Malignant Melanoma 

Practice EssentialsMalignant melanoma 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.

Essential update: FDA approves trametinib/dabrafenib combo for treating advanced melanoma in patients with BRAF mutations

The FDA has approved a combination of trametinib (Mekinist), a MEK inhibitor, and dabrafenib (Tafinlar), a BRAF inhibitor, for the treatment of patients with unresectable or metastatic melanoma and BRAF V600E or V600K mutations. Accelerated approval was granted based on response rate and duration in a randomized, phase 2, open-label study, in which patients who received combination treatment had an overall response rate of 76%, compared with 54% for those who received only dabrafenib. Median duration of response was longer with combination treatment (10.5 vs 5.6 months). These results, reported by the investigators, were superior to those reported by a blinded independent radiologic review committee.[3, 4]

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 adjunctsSkin 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 Granulocyte-macrophage colony-stimulating factor (GM-CSF) BRAF inhibitors (vemafurenib and dabrafenib)

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[5]

Carboplatin and paclitaxel (sometimes combined with sorafenib) Thymosin alpha 1 Melanoma vaccines and gene therapy Ipilimumab Peginterferon alfa-2b[6]

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.

Image library

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

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 over the past few decades, as have deaths from melanoma. (See the images of malignant melanoma below.) (See Etiology and Epidemiology.)

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

Malignant melanoma. Image courtesy of Hon Pak, MD.Also see Lentigo Maligna Melanoma, Oral Malignant Melanoma, and Head and Neck Mucosal Melanomas.

Growth

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

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

Histologic types of melanoma

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

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

Superficial spreading melanomas

Approximately 70% of cutaneous malignant melanomas are the superficial spreading melanoma (SSM) type. 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.Acral lentiginous melanomas

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

Mucosal lentiginous melanomas

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

Sites other than the skin

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

Staging

Clark staging is as follows:

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

dermis) level V - Tumor invasion of subcutaneous tissue

Breslow classification (thickness) is as follows:

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

The staging system for cutaneous melanoma was revised by the American Joint Committee on Cancer (AJCC) in early 2002.[1, 2] AJCC groupings based on TNM classification are as follows:

Stage 0 - Tis, N0, M0 Stage IA - T1a, N0, M0

Stage IB - T1b, N0, M0; T2b, N0, M0 Stage IIA - T2b, N0, M0; T3a, N0, M0 Stage IIB - T3b, N0, M0; T4a, N0, M0 Stage IIC - T4b, N0, M0 Stage III - Any T, N 1-3, M0 Stage IIIA - pT1-4a, N1a, M0; pT1-4a, N2a, M0 Stage IIIB - pT1-4b, N1a, M0; pT1-4b, N2a, M0; pT1-4a, N1b, M0; pT1-4a, N2b, M0; pT1-4a/b, N2c,

M0 Stage IIIC - pT1-4b, N1b, M0; pT1-4b, N2b, M0; any T, N3, M0 Stage IV - Any T, Any N, Any M

T classification (thickness) is as follows:

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

N classification is as follows:

N1 - 1 lymph node; a: micrometastasis (clinically occult), b: macrometastasis (clinically apparent) N2 - 2-3 lymph nodes; a: micrometastasis, b: macrometastasis, c: in transit met(s), satellite(s),

without metastatic lymph nodes (N2a: 2-3 nodes positive for micrometastasis; N2b: 2-3 nodes positive for macrometastasis; N2c: In transit met(s) or satellite(s) without metastatic nodes)

N3 - 4 or more metastatic nodes or matted nodes or in-transit metastases or satellite(s) with metastatic node(s)

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

M classification is as follows:

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

Also see Malignant Melanoma Staging.

EtiologyMelanomas 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

EpidemiologyOccurrence in the United States

The American Cancer Society estimates that 76,100 cases of cutaneous melanoma will be diagnosed in the United States in 2014—43,890 in men and 32,210 in women.[7] 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.

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 American Cancer Society estimates that 9,710 people in the US (6,470 men and 3,240 women) will die of melanoma in 2014.[7]

International statistics

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.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

Melanoma is slightly more common in men than in women (1.2:1). Melanoma is the fifth most common malignancy in men and the sixth most common malignancy in women, accounting for 5% and 4% of all new cancer cases, respectively.[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.

PrognosisIf 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 EducationThe 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.

