Approach Considerations
In addition to a CBC, the studies below are indicated.
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.[10] 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 (PET) computed tomography (CT) scanning is the best imaging study to look for other sites of metastasis.[11]
Complete Chemistry Panel
The chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase level may signal metastatic disease to the bone or liver, while elevation of liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastatic disease 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 Study
The LDH level is elevated in many conditions, including many malignancies. Although LDH 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.
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.
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 reserved for those patients who are symptomatic.
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.
Positron Emission Tomography
A PET scan may aid in staging patients with known node disease or in transit or satellite lesions. Many studies report a greater sensitivity with PET scans compared with conventional radiographic studies for the detection of metastatic disease.
PET scans often are useful in evaluating the response of metastatic disease to therapy.
PET scans are not indicated in early-stage disease (Stage I or II).
One meta-analysis found PET CT scanning to be the best imaging study to utilize for finding other sites of metastasis.[11] In particular, FDG PET CT scans are a valuable tool for detecting additional metastasis as part of preoperative evaluation of patients with advanced and metastatic melanoma.[12]
Biopsy of a Suggestive Lesion
A complete excisional biopsy is preferred and should include a 1-2 mm margin of healthy skin, to include all layers of skin and some subcutaneous fat. Although not standard in patients with melanoma, investigators at the Mayo Clinic recommend sparing the deep fascia in some patients.[13]
If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy should be taken from the most abnormal area of the lesion.
Because all layers of the skin must be included in the biopsy, a shave biopsy is contraindicated.
In some cases where a shave biopsy was done on a lesion, a complete excisional biopsy 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.
Current recommendations for margins of excision are as follows:
- Lesions less than 1 mm in thickness - 1 cm margin
- Lesions 1-4 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 reliant resection margin to treat lesions thicker than 2 mm.[14]
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.
Sentinel Lymph Node Dissection
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 2 techniques, often in combination, are used. The combination of the 2 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 and, through a small incision over the nodal basin, determining the location of the sentinel node. The node is then removed for pathologic evaluation.
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.
Sentinel node biopsy is now known to offer important prognostic, diagnostic, and therapeutic information.[15]
Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that it is reasonable to offer sentinel lymph node biopsy to patients with thick melanoma (4 mm or greater) in whom the probability of a positive sentinel node is 30-40% and in whom sentinel lymph node status is a strong independent predictor of outcome.[16] Sentinel node biopsy may be offered either as standard care or in the context of a clinical trial.
The NCCN does not recommend sentinel lymph node biopsy for patients with in situ melanoma (stage 0) or stage IA melanoma that is 1 mm or less with no adverse features. Although there appears to be a subset of patients with thin melanoma who are at sufficient risk for a positive sentinel lymph node to justify a biopsy, there is not yet clear consensus regarding which factors best predict this risk; possible factors include thickness over 0.75 mm, high mitotic rate, and young patient age; other possible factors include positive deep margins and lymphovascular invasion.[17]
Although current standards of practice suggest completion lymph node dissection (CLND) for patients with a positive result on sentinel lymph node biopsy, 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. 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.[18]
Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.
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.
A pagetoid growth pattern with upward growth of the melanocytes, so they are no longer confined to the basal layer, is considered pathognomonic for melanoma by some pathologists.
Although 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.
Balch CM, Buzaid AC, Soong SJ, Atkins MB, Cascinelli N, Coit DG, et al. Final version of the American Joint Committee on Cancer staging system for cutaneous melanoma. J Clin Oncol. Aug 15 2001;19(16):3635-48. [Medline].
American Joint Committee on Cancer. AJCC Staging Manual. 6th edition. 2002.
American Cancer Society. Cancer Facts & Figures 2009. Available at http://www.cancer.org/downloads/STT/500809web.pdf. Accessed August 25, 2009.
