Malignant Melanoma Workup

Updated: Feb 17, 2019
  • Author: Winston W Tan, MD, FACP; Chief Editor: Dirk M Elston, MD  more...
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Workup

Approach Considerations

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]

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Histologic Findings

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

Immunohistochemical stains usually are not necessary for diagnosis; they 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.

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Complete Chemistry Panel

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

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

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

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Lactate Dehydrogenase Assay

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.

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Chest Radiography

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.

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MRI

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. 

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CT Scanning

Chest CT scan

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.

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Positron Emission Tomography

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.

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Biopsy of a Suggestive Lesion

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.

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Surgical Excision or Reexcision After Biopsy

Because failure to perform a reexcision after biopsy of a melanoma is associated with a local recurrence rate of as high as 40%, a reexcision must 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]

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Elective Lymph Node Dissection

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.

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Sentinel Lymph Node Biopsy

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

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

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

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Staging

Clark staging is as follows:

  • 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.

AJCC prognostic staging is as follows:

  • Stage 0 - Tis/N0/M0
  • Stage IA - T1a,/N0/M0
  • Stage IB - T1b, T2b/ N0/ M0
  • Stage IIA - T2b, t3a/N0/M0
  • Stage IIB - T3b, T4a/N0/M0
  • Stage IIC - T4b/N0/M0
  • Stage III (clinical staging) - Any T, Tis/≥N1/M0
  • Stage IIIA (pathologic staging) - T1a/b, T2a/N1a, N2a/M0
  • Stage IIIB (pathologic staging) - T0/N1b, N1c/M0; T1a-b, T2a/N1b-c, N2b/M0; T2b,T3a/N1a-c, N2a-b/M0
  • Stage IIIC (pathologic staging) -  T0/N2b-c, N3b-c/M0; T1a-T3a/N2c, N3a-c/M0; T4b/N1a-c, N2a-c/MO
  • Stage IV - Any T/Any N/M1t

Also see Malignant Melanoma Staging.

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