HistoryFamily 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 CDKN2Atumor 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 those patients are at 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 ExaminationTotal 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 on initial evaluation of the patient and during 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.[13]

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 images below depict examples of melanomas.) The ABCDs for differentiating early melanomas from benign nevi include the following:

A - Asymmetry (melanoma lesion more likely to be asymmetrical) B - Border irregularity (melanoma more likely to have irregular borders) C - Color (melanoma more likely to be very dark black or blue and to have variation in color than

would a benign mole, which more often is uniform in color and light tan or brown) D - Diameter (mole < 6 mm in diameter usually benign)

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.

Lymph node examination

If a patient is diagnosed with a melanoma, examine all lymph node groups. Melanoma may disseminate through the lymphatics, leading to the involvement of regional lymph nodes, and hematogenously, leading to the involvement of any node basin in the body.

Diagnostic ConsiderationsDifferentials to consider in the diagnosis of malignant melanoma include the following conditions:

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

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

Differential Diagnoses

Basal Cell Carcinoma Lentigo Maligna Melanoma Mycosis Fungoides

Histologic FindingsAlthough 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.

Approach ConsiderationsThe diagnosis of melanoma is confirmed by excisional biopsy. Patients with clinically enlarged lymph nodes and no evidence of distant disease should undergo a complete regional lymph node dissection. Sentinel lymph node biopsy is appropriate in selected patients.

Laboratory studies that are indicated include the following:

Complete blood cell count (CBC) Comprehensive serum chemistry panel Lactate dehydrogenase (LDH) level

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.[14] One meta-analysis of diagnostic tests used in staging melanoma has shown that ultrasonography is the best imaging study to diagnose lymph node involvement and that positron emission tomography computed tomography scanning (PET/CT) is the best imaging study to look for other sites of metastasis.[15]

Complete Chemistry PanelThe chemistry panel may give a clue to possible metastatic disease. For example, an elevated alkaline phosphatase level may signal metastasis to the bone or liver, while elevated levels on liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) may represent metastasis 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 StudyThe LDH level is elevated in 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.

Chest RadiographyFor 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.

MRIMagnetic resonance imaging (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.

CT ScanningChest 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.

Positron Emission TomographyPET scans are not indicated in early-stage disease (Stage I or II), but a PET scan may aid in staging patients with known node involvement or in-transit or satellite lesions. Many studies report that PET scans have greater sensitivity than conventional radiographic studies for the detection of metastatic disease.

One meta-analysis found PET CT scanning to be the best imaging study to utilize for finding other sites of metastasis.[15] In particular, fluorodeoxyglucose (FDG) PET/CT scans are a valuable tool for detecting additional metastasis as part of the preoperative evaluation of patients with advanced and metastatic melanoma.[16]Finally, PET scans often are useful in evaluating the response of metastatic disease to therapy.

Biopsy of a Suggestive LesionA complete excisional biopsy is preferred. The sample should have a 1-2 mm margin of healthy skin and should include all layers of skin and some subcutaneous fat. Although sparing of the deep fascia is not standard in biopsies for suspected melanoma, investigators at the Mayo Clinic recommend this practice in some patients.[17]

If the suggestive lesion is large or situated in a cosmetically sensitive area, an incisional or punch biopsy may be appropriate. The incisional biopsy specimen 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 BiopsyBecause failure to perform a reexcision after biopsy of a melanoma is associated with a local recurrence rate of 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

A study by Gillgren et al determined that a 2-cm excision provided a safe and reliant resection margin to treat lesions thicker than 2 mm.[18]

Elective Lymph Node DissectionPatients 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. However, 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 DissectionLymphatics 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.[19]

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.[20] 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.[21]

Joint guidelines from the American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) recommend sentinel lymph node biopsy for patients with intermediate-thickness melanomas (Breslow thickness 1–4 mm) of any anatomic site. There is less evidence for patients with thick melanomas (T4; Breslow thickness >4 mm), but sentinel lymph node biopsy is recommended for staging and facilitating regional disease control. Evidence supporting routine sentinel lymph node biopsy for patients with thin melanomas (T1; Breslow thickness < 1 mm) is lacking, but it may be an option in selected patients with high-risk features in whom the benefits of staging outweigh the risks of the procedure.

