MALIGNANT MELANOMA

Introduction
Background

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 last few decades, as have deaths from melanoma.

Prognosis of a melanoma lesion can be predicted based on the following: the depth of invasion, presence or absence of ulceration and to nodal status at diagnosis. 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 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, depicted in the images below, to make an early diagnosis. Prognosis also is related to the type of melanoma.

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

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A 1.5-cm melanoma with characteristic asymmetry, ...

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

Malignant melanoma. Image courtesy of Hon Pak, MD.
Malignant melanoma. Image courtesy of Hon Pak, MD.

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Malignant melanoma. Image courtesy of Hon Pak, MD.

Malignant melanoma. Image courtesy of Hon Pak, MD.

Lentigo maligna melanoma, right lower cheek. The ...
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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Lentigo maligna melanoma, right lower cheek. The ...

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.

Pathophysiology

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. The greatest risk of sun exposure–induced melanoma is associated with acute, intense, and intermittent blistering sunburns. This risk is different than that of squamous and basal cell skin cancers, which are associated with prolonged, long-term sun exposure.

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.

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.

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.

Five different forms or histologic types of melanoma exist, as follows:

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. A 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 in color. 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. For more information, see Lentigo Maligna Melanoma.

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.
Frequency
United States

The American Cancer Society has estimated that 68,720 cases of melanoma will be diagnosed in the United States in 2009 — 39,080 in men and 29,640 in women.1 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

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. Melanoma is notorious for affecting young and middle-aged people, unlike other solid tumors, which mainly affect older adults.
Mortality/Morbidity

If detected early, melanoma can be cured with surgical excision. Clinically, lesions are classified as thin if they are 1 mm or less in depth; moderate if 1-4 mm; and thick if less than 4 mm in depth.

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%.
Race

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 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

Melanoma is slightly more common in men than 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.1 Women tend to have lesions that are nonulcerated and thinner than those in men.
Age

Melanoma may occur at any age, although children younger than 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.

It is commonly found in patients younger than 55 years, and it accounts for the third highest number of lives lost across all cancers.
Clinical
History

Family history

Carefully obtain any family history of melanoma or skin cancer. Also, a family history of irregular, prominent moles is important. Approximately 10% of all patients with melanoma have a family history of melanoma. These patients typically develop melanoma at an earlier age and tend to have multiple dysplastic nevi. These patients also are more likely to have multiple primaries. Presence of a familial melanoma syndrome should be considered in patients with a family history of pancreatic cancer or astrocytoma. Mutations in the CDKN2A tumor suppressor gene (also known as p16) are the most common genetic abnormalities found in these families.

Patient history

Any previous history of melanoma must be elicited from patients, because these patients are at an increased risk of developing a second melanoma. Patients have reported as many as 8 or more primary melanomas. Multiple primaries especially are prevalent in patients with multiple dysplastic nevi. The term familial atypical mole or melanoma (FAMM) syndrome is used to describe this hereditary tendency to develop multiple dysplastic nevi and melanomas.

Sun exposure

Question the patient extensively about previous sun exposure, including severe sunburns in childhood. The capacity to tan is also important because individuals who tan easily are less likely to develop a melanoma than those who burn easily.

Moles

Question the patient about any changes noted in moles. Any history of change in size, color, or symmetry, as well as knowledge of bleeding or ulceration of the lesion must be obtained. Also elicit any history or family history of multiple nevus syndrome.
Physical

Total body examination

A total-body skin examination is crucial when evaluating a patient with an atypical nevus or a melanoma. The skin examination should be performed both on initial evaluation of the patient and at all subsequent visits. A study from a general dermatology practice found that most melanomas diagnosed during a 3-year period were not the presenting complaint but were discovered only because a dermatologist performed a total-body skin examination; moreover, these incidentally discovered melanomas were more likely to be thinner or in-situ lesions.2

Crucial to a good skin examination is a well-lit examining room and a completely disrobed patient.

Serial photography and new techniques, such as epiluminescence microscopy and computerized image analysis, are useful adjuncts. Epiluminescence microscopy uses a magnifying lens to examine a lesion that has had oil applied. Computerized image analysis stores images of the lesions and makes them available for comparison over time.

