Melanoma is a malignancy of melanocytes and one of the leading causes of skin cancer morbidity and mortality. This malignancy can occur as a result of environmental factors, such as chronic or intense sun exposure, although a family history of melanoma or the presence of specific genetic mutations or polymorphisms can predispose individuals to develop melanoma. Cutaneous melanoma is the primary form of the disease, but other forms can also occur (eg, uveal or mucosal melanoma). Histology is the mainstay of diagnosis, and other laboratory testing is not generally used for melanoma diagnosis or staging. However, molecular testing may be useful in cases of metastasis or equivocal histologic results, in the selection of patients for targeted gene therapy, and in genetic risk assessment for select patients. Laboratory testing may also be useful for prognosis and monitoring.
Quick Answers for Clinicians
The preferred approach to melanoma diagnosis involves clinical examination followed by biopsy of lesions suspicious for melanoma. Biopsy margins of 1 to 3 mm are recommended; wider margins are discouraged. The orientation of the excisional biopsy (eg, longitudinal orientation in the extremities, parallel to lymphatics) should take into account definitive treatment. Complete excision is preferred, but a full-thickness incisional or punch biopsy of the thickest or most atypical area of a lesion is acceptable for particularly large lesions and for lesions in specific anatomic sites, such as the palm, the sole of the foot, digits, facial area, or ear. Shave biopsies can be inadequate for pathologic examination and diagnosis and are discouraged except when suspicion for malignancy is low. If the lesion cannot be excised according to these recommendations, the patient should be referred to a specialist for biopsy.
Risk factors for primary melanoma include male sex; older age (>60 years); phenotypic predisposition (eg, prone to sunburn); history of multiple or blistering sunburns; environmental factors such as chronic sun exposure; a high number of moles or large/atypical moles; cancer or precancerous conditions; immune suppression or dysregulation; rare inherited skin conditions; and genetic variants associated with melanoma, some of which are also associated with other malignancies such as pancreatic cancer, astrocytoma, or mesothelioma. (See Molecular Testing.)
Uveal melanoma, which comprises only 3-5% of melanomas, arises from melanocytes found in the iris, ciliary body, and/or choroid of the eye. Mucosal melanomas comprise about 1.4% of all melanomas and originate in melanocytes in the mucosal tissue of the respiratory, gastrointestinal, or urogenital tracts. Leptomeningeal melanomas can also occur, and rarely, melanomas can arise in internal organs.
Indications for Testing
Laboratory testing for melanoma should be considered in patients with equivocal histopathologic results following a biopsy, metastatic disease, and in those considering or undergoing treatment for melanoma.
Next generation sequencing (NGS), single-gene assays, and small multigene panels can be used for molecular testing. Immunohistochemistry (IHC) staining can be used as an indirect approach to identify genetic variants by detecting protein aberrations (eg, BRAF V600E and c-KIT).
Diagnosis and Staging
Histopathologic examination of a skin biopsy is the mainstay for diagnosis of melanocytic lesions. Although not recommended for routine diagnostic evaluation in cutaneous melanoma, molecular testing may be useful in patients with metastatic disease and in patients being considered for clinical trial participation. Molecular testing using cytogenetic methods (eg, comparative genomic hybridization, fluorescence in situ hybridization [FISH], gene expression profiling, or IHC) may also be useful when histopathologic findings are inconclusive.
In patients with stage III melanoma who have a high risk for recurrence, BRAF mutation testing can help determine whether future BRAF-directed therapy would be advisable; however, this testing is not recommended in patients with stage I-II melanoma unless they are being considered for clinical trials. The most common BRAF mutations in melanoma are V600 mutations, which are associated with sensitivity to BRAF inhibitors, MEK inhibitors, and a combination of the two. Available data indicate that patients without BRAF V600 mutations should not be considered for BRAF inhibitor treatment.
Testing for KIT mutations can be considered in patients with stage IV disease at presentation or with disease recurrence. KIT mutations are found in 10-15% of melanomas of mucosal and acral origin and may be found in a small number of melanomas (2-3%) that result from chronic sun exposure. Therefore, clinical characteristics help inform whether to perform KIT mutation testing. KIT exon 11 and exon 13 mutations appear to be highly sensitive to KIT inhibitors, whereas KIT exon 17 mutations and KIT amplifications have limited or no sensitivity to KIT inhibitors.