The guidelines recommend completion lymph node dissection (CLND) for all patients with a positive sentinel lymph node biopsy; CLND achieves good regional disease control. Whether CLND improves survival after a positive sentinel lymph node biopsy is being examined in the ongoingMulticenter Selective Lymphadenectomy Trial II.[22]

Although current standards of practice suggest 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 less than 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.[23]

Go to Sentinel Lymph Node Biopsy in Patients With Melanoma for complete information on this topic.

Approach ConsiderationsSurgery is the definitive treatment for early-stage melanoma. Wide local excision with sentinel lymph node biopsy and/or elective lymph node dissection (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.[24]

Because the definitive treatment of cutaneous melanoma is surgery, medical management is reserved for adjuvant therapy of patients with advanced melanoma. Less than one half of patients with deep primaries (>4 mm) or regional lymph node involvement have long-term disease-free survival; consequently, these patients are classified as high risk and should be considered for adjuvant therapy.

Interferon alfa is approved for adjuvant treatment after excision in patients who are free of disease but are at high risk for recurrence. 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.

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

Adjuvant TherapyGould Rothberg et al 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.[25] 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 following criteria:

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

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).

Interferon alfa

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).[26] On the basis of ECOG-1684, the US 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 = .006) but not overall survival (P = .42).[27]

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.[28]

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 wk and 5 times weekly subcutaneously for another 2 wk) 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.[29]

Hauschild et al also studied optimal duration of treatment of malignant melanoma with low-dose IFN alfa-2a and 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. 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.[30]

Meta-analysis data shows that ulceration and tumor stage are important predictors of response to interferon alfa/pegylated-interferon.[31]

Granulocyte-macrophage colony-stimulating factor

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/m2for 2 weeks on and 2 weeks off for a year and found that the improvement in progression-free survival over historical controls was 37 vs 12 months.[32] Based on this promising result, a trial was done to test the efficacy of this regimen compared with placebo and a vaccine (ECOG-4697). The results of the trial are still pending at this time.

Treatment of Advanced-Stage Melanoma (Stage IV)Treatment of patients with advanced-stage melanoma (stage IV) has not improved significantly in recent years.

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.

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.[33]

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.[34]

Biologic 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.

Dacarbazine

DTIC 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 3 study of dacarbazine compared with temozolomide, the response rate was 12% versus 13%.[39] 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.

Interleukin 2

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.[40]

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

Carboplatin and paclitaxel have been tested in 2 small phase 2 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 3 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.[41, 42]

Thymosin alpha 1

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 DTIC and IFN alfa in a randomized study of 488 patients with metastatic melanoma. Their results suggested that Talpha1 has activity in these patients. Tumor responses were higher in the groups who received Talpha1 (in a dose of 3.2 mg) with DTIC and IFN (10 responses) or with DTIC (12 responses) than in the DTIC/IFN control group (4 responses).[43]

Treatment of melanoma with BRAF mutations

BRAF mutations are present in 40-60% of melanomas. When detected, this mutation can help to guide treatment. In a multicenter, phase 1, dose-escalation trial, 32 patients with metastatic melanoma who had a BRAF mutation were treated with vemurafenib (PLX4032).[44] Two patients had a complete response, and 24 had a partial response.

Vemurafenib (Zelboraf) was approved by the US Food and Drug Administration (FDA) in August 2011. It is an inhibitor of some mutated forms of BRAF serine-threonine kinase, including BRAF -V600E. The drug is indicated for the treatment of unresectable or metastatic melanoma with BRAF -V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

In May 2013 the FDA approved dabrafenib (Taflinar), a BRAF inhibitor in the same class as vemurafenib, for patients with unresectable or metastatic melanoma withBRAF V600E mutation confirmed by the THxID BRAF mutation test.[45] In a multicenter, open-label, phase 3 randomized controlled trial, treatment with dabrafenib significantly improved progression-free survival in patients with BRAF-mutated metastatic melanoma, compared with dacarbazine (5.1 vs 2.7 mo).[46]

Phase 3 trial results for the investigational BRAF inhibitor vemurafenib included a 63% relative reduction in the risk of death as well as a 74% relative reduction in the risk of tumor progression in patients with previously untreated metastatic melanoma with the BRAF V600E mutation compared with dacarbazine, the only chemotherapeutic drug currently approved by the US Food and Drug Administration (FDA) for this disease.[47]

