Melanoma
Malignancy of melanocytes; deadliest common skin cancer; early detection by ABCDE criteria saves lives.
Also known as: melanoma, malignant melanoma, superficial spreading melanoma, nodular melanoma, lentigo maligna, acral lentiginous melanoma
Overview
A malignancy arising from melanocytes (most commonly cutaneous, but also ocular, mucosal). Early-stage disease is curable by excision; metastatic disease has been transformed by immune checkpoint inhibitors and targeted therapy.
Epidemiology
Incidence rising for decades — ~100,000 new US invasive cases annually + ~100,000 in situ. Median age at diagnosis ~65. ~7,000 US deaths annually. Lifetime risk ~1 in 30 for whites, 1 in 1000 for Black Americans (though acral and mucosal melanoma more common). Fastest growing cancer in adolescents and young adults.
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Risk factors
- UV exposure, especially intermittent intense (blistering sunburns); tanning bed use (risk increases 75% if first use before age 35)
- Fair skin (Fitzpatrick I-II), light/red hair, blue/green eyes, freckles
- Personal history of melanoma (~5% develop second primary)
- Family history of melanoma in ≥2 first-degree relatives (CDKN2A, CDK4, BAP1 germline mutations)
- Multiple (>50) common nevi or any atypical/dysplastic nevi
- Giant congenital nevus (>20 cm) — ~5% lifetime melanoma risk
- Immunosuppression
- Xeroderma pigmentosum, FAMMM syndrome
Pathophysiology
UV-induced DNA damage drives MAPK pathway activation. Common driver mutations: BRAF V600E/K (~50%), NRAS (~20%), NF1 (~15%), KIT (acral/mucosal/CSD). PTEN, TP53, CDKN2A loss contribute. Tumor mutational burden among highest of all cancers, supporting immunotherapy response.
Clinical presentation
Symptoms
- New or changing pigmented lesion (ABCDE criteria)
- Pruritus, bleeding, tenderness, ulceration (later signs)
- Most patient-detected — emphasize self-examination and 'ugly duckling' sign
Signs / physical exam
- ABCDE criteria: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, Evolution (change over time)
- 'Ugly duckling sign': a pigmented lesion that looks different from a patient's other nevi
- Subtypes:
- • Superficial spreading melanoma (SSM, ~70%): variable color/shape, radial growth phase years, then vertical growth; trunk (men), legs (women)
- • Nodular melanoma (~15%): dark blue-black or amelanotic pink nodule, rapidly growing, often ulcerated; vertical growth from outset
- • Lentigo maligna / lentigo maligna melanoma (~10%): slow-growing irregular tan-brown patch on chronically sun-damaged skin of older adults; face/scalp
- • Acral lentiginous melanoma (~5%, but predominant subtype in skin of color and Asians): palms, soles, subungual (look for Hutchinson sign — pigment extending onto nail fold from nail matrix)
- • Mucosal, ocular, desmoplastic, amelanotic variants
Classic findings
ABCDE positive pigmented lesion + ugly duckling; for acral/subungual — Hutchinson sign (periungual pigment extension).
Differential diagnosis
- Atypical (dysplastic) nevus — Asymmetric, irregular border, varied color, but stable; biopsy if changing
- Seborrheic keratosis — Waxy 'stuck-on' appearance, sharply demarcated; dermoscopy shows milia-like cysts, comedo-like openings
- Pigmented BCC — Pearly rolled border, telangiectasias, blue-gray pigment globules
- Solar lentigo — Uniformly tan-brown macule on sun-damaged skin; stable
- Blue nevus — Uniform blue-black papule; stable
- Subungual hematoma (vs acral melanoma) — Trauma history, grows out with nail, no Hutchinson sign
- Pyogenic granuloma (amelanotic melanoma DDx) — Rapidly growing red friable papule; biopsy
- Spitz nevus — Pink dome-shaped papule in children/young adults; can mimic melanoma — refer for expert review
Diagnostic workup
Diagnostic criteria
Histopathology + AJCC 8th edition staging based on Breslow depth, ulceration, mitotic rate (T), nodal status (N), distant metastases and LDH (M).
