Melanoma

Incidence rising in White populations; lower overall incidence but higher stage at presentation and worse survival in Black and Hispanic patients. US 5-year survival: ~94% White, ~71% Black.

Subtype distribution differs by ancestry:

• White populations: superficial spreading ~70%, nodular ~15%, lentigo maligna ~10%, acral lentiginous ~2–5%.
• Black populations: acral lentiginous up to 50–70%, often sole, subungual, palm. Acral melanoma is not more common in Black patients — other subtypes are simply less common, so acral dominates the distribution.
• Asian populations: acral lentiginous commonly exceeds superficial spreading.

Melanoma is the deadliest skin cancer; mortality has decreased with earlier detection and immune/targeted therapy.

UV-driven subtypes (superficial spreading, nodular, lentigo maligna): accumulate UV signature mutations — BRAF V600E (~50%), NRAS (~20%), NF1 (~15%). High mutational burden underpins response to immune checkpoint blockade.

UV-independent subtypes (acral lentiginous, mucosal, uveal): lower mutational burden; KIT mutations, structural rearrangements, copy-number alterations; GNAQ/GNA11 in uveal. Less responsive to single-agent checkpoint inhibition; KIT inhibitors (imatinib) for KIT-mutated.

ABCDE evaluation + ugly duckling sign:

• Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, Evolution/evolving.
• Ugly duckling: the lesion that looks different from the patient's other moles. Often more sensitive than individual ABCDE criteria.

Subtypes:

• Superficial spreading: horizontal radial growth phase, variegated color, most common overall, trunk/legs.
• Nodular: rapid vertical growth, often pigmented-black or amelanotic-pink, blood vessels prominent; worst prognosis per Breslow depth because it is vertical from the start.
• Lentigo maligna → lentigo maligna melanoma: chronically sun-damaged skin (face, head/neck); slow radial growth over years; can be extensive before invasion.
• Acral lentiginous: palms, soles, subungual. Often mis-dx as trauma, verruca, fungal nail.
• Amelanotic: pink, red, or skin-colored; frequently missed — consider on every growing atypical lesion.
• Desmoplastic: sclerotic plaque on sun-damaged skin; neurotropism; may present as scar-like.

This section carries disproportionate clinical importance. Acral lentiginous melanoma (ALM) is under-taught and over-missed.

• Examine the palms, soles, nails, and mucosa at every full skin exam. If this is not part of your routine in SoC patients, you will miss melanomas.
• Subungual melanoma: begins as a longitudinal pigmented band (melanonychia). Suspicious features: width >3 mm, non-uniform pigmentation, proximal widening, rapid change, Hutchinson sign (pigment on proximal nail fold/cuticle), single digit (especially thumb/great toe), older age. Benign melanonychia can occur in Black patients but stable, uniform, thin bands with longstanding history are reassuring; anything evolving requires biopsy.
• Hutchinson sign: pigment extending beyond the nail matrix onto the cuticle or nail fold — specific for subungual melanoma. Pseudo-Hutchinson (benign pigment visible through transparent cuticle) is real but uncommon; biopsy in doubt.
• Plantar lesions: often mis-dx as trauma, corn, callus, verruca. Acral dermoscopy: parallel ridge pattern = concerning; parallel furrow pattern = benign (palmar creases: furrows = lower lines, ridges = raised lines between).
• Delayed dx is the disparity driver. Systemic bias, lack of SoC training in derm curricula, and patient lack of awareness all contribute. The mandate: teach SoC self-exam including acral sites and nails.
• Amelanotic ALM exists and is especially treacherous.

Breslow depth (tumor thickness in mm) is the dominant prognostic variable. Stage grouping (AJCC 8th):

• Stage 0: in situ.
• Stage I: ≤1 mm, or ≤2 mm without ulceration; 5-yr survival >90%.
• Stage II: thicker or ulcerated primary, node-negative.
• Stage III: regional nodal involvement.
• Stage IV: distant metastasis.

Other prognostic features: ulceration (upstages), mitotic rate, lymphovascular invasion, Clark level (secondary), microsatellites.