Shaikh WR, Xiong M, Weinstock MA. The contribution of nodular subtype to melanoma mortality in the United States, 1978 to 2007. Arch Dermatol. Jan 2012;148(1):30-6. [Medline].
Murali R, Desilva C, Thompson JF, Scolyer RA. Factors predicting recurrence and survival in sentinel lymph node-positive melanoma patients. Ann Surg. Jun 2011;253(6):1155-64. [Medline].
Mocellin S, Pasquali S, Riccardo Rossi C, Nitti D. Validation of the prognostic value of lymph node ratio in patients with cutaneous melanoma: A population-based study of 8,177 cases. Surgery. Jul 2011;150(1):83-90. [Medline].
Brewer JD, Christenson LJ, Weaver AL, et al. Malignant melanoma in solid transplant recipients: collection of database cases and comparison with surveillance, epidemiology, and end results data for outcome analysis. Arch Dermatol. Jul 2011;147(7):790-6. [Medline].
Jethanamest D, Vila PM, Sikora AG, Morris LG. Predictors of survival in mucosal melanoma of the head and neck. Ann Surg Oncol. Oct 2011;18(10):2748-56. [Medline]. [Full Text].
Kantor J, Kantor DE. Routine dermatologist-performed full-body skin examination and early melanoma detection. Arch Dermatol. Aug 2009;145(8):873-6. [Medline].
Sabel MS, Wong SL. Review of evidence-based support for pretreatment imaging in melanoma. J Natl Compr Canc Netw. Mar 2009;7(3):281-9. [Medline].
Xing Y, Bronstein Y, Ross MI, Askew RL, Lee JE, Gershenwald JE, et al. Contemporary diagnostic imaging modalities for the staging and surveillance of melanoma patients: a meta-analysis. J Natl Cancer Inst. Jan 19 2011;103(2):129-42. [Medline]. [Full Text].
Bronstein Y, Ng CS, Rohren E, Ross MI, Lee JE, Cormier J, et al. PET/CT in the Management of Patients With Stage IIIC and IV Metastatic Melanoma Considered Candidates for Surgery: Evaluation of the Additive Value After Conventional Imaging. AJR Am J Roentgenol. Apr 2012;198(4):902-8. [Medline].
Grotz TE, Markovic SN, Erickson LA, et al. Mayo Clinic consensus recommendations for the depth of excision in primary cutaneous melanoma. Mayo Clin Proc. Jun 2011;86(6):522-8. [Medline]. [Full Text].
Gillgren P, Drzewiecki KT, Niin M, et al. 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: a randomised, multicentre trial. Lancet. Nov 5 2011;378(9803):1635-42. [Medline].
Bachter D, Michl C, Büchels H, Vogt H, Balda BR. The predictive value of the sentinel lymph node in malignant melanomas. Recent Results Cancer Res. 2001;158:129-36. [Medline].
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Melanoma v.2. Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Accessed August 25, 2009.
Andtbacka RH, Gershenwald JE. Role of sentinel lymph node biopsy in patients with thin melanoma. J Natl Compr Canc Netw. Mar 2009;7(3):308-17. [Medline].
[Best Evidence] Cadili A, McKinnon G, Wright F, Hanna W, Macintosh E, Abhari Z, et al. Validation of a scoring system to predict non-sentinel lymph node metastasis in melanoma. J Surg Oncol. Mar 1 2010;101(3):191-4. [Medline].
McWilliams RR, Rao RD, Buckner JC, Link MJ, Markovic S, Brown PD. Melanoma-induced brain metastases. Expert Rev Anticancer Ther. May 2008;8(5):743-55. [Medline].
[Best Evidence] Gould Rothberg BE, Berger AJ, Molinaro AM, Subtil A, Krauthammer MO, Camp RL, et al. Melanoma prognostic model using tissue microarrays and genetic algorithms. J Clin Oncol. Dec 1 2009;27(34):5772-80. [Medline]. [Full Text].
Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. Jan 1996;14(1):7-17. [Medline].