Labs
- EXCISIONAL biopsy with 1-3 mm margins down to subcutaneous fat is the diagnostic standard (preserves architectural assessment for Breslow depth)
- Shave biopsy may transect deep margin and underestimate depth — avoid if melanoma strongly suspected
- Histopathology: report Breslow depth (mm), ulceration, mitotic rate, regression, lymphovascular invasion, microsatellites, margin status
- BRAF mutation testing for clinical stage IIC and higher (drives targeted therapy decisions); also NRAS, KIT, TERT in select cases
- LDH baseline (stage IV prognostic)
- CBC, CMP, LDH for advanced disease
Imaging
- Stage IA-IIA: typically no imaging if asymptomatic
- Stage IIB-IIIA: consider chest X-ray, CT chest/abdomen/pelvis; brain MRI for stage IIIC+
- PET/CT for stage IIIB and higher; brain MRI for stage III/IV
- Sentinel lymph node biopsy considered for Breslow ≥0.8 mm or any thickness with ulceration or other high-risk features
Diagnostic algorithm
| ABCDE Feature | Concerning Finding |
|---|---|
| A — Asymmetry | Lesion halves do not mirror each other |
| B — Border | Irregular, scalloped, or notched borders |
| C — Color | Variation (brown, black, red, white, blue) within lesion |
| D — Diameter | Larger than 6 mm (pencil eraser); smaller does not rule out |
| E — Evolution | Change in size, shape, color, symptoms over weeks-months |
| Ugly duckling | Lesion that looks unlike patient's other nevi |
Treatment
First-line
- Wide local excision based on Breslow depth (AAD/NCCN):
- • In situ — 5-10 mm margins
- • ≤1.0 mm — 1 cm margins
- • 1.01-2.0 mm — 1-2 cm margins
- • >2.0 mm — 2 cm margins
- Sentinel lymph node biopsy for stages T1b (≥0.8 mm or ulcerated) through T4
- Mohs micrographic surgery for lentigo maligna and selected facial/acral melanomas (specialized centers)
- Adjuvant therapy for resected stage III and high-risk stage IIB/IIC:
- • Anti-PD-1 (pembrolizumab or nivolumab) × 1 year (most patients)
- • Targeted therapy for BRAF V600E/K mutant: dabrafenib + trametinib × 1 year
- Surveillance after curative resection: skin exam every 3-12 months depending on stage; total body photography for high-risk patients
Stage IV (metastatic) melanoma
- First-line immunotherapy:
- • Anti-PD-1 monotherapy (nivolumab or pembrolizumab) — favorable side-effect profile
- • Combination anti-PD-1 + anti-CTLA-4 (nivolumab + ipilimumab) — higher response but more toxicity
- • Anti-PD-1 + anti-LAG-3 (nivolumab + relatlimab) — newer combination
- Targeted therapy for BRAF V600 mutant: dabrafenib + trametinib, encorafenib + binimetinib, vemurafenib + cobimetinib
- Tumor-infiltrating lymphocyte therapy (lifileucel) — newer option for refractory disease
- Stereotactic radiosurgery for brain metastases
- Talimogene laherparepvec (T-VEC) — oncolytic HSV-1 for unresectable cutaneous/nodal disease
Lentigo maligna (in situ on face/scalp)
- Mohs or staged excision (preferred at specialized centers)
- Topical imiquimod 5% cream — alternative for non-surgical candidates
- Radiation as alternative
Second-line / adjunct
- Annual to biannual total body skin examination + self-skin exams monthly
- Genetic counseling for familial cases (CDKN2A) and offer cascade testing
- Sun protection: SPF 30+ daily, sun-protective clothing, hat, shade, avoid tanning beds
- USPSTF 2023: insufficient evidence for routine population screening, but high-risk patients benefit from dermatology surveillance
Complications
- Regional and distant metastasis — lymph nodes (most common), lung, liver, brain, bone, intestine
- Locoregional recurrence (satellite/in-transit metastases)
- Immune-related adverse events from immunotherapy: thyroiditis, hypophysitis, colitis, hepatitis, pneumonitis, dermatitis, type 1 diabetes — can be life-threatening; permanent endocrine dysfunction common
- Targeted therapy adverse effects: pyrexia, photosensitivity, secondary cutaneous SCC (with single-agent BRAFi — combination therapy reduces risk)
- Psychological distress, depression, fear of recurrence
- Lymphedema after lymph node dissection
PANCE pearls
- ABCDE + ugly duckling: any one feature alone is non-specific, but combinations and change over time are highly suspicious.
- Excisional biopsy (1-3 mm margins, down to fat) is the diagnostic standard — shave biopsy may transect and obscure depth.
- Hutchinson sign (periungual pigment extension onto nail fold) is highly suspicious for subungual melanoma — biopsy required.
- Acral melanoma is the most common subtype in skin of color — check palms, soles, and nails routinely.
- Anti-PD-1 immunotherapy has transformed metastatic melanoma — survival has shifted from <1 year to >50% 5-year survival in many series.
References
- NCCN 2024 — NCCN Clinical Practice Guidelines in Oncology — Cutaneous Melanoma (Version 2.2024)
- AAD 2019 — Guidelines of Care for the Management of Primary Cutaneous Melanoma (Swetter et al., J Am Acad Dermatol 2019)
- AJCC 8th Edition — American Joint Committee on Cancer Staging Manual — Cutaneous Melanoma (Gershenwald et al., CA Cancer J Clin 2017)
- USPSTF 2023 — USPSTF Recommendation: Screening for Skin Cancer (JAMA 2023)
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