Sections

Workup

Approach Considerations

The diagnosis of melanoma is confirmed by excisional biopsy. Sentinel lymph node biopsy or gene profile assay may be appropriate as prognostic studies in selected patients, but there is little evidence that they affect longevity.

In early-stage disease, laboratory and imaging studies are rarely indicated. In all stages, they are generally appropriate when prompted by signs or symptoms. Routine testing can lead to frequent false-positive results and a cascade of unnecessary tests.

Preoperative imaging studies have significant costs and offer minimal benefit in most patients with melanoma.^[19]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.^[20] In general, these studies are appropriate in high-risk patients or when localizing signs or symptoms are present.

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. Inclusion of fascia is no longer standard.

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.

Shave biopsy should generally not be done, as it can lead to inadequate staging and diagnosis. The National Comprehensive Cancer Network acknowledges that superficial shave biopsy may compromise pathologic diagnosis and complete assessment of Breslow thickness, but considers shave biopsy acceptable when the index of suspicion is low, and advises that a broad shave biopsy may be optimal for histologic assessment of melanoma in situ, lentigo maligna (LM) type (ie, melanoma on skin with high cumulative sun damage).^[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.

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. Recommendations are evolving.

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]

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 may be necessary in cases with indeterminate findings on routine histology. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanocytes and the latter shows a gradient in most benign nevi other than blue nevi. S-100 and SOX-10 are highly sensitive, although not specific, for melanocytes. They are particularly helpful in poorly differentiated or spindled tumors.

PRAME (preferentially expressed antigen in melanoma) can stain the junctional component of benign nevi but dermal staining is suggestive of melanoma. It is not completely specific and stains other tumors, including testicular tumors and cellular neurothekeoma. It is particularly helpful in distinguishing preexisting nevus remnants from melanoma.^{[23, 24, 25, 26]}

Mart-1/MelanA as well as MITF are sometimes used to establish the pattern of melanocytes, but all 3 may stain pseudonests in lichenoid tissue reactions. S100 is often poorly expressed in the nail matrix; HMB-45 and Mart-1 may be superior in that location. Next-generation gene sequencing and microarray genomic hybridization are becoming commonplace for the diagnosis of unique types of nevi and difficult melanocytic lesions. Fluorescent in situ hybridization (FISH) assays also have evolving applications and molecular predictors of biologic response to targeted immunotherapy are in common use, with BRAF testing being the most frequent.^{[27, 28, 29, 30]}

Elective Lymph Node Dissection

Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a lymph node biopsy. For years, patients without clinically enlarged nodes underwent lymph node dissection (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.

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.^[31]

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.^[32]

Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.

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.

Lactate Dehydrogenase Assay

The lactate dehydrogenase (LDH) level is elevated in many conditions, including many malignancies. Although LDH elevation is not specific for melanoma, it may be useful in the follow-up care of some 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.

Chest Radiography

To date, no studies support obtaining a routine radiograph in patients with melanoma. However, 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 computed tomography (CT) scan of the chest, because the lungs often are the first site of metastatic disease.

Magnetic Resonance Imaging

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 neurologic symptoms.

Computed Tomography

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.

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 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.

Positron Emission Tomography

PET/CT is currently the most sensitive tool for the diagnosis of metastatic disease. 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 for finding other sites of metastasis.^[20]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.^[33]Finally, PET scans often are useful in evaluating the response of metastatic disease to therapy.

Staging

The American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging systems for cutaneous melanoma are provided below.^[34] The TNM system has incorporated the older Breslow classification of melanoma thickness, whose four classes of lesion depth correspond with levels T1-4. Clark levels, another older classification of melanoma, are now largely used for historical reference.

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.

Treatment & Management

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Media Gallery

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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Author

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

Winston W Tan, MD, FACP is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology, Philippine Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Mohsin R Mir, MD Private Practice, Mohs Micrographic Surgery and Dermatologic Surgery, Kelsey-Seybold Clinic; Assistant Professor, Baylor College of Medicine

Mohsin R Mir, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.

Wesley Wu, MD Mohs Surgeon, Department of Dermatology, VA Puget Sound and University of Washington School of Medicine

Wesley Wu, MD is a member of the following medical societies: American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery

Disclosure: Nothing to disclose.