Melanoma

Melanoma, a malignancy arising from melanocytes, is the most common cause of skin cancer-related death. Risk factors include UV radiation exposure (especially in individuals with light skin), dysplastic nevi, a family history of melanoma, and immunosuppression. Melanoma is most commonly cutaneous in origin, but may also arise in mucosal surfaces and in the uvea. There are four main histological subtypes of melanoma. Superficial spreading melanoma is the most common, while nodular melanoma tends to grow rapidly in depth and has the worst prognosis of all the subtypes. Clinical features concerning for melanoma include asymmetry, border irregularity, color variegation, diameter > 6 mm, and evolving size, shape, and/or color over time (i.e., the ABCDE criteria). Full-thickness excisional biopsy of skin lesions is the best diagnostic test for melanoma and should be performed immediately in all patients with suspicious lesions. Additional diagnostic and staging tests (e.g., sentinel lymph node biopsy and/or imaging) may be indicated in certain patients. Tumor thickness is a key prognostic factor. Treatment is primarily surgical and includes wide excision of the lesion with surgical margins determined by the tumor thickness. Systemic drug therapy (e.g., with immune checkpoint inhibitors, BRAF inhibitors, and MEK inhibitors) or radiation therapy may be indicated in patients with metastatic or unresectable disease.

• Most common cause of skin cancer-related death ^[1][2]
• Incidence is higher among individuals who are: ^[3]
  • Non-Hispanic White
  • Male
  • ≥ 75 years of age

Epidemiological data refers to the US, unless otherwise specified.

Risk factors for cutaneous melanoma ^[4][5]

• UV radiation exposure (e.g., nonadherence to photoprotective measures, previous episodes of sunburn, use of tanning beds) ^[6]
• Light skin types ^[7]
• Precursor lesions, including: ^[8]
  • Dysplastic nevi
  • Giant congenital nevi
• Personal or family history of melanoma or other skin cancer ^[5]
• Predisposing inherited skin conditions (e.g., xeroderma pigmentosum, familial atypical multiple mole melanoma syndrome)
• Genetic mutations, including:
  • BRAF gene mutations
    • Seen in 50% of melanomas ^[9]
    • V600E mutation (most common): an activating mutation in the BRAF gene that substitutes glutamic acid for valine at amino acid position 600 ^[10]
  • CDKN2A gene mutations
• Immunosuppression

The following are general features of cutaneous melanoma. See “Types of melanoma” for specific features of various melanoma subtypes.

ABCDE criteria ^[11]

The following skin lesion characteristics are concerning for melanoma:

• A = Asymmetry
• B = Border (irregular border with indistinct margins)
• C = Color (variegated pigmentation within the same lesion)
• D = Diameter > 6 mm
• E = Evolving (a lesion that changes in size, shape, or color over time)

Other signs and symptoms ^[11][12]

• Ugly duckling sign: A nevus that appears different from other nevi in the same patient should be considered suspicious. ^[13]
• Pruritus
• Bleeding or ulceration

By site of origin ^[14][15]

• Cutaneous melanoma originates from melanocytes in the epidermis.
• Noncutaneous melanoma (much less common)
  • Mucosal melanoma originates from melanocytes in mucosal membranes, most commonly in:
    • Head and neck
    • Anorectal and female genital regions
  • Uveal melanoma originates from melanocytes in the uvea.

By histology ^[11][16]

Both cutaneous melanomas and mucosal melanomas may be categorized by these subtypes.

Nodular melanomas have a rapid vertical growth rate and may be better identified by use of the EFG criteria (Elevation, Firmness to touch, Growth) than the more general ABCDE criteria. ^[19]

Amelanotic melanoma ^[16]

• Any of the other histological subtypes may present; , less commonly, as amelanotic melanoma.
• Melanocytes in the lesion produce little to no pigment, causing the color to range from skin-colored to bright pink or red. ^[20]
• Diagnosis typically requires histological confirmation.

Genitourinary melanoma (GU melanoma) ^[21]

Overview

• Rare (< 5%)
• Approx. 45% of all mucosal melanomas
• Most commonly affects female individuals (approx. 90%)
• Cause remains unknown.
• Expression of cell biomarkers such as PD-1 and PD-L1 in vulvar melanoma is significantly higher than in cutaneous melanomas.
• Prognosis is generally poor.