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

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A 1.5-cm melanoma with characteristic asymmetry, ...

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

Malignant melanoma. Image courtesy of Hon Pak, MD.
Malignant melanoma. Image courtesy of Hon Pak, MD.

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Malignant melanoma. Image courtesy of Hon Pak, MD.

Malignant melanoma. Image courtesy of Hon Pak, MD.

Lentigo maligna melanoma, right lower cheek. The ...
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.

[ CLOSE WINDOW ]

Lentigo maligna melanoma, right lower cheek. The ...

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.

Skin examination

During a skin examination, assess the total number of nevi present on the patient's skin. Attempt to differentiate between typical and atypical lesions. The images above depict examples of melanomas. The ABCDs for differentiating early melanomas from benign nevi include the following:

* A - Asymmetry (melanoma lesion more likely to be asymmetric)
* B - Border irregularity (melanoma more likely to have irregular borders)
* C - Color (melanoma more likely to be very dark black or blue and have variation in color than a benign mole, which more often is uniform in color and light tan or brown)
* D - Diameter (mole <6 mm in diameter usually benign) Lymph node examination If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate both through the lymphatics, leading to involvement of regional lymph nodes, and hematogenously, leading to involvement of any node basin in the body. Causes Exposure to ultraviolet radiation (UVR) is a critical factor in the development of most melanomas. Both 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. The greatest risk for melanoma is associated with acute, intermittent, blistering sunburns, especially on areas that occasionally receive 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. 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 * Greater 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 * FrecklingDifferential Diagnoses Basal Cell Carcinoma Lentigo Maligna Melanoma Mycosis Fungoides Other Problems to Be Considered Benign melanocytic lesions Dysplastic nevus Squamous cell carcinoma Metastatic tumors to the skin Blue nevus Epithelioid (Spitz) tumor Pigmented spindle cell tumor Halo nevus Atypical fibroxanthoma Pigmented actinic keratosis Sebaceous carcinoma Histiocytoid hemangioma Workup Laboratory Studies In addition to a CBC count, the studies below are indicated. Chemistry panel (complete) The chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase level may signal metastatic disease to the bone or liver, while elevation of liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastatic disease to the liver. Total protein and albumin provide information concerning the overall health and nutritional status of the patient and may afford prognostic information. Many chemotherapy regimens may be toxic to the kidneys; therefore, a creatinine level is necessary prior to initiation of any treatment. Lactate dehydrogenase Lactate dehydrogenase (LDH) level is elevated with many conditions, including many malignancies. Although LDH is not specific for melanoma, it may be useful at diagnosis and also in the follow-up care of patients with melanoma. A markedly elevated LDH at diagnosis or at a follow-up visit may indicate distant metastases, especially in the lung and liver. Although the specificity and sensitivity of this test are low, multiple studies show an elevated LDH level to be an independent predictive factor for poor prognosis. LDH level now is considered part of the staging system for melanoma. Imaging Studies Imaging studies are often obtained in patients with newly diagnosed melanoma, to rule out clinically occult distant disease. Nevertheless, available evidence suggests that preoperative imaging studies have significant costs and offer minimal benefit in most patients with melanoma.3 Chest radiograph For patients with stage I or II disease, a chest radiograph is often obtained, although its result will likely be negative. To date, no studies support obtaining a radiograph in these patients, but a normal chest radiograph finding at diagnosis provides a baseline for future comparison. Patients with stage III disease, in transit disease, or local recurrence should have a chest radiograph or CT scan of the chest because the lungs often are the first site of metastatic disease. CT scan or MRI of the brain MRI of the brain should be obtained during the workup of a patient with known distant metastases to detect additional asymptomatic metastatic disease. This is especially true for patients being considered for high-dose interleukin-2 treatment. MRI of the brain in patients without known metastatic disease should be reserved for those patients who are symptomatic. Chest CT scan A chest CT scan should be included in the staging workup of a patient with stage IV disease (ie, the patient with known distant metastases) to detect asymptomatic metastatic lesions. In patients with stage I, II, or III disease, a chest CT scan should be performed only if clinically indicated. CT scan of the abdomen A CT scan of the abdomen often is obtained when evaluating a patient with stage III, locally recurrent, or in transit disease. Although the yield is low, a negative CT scan provides a baseline study for future comparison. CT scan of the pelvis This study is indicated only if a patient has local regional recurrence below the waist, is symptomatic, or has known metastatic disease with a history of primary tumors below the waist. PET scan A positron emission tomography (PET) scan may aid in staging patients with known node disease or in transit or satellite lesions. Many studies report a greater sensitivity with PET scans compared with conventional radiographic studies for the detection of metastatic disease. PET scans often are useful in evaluating the response of metastatic disease to therapy. PET scans are not indicated in early-stage disease (Stage I or II). Procedures Biopsy of a suggestive lesion A complete excisional biopsy is preferred and should include a 1-2 mm margin of healthy skin, to include all layers of skin and some subcutaneous fat. If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy should be taken from the most abnormal