Malignant melanoma (see the image below) is a neoplasm of melanocytes or a neoplasm 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 advanced melanoma.
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Malignant melanoma. Image courtesy of Hon Pak, MD.
See Mole or Melanoma? Test Yourself With These Suspicious Lesions, a Critical Images slideshow, to help identify various skin lesions.
Also, see The Case of the Middle-Aged Woman with Sudden Unilateral Vision Loss slideshow to help identify and treat malignant intraocular melanomas.
Signs and symptoms
The history should address the following:
Family history of melanoma or skin cancer
Family history of irregular, prominent moles
Family history of pancreatic cancer or astrocytoma
Previous melanoma (sometimes multiple; patients have reported as many as 8 or more primary melanomas)
Previous sun exposure
Changes noted in moles (eg, size, color, symmetry, bleeding, or ulceration)
History or family history of multiple nevus syndrome
Physical examination includes the following:
Total-body skin examination, to be performed on initial evaluation and during all subsequent visits
Serial photography, epiluminescence microscopy, and computerized image analysis, to be considered as adjuncts
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 ABCDs, as follows:
A - Asymmetry
B - Border irregularity
C - Color that tends to be very dark black or blue and variable
D - Diameter ≥6 mm
If a patient is diagnosed with a melanoma, examine all lymph node groups.
See Presentation for more detail.
Diagnosis
The following laboratory studies are indicated:
Complete blood count
Complete chemistry panel (including alkaline phosphatase, hepatic transaminases, total protein, and albumin)
Lactate dehydrogenase
The following imaging modalities may be considered:
Chest radiography
Magnetic resonance imaging of the brain
Ultrasonography (possibly the best imaging study for diagnosing lymph node involvement)
Computed tomography of the chest, abdomen, or pelvis
Positron emission tomography (PET; PET-CT may be the best imaging study for identifying other sites of metastasis)
Procedures to be considered in the workup include the following:
Complete excisional biopsy of a suggestive lesion
Surgical excision or reexcision after biopsy
Sentinel lymph node biopsy (SLNB; see Sentinel Lymph Node Biopsy in Patients With Melanoma)
Characteristic histologic findings include the following:
Cytologic atypia, with enlarged cells containing large, pleomorphic, hyperchromic nuclei with prominent nucleoli
Numerous mitotic figures
Pagetoid growth pattern with upward growth of the melanocytes
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. Medical management is reserved for adjuvant therapy in patients with advanced melanoma.
Adjuvant therapy for resectable stage III melanoma includes the following agents[1] :
Immunotherapy with ipilumimab
Interferon alfa
Pegylated interferon[2]
Nivolumab
Aduvant therapy for unresectable stage III, stage IV, and recurrent melanoma may include the following[1] :
Immunotherapy
Signal-transduction inhibitors
Intralesional therapy (talimogene laherparepvec)
Chemotherapy
Palliative local therapy
Agents used in immunotherapy include the following:
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. (See Etiology and Workup.)
Clinically, lesions are classified according to their depth, as follows:
Thin: 1 mm or less]
Moderate: 1-4 mm
Thick: >4 mm
Histologic types of melanoma
There are five different forms, or histologic types, of melanoma:
Superficial spreading
Nodular
Lentigo maligna
Acral lentiginous
Mucosal lentiginous
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. These lesions account for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus.
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 because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas.
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.
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. 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:
Common acquired nevus
Dysplastic nevus
Congenital nevus
Cellular blue nevus
Genetics
Many genes are implicated in the development of melanoma, including 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 radiation (UVR) 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.
UVR 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. This sun-associated risk factor is different than that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.
LMM is an exception to this rule, because it frequently appears on the head and neck of older individuals who have a history of 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.[6, 7]
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).[6, 7]
Additional risk factors
Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses are 2 etiologic agents that also have been implicated in the development of melanoma.
Greatly elevated risk factors for cutaneous melanoma include the following:
Changing mole
Dysplastic nevi in familial melanoma
More than 50 nevi, 2 mm or greater in diameter
Moderately elevated risk factors for cutaneous melanoma include the following:
One family member with melanoma
Previous history of melanoma
Sporadic dysplastic nevi
Congenital nevus
Slightly elevated risk factors for cutaneous melanoma include the following:
The American Cancer Society estimates that 96,480 cases of cutaneous melanoma will be diagnosed in the United States in 2019 (57,220 in men and 39,260 in women). Overall rates of melanoma rose rapidly over the past 3 decades. From 2006 to 2015, the rate increased by 3% per year in men and women ages 50 and older, but remained stable in persons younger than age 50.[8]
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 7,230 people in the US (4,740 men and 2,490 women) will die of melanoma in 2019.[8]
International statistics
The incidence of malignant melanoma has been increasing rapidly worldwide, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women. Queensland, Australia, has the highest incidence of melanoma in the world, approximately 57 cases per 100,000 people per year. Israel also has one of the highest incidences, approximately 40 cases per 100,000 people annually.
