving talimogene laherparepvec.[71]

The ORR was also higher with talimogene laherparepvec (26.4% vs 5.7%; P < 0.001). 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 [HR], 0.42). Median OS was 23.3 months and 18.9 months, respectively (HR, 0.79; P = 0.051), which just missed being statistically significant.[71]

The use of talimogene laherparepvec in combination with immune checkpoint inhibitors is currently being assessed. Early results  indicate that the combination of talimogene laherparepvec with ipilimumab or pembrolizumab has greater efficacy in melanoma than either therapy alone, and without additional safety concerns above those expected for each monotherapy.[72]

Pegylated interferon alfa

Interferon (IFN) alfa-2b was the first drug approved by the FDA, in 1995, for adjuvant treatment of melanoma after excision in patients who are free of disease but are at high risk for recurrence. It was supplanted by other agents and was discontinued in 2021.

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in 2011 as adjuvant therapy for melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than in patients who did not take the drug.[73]

Granulocyte-macrophage colony-stimulating factor

In addition to its approved indication — accelerating bone marrow recovery in diverse settings of bone marrow failure — granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used as adjuvant treatment of high-risk melanoma.[74] GM-CSF is no longer used in this setting, due to the availability of more effective treatments.[75] However, GM-CSF continues to be studied for its possible benefit as an immune modulator when used in combination with conventional therapies.[76]

Treatment of Advanced-Stage Melanoma (Stage IV)

In addition to intralesional therapy with talimogene laherparepvec, increasing numbers of biologic therapies are available for the treatment of patients with advanced-stage (stage IV) melanoma. Chemotherapy is used less frequently due to the more efficacious drugs have been developed, including immunotherapy and BRAF and MEK inhibitors. The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies.

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 40-60% of cutaneous melanomas, and of those, about 90% are BRAF V600E mutations. Detection of BRAF mutations is important prior to starting treatment in any melanoma patient. First-line treatment of patients with BRAF V600 wild-type or mutation-positive, unresectable or metastatic melanoma is with nivolumab as a monotherapy or in combination with ipilimumab.[77, 78]

Vemurafenib

Vemurafenib (Zelboraf) was approved by the FDA in 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with the BRAF V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied in wild-type BRAF melanoma.

Phase 3 trial results for vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation, compared with dacarbazine. In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.[79]  Despite the short follow-up period, these results have significant clinical implications, given the frequency of BRAF V600E mutations in cutaneous melanomas. Moreover, a response to vemurafenib in four of 10 patients with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.[79]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.[79]  Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib

In 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma with BRAF V600E mutation confirmed by the THxID BRAF mutation test.[80]  In a multicenter, open-label, phase 3 randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival (PFS) in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[81]

Trametinib

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[80]  Approval was based on a phase 3 open-label trial in which median PFS was 4.8 months with trametinib versus 1.5 months in patients receiving dacarbazine or paclitaxel. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% confidence interval [CI], 0.32 to 0.92).[82]

Dabrafenib plus trametinib

In 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase 1/2 study. Median PFS in the full-dose combination therapy group was 9.4 months, compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval [CI], 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76%, compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival was demonstrated for this combination.[83, 84]

Cobimetinib

In 2015, the FDA approved cobimetinib, a MEK1 and MEK2 inhibitor, for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation, in combination with vemurafenib. Approval was based on results in 495 patients with advanced melanoma from the phase 3 coBRIM study, in which median PFS was longer with cobimetinib plus vemurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; HR, 0.58; 95% CI, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P < 0.0001).[85]

Binimetinib plus encorafenib

The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in 2018 for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. Approval was based on results from the phase 3 COLUMBUS trial, which demonstrated that the combination doubled median PFS compared with vemurafenib alone (14.9 months versus 7.3 months, respectively (P < 0.0001).[86]

Triple therapy

In 2020, the FDA approved the triple-therapy combination of the programmed cell death ligand–1 protein (PD-L1) inhibitor atezolizumab (Tecentriq), the MEK inhibitor cobimetinib (Cotellic), and the BRAF kinase inhibitor vemurafenib for the treatment of BRAF V600 mutation–positive advanced melanoma. Approval was based on results of the double-blind, randomized, placebo-controlled, multicenter IMspire150 trial (n=514) in which median PFS was 15.1 months (95% CI: 11.4-18.4) with triple therapy, versus 10.6 months (95% CI: 9.3-12.7) with cobimetinib/vemurafenib plus placebo.[87]

The most common adverse reactions (≥ 20%) with atezolizumab in combination with cobimetinib and vemurafenib in patients with melanoma were rash, musculoskeletal pain, nausea, fatigue, hepatotoxicity, pyrexia, nausea pruritus, edema, stomatitis, hypothyroidism, and photosensitivity reaction.

The recommended atezolizumab dose, following completion of a 28-day cycle of cobimetinib and vemurafenib, is 840 mg every 2 weeks with cobimetinib 60 mg orally once daily (21 days on /7 days off) and vemurafenib 720 mg orally twice daily.