area of the lesion. Because all layers of the skin must be included in the biopsy, a shave biopsy is contraindicated. In some cases where a shave biopsy was done on a lesion, a complete excisional biopsy should be performed if possible to determine the depth and extent of the lesion. Surgical excision or reexcision after biopsy Because failure to perform a reexcision after biopsy of a melanoma is associated with a local recurrence rate as high as 40%, a reexcision must be performed. Current recommendations for margins of excision are as follows: * Lesions less than 1 mm in thickness - 1 cm margin * Lesions 1-4 mm in thickness - 2 cm margin * Lesions greater than 4 mm in thickness - at least 2 cm margin Elective lymph node dissection Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a complete regional lymph node dissection (LND). For years, patients without clinically enlarged nodes underwent LND. Recent studies show that, in patients with melanomas that are 1-4 mm thick, LND may not yield a significant survival advantage. The only patients who seem to benefit from LND are those with lesions 1.1–2 mm thick and who are younger than 60 years. Patients with lesions greater than 4 mm in thickness are widely considered not to benefit from removal of clinically negative nodes. Sentinel lymph node dissection Lymphatics from any given region on the skin drain to a single lymph node. This node is called the sentinel lymph node and almost always is the first site of nodal involvement when melanoma spreads to regional nodes. To determine which node is the sentinel node, the following 2 techniques, often in combination, are used. The combination of the 2 techniques allows detection of the sentinel node in as many as 98% of cases. The first technique involves injecting a blue dye at the site of the primary and, through a small incision over the nodal basin, determining the location of the sentinel node. The node is then removed for pathologic evaluation. The second technique involves a radiolabeled solution injected into the site of the primary and the use of a hand-held gamma detector to determine the location of the sentinel node. Sentinel node biopsy is now known to offer important prognostic, diagnostic, and therapeutic information.4 Guidelines from the National Comprehensive Cancer Network (NCCN) suggest that it is reasonable to offer sentinel lymph node biopsy to patients with thick melanoma (4 mm or greater), in whom the probability of a positive sentinel node is 30-40% and in whom sentinel lymph node status is a strong independent predictor of outcome.5 Sentinel node biopsy may be offered either as standard care or in the context of a clinical trial. The NCCN does not recommend sentinel lymph node biopsy for patients with in situ melanoma (stage 0) or stage IA melanoma that is 1 mm or less with no adverse features. Although there appears to be a subset of patients with thin melanoma who are at sufficient risk for a positive sentinel lymph node to justify a biopsy, there is not yet clear consensus regarding which factors best predict this risk; possible factors include thickness over 0.75 mm, high mitotic rate, and young patient age; other possible factors include positive deep margins and lymphovascular invasion.6 Although current standards of practice suggest completion lymph node dissection (CLND) for patients with a positive result on sentinel lymph node biopsy, Cadili et al reported that the likelihood of non – sentinel lymph node metastasis can be predicted on the basis of total metastasis within the sentinel lymph node. Patients with ≥ 5 mm of metastasis have a 30% risk of metastasis. In contrast, those with <2 mm of total sentinel lymph node metastasis are unlikely (<3.67% likelihood) to harbor metastasis in non-sentinel nodes, and those patients may not benefit from additional nodal dissection.7 Histologic Findings Although no single histologic feature is pathognomonic for melanoma, many characteristic features exist. Cytologic atypia virtually always is noted, with enlarged cells containing large pleomorphic hyperchromic nuclei with prominent nucleoli. Numerous mitotic figures often are noted. A pagetoid growth pattern with upward growth of the melanocytes, so they are no longer confined to the basal layer, is considered pathognomonic for melanoma by some pathologists. Although immunohistochemical stains usually are not necessary for diagnosis, they are generally performed for completeness. Both S-100 and homatropine methylbromide (HMB45) stains are positive in melanoma. The S-100 is highly sensitive, although not specific, for melanoma, while the HMB45 is highly specific and moderately sensitive for melanoma. The 2 stains, in concert, can be useful in diagnosing poorly differentiated melanomas. Staging The staging system for cutaneous melanoma was revised by the American Joint Committee on Cancer (AJCC) in early 2002.8,9 Clark staging * 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) * Less than or equal to 0.75 mm * 0.76-1.5 mm * 1.51-4 mm * Greater than or equal to 4 mm AJCC groupings based on TNM classification * Stage 0 - Tis, N0, M0 * Stage 1A - T1a, N0, M0 * Stage 1B o T1b, N0, M0 o T2b, N0, M0 * Stage IIA o T2b, N0, M0 o T3a, N0, M0 * Stage IIB o T3b, N0, M0 o T4a, N0, M0 * Stage IIC - T4b, N0, M0 * Stage III - Any T, N 1-3, M0 * Stage IIIA o pT1-4a, N1a, M0 o pT1-4a, N2a, M0 * Stage IIIB o pT1-4b, N1a, M0 o pT1-4b, N2a, M0 o pT1-4a, N1b, M0 o pT1-4a, N2b, M0 o pT1-4a/b, N2c, M0 * Stage IIIC o pT1-4b, N1b, M0 o pT1-4b, N2b, M0 o Any T, N3, M0 * Stage IV - Any T, Any N, Any M T classification (thickness) * 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 * 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 o N2a - 2-3 nodes positive for micrometastasis o N2b - 2-3 nodes positive for macrometastasis o 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: 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 * M1a - Distant skin, subcutaneous, or nodal metastases, normal LDH level * M1b - Lung metastases, normal LDH level * M1c - All other visceral metastases or any distant metastases with an elevated LDH leveTreatment Medical Care Adjuvant therapy Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Because fewer than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival, these patients are classified as high risk and should be considered for adjuvant therapy.

