1. Etiology and epidemiology. Melanoma arises from pigmentproducing melanocytes that migrate to the skin and eye from the neural crest during embryologie development. Approximately 5% of melanoma occurs in noncutaneous sites such as the eye and mucous membranes of the oropharynx, sinuses, vagina, and anus. Patients can present with regional lymph node involvement or distant metastatic disease without any primary being identified. This occurs in approximately 5% of patients. Melanoma occurs more commonly in men than women and has a peak age at incidence of approximately 50 years. Owing to the young age of many melanoma patients, this disease takes a striking toll in terms of the average number of years of life lost per patient in the United States. The incidence of the disease has increased in the United States to the point where melanoma is now the sixth most common cancer in men or women. The substantial increase in incidence is presumably due to increased
exposure to sunlight (primarily ultraviolet B radiation), with the greatest risk of melanoma felt to be in those who have intermittent intense sun exposure, particularly in fair-skinned, lighthaired individuals with red and blonde hair, and blue or green eyes. The cultural emphasis on sun-tanned skin as an indicator of physical health and beauty has played a major role in this increase. Depletion of the ozone layer may contribute as well. Sunny parts of the United States have the highest incidence of the disease, especially California, Florida, Arizona, and Texas, which include three of the four most populous states in the United States. One particular melanoma subtype, lentigo maligna melanoma, which often occurs on the face, may be more closely associated with long-term occupational sun exposure and is seen in farmers and other outdoor workers. Patient education in prevention, including use of sun-protective clothing, performing outdoor activities at times other than the brightest sunlit hours of the day, use of topical sunscreens, refraining from use of sun-tan parlors, use of skin self-examination, and avoiding sun-tanning (“tanned skin = damaged skin”), should be emphasized. Individuals with xeroderma pigmentosa, an autosomal recessive disorder, typically incur multiple basal and squamous skin cancers and melanoma because their skin lacks the ability to repair damage induced by ultraviolet radiation.

2. Precursor lesions, genetics, and familial melanoma. Melanomas arise not only from sporadic or familial atypical nevi but also from other congenital and acquired nevi; however, approximately half of cutaneous melanomas arise without a clear cut precursor lesion. Individuals who have more than 20 benign nevi are at increased risk for melanoma. Approximately 10% of patients with melanoma have a family history of this cancer. Careful surveillance should be carried out in patients with these risk factors. Suspicious-appearing lesions or lesions that appear to have changed coloration, shape, height, or have bled should be excised. The familial atypical multiple mole melanoma syndrome is characterized by a young mean age at diagnosis (34 years) and multiple lesions. The most common germline mutation seen in familial melanoma occurs in the tumor suppressor gene CDKN2A. CDKN2A, PTEN, NRAS, and BRAF mutations have also been seen in nonfamilial melanoma.

3. Types and appearance of primary lesions. Clinical features, classically known as “ABCD,” that raise suspicion for melanoma include:

Other characteristics of concern include history of recent growth, change in pigmentation, ulceration, itching, or bleeding. Any pigmented lesion that returns after excision should be reevaluated with biopsy. Nonpigmented skin lesions that behave like melanoma should be examined with immunohistochemical stains S-100 and HMB-45 as 1% to 2% of melanomas are amelanotic.

There are four clinical types of primary cutaneous melanoma. Superficial spreading melanoma is the most common type, accounting for 70% of melanomas. It is commonly found on the trunks of men and lower extremities of women. Nodular melanoma comprises 10% to 15% of melanomas and has an early vertical growth phase. It is commonly found on the trunks of men. Those lesions associated with intermittent sun exposure are often (50% to 60%) B-RAF mutated but C-KIT wild-type. Lentigo malignant melanoma accounts for approximately 10% of cases. It is characterized by flat, large (1- to 5-cm) lesions located on the arms, hands, and face of the elderly (median age 70 years) in particular and is known for a relatively longer radial phase. Acral lentiginous melanoma is seen in approximately 3% to 5% of cases and occurs primarily on the palmar surfaces of the hands, plantar surfaces of the feet, and under nails on the digits. This melanoma subtype is most commonly seen in individuals with darker-pigmented skin and is felt not to be as closely related to sun exposure as the other subtypes. Mutations in exons 9 and 11 of the C-KIT gene are more commonly observed in acral lentiginous and mucosal melanomas than other subtypes, but still only occur in about 20% to 30% of these cases.

In general, melanoma is felt to show two distinct growth phases: an initial radial phase during which the melanoma enlarges in a horizontal/superficial pattern above the basal lamina of the skin, followed eventually by a vertical growth phase characterized by invasion deeply with exposure to lymphatic vessels and the vasculature. It is during the vertical growth phase that metastases are felt to be most likely to occur.

4. Patterns of metastases. Melanoma has a proclivity for direct nodal spread presumably through the lymphatics, but a significant proportion of lesions exhibit hematogenous spread as well. Common sites of metastases include lung, liver, bone, subcutaneous areas, and, primarily in late stages, brain. However, melanoma can spread to virtually any site and can imitate virtually any solid malignancy in its pattern of spread. Following diagnosis, approximately 25% of patients will develop visceral metastases. An additional 15% may develop disease limited to lymph nodes. Patients who present with lymph
nodal or metastatic involvement without any obvious primary site may have undergone spontaneous remission of the primary, a phenomenon that may be attributable to some degree of immune system involvement. Interestingly, those patients may have a better outcome than similarly staged patients with known primaries. Patients with “cancer of unknown primary” should have their biopsy material analyzed with the immunohistochemical stains S-100 and HMB-45 to consider the possibility of melanoma.

5. Ocular melanoma. Ocular melanoma is the most common malignancy of the eye in adults. It may occur in any eye structure that contains melanocytes, although uveal tract sites predominate, followed by choroid, ciliary body, and iris in decreasing frequency. Standard therapy may consist of either enucleation (often utilizing a “no touch” technique) or brachytherapy with radioisotopes such as iodine-125. A recently published large randomized study of those two treatments revealed that for primary uveal tumors less than 5 mm in depth, the outcome for survival was identical. This tumor metastasizes most frequently to the liver and appears to be no less sensitive to both biologic agents and chemotherapy than is cutaneous melanoma.