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 people per year.
Sex- and age-related demographics
Overall, melanoma is the fifth most common malignancy in the US population, accounting for 7% of all new cancer cases in men and 5% of all new cases in women. However, the relative incidence of melanoma in men and women varies markedly by age: in people younger than 50 years of age, incidence rates are higher in women than in men, but by age 65, they are twice as high in men as in women, and by age 80 they are three times as high as in men. Those differences primarily reflect differences in occupational and recreational sun exposure, which have changed over time.[8] 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 64 years, and 63% of patients are 45 to 84 years old.[9]
Melanoma is the most common malignancy in women aged 25-29 years and accounts for more than 7000 deaths annually in that age group. Melanoma is notorious for affecting young and middle-aged people, unlike other solid tumors, which mainly affect older adults. It is commonly found in patients younger than 55 years, and it accounts for the third highest number of lives lost across all cancers.
Malignant melanomas usually present at 2 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 nil, 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.[10] This confirms prior studies.
The most important prognostic factors include the following[1] :
Thickness and/or level of invasion
Mitotic index (mitoses per millimeter)
Ulceration or bleeding at the primary site
Number of regional lymph nodes involved, with distinction of macrometastasis and micrometastasis
Systemic metastasis, including the site (nonvisceral versus lung versus all other visceral sites) and serum lactate dehydrogenase (LDH) level elevation
In general, positive prognostic factors include the following[1] :
Younger age
Female sex
Melanoma located on the extremities
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.[11]
Prognosis is also worse in patients with immune compromise.[12] 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.[13]
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.[14]
Stage and prognosis
Prognosis depends on the disease stage at diagnosis. According to SEER data from 2008-2014, 5-year relative survival rates are as follows[9] :
Localized (confined to primary site) - 98.4%
Regional (spread to regional lymph nodes) - 63.6%
Distant (metastatic) - 22.5%
For stage IV melanoma, prognosis varies according to the site of metastasis; survival is progressively worse with metastasis to extra-regional lymph nodes or distant skin, lung, digestive tract, or brain, respectively.[15] Prognosis is also poorer in older patients and those with immune compromise (eg, organ transplant recipients, persons with HIV infection).[12]
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 8 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.
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.[16]
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 ABCDs for differentiating early melanomas from benign nevi include the following:
A - Asymmetry (melanoma lesion more likely to be asymmetrical)
B - Border irregularity (melanoma more likely to have irregular borders)
C - Color (melanoma more likely to be very dark black or blue and to have variation in color than would a benign mole, which more often is uniform in color and light tan or brown)
D - Diameter (mole < 6 mm in diameter usually benign)
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A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.
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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.
The diagnosis of melanoma is confirmed by excisional biopsy. Sentinel lymph node biopsy is appropriate in selected patients.
Laboratory studies that are indicated include the following:
Complete blood cell count (CBC)
Comprehensive serum chemistry panel
Serum lactate dehydrogenase (LDH) level
Imaging studies are often obtained in patients with newly diagnosed melanoma, to rule out clinically occult distant disease. Nevertheless, available evidence suggests that preoperative imaging studies have significant costs and offer minimal benefit in most patients with melanoma.[17] 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.[18]
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 are generally performed for completeness. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanoma. The S-100 is highly sensitive, although not specific, for melanoma, while the HMB45 is highly specific and moderately sensitive for melanoma. The 2 stains, in concert, can be useful in diagnosing poorly differentiated melanomas.
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.
The LDH level is elevated in many conditions, including many malignancies. Although LDH elevation is not specific for melanoma, it may be useful at diagnosis and also in the follow-up care of 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 now is considered part of the staging system for melanoma.
For patients with stage I or II disease, a chest radiograph is often obtained, although its result will likely be negative. To date, no studies support obtaining a radiograph in these patients, but 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 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 neurological symptoms.
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.
CT scan of the abdomen
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
This study 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.
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 to utilize for finding other sites of metastasis.[18] 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.[19] Finally, PET scans often are useful in evaluating the response of metastatic disease to therapy.
A complete excisional biopsy is preferred. The sample should have a 1-3 mm margin of healthy skin and should include all layers of skin and some subcutaneous fat. Although sparing of the deep fascia is not standard in biopsies for suspected melanoma, investigators at the Mayo Clinic recommend this practice in some patients.[20]
If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy specimen should be taken from the most abnormal area of the lesion.
