Malignant Melanoma 

Malignant melanoma is a neoplasm of melanocytes or of the cells that develop from melanocytes. Although melanoma was once considered an uncommon disease, the annual incidence has increased dramatically over the over the past few decades, as have deaths from melanoma. (See the images of malignant melanoma below.) (See Etiology and Epidemiology.)

Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

Growth

Melanomas have 2 growth phases, radial and vertical. During the radial growth phase, malignant cells grow in a radial fashion in the epidermis. With time, most melanomas progress to the vertical growth phase, in which the malignant cells invade the dermis and develop the ability to metastasize. (See Etiology and Workup.)

Clinically, lesions are classified as thin if they are 1 mm or less in depth; moderate if they are 1-4 mm in depth; and thick if they are greater than 4 mm in depth.

Histologic types of melanoma

There are 5 different forms, or histologic types, of melanoma:

• Superficial spreading melanomas
• Nodular melanomas
• Lentigo maligna melanomas
• Acral lentiginous melanomas
• Mucosal lentiginous melanomas

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type and often arise from a pigmented dysplastic nevus. SSMs typically develop after a long-standing stable nevus changes; typical changes include ulceration, enlargement, or color changes. An SSM may be found on any body surface, especially the head, neck, and trunk of males and the lower extremities of females.

Nodular melanomas

Nodular melanomas (NMs) represent approximately 10-15% of melanomas and also are found commonly on all body surfaces, especially the trunk of males. These lesions are the most symmetrical and uniform of the melanomas and are dark brown or black. The radial growth phase may not be evident in NMs; however, if this phase is evident, it is short-lived, because the tumor advances rapidly to the vertical growth phase, thus making the NM a high-risk lesion. Approximately 5% of all NMs are amelanotic melanomas.

Lentigo maligna melanomas

Lentigo maligna melanomas (LMMs) also account for 10-15% of melanomas. They typically are found on sun-exposed areas (eg, hand, neck). LMMs may have areas of hypopigmentation and often are quite large. LMMs arise from a lentigo maligna precursor lesion. (See the image of lentigo maligna melanoma below.)

Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal frequency among blacks and whites. They occur on the palms, soles, and subungual areas. Subungual melanomas often are mistaken for subungual hematomas (splinter hemorrhages). Like NM, ALM is extremely aggressive, with rapid progression from the radial to vertical growth phase.

Mucosal lentiginous melanomas

Mucosal lentiginous melanomas (MLMs) develop from the mucosal epithelium that lines the respiratory, gastrointestinal, and genitourinary tracts. These lesions account for approximately 3% of the melanomas diagnosed annually and may occur on any mucosal surface, including the conjunctiva, oral cavity, esophagus, vagina, female urethra, penis, and anus. Noncutaneous melanomas commonly are diagnosed in patients of advanced age. MLMs appear to have a more aggressive course than cutaneous melanomas, although this may be because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas.

Sites other than the skin

The majority of melanomas are in the skin, but other sites include the eyes, mucosa, gastrointestinal tract, genitourinary tract, and leptomeninges. Metastatic melanoma with an unknown primary site may be found in lymph nodes only.

Staging

Clark staging is as follows:

• level I - All tumor cells above basement membrane (in situ)
• level II - Tumor extends into papillary dermis
• level III - Tumor extends to interface between papillary and reticular dermis
• level IV - Tumor extends between bundles of collagen of reticular dermis (extends into reticular dermis)
• level V - Tumor invasion of subcutaneous tissue

Breslow classification (thickness) is as follows:

• Less than or equal to 0.75 mm
• 0.76-1.5 mm
• 1.51-4 mm
• Greater than or equal to 4 mm

The staging system for cutaneous melanoma was revised by the American Joint Committee on Cancer (AJCC) in early 2002.^{[1, 2]}

AJCC groupings based on TNM classification are as follows:

• Stage 0 - Tis, N0, M0
• Stage IA - T1a, N0, M0
• Stage IB - T1b, N0, M0; T2b, N0, M0
• Stage IIA - T2b, N0, M0; T3a, N0, M0
• Stage IIB - T3b, N0, M0; T4a, N0, M0
• Stage IIC - T4b, N0, M0
• Stage III - Any T, N 1-3, M0
• Stage IIIA - pT1-4a, N1a, M0; pT1-4a, N2a, M0
• Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0; pT1-4a/b, N2c, M0
• Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0
• Stage IV - Any T, Any N, Any M

T classification (thickness) is as follows:

• TX - Primary tumor cannot be assessed (shave biopsy, regressed primary)
• Tis - Melanoma in situ
• T1 - ≤1.0 mm (a: without ulceration, b: with ulceration)
• T2 - 1.01-2.0 mm (a: without ulceration, b: with ulceration)
• T3 - 2.01-4.0 mm (a: without ulceration, b: with ulceration)
• T4 - < 4.0 mm (a: without ulceration, b: with ulceration)

N classification is as follows:

• N1 - 1 lymph node; a: micrometastasis (clinically occult), b: macrometastasis (clinically apparent)
• N2 - 2-3 lymph nodes; a: micrometastasis, b: macrometastasis, c: in transit met(s), satellite(s), without metastatic lymph nodes (N2a: 2-3 nodes positive for micrometastasis; N2b: 2-3 nodes positive for macrometastasis; N2c: In transit met(s) or satellite(s) without metastatic nodes)
• N3 - 4 or more metastatic nodes or matted nodes or in-transit metastases or satellite(s) with metastatic node(s)

Note that micrometastases are diagnosed after elective or sentinel lymphadenectomy. Macrometastases are defined as clinically detectable nodal metastases confirmed by therapeutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

M classification is as follows:

• M1a - Distant skin, subcutaneous, or nodal metastases, normal lactate dehydrogenase (LDH) level
• M1b - Lung metastases, normal LDH level
• M1c - All other visceral metastases or any distant metastases with an elevated LDH level

Also see Malignant Melanoma Staging.

Melanomas originate from melanocytes, which arise from the neural crest and migrate to the epidermis, uvea, meninges, and ectodermal mucosa. The melanocytes, which reside in the skin and produce a protective melanin, are contained within the basal layer of the epidermis, at the junction of the dermis and epidermis.

Melanomas may develop in or near a previously existing precursor lesion or in healthy-appearing skin. A malignant melanoma developing in healthy skin is said to arise de novo, without evidence of a precursor lesion. Many of these melanomas are induced by solar irradiation. Melanoma also may occur in unexposed areas of the skin, including the palms, soles, and perineum. Certain lesions are considered to be precursor lesions of melanoma, including the common acquired nevus, dysplastic nevus, congenital nevus, and cellular blue nevus.

Genetics

Many genes are implicated in the development of melanoma, including CDKN2A (p16), CDK4, RB1, CDKN2A (p19), PTEN/MMAC1, and ras. CDKN2A (p16) appears to be especially important in both sporadic and hereditary melanomas. This tumor suppressor gene is located on band 9p21, and its mutation plays a role in various cancers.

Ultraviolet radiation

Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most melanomas. Ultraviolet A (UVA), wavelength 320-400 nm, and ultraviolet B (UVB), 290-320 nm, potentially are carcinogenic and actually may work in concert to induce a melanoma.

UVR appears to be an effective inducer of melanoma through many mechanisms, including suppression of the immune system of the skin, induction of melanocyte cell division, free radical production, and damage of melanocyte DNA.

Interestingly, melanoma does not have a direct relationship with the amount of sun exposure because it is more common in white-collar workers than in those who work outdoors.

Sunburn

Acute, intense, and intermittent blistering sunburns, especially on areas of the body that only occasionally receive sun exposure, are the greatest risk factor for the development of sun exposure–induced melanoma. This sun-associated risk factor is different than that for squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

LMM is an exception to this rule, because it frequently appears on the head and neck of older individuals who have a history of long-term sun exposure.