Treatment of BRAF V600 wild-type melanoma

For patients with BRAF V600 wild-type, unresectable or metastatic melanoma, nivolumab plus ipilimumab is a preferred choice for first-line treatment.[1] The FDA approved nivolumab plus ipilimumab for this indication in 2015. Approval was based on results from the phase 2 CheckMate 069 study. Of the 142 patients enrolled, 109 had BRAF wild-type melanoma. In patients with BRAF wild-type melanoma treated with the combination regimen, the objective response rate (the primary study endpoint) was 61% (95% CI: 48-71), compared with 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P < 0.001).[88]

Additional analysis of CheckMate 069 showed that complete responses were seen in 22% of patients in the combination therapy arm but in none of the patients in the ipilimumab arm. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0-NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3).[88]

Additional analysis showed that complete responses were seen in 22% of patients. Partial responses were seen in 43% of the combination group and 11% of the ipilimumab monotherapy group. The combination group had a 60% reduction in the risk of progression compared with ipilimumab alone (HR=0.40; 95% CI: 0.22-0.71; P < 0.002). Median PFS was 8.9 months with the combination (95% CI: 7.0, NA) and 4.7 months with ipilimumab alone (95% CI: 2.8-5.3). [94]

In pharmacovigilance studies, myocarditis occurred in 0.27% of patients treated with the combination of ipilimumab and nivolumab. Johnson et al reported fatal myocarditis in two patients with melanoma who were receiving treatment with ipilimumab and nivolumab. Both patients developed myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates.[89]

The phase 3 CheckMate 067 study in previously untreated patients with unresectable or metastatic melanoma randomized patients into three arms: combination therapy with nivolumab plus ipilimumab, monotherapy with nivolumab, and ipilimumab monotherapy. On 6.5-year follow-up, overall survival in patients with BRAF wild-type tumors was 46% in the nivolumab-plus-ipilimumab group, compared with 42% in the nivolumab group and 22% in the ipilimumab group. Overall survival rates in patients with BRAF-mutant tumors were 57%, 43%, and 25%, respectively.[90]

Nivolumab monotherapy

Nivolumab was first approved for use in melanoma in 2014, when the FDA granted accelerated approval for treatment of unresectable or metastatic melanoma unresponsive to other drugs. Approval was based on interim results of a randomized clinical trial in patients with unresectable or metastatic melanoma that had progressed after ipilimumab. Interim analysis confirmed objective responses in 38 of the first 120 patients treated with nivolumab (31.7%; 95% CI 23.5-40.8) versus five of 47 patients who received investigator's choice of chemotherapy (10.6%; CI, 3.5-23.1).[4]

Nivolumab monotherapy was approved in 2015 on the basis of data from the randomized phase 3 CheckMate-066 trial, which compared nivolumab monotherapy with dacarbazine in the first-line treatment of 418 patients with advanced BRAF wild-type melanoma. In an interim analysis, nivolumab demonstrated superior overall survival, which was the primary outcome. The overall survival rate at 1 year with nivolumab versus dacarbazine was 72.9% versus 42.1%, respectively. In addition, median PFS was longer in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < 0.001).[91] In 2016, the indication for nivolumab was expanded to include mutation-positive metastatic melanoma, making nivolumab effective across BRAF status.[77]

Pembrolizumab

Programmed cell death–1 protein (PD-1) and the related target PD-ligand 1 (PD-L1) are expressed on the surface of activated T cells under normal conditions. The PD-L1/PD-1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PD-L1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.

In 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.[92]  It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Data supporting approval included the results of a study in which approximately 24% of patients experienced tumor shrinkage.[3]

In 2015, the FDA approved pembrolizumab as first-line treatment for unresectable or metastatic melanoma. Approval was based on the phase 3 KEYNOTE-006 trial. Patients with advanced melanoma were randomized to receive either pembrolizumab 10 mg/kg every 2 weeks or every 3 weeks, or 4 doses of ipilimumab (3 mg/kg every 3wk). PFS for the pembrolizumab groups were 47.3% and 46.4% respectively; PFS for the ipilimumab group was 26.5%. Note that the dose of pembrolizumab used in the trial is higher than that approved by the FDA, which is 2 mg/kg every 3 weeks.[93]

Ipilimumab

Ipilimumab is an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). It is a humanized antibody directed at a down-regulatory receptor on activated T cells.[94]  The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T cells.

Ipilimumab was approved by the FDA in 2011 for treatment of adults with unresectable or metastatic melanoma. In 2017, approval was extended to adolescents aged 12 years or older.[95]

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. In a phase 3 study, 676 patients with unresectable stage III or IV melanoma whose disease had progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus a glycoprotein 100 (gp100) peptide vaccine, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy.[96]

The median overall survival was 10 months in patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab plus gp100 arm. Because of these findings, ipilimumab was approved as a treatment for metastatic melanoma.[96]

In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival in patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, those patients had more grade 3 and 4 toxicity.[97]

The MDX010-20 trial evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive one of the following three treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus gp100; (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[98]  Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.[98]

Ipilimumab is also approved in the adjuvant setting. 

Relatlimab plus nivolumab

Opdualag, a fixed-dose combination of nivolumab and the LAG-3-blocking antibody relatlimab, was approved by the FDA in 2022 for treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Efficacy was demonstrated in the phase 3 RELATIVITY-047 trial, a randomized, double-blind study in 714 patients with previously untreated metastatic or unresectable stage III or IV melanoma.[99]

In RELATIVITY-047, patients were randomized to receive nivolumab 480 mg and relatlimab 160 mg by intravenous (IV) infusion every 4 weeks or nivolumab 480 mg by IV infusion every 4 weeks until disease progression or unacceptable toxicity. Patients receiving nivolumab plus relatlimab had significantly longer PFS than those receiving nivolumab alone (10.1 versus 4.6 months, respectively), but also had a higher rate of grade 3 or 4 treatment-related adverse events (18.9% vs 9.7%). The final analysis of overall survival (OS) did not show a statistically significant difference (HR=0.80; 95% CI: 0.64-1.01) with median OS not reached (NR) in the Opdualag arm (95% CI: 34.2-NR) and 34.1 months (95% CI: 25.2-NR) in the nivolumab arm.[99]