In addition, the overall survival rate at 6 months in the vemurafenib group was 84% relative to 64% in the dacarbazine group.[47] Despite the short follow-up period, these results have significant clinical implications, as, of the previously mentioned 40-60% of cutaneous melanomas with BRAF mutations, about 90% involve theBRAF V600E mutation. Moreover, a response to vemurafenib in 4 of 10 patients

with the BRAF V600K mutation was noted, suggesting sensitivity of this mutation variant to vemurafenib.[47]

Vemurafenib was generally well tolerated, with cutaneous events (squamous cell carcinoma, keratoacanthoma, or both; all were treated with simple excision), arthralgia, fatigue, and photosensitivity the most common adverse events; such events led to dose modification or interruption in 38% of patients.[47] Adverse events seen with dacarbazine were primarily fatigue, nausea, vomiting, and neutropenia and led to dose modification or interruption in 16% of patients.

Dabrafenib was shown to significantly improve progression-free survival compared with dacarbazine (5.1 vs 2.7 mo) in patients with BRAF -mutated metastatic melanoma in a multicenter, open-label, phase 3 randomized controlled trial.[48]

Trametinib (Mekinist) is a mitogen-activated, extracellular signal-regulated kinase (MEK) inhibitor that was approved by the FDA in May 2013 for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by the THxID BRAF mutation test.[45] Approval was based on a phase 3 open-label trial that compared trametinib to either dacarbazine or paclitaxel. Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group. At 6 months, the rate of overall survival was 81% in the trametinib group and 67% in the chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92).[49]

In January 2014, the FDA approved trametinib for use in combination with dabrafenib for treating patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Approval was based on the demonstration of response rate and median duration of response in a phase 1/2 study. Median progression-free survival in the combination full-dose 150 mg/2 mg group was 9.4 months compared with 5.8 months in the dabrafenib monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62). The rate of complete or partial response with combination therapy was 76% compared with 54% with monotherapy. Improvement in disease-related symptoms or overall survival has not been demonstrated for this combination.[50]

Vaccines

Melanoma vaccines and gene therapy are 2 additional treatment options that may become available.[51]

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.[52]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 are still a reasonable area of research in the adjuvant setting.

External-beam radiation

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, although the combination of chemotherapy with external-beam radiation is being investigated.[24]

Future therapies

In a multicenter phase 2 trial, targeted therapy with imatinib was an effective treatment option in patients with advanced melanoma harboring mutations or amplification of the KIT proto-oncogene.[35, 36,

37] Of 50 patients with melanomas arising from acral, mucosal, or chronically sun-damaged sites with KIT alterations, 24 evaluable patients with KIT-mutant (n = 8), KIT-amplified melanoma (n = 11), or both (n = 5) were treated with imatinib. Of these 24 patients, 7 achieved a partial response to therapy, with 5 patients' responses confirmed on subsequent imaging studies, for an overall confirmed response rate of 21%.[35, 36]

These findings reinforce similar findings in 2 earlier studies.[5, 38]

IpilimumabAnti–cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a humanized antibody directed at a down-regulatory receptor on activated T-cells.[53] The proposed mechanism of action is inhibition of T-cell inactivation, allowing expansion of naturally developed melanoma-specific cytotoxic T-cells.

Ipilimumab, a CTLA-4 blocker, has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently under way.[54] Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.

Hodi et al reported improved survival with ipilimumab in patients with metastatic melanoma. Ipilimumab blocks CTLA-4 to a potentiate T-cell response. In a phase 3 study, 676 patients with HLA2-positive patients with unresectable stage III or IV melanoma who disease progressed while receiving therapy for metastatic disease were randomly assigned in a 3:1:1 ratio to ipilimumab plus gp100, ipilimumab, or gp100 alone. Ipilimumab was given at a dose of 3 mg/kg and was administered with or without gp100 every 3 weeks for up to 4 treatments; subsequently, patients would receive reinduction therapy. The median overall survival was 10 months among patients receiving ipilimumab plus gp100, compared with 6.4 months in those receiving gp100 alone. There was no difference in survival in the other ipilimumab arm compared with the ipilimumab-plus-gp100 arm. Because of these findings, ipilimumab has been approved as a treatment for metastatic melanoma.[54]

