Dermatology · PANCE / PANRE

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

ABCDE criteria for melanoma screening.

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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