NRAS mutations are associated with poor survival in both localized and advanced melanoma and are found in roughly 15% of both melanomas of acral or mucosal origin and melanomas that result from increased sun exposure. Some evidence suggests patients with NRAS mutations may respond to MEK inhibitors, although the value of routine MEK inhibitor use in these patients has not been established. Because targetable mutations (including BRAF and KIT mutations) are unlikely to overlap, patients with NRAS mutations may not benefit from additional molecular testing.
Genetic Risk Assessment
Patients with variants in certain genes (eg, CDKN2A, CDK4, TERT promoter, MITF E318K, and BAP1) may be predisposed to melanoma and other cancers. Although rare, BAP1 tumor syndrome has been shown to be a cause of hereditary melanoma; it has high penetrance for uveal melanoma and medium penetrance for cutaneous melanoma. Patients with cutaneous melanoma should be considered for genetic risk assessment if they have :
- Two or more blood relatives with a history of invasive cutaneous melanoma or pancreatic cancer
- Multiple primary invasive cutaneous melanomas (three or more), one of which occurs by or before 45 years of age
- One or more melanocytic BAP1-mutated atypical intradermal tumors (MBAITs) and a family history of mesothelioma, meningioma, or uveal melanoma
- Two or more MBAITs
Serum lactate dehydrogenase (LDH) testing is recommended in patients with advanced-stage melanoma; increased LDH concentrations are associated with worse survival and may also predict response to therapy. LDH results are taken into account by the American Joint Committee on Cancer (AJCC) staging system for melanoma and are an important factor in determining prognosis in patients with stage IV disease. Serum LDH testing is not considered adequately sensitive or specific to detect metastases and is not recommended at baseline or for surveillance in patients with in situ melanoma or early-stage cutaneous melanoma who do not have signs or symptoms of metastasis.
S-100B protein has been investigated both for its relevance as a prognostic marker and as a way to detect disease progression, but this testing is not currently recommended at baseline or for surveillance in asymptomatic patients with cutaneous melanoma.
Although gene expression profiling has been proposed as useful for distinguishing melanomas that are more likely to metastasize, evidence is insufficient to recommend gene expression profiling in place of or in addition to standard staging approaches that take into account age, sex, tumor location, tumor thickness, mitotic rate, sentinel lymph node biopsy status, and other factors.
During active treatment (ie, in patients who have not undergone complete surgical resection), clinical examination and imaging are typically used to evaluate treatment response. Laboratory assessment using CBC, liver function, and renal function tests may be useful to evaluate the functioning of the bone marrow, liver, and kidneys during treatment.
Recommended monitoring in patients undergoing follow-up for melanoma includes skin examination (at least annually). Imaging (computed tomography [CT] or positron emission tomography [PET]) may also be useful in the event of nodal metastasis. Routine laboratory blood tests are not recommended as part of regular melanoma follow-up.
ARUP Laboratory Tests
Use to detect activating BRAF mutations at codon 600, which can indicate responsiveness to BRAF inhibitors in melanoma
Polymerase Chain Reaction/Pyrosequencing
Use to determine BRAF V600E mutation status in patients with solid tumors to select candidates for targeted therapy with kinase (BRAF and/or MEK) inhibitors
Use to monitor response to therapy and disease progression in patients carrying BRAF V600E mutation
Polymerase Chain Reaction
Use to predict response to anti-EGFR and MAPK pathway therapies in melanoma
Use to detect activating mutations in KIT and PDGFRA
Use to predict response to targeted therapy
Recommended test to confirm a hereditary cause of melanoma in individuals with a personal or family history of disease
Massively Parallel Sequencing/Sequencing
For additional information, refer to the Hereditary Melanoma Panel, Sequencing and Deletion/Duplication Test Fact Sheet
Use to assess for targeted variants that are useful for prognosis and/or treatment of individuals with solid tumor cancers, including melanoma
Recommended test to confirm a diagnosis of a hereditary cancer syndrome in individuals with personal or family history consistent with features of >1 cancer syndrome
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
For additional test information, refer to the Hereditary Cancer Panel Test Fact Sheet
Use to monitor treatment and determine prognosis of patients with malignant melanoma
May be useful as a tumor marker for malignant melanoma
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