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Malignant Melanoma

By: ALLAN W. SILBERMAN, M.D., Ph.D..Cedars-Sinai Comprehensive Cancer Center


Malignant melanoma currently accounts for approximately 1% of all cancer deaths. However, the worldwide incidence of melanoma is increasing at a faster rate than any other neoplasm, with the exception of lung cancer in women. In the United States alone, the incidence has tripled in the last forty years and has nearly doubled in the last decade. An estimated 40,300 Americans will develop melanoma in 1997, of whom 7300 will succumb to their disease. Based on current projections, by the year 2000, 1 in every 90 whites will eventually develop melanoma.

Melanoma can affect all ethnic and racial groups; however, the typical melanoma patient has a fair complexion and a tendency to sunburn rather than tan, even after a brief exposure to sunlight. Although there is no conclusive evidence that exposure to sunlight is causally related to the development of melanoma, lesions are most commonly found on sun-exposed areas of the body. Other epidemiologic risk factors include the occurrence of a previous melanoma and an afflicted first-degree relative. Patients with the dysplasticnevus syndrome, an autosomal dominant disorder characterized by the presence of many large, irregularly shaped nevi, are also at increased risk for developing melanoma.

SIGNS AND SYMPTOMS
Benign skin lesions can usually be differentiated from malignant ones by each of the following properties, which can be remembered using the mnemonic ABCD: (1) Asymmetry. Pigment asymmetry is more frequently found in malignant lesions. (2) Border irregularity. Well-circumscribed lesions are more likely to be benign. (3) Color variation. Lesions with any combination of brown, black, gray, or red hues are more likely to be malignant than lesions of uniform color. (4) Diameter. Lesions larger than 5 to 10 mm in diameter or lesions that have increased in size are more likely to be malignant. Although melanomas may have a variety of clinical appearances, the common denominator is their changing nature. Any pigmented lesion that undergoes a change in size, configuration, or color should be considered a melanoma, and an excisionalbiopsy should be performed.

TYPES OF CUTANEOUS MELANOMA
There are four pathologic types of cutaneous melanoma each with a characteristic growth pattern. (1) Superficial spreading melanoma is the most common type, accounting for 70% of all cases. This type typically arises from a pre-existing nevus and expands in a radial fashion before it enters a vertical growth phase. (2) Nodular melanoma, a more aggressive tumor, accounts for approximately 15 to 30% of cases. This lesion arises de novo from normal skin and has no radial growth phase. It is found more commonly in males. (3) Lentigo maligna melanoma accounts for less than 10% of cases. This type of lesion is found more commonly in females and the elderly population. The lesions are typically large and flat, follow an indolent growth course, and rarely metastasize. (4) Acrallentiginous melanoma also accounts for less than 10% of lesions, but occurs in a higher proportion (35 to 60%) of nonwhite patients.

BIOPSY TECHNIQUE
An excisional biopsy, when possible, or an incisional biopsy should be performed on every suspicious skin lesion. Care must be taken to ensure that the full thickness of the lesion is included in the biopsy specimen because staging, treatment, and prognosis depend on accurate assessment of depth and level of infiltration of the lesion. A shave biopsy should not be performed because this technique fragments the lesion preventing accurate assessment of the depth and thickness of the melanoma.

STAGING SYSTEMS
Microstaging is an integral part of the staging and clinical management of melanoma. Two methods have been used. The Breslow microstaging method measures the thickness of the lesion in millimeters using an ocular micrometer. The total vertical height of the melanoma is measured from the granular layer to the area of deepest penetration. If the lesion is ulcerated, measurements are made from the surface of the ulcer to the deepest part of the lesion. The Clark method assesses the level of penetration into the various skin layers (Table 1).

TABLE 1. Clark Classification System of Microstaging


 

Level I: Confined to the epidermis (in situ)
Level II: Invasion into the papillary dermis
Level III: Penetration to the papillary-reticular interface
Level IV: Invasion into the reticular dermis
Level V: Penetration into subcutaneous fat

Although the tumor thickness and the level of invasion can predict the risk for metastases, data from several institutions have demonstrated that tumor thickness is a more accurate and reproducible prognostic parameter than interpreting the level of invasion. Significant regression of the tumor invalidates the prognostic value of these microstaging methods. Clinical staging criteria can be found in Table 2.

