Malignant malanoma

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Malignant Melanoma

Malignant melanoma is the most dangerous form of skin cancer, arising from melanocytes - the pigment-producing cells at the dermoepidermal junction (DEJ). Although it represents only ~1% of skin cancers, it accounts for the majority of skin cancer deaths due to its high metastatic potential.

Epidemiology & Risk Factors

The incidence of melanoma has been rising steadily in light-skinned populations. Key risk factors include:

Phenotypic/Constitutional:

Light complexion, blue/green eyes, blond or red hair
Tendency to sunburn easily and tan poorly
Heavy freckling
Blistering sunburns in childhood
Immunosuppression (increases risk 20-30-fold)
Male gender (associated with thicker tumors at diagnosis)

Acquired/Environmental:

Excessive UV radiation (solar or tanning salon)
High number of common or dysplastic nevi (>50)
Giant congenital nevi
Prior history of melanoma or family history
PUVA therapy, xeroderma pigmentosum, burn scars

Molecular Genetics:

BRAF V600E mutations - present in 50-60% of cutaneous melanomas, especially on non-chronically sun-exposed skin in Caucasians
KIT gene mutations and cyclin D1/CDK4 amplifications - associated with acral and mucosal lentiginous melanomas
p16/CDKN2A mutations - potent risk factor; familial forms

Acral lesions account for a disproportionate share of melanomas in darker-skinned individuals. The lowest overall incidence is in Asians.

Pathogenesis & Growth Phases

Melanomas arise predominantly from melanocytes at the DEJ. About 10-20% develop in pre-existing nevi; the rest arise de novo on previously normal skin.

There are two distinct growth phases:

Radial (horizontal) growth phase - cells spread laterally along the DEJ with little dermal invasion; low metastatic potential
Vertical growth phase - invasion into the dermis; metastatic potential increases substantially with depth

The single greatest risk factor for metastasis is depth of invasion (Breslow thickness).

Clinical Types

1. Superficial Spreading Melanoma (SSM) - Most Common (70%)

Usually arises in a pre-existing nevus after years of slow change, followed by rapid growth. Nodularity within SSM heralds the vertical growth phase.

Fig. Superficial spreading malignant melanoma showing the classic dark, irregular lesion (Andrews' Diseases of the Skin)

2. Nodular Melanoma (NM) - 15%

More aggressive; shorter clinical onset; often arises de novo. Typically a blue/black papule 1-2 cm on the trunk, head, or neck in middle-aged men. Lacks a horizontal growth phase, so it tends to be sharply demarcated. Up to 5% are amelanotic.

Fig. Nodular melanoma (Bailey & Love's Short Practice of Surgery)

3. Lentigo Maligna Melanoma (LMM) - 5-10%

Also called Hutchinson's melanotic freckle. Slow-growing, variegated brown macule on the face, neck, or hands of the elderly. Correlates with prolonged sun exposure; more common in women. Has a long radial growth phase (5-20 years) before vertical invasion. Once it invades, metastatic potential equals other variants.

Fig. Lentigo maligna melanoma on the face (Andrews' Diseases of the Skin)

4. Acral Lentiginous Melanoma (ALM) - 2-8% in whites; 35-60% in Afro-Caribbean/Hispanic/Asian

Affects soles and palms. Presents as a flat, irregular macule in later life. 25% are amelanotic (may mimic fungal infection or pyogenic granuloma). Associated with KIT mutations and cyclin D1 amplifications.

Fig. Acral lentiginous melanoma on the heel (Andrews' Diseases of the Skin)

Other Subtypes

Desmoplastic melanoma - head/neck; propensity for perineural infiltration; often amelanotic; high local recurrence if not widely excised
Mucosal melanoma - rare; arises from mucosal melanocytes; head and neck (15-20%) and anogenital region
Uveal (ocular) melanoma - most common primary intraocular malignancy in adults; arises in uveal tract; metastasizes predominantly to liver
Conjunctival melanoma - arises from primary acquired melanosis; early metastasis possible even at small tumor size

Clinical Recognition: The ABCDE Criteria

Letter	Feature
A	Asymmetry
B	Border irregularity
C	Color variegation
D	Diameter >6 mm
E	Evolution (change over time)

Additional warning signs in pre-existing nevi: change in size, shape, color, thickness (elevation/ulceration), satellite lesions, tingling/itching/serosanguineous discharge.

