Diagnosis and Management of Malignant Melanoma

Author: Beth G. Goldstein, Adam O. Goldstein
Date: April 1, 2001

The incidence of malignant melanoma has increased in recent years more than that of any other cancer in the United States. About one in 70 people will develop melanoma during their lifetime. Family physicians should be aware that a patient with a changing mole, an atypical mole or multiple nevi is at considerable risk for developing melanoma. Any mole that is suggestive of melanoma requires an excisional biopsy, primarily because prognosis and treatment are based on tumor thickness. Staging is based on tumor thickness (Breslow's measurement) and histologic level of invasion (Clark level). The current recommendations for excisional removal of confirmed melanomas include 1-cm margins for lesions measuring 1.0 mm or less in thickness and 2-cm margins for lesions from 1.0 mm to 4.0 mm in thickness or Clark's level IV of any thickness. No evidence currently shows that wider margins improve survival in patients with lesions more than 4.0 mm thick. Clinically positive nodes are typically managed by completely removing lymph nodes in the area. Elective lymph node dissection is recommended only for patients who are younger than 60 years with lesions between 1.5 mm and 4.0 mm in thickness. In the Eastern Cooperative Oncology Group Trial, interferon alfa-2b was shown to improve disease-free and overall survival, but in many other trials it has not been shown to be effective at prolonging overall survival. Vaccine therapy is currently being used to stimulate the immune system of melanoma patients with metastatic disease. (Am Fam Physician 2001;63:1359-68,1374.)

Malignant melanoma is the eighth most common cancer in the United States and causes 1 to 2 percent of all cancer deaths.(1,2) Melanoma is a proliferation of transformed melanocytes or pigment-producing cells. These tumors occur primarily on the skin but may also arise in other tissues where pigment cells are found.

In men, melanomas occur most frequently on the trunk, whereas in women, melanomas occur most frequently on the lower extremities. Melanoma is almost exclusively a disease of adults. In children, melanoma predominantly occurs in the setting of giant congenital nevi or atypical/dysplastic nevus syndrome, or in the setting of xeroderma pigmentosum (an inherited condition of abnormal DNA repair leading to multiple skin cancers at an early age).

Incidence and Impact

The incidence of melanoma has increased in recent years more than that of any other cancer in the United States. In 1999, in the United States, 44,200 people developed invasive melanoma, and 7,300 died from the disease. An additional 30,000 to 50,000 persons developed in situ disease.(3) In 1960, one in 1,500 Americans was expected to develop melanoma during their lifetime. In the year 2000, that number was expected to be one in 70.(4)

Melanoma ranks sixth in cancer incidence in males and seventh in females, and these incidences have doubled in the past decade.(2) This increase is not an artifact resulting from improved surveillance techniques, because histologic criteria have remained stable over the decades.(4) Because melanoma is not a reportable cancer in all states, and because many cases are treated in an outpatient setting, the true number of melanoma cases may be underreported.(5) The mortality rate is increasing by 2 percent per year, while survival rates are improving--which tends to confirm the impression of a true increase in incidence rather than simply an increase in detection.(4,6)

Risk Factors

Table 1(7) lists the risk factors for development of malignant melanoma. A patient with two or more risk factors, such as an atypical nevus that is changing in color or size, has a high risk of having a melanoma.

SKIN TYPE AND SUNBURN HISTORY

People with a white racial background have at least a 10-fold increase in the incidence of melanoma compared with blacks and a sevenfold increased incidence compared with American Hispanics.(8) Sun sensitivity refers to a person's tendency to sunburn rather than tan. Persons who have a tendency to burn and freckle rather than tan also have an increased melanoma risk. A history of sunburns, even after the age of 20, is associated with an increased risk of melanoma.(9) Blue eyes and red or blonde hair color, although useful as indicators of increased melanoma risk, are not as directly related to increased risk as skin type has been shown to be.(10)

NONMELANOMA SKIN CANCER

A history of a nonmelanoma (e.g., basal cell or squamous cell) skin cancer may increase a person's risk of developing melanoma by threefold to fivefold.(11) This risk is in part compounded when a person has a tendency to sunburn rather than tan and also has a history of cumulative sun exposure.