Additional risk factors

Importantly, other factors exist that may predispose an individual to melanoma; chemicals and viruses are 2 etiologic agents that also have been implicated in the development of melanoma.

Greatly elevated risk factors for cutaneous melanoma include the following:

• Changing mole
• Dysplastic nevi in familial melanoma
• More than 50 nevi, 2 mm or greater in diameter

Moderately elevated risk factors for cutaneous melanoma include the following:

• One family member with melanoma
• Previous history of melanoma
• Sporadic dysplastic nevi
• Congenital nevus

Slightly elevated risk factors for cutaneous melanoma include the following:

• Immunosuppression
• Sun sensitivity
• History of acute, severe, blistering sunburns
• Freckling

Occurrence in the United States

The American Cancer Society estimated that 68,720 cases of melanoma were diagnosed in the United States in 2009—39,080 in men and 29,640 in women.^[3] Although melanoma accounts for only approximately 5% of skin cancers, it is responsible for 3 times as many deaths each year as nonmelanoma skin cancers. The incidence of melanoma increases by 5-7% yearly, an annual increase second only to lung cancer in women. While the lifetime risk of developing melanoma in 1935 was only 1 per 1500, the lifetime risk in 2000 was estimated at 1 per 75.

International statistics

Queensland, Australia, has the highest incidence of melanoma in the world, approximately 57 cases per 100,000 people per year. Israel also has one of the highest incidences, approximately 40 cases per 100,000 people annually. The incidence of malignant melanoma is increasing rapidly worldwide, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women.

Racial demographics

Melanoma is more common in whites than in blacks and Asians. The rate of melanoma in blacks is estimated to be one twentieth that of whites. White people with dark skin also have a much lower risk of developing melanoma than do those with light skin. The typical patient with melanoma has fair skin and a tendency to sunburn rather than tan. White people with blond or red hair and profuse freckling appear to be most prone to melanomas. In Hawaii and the southwestern United States, whites have the highest incidence, approximately 20-30 cases per 100,000 people per year.

Sex demographics

Melanoma is slightly more common in men than in women (1.2:1). Melanoma is the fifth most common malignancy in men and the sixth most common malignancy in women, accounting for 5% and 4% of all new cancer cases, respectively.^[3] Women tend to have lesions that are nonulcerated and thinner than those in men.

Age demographics

Melanoma may occur at any age, although children younger than age 10 years rarely develop a de novo melanoma.

The average age at diagnosis is 57 years, and up to 75% of patients are younger than 70 years.

Melanoma is the most common malignancy in women aged 25-29 years and accounts for more than 7000 deaths annually.

Melanoma is notorious for affecting young and middle-aged people, unlike other solid tumors, which mainly affect older adults. It is commonly found in patients younger than 55 years, and it accounts for the third highest number of lives lost across all cancers.

If detected early, melanoma can be cured with surgical excision.

Superficial spreading and nodular types of melanoma are the 2 most common fatal melanomas, based on a review of data from the original 9 registries of the Surveillance, Epidemiology, and End Results Program from 1978-2007.^[4] This confirms prior studies.

Factors predicting the likelihood of response to treatment include the following:

• Good performance status
• Soft-tissue disease or only a few visceral metastases
• Age younger than 65 years
• No prior chemotherapy
• Normal hepatic and renal function
• Normal complete blood count (CBC)
• Absence of central nervous system (CNS) metastases

The prognosis of a melanoma lesion can be predicted based on the following: the depth of invasion, the presence or absence of ulceration, and the nodal status at diagnosis. Important factors that also affect melanoma-specific survival include age, lymph node involvement, and extranodal extension.^[5]

Malignant melanomas usually present at 2 extremes: at one end of the spectrum are patients with small skin lesions that are easily curable by surgical resection, and at the other are patients with widely metastatic disease, in whom the therapeutic options are limited and the prognosis is nil, with a median survival of only 6-9 months. For this reason, physicians must be aware of the clinical characteristics of melanoma to make an early diagnosis. Prognosis also is related to the type of melanoma.