Gould Rothberg et al have developed and validated a multimarker prognostic assay for determining survival in stage II melanoma, which these researchers suggest might be beneficial in improving the selection of patients for adjuvant therapy.10 Multiple iterations of a genetic algorithm using the automated quantitative analysis (AQUA) method for immunofluorescence-based immunohistochemistry on 246 serial primary melanomas yielded a consistent 5-marker solution. A favorable prognosis was predicted by the criteria below. Primary tumors that met at least 4 of these 5 conditions were considered low risk. Validation of the score showed that tumors in the high-risk group (those that met 3 or fewer conditions) were associated with significantly reduced survival (hazard ratio, 2.72; 95% confidence interval, 1.12-6.58; P = .027).

* ATF2 ln(non-nuclear/nuclear AQUA score ratio) >-0.052
* p21(WAF1) nuclear compartment AQUA score >12.98
* p16(INK4A) ln(non-nuclear/nuclear AQUA score ratio) -0.083 or less
* Beta-catenin total AQUA score >38.68
* Fibronectin total AQUA score 57.93 or less

A large multicenter study, Eastern Cooperative Group (ECOG) 1684, showed improvement in disease-free survival using high-dose interferon-alfa-2b (IFN) and survival benefit (time to progression improvement of 8 months, with a 1-year survival benefit (P=0.0297).11 On the basis of ECOG-1684, the Food and Drug Administration (FDA) approved IFN as adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence.