A shave biopsy is usually contraindicated, as it may compromise pathologic diagnosis and complete determination of Breslow thickness. However, the National Comprehensive Cancer Network suggests that shave biopsy is acceptable when the index of suspicion is low, and a broad shave biopsy may help optimize diagnostic sampling in cases of lentigo maligna melanoma in situ.[21] In cases where a shave biopsy was done inappropriately, a complete excisional biopsy of the lesion should be performed if possible to determine the depth and extent of the lesion.
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 be performed.
Current recommendations for surgical margins of excision are as follows[21] :
In situ lesions - 0.5-1 cm margin
Lesions ≤ 1 mm in thickness - 1 cm margin
Lesions 1.01 - 2 mm in thickness - 1-2 cm margin
Lesions 2.01-4 mm in thickness - 2 cm margin
Lesions greater than 4 mm in thickness - At least 2 cm margin
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.[22]
Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a complete regional lymph node dissection (LND).
For years, patients without clinically enlarged nodes underwent 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.
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.[1]
Sentinel lymph node biopsy (SLNB) is now known to offer important prognostic, diagnostic, and therapeutic information.[23]
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.[21] 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.[21]
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.[24]
Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.
Level I - All tumor cells above basement membrane (in situ)
Level II - Tumor extends into papillary dermis
Level III - Tumor extends to interface between papillary and reticular dermis
Level IV - Tumor extends between bundles of collagen of reticular dermis (extends into reticular dermis)
Level V - Tumor invasion of subcutaneous tissue
Breslow classification (thickness) is as follows:
0.75 mm or less
0.76-1.5 mm
1.51-4 mm
4 mm or more
The American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging system for cutaneous melanoma are provided below.[25]
T classification (thickness) is as follows:
TX: Primary tumor cannot be assessed (shave biopsy)
T0 : No evidence of primary tumor
Tis: Melanoma in situ
T1: ≤1.0 mm (ulceration unknown or unspecified)
T1a: < 0.8 mm without ulceration
T1b: < 0.8 mm with ulceration; 0.8-1.0 mm with or without ulceration
T2 : >1.0-2.0 mm (ulceration unknown or unspecified)
T2a: >1.0-2.0 mm without ulceration
T2b: >1.0-2.0 mm with ulceration
T3: >2.0-4.0 mm (ulceration unknown or unspecified)
T3a: >2.0-4.0 mm without ulceration
T3b: >2.0-4.0 mm with ulceration
T4: >4.0 mm (ulceration unknown or unspecified)
T4a: >4.0 mm without ulceration
T4b: >4.0 mm with ulceration
N classification (regional lymph node and/or lymphatic metastasis) is as follows:
NX: Regional nodes not assessed
N0: No regional metastases detected
N1: One tumor-involved node; or in-transit, satellite, and/or microsatellite metastases with no tumor-involved nodes
N1a: One clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
N1b: One clinically detected; no in-transit, satellite, or microsatellite metastases
N1c: No regional lymph node disease; in-transit, satellite, and/or microsatellite metastases found
N2: Two or three tumor-involved nodes; or in-transit, satellite, or microsatellite metastases
N2a: Two or three clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
N2b: Two or three clinically detected; no in-transit, satellite, or microsatellite metastases
N2c: One clinically occult or clinically detected; in-transit, satellite, and/or microsatellite metastases found
N3: ≥4 tumor-inolved nodes or in-transit, satellite, and/or microsatellite metastases with ≥2 tumor-involved nodes or any number of matted nodes without or with in-transit, satellite, and/or microsatellite metastases
N3a: ≥4 clinically occult (ie, detected by sentinel lymph node biopsy); no in-transit, satellite, or microsatellite metastases
N3b: ≥4, at least one of which was clinicallly detected, or presence of any matted nodes; no in-transit, satellite, or microsatellite metastases
N3c: ≥2 clinically occulr or clinically detected and/or presence of any matted nodes, with presence of in-transit, satellite, and/or microsatellite metastases
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:
M0: No evidence of distant metastasis
M1a: Distant skin, subcutaneous, or nonregional nodal metastases;
M1a: Distant skin, subcutaneous, or nonregional nodal metastases
M1b: Lung metastasis, with or without M1a involvement
M1c - Distant metastasis to non–central nervous system (CNS) visceral sites, with or without M1a or M1b involvement
M1d: Distant metastasis to CNS, with or without M1a-c involvement
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.
Surgery is the definitive treatment for early-stage melanoma. Wide local excision with completion lymph node dissection (CLND) in patients with positive sentinel lymph node biopsy results is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease.[26]
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[1]
Stage 0 - Excision
Stage I - Excision, with or without lymph node management
Stage II - Excision, with or without lymph node management
Resectable stage III - Excision, with or without lymph node management; adjuvant therapy and immunotherapy
Unresectable stage III, stage IV, and recurrent melanoma - Intralesional therapy, immunotherapy, signal transduction inhibitors, chemotherapy, palliative local therapy
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 V600mutation.