MULTIPLE NEVI

Persons with multiple nevi, particularly nevi that are atypical in appearance, have a significantly increased risk for developing melanoma. Persons with more than 50 common acquired nevi, all of which are greater than 2 mm in diameter, have five to 17 times the risk of developing melanoma than do persons with fewer nevi.(10,12) The development of about one melanoma in four is closely associated with a previously existing nevus.(13) Thus, patients with multiple benign-appearing nevi must be examined carefully, preferably at least annually, with special attention to any new lesions or changes in existing lesions.

GIANT CONGENITAL NEVI

Giant congenital nevi--those that measure 15 cm in diameter or that are at least twice the size of the palm of an affected person (Figure 1) --have a 6 percent estimated lifetime risk of developing into melanomas. One half of the cases in which melanomas develop in giant nevi occur within the first five years of life. Such melanomas are often quite deep, extending into noncutaneous tissue.(14) It is unclear whether medium-sized congenital nevi (1.5 to 15 cm in diameter) have an increased risk of melanoma.(15)

ATYPICAL/DYSPLASTIC NEVI

Atypical, or dysplastic, nevi (Figures 2a and 2b) are described clinically as intermediate between common nevi and melanoma. Atypical nevi are usually greater than 5 mm in diameter, are irregularly pigmented and have blurred borders and a textured surface. Such nevi may have the morphology of a raised, central papule with a surrounding macular component, thereby giving a "fried-egg" appearance. Not all atypical nevi, however, have the "fried-egg" appearance or textured surface.

The issue of whether one isolated, slightly atypical or dysplastic nevus is a clinical marker for an increased risk of melanoma is controversial. A patient with only one atypical nevus most likely does not have an increased lifetime risk; but those with multiple atypical nevi (Figure 3) have a relative risk for developing melanoma that may be seven times that of other persons. Patients with multiple atypical nevi, a family history of atypical nevi and two or more family members with melanoma (B-K mole syndrome) have virtually a 100 percent chance of developing a melanoma during their lifetime.(16)

HISTORY OF A CHANGING MOLE

The most predictive features for melanoma development are a history of change in an existing nevus or a new and changing pigmented lesion. The estimated relative risk of the association between melanoma and a changing mole is greater than 400 percent.(7) The most important early changes are change in color, diameter increase and border change. Later, when the lesion is more invasive, an increase in height heralds a corresponding growth in depth. Bleeding, ulceration or discomfort are late signs and are associated with a worse prognosis. Because pruritus remains a prevalent early symptom in almost one half of patients with a melanoma, the onset of itching in a new or longstanding mole should not be ignored.

HEREDITY

A family history of melanoma increases a person's risk of developing melanoma by three to eight times compared with persons who have no such history. Persons

with familial melanoma D2 (a personal and family history of melanoma in which two or more family members have had melanoma) have virtually a 100 percent lifetime risk of developing melanoma. Approximately 32,000 people in the United States are estimated to be in this familial category.(16)

TANNING BED USE

The use of a tanning bed 10 times per year or more is linked to a twofold increased risk of melanoma for those older than 30 years. For those younger than 30, this exposure is associated with a risk increased by a factor of 7.7.(17)

IMMUNOSUPPRESSSION

Immunosuppressed patients--such as those with lymphoma, leukemia or organ transplants--have an increased risk of melanoma.(18)

Types of Melanomas

Various subtypes of melanomas have been identified: lentigo maligna, superficial spreading, nodular, acral and amelanotic melanomas.

LENTIGO MALIGNA MELANOMAS

(26.) Veronesi U, Cascinelli N, Adamus J, Balch C, Bandiera D, Barchuk A, et al. Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 1988;318:1159-62 [Published erratum appears in N Engl J Med 1991;325:292].

(27.) Houghton A, Coit D, Bloomer W, Buzaid A, Chu D, Eisenburgh B, et al. NCCN melanoma practice guidelines. National Comprehensive Cancer Network. Oncology [Huntingt] 1998;12:153-77.

(28.) Balch CM, Soong SJ, Bartolucci AA, Urist MM, Karakousis CP, Smith TJ, et al. Efficacy of an elective regional lymph node dissection of 1 to 4 mm thick melanomas for patients 60 years of age and younger. Ann Surg 1996;224:255-63.