A pooled analysis of 1016 patients and 716 observational controls from all ECOG trials showed a significant increase in relapse-free survival (P=0.006) but not overall survival (P=0.42).12

Concerns about toxicity associated with high-dose adjuvant interferon alfa have prompted several investigators to test lower doses of the drug. Lower-dose adjuvant interferon alfa has demonstrated less toxicity than high-dose interferon alfa but also less efficacy in delaying progression, with no survival advantage.

To investigate the possibility that the survival benefit seen in ECOG-1684 had to do with its incorporation of an induction phase of maximally tolerated dosages of IFN given intravenously for the initial 4 weeks, Pectasides et al conducted a prospective randomized study in 364 patients with stage IIB, IIC, or III melanoma who had undergone curative surgery. Patients were randomly assigned to receive IFN-alpha-2b IV for 5/7 days weekly for 4 weeks (arm A) versus the same induction regimen followed by IFN-alpha-2b administered subcutaneously 3 times a week for 48 weeks (arm B). At a median follow-up of 63 months, there were no significant differences in overall survival and relapse-free survival between the 2 arms, and patients in arm B had more grade 1 to 2 hepatotoxicity, nausea/vomiting, alopecia, and neurologic toxicity.13

On the other hand, Hauschild et al found that the addition of a 4-week modified high-dose IFN-alpha induction phase to a 2-year low-dose adjuvant IFN-alpha-2b treatment schedule did not improve the clinical outcome. In their prospective randomized multicenter trial in 674 lymph node–negative patients with resected primary malignant melanoma of more than 1.5-mm tumor thickness, there was no significant difference in 5-year relapse-free survival and overall survival between patients who received an induction phase (IFN-alpha-2b 5 times weekly IV for 2 weeks and 5 times weekly subcutaneously for another 2 weeks) followed by 23 months of low-dose IFN-alpha-2b, and patients who received low-dose subcutaneous treatment 3 times a week for 24 months.14

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN-alfa-2a. Patients with resected cutaneous melanoma of at least 1.5 mm tumor thickness and lymph node negative were included in this prospective randomized, multicenter trial (n=850). Patients were randomly assigned to receive 3 MU IFN alfa-2a SC 3 times/wk for either 18 or 60 months. Median follow-up was 4.3 years. Relapse-free survival and distant-metastasis-free survival did not differ between the 2 groups. The authors concluded that prolonging treatment with conventional low-dose IFN alfa-2a from 18 to 60 months showed no clinical benefit in patients with intermediate- and high-risk primary melanoma.15

