Oncology: Malignant Melanoma

Synonyms and related keywords: melanoma skin cancer, lentigo maligna melanoma, atypical nevus, atypical nevi, dysplastic nevus, dysplastic nevi, ultraviolet radiation, sentinel lymph node dissection, sentinel node dissection, malignant melanoma

INTRODUCTION

Background: Malignant melanoma is a neoplasm of melanocytes or of the cells that develop from melanocytes. Once considered an uncommon disease, the annual incidence of melanoma has increased dramatically over the last few decades.

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, when 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. Amelanotic melanomas represent approximately 5% of all NMs.

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 the 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 systems. 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. When compared to cutaneous melanomas, MLMs appear to have a more aggressive course, although this may be because they commonly are diagnosed at a later stage of disease than the more readily apparent cutaneous melanomas.

Frequency:

In the US: 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.

Internationally: 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, at approximately 40 cases per 100,000 people annually.

Mortality/Morbidity: If detected early, melanoma can be cured with surgical excision.

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 excessive 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 sixth most common malignancy in women and the seventh most common malignancy in men. Women tend to have thinner, nonulcerated lesions than 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.

CLINICAL

History:

Family history: Carefully obtain the family history of melanoma or skin cancer. Also, a family history of irregular, prominent moles is important. Approximately 10-20% 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 more likely have multiple primaries.

Patient history: 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 also is 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 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.

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.

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 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 less than 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

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

Moderately elevated risk factors for cutaneous melanoma

One family member with melanoma

Previous history of melanoma

Sporadic dysplastic nevi

Congenital nevus

Slightly elevated risk factors for cutaneous melanoma

Immunosuppression

Sun sensitivity

History of acute, severe, blistering sunburns

Freckling

DIFFERENTIALS

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

Lab Studies:

CBC count

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:

Chest radiograph

For patients with stage I or II disease, a chest radiograph is 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

A CT scan or MRI of the brain should be obtained during the workup of a patient with known distant metastases to detect additional asymptomatic metastatic disease.

A CT scan or 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 intransit 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:

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.

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:

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.

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.

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

T classification (thickness)

N classification

M classification

TREATMENT

Medical Care:

Adjuvant therapy

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy and treatment 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 considered high risk and should be considered for adjuvant therapy.
Although controversy surrounds the use of adjuvant therapy in these patients, a recent large, multicenter study showed improvement in both long-term survival and disease-free survival using high-dose interferon-alpha-2b (IFN). Based on this study, 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.

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.
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.
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 added to DTIC is better than DTIC alone.

Immunotherapy with high-dose interleukin-2 (IL-2) shows promise because it may cure a small percentage (less than 5%) of patients with advanced-stage disease.

Melanoma vaccines and gene therapy are 2 additional treatment options that may become available. Because numerous protocols for patients with advanced-stage melanoma exist, eligible patients should be referred to an oncology center participating in these studies.

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.

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

Drug Category: Antineoplastics -- Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Site reactions can occur with IV route; tissue damage and severe pain may result

Drug Name	Cisplatin (Platinol) -- Alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of double helix.
Adult Dose	CVD regimen: 20 mg/m² /d IV days 2-5 Dartmouth regimen: 25 mg/m²/d IV days 1-3 and 22-24
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
Interactions	Increases toxicity of bleomycin and ethacrynic acid
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	Vinblastine (Velban) -- Inhibits microtubule formation, which disrupts formation of mitotic spindle, causing cell proliferation to arrest at metaphase. Component of CVD regimen.
Adult Dose	1.6 mg/m²/d IV days 1-5, repeat q21-28d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow suppression
Interactions	May reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	Carmustine (BiCNU) -- Alkylates and cross-links DNA strands, inhibiting cell proliferation. Used in Dartmouth regimen.
Adult Dose	150 mg/m² IV day 1 q6wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; myelosuppression from previous chemotherapy
Interactions	Cimetidine may increase toxicity; etoposide may cause severe hepatic dysfunction (hyperbilirubinemia, ascites, thrombocytopenia)
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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.
Adult Dose	10 mg PO bid starting day 4 or 20 mg qd PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	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
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in leukopenia, thrombocytopenia, and hyperlipidemia; decreased visual acuity, corneal changes, and retinopathy may occur with >1 y of use; may induce ovulation

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

Drug Name	Interferon-alpha-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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Potential risk of renal failure when administered concurrently with IL-2; cimetidine may increase antitumor effects; zidovudine, theophylline, and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Depression and suicidal ideation may be adverse effects of treatment

Drug Name	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.
Adult Dose	9 million U/m²/d IV for 4 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antihypertensives may potentiate hypotension seen with IL-2; glucocorticoids may reduce antitumor effectiveness; protease inhibitors increase concentrations and risk of toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Associated with hypotension, requiring IV fluid replacement and, occasionally, pressor support; vascular leak syndrome and cardiorespiratory insufficiency often observed in patients treated with high doses

FOLLOW-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.

Although no absolute guidelines exist, the patient with a primary less than 1 mm in thickness should be examined every 6 months for the first 2 years and every year after that for the next 8 years. Blood chemistries should be obtained at every other visit, and chest x-rays should be obtained yearly for 5 years and then every 2 years for the next 5 years.

Suggested follow-up care for patients with primaries 1-4 mm in thickness consists of a physical examination every 3-4 months for the first 3 years, every 6 months for the 2 years after that, and yearly for the next 5 years. Blood chemistries should be obtained at every other visit, and chest x-rays should be obtained yearly for the first 5 years and every other year for the 5 years after that.

Patients with a primary greater than 4 mm in thickness and negative nodes should have a physical examination every 3-4 months for the first 3 years, every 6 months for the 2 years after that, and yearly for years 5-10. Blood chemistries should be obtained at every other visit for the first 5 years and yearly after that.

Patients with any thickness primary and positive nodes should be examined every 3 months for the first 3 years, every 6 months for the 2 years after that, and yearly for years 5-10. Blood chemistries and chest x-rays should be obtained at every other visit for the first 5 years and yearly after that.

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. On the contrary, at least 1 large French study has shown that the use of sunscreen actually may lead to a false sense of protection and thus cause the individual to spend more time in the sun, increasing the risk of melanoma.

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

Medical/Legal Pitfalls: