Melanoma is the most serious form of skin cancer, arising from the pigment-producing melanocytes. The American Cancer Society estimates approximately 100,640 new melanomas are diagnosed in the United States each year, with roughly 8,290 deaths. Although melanoma accounts for only about 1% of all skin cancers, it is responsible for the majority of skin cancer deaths. However, when detected early, melanoma is highly curable, and recent breakthroughs in immunotherapy and targeted therapy have transformed outcomes for advanced disease.
Melanoma incidence has risen steadily over the past several decades, particularly among young adults. Ultraviolet (UV) radiation from sunlight and tanning beds is the primary modifiable risk factor. Understanding the subtypes, staging, and modern treatment landscape is essential for patients and caregivers navigating a diagnosis.
Types of Melanoma
Superficial Spreading Melanoma
The most common subtype, accounting for approximately 70% of all melanomas. It typically presents as a flat or slightly raised lesion with irregular borders and color variation. Superficial spreading melanoma tends to grow outward (radial growth phase) before invading deeper layers of the skin, providing a window for early detection and excision.
Nodular Melanoma
Represents about 15–20% of melanomas and is the most aggressive subtype. Nodular melanoma often presents as a rapidly growing, dome-shaped, dark or amelanotic (skin-colored) nodule. It enters the vertical growth phase early, invading deeper tissue quickly, which contributes to a poorer prognosis at diagnosis.
Lentigo Maligna Melanoma
Accounts for approximately 5–10% of melanomas and occurs predominantly on chronically sun-damaged skin in older adults. It begins as lentigo maligna (melanoma in situ) and may progress slowly over years before becoming invasive. Common sites include the face, ears, and forearms.
Acral Lentiginous Melanoma
The least common subtype in Caucasian populations but the most common melanoma type in people of African, Asian, and Hispanic descent. It occurs on the palms, soles, and under the nails (subungual). Acral lentiginous melanoma is often diagnosed at a later stage because it arises in areas not typically associated with sun exposure.
The ABCDE Rule for Early Detection
Dermatologists recommend the ABCDE criteria for evaluating suspicious skin lesions:
- A — Asymmetry: One half of the mole does not match the other half.
- B — Border: Edges are ragged, notched, or blurred.
- C — Color: The color is uneven, with shades of brown, black, tan, red, white, or blue.
- D — Diameter: The spot is larger than 6 mm (about the size of a pencil eraser), though melanomas can be smaller.
- E — Evolving: The mole is changing in size, shape, or color.
Risk Factors
- UV radiation exposure — Intermittent intense sun exposure and sunburn history, particularly in childhood, significantly increase risk. Indoor tanning increases melanoma risk by 75% when started before age 35.
- Fair skin, light hair, and light eyes — People with less melanin pigment have less UV protection.
- Numerous or atypical moles — Having more than 50 common moles or atypical/dysplastic nevi increases risk substantially.
- Family history — Approximately 10% of melanoma patients have a family history. CDKN2A and CDK4 are established high-penetrance melanoma susceptibility genes.
- Personal history of melanoma or non-melanoma skin cancer — Prior melanoma increases the risk of developing a second primary melanoma by 2–10 fold.
- Immunosuppression — Organ transplant recipients and immunocompromised individuals are at elevated risk.
Melanoma Staging
Melanoma staging uses both the Breslow depth (thickness in millimeters) and ulceration status as primary prognostic factors. The AJCC 8th Edition staging system incorporates tumor thickness, ulceration, mitotic rate, lymph node involvement, and distant metastasis.
| Stage | Description | 5-Year Survival Rate |
|---|---|---|
| Stage 0 (in situ) | Melanoma confined to the epidermis | ~99% |
| Stage I | Breslow depth ≤2 mm, no ulceration (IA) or ≤1 mm with ulceration (IB) | ~92–99% |
| Stage II | Breslow depth >1–4 mm with or without ulceration | ~53–82% |
| Stage III | Regional lymph node involvement, in-transit or satellite metastases | ~40–78% |
| Stage IV | Distant metastasis (lung, brain, liver, bone, distant skin/nodes) | ~15–30% (with modern therapy) |
Survival rates from SEER data and AJCC 8th Edition. Modern immunotherapy and targeted therapy have significantly improved Stage IV outcomes beyond historical rates.
Treatment Options
Surgery
Surgical excision with appropriate margins is the primary treatment for melanoma. Wide local excision margins are determined by Breslow depth: in situ melanoma requires 0.5–1 cm margins, while tumors greater than 2 mm require 2 cm margins. Sentinel lymph node biopsy (SLNB) is recommended for melanomas greater than 0.8 mm in thickness or those with ulceration to assess regional spread.
Immunotherapy
Immune checkpoint inhibitors have revolutionized melanoma treatment and represent the most significant advance in the field:
- Pembrolizumab (Keytruda) — Anti-PD-1 antibody approved for adjuvant treatment of stage IIB–IV melanoma after surgical resection, and as first-line treatment for unresectable or metastatic melanoma.
- Nivolumab (Opdivo) — Anti-PD-1 antibody with similar indications. The CheckMate-238 trial demonstrated superior recurrence-free survival versus ipilimumab in the adjuvant setting.
- Ipilimumab (Yervoy) — Anti-CTLA-4 antibody, often used in combination with nivolumab. The combination of nivolumab plus ipilimumab achieves five-year overall survival rates exceeding 50% in metastatic melanoma (CheckMate-067 trial).
- Relatlimab + nivolumab (Opdualag) — A newer combination targeting LAG-3 and PD-1, approved for unresectable or metastatic melanoma.
Targeted Therapy (BRAF/MEK Inhibitors)
Approximately 40–50% of cutaneous melanomas harbor a BRAF V600 mutation. Combination BRAF and MEK inhibitor therapy is standard for BRAF-mutant melanoma:
- Dabrafenib + trametinib (Tafinlar + Mekinist) — Approved for adjuvant and metastatic BRAF V600E/K-mutant melanoma.
- Encorafenib + binimetinib (Braftovi + Mektovi) — Another approved BRAF/MEK combination with a favorable toxicity profile.
- Vemurafenib + cobimetinib (Zelboraf + Cotellic) — The first approved BRAF/MEK combination for melanoma.
Radiation Therapy
Radiation therapy may be used as adjuvant treatment after lymph node dissection in high-risk cases, for in-transit metastases, or for palliation of brain or bone metastases. Stereotactic radiosurgery is effective for limited brain metastases.
Emerging Therapies
Melanoma research continues to advance rapidly. Tumor-infiltrating lymphocyte (TIL) therapy (lifileucel/Amtagvi) received FDA approval in 2024 for previously treated advanced melanoma. mRNA-based personalized cancer vaccines (such as mRNA-4157/V940 in combination with pembrolizumab) have shown promising results in the adjuvant setting in the KEYNOTE-942 trial and are under further investigation.