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 or combination therapy with nivolumab plus ipilimumab.[21]
For patients with a BRAF mutation, the NCCN recommends targeted combination therapy with dabrafenib/trametinib or vemurafenib/cobimetinib.[21] 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).
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.[1]
Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.
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). CLND achieves good regional disease control. Careful observation is an alternative for patients with low-risk micrometastatic disease, with due consideration of clinicopathologic factors. For higher-risk patients, however, the guidelines advise that careful observation may be considered only after a thorough discussion with patients about the potential risks and benefits of foregoing CLND.[27]
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.[28, 29]
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).[28, 29]
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%.[28, 29]
In patients whose SLNB reveals micrometastases, a randomized phase III 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.[30]
Adjuvant therapy is used for metastatic, unresectable melanoma, and most recently, resected advanced-stage disease. Although observation rather than adjuvant therapy is standard for stage II melanoma, 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.[31]
Dabrafenib plus trametinib
In 2018, the 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% 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 0.47; 95% confidence interval 0.39, 0.58; P< 0.0001).[32]
Pembrolizumab
Pembrolizumab is indicated for first-line treatment of unresectable or metastatic melanoma. In addition, in February 2019, pembrolizumab gained FDA approval for adjuvant treatment of resected, high-risk stage 3 melanoma. Approval was based on data from the EORTC1325/KEYNOTE-054 trial (n=1019) showing a significantly prolonged 1-year recurrence-free survival compared with placebo (75.4% vs 61%; P < 0.001).[33]
Nivolumab
In 2017, the FDA approved nivolumab as an adjuvant treatment for patients with lymph node involvement or metastatic disease who have undergone complete resection. Approval was based on findings from the phase III 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 recurrence-free survival rate was 70.5% in the nivolumab arm compared with 60.8% in the ipilimumab arm (hazard ratio for disease recurrence or death, 0.65; 97.56% confidence index, 0.51 to 0.83; P< 0.001).[34] 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 greater proportion of patients achieving an objective response and fewer toxic effects in patients treated with nivolumab (n=272) than in those treated with dacarbazine, or paclitaxel plus carboplatin (objective response rates 31.7 versus 10.6, respectively).[4]
Ipilimumab
In a phase III trial in patients with high-risk stage III melanoma, adjuvant therapy with the checkpoint inhibitor ipilimumab resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis–free survival compared with placebo.[35] 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 recurrence-free survival—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—38.6% 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.[35]
Intralesional therapy
In October 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.[36]
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 III 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).[37]
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.[37]
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.[37]
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.[38]
Interferon alfa
A large multicenter study using high-dose interferon (IFN) alfa-2b, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit).[39] On the basis of ECOG-1684, the US Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.
A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P = 0.006) but not overall survival (P = 0.42).[40]
Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.
To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective, randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomized to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.[41]
On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome. In their prospective, randomized, multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 wk and 5 times weekly subcutaneously for another 2 wk) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months.[42]
Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective, randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups.[43]
Meta-analysis data show that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.[44]
Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy following 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.[2]
Granulocyte-macrophage colony-stimulating factor
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high-risk melanoma. In a study of 46 patients with resected stage III or IV melanoma treated with a subcutaneous dose of 125 mg/m2 for 2 weeks on and 2 weeks off for a year, progression-free survival was 37 months, vs 12 months in historical controls.[45] . This treatment is no longer used due to the availability of more effective treatments.
However, a subsequent double-blind, placebo-controlled trial that compared the effect of GM-CSF and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in 815 patients with resected high-risk melanoma (locally advanced and/or stage 4) found that neither adjuvant GM-CSF nor PV significantly improved RFS or OS. Exploratory analyses did show a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases.[46]
Treatment of patients with advanced-stage (stage IV) melanoma has continued to improve despite the challenges. Chemotherapy is used less frequently due to the more efficacious drugs have been developed, including immunotherapy and BRAF and MEK inhibitors.
Single-agent dacarbazine (DTIC) yields only a 10-15% response rate.[47] Two combination regimens that were once commonly used in the treatment of patients with advanced-stage melanoma are cisplatin, vinblastine, and DTIC (CVD), and the Dartmouth regimen, which consists of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens.[48] . Due to increased toxicity it is not used today.
Dacarbazine
Dacarbazine was the first drug approved by the US Food and Drug Administration (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 III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%, respectively.[49] On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists prefer temozolomide as a first-line chemotherapy drug for 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. The overall median survival was 11.4 months.[50]
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 renal and hepatic function.
