Melanoma Origins: From Melanocytes to Malignancy

Melanoma arises from melanocytes—the pigment-producing cells responsible for skin color. Understanding their biology clarifies melanoma development.

Melanocyte Biology

• Location: Primarily in the basal layer of the epidermis (every 5-10 keratinocytes); also in hair follicles, eyes, meninges, inner ear, mucosa.
• Origin: Neural crest-derived; migrate during embryogenesis.
• Function: Synthesize melanin (eumelanin = brown/black; pheomelanin = red/yellow) in melanosomes, transferred to keratinocytes for UV protection.
• Regulation: MC1R receptor activation by α-MSH (UV-induced) stimulates eumelanin production.

Melanoma Pathogenesis

Genetic Drivers

• BRAF V600E mutation: ~50% cutaneous melanomas; activates MAPK pathway.
• NRAS mutations: ~15-20%; mutually exclusive with BRAF.
• NF1 loss: ~10-15%; RAS pathway dysregulation.
• TERT promoter mutations: >70%; immortalization via telomerase.
• CDKN2A (p16) loss: Familial melanoma; cell cycle dysregulation.
• PTEN loss, TP53 mutations: Later progression events.

UV Radiation Role

UVB causes direct DNA damage (C→T transitions); UVA generates oxidative stress. Both create "UV signature" mutations. Intermittent intense exposure (sunburns) strongly correlates with trunk/leg melanomas; chronic exposure with face/neck/scalp.

Melanoma Subtypes by Origin Site

Subtype	Primary Site	Key Features
Superficial spreading	Trunk (M), legs (F)	Radial growth phase; BRAF mutant
Nodular	Anywhere	Vertical growth from onset; aggressive
Lentigo maligna	Sun-damaged face/neck	Slow radial growth; elderly; UV signature
Acral lentiginous	Palms, soles, nail beds	Non-UV; KIT mutations; all skin types
Mucosal	Genital, oral, sinus	Non-UV; KIT, SF3B1 mutations
Uveal	Eye (choroid, ciliary body, iris)	GNAQ/GNA11 mutations; distinct biology

Precursor Lesions

• Congenital melanocytic nevi: Large/giant (>20 cm) → 5-10% lifetime melanoma risk.
• Atypical/dysplastic nevi: Marker of increased risk; not obligate precursors.
• Melanoma in situ: Confined to epidermis; 100% curable with excision.

Melanoma is a malignancy of transformed melanocytes. Early detection (ABCDE: Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution) and excision offer cure.