Cancer, Melanoma, Malignant

A melanoma is a tumor produced by the malignant transformation of melanocytes. Melanocytes are derived from the neural crest; consequently, melanomas, although they usually occur on the skin, can arise in other locations where neural crest cells migrate, such as the gastrointestinal tract and brain. The five-year relative survival rate for patients with stage 0 melanoma is 97%, compared with about 10% for those with stage IV disease.

 The causes may be related to:

• Family history - Positive family history in 5% to 10% of patients; a2.2-fold higher risk with at least one affected relative 
• Personal characteristics - Blue eyes, fair and/or red hair, pale complexion; skin reaction to sunlight (easily sunburned); freckling; benign and/or dysplastic melanocytic nevi (number has better correlation than size); immunosuppressive states (transplantation patients, hematologic malignancies)
• Sun exposure over a lifetime - High UVB and UVA radiation exposure (Recent evidence has shown that the risk of melanoma is higher in people who use sunscreen. Because sunscreen mostly blocks UVB, people using sunscreen may be exposed to UVA more than the general public, provided those people are exposed to the sun more than the public at large); low latitude; number of blistering sunburns; use of tanning beds
• Atypical mole syndrome (formerly termed B-K mole syndrome, dysplastic nevus syndrome, familial atypical multiple mole melanoma) - Over ten years, 10.7% risk of melanoma (vs 0.62% of controls); higher risk of melanoma depending on number of family members affected (nearly 100% risk if two or more relatives have dysplastic nevi and melanoma)
• Socioeconomic status - Lower socioeconomic status may be linked to more advanced disease at the time of detection. One survey of newly-diagnosed patients found that low-SES individuals have decreased melanoma risk perception and knowledge of the disease.

The incidence of malignant melanoma is rapidly increasing worldwide, and this increase is occurring at a faster rate than that of any other cancer except lung cancer in women. Melanoma is more common in Whites than in Blacks and Asians. Overall, melanoma is the fifth most common malignancy in men and the seventh most common malignancy in women, accounting for 5% and 4% of all new cancer cases, respectively. The average age at diagnosis is 57 years, and up to 75% of patients are younger than 70 years. 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.

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. Solar irradiation induces many of these melanomas. 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
• Congenital nevus
• Cellular blue nevus

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

Clinically, lesions are classified according to their depth, as follows:

• Thin - 1 mm or less
• Moderate - 1 mm to 4 mm
• Thick- greater than 4 mm

The 4 major types of melanoma, classified according to growth pattern, are as follows:

• Superficial spreading melanoma constitutes approximately 70% of melanomas; usually flat but may become irregular and elevated in later stages; the lesions average 2 cm in diameter, with variegated colors, as well as peripheral notches, indentations, or both
• Nodular melanoma accounts for approximately 15% to 30% of melanoma diagnoses; the tumors typically are blue-black but may lack pigment in some circumstances
• Lentigo maligna melanoma represents 4% to 10% of melanomas; the tumors are often larger than 3 cm, flat, and tan, with marked notching of the borders; they begin as small, freckle-like lesions
• Acral lentiginous melanoma constitutes 2% to 8% of melanomas in Whites and 35% to 60% of them in dark-skinned people; may appear on the palms and soles as flat, tan, or brown stains with irregular borders; subungual lesions can be brown or black, with ulcerations in later stages.

Most commonly, the history includes either changing characteristics in an existing mole or the identification of a new mole.

The characteristics of melanoma are commonly known by the acronym ABCDE and include the following:

• A - Asymmetry
• B - Irregular border
• C - Color variations, especially red, white, and blue tones in a brown or black lesion
• D - Diameter greater than 6 mm
• E - Elevated surface

Also, melanomas may itch, bleed, ulcerate, or develop satellites. Patients who present with metastatic disease or with primary sites other than the skin have signs and symptoms related to the affected organ system(s).

It is also important to examine all lymph node groups.

Perform excisional biopsy on suggestive lesions so that a pathologist can confirm the diagnosis. Shave biopsies and electrodesiccation are inadequate; a full thickness of skin is essential for proper histologic diagnosis and classification. The most important prognostic indicator for stage I and II tumors is thickness; obtain a full-thickness biopsy specimen for adequate pathologic interpretation. Biopsy results ultimately determine the margins of resection and which patients are candidates for sentinel lymph node biopsy and other adjuvant treatment.

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

Surgery such as wide local excision with sentinel lymph node biopsy, elective node dissection, or both is the definitive treatment for early-stage melanoma. When performing the wide local excision, first consider the surgical margins. If the primary closure is not feasible, skin grafting or tissue transfers may be needed. Medical management is reserved for adjuvant therapy of patients with advanced melanoma.

Agents that may be used in adjuvant therapy include the following:

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

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

• Dacarbazine
• Temozolomide
• Interleukin-2
• Cisplatin, vinblastine, and dacarbazine (CVD)
• Cisplatin, dacarbazine, carmustine, and tamoxifen
• Carboplatin and paclitaxel
• Ipilimumab
• Pembrolizumab
• Trametinib
• Vemurafenib (BRAF Positive)
• Dabrafenib (BRAF Positive)
• Peginterferon alfa-2b
• Nivolumab*

Poor prognostic factors include the following:

• Tumor thickness (worse prognosis in thicker lesions)
• Evidence of tumor in regional lymph nodes (stage III disease)
• Higher number of positive lymph nodes
• Presence of distant metastasis (stage IV disease)
• Anatomic site (trunk and/or face lesions have worse prognoses than extremity lesions)
• Presence of ulceration
• Presence of regression on histologic examination (controversial)
• Male sex

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

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

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