[Best Evidence] Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U. Eastern Cooperative Oncology Group. A pooled analysis of Eastern Cooperative Oncology Group and intergroup trials of adjuvant high dose alpha interferon for melanoma. Clin Cancer Res. 2004;10:1670-77.
[Best Evidence] Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. Feb 20 2009;27(6):939-44. [Medline].
[Best Evidence] Hauschild A, Weichenthal M, Rass K, Linse R, Ulrich J, Stadler R, et al. Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma. J Clin Oncol. Jul 20 2009;27(21):3496-502. [Medline].
[Best Evidence] Hauschild A, Weichenthal M, Rass K, Linse R, Berking C, Böttjer J, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >= 1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol. Feb 10 2010;28(5):841-6. [Medline].
Eggermont AM, Suciu S, Testori A, et al. Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer. Jan 2012;48(2):218-25. [Medline].
Spitler LE, Grossbard ML, Ernstoff MS, Silver G, Jacobs M, Hayes FA, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. Apr 2000;18(8):1614-21. [Medline].
Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. Aug 26 2010;363(9):809-19. [Medline].
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. Jun 30 2011;364(26):2507-16. [Medline].
Fecher LA, Flaherty KT. Where are we with adjuvant therapy of stage III and IV melanoma in 2009?. J Natl Compr Canc Netw. Mar 2009;7(3):295-304. [Medline].
Lens MB, Reiman T, Husain AF. Use of tamoxifen in the treatment of malignant melanoma. Cancer. Oct 1 2003;98(7):1355-61. [Medline].
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. Jun 8 2011;305(22):2327-34. [Medline].
Middleton MR, Grob JJ, Aaronson N, Fierlbeck G, Tilgen W, Seiter S, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol. Jan 2000;18(1):158-66. [Medline].
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. Jul 1999;17(7):2105-16. [Medline].
Hauschild A, Agarwala SS, Trefzer U, Hogg D, Robert C, Hersey P, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol. Jun 10 2009;27(17):2823-30. [Medline].
Perez DG, Suman VJ, Fitch TR, Amatruda T III, Morton RF, Jilani SZ, et al. Phase II trial of carboplatin, weekly paclitaxel, and weekly bevacizumab in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group study, N047A. Cancer. Jan 2009;115(1):119-27.
[Best Evidence] Maio M, Mackiewicz A, Testori A, Trefzer U, Ferraresi V, Jassem J, et al. Large randomized study of thymosin alpha 1, interferon alfa, or both in combination with dacarbazine in patients with metastatic melanoma. J Clin Oncol. Apr 1 2010;28(10):1780-7. [Medline].
Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. May 1 2001;19(9):2370-80. [Medline].
Sasse AD, Sasse EC, Clark LG, Ulloa L, Clark OA. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev. Jan 24 2007;CD005413. [Medline].
Sarnaik AA, Weber JS. Recent advances using anti-CTLA-4 for the treatment of melanoma. Cancer J. May-Jun 2009;15(3):169-73. [Medline].
Hodi FS, O'Day SJ, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. Aug 19 2010;363(8):711-23. [Medline].
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. Jun 30 2011;364(26):2517-26. [Medline].
Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. Jul 12 2008;372(9633):117-26. [Medline].
Huncharek M, Kupelnick B. Use of topical sunscreen and the risk of malignant melanoma. Results of a meta-analysis of 9,067 patients. Ann Epidemiol. Oct 1 2000;10(7):467. [Medline].
Autier P, Boniol M, Doré JF. Sunscreen use and increased duration of intentional sun exposure: still a burning issue. Int J Cancer. Jul 1 2007;121(1):1-5. [Medline].
Hancock BW, Wheatley K, Harris S, Ives N, Harrison G, Horsman JM, et al. Adjuvant interferon in high-risk melanoma: the AIM HIGH Study--United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol. Jan 1 2004;22(1):53-61. [Medline].
Print