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in the adjuvant setting to treat high risk melanoma. Spitler et al treated 46 patients with resected stage III or IV melanoma with a subcutaneous dose of 125 mg/m2 for 2 weeks on and 2 weeks off for a year. The improvement in progression-free survival over historical controls was 37 vs 12 months (P<.001).16 Based on this promising result, a trial was done to test the efficacy of this regimen compared to placebo and a vaccine (ECOG-4697). The results of the trial are still pending at this time. BRAF mutations are present in 40-60% of melanomas. When detected, this mutation can help guide treatment. In a recent multicenter, phase 1, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with PLX4032.17 Two patients had a complete response, and 24 had a partial response. Due to the efficacy of this treatment, a phase 3 trial investigating this BRAF mutation inhibitor is underway. Advanced-stage melanoma (stage IV) Treatment of patients with advanced-stage melanoma (stage IV) has not improved significantly in recent years. At this time, no combination chemotherapy regimen has proven to be significantly better than single-agent dacarbazine (DTIC), which yields only a 10-15% response rate.18 Two combination regimens commonly are used in the treatment of patients with advanced-stage melanoma. The first regimen is the cisplatin, vinblastine, and DTIC (CVD) regimen. The second commonly used regimen is the Dartmouth regimen, which is a combination of cisplatin, DTIC, carmustine, and tamoxifen. However, a meta-analysis found that the strength of evidence does not support the addition of tamoxifen to combined chemotherapy regimens.19 Dacarbazine was the first drug approved for the treatment of metastatic melanoma. In the initial studies with dacarbazine, the overall response rate was 22% with no impact on survival. In a phase III study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%.20 On the basis of this trial, and the greater ease of administration of temozolomide versus dacarbazine (oral versus intravenous), most oncologists currently use temozolomide as their first-line drug for melanoma. Biological therapies now are being used alone and with chemotherapy regimens in the treatment of patients with advanced-stage melanoma. To date, studies do not show that IFN and interleukin-2 added to DTIC is better than DTIC alone. The second drug approved by the Food and Drug administration (FDA) was interleukin-2 (IL-2), a recombinant hormone of the immune system originally described as a T-cell derived growth factor and used as a lymphokine-activated cell killer therapy. A pooled analysis of 270 patients treated with a high-dose IL-2 bolus (600,000-720,000 units/kg administered every 8 hours for 5 days) resulted in an objective response rate of 16% (complete response of 6%) with the best response in patient with soft tissue and lung metastases. The overall median survival was 11.4 months.21 The treatment was quite toxic, with some patients requiring intensive care unit support. The more common toxicities included hypotension (45%), vomiting (37%), diarrhea (32%), and oliguria (39%). Consequently, this therapy is offered only in centers that have adequately trained staff and facilities. To qualify for this type of treatment, patients must have normal results on pulmonary function testing, brain MRI, and cardiac stress testing, plus adequate renal and hepatic function. Carboplatin and paclitaxel have been tested in 2 small phase II studies, and when used in combination with sorafenib, the response rate was 11-17%. This sometimes is being used by clinicians in clinical practice because of lesser toxicity than dacarbazine and also as a second- or third-line regimen. However, a randomized, placebo-controlled phase III study by Hauschild et al found that the addition of sorafenib to carboplatin and paclitaxel did not improve outcome in patients with unresectable stage III or IV melanoma; these investigators recommend against this combination in the second-line setting for patients with advanced melanoma.22 A trial of similar design for the first-line treatment of patients with advanced melanoma is currently ongoing. Thymosin alpha 1 (Talpha1) is an immunomodulatory polypeptide that enhances effector T-cell responses. Maio et al evaluated the efficacy and safety of Talpha1 when combined with dacarbazine (DTIC) and interferon alfa (IFN) in a large randomized study of patients with metastatic melanoma (n=488). Tumor responses were observed in the DTIC/IFN/Talpha1 (3.2mg) (10 responses) and DTIC/Talpha1 (3.2 mg) (12 responses) groups versus 4 tumor responses in the DTIC/IFN (control group). The authors concluded that these results suggest Talpha1 has activity in patients with metastatic melanoma and provide rationale for further clinical evaluation of this agent.23 Anti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody directed at a down-regulatory receptor on activated T-cells.24 This is not yet approved by the FDA. The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T-cells. Several phase III studies are being done to test its efficacy. Ipilimumab, a CTLA-4 blocker, enhances the T-cell response in HLA2-positive patients to improve survival in patients with metastatic melanoma compared with gp120 vaccine (10 vs 6 months). Ipilimumab is the first drug to show significant survival for disease in the past 20 years.25 Melanoma vaccines and gene therapy are 2 additional treatment options that may become available.26 A 2007 review found no clear evidence that the addition of immunotherapy to chemotherapy increases survival