Types of GU melanoma

Subungual melanoma ^[24][25]

• Rare subtype of cutaneous acral lentiginous melanoma that develops within the nail unit
• Commonly manifests as melanonychia (a brown to black longitudinal band), with additional features suggestive of malignancy:
  • Extension of pigmentation proximally or laterally to involve the nail folds (Hutchinson sign of the nail)
  • Width of pigmentation > 3 mm with triangular shape (distal tapering)
  • Nail dystrophy, fissuring, or splitting ^[16]
  • Involvement of a single nail

Approach ^[11][26][27]

• Individuals with suspicious skin lesion(s)
  • Assess for clinical features of melanoma.
  • Use dermoscopy (if available) to obtain a magnified view of the lesion(s).
  • Confirm the diagnosis with a skin biopsy of the lesion.
• Individuals with biopsy-confirmed melanoma: See “Melanoma staging.”

Skin biopsy ^[26][27]

• Full-thickness excisional biopsy: preferred for all suspicious lesions ^[27]
  • The sample should include:
    • The full depth of the lesion (i.e., avoid transection of the lesion)
    • 1–3 mm surgical margins
  • Methods
    • Fusiform (elliptical) excision biopsy
    • Punch biopsy
    • Deep shave biopsy
• Incisional (partial) biopsy
  • May be performed for certain lesions (e.g., on the face or digits, or that are large in size)
  • If the full thickness of the lesion is not captured on biopsy, accurate melanoma staging may not be possible.

Excisional biopsy of suspected melanoma should encompass the full depth of the lesion, as lesion depth is important for staging and prognostic purposes. ^[27]

Clearly document the lesion dimensions, size of surgical margins, and type of biopsy to guide subsequent management. ^[11][27]

• Atypical melanocytes may be: ^[28]
  • Epithelioid cells with large eosinophilic nucleoli and eosinophilic cytoplasm
  • Hyperchromatic, spindle-shaped cells
• Negative prognostic features
  • Increased Breslow depth (thickness from the stratum granulosum to the lowest detectable tumor cell, which correlates with the risk of metastasis) ^[27]
  • Ulceration
  • High mitotic rate
  • Melanoma microsatellitosis
  • Malignant cells at the margins of the biopsy specimen
• Specialized studies: may be obtained in select cases.
  • Atypical lesions : to confirm the diagnosis (e.g., by testing for expression of s100-protein, a tumor marker for melanoma) ^[29]
  • Metastatic disease: to help determine treatment choices (e.g., by testing for BRAF mutations)

Determination of stage

• Perform a comprehensive clinical evaluation, including:
  • History of recent systemic symptoms (e.g., weight loss) or headaches
  • Total body skin examination for other suspicious lesions
  • Lymph node examination in the areas surrounding the melanoma
• Obtain additional studies as needed for melanoma staging, e.g.:
  • Sentinel lymph node biopsy
  • Laboratory studies
  • Imaging

Sentinel lymph node biopsy (SLNB) ^[26][27]

SLNB is recommended in certain patients, after careful discussion of risks and benefits and with the involvement of surgical oncology.

• Offer SLNB for cutaneous melanoma ≥ 1 mm in depth.
• Consider SLNB for cutaneous melanoma that is:
  • 0.8–1.0 mm in depth
  • < 0.8 mm in depth with concerning features ^[27]

SLNB is not indicated in patients with cutaneous melanoma < 0.8 mm in depth without ulceration or other concerning features. ^[27]

Additional studies ^[27]

• Not routinely recommended in asymptomatic patients with stage II melanoma or lower
• Indicated to evaluate for metastasis in select patients, e.g., with:
  • Signs or symptoms of metastatic disease
  • Positive SLNB
• May include:
  • Laboratory studies, e.g., CBC, BMP, liver chemistries
  • Imaging, e.g.:
    • CT or PET-CT of the chest, abdomen, and pelvis
    • MRI brain
    • Lymph node US
    • Bone scintigraphy

LDH is not used to evaluate for metastasis, but may be used as a prognostic indicator in patients with stage IV melanoma. ^[27]

AJCC staging of cutaneous melanoma

Melanoma is staged using the American Joint Committee for Cancer (AJCC) TNM staging system.

Benign skin lesions ^[31]

These may include:

• Seborrheic keratosis
• Cherry angioma
• Angiokeratoma
• Dermatofibroma
• Irritated benign nevi
• Solar lentigo

Benign skin lesions can resemble melanomas; biopsy should be performed to rule out melanoma. ^[32]

Precancerous skin lesions ^[32]

These may include:

• Actinic keratosis
• Dysplastic nevi
• Bowen's disease

Other skin cancers ^[16][32]

The differential diagnoses listed here are not exhaustive.

Approach ^[9][26][27]

• Establish multidisciplinary cancer care, including referrals to specialists (e.g., dermatology, surgery, oncology, and/or radiation oncology) for:
  • Complete surgical excision of the cutaneous lesion, if possible ^[34]
  • Consideration of additional medical therapy for melanoma for specific indications, e.g., metastatic or unresectable disease
• Ensure regular follow-up care for melanoma based on disease stage.
• Educate patients on: ^[35]
  • Self-examination for new or changing skin lesions and/or lymphadenopathy
  • Photoprotective measures
  • Increased risk of melanoma in family members

Wide local excision ^{[9][26][27][36]}

• Indicated for nearly all patients
• Excision should be performed with surgical margins determined by the Breslow depth.

First-line treatment for melanoma is prompt, complete excision of the tumor. ^[11][27]

Tissue-sparing Mohs micrographic surgery may alternatively be considered for lentigo maligna on certain areas of the head and neck (e.g., face, ears, or scalp). ^[27][36]

Medical therapy for melanoma ^{[9][26][27][37]}

Systemic drug therapy

• Indications
  • Complete surgical resection not possible
  • Stage IV melanoma
  • Adjuvant therapy for stage III melanoma
• Regimens may include either or both of the following therapies:
  • Immune checkpoint inhibitor combination therapy, e.g.:
    • Anti-CTLA-4 monoclonal antibodies (ipilimumab)
    • PLUS anti PD-1 monoclonal antibodies (nivolumab or pembrolizumab)
  • Targeted combination therapy in patients with BRAF mutations, e.g.:
    • BRAF kinase inhibitors (e.g., vemurafenib; , dabrafanib)
    • PLUS MEK kinase inhibitors (e.g., trametinib, cobimetinib) ^[9]
• Adverse effects
  • More common with immune checkpoint inhibitor therapy (see “Adverse effects of immunosuppressants”)
  • Management may include: ^[9][27]
    • Dosing adjustments
    • Topical or oral glucocorticoids
    • Antihistamines

Other therapies

• Lentigo maligna that cannot be resected may be treated with nonsurgical options such as: ^[17][38][39]
  • Topical imiquimod
  • Radiation therapy
  • Cryotherapy, laser ablation (limited evidence)
  • Expectant management may be considered in individuals with limited life expectancy.
• Metastatic disease may be treated with radiation therapy for palliation or if systemic therapy cannot be used. ^[40]

Follow-up care for melanoma ^[27]

Dermatologic examinations

• All patients should have lifelong follow-up with a dermatologist, focusing on:
  • Monitoring for melanoma recurrence
  • Screening for new primary melanoma
• Tailor frequency of visits to disease stage, e.g., as shown in the table below.

Surveillance imaging

Suveillance imaging to detect occult metastasis may be performed in select patients for up to 3–5 years after diagnosis.

• Lymph node ultrasound surveillance is recommended if:
  • SLNB is positive ^[26][27]
  • SLNB was indicated but not performed ^[27]
• Other modalities
  • May be considered in asymptomatic patients with stage IIB melanoma or higher ^[27]
  • May include:
    • MRI brain
    • CT or PET-CT of the chest, abdomen, and pelvis
    • Chest x-ray (less preferred)

Patients with positive SLNB (i.e., stage III melanoma) are now typically managed with lymph node ultrasound surveillance instead of complete lymph node dissection. ^[26][27]

Metastatic disease ^[41]

• Metastatic melanoma may spread to lymph nodes, liver, lung, brain, and bone
• May also metastasize to locations not typically affected by metastatic malignancies ^[42]
• Up to 5% of metastatic cases have no known primary tumor.
• Characteristic black pigmentation

We list the most important complications. The selection is not exhaustive.

• Negative prognostic features
  • Increased Breslow depth (thickness from the stratum granulosum to the lowest detectable tumor cell, which correlates with the risk of metastasis) ^[27]
  • Ulceration
  • High mitotic rate
  • Melanoma microsatellitosis
  • Malignant cells at the margins of the biopsy specimen

Lentigo maligna, the premalignant lesion of lentigo maligna melanoma, has excellent prognosis if treated appropriately. ^[39]

Primary prevention ^[7][29]

• Provide advice on the importance of minimizing UV radiation exposure to reduce the risk of melanoma, including:
  • Adherence to photoprotective measures
  • Avoidance of other sources of UV radiation exposure (e.g., tanning beds)
• The USPSTF specifically recommends providing advice to individuals who have light skin and are: ^[7]
  • ≤ 24 years of age
  • > 24 years of age with risk factors for cutaneous melanoma

Screening

• Asymptomatic individuals with no prior skin cancer: The USPSTF has found insufficient evidence to recommend for or against screening. ^[7][43]
• Adults with risk factors for cutaneous melanoma: Clinicians may consider performing periodic total body skin examinations. ^[29][44]

• One-Minute Telegram 74-2023-1/3: Unclear benefit of skin cancer screening