In patients receiving nivolumab plus relatlimab, the most common laboratory abnormalities (≥20%) were decreased hemoglobin, decreased lymphocytes, increased liver transaminase values, and decreased serum sodium. The recommended dosage for patients 12 years of age or older who weigh at least 40 kg is 480 mg nivolumab and 160 mg relatlimab administered intravenously every 4 weeks until disease progression or unacceptable toxicity.[99]

KIT inhibitor therapy

In a multicenter phase 2 trial, targeted therapy with imatinib was effective in patients with advanced melanoma harboring mutations and/or amplification of the KIT proto-oncogene.[100, 101] Hodi et al reported that in patients with metastatic melanomas arising from acral, mucosal, or chronically sun-damaged sites and containing KIT amplifications, mutations, or both, 7 of 24 patients achieved a partial response to therapy, with five patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.[100]

Those findings reinforce similar findings in two earlier studies.[7, 102] Japanese researchers are currently recruiting patients for a study of imatinib combined with pembrolizumab in patients with advanced KIT-mutant melanoma that has progressed on standard therapy.[103]

Vaccines

Various vaccines have been studied in the treatment of melanoma. A phase 3 trial found that multiepitope peptide vaccination did not significantly improve relapse-free survival or overall survival in patients with high-risk resected melanoma.[104]  In contrast, several small studies using a personalized peptide-based DNA or RNA vaccine targeting a number of tumor neoantigens reported that some treated patients remained recurrence-free for up to 25 months, while other patients experienced recurrences but responded to treatment with pembrolizumab.[105] Phase 1 trials of vaccination against telomerase human telomerase reverse transcriptase (hTERT), in combination with checkpoint inhibitors, have suggested clinical efficacy with negligible added toxicity.[106]

Less frequently used therapies

With the advent of biologic therapies — most notably, agents that inhibit PD-1, BRAF, and MEK — the role of cytotoxic and immunotherapy agents such as dacarbazine and interleukin-2 (IL-2) has steadily diminished. For example, current NCCN guidelines recommend that use of cytotoxic agents (eg, carboplatin plus paclitaxel, or single-agent temozolomide) may be considered in symptomatic patients who are not candidates for further standard, immune-based, BRAF/MEK inhibitor therapy. However, the NCCN notes that cytotoxic therapy has a limited impact on overall survival in this setting.[1]

Dacarbazine

Dacarbazine was the first drug approved by the FDA for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22%, with no impact on survival. In a phase 3 study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%, respectively.[107] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists prefer temozolomide for melanoma chemotherapy. Temozolomide has orphan drug designation for treatment of advanced metastatic melanoma.

Interleukin-2

The second drug approved by the FDA for the treatment of metastatic melanoma was interleukin-2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell–derived growth factor and used as a lymphokine-activated cell killer therapy. A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patients with soft tissue and lung metastases. Median overall survival was 11.4 months.[108]

The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for IL-2 therapy, patients must have normal results on pulmonary function testing, brain imaging, and cardiac stress testing, plus adequate kidney and liver function.

Carboplatin plus paclitaxel

Combination therapy with carboplatin and paclitaxel has been tested in two small phase 2 studies, and when used together with sorafenib, the response rate was 11-17%. This regimen sometimes is used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen.

However, a randomized, placebo-controlled phase 3 study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.[109, 110]

Treatment of brain metastases

The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis; they tend to progress rapidly and display resistance to conventional therapies.

Stereotactic radiosurgery is used increasingly in patients with a limited number of brain metastases (fewer than 3); it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, although the combination of chemotherapy with external-beam radiation is being investigated.[38]

Cellular Therapy

Lifileucel (Amtagvi) is a preparation of autologous tumor-infiltrating lymphocytes (TILs) selected on the basis of antigen specificity and tumor reactivity. For this treatment, the melanoma tumor is surgically excised and T cells are collected from the specimen. The harvested TILs are then sent to a specialized laboratory where they undergo in vitro expansion by culturing them with interleukin-2 (IL-2), a cytokine that promotes T-cell proliferation. The patient then receives a non-myeloablative lymphodepletion regimen to reduce the lymphocyte count and thus provide a more favorable environment for the TILs, after which the TILs are reinfused into the patient.

Following lifileucel infusion, IL-2 (aldesleukin) is administered to support TIL expansion in vivo. Upon their reintroduction into the patient, the TILs re-infiltrate the tumor, specifically recognize tumor-associated antigens (TAAs), and initiate tumor cell lysis. Adverse effects include chills, fever, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, and hair loss.

Lifileucel is indicated for unresectable or metastatic melanoma in adults previously treated with a PD-1 blocking antibody and, if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. It is the first autologous T-cell therapy approved for a solid tumor cancer. 

Accelerated approval was based on overall response rate (ORR) and duration of response in the C-144-01 clinical trial. The primary efficacy analysis showed that in the cohort of 73 patients who received the recommended lifileucel dose, 31.5% achieved an objective response, with a median duration of response not reached at 18.6 months follow-up (43.5% of responses lasted > 12 months). In a supporting pooled efficacy set that included 153 patients, 31.4% achieved an objective response, with a median duration of response not reached at 21.5 months follow-up (54.2% of responses lasted > 12 months).[6]  Researchers have reported surviveal  for 4 years in at least 50% of those treated with TIL.