Desmoplastic melanoma: distinct entity; spindle-cell morphology, neurotropism, often S100+ but MelanA/HMB-45 may be negative — diagnostic trap.

• Atypical/dysplastic nevus — dermoscopy + clinical + biopsy if uncertain.
• Spitz nevus — often pink, dome-shaped, children; 'atypical Spitz tumor' is a gray zone requiring expert pathology.
• Blue nevus — deep blue-black, stable, common on dorsum hand/scalp.
• Pigmented BCC — pearly, telangiectatic, often central ulceration.
• Pigmented Bowen disease (SCC in situ) — scaly plaque, may be pigmented in SoC.
• Seborrheic keratosis — 'stuck-on', warty, horn cysts; dermoscopy: milia-like cysts, comedo-like openings.
• Subungual hematoma — acute onset, grows distally with the nail, limited proximal persistence.
• Traumatic nail pigmentation — usually resolves.
• Melanonychia of racial origin — stable longitudinal bands, common in Fitzpatrick V–VI, often multiple digits.

• Full-body skin examination including scalp, oral mucosa, palms, soles, interdigital, nail beds, genital/perianal — every time.
• Dermoscopy: trained use improves diagnostic accuracy. Key patterns: ABCD-dermoscopy, 7-point checklist, chaos-and-clues.
• Excisional biopsy with 1–3 mm narrow margins — full thickness. Do not shave a pigmented lesion suspicious for melanoma; do not punch the center of a larger lesion (compromises Breslow depth and staging).

- Acceptable alternatives when excisional is impractical: incisional biopsy through the most atypical area, or saucerization for thin superficial spreading lesions.

- Nail unit: biopsy the matrix (longitudinal excision) for subungual pigmented bands with concerning features.

• Pathology report must include: Breslow, ulceration, mitotic rate per mm², margins, lymphovascular invasion, microsatellites, regression, perineural invasion (desmoplastic).
• Molecular: BRAF for stage III/IV to guide targeted therapy; consider NRAS, KIT (acral/mucosal) for trial eligibility.
• Staging: clinical exam of lymph nodes; SLNB if Breslow >0.8 mm or 0.8 mm + ulceration/mitoses; imaging (CT chest/abd/pelvis ± brain MRI) for stage III/IV or symptomatic.
• Baseline labs: LDH (prognostic in stage IV).

Diagnostic features (any combination):

• Atypical melanocytes: pleomorphism, hyperchromatic nuclei, prominent nucleoli, coarse chromatin.
• Pagetoid upward spread: melanocytes above the basal layer — highly suspicious.
• Lack of maturation with descent (normal nevi: cells become smaller, less atypical deeper).
• Asymmetry, poor circumscription.
• Mitotic figures, especially deep or atypical.
• Ulceration, microsatellites, lymphovascular invasion, perineural invasion (desmoplastic).

Subtype-specific:

• Superficial spreading: horizontal radial growth phase with pagetoid spread.
• Nodular: dermal nodule with minimal horizontal component — vertical growth from the start.
• Lentigo maligna: lentiginous melanocytic proliferation along sun-damaged basal layer; severe solar elastosis; atypical melanocytes in adnexal epithelium.
• Acral lentiginous: lentiginous junctional proliferation on acral skin; often large cells with abundant cytoplasm; pagetoid spread common.
• Desmoplastic: spindle cells in a sclerotic dermis, neurotropism; may be subtle and mis-dx as scar.

Immunohistochemistry: SOX10 (most sensitive, nuclear), S100 (sensitive not specific), MelanA/Mart-1 (sensitive, loses in dedifferentiated/desmoplastic), HMB-45 (shows maturation gradient — decreases with depth in nevi, retained in melanoma), Ki-67 (proliferation index), PRAME (emerging, helps distinguish melanoma from nevus).

Molecular: BRAF V600 IHC (VE1) for rapid BRAF status; sequencing for NRAS, KIT, NF1, GNAQ.