in metastatic melanoma and recommended that combined immunotherapy and chemotherapy be limited to clinical trials.27 Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies. Vaccines have not been successful as a treatment for metastatic melanoma but is still a reasonable area of research in the adjuvant setting. Currently, there are no standard systemic therapeutic regimens that offer significant prolongation of survival for most patients with metastatic melanoma without significant risk of toxicities. The brain is a common site of metastasis in malignant melanoma. Brain metastases are associated with a poor prognosis. Management of brain metastases can be difficult due to rapid progression of disease and resistance to conventional therapies. Stereotactic radiosurgery is used increasingly in patients with a limited number of metastases; it is less invasive than craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, though the combination of chemotherapy with external-beam radiation is being investigated.28 Surgical Care Surgery is the definitive treatment for early stage melanoma. A wide local excision with sentinel lymph node biopsy and/or elective LND is considered the mainstay of treatment for patients with primary melanoma. In patients with solitary or acutely symptomatic brain metastases, surgical management may alleviate symptoms and provide local control of disease.28 Consultations A patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy. If diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed. Medication 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 CBC count * Absence of CNS metastases Antineoplastics Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen. Dacarbazine (DTIC) Although mechanism of action unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. End result is inhibition of DNA, RNA, and protein synthesis. * Dosing * Interactions * Contraindications * Precautions Adult Monotherapy: 2-4.5 mg/kg IV for 10 d, repeat q4wk; or 250 mg/m2 IV qd for 5 d, repeat q3wk Combination therapy: 150 mg/m2 IV qd for 5 d, repeat q4wk; or 375 mg/m2 IV on day 1, repeat q15d; or 800 mg/m2 IV on day 1, repeat q21-28d; or 220 mg/m2 IV days 1-3 and 22-24 Pediatric Not established * Dosing * Interactions * Contraindications * Precautions None reported * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Site reactions can occur with IV route; tissue damage and severe pain may result Cisplatin (Platinol) Alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix. * Dosing * Interactions * Contraindications * Precautions Adult CVD regimen: 20 mg/m2/d IV days 2-5 Dartmouth regimen: 25 mg/m2/d IV days 1-3 and 22-24 Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Increases toxicity of bleomycin and ethacrynic acid * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Administer adequate hydration before and for 24 h after dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur; pretreatment with antiemetics encouraged Vinblastine (Velban) Inhibits microtubule formation, which disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase. Component of CVD regimen. * Dosing * Interactions * Contraindications * Precautions Adult 1.6 mg/m2/d IV days 1-5, repeat q21-28d Pediatric Not established * Dosing * Interactions * Contraindications * Precautions May reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; bone marrow suppression * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Caution in patients diagnosed with impaired liver function and neurotoxicity; when patient is receiving mitomycin-C, monitor closely for shortness of breath and bronchospasm; extravasation may lead to severe pain, inflammation, and tissue damage Carmustine (BiCNU) Alkylates and cross-links DNA strands, inhibiting cell proliferation. Used in Dartmouth regimen. * Dosing * Interactions * Contraindications * Precautions Adult 150 mg/m2 IV day 1 q6wk Pediatric Not established * Dosing * Interactions * Contraindications * Precautions Cimetidine may increase toxicity; etoposide may cause severe hepatic dysfunction (hyperbilirubinemia, ascites, thrombocytopenia) * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity; myelosuppression from previous chemotherapy * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Caution in patients with depressed platelet, leukocyte, or erythrocyte counts or hepatic or renal impairment; perform baseline pulmonary function tests; delayed myelosuppression (3-6 wk) may occur, do not administer more frequently than every 6 wk; amphotericin may enhance toxicity; secondary leukemia has been reported Tamoxifen (Nolvadex) Competitively binds to estrogen receptor, producing nuclear complex that decreases DNA synthesis and inhibits estrogen effects. Used in Dartmouth regimen to possibly abrogate multidrug resistance phenotype. * Dosing * Interactions * Contraindications * Precautions Adult 10 mg PO bid starting day 4 or 20 mg qd PO Pediatric Not established * Dosing * Interactions * Contraindications * Precautions May exacerbate hepatotoxic effects of allopurinol; may increase cyclosporine serum levels; increases anticoagulant effects of warfarin; aminoglutethimide reduces serum concentration; cyclophosphamide, methotrexate, and 5-FU increase thrombotic risk * Dosing * Interactions * Contraindications * Precautions Documented hypersensitivity * Dosing * Interactions * Contraindications * Precautions Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Caution in leukopenia, thrombocytopenia, and hyperlipidemia; decreased visual acuity, corneal changes, and retinopathy may occur with > 1 y of use; may induce ovulation
Recombinant cytokines

