Tests
1st tests to order
dermoscopy
Test
In dermoscopic evaluation, the skin lesion is usually covered with an immersion fluid. The skin lesion is then inspected using a handheld magnifying lens attached to a light source. Dermoscopes with a polarized light source do not require an immersion liquid.
The use of dermoscopy by trained individuals results in increased diagnostic accuracy compared with naked-eye examination alone.[60] Using dermoscopy, the nonabsolute sensitivity for diagnosing melanoma increased by 19% (83.2% with dermoscopy vs. 69.6% without dermoscopy) and the mean specificity increased by 6.2% (85.8% with dermoscopy vs. 80.8% without).[61]
Result
melanocytic lesion with abnormal appearance concerning for melanoma; bluish-white veiled appearance within a melanocytic lesion corresponds to dermal fibrosis (regressive melanoma); dermoscopic findings may also include atypical globules and dots of different sizes and shapes, patches of atypical network, diffuse polymorphous vasculature, superficial spreading melanoma with pseudopods distributed asymmetrically around the lesion
skin biopsy
Test
Histopathologic analysis of a new or changing atypical pigmented lesion is essential in the diagnosis.
The ideal management is a complete full-thickness excision of the entire lesion with a 1-3 mm margin.[14][62] Full-thickness incisional or punch biopsy of clinically thickest or most atypical portion of lesion is acceptable and may be preferred in certain anatomic areas (e.g., palm/sole, digit, face, ear) or for very large lesions. Multiple "scouting" biopsies may help guide management for very large lesions.[14]
Melanoma shows severely cytologically atypical melanocytes, with architectural disorder characterized by an asymmetric growth pattern within the epidermis, poor lateral circumscription of the junctional melanocytic component, Pagetoid scatter of melanocytes above the basal cell layer of the epidermis, confluent growth with a loss of the normal nested growth pattern of junctional melanocytes, and an absence of maturation of the dermal melanocytic component with depth in the dermis.
Other abnormal features include regression (seen as dermal fibrosis with pigmented melanophages) and mitotic figures in the dermal melanocytic component.[79]
Skin biopsy confirms the diagnosis of melanoma and provides prognostic information. Prognostic indicators include tumor thickness measured as Breslow thickness (depth of invasion measured in millimeters from the top of the granular cell layer to the point of deepest tumor penetration in the dermis or subcutis), ulceration, mitotic count, lymphovascular invasion, and microscopic satellites.[14][63] An unfavorable prognosis is associated with greater depth of invasion, ulceration, increased mitotic count, vascular invasion, regression, and the presence of microscopic satellites.[14]
Result
abnormal melanocytic proliferation in the epidermis and/or dermis typical of melanoma
immunohistochemistry
Test
Immunohistochemistry is increasingly used to interpret biopsies that are not easily classified based on histopathologic features.[64][65] It can help to distinguish melanocytic lesions from tumors with different origin, and benign from malignant melanocytic lesions.[66]
Melanocytic markers that can be used in the immunohistochemical analysis include Melan-A/MART-1, S100, MITF, tyrosinase, HMB45, SOX10, PRAME.[14][64][67][68]
Result
presence of melanocytic markers consistent with malignant melanoma
Tests to consider
sentinel lymph node biopsy
Test
Sentinel lymph node biopsy (SLNB) is based on the concept that a tumor will drain to a particular first lymph node within a lymph node basin. There may be multiple draining lymph node basins and multiple sentinel nodes, depending on individual lymphatic drainage patterns.
A radiotracer or a blue dye is injected intradermally at the site of the primary lesion (before wide local excision [WLE]) to identify the sentinel node.[14]
SLNB may be performed for selected patients with stage I and stage II melanoma.[14] It permits accurate staging of patients with no clinical or radiologic evidence of nodal metastases, and provides prognostic information.
In the US, SLNB should be discussed with, and considered for patients with stage IB or II disease with the following considerations; tumor thickness <0.8 mm with ulceration; tumor thickness 0.8 to 1.0 mm with or without ulceration; tumor thickness >0.5 mm who have additional adverse prognostic features (e.g., age ≤42 years, head/neck location, lymphovascular invasion, and/ or mitotic index ≥2/mm²)
The probability of a positive SLNB is 5% to 10% for these patients, with an increased risk for patients with multiple adverse prognostic features.[14]
SLNB is not generally recommended for patients with tumors <0.8 mm thick without ulceration or adverse prognostic features, unless there is significant uncertainty about the adequacy of microstaging (e.g., positive deep margins or limited sampling of a larger lesion). The risk of positive SLNB in these patients is <5%.[14]
SLNB does not improve overall survival for patients with melanoma, but subgroup analysis of the Multicenter Selective Lymphadenectomy Trial (MSLT)-I showed that SLNB improves the 10-year distant disease-free survival for patients with melanomas between 1.2 mm and 3.5 mm in thickness.[74]
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UK guidelines recommend considering SLNB as a staging (rather than therapeutic) procedure for patients with a Breslow thickness of 0.8 to 1.0 mm with one adverse prognostic feature (e.g., ulceration, lymphovascular invasion, or mitotic index of 2 or more). For people without adverse prognostic features, SLNB should be considered with a Breslow thickness of greater than 1.0 mm.[56] Consider delaying SLNB for pregnant women until postpartum.[56]
Result
presence or absence of metastatic disease
chest/abdominal/pelvic CT scan
Test
In the UK, whole-body contrast-enhanced computed tomography (CE-CT) should be considered for people with stage IIB melanoma.[56] Staging with CE-CT should be offered to all patients with IIC to IV melanoma.
