Related narrative: Melanoma
Background: Epidemiology and Risk Factors
Melanoma represents 4% to 5% of all skin malignancies. The incidence of melanoma is increasing more rapidly than that of any other malignancy, with over 30,000 cases diagnosed each year in the United States, and a mortality of 25% to 30%. Lightly pigmented individuals, especially those of Celtic ancestry, are at higher risk for the development of melanoma than are darkly pigmented individuals. Women develop melanoma slightly more often than men, and their melanomas arise more commonly on the lower extremities versus the trunk in men. Women also have a better prognosis than men with equivalent lesions. Other risk factors include xeroderma pigmentosum, a history of nonmelanoma skin cancer, higher socioeconomic status, and family history of melanoma. Ten percent of melanomas appear to have a genetic basis (chromosomes 1, 6, and 9 and tumor suppressor gene p16 abnormalities) and these cases are often associated with multiple dysplastic nevi.
Much attention has been focused on the heritable form of melanoma and the nonheritable variety remains poorly understood. At present, the only avoidable presumed risk factor for melanoma is sun exposure. While severe sunburns early in life are associated with an increased risk of melanoma, the exact role of sun exposure in melanoma oncogenesis is uncertain.
Clinical Presentation, Diagnosis, and Staging
The clinical warning signs of melanoma are (1) enlargement of a preexisting mole, (2) itching or pain in a preexisting mole, (3) development of a new pigmented lesion during adult life, (4) irregularity of the borders of a pigmented lesion, and (5) variegation of color within a pigmented lesion.
Melanoma is believed to begin with a slow growing superficial radially spreading phase followed by a more rapid vertical invasive phase. The vertical phase is associated with the potential for metastasis.
In 1970, Breslow proposed that the tumor thickness (in millimeters) rather than histologic depth (Clark classification) was a better predictor the behavior of cutaneous melanoma. A lesion less than 0.76 mm thick is considered a thin melanoma (rate of recurrence after excision 5% or less). Lesions 0.76 to 4.0 mm are considered intermediate thickness lesions, and lesions more than 4 mm thick are considered thick. In addition to histopathologic variables, multifactorial analyses have shown that the clinical factors of anatomic site, ulceration, and gender may be independent prognostic factors for survival.
Full thickness biopsy (punch, incisional, or saucerization) should sample the thickest, and/or most clinically suspect part of the lesion. Suspicious lesions should not be cauterized or shaved off because critical staging data is lost.
The American Joint Committee on Cancer bases melanoma staging on tumor thickness, nodal status, and distant metastases.
Stage I: early local disease (thin melanomas without evidence of metastases); five-year survival 90-100%.
Stage II: more advanced local disease (intermediate depth melanomas without metastases); five-year survival 70-80%.
Stage III: thick primary melanomas, regional lymph node and/or in-transit metastases; five-year survival 40-50%.
Stage IV: the presence of distant metastatic disease; five-year survival 0-10%.
Sentinel lymph node biopsy (SLNB) has revolutionized the staging and treatment of patients with melanoma. The SLN is the first draining node(s) in the pathway between the primary tumor and the nodal basin(s). It is identified by a combination of radiocolloid and dye injection and tracking and is sampled on the proven assumption that metastatic cells predictably follow the same pathway as the tracers to a specific first node in a nodal basin. The node(s) is subjected to rigorous histologic and immunohistochemical examination to detect micrometastases. In a study of 223 patients, the status of their SLN predicted the status of their nodal basins 99% of the time. Less than 5% of patients with negative SLNBs have subsequently developed metastatic disease in the tested nodal basin. Prior prediction of probable lymph node involvement based on depth (especially the controversy over intermediate depth lesions) is thus being supplanted with reliable information, and morbid, unnecessary lymph node dissections are avoided.
Specialists suggest that most patients with melanomas more than 1 mm thick and no evidence of metastatic disease should be offered SLNB to more accurately stage them and direct decisions about participation in postoperative adjuvant therapy trials. Sentinel lymph node biopsy is a highly technical procedure requiring each surgeon to achieve qualification through training and validation of results in multiple cases with conventional completion lymphadenectomy before relying on SLNB alone. Teamwork with equally qualified nuclear medicine specialists and pathologists in large, high volume medical centers is essential.
Treatment: Wide Excision
Once the diagnosis of melanoma has been made from the initial biopsy, a wide re-excision (wide local excision) should be performed. A wide local excision should reduce the risk of local recurrence. Wide excision consists of en bloc removal of the tumor or biopsy site with a margin of normal skin and underlying subcutaneous tissue. The goals of surgical treatment are to remove all of the melanoma cells at the primary site to cure patients at low risk of concealing occult metastases and to control local disease even if a cure is unlikely.
The current data and current practice, based on randomized, prospective comparisons, have shown that 5-cm margins are excessive. Margins of 5 mm are recommended for melanoma in situ and 1cm margins are recommended for invasive melanomas up to 1 mm thick. Beyond that, 2 cm margins suffice for most lesions. On the basis of study data, margins beyond 2 to 3 cm do not seem justified even for thick melanomas. However, the risk of local recurrence is a function of tumor thickness and the adequacy of excision. Clinical judgment must be used in certain critical areas where melanomas cannot be excised widely without functional or cosmetic impairment.
Treatment: Adjuvant Therapy
The first adjuvant therapy shown to be at all efficacious in high-risk primary melanomas is high-dose interferon alpha-2b. However, these high doses are significantly toxic. Numerous, less toxic, biologic and chemotherapeutic strategies are being developed and tested in multicenter, prospective, randomized trials. Combinations of various agents and doses have shown some promise in clinical trials. Another area of intense interest is an immunotherapeutic approach using tumor vaccines intended to induce cellular immune responses against melanoma.
Most patients with melanoma are cured. Up to 80% of recurrences appear by 3 years after treatment of the primary tumor. Thick tumors and ulcerated lesions tend to recur earlier and thin melanomas at later post-treatment intervals. Rarely (<1%), recurrent melanoma may present 10-20 years after apparently successful treatment of the primary lesion.
Cotran RS, Kumar V, Collins T. editors. Robbins Pathologic Basis of Disease, Sixth ed. Philadelphia: W. B. Saunders Company; 1999.
National Cancer Institute CancerNet. Melanoma (PDQ) Treatment for Health Professionals. Available from NCI CancerNet.
Reeves ME, Coit DG. Melanoma. A multidisciplinary approach for the general surgeon. Surg Clin North Am. 2000 Apr; 80(2): 581-601.
Slingluff Jr CL, Seigler HF. Melanoma. In: Sabiston: Textbook of Surgery, 15th ed., Philadelphia: W. B. Saunders Company; 1997. p. 515-28.
Wagner JD, Gordon MS, Chuang TY, Coleman III JJ. Current therapy of cutaneous melanoma. Plast Reconstr Surg 2000, 105(5): 1774-1801.
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