In a phase 3 study of ipilimumab and dacarbazine compared with dacarbazine and placebo, survival among patients with metastatic melanoma was improved by 2 months (11 mo vs 9 mo) in the ipilimumab arm; however, they had more grade 3 and 4 toxicity.[55]

In the MDX010-20 trial, researchers evaluated immune-related adverse events (AEs) in 676 patients previously treated for metastatic melanoma who were randomly assigned to receive 1 of the following 3 treatment regimens (in a 3:1:1 ratio): (1) ipilimumab plus glycoprotein 100 melanoma antigen vaccine (gp100); (2) ipilimumab plus placebo; or (3) gp100 plus placebo.[56, 57] Most of the immune-related AEs developed within 12 weeks of initial dosing, typically resolving in 6-8 weeks. Fewer than 10% of patients receiving any ipilimumab treatment experienced an immune-related AE more than 70 days after their last drug dose, and all of these AEs were grade 1 or 2 in severity. Most immune-related AEs, even grade 3/4 events, were readily managed with monitoring and early corticosteroid therapy; only 5 patients needed infliximab for gastrointestinal AEs, and all 5 subsequently improved.[56,

57]

Peginterferon Alfa-2bPeginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy.

The drug’s approval was based on a 5-year, open-label, multicenter trial in which cancer recurrence was delayed about 9 months longer in patients who took peginterferon alfa-2b than it was in patients who did not take the drug.[6]

Talimogene laherparepvecTalimogene laherparepvec (T-VEC) is an oncolytic immunotherapeutic vaccine engineered through the genetic alteration of the herpes simplex type I virus. In this process, the gene ICP 34.5 is deleted and replaced with the coding sequence for granulocyte-macrophage colony-stimulating factor (GM-CSF). T-VEC promoted shrinkage in 64% of patients with advanced melanoma. A phase 3 study, OPTIM, compared T-VEC with GM-CSF in stages IIIB, IIIC and 4 melanoma. T-VEC was administered at < 4 ml x 106 pfu/ml for 3 weeks followed by the same dose every 2 weeks and GM-CSF was administered at 125 μ g/m2 for 14 days every 28 days. T-VEC produced a durable response rate in 16.3% compared with 2.1% in patients treated with GM-CSF. Response rate (RR) was 26.4% and complete response (CR) was 10.8% with T-VEC compared with an RR of 5.7% and CR of 0.7% for GM-CSF.[62]

Prevention of Malignant MelanomaThe 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 exposure to ultraviolet radiation, 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.[58] 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.[59]

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

ConsultationsA patient with a suggestive lesion should be referred to a dermatologist or surgical oncologist for excisional biopsy.

If the diagnosis of melanoma is made, the patient should be referred to an oncologist after definitive surgery is performed.

Long-Term MonitoringFollow-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.[20]

Follow-up for stage 0 in situ is as follows:

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

Follow-up for stage IA is as follows:

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-examination of skin and lymph nodes

Follow-up for stage IB-IV (patients with no evidence of disease) is as follows:

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, lactate dehydrogenase (LDH) level, and complete blood cell count (CBC) 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-examination of skin and lymph nodes

Medication SummaryHigh-dose interferon (IFN) alfa-2b is the only adjuvant therapy approved by the US Food and Drug Administration (FDA) for high-risk resected melanoma, defined as deep primaries greater than 4 mm in Breslow depth (AJCC stage IIB) and regional lymph node metastasis (stage III). Various trials of low-dose IFN have shown no benefit in disease-free relapse or overall survival (OS) rates.[60]

Similarly, multiple melanoma vaccine trials are in progress, predominantly for stage III and IV disease, but they have not demonstrated an OS advantage to date.

Ipilimumab, a CTLA-4 blocker, enhances the T-cell response in HLA2-positive patients and demonstrates remarkable promise in patients with metastatic melanoma. It is being studied by itself and in combination with other immunotherapies and vaccines.[54]

Antineoplastic AgentsClass Summary

These agents inhibit cell growth and differentiation. Chemotherapeutic agents used to treat melanoma include dacarbazine, cisplatin, vinblastine, carmustine, and tamoxifen.

View full drug information

Dacarbazine 

Although the mechanism of action for dacarbazine is unknown, possible actions include alkylating agent, purine metabolite, or interaction with sulfhydryl groups. The end result is inhibition of DNA, ribonucleic acid (RNA), and protein synthesis.

