Melanoma

Detailed Overview

The disease is primarily driven by ultraviolet (UV) radiation exposure combined with genetic susceptibility. It frequently presents as a new, unusual, or changing mole (the 'ugly duckling'). Prognosis is heavily dependent on the Breslow depth—the microscopic thickness of the tumor. Early-stage melanoma is highly curable with surgical excision, but metastatic melanoma requires complex systemic therapies, including targeted BRAF inhibitors and immune checkpoint inhibitors.

Epidemiology & Demographics

Incidence is rising globally. In the US, it is the 5th most common cancer. Median age of diagnosis is 65, but it is one of the most common cancers in young adults (ages 25-29). Significantly more common in fair-skinned (Caucasian) populations.

Etiological Mechanism

Result of DNA damage primarily from intermittent, intense ultraviolet (UV) radiation (sunburns) in genetically susceptible individuals.

Primary Causes

UV-induced mutations in key oncogenes (BRAF, NRAS) or tumor suppressor genes (CDKN2A, PTEN).

• UV Exposure & Sunburns: History of blistering sunburns, especially in childhood, and use of tanning beds.
• Phenotype: Fair skin (Fitzpatrick I/II), light eyes, red/blond hair, and tendency to burn rather than tan.
• Multiple Nevi: Having > 50 common moles or > 5 atypical (dysplastic) moles significantly increases risk.

UV radiation causes pyrimidine dimers and oxidative DNA damage in melanocytes. About 50% of melanomas harbor an activating mutation in the BRAF gene (most commonly V600E), leading to constitutive activation of the MAPK/ERK signaling pathway, driving uncontrolled cellular proliferation. The melanoma progresses from radial growth (superficial spreading within the epidermis) to a vertical growth phase (invading the dermis), gaining the ability to enter lymphatic and blood vessels, leading to metastasis to lymph nodes, lungs, brain, and liver.

Characteristic Clinical Presentation

• Changing Mole: A preexisting mole that changes in size, shape, color, or elevation.
• Bleeding or Itching: A skin lesion that spontaneously bleeds, oozes, or becomes persistently pruritic.
• New Pigmented Lesion: A new, unusual-looking dark spot appearing on normal skin, common in adults.

Physical Examination Signs

• The ABCDEs: Asymmetry, Border irregularity, Color variation (black, blue, red), Diameter > 6mm, Evolving
• Palpable regional lymphadenopathy (in advanced cases)
• 'Ugly Duckling' sign: A mole that looks noticeably different from all the patient's other moles

• Brain Metastases: Melanoma has a high tropism for the brain, causing seizures, focal deficits, and hemorrhage.
• Lymphedema: Chronic swelling of limbs resulting from therapeutic surgical removal of regional lymph nodes.

Diagnostic Criteria & Guidelines

Diagnosis is definitively established by a full-thickness excisional skin biopsy (with 1-3 mm margins) of the suspicious lesion. The pathology report must detail the Breslow thickness, ulceration status, and mitotic rate. Shave biopsies are contraindicated as they may transect the tumor, destroying critical staging information.

Differential Diagnosis

• Dysplastic Nevus
• Seborrheic Keratosis
• Pigmented Basal Cell Carcinoma
• Blue Nevus

Laboratory Tests & Biomarkers

• BRAF V600 Mutation Analysis: Positive in ~50% of advanced melanomas (crucial for targeted therapy)
• Serum LDH (Lactate Dehydrogenase): Elevated in advanced Stage IV disease (an independent negative prognostic marker)

Imaging Modalities & Findings

• PET-CT and Brain MRI: Used for staging Stage III and IV disease. Shows hypermetabolic foci in lymph nodes or visceral organs.

• Stage I & II
  Localized disease. Stage I is thin (≤ 1mm) without ulceration. Stage II is thicker (> 1mm) or ulcerated, but no lymph node spread.
• Stage III
  Regional disease. Tumor has spread to regional lymph nodes or in-transit lymphatic channels.
• Stage IV
  Distant metastasis. Spread to visceral organs (lung, liver, brain, bone).

Second-Line & Adjunctive Therapy

For Stage III/IV (Systemic Therapy): Immune Checkpoint Inhibitors (Anti-PD-1: Pembrolizumab 200mg IV q3w or Nivolumab; Anti-CTLA-4: Ipilimumab). For BRAF V600 positive tumors: Targeted therapy using BRAF/MEK inhibitors (Dabrafenib 150mg PO BID + Trametinib 2mg PO daily).

Surgical & Procedural Management

Completion Lymph Node Dissection (CLND) is sometimes performed if SLNB is positive. Metastasectomy for isolated, resectable distant metastases (e.g., solitary brain or lung lesion).

Recommended Lifestyle Changes

• Strict sun protection: Broad-spectrum SPF 30+ applied daily, protective clothing, and wide-brimmed hats.
• Absolute avoidance of artificial tanning beds.
• Monthly thorough self-skin examinations (SSE) using a mirror.

Patient Counseling & Advice

Emphasize that a history of melanoma severely increases the risk of developing subsequent primary melanomas. First-degree relatives should also be counseled to undergo professional skin checks due to genetic risk.

Follow-Up & Monitoring Schedule

Total body skin exam by a dermatologist every 3-6 months for the first 1-3 years, then annually for life. For high-risk stages, routine imaging (CT/PET) every 6-12 months for 3-5 years.

Preventive Strategies

Primary prevention involves diligent UV protection starting in childhood. Secondary prevention involves regular skin cancer screenings for high-risk individuals.

Highly dependent on stage at diagnosis. Stage I: >99% 5-year survival. Stage III: 63% 5-year survival. Stage IV: Historically dismal (5%), but with modern immunotherapy and targeted therapy, 5-year survival has remarkably improved to over 30-50%.