DEFINITION

Cutaneous malignant melanoma is a neoplasm arising from the melanocytes that can occur de novo or from a preexisting lesion such as a congenital, acquired, or atypical (dysplastic) nevus. Noncutaneous primary sites of melanocytes also include the mucosal epithelium, retinas, and leptomeninges. Because melanoma is potentially curable with surgical excision of early, thin lesions, prompt detection, diagnosis, and adequate removal of such lesions are of utmost importance. Education of the public with regard to the technique of routine self-examination and proper methods of sun protection can greatly improve the chances for early detection and adequate treatment of melanoma (Box 1). A multidisciplinary approach, including primary care physicians, dermatologists, surgeons, oncologists, immunologists, radiologists, pathologists, and epidemiologists is necessary to optimize detection and treatment of this increasingly common cancer.

Box 1 American Academy of Dermatology Sun Safety Tips

Adapted from Sober AJ, Chuang TY, Duvic M, et al, for the Guidelines/Outcomes Committee. Guidelines of care for primary cutaneous melanoma. J Am Acad Dermatol 2001;45:579-586.

Because overt exposure to ultraviolet light contributes to the formation of skin cancer, dermatologists recommend the following precautions.

Avoid peak sunlight hours—10 A.M. until 4 P.M.—when the sun’s rays are the strongest.

Reapply sunscreen every 2 hours, especially after swimming or heavy perspiration.

Wear protective clothing including a wide-brimmed hat, sunglasses, long-sleeved shirt, and long pants.

Apply lip balm that contains sunscreen with SPF 15 or higher.

Seek shade while outdoors during the day.

Protect children by minimizing sun exposure and regularly applying sunscreen. This is crucial because excessive sun exposure in the first 18 years of life increases a person’s chances of developing melanoma. Eighty percent of lifetime sun exposure occurs before age 18 years.

Avoid reflective surfaces such as water, snow, and sand that can reflect up to 85% of the sun’s damaging rays.

Avoid tanning beds.

SPF, sun protection factor; UVA, ultraviolet A; UVB, ultraviolet B.

PREVALENCE AND RISK FACTORS

Recent U.S. incidence figures estimate that there were about 108,230 new cases of melanoma in 2007: 48,290 in situ (noninvasive) and 59,940 invasive (33,910 men and 26,030 women). At current rates, 1 in 63 Americans will develop an invasive melanoma over a lifetime. One person dies of melanoma every hour. In 2007, about 8110 deaths were attributed to melanoma: 5220 men and 2890 women. Older white men have the highest mortality rates from melanoma. Melanoma is the sixth most common cancer in men and women. Melanoma is the second most common cancer in women ages 20 to 29 in the United States. The incidence of melanoma has increased 690% from 1950 to 2001. Apart from these statistics, if melanoma is detected and treated before it spreads, the 5-year survival rate is 99%.^1,²

PATHOPHYSIOLOGY

Evidence from epidemiologic studies shows that exposure to solar irradiation is the main cause of cutaneous melanoma in fair-complected persons.^3,⁴ This causal relation is supported by anatomic differences by sex, migration studies, difference in latitude of residence, and racial differences.

The most common site for melanoma in men is the upper back; in women, the most common sites are the lower legs and upper back.³ Studies have also shown that persons who immigrated to countries with higher levels of ambient solar radiation have increased rates of melanoma compared with similar people who did not move. Likewise, melanoma incidence and mortality rates in white persons were inversely correlated with distance from the equator. Racial differences also exist with respect to melanoma. The lower rate of melanoma in darkly pigmented persons results from the protective effect of melanin and smaller number of nevi that can serve as precursor lesions for melanoma. The main risk factors for cutaneous melanoma include phenotype (blue eyes, blond or red hair, and fair complexion), cutaneous reaction to sun exposure (freckling, inability to tan, sunburn tendency), history of severe (blistering) sunburns or intense intermittent sun exposures, upper socioeconomic status, family history of melanoma, number and subtypes of nevi (atypical nevi or giant melanocytic nevi), history of prior melanoma, and immunosuppression.^3,⁵

Genetic studies have also shown that 50% of familial melanomas and 25% of sporadic melanomas may be due to mutations in the tumor suppressor gene p16.⁶ Linkage studies have identified chromosome 9p21 as the familial melanoma gene.⁶ About 8% to 12% of all melanoma cases are familial melanoma. The familial melanoma syndrome (also known as the dysplastic nevus syndrome) has been defined as melanoma in one or more first- or second-degree relatives; large numbers of melanocytic nevi (often 50 to 100 or more), some of which are atypical and varied in size; and melanocytic nevi demonstrating certain histologic features. The mode of inheritance is most likely polygenic. The cumulative risk of developing cutaneous melanoma among persons with a history of familial melanoma is estimated to be approximately 50% by 50 years of age.⁶

Mutations in the gene CDKN2A within the 9p21 region have been demonstrated in familial melanoma kindreds. The CDKN2A gene is complex and codes for p16 and p14ARF, which both function to suppress cellular growth. An intact p16 inhibits cyclin-dependent kinases, a critical class of enzymes, whose function is to promote cellular proliferation by inhibiting the retinoblastoma protein. Therefore, an intact p16 is essential to arrest the cell cycle. p14ARF may be important in enhancing the effect of another tumor suppressor, p53.⁶

Five stages of tumor progression have been suggested:

1 Benign melanocytic nevi

2 Melanocytic nevi with architectural and cytologic atypia (dysplastic nevi)

3 Primary malignant melanoma, radial growth phase

4 Primary malignant melanoma, vertical growth phase

5 Metastatic malignant melanoma

Each step in tumorigenesis is marked by a new clone of cells with growth advantages over the surrounding tissues.