Carboplatin and paclitaxel
Carboplatin and paclitaxel have been tested in two small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This regimen sometimes is being 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 III 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.[51, 52]
Treatment of melanoma with BRAF mutations
BRAF mutations are present in 60% of melanomas. Detection of this mutation is important prior to starting treatment in any melanoma patient. In a multicenter, phase I, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032).[53] Two patients had a complete response and 24 had a partial response.
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.[54]
Vemurafenib (Zelboraf) was approved by the FDA in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF -V600E. This agent is indicated for the treatment of unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.
In May 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.[55] In a multicenter, open-label, phase III randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[56]
Phase III trial results for the BRAF inhibitor 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.[57]
In addition, the overall survival rate at 6 months in the vemurafenib group was 84%, versus 64% in the dacarbazine group.[57] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve the BRAF V600E mutation. 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.[57]
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.[57] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.
Dabrafenib was shown to significantly improve progression-free survival compared with dacarbazine (5.1 vs 2.7 mo) in patients with BRAF-mutated metastatic melanoma in a multicenter, open-label, phase III randomized controlled trial.[58]
Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[55] Approval was based on a phase III open-label trial in which median progression-free survival 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).[59]
In January 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 I/II study. Median progression-free survival in the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% 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 has not been demonstrated for this combination.[60, 61, 62]
In November 2015, the FDA approved cobimetinib, an 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 progression-free survival was longer with cobimetinib plus vemurafenib than with vemurafenib monotherapy (12.3 vs 7.2 months; hazard ratio, 0.58; 95% confidence interval, 0.46 - 0.72). Additionally, the objective response rate was higher with the combination than with vemurafenib alone (70% vs 50%; P < 0.0001).[63]
The combination of binimetinib (Mektovi), a MEK inhibitor, plus encorafenib (Braftovi), a BRAF inhibitor, was approved by the FDA in June 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 progression-free survival compared with vemurafenib alone (14.9 months versus 7.3 months, respectively (P< 0.0001).[64]
Treatment of BRAF V600 wild-type melanoma
The first choice of first-line treatment for patients with BRAF V600 wild-type, unresectable or metastatic melanoma is nivolumab plus ipilimumab.
Nivolumab (Opdivo), another PD-1 inhibitor, was granted accelerated approval in December 2014 for unresectable or metastatic melanoma and disease progression following ipilimumab treatment and, if BRAF V600 mutation positive, a BRAF inhibitor. 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% confidence interval [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 November 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 was 72.9% (95% CI, 65.5 to 78.9) in the nivolumab group versus 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group.[65]
A significant benefit with respect to overall survival was observed in the nivolumab group, as compared with the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P< 0.001). Median progression-free survival was also improved in the nivolumab-treated patients compared with dacarbazine (5.1 vs 2.2 months; HR, 0.43; P < 0.001).[65]
The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma. Approval was based on results from the phase 2 CheckMate-069 study Of the 142 patients enrolled, 109 had both BRAF wild-type and BRAF mutation-positive melanoma. The primary endpoint was objective response rate (ORR) in patients. In patients with BRAF wild-type melanoma treated with the combination regimen, the overall response rate was 61% (95% CI: 48-71) compared to 11% (95% CI: 3-25) in patients given ipilimumab monotherapy (P < 0.001).
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).[66]
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. [67]
In January 2016, the indication for nivolumab was expanded to include mutation-positive melanoma, making nivolumab effective across BRAF status.[54]
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 September 2014, the FDA granted accelerated approval for pembrolizumab (Keytruda). Pembrolizumab is the first monoclonal antibody for inhibition of PD-1.[68] It was initially indicated for unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on data including a study in which approximately 24% of patients experienced tumor shrinkage.[3]
In December 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 2wk or every 3wk, or 4 doses of ipilimumab (3 mg/kg every 3wk). Progression-free survival for the pembrolizumab groups were 47.3% and 46.4% respectively and 26.5% for ipilimumab. Note that the trial used a higher dose of pembrolizumab than the dose that is approved by the FDA, which is 2 mg/kg every 3 wk.[69]
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.[70] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T cells.
Ipilimumab has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently under way.[71] Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma. In July 2017, ipilimumab was approved in adolescents aged 12 years or older for treatment of unresectable or metastatic melanoma.[72]
Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. In a phase III 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.[71]
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.[71]
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.[73]
In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus gp100; (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[74] 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.[74]
The FDA approved the combination regimen of nivolumab plus ipilimumab on September 30, 2015 in previously untreated patients with BRAF V600 wild-type unresectable or metastatic melanoma.[66] Additionally, it is indicated for the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection, including total lymphadenectomy.[75]
The use of immune checkpoint inhibitors for the treatment of advanced melanoma has evolved beyond monotherapies to combination strategies. This combination approach results in response rates around 60% and superior progression-free survival compared with ipilimumab monotherapy (median 11.5 versus 2.9 months).[76]
Ipilimumab is also approved in the adjuvant setting. See Adjuvant therapy, above.