The phase 3 TILVANCE-301 trial is being conducted to confirm clinical benefit of lifileucel. It will compare lifileucel plus pembrolizumab with pembrolizumab alone in patients with untreated unresectable or metastatic melanoma.[111]

Uveal Melanoma Immunotherapy

Unlike advanced cutaneous melanoma, metastatic uveal melanoma does not respond to standard immunotherapies. However, a new class of immunotherapy agents, immune-mobilizing monoclonal T-cell receptors against cancer (ImmTACs), has shown benefit. ImmTACs enhance the function of tumor-specific T cells, which otherwise tend to have weak binding with tumor antigens.[112]

The first ImmTAC to become clinically available, tebentafusp-tebn (Kimmtrak), was approved by the FDA in 2022 for HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma. This agent is a bispecific fusion protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function. It places T cells in proximity to melanoma cells by targeting the gp100 protein, a lineage antigen expressed in melanocytes and melanoma.

The efficacy of tebentafusp-tebn was demonstrated in IMCgp100-202 (NCT03070392), an open-label, multicenter trial in which patients with metastatic uveal melanoma were randomized to receive tebentafusp-tebn (n=252) or investigator’s choice (n=126) of pembrolizumab, ipilimumab, or dacarbazine. Median overall survival was 21.7 months for patients treated with tebentafusp-tebn versus 16 months in patients who received the investigator’s choice of therapy (hazard ratio [HR]=0.51, 95% CI: 0.37, 0.71, P< 0.0001), and progression-free survival was 3.3 versus 2.9 months (HR=0.73, 95% CI: 0.58, 0.94, P=0.0139).[113]

In the tebentafusp-tebn arm, the most common adverse reactions (≥30%) were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common laboratory abnormalities (≥50%) were decreased lymphocyte count, increased creatinine, increased glucose, increased aspartate aminotransferase, increased alanine aminotransferase, decreased hemoglobin, and decreased phosphate.

For full discussion of this form of melanoma, see Choroidal Melanoma.

Prevention of Malignant Melanoma

The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should do the following:

In various studies, the benefit of sunscreen for preventing melanoma has ranged from substantial to imperceptible.[114, 115, 116]  In addition, more than one study has reported that sunscreen users have greater intentional sun exposure and more frequent sunburns.[114, 117]

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations. Individuals with other risk factors for melanoma should seek regular screening or do self-screening.

Consultations

A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

Long-Term Monitoring

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[1]

Follow-up for stage 0 in situ is as follows:

Follow-up for stage IA is as follows:

Follow-up for stage IB-IV (in patients with no evidence of disease) is as follows:

Guidelines Summary

Guidelines contributors: Wesley Wu, MD, Resident Physician, Department of Dermatology, Baylor College of Medicine; Mohsin R Mir, MD, Director, High Risk Skin Cancer Clinic, Assistant Professor, Mohs Surgery, Laser and Cosmetic Surgery, Department of Dermatology, Baylor College of Medicine

Screening

In 2023, the U.S. Preventive Services Task Force (USPSTF) concluded there is not enough evidence to recommend for or against visual skin examination by a clinician to screen for skin cancer in asymptomatic adolescents and adults..[118]  

The USPSTF did note the following clinical considerations:

The American Academy of Dermatology (AAD) promotes free skin examinations by volunteer dermatologists for the general population through the Academy's SPOTme™ Screening Program. The program also provides education about the importance of sun protection and early cancer detection.[119]

Clinical Presentation and Workup

Guidelines from the American Academy of Dermatology (AAD), established in 2011 and updated in 2019, are as follows[120, 121] :

The 2019 guidelines from the European Society for Medical Oncology (ESMO) require diagnosis based on a full-thickness excisional biopsy with a minimal side margin that has been processed by an experienced pathology institute. Histology reports should include the following[122] :

ESMO guidelines consider mutation testing for actionable mutations mandatory in patients with resectable or unresectable stage III or stage IV, and highly recommended in high-risk resected disease stage IIC, but not for stage I or stage IIA–IIB. BRAF testing is mandatory.

Physical examination with special attention to other suspicious pigmented lesions, tumor satellites, in-transit metastases, regional lymph nodes, and distant metastases is requred. Imaging is not needed for low-risk melanomas but  in higher-stage tumors, US, CT, and/or PET scans are recommended to allow proper tumor assessment for accurate staging.[122]

The National Comprehensive Cancer Network (NCCN) guidelines recommend the following for biopsy of a suspicious pigmented lesion[1]

The NCCN guidelines support the concept that most melanoma recurrences are diagnosed clinically. Current NCCN guidelines state that no further workup (ie, baseline laboratory tests and imaging studies) is required in stage 0 (melanoma in situ) and for asymptomatic patients with stage IA, IB, or IIA melanoma. (Physician Quality Reporting System [PQRS] measure #224 concerns overutilization of imaging studies in melanoma.)

