Melanoma skin cancer

Definition
Melanoma is a malignant tumor originating from melanocytes, the pigment-producing cells located primarily in the basal layer of the epidermis. It is the most aggressive form of skin cancer, with a high potential for local invasion and distant metastasis if not detected and treated early.

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Epidemiology

• Accounts for approximately 1–2% of all skin cancers but is responsible for the majority of skin cancer-related deaths.

• Incidence is higher in fair-skinned individuals, particularly those with high ultraviolet (UV) exposure.

• Peak incidence occurs in middle-aged and older adults, but it also affects younger populations.

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Risk Factors

• Environmental:

  • Chronic or intermittent intense UV exposure, especially sunburns during childhood.

  • Use of tanning beds.

• Genetic:

  • Family history of melanoma.

  • Presence of atypical/dysplastic nevi.

  • Inherited mutations (e.g., CDKN2A, BRAF, NRAS).

• Phenotypic:

  • Fair skin, light hair, blue/green eyes.

  • Tendency to freckle.

• Medical:

  • Immunosuppression (post-transplant, HIV infection).

  • History of other skin cancers.

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Pathophysiology

Melanoma develops when melanocytes acquire genetic alterations that lead to uncontrolled proliferation, resistance to apoptosis, and enhanced metastatic potential. Key molecular pathways involved include the MAPK pathway (BRAF, NRAS mutations) and PI3K/AKT pathway.

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Clinical Features

ABCDE Criteria for Suspicious Lesions

• Asymmetry – One half unlike the other.

• Border irregularity – Edges notched, blurred, or poorly defined.

• Color variation – Different shades (brown, black, red, white, blue).

• Diameter – Greater than 6 mm (although smaller melanomas can occur).

• Evolving – Changes in size, shape, or color, or new symptoms (itching, bleeding).

Other warning signs: New pigmented lesion in an adult, lesion that looks different from the patient’s other moles (“ugly duckling sign”), or nodular lesion growing rapidly.

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Histological Subtypes

1. Superficial spreading melanoma – Most common; radial growth phase dominant initially.

2. Nodular melanoma – Aggressive; vertical growth phase early.

3. Lentigo maligna melanoma – Slow-growing; occurs in chronically sun-damaged skin (face, elderly).

4. Acral lentiginous melanoma – Palms, soles, subungual areas; more common in darker-skinned individuals.

5. Desmoplastic melanoma – Fibrous stroma; often amelanotic.

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Staging

Staging is based on the AJCC (American Joint Committee on Cancer) TNM classification, which incorporates:

• T: Tumor thickness (Breslow depth) and ulceration.

• N: Nodal involvement.

• M: Distant metastases.

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Diagnosis

• Full skin examination.

• Dermatoscopy: Improves diagnostic accuracy.

• Excisional biopsy with narrow margins (1–3 mm) for histopathologic confirmation.

• Histopathology: Breslow thickness, ulceration, mitotic rate, and margin status are critical prognostic indicators.

• Imaging (CT, PET, MRI) for advanced disease or suspected metastases.

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Management

1. Surgical Excision (Primary treatment for localized disease)

• Margins based on Breslow thickness:

  • ≤1 mm: 1 cm margin.

  • 1.01–2 mm: 1–2 cm margin.

  • 2 mm: 2 cm margin.

• Sentinel lymph node biopsy (SLNB) indicated for tumors >1 mm thickness or with high-risk features.

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2. Adjuvant Therapy

• Indicated for high-risk stage III/IV disease after surgery.

• Immune checkpoint inhibitors:

  • Nivolumab (anti–PD-1): 240 mg IV every 2 weeks or 480 mg IV every 4 weeks.

  • Pembrolizumab (anti–PD-1): 200 mg IV every 3 weeks or 400 mg IV every 6 weeks.

• Targeted therapy for BRAF V600E or V600K mutations:

  • Dabrafenib 150 mg orally twice daily + Trametinib 2 mg orally once daily.

  • Vemurafenib 960 mg orally twice daily + Cobimetinib 60 mg orally daily (21 days on, 7 days off).

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3. Advanced/Metastatic Disease

• First-line:

  • Immune checkpoint inhibitors (nivolumab, pembrolizumab, or nivolumab + ipilimumab combination; ipilimumab dose 3 mg/kg IV every 3 weeks × 4 doses).

  • Targeted therapy for BRAF-mutant melanoma.

• Second-line:

  • Alternate immune therapy or targeted agents depending on prior treatment.

• Palliative radiotherapy for symptomatic metastases.

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4. Palliative & Supportive Care

• Symptom control (pain management, management of brain metastases, skin care).

• Psychological support and palliative oncology services for advanced stages.

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Prognosis

• Dependent on Breslow thickness, ulceration, nodal involvement, and metastasis.

• Early detection (in situ melanoma) yields nearly 100% 5-year survival.

• Advanced metastatic melanoma survival is significantly improved with modern immunotherapy but remains guarded in widespread disease.

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Prevention

• Minimize UV exposure (protective clothing, broad-spectrum sunscreens SPF ≥30).

• Avoid tanning beds.

• Regular self-examination and dermatologist skin checks, especially for high-risk individuals.