Wide local excision with margins by Breslow depth:

• In situ: 0.5–1.0 cm.
• ≤1.0 mm: 1 cm.
• 1.01–2.0 mm: 1–2 cm (usually 2 if feasible).
• >2.0 mm: 2 cm.

Sentinel lymph node biopsy:

• Offer if Breslow >0.8 mm, or 0.8 mm with ulceration or high mitotic rate.
• SLNB is staging, not therapeutic — completion lymph node dissection is largely replaced by nodal observation after MSLT-II.

Adjuvant therapy for stage IIB/IIC or node-positive resected disease:

• Anti-PD-1 (pembrolizumab, nivolumab) — adjuvant for stage IIB–IV resected.
• BRAF/MEK inhibitors (dabrafenib + trametinib) — adjuvant for BRAF V600-mutated stage III.

Lentigo maligna (in situ on face): wide excision with staged margin assessment; consider Mohs with MART-1/MelanA stains, or topical imiquimod for inoperable disease with expert input.

Transformed over the past decade. Choice depends on BRAF status, burden, and brain metastases.

• Immune checkpoint inhibitors (first-line unless contraindication):

- Pembrolizumab or nivolumab monotherapy.

- Nivolumab + ipilimumab combination — higher response and durability, more immune-related adverse events.

- Nivolumab + relatlimab (anti-LAG-3 combo) — alternative.

• BRAF/MEK inhibitors for BRAF V600-mutated: dabrafenib + trametinib, encorafenib + binimetinib, vemurafenib + cobimetinib. Rapid responses, eventual resistance.
• KIT inhibitors (imatinib) for KIT-mutated acral/mucosal melanoma.
• Oncolytic viral therapy (T-VEC) for accessible cutaneous/subcutaneous disease.
• Radiation for palliation, brain metastases (stereotactic), bone.
• Clinical trials — especially for acral/mucosal and checkpoint-resistant disease.

By stage (5-year survival, AJCC 8th, pre-immunotherapy era for advanced):

• Stage 0: ~99%.
• Stage IA: ~97%.
• Stage IB: ~92%.
• Stage IIA: ~81%.
• Stage IIB: ~70%.
• Stage IIC: ~53%.
• Stage III: 40–80% depending on substage.
• Stage IV: historically 10–20%; now 30–50% with immunotherapy/targeted therapy.

Disparity: Black patients present at higher stage with acral disease; 5-year survival ~71% Black vs. ~94% White — the gap is largely driven by stage at diagnosis, acral subtype biology, and access to immunotherapy.

• Examine palms, soles, nails, and mucosa every time, especially in SoC patients. If you don't look, you won't find it.
• Hutchinson sign warrants biopsy. Pseudo-Hutchinson is a diagnosis of exclusion.
• Never shave a suspicious pigmented lesion. It compromises staging. Use excisional or incisional biopsy.
• Biopsy the most atypical area if you cannot excise entirely (nail matrix for nail; darkest/thickest/asymmetric portion for large lesions).
• Amelanotic nodular melanoma is a commonly missed subtype — pink, rapid growth, blood vessels prominent.
• Desmoplastic melanoma can present as a scar-like sclerotic plaque on sun-damaged skin — think of it in otherwise unremarkable indurated lesions. S100/SOX10, not MelanA/HMB-45.
• Ugly duckling outperforms individual ABCDE.
• Subungual melanoma vs. hematoma: hematoma grows out distally with the nail over weeks; melanoma persists/widens.
• Dermoscopy changes the game on acral skin — parallel ridge = concerning, parallel furrow = reassuring.

You have (or may have) a melanoma. Early-stage disease has an excellent prognosis with complete excision. You will need close follow-up for at least 5 years — typically every 3–6 months early, then annually. Examine your own skin monthly and know how to look at your palms, soles, and nails. Protect your skin from UV (sunscreen, shade, clothing) — this matters even if your melanoma was not UV-driven (still reduces risk of a second primary). First-degree relatives have ~2× the risk and should see a dermatologist. In Black/Hispanic/Asian patients: acral and nail sites are the most important — teach your family to check these too.