Current NCCN 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 (chest radiograph, CT and/or PET-CT) should be obtained as clinically indicated for confirmation of suspected metastasis or to delineate the extent of disease.[1]

The NCCN advises that imaging studies may be considered to screen for recurrent/metastatic disease in patients with stage IIB-IV disease, although this recommendation remains controversial. Routine laboratory or radiologic imaging in asymptomatic melanoma patients of any stage is not recommended after 5 years of follow-up.[1]

While abnormal laboratory test results are rarely the sole indicator of metastatic disease, serum lactate dehydrogenase (LDH) levels are incorporated into the American Joint Committee on Cancer (AJCC) melanoma staging guidelines for the classification of stage IV (distant) disease. Elevated LDH levels are associated with worse survival in this subgroup.[37]

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on diagnosis of melanoma[123] :

Surgical Management

American Academy of Dermatology

American Academy of Dermatology (AAD) recommendations for surgical management of primary cutaneous melanoma are as follows[121] :

European Society for Medical Oncology

The European Society for Medical Oncology (ESMO) updated its guidelines on the management of locoregional melanoma in 2020.[124]

Wide local excision:

Radical lymph node dissection:

Treatment of satellite or in-transit metastases:

Adjuvant radiotherapy after node dissection:

Neoadjuvant therapy:

BRAF-mutated melanomas:

Adjuvant therapy in stage IIIA melanoma:

Management of toxicity in the adjuvant setting:

Adjuvant therapy for in-transit metastases and resected stage IV disease:

Sentinel Lymph Node Dissection

The melanoma guidelines from the National Comprehensive Cancer Network (NCCN) do not recommend sentinel lymph node biopsy for patients with in situ melanoma (stage 0).[1]

Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking and recommendations remain controversial. The NCCN does not recommend sentinel lymph node biopsy for patients with lesions 0.75 mm or thinner.[73]

The 2020 update of the European Society for Medical Oncology melanoma guidelines includes the following recommendations on sentinel lymph node biopsy[124] :

The American Academy of Dermatology (AAD) recommends consideration of sentinel lymph node biopsy in patients with lesions, including those less than 0.76 mm, with any of the following high-risk features[120, 121] :

However, data suggest that the presence of a single mitotic figure may not correlate well with sentinel node status in thin lesions.[125]  In addition, the presence of regression in thin lesions is associated with a lower risk of nodal metastasis.[126]

The 2018 update of joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) includes the following recommendations[127] :

In the case of a positive sentinel lymph node biopsy, completion lymph node dissection (CLND) or careful observation are options for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors. For higher-risk patients, careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND.[127]

Mohs Surgery

The NCCN cites a study of Mohs micrographic surgery (MMS) that employed MMS enhanced by immunohistochemical staining as the primary treatment modality for melanoma in situ, which resulted in 99% removal of melanoma in situ when a total surgical margin of 9 mm was used, versus an 86% rate of removal with 6-mm margins. The stain comprised antibodies to a melanoma antigen recognized by T cells (MART-1).[1, 128]

The appropriate-use criteria for MMS from the AAD, American College of Mohs Surgery (ACMS), American Society for Dermatologic Surgery Association (ASDSA), and the American Society for Mohs Surgery (ASMS) further state that MMS is appropriate for all recurrent melanoma in situ and lentigo maligna, as well as primary lesions at the following sites[129] :

For melanoma in situ, lentigo maligna type type, the AAD recommends permanent section analysis of the central MMS debulking specimen to identify and appropriately stage potential invasive cutaneous melanoma. If invasive cutaneous melanoma is identified on an MMS section intraoperatively, the tissue should be submitted for formal pathology review.[121]

Wide Excision Surgical Margins

For wide excision of primary melanoma, the NCCN, AAD, and ESMO practice guidelines agree on the following surgical margin recommendations for primary melanoma[1, 121, 122]

The AAD guidelines note that margins may be narrower to accommodate function and/or anatomic location.However, for primary invasive melanomas at anatomically constrained sites (eg, head and neck, acral), margins of < 1 cm (by either wide excision or Mohs micrographic surgery) are generally not recommended until further studies are available.[121]

Radiation Therapy

NCCN guidelines recommend consideration of radiation therapy in the following situations[1] :

ESMO recommends considering stereotactic radiation of regional or single distant metastatic disease.[122]

Treatment for Advanced Melanoma

NCCN recommendations for treatment of melanoma stage IV disease with distant metastasis include the following[1] :

First-line immunotherapy regimens for systemic therapy (category 1), according to the NCCN guidelines, are as follows[1] :

If the tumor contains a BRAF V600 activating mutation, category 1 recommendations for first-line therapy are as follows[1] :

Second-line or subsequent therapy recommendations are as follows[1] :

Joint guidelines from the European Dermatology Forum, the European Association of Dermato-Oncology, and the European Organization for Research and Treatment of Cancer include the following recommendations on adjuvant therapy in stage III disease[130] :

The joint European guidelines include the following recommendations for stage IV melanoma[130] :

The joint European guidelines include the following recommendations for brain metastases[130] :

Follow-up for Melanoma Cancer Survivors

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.[1]

Follow-up for stage 0 in situ is as follows:

Follow-up for stage IA-IIA is as follows:

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

Mucosal Melanomas

Mucosal melanomas are rare and data to support the development of recommendations are limited. Notwithstanding those challenges, the United Kingdom has developed guidelines for the diagnosis, treatment, and surveillance of patients with ano-uro-genital mucosal melanoma[131]  and head and neck mucosal melanoma.[9]

Medication Summary

Pharmacotherapy for melanoma—both as adjuvant therapy in locally advanced disease and first-line therapy in unresectable and stage IV melanoma—increasingly relies on biologic agents, often used in combination. Pegylated interferon and the chemotherapy agents dacarbazine, cisplatin, and vinblastine are approved by the US Food and Drug Administration (FDA) for use as adjuvant therapy in melanoma. However, those have largely been supplanted by biologic agents.