Combined nivolumab and ipilimumab
Nivolumab and ipilimumab have complementary activity in metastatic melanoma. In the CheckMate 067 study, a randomized, double-blind, multicenter, phase 3 trial in 945 previously untreated patients with metastatic melanoma, nivolumab combined with ipilimumab and nivolumab alone resulted in significantly longer progression-free survival than ipilimumab alone; in those patients with PD-L1–negative tumors, combination therapy was more effective than either agent alone.[54]
On 5-year follow-up of CheckMate 067 patients, overall survival was 52% in the nivolumab-plus-ipilimumab group, compared with 44% in the nivolumab group and 26% in the ipilimumab group. Median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group, 36.9 months in the nivolumab group, and 19.9 months in the ipilimumab group. Hazard ratios for death were 0.52 with nivolumab plus ipilimumab vs. ipilimumab, and 0.63 with nivolumab vs. ipilimumab.97 Current National Comprehensive Cancer Network guidelines include nivolumab plus ipilimumab as one of the preferred first-line therapeutic options for unresectable or malignant melanoma.[21]
External-beam radiation
The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; 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.[26]
KIT inhibitor therapy
In a multicenter phase II trial, targeted therapy with imatinib was an effective treatment option in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene.[77, 78, 79] Of 50 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT -mutant (n = 8), KIT -amplified melanoma (n = 11), or both (n = 5) were treated with imatinib. Seven of these 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%.[77, 78]
These findings reinforce similar findings in two earlier studies.[5, 80]
Vaccines
A phase III trial found that peptide vaccination did not significantly improve relapse-free survival or overall survival in patients with high-risk resected melanoma.[46] However, in two small phase I studies, personalized treatment vaccines for melanoma generated a robust immune response and may have helped prevent recurrences. In the studies, researchers identified genetic mutations specific to each patient’s tumor and the neoantigens associated with those mutations. They then produced a peptide-based DNA or RNA vaccine targeting a number of those neoantigens.[81]
In these studies, some of the treated patients remained recurrence free for up to 25 months. Other patients experienced recurrences but responded to treatment with the checkpoint inhibitor pembrolizumab. [81]
The focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against exposure to ultraviolet radiation, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15.
This last recommendation is considered somewhat controversial, because no study has shown sunscreen to reduce the incidence of melanoma.[82] Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.[83]
In addition, a study of 499 white children who were enrolled at birth or at age 6 and stratified colorimetrically by skin tone found no association between sunscreen use and the overall number of moles at the age of 15 years. The only significant association was for lighter-skinned children who had at least three sunburns at 12 to 14 years old, who had fewer moles if they used sunscreen. However, even that association might have occurred by chance.[84]
First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.
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.[21]
Follow-up for stage 0 in situ is as follows:
At least annual skin examination for life
Educate patient in monthly self-examination of skin
Follow-up for stage IA is as follows:
History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:
H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
Chest radiography, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) every 6-12 mo (optional)
Routine imaging is not recommended for stage IB or IIA disease
CT scans to follow up for specific signs and symptoms
Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
At least annual skin examination for life
Educate patient in monthly self-examination of skin and lymph nodes
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 2016, the U.S. Preventive Services Task Force (USPSTF) concluded there is not enough evidence to recommend for or against routine screening (total body examination by a primary care physician or patient self-examination) for early detection of skin cancers in the adult general population.[85]
The USPSTF did note the following clinical considerations:
Skin cancer of any type occurs more commonly in men than in women and among persons with a fair complexion, persons who use indoor tanning beds, and persons with a history of sunburns or previous skin cancer.
Specific risk factors for melanoma include having an atypical mole, multiple (ie, ≥100) moles, and having a family history of melanoma.
The risk of melanoma increases with age; the median age at diagnosis is 63 years, and the median age at death is 69 years.
Clinical visual skin examination should assess skin lesions for asymmetry, border irregularity, color variability, diameter greater than 6 mm or evolution over time (ABCDE criteria)
Guidelines from the American Academy of Dermatology (AAD), established in 2011 and updated in 2019, are as follows[86, 87] :
Skin biopsy remains the first step to establish a definitive diagnosis of cutaneous melanoma.
Preferred biopsy technique is a narrow excisional/complete biopsy with 1- to 3-mm margins that encompass the entire breadth of lesion and is of sufficient depth to prevent transection at the base. Diagnostic excisional biopsy can be accomplished by (1) elliptical (fusiform) excision, (2) punch excision around the clinical lesion, or (3) deep shave/saucerization to a depth below the anticipated plane of the lesion, usually extending to the deep reticular dermis.
