Malignant Melanoma: Practice Essentials, Background, Etiology

Sections

Overview

Practice Essentials

Malignant melanoma (see the image below) is a neoplasm of melanocytes or a neoplasm of the cells that develop from melanocytes. Although it was once considered uncommon, the annual incidence has increased dramatically over the past few decades. Surgery is the definitive treatment for early-stage melanoma, with medical management generally reserved for adjuvant treatment of advanced melanoma.

Malignant melanoma. Image courtesy of Hon Pak, MD.

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See Mole or Melanoma? Test Yourself With These Suspicious Lesions, a Critical Images slideshow, to help identify various skin lesions.

Also, see The Case of the Middle-Aged Woman with Sudden Unilateral Vision Loss slideshow to help identify and treat malignant intraocular melanomas.

Signs and symptoms

The history should address the following:

Family history of melanoma or skin cancer
Family history of irregular, prominent moles
Family history of pancreatic cancer or astrocytoma
Previous melanoma (sometimes multiple; patients have reported as many as 8 or more primary melanomas)
Previous sun exposure
Changes noted in moles (eg, size, color, symmetry, bleeding, or ulceration)
History or family history of multiple nevus syndrome

Physical examination includes the following:

Total-body skin examination, to be performed on initial evaluation and during all subsequent visits
Serial photography, epiluminescence microscopy, and computerized image analysis, to be considered as adjuncts

Skin examination involves assessing the number of nevi present and distinguishing between typical and atypical lesions. (The images below depict examples of melanomas.) Early melanomas may be differentiated from benign nevi by the ABCDs, as follows:

A - Asymmetry
B - Border irregularity
C - Color that tends to be very dark black or blue and variable
D - Diameter ≥ 6 mm

If a patient is diagnosed with a melanoma, examine all lymph node groups.

See Clinical Presentation for more detail.

Diagnosis

The following laboratory studies are indicated:

Complete blood count
Complete chemistry panel (including alkaline phosphatase, hepatic transaminases, total protein, and albumin)
Lactate dehydrogenase

The following imaging modalities may be considered:

Chest radiography
Magnetic resonance imaging of the brain
Ultrasonography (possibly the best imaging study for diagnosing lymph node involvement)
Computed tomography of the chest, abdomen, or pelvis
Positron emission tomography (PET; PET-CT may be the best imaging study for identifying other sites of metastasis)

Procedures to be considered in the workup include the following:

Complete excisional biopsy of a suggestive lesion
Surgical excision or reexcision after biopsy
Elective lymph node dissection (ELND) for patients with clinically enlarged nodes and no evidence of distant disease
Sentinel lymph node biopsy (SLNB; see Sentinel Lymph Node Biopsy in Patients With Melanoma)

Characteristic histologic findings include the following:

Cytologic atypia, with enlarged cells containing large, pleomorphic, hyperchromic nuclei with prominent nucleoli
Numerous mitotic figures
Pagetoid growth pattern with upward growth of the melanocytes

See Workup for more detail.

Management

Surgery (eg, wide local excision with SLNB, ELND, or both) is the definitive treatment for early-stage melanoma. Medical management is reserved for adjuvant therapy of patients with advanced melanoma.

Agents used in adjuvant therapy include the following:

Interferon alfa
Pegylated interferon
Granulocyte-macrophage colony-stimulating factor (GM-CSF)

Agents that may be considered for treatment of advanced-stage (stage IV) melanoma include the following:

Dacarbazine
Temozolomide (currently used as the first-line drug for melanoma by most oncologists)
Interleukin-2
Cisplatin, vinblastine, and dacarbazine (CVD)
Cisplatin, dacarbazine, carmustine, and tamoxifen (Dartmouth regimen)
Imatinib mesylate ^[1]
Carboplatin and paclitaxel (sometimes combined with sorafenib)
Ipilimumab
Pembrolizumab ^[2]
Trametinib
Vemurafenib
Dabrafenib
Peginterferon alfa-2b ^[3]
Nivolumab ^[4]

The following procedures may be used to treat brain metastases:

Stereotactic radiosurgery (for patients with a limited number of metastases)
External-beam radiation

See Treatment and Medication for more detail.

Background

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

A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.

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Malignant melanoma. Image courtesy of Hon Pak, MD.

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

Growth

Melanomas have two 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 according to their depth, as follows:

Thin: 1 mm or less
Moderate: 1-4 mm
Thick: >4 mm

Histologic types of melanoma

There are five 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. Many SSMs arise from a pigmented dysplastic nevus, often one that has long been stable. 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.)

Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

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Acral lentiginous melanomas

Acral lentiginous melanomas (ALMs) are the only melanomas that have an equal frequency in 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:

0.75 mm or less
0.76-1.5 mm
1.51-4 mm
4 mm or more

The staging system for cutaneous melanoma was revised by the American Joint Committee on Cancer (AJCC) in early 2002.^{[5, 6]}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.

Etiology

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. These include the following nevi:

Common acquired nevus
Dysplastic nevus
Dongenital nevus
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 estimates that 73,870 cases of cutaneous melanoma will be diagnosed in the United States in 2015 (42,670 in men and 31,200 in women). Overall rates of melanoma rose rapidly over the past 3 decades. From 2007 to 2011, however, incidence rates remained stable in men and women younger than age 50, while increasing 2.6% per year in those 50 or older.^[7]

Although melanoma accounts for less than 2% of skin cancers, it is responsible for the vast majority of deaths from skin cancers. The American Cancer Society estimates that 9,940 people in the US (6,640 men and 3,300 women) will die of melanoma in 2015.^[7]

International statistics

The incidence of malignant melanoma has been increasing rapidly worldwide, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women. 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.

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

Overall, melanoma is the fifth most common malignancy in men and the seventh most common malignancy in women, accounting for 5% and 4% of all new cancer cases, respectively. However, the relative incidence of melanoma in men and women varies markedly by age: in people younger than 50 years of age, incidence rates are higher in women than in men, but by age 65, they are twice as high in men as in women, and by age 80 they are three times as high in men. Those differences primarily reflect differences in occupational and recreational sun exposure, which have changed over time.^[7]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.

Prognosis

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.^[8]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.^[9]

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 review of 3,872 cases of lymph node–positive melanoma, the proportion of examined lymph nodes found to be positive (the lymph node ratio) independently predicted disease-specific survival. These researchers concluded that the lymph node ratio consistently improved the prognostic accuracy of the TNM system.^[10]

A study of patients who developed melanoma after solid organ transplantation found that their overall survival was worse than the rate reported in a national sample of patients with melanoma. Among transplant recipients with thicker melanomas, disease-specific survival was significantly poorer than in patients without a prior history of transplantation.^[11]

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.^[12]

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.

Patient Education

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.

Clinical Presentation

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Media Gallery

A 1.5-cm melanoma with characteristic asymmetry, irregular borders, and color variation.
Malignant melanoma. Image courtesy of Hon Pak, MD.
Lentigo maligna melanoma, right lower cheek. The centrally located erythematous papule represents invasive melanoma with surrounding macular lentigo maligna (melanoma in situ). Image courtesy of Susan M. Swetter, MD.

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Malignant Melanoma

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