In the US, baseline cross-sectional staging imaging should be considered for patients with stage IIIa melanoma (sentinel lymph node positive), and is indicated for all patients with stage IIIb, IIIc, IIId, and IV melanoma. Imaging studies should include the chest, abdomen, and pelvis, plus the neck if clinically indicated. CT or fluorodeoxyglucose positron emission tomography/computed tomography (FDG-CT/PET) may be used.[14]
Imaging should also be performed to evaluate any symptoms or signs suggestive of possible metastases, e.g., headache if present, at any stage of disease.[14]
Result
may show metastases
whole-body PET scan
Test
In the US, baseline cross-sectional staging imaging should be considered for patients with stage IIIa melanoma (sentinel lymph node positive), and is indicated for all patients with stage IIIb, IIIc, IIId, and IV melanoma. Imaging studies should include the chest, abdomen, and pelvis, plus the neck if clinically indicated. CT or fluorodeoxyglucose positron emission tomography/computed tomography (FDG-CT/PET) may be used.[14] FDG-CT/PET has the highest specificity, sensitivity, and diagnostic odds ratio for distant metastases.[73]
Imaging should also be performed to evaluate any symptoms or signs suggestive of possible metastases, if present, at any stage of disease.[14]
Result
may show metastases
brain imaging (CT or MRI)
Test
In the UK, brain CT should be considered for people with stage IIB melanoma.[56] Staging with CT should be offered to all patients with IIC to IV melanoma. If available, a brain magnetic resonance imaging (MRI) can be used instead of a brain CT.[56]
Brain MRI should be offered, instead of CT, to children and young adults (from birth to 24 years), and pregnant women with stage IIB to IV melanoma, and for people with IIIC to IV melanoma with poor prognostic factors.[56]
One European guideline recommends baseline brain imaging with magnetic resonance imaging (MRI) with intravenous contrast or CT should be considered for patients with stage IIC melanoma with a poor prognosis, and is indicated for all patients with stage III to IV melanoma.[67] MRI with intravenous contrast is the preferred method for brain imaging, as it is better at detecting brain metastases than CT scan.[67]
In the US, for stages IIIb, IIIc, and IIId, brain imaging for baseline staging may be indicated prior to initiation of therapy, and it is recommended for all patients with stage IV melanoma.[14]
Imaging should also be performed to evaluate any symptoms or signs suggestive of possible metastases, if present, at any stage of disease.[14]
Result
may show metastases
BRAF mutational analysis
Test
Recommendations for BRAF mutational analysis vary by country. It is generally performed in patients who will require systemic therapy, and those at high risk of recurrence for whom future BRAF-directed therapy may be appropriate.[14][56]
All patients who test positive for any BRAF V600 mutation are suitable for BRAF/MEK inhibitor therapy.
Some centers employ immunohistochemistry with the VE1 antibody as the initial test. This is rapid and cheap, with high sensitivity and specificity for BRAF V600E.[69] If immunohistochemistry is negative, molecular testing for rarer mutant genotypes can be performed.
An automated molecular assay to identify BRAF mutations at position V600 is available, but it only readily detects the V600E mutation.[70] Several other platforms, including pyrosequencing, next generation sequencing, and Sanger sequencing, detect all known V600 mutations.
If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[14][72]
Result
may show mutation in the BRAF gene/protein
NRAS mutational analysis
Test
NRAS mutation is found in approximately 15% to 25% of melanomas and is associated with rapidly progressing disease.[25][71]
NRAS mutations activate the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways, thereby promoting tumor proliferation and survival.
Mutations of NRAS in melanoma are generally mutually exclusive of BRAF mutations.
Detection methods include post-polymerase chain reaction high resolution melt analysis.
If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[14][72]
Result
may show mutation in the NRAS gene/protein
serum lactate dehydrogenase (LDH)
Test
Serum LDH has prognostic value in patients with stage IV melanoma and has been incorporated into the American Joint Committee on Cancer (AJCC) staging system for melanoma.[14][62][76]
Patients with distant metastases and elevated LDH are in the highest risk category.[14]
No blood work is usually necessary in patients with other stages of melanoma unless they have systemic symptoms.
Result
may be elevated in metastatic disease
Emerging tests
CDKN2A mutational analysis
Test
Mutations in the CDKN2A gene on chromosome 9 have been found in families with the atypical nevus syndrome and in 39% of melanoma-prone families.[18][38]
Next generation sequencing or single gene assays may be used for molecular testing in the research setting.
If there are existing genetic test results, do not order a duplicate test unless there is uncertainty about the existing result, for example the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[14][72]
Result
may show mutation in the CDKN2A gene/proteins
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