Melanoma

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

What is the role of medical laboratory testing in melanoma?

Medical laboratory testing may be useful in patients with metastatic melanoma and when considering patients for clinical studies. In patients with metastatic cancer, laboratory testing can be useful in guiding therapy in some instances. Laboratory testing for nonmetastatic melanomas does not often provide beneficial information and is not recommended unless considering a patient for clinical trials.

When should germline genetic testing be considered for hereditary melanoma?

Germline genetic testing should be considered in individuals with multiple melanomas; in individuals with a combination of melanomas, astrocytomas, and/or pancreatic cancer; and in individuals with at least two relatives with a history of melanoma or pancreatic cancer.^, When a first-degree relative has a history of melanoma or pancreatic cancer, genetic counseling is particularly recommended.

Indications for Testing

Laboratory testing for melanoma should be considered in patients with equivocal histopathologic results following a biopsy, patients with metastatic disease, and in those considering or undergoing treatment for melanoma.

Laboratory Testing

Molecular Testing of Biopsy Tissue

Next generation sequencing (NGS), single-gene assays, and small multigene panels can be used to identify potential therapeutic targets. 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 participation in clinical trials. 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.^, Sentinel lymph node biopsy is recommended only in patients with T2 and T3 tumors and can be considered for patients with T1b and T4 tumors.

BRAF Mutations

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.

KIT Mutations

Testing for KIT mutations can be considered in patients with stage IV disease at presentation or with disease recurrence. KIT mutations are found in a minority of melanomas of mucosal and acral origin and are even less commonly found in melanomas 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

NRAS mutations are associated with poor survival in both localized and advanced melanoma and are found in a minority 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.

Other Mutations

Fusions in NTRK1, NTRK2, NTRK3, ALK, and ROS1 genes can occur in melanoma subtypes but are rare. Patients with these mutations may respond well to targeted treatment.

Prognosis

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 prognostic gene expression profiling in melanoma is currently being investigated, evidence is not yet sufficient to recommend it for routine use.

Monitoring

Routine laboratory blood tests are not recommended as part of regular melanoma follow-up. 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.

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