SIGNS AND SYMPTOMS

Early signs of melanoma include the ABCDEs: asymmetry of lesion; border irregularity, bleeding, or crusting; color change or variegation (some lesions are amelanotic [nonpigmented]); diameter larger than 6 mm or growing lesion; evolving (surface changes [raised, bleeding, crusting] or symptomatic [itchiness or tenderness]). About 1% to 2% of primary melanomas arise from mucous membrane melanocytes. Approximately 5% to 10% of patients present with metastatic disease (usually in the lymph node basin) without an identifiable primary lesion. Less than 2% of patients present with visceral metastases in the absence of an unknown primary lesion.

Precursor Lesions

Acquired dysplastic nevi (Fig. 1) are atypical-appearing melanocytic tumors that are histologically characterized by intraepidermal melanocytic dysplasia. Dysplastic nevi are important because they are potential histogenic precursors of melanoma and markers of increased melanoma risk. Dysplastic nevi are fairly common; in the United States, 1.8% to 4.9% of white adults have dysplastic nevi. Dysplastic nevi start as rather large moles during the first decade of life. Almost 40% of children from families with dysplastic nevi melanoma have dysplastic nevi, and all children in whom melanoma eventually develops have dysplastic nevi. At least 17% of white adults with melanoma outside the familial melanoma setting have one or more dysplastic nevi, illustrating that dysplastic nevi are markers of risk, as well as potential precursors.

Figure 1 Atypical nevus on the chest.

Clinically, dysplastic nevi appear by age 20 years as two or more disorderly distributed shades of brown and black. They may be round, oval, or misshapen with an irregular or fuzzy outline. Any site may be affected, even sun-protected sites. The horse-collar area is usually most heavily involved.⁷

Management for patients who have dysplastic nevi, with or without a personal or family history of melanoma, is controversial. Pathologic confirmation of the clinical diagnosis provides a more solid basis for making further management decisions. For people who have one or two suspected dysplastic nevi, excision is reasonable, but periodic examinations should be offered for a lifetime.⁷ Prophylactic removal of suspected dysplastic nevi is not feasible for people who have numerous dysplastic nevi. In patients with many dysplastic nevi, excision for hard-to-monitor areas (scalp, perineum, etc.) should be considered, and serial clinical photography of other lesions should be performed to detect new or changing lesions. Persons with dysplastic nevi should also be instructed on how to practice skin self-examination every 4 to 6 weeks at home.

For the removal of dysplastic nevi, lateral margins of about 2 to 3 mm should be taken to ensure complete removal.⁷ Dysplastic nevi can remain unchanged, progress to melanoma, or even regress over time. Only a small fraction of dysplastic nevi ever progress to melanoma, even in the familial melanoma setting. It is probable that both environmental and genetic factors play a role in the transition from dysplastic nevus to melanoma. In Greene and colleagues’ study of dysplastic nevi-melanoma kindreds, they found the actuarial probability of melanoma developing in persons who have dysplastic nevi in the familial melanoma setting may be as high as 56% from age 20 to 59 years and 100% by age 76 years.⁸

In summary, dysplastic nevi should be considered potential precursor lesions to melanoma and deserve careful surveillance and prompt treatment when required.

A short discussion on congenital nevi (Fig. 2) is presented here because patients often are concerned with the malignant potential of these lesions. A congenital nevus is defined as a melanocytic nevus that is present at birth or appears within the first few months of life. They are classified by size as small (<1.5 cm), medium (1.5-20.0 cm), and large (>20.0 cm). The risk of developing cutaneous melanoma within small- and medium-sized lesions is low but can be 1% over a lifetime. Conversely, large congenital nevi have an increased incidence of melanoma of up to 10% over a lifetime. Approximately 50% of the melanomas that develop within large congenital nevi do so by age 3 to 5 years, and patients have a melanoma risk of approximately 5% during the first 5 years of life.⁹ Therefore, smaller congenital nevi can be followed clinically, but early and complete surgical excision of large congenital nevi is usually recommended. If complete removal is not possible, the lesion should be closely observed and any nodules or suspicious changes should be biopsied.

Figure 2 A, Congenital nevus on the lower back. B, Large congenital nevus on the right flank and abdomen.

Subtypes

The subtypes of melanoma are distinguished by clinical and pathologic growth patterns: superficial spreading, lentigo maligna, nodular, and acral lentiginous.

Lentigo Maligna and Lentigo Maligna Melanoma

Lentigo maligna (melanoma in situ) (Fig. 3) begins as a tan irregular macule that extends peripherally, with differing shades throughout. It occurs on sun-damaged atrophic skin in elderly persons. Lentigo maligna occurs equally in men and women, usually in the seventh and eighth decades of life.⁷ The exact percentage of lentigo maligna that progress to invasive lentigo maligna melanoma is unknown, but it is estimated to be less than 30% to 50%. The lesion can grow slowly for 5 to 15 years in the precursor form before invasion.⁷ Although lentigo maligna has a prolonged radial growth phase, when invasion occurs, the result can be lethal. Long-term cumulative rather than intermittent sun exposure is believed to confer the greatest risk for developing lentigo maligna.