Immunotherapy (biotherapy) currently used to treat patients with melanoma includes IFN and IL-2. An oncologist should administer these treatments.

Interferon-alfa-2b (Intron)

Protein product manufactured by recombinant DNA technology. Mechanism of antitumor activity not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. DOC for adjuvant therapy in patients with high-risk melanoma. Immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

20 million U/m2 IV for 5 consecutive d/wk for 4 wk; then, 10 million U/m2 SC 3 times/wk for 48 wk
Pediatric

Not established

* Dosing
* Interactions
* Contraindications
* Precautions

Potential risk of renal failure when administered concurrently with IL-2; cimetidine may increase antitumor effects; zidovudine, theophylline, and vinblastine may increase toxicity

* Dosing
* Interactions
* Contraindications
* Precautions

Documented hypersensitivity

* Dosing
* Interactions
* Contraindications
* Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Depression and suicidal ideation may be adverse effects of treatment

Interleukin-2 (Proleukin)

IL-2 is only therapy known to cure advanced-stage melanoma. Activates T cells and amplifies their responses. Enhances NK cell antitumor activity.

* Dosing
* Interactions
* Contraindications
* Precautions

Adult

600,000 -720,000 units/kg IV q8h for up to 14 doses in 5 days; repeat 7-9 days later for 28 doses total; retreat if necessary 8-12 wk after initial course
Pediatric

Not establishedFollow-up
Further Outpatient Care

Follow-up care of a patient with melanoma is based on the stage of the primary. The follow-up examination should be performed with the knowledge that the patient has an increased risk for a second primary and that, of all solitary sites of visceral recurrence, the lungs are the most frequent.

Follow-up guidelines from the National Comprehensive Cancer Network are listed below.5

Stage 0 in situ

* At least annual skin examination for life
* Educate patient in monthly self skin examination

Stage IA

* History and physical examination (H&P) (with emphasis on nodes and skin) every 3-12 mo for 5 y, then annually as clinically indicated
* At least annual skin examination for life
* Educate patient in monthly self skin and lymph node examination

Stage IB-IV (patients with no evidence of disease)

* H&P (with emphasis on nodes and skin) every 3-6 mo for 2 y, then every 3-12 mo for 2 y, then annually as clinically indicated
* Chest radiography, LDH, CBC count every 6-12 mo (optional)
* Routine imaging is not recommended for stage IB or IIA disease
* CT scans to follow up for specific signs and symptoms
* Consider CT scans to screen stage IIB and higher for recurrent/metastatic disease
* At least annual skin examination for life
* Educate patient in monthly self skin and lymph node examination

Deterrence/Prevention

The main focus of melanoma prevention is avoidance of sun exposure. Everyone, especially those individuals at high risk of developing a melanoma, should wear protective clothing, avoid peak sun hours, protect children against UVR exposure, avoid tanning booths, and wear sunscreen with a sun protection factor (SPF) of at least 15. This last recommendation is considered somewhat controversial because no study has shown sunscreen to reduce the incidence of melanoma.29 Moreover, a systematic review found that sunscreen use leads to longer duration of intentional sun exposure, and sunburns tend to be more frequent among sunscreen users.30

First-degree relatives of a patient diagnosed with familial melanoma should be encouraged to have annual skin examinations.
Prognosis

Prognosis depends on the stage at diagnosis.

Patents with stage I disease have a 5-year survival rate greater than 90%.

Patients with stage II disease have a 5-year survival rate ranging from 45-77%.

Patients with stage III disease have a 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%.
Patient Education

The main focus of melanoma prevention and patient education is avoidance of sun exposure (see Deterrence/Prevention).

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center and Procedures Center. Also, see eMedicine's patient education articles Skin Cancer, Skin Biopsy, and Mole Removal.
Miscellaneous
Medicolegal Pitfalls

The following pitfalls are noted:

* Failure to correctly biopsy a suggestive lesion (shave biopsies are contraindicated)
* Failure to identify need for wide excision
* Failure to correctly diagnose a melanoma
* Failure to prescribe a treatment regimen that is considered the standard of care.