Current biologic agents for melanoma include the programmed cell death-1 protein (PD-1) inhibitors pembrolizumab, nivolumab, and atezolizumab; ipilimumab, which inhibits T-cell inactivation; and a growing number of biologic agents for targeted therapy, such as BRAF and MEK inhibitors (eg, vemurafenib, dabrafenib, trametinib), which are used for melanoma with BRAF V600E or V600K mutations. In addition, intralesional injection with talimogene laherparepvec is approved for skin metastasis. 

The first autologous tumor-infiltrating lymphocytes (TILs) preparation, lifileucel, was approved by the FDA for unresectable or metastatic melanoma. 

Dacarbazine (DTIC Dome)

Clinical Context:  Although the mechanism of action for dacarbazine is unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.

Cisplatin

Clinical Context:  Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.

Vinblastine (Velban)

Clinical Context:  Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD regimen.

Ipilimumab (Yervoy)

Clinical Context:  Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. The marker CTLA-4 is associated with promoting a regulatory response by the immune system. This regulatory response has a dampening effect on the immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is the first new agent to be approved for melanoma in over a decade.

It is indicated for the treatment of unresectable or metastatic melanoma in adults and adolescents aged 12 y or older. Additionally, it is indicated for the adjuvant treatment of adults with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy. It is also used off-label in previously untreated patients with BRAF V600 wild-type, unresectable or metastatic melanoma in combination with nivolumab. Note, nivolumab is approved in combination with ipilimumab.

Dabrafenib (Tafinlar)

Clinical Context:  Dabrafenib inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. It is indicated as a single agent for unresectable or metastatic melanoma with BRAF V600 E mutation. It is indicated in combination with trametinib for BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma. Additionally, it is approved for adjuvant therapy in combination with trametinib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

Trametinib (Mekinist)

Clinical Context:  Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation, and of MEK1 and MEK2 kinase activity. It is indicated as a single agent or in combination with dabrafenib for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by with the THxID BRAF mutation test. Additionally, it is approved for adjuvant therapy in combination with dabrafenib for melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection.

Pembrolizumab (Keytruda)

Clinical Context:  Pembrolizumab is a programed cell death-1 protein (PD-1) inhibitor. It is indicated as first-line treatment for unresectable or metastatic melanoma. It is also indicated for adjuvant treatment of resected, high-risk stage 3 melanoma.

Vemurafenib (Zelboraf)

Clinical Context:  Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E. The drug is indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Nivolumab/relatlimab (Nivolumab/relatlimab-rmbw, Opdualag)

Clinical Context:  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 greater T-cell activation than with either antibody alone. 

Nivolumab (Opdivo)

Clinical Context:  Nivolumab is a monoclonal antibody to programmed cell death-1 protein (PD-1). It blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is indicated as a single agent for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. It is also indicated as a single agent in the first-line treatment of unresectable or metastatic BRAF V600 wild-type or mutation-positive melanoma. Combination therapy with ipilimumab is superior to either drug alone for treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma.

Cobimetinib (Cotellic)

Clinical Context:  Reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation.

Cobimetinib is indicated for unresectable or metastatic melanoma in patients with a BRAF V600E or V600K mutation in combination with vemurafenib. Cobimetinib and vemurafenib target 2 different kinases in the RAS/RAF/MEK/ERK pathway; compared with either drug alone, coadministration resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations.

Binimetinib (Mektovi)

Clinical Context:  Inhibits mitogen-activated extracellular signal regulated kinase (MEK) 1 and MEK 2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK)-related phosphorylation and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. It is indicated in combination with encorafenib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Encorafenib (Braftovi)

Clinical Context:  Kinase inhibitor that targets BRAF V600E. This pathway regulates several key cellular activities, including proliferation, differentiation, survival, and angiogenesis; inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma. It is indicated in combination with binimetinib for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

Atezolizumab (Tecentriq)

Clinical Context:  Monoclonal antibody to programmed cell death ligand-1 protein (PDL1); indicated for unresectable or metastatic BRAF V600 mutation–positive melanoma in combination with cobimetinib and vemurafenib.

Atezolizumab/hyaluronidase (Atezolizumab/hyaluronidase-tqjs, Tecentriq Hybreza)

Clinical Context:  Formulation of atezolizumab with hyaluronidase, an endoglycosidase, which enables subcutaneous administration.

Class Summary

A variety of agents are used, depending on melanoma stage, biomarkers, surgical resection. 

Peginterferon alfa 2b (PEG Intron, PegIntron Redipen, Sylatron)

Clinical Context:  Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors, which, once activated, are known to inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase the phagocytic activity of macrophages, and enhance the cytotoxicity of lymphocytes for target cells.

A covalent attachment of polyethylene glycol polymer chains to interferon molecules (known as PEGylation) can significantly increase the time the drug remains in the bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce the severity and frequency of adverse effects.

It was approved by the FDA in 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.

Aldesleukin (Interleukin 2, Proleukin)

Clinical Context:  IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells and amplifies their responses. It enhances natural killer cell antitumor activity.

Class Summary

Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and interleukin (IL)-2. An oncologist should administer these treatments.

Talimogene laherparepvec (Imlygic)

Clinical Context:  The exact mechanism of action is unknown. Talimogene laherparepvec is a genetically modified, live, attenuated herpes simplex virus programmed to replicate within tumors and to produce the immune stimulatory protein GM-CSF. Causes lysis of tumors, followed by 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.

Class Summary

Local treatment of lesions or nodal lesions may be needed following resection.