In a retrospective study of patients with melanoma, the lymph node ratio can be calculated and used as a prognostic parameter.^[6]

A study by Brewer et al examined patients who underwent solid transplant and developed melanoma; base on several retrospective database studies, these patients had a poorer outcome compared with patients who did not have a transplant.^[7]

In patients with mucosal melanoma, a multivariable analysis determined that anatomic primary site was an independent predictor of overall survival and disease-specific survival. Tumors in the nasal cavity and oral cavity were associated with survival superior compared with tumors in the nasopharynx and paranasal sinuses. Age older than 70 years, tumor size, nodal status, and distant metastasis status were also predictive of outcome.^[8]

Stage and prognosis

Prognosis depends on the disease stage at diagnosis, as follows:

• Patents with stage I disease - 5-year survival rate of greater than 90%
• Patients with stage II disease - 5-year survival rate ranging from 45-77%
• Patients with stage III disease - 5-year survival rate ranging from 27-70%

Patients with metastatic disease have a grim prognosis, with a 5-year survival rate of less than 20%.

Stage IA

Lesions less than or equal to 1 mm thick with no evidence of ulceration or metastases (T1aN0M0) are associated with a 5-year survival rate of 95%.

Stage IB

Lesions less than or equal to 1 mm thick with ulceration noted but without lymph node involvement (T1bN0M0) or lesions 1.01-2 mm thick without ulceration or lymph node involvement (T2aN0M0) are associated with a 5-year survival rate of approximately 91%.

Stage IIA

Melanomas greater than 1 mm but less than 2.01 mm in thickness with no evidence of metastases but with evidence of ulceration (T2bN0M0) or lesions 2.01-4.0 mm without ulceration or lymph node involvement (T3aN0M0) are associated with an overall 5-year survival rate of 77-79%.

Stage IIB

Melanomas 2.01-4 mm thick with ulceration but no lymph node involvement (T3bN0M0) or lesions greater than 4 mm without ulceration or lymph node involvement (T4aN0M0) are associated with a 5-year survival rate of 63-67%.

Stage IIC

Lesions greater than 4 mm with ulceration but no lymph node involvement (T4bN0M0) are associated with a 5-year survival rate of 45%.

Stage IIIA

Patients with any depth lesion, no ulceration and 1 positive (micrometastatic) lymph node (T1-4a,N1a,M0) have a 5-year survival rate of 70%. T1-4a,N2a,M0 lesions (any depth lesion, no ulceration but 2-3 nodes positive for micrometastasis) are associated with a 5-year survival rate of 63%.

Stage IIIB

Patients with any depth lesion, positive ulceration, and 1 lymph node positive for micrometastasis (T1-4b,N1a,M0) or 2-3 nodes positive for micrometastasis (T1-4b,N2a,M0) have a 5-year survival rate of 50-53%. Patients with any depth lesion, no ulceration, and 1 lymph node positive for macrometastasis (T1-4a,N1b,M0) or 2-3 nodes positive for macrometastasis (T1-4a,N2b,M0) have a 5-year survival rate of 46-59%.

Stage IIIC

Patients with any depth lesion, positive ulceration, and 1 lymph node positive for macrometastasis (T1-4b,N1b,M0) or 2-3 nodes positive for macrometastasis (T1-4b,N2b,M0) or 4 or more metastatic lymph nodes, matted lymph nodes, or in transit met(s)/satellite(s) have a 5-year survival rate of 24-29%.

Stage IV

Melanoma metastatic to skin, subcutaneous tissue, or lymph nodes with normal LDH (M1a) is associated with a 5-year survival rate of 19%. M1b disease (metastatic disease to lungs with normal LDH) has a 5-year survival rate of 7%. M1c disease (metastatic disease to all other visceral organs and normal LDH or any distant disease with elevated LDH) is associated with a 5-year survival rate of 10%.

Also see Malignant Melanoma Staging.

The focus of melanoma prevention and patient education is avoidance of sun exposure.

For patient education information, see the Cancer Center, as well as Skin Cancer, Skin Biopsy, and Mole Removal.