(29.) Glass FL, Cottam JA, Reintgen DS, Fenske NA. Lymphatic mapping and sentinel node biopsy in the management of high-risk melanoma. J Am Acad Dermatol 1998;39:603-10.

(30.) 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 1996;14:7-17.

(31.) Kirn TF. Don't waste more time on interferon in malanoma. Skin Allergy News June 2000:34.

(32.) Ollila DW, Kelley MC, Gammon G, Morton DL. Overview of melanoma vaccines: active specific immunotherapy for melanoma patients. Semin Surg Oncol 1998;14:328-36.

(33.) Fraker DL, Coit DG. Isolated perfusion of extremity tumors. In: Lotze MT, Rubin JT, et al., eds. Regional therapy of advanced cancer. Philadelphia: Lippincott-Raven, 1997:333-50.

(34.) Greene MH, Clark WH, Tucker MA, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-65.

(35.) MacKie RM. Pregnancy and exogenous female sex hormones in melanoma patients. In: Balch CM, Houghton AN, Sober AJ, Soong S, eds. Cutaneous melanoma. 3d ed. St. Louis: Quality Medical, 1998:187-93.

BETH G. GOLDSTEIN, M.D., is adjunct clinical assistant professor in the Department of Dermatology at the University of North Carolina at Chapel Hill School of Medicine and has a private practice in Chapel Hill. She graduated from the Medical College of Georgia School of Medicine, Augusta, where she also completed a residency in dermatology. She is co-author, with her husband, of a book on practical dermatology.

ADAM O. GOLDSTEIN, M.D., is assistant professor in the Department of Family Medicine at the University of North Carolina at Chapel Hill School of Medicine. He graduated from the Medical College of Georgia School of Medicine, Augusta, where he also completed a residency in family medicine.

Address correspondence to Beth G. Goldstein, M.D., Central Dermatology Center, P.A., 2238 Nelson Hwy., Ste. 500, Chapel Hill, NC 27514. Reprints are not available from the authors.

TABLE 2'ABCD' Warning Signs of a MelanomaA Asymmetry of moleB Border irregularity of moleC Color variability within a lesionD Diameter increasing, especially to more than 6 mmTABLE 3Differential Diagnosis for MelanomaCondition Distinguishing characteristicsSeborrheic keratosis "Stuck-on" appearance, symmetric, often multipleTraumatized or Returns to normal appearance within irritated nevus 7 to 14 daysPigmented basal Waxy appearance, telangiectasias cell carcinomaLentigo Prevalent in sun-exposed skin, evenly pigmented, symmetricBlue nevus Darkly pigmented from dermal melanocytes, no history of changeAngiokeratoma Vascular tumors, difficult to distinguish from melanomaTraumatic hematoma May mimic melanoma but resolves in 7 to 14 daysVenous lake Blue, compressible, found on ears and lipsHemangioma Compressible, stableDermatofibroma Firm growths of fibrous histiocytes, "button-hole" when pinchedPigmented actinic Sandpapery feel; sun-exposed areas keratosisTABLE 5Suggested Follow-up for Patients with a History of MelanomaPatient criteria Skin examination/ physical examinationLesions less than 1 mm in Every six months for two years, thickness without atypical then annually nevus syndrome and/or family history of melanomaLesions more than 1 mm in Every three to six months for three thickness and/or Clark's level IV years, then every six to 12 months for two years, then annuallyClark's level III or IV Every three to six months for three years, then every four to 12 months for two years, then annuallyPatient criteria Other examinationsLesions less than 1 mm in -- thickness without atypical nevus syndrome and/or family history of melanomaLesions more than 1 mm in Chest x-ray plus LFTs every six thickness and/or Clark's level IV to 12 months; CT scan as clinically indicatedClark's level III or IV Chest x-ray, LFTs and CBC every three to 12 months; CT scan as clinically indicatedLFTs = liver function tests; CBC = complete blood cell count;CT = computed tomographic.Information from Houghton A, Coit D, Bloomer W, Buzaid A, Chu D,Eisenburgh B, et al. NCCN melanoma practice guidelines.National Comprehensive Cancer Network. Oncology [Huntingt] 1998;12:153-77.

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