Tebentafusp (Kimmtrak, Tebentafusp-tebn)

Clinical Context:  Bispecific protein comprised of a soluble T-cell receptor fused to an anti-CD3 immune-effector function that specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. Indicated for treatment of HLA-A*02:01-positive adults with unresectable or metastatic uveal melanoma.

Lifileucel (Amtagvi)

Clinical Context:  It is indicated for unresectable or metastatic melanoma in adults previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. It is the first autologous T-cell therapy approved for a solid tumor cancer. 

Class Summary

Preparation of autologous tumor-infiltrating lymphocytes (TILs) selected on the basis of antigen specificity and tumor reactivity. TILs are reintroduced into the patient and re-infiltrate the tumor, specifically recognize the tumor-associated antigens (TAAs), and initiate tumor cell lysis. 

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(SLNB) in the workup of malignant melanoma?What are the recommendations by the National Comprehensive Cancer Network (NCCN) for sentinel lymph node biopsy (SLNB) in the workup of malignant melanoma?What are the recommendations by the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) for sentinel lymph node biopsy (SLNB) in the workup of malignant melanoma?What is the role of a sentinel lymph node biopsy (SLNB) in determining metastasis in malignant melanoma?What is the role of chemistry panels in the workup of malignant melanoma?What is the role of high lactate dehydrogenase (LDH) measurement in the diagnosis of malignant melanoma?What is the role of chest radiography in the evaluation of malignant melanoma?What is the role of imaging studies in stage III malignant melanoma?What is the role of positron emission tomography (PET) scans in the workup of malignant melanoma?Which tests are included in the workup of locally advanced or metastatic melanoma?What is the Clark staging for malignant melanoma?What is the Breslow classification for malignant melanoma?What is the T classification (thickness) for malignant melanoma?What is the N classification for malignant melanoma?What is the M classification for malignant melanoma?What is the AJCC prognostic staging system for malignant melanoma?What is the role of MRI in the evaluation of malignant melanoma?When is MRI of the brain indicated in the evaluation of malignant melanoma?What is the role of chest CT scan in stage IV malignant melanoma management?What is the role of chest CT scan in the management of stage I, II, or III malignant melanoma?When is a CT scan of the abdomen indicated in the workup of malignant melanoma?When is a CT scan of the pelvis indicated in the workup of malignant melanoma?What is the role of surgery in the treatment of early-stage malignant melanoma?What is the role of medical therapy in the treatment of malignant melanoma?What are the standard treatment options for malignant melanoma by stage?How does the BRAF mutation affect the treatment options for malignant melanoma?What is the role of interferon alfa-2b in the treatment of malignant melanoma?What are the American Society of Clinical Oncology and the Society of Surgical Oncology recommendations for treatment of malignant melanoma following a positive sentinel lymph node biopsy (SLNB)?What is the role of completion lymph node dissection (CLND) in the treatment of malignant melanoma?What is the efficacy of completion lymph node dissection (CLND) in the treatment of malignant melanoma?What are the benefits of completion lymph node dissection (CLND) in patients with micrometastases on SLNB in malignant melanoma?What is the role of adjuvant therapy in the treatment of malignant melanoma?What is the efficacy of combination dabrafenib and trametinib for the treatment of malignant melanoma?What is the role of pembrolizumab in the treatment of malignant melanoma?What is the role of nivolumab in the treatment of malignant melanoma?What is the role of ipilimumab in the treatment of malignant melanoma?What is the role of talimogene laherparepvec (Imlygic) in the treatment of malignant melanoma?What is the efficacy of interferon (IFN) alfa-2b in the treatment of malignant melanoma?Which factors are predictors of response to interferon alfa/pegylated-interferon in the treatment of malignant melanoma?What is the role of peginterferon alfa-2b in the treatment of malignant melanoma?What is the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment of malignant melanoma?What are the treatment options for advanced-stage malignant melanoma?What is the efficacy of dacarbazine in the treatment of advanced-stage malignant melanoma?What is the efficacy of interleukin-2 (IL-2) in the treatment of advanced-stage malignant melanoma?What are the adverse effects of interleukin-2 (IL-2) in the treatment of malignant melanoma?What is the role of combination carboplatin and paclitaxel in the treatment of malignant melanoma?What is the prevalence of BRAF mutations in patients with malignant melanoma and how does it affect treatment selection?What is the first-line treatment for malignant melanoma in patients with BRAF mutations?What is the role of vemurafenib (Zelboraf) in the treatment of malignant melanoma?What is the role of dabrafenib (Taflinar) in the treatment of malignant melanoma?What is the role of vemurafenib (Zelboraf) in the treatment of malignant melanoma?What are possible adverse events from vemurafenib for the treatment of malignant melanoma?What is the efficacy of dabrafenib in the treatment of malignant melanoma?What is the role of trametinib (Mekinist) in the treatment of malignant melanoma?What is the role of trametinib in the treatment of malignant melanoma?What is the role of cobimetinib in the treatment of malignant melanoma?What is the role of binimetinib plus encorafenib in the treatment of malignant melanoma?What is the first-line treatment for BRAF V600 wild-type, unresectable, or metastatic malignant melanoma?How is nivolumab (Opdivo) used in the treatment of malignant melanoma?What was the efficacy of nivolumab in the treatment of malignant melanoma?What is the benefit of nivolumab to treat unresectable or metastatic malignant melanoma?When is nivolumab indicated for the treatment of malignant melanoma?What is the role of pembrolizumab (Keytruda) in the treatment of malignant melanoma?What is the mechanism of action of ipilimumab in the