Partial/incomplete sampling (incisional biopsy) is acceptable for lesions whose large size or location in a challenging anatomic site (eg, facial, acral) precludes excisional biopsy, and for lesions with low clinical suspicion or uncertainty of diagnosis. Such biopsies should include the most clinically and/or dermoscopically atypical portion(s) of the lesion
Narrow-margin excisional biopsy may be performed if an initial partial biopsy is inadequate for diagnosis or microstaging, but it should not generally be performed if the initial specimen meets the criteria for consideration of sentinel lymph node biopsy.
Dermoscopy can improve diagnostic accuracy in lesions of clinical concern; it may help direct optimal and adequate tissue sampling of very large lesions or those in cosmetically or functionally sensitive areas.
Prebiopsy photographs are an important aid to clinical/pathologic correlation and help to prevent wrong-site surgery if further treatment is required. Photographs may be taken by the patient and/or health care provider and should include a regional photograph that encompasses anatomic landmarks.
Findings from history and physical examination should direct need for further studies to detect local, regional, and distant metastasis
Ancillary diagnostic molecular techniques (eg, comparative genomic hybridization; fluorescence in situ hybridization, gene expression profiling [GEP]) may be used for equivocal melanocytic neoplasms, but routine molecular testing, including GEP, for prognostication is discouraged until better use criteria are defined. Testing of the primary cutaneous melanoma for oncogenic mutations (eg, BRAF, NRAS) is not recommended in the absence of metastatic disease.
The 2015 guidelines from the European Society of 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[88] :
Information on the type of melanoma
Actinic damage
Maximum vertical thickness in millimetres
Information on mitotic rate in case of pT1
Presence of ulceration
Presence and extent of regression
Clearance of the surgical margins
Physical examination with special attention to other suspicious pigmented lesions, tumour satellites, in-transit metastases, regional LN and distant metastases is requried. Imaging is not needed for low-risk melanomas but is required in higher tumor stages for accurate staging.[88]
The National Comprehensive Cancer Network (NCCN) supports 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.[21]
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.[21]
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.[25]
American Academy of Dermatology (AAD) recommendations for surgical management of primary cutaneous melanoma are as follows[87] :
Surgical excision with histologically negative margins is the recommended and first-line treatment for primary cutaneous melanoma of any thickness, as well as for melanoma in situ.
Surgical margins should be based on tumor thickness.
Depth of excision is recommended to (but not including) the fascia.
Sentinel lymph node biopsy, when indicated, should be performed before wide excision of the primary tumor, and in the same operative setting, whenever possible.
Mohs micrographic surgery or staged excision with paraffin-embedded permanent sections may be utilized for melanoma in situ, lentigo maligna type, on the face, ears, or scalp for tissue-sparing excision and exhaustive histologic assessment of peripheral margins.
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).[21]
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.[2] ESMO recommends sentinel lymph node biopsy with lesions >1 mm and/or ulceration for precise staging. In addition, sentinel lymph node biopsy should be discussed with patients with a T1b tumor greater than 0.75 mm.[88]
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[86, 87] :
Ulceration
Mitosis
Angiolymphatic invasion
Positive deep margin
Young patient age
However, data suggest that the presence of a single mitotic figure may not correlate well with sentinel node status in thin lesions.[89] In addition, the presence of regression in thin lesions is associated with a lower risk of nodal metastasis.[90]
The 2018 update of joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) includes the following recommendations[27] :
Routine sentinel lymph node biopsy is not recommended for patients with thin melanomas that are T1a (non-ulcerated lesions < 0.8 mm in Breslow thickness).
Sentinel lymph node biopsy may be considered for thin melanomas that are T1b (0.8 to 1.0 mm Breslow thickness or < 0.8 mm Breslow thickness with ulceration) after a thorough discussion with the patient of the potential benefits and risk of harms associated with the procedure.
Sentinel lymph node biopsy is recommended for patients with intermediate-thickness melanomas (T2 or T3; Breslow thickness of >1.0 to 4.0 mm).
Sentinel lymph node biopsy may be recommended for patients with thick melanomas (T4; > 4.0 mm in Breslow thickness), after a discussion of the potential benefits and risks of harm.