Dermoscopy (epiluminescence microscopy) makes subsurface structures visible and, in experienced hands, improves diagnostic accuracy.

Diagnosis & Biopsy

Excision biopsy with 2-3 mm margin of skin and subdermal fat is the standard
Incision biopsy is acceptable for large facial lesions where full excision would be disfiguring
Pathological examination provides Breslow thickness - measured to the nearest 0.1 mm from the granular layer to the base of the tumor
Sentinel node biopsy (SNB) is used for staging regional lymph node involvement

AJCC Staging (T Classification)

Stage	Thickness	Notes
Tis	In situ	Confined to epidermis
T1a	<0.8 mm	No ulceration
T1b	<0.8 mm with ulceration, OR 0.8-1.0 mm
T2a	1.01-2.0 mm	No ulceration
T2b	1.01-2.0 mm	With ulceration
T3a	2.01-4.0 mm	No ulceration
T3b	2.01-4.0 mm	With ulceration
T4a	>4.0 mm	No ulceration
T4b	>4.0 mm	With ulceration

Breslow thickness is the most important prognostic indicator in the absence of lymph node metastases. Ulceration upstages the tumor.

Treatment

Surgery

Wide local excision with margins determined by Breslow thickness
Sentinel lymph node biopsy for staging

Adjuvant Therapy (High-Risk Resected Disease)

For nearly 25 years, high-dose interferon-alfa (IFN-alpha) was the only adjuvant option. This has now been replaced by:

Immune checkpoint inhibitors: nivolumab, pembrolizumab (anti-PD-1), ipilimumab (anti-CTLA-4) - approved as single agents
Targeted therapy (BRAF V600E/K mutant + lymph node involvement): dabrafenib + trametinib combination

Metastatic Disease

Immunotherapy:

Ipilimumab (anti-CTLA-4): enhances T-cell activation/proliferation; approved for metastatic melanoma
Nivolumab and pembrolizumab (anti-PD-1 IgG4 antibodies): block PD-L1/PD-L2 interaction, restoring T-cell anti-tumor response; approved as monotherapy
Nivolumab + ipilimumab combination: approved for unresectable/metastatic melanoma
High-dose IL-2: can produce durable responses in a small subset

BRAF-targeted therapy (for BRAF V600E/V600K mutant tumors ~50-60%):

BRAF inhibitors: vemurafenib, dabrafenib, encorafenib
MEK inhibitors (combined with BRAF inhibitors): trametinib, cobimetinib, binimetinib
Combination BRAF + MEK inhibition is the preferred approach

Cytotoxic agents (now rarely used): dacarbazine, temozolomide, cisplatin - historically the backbone but low response rates

Uveal melanoma metastases: tebentafusp (bispecific T-cell engager targeting gp100 via a TCR-anti-CD3 fusion) prolongs survival

Prognosis

Breslow thickness remains the key prognostic factor
Patients with distant metastases have approximately 40% 5-year survival
Uveal melanoma: survival as low as 50% at 15 years for large lesions; most metastases go to liver
Conjunctival melanoma has worse prognosis than cutaneous forms due to early metastasis at small tumor size

Special Situations

Pregnancy: Nevi may uniformly darken due to estrogen/progesterone receptor changes. Any irregular pigmentation or asymmetric growth warrants biopsy. Women who develop melanoma during pregnancy have a shorter disease-free interval but no adverse overall survival effect.

Pediatric melanoma: Rare; occurs >50% of the time from previously normal skin. Recognition often delayed. May develop within giant congenital nevi.

Sources:

Andrews' Diseases of the Skin: Clinical Dermatology, Ch. 30
Bailey and Love's Short Practice of Surgery, 28th Ed., Ch. 45
Katzung's Basic and Clinical Pharmacology, 16th Ed., Ch. 11
Goldman-Cecil Medicine, International Ed., Ch. 391

Recent evidence note (2026): A 2026 meta-analysis (PMID 41478279) identified immune signatures that can potentially uncouple checkpoint inhibitor efficacy from toxicity in melanoma - a potentially important development for personalizing immunotherapy selection.

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