View full drug information

Cisplatin 

Cisplatin is an alkylating agent that inhibits DNA synthesis and, thus, cell proliferation by causing DNA cross-links and denaturation of the double helix.

View full drug information

Vinblastine 

Vinblastine inhibits microtubule formation, which disrupts formation of the mitotic spindle, causing cell proliferation to arrest at metaphase. It is a component of the CVD regimen.

View full drug information

Ipilimumab (Yervoy) 

Anticytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a humanized antibody that overcomes CTLA-4-mediated T-cell suppression to enhance the immune response against tumors. The marker CTLA-4 is associated with promoting a regulatory response by the immune system. This regulatory response has a dampening effect on the immune system. Ipilimumab is able to inhibit the effects of CTLA-4 on T cells and allows the expansion of naturally developed melanoma-specific cytotoxic T-cells. This agent is the first new agent to be approved for melanoma in over a decade.

Ipilimumab has demonstrated remarkable promise in patients with metastatic melanoma. Clinical trials for monotherapy and in combination with other immunotherapies and vaccines have been concluded or are currently underway. Ipilimumab was approved by the FDA in March 2011 for unresectable or metastatic melanoma.

View full drug information

Carmustine (BiCNU) 

This agent alkylates and cross-links DNA strands, inhibiting cell proliferation. It is used in the Dartmouth regimen.

View full drug information

Dabrafenib (Tafinlar) 

Dabrafenib inhibits some mutated forms of BRAF kinases with in vitro IC50 values of 0.65, 0.5, and 1.84 nM for BRAF V600E, BRAF V600K, and BRAF V600D enzymes, respectively. It is indicated for unresectable or metastatic melanoma with BRAF V600 E mutation confirmed by with the THxID BRAF mutation test.

View full drug information

Trametinib (Mekinist) 

Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activation, and of MEK1 and MEK2 kinase activity. It is approved for unresectable or metastatic melanoma with BRAF V600E or V600K mutations confirmed by with the THxID BRAF mutation test.

View full drug information

Tamoxifen 

Tamoxifen competitively binds to the estrogen receptor, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is used in the Dartmouth regimen to possibly abrogate the multidrug resistance phenotype.

View full drug information

Vemurafenib (Zelboraf)

 

Inhibits some mutated forms of BRAF serine-threonine kinase, including BRAF-V600E. The drug is indicated for unresectable or metastatic melanoma with BRAF-V600 mutation as detected by the cobas 4800 BRAF V600 Mutation Test (Roche Molecular Systems). Vemurafenib has not been studied with wild-type BRAF melanoma.

Biological Response ModulatorsClass Summary

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

View full drug information

Interferon alfa 2b (Intron A) 

IFN alfa-2b is a protein product manufactured by recombinant DNA technology. The mechanism of antitumor activity is not clearly understood; however, direct antiproliferative effects against malignant cells and modulation of host immune response may play important roles. It is the drug of choice for adjuvant therapy in patients with high-risk melanoma. Its immunomodulatory effects include suppression of tumor cell proliferation, enhancement of macrophage phagocytic activity, and augmentation of lymphocyte cytotoxicity.

IFN alfa-2b is generally initiated within 56 days of surgery and typically administered by medical oncologists.

View full drug information

Peginterferon alfa 2b (Sylatron) 

Peginterferon alfa-2b is an immunomodulatory cytokine that enhances phagocyte and lymphocyte activity. Alfa interferons act through high-affinity cell surface receptors, which, once activated, are known to inhibit cellular growth, alter the state of cellular differentiation, interfere with oncogene expression, alter cell surface antigen expression, increase the phagocytic activity of macrophages, and enhance the cytotoxicity of lymphocytes for target cells.

A covalent attachment of polyethylene glycol polymer chains to interferon molecules (known as PEGylation) can significantly increase the time the drug remains in the bloodstream, which, in turn, can reduce the frequency of dosing and potentially reduce the severity and frequency of adverse effects.

It was approved by the FDA in March 2011 as adjuvant therapy following definitive surgical resection, including complete lymphadenectomy. It is the first therapy approved for the adjuvant treatment of melanoma in 15 years.

View full drug information

Interleukin 2 (Proleukin) 

IL-2 is the only therapy known to cure advanced-stage melanoma. It activates T cells and amplifies their responses. It enhances natural killer cell antitumor activity.