TABLE 2. Clinical Staging System Adopted by the American Joint Committee on Cancer


 

Stage Criteria
IA Localized melanoma <0.75 mm or Clark level II
IB Localized melanoma 0.76 to 1.5 mm or level III
IIA Localized melanoma 1.5 to 4 mm or level IV
IIB Localized melanoma >4 mm or level V
III Limited nodal metastases involving only one regional lymph node basin, or fewer than 5 in-transit metastases without nodal metastases
IV Advanced regional metastases or any patient with distant metastases

PROGNOSIS
Many factors are known to predict risk in patients with melanoma including Breslow depth, Clark level, anatomic location, gender, tumor ulceration, and growth pattern. Multifactorial analysis in Stage I and II patients demonstrates that tumor thickness is the single most important prognostic factor. Other important risk factors include the presence of ulceration and anatomic location, with extremity lesions having a better prognosis than those on the trunk or head and neck. Multifactorial analysis of Stage III patients shows that the number of metastatic nodes, the anatomic site of the primary lesion, and tumor ulceration are the dominant prognostic variables. Patients with primary lesions less than 0.76 mm have a 10-year survival rate of greater than 90%. However, the presence of positive nodes lowers the survival rate to 13 to 40%. There are virtually no survivors with Stage IV disease.

TREATMENT
The treatment of Stage I cutaneous melanoma (i.e., local disease not clinically involving the regional lymph nodes) is wide excision of the lesion. Current recommendations are that surgical margins should be proportional to the depth of the lesion with 0.5- to 1.0-cm margins for in situ lesions; 1.0-cm margins for 1.0-mm lesions; 2- to 3-cm margins for 1.0 to 2.0-mm lesions; and 3 to 4 cm for lesions greater than 2.0-mm. The excision should include the underlying subcutaneous fat up to and including the deep fascia. Surgeons often select margins wide enough to constitute adequate excision but modest enough to allow primary closure. Sensible compromise is obviously required for lesions on the face and extremities. Skin grafts are advisable when primary closure would compromise appropriate margins. It remains controversial whether prophylactic regional lymph node dissection (PRLND) should be considered in patients who have primary malignant melanoma and clinically negative regional lymph nodes. The advocates of this method point out correctly that surgery is the only effective therapy for regional lymph node disease; moreover, in several retrospective studies, a survival advantage of as much as 25% has been demonstrated in patients with clinically negative but pathologically positive lymph nodes. The opponents of PRLND point to the randomized, prospective, multi-institutional study by the WHO Melanoma Group, which failed to demonstrate any survival advantage in patients who have prophylactic lymph node dissection. However, besides the potential but inconclusively demonstrated survival advantage, there are two other reasons for performing PRLND. First, clinically negative nodes that are found to be histologically positive for micrometastatic disease provide important prognostic information. In addition, patients found to have histologically positive nodes become eligible for adjuvant protocols.

More recently, the technique of sentinel node biopsy (intraoperative lymphatic mapping and selective lymphadenectomy) has been developed in an attempt to identify those patients who may benefit from an elective node dissection while sparing patients without occult metastases the morbidity of an elective lymph node dissection. Current methods of performing a sentinel node biopsy include vital blue dyes and/or lymphscintigraphy.

The treatment for patients with clinically positive regional lymph nodes without evidence of distant metastatic disease (Stage III and some Stage IV patients) would include wide excision of the primary lesion and therapeutic lymphadenectomy. These patients would be candidates for adjuvant protocols after surgery. Only interferon alpha-2b has been shown to be effective in the adjuvant setting.

The most common sites of metastatic melanoma include skin and subcutaneous tissue, distant lymph nodes, and visceral spread to lung, liver, and brain. At present, after 20 years of experimentation, dacarbazine (DTIC) is the only agent approved by the FDA for treatment of metastatic melanoma, and no combination of chemotherapeutic agents has been shown to be more effective than DTIC alone. DTIC therapy is associated with a response rate of 15 to 25%, with only 5% of patients achieving a complete response.

Current research in melanoma is focused on finding effective systemic therapy. Avenues of current work include combination chemotherapy including tamoxifen (Nolvadex), high-dose chemotherapy with autologous bone marrow support; use of biologic agents, including the interferons, interleukin-2, and tumor necrosis factor, and active and passive specific immunotherapy.


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