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.[27]
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).[21, 91]
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[92] :
Head
Neck
Hands
Feet
Pretibial surface
Nails
Ankles
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.[87]
For wide excision of primary melanoma, the NCCN, AAD, and ESMO practice guidelines agree on the following surgical margin recommendations for primary melanoma[21, 87, 88]
Tumor in situ – Margin size 0.5-1.0 cm
Tumor ≤ 1 mm – Margin size 1 cm
Tumor > 1 to 2 mm – Margin size 1-2 cm
Tumor > 2 mm – Margin size 2 cm
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.[87]
NCCN guidelines recommend consideration of radiation therapy in the following situations[21] :
Primary disease: As adjuvant treatment in selected patients with factors that include deep desmoplastic melanoma with narrow margins, extensive neurotropism, or locally recurrent disease
Regional disease: As adjuvant treatment following resection of category 2B nodes and LDH < 1.5 times the upper limit of normal, and extranodal tumor extension; as palliative treatment for unresectable disease
Metastatic disease: As either adjuvant or primary treatment for brain metastases
ESMO recommends considering stereotactic radiation of regional or single distant metastatic disease.[88]
NCCN recommendations for treatment of melanoma stage IV disease with distant metastasis include the following[21] :
Treatment depends on whether melanoma is limited (resectable) or disseminated (unresectable)
In limited disease, resection is recommended; alternatively, observation or systemic therapy may be chosen
Treatment for limited disease includes clinical trial enrollment or systemic therapy
For patients with unresectable disease without brain metastases, treatment includes systemic therapy; patients with brain metastases require treatment of the central nervous disease
First-line immunotherapy regimens for systemic therapy (category 1), according to the NCCN guidelines, are as follows[21] :
Anti–PD-1 monotherapy: Pembrolizumab or nivolumab
Nivolumab/ipilimumab
If the tumor contains a BRAF V600 activating mutation, category 1 recommendations for first-line therapy are as follows[21] :
Dabrafenib plus trametinib
Vemurafenib plus cobimetinib
Encorafenib plus binimetinib
Second-line or subsequent therapy recommendations are as follows[21] :
Anti PD-1 monotherapy: Pembrolizumab or nivolumab
Nivolumab/ipilimumab
Targeted therapy if a BRAF V600 activating mutation is present: Dabrafenib/trametinib or vemurafenib/cobimetinib
Ipilimumab
High-dose interleukin-2 (IL-2)
Cytotoxic agents
Imatinib for tumors with activating mutations of KIT
Chemotherapy agents used for adjuvant treatment of melanoma include dacarbazine, cisplatin, and vinblastine. Nivolumab, ipilimumab, or interferon (IFN) alfa-2b are options for adjuvant therapy approved by the US Food and Drug Administration (FDA) for high-risk resected melanoma, defined as deep primaries greater than 4 mm in Breslow depth (American Joint Committee on Cancer [AJCC] stage IIB) and regional lymph node metastasis (stage III). IFN is given in high doses, as trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates.[93] Nivolumab and pembrolizumab are options for adjuvant therapy of resected advanced melanoma.
Dabrafenib plus trametinib is also a useful combination 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.[32]
Intralesional injection with talimogene laherparepvec is approved for skin metastasis.
For metastatic melanoma, the first approach would be to determine the BRAF status of the melanoma. If BRAF mutation is present, the therapy of choice would be the combination of a BRAF inhibitor and MEK inhibitor. For tumors with wild-type BRAF, the option would be combination treatment with nivolumab and ipilimumab or nivolumab or pembrolizumab. The treatment approach should be individualized depending on the patient's performance status and underlying comorbidities.
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.
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.
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.
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.
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.
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.
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.
Clinical Context:
Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is used in the Dartmouth regimen to possibly abrogate the multidrug resistance phenotype.
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.
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 for treatment of patients with BRAF V600 wild-type or mutation-positive unresectable or metastatic melanoma is superior to either drug alone.
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.
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.
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.
These agents inhibit cell growth and differentiation. Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.
Clinical Context:
IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is the drug of choice for adjuvant therapy in patients with high-risk melanoma. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.
IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.
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 March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. It is the first therapy approved for the adjuvant treatment of melanoma in 15 years.
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.
Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and interleukin (IL)-2. An oncologist should administer these treatments.
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.
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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?When is talimogene laherparepvec (Imlygic) indicated in the treatment of malignant melanoma?What is the mechanism of action for talimogene laherparepvec (Imlygic) in the treatment of malignant melanoma?What is the efficacy of talimogene laherparepvec (Imlygic) against malignant melanoma?What is the durable response rate (DRR) for talimogene laherparepvec (Imlygic) in the treatment of malignant melanoma?What is the overall response rate (ORR) for talimogene laherparepvec (Imlygic) in the treatment of malignant melanoma?What is the efficacy of combination therapy for malignant melanoma with talimogene laherparepvec (Imlygic) and immune checkpoint inhibitors?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 USPSTF 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 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 NCCN guidelines for sentinel lymph node biopsy in patients with malignant 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 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 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?
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: Nothing to disclose.
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
Disclosure: Nothing to disclose.
References
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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.
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.
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.
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