treatment of malignant melanoma?What is the efficacy of ipilimumab in the treatment of malignant melanoma?What are the immune-related adverse events (AEs) of ipilimumab in the treatment of malignant melanoma?What are the indications for the treatment of malignant melanoma with the combination regimen of nivolumab plus ipilimumab?What is the efficacy of ipilimumab combination regimens in the treatment of melanoma?Which drug is approved for adjuvant therapy and for treatment of advanced stage malignant melanoma?What is the efficacy of combination nivolumab and ipilimumab in the treatment of malignant melanoma?What are the treatment options for brain metastases in malignant melanoma?How is malignant melanoma treated in patients with KIT mutations?What is the role of vaccines in the treatment of malignant melanoma?What is the focus of malignant melanoma prevention?What is the role of sunscreen in the prevention of malignant melanoma?Which patients should have annual skin exams for malignant melanoma prevention?When is consultation with a dermatologist or surgical oncologist warranted in the evaluation of malignant melanoma?When is an oncology consultation needed for the treatment of malignant melanoma?Which factors determine the follow-up care for a patient with malignant melanoma?What is the NCCN recommended follow-up care for stage 0 in situ malignant melanoma?What is the follow-up care for stage IA malignant melanoma?What is the NCCN recommended follow-up care for stage IB-IV (patients with no evidence of disease) malignant melanoma?What are the guidelines for routine screening for malignant melanoma?What are the recommendations of the National Comprehensive Cancer Network (NCCN) for the workup of malignant melanoma?What are the joint European guidelines for the diagnosis of malignant melanoma?What are the European Society of Medical Oncology (ESMO) diagnostic guidelines for malignant melanoma?What are the American Academy of Dermatology (AAD) diagnostic guidelines for malignant melanoma?What are the NCCN guidelines for surveillance of asymptomatic patients with stage IA, IB, and IIA malignant melanoma?What are the NCCN guidelines for use of imaging studies in malignant melanoma?What is the American Joint Committee on Cancer (AJCC) recommendation for use of serum lactate dehydrogenase (LDH) levels for staging malignant melanoma?What are the AAD guidelines for the surgical management of malignant melanoma?What are the ESMO guidelines for the surgical management of malignant melanoma?no textWhat are the NCCN guidelines for sentinel lymph node biopsy in patients with malignant melanoma?What are the ESMO guidelines for sentinel lymph node dissection in patients with malignancy melanoma?What are the American Academy of Dermatology (AAD) guidelines for sentinel lymph node biopsy in patients with malignant melanoma?What are the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) guidelines for sentinel lymph node biopsy in patients with malignant melanoma?What are the NCCN guidelines for use of Mohs surgery in the treatment of malignant melanoma?What are the AAD, American College of Mohs Surgery (ACMS), American Society for Dermatologic Surgery Association (ASDSA), and the American Society for Mohs Surgery (ASMS) appropriate-use criteria for Mohs surgery for malignant melanoma?What are the surgical margin recommendations for primary malignant melanoma?What are the NCCN recommendations for radiation therapy in the treatment of malignant melanoma?What are the NCCN recommendations for treatment of melanoma stage IV disease with distant metastasis?What are the NCCN recommended first-line immunotherapy regimens for systemic therapy of malignant melanoma?What are the NCCN category 1 recommendations for first-line therapy of malignant melanoma in patients with a BRAF V600 activating mutation?What is the NCCN second-line therapy for the treatment of malignant melanoma?What are the joint European guidelines for the treatment of stage III malignant melanoma?What are the joint European guidelines for the treatment of stage IV malignant melanoma?What are the joint European guidelines for the treatment of brain metastases in patients with malignant melanoma?What is the NCCN recommendations for follow-up of stage 0 in situ malignant melanoma cancer survivors?What is the NCCN recommendations for follow-up of stage IA-IIA malignant melanoma cancer survivors?What are the NCCN recommendations for follow-up of stage IB-IV (patients with no evidence of disease) malignant melanoma cancer survivors?Which medications are used in the treatment of malignant melanoma?Which medications in the drug class Oncolytic Immunotherapy are used in the treatment of Malignant Melanoma?Which medications in the drug class Biological Response Modulators are used in the treatment of Malignant Melanoma?Which medications in the drug class Antineoplastic Agents are used in the treatment of Malignant Melanoma?

Author

Winston W Tan, MD, FACP, Associate Professor of Medicine, Mayo Medical School; Consultant and Person-in-Charge of Genitourinary Oncology-Medical Oncology, Division of Hematology/Oncology, Department of Internal Medicine, Mayo Clinic Jacksonville; Vice Chairman, Division of Hematology/Oncology Education, Chair, Cancer Survivorship Program, Associate Chair, Department of Medicine Faculty Development, Mayo Clinic Florida; Vice President, Florida Society of Clinical Oncology

Disclosure: research discussions on treatment of prostate cancer molecular testing for: Early for good.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Mohsin R Mir, MD, Private Practice, Mohs Micrographic Surgery and Dermatologic Surgery, Kelsey-Seybold Clinic; Assistant Professor, Baylor College of Medicine

Disclosure: Nothing to disclose.

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Disclosure: Nothing to disclose.

Wesley Wu, MD, Mohs Surgeon, Department of Dermatology, VA Puget Sound and University of Washington School of Medicine

Disclosure: Nothing to disclose.

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Malignant melanoma. Image courtesy of Hon Pak, MD.

Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

Malignant melanoma. Image courtesy of Hon Pak, MD.

Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.

Malignant melanoma. Image courtesy of Hon Pak, MD.

Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.