Melanoma Study Guide

📖 Core Concepts Melanoma – malignant tumor of melanocytes; most lethal skin cancer. ABCDEEFG Mnemonic – quick visual check: Asymmetry, Border irregularity, Colour variation, Diameter > 6 mm, Evolving, Elevated, Firm. Breslow depth – vertical thickness (mm) of invasive melanoma; >1 mm = higher metastasis risk. Clark level – anatomic level of invasion (I‑V); levels IV‑V indicate deep dermal/subcutaneous spread. Radial vs. Vertical growth – radial = horizontal spread, thin (<1 mm); vertical = deeper invasion, thicker, higher metastatic potential. AJCC 8th edition staging – T based on Breslow, N on nodal burden, M on distant disease. Key genes – BRAF (V600E/K, 50 %); NRAS (30 %); loss‑of‑function in NF1, TP53, CDKN2A; MC1R variants increase risk. UV radiation – UVB (280‑315 nm) creates cyclobutane pyrimidine dimers → C>T “UV fingerprint”; UVA (315‑400 nm) generates ROS. Sentinel lymph node biopsy (SLNB) – indicated for tumors >0.8 mm or ulcerated; detects occult nodal metastasis. Adjuvant therapy – checkpoint inhibitors (PD‑1, CTLA‑4) or BRAF/MEK inhibitors after high‑risk resection to lower recurrence. --- 📌 Must Remember Risk factors: >50 nevi, dysplastic nevus syndrome, fair skin/red hair, childhood severe sunburns, tanning‑bed use before age 30 (↑75 % risk), first‑degree relative with melanoma (↑1.74 ×). BRAF mutation → treat with BRAF inhibitor + MEK inhibitor (dabrafenib + trametinib). Surgical margins: In situ / lentigo maligna: 0.2–0.5 cm. ≤1 mm Breslow: 1 cm. 1.01–2 mm: 1–2 cm. >2 mm: 2 cm. Five‑year survival: localized = 100 %; regional nodes = 76 %; distant metastasis = 35 %. Immunotherapy hierarchy: PD‑1 inhibitors (pembrolizumab/nivolumab) > CTLA‑4 (ipilimumab) in efficacy & toxicity. SLNB threshold: thickness > 0.8 mm or ulceration. Ulceration and mitotic rate are independent adverse prognostic factors. --- 🔄 Key Processes Diagnosis workflow Visual exam → dermoscopy → total‑body photography (high‑risk) → excisional biopsy (elliptical) → histopathology (Breslow, ulceration, mitoses) → staging. Sentinel node mapping Inject radioactive tracer + blue dye → lymphoscintigraphy → intra‑operative gamma probe → remove sentinel node → pathologic analysis. Targeted therapy initiation Test tumor for BRAF V600E/K → if positive → start BRAF inhibitor + MEK inhibitor → monitor for resistance (repeat imaging q 2–3 mo). Adjuvant checkpoint‑inhibitor regimen Post‑resection (stage IIB‑C or higher) → PD‑1 inhibitor for up to 1 yr → surveillance imaging every 3–6 mo. --- 🔍 Key Comparisons BRAF inhibitor alone vs. BRAF + MEK inhibitor – Combination → faster, more durable responses; delays resistance. PD‑1 inhibitor vs. CTLA‑4 inhibitor – PD‑1: higher efficacy, lower systemic toxicity. Excisional vs. punch biopsy – Excisional provides full thickness for Breslow measurement; punch may underestimate depth. Melanoma in situ vs. invasive – In situ: confined above basement membrane, 100 % 5‑yr survival; invasive: breaches basement membrane, risk of metastasis. --- ⚠️ Common Misunderstandings “All melanomas are pigmented.” – Amelanotic and acral melanomas may lack pigment; rely on shape/size changes. “Diameter >6 mm is required for diagnosis.” – Small lesions can be malignant; Evolving is a more reliable cue. “SLNB improves overall survival.” – It improves staging accuracy but has not shown a survival benefit in trials. “Only UVB causes melanoma.” – UVA also contributes via ROS; both UVA and UVB are carcinogenic. --- 🧠 Mental Models / Intuition “Depth drives danger.” – Think of a needle: the deeper it penetrates skin, the more likely it reaches vessels (metastasis). “UV fingerprint = C>T mutation.” – Visualize UV light writing a C→T “signature” in DNA, which accumulates over lifetime exposure. “ABCDEEFG = rapid triage tool.” – If any letter flags abnormal → prioritize biopsy. --- 🚩 Exceptions & Edge Cases Acral & mucosal melanomas – Often BRAF‑wildtype; consider KIT or NRAS mutations instead. Thin (<0.8 mm) ulcerated melanomas – Still qualify for SLNB because ulceration upgrades risk. Patients with Xeroderma pigmentosum – Extremely high UV‑induced DNA damage; surveillance starts earlier. --- 📍 When to Use Which Biopsy type: Use excisional when lesion ≤2 cm; punch only if excision would cause functional loss. Adjuvant therapy choice: BRAF‑mutant, high‑risk → BRAF + MEK inhibitors. BRAF‑wildtype, high‑risk → PD‑1 inhibitor (nivolumab/pembrolizumab). Imaging modality: Stage I–II: consider CT chest/abdomen if high‑risk features. Stage III‑IV: PET/CT for whole‑body assessment. --- 👀 Patterns to Recognize Rapid vertical growth (nodular melanoma) → early ulceration, “elevated & firm”. Multiple colors within a single lesion → higher likelihood of malignancy. Ugly duckling sign – a mole that looks different from a patient’s “mole family”. C>T transitions on sequencing → suggest UV‑induced pathogenesis. --- 🗂️ Exam Traps “All lesions >6 mm are malignant.” – Size alone is insufficient; evolution matters more. “SLNB is mandatory for all melanomas.” – Only indicated for >0.8 mm thickness or ulceration. “BRAF inhibitors cure melanoma.” – They improve response but resistance develops; combination with MEK is essential. “Chemotherapy (dacarbazine) improves overall survival.” – Trials have not shown a survival benefit; now largely superseded by immunotherapy/targeted therapy. “UVB is the only UV type that matters.” – UVA also contributes via oxidative DNA damage. ---