Squamous Cell Carcinoma — SCE Dermatology MCQ
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Correct answer: A — Azathioprine-induced photosensitisation to UVA
The correct answer is A, azathioprine-induced photosensitisation to UVA. Azathioprine is metabolised to 6-thioguanine, which is incorporated into cellular DNA and acts as a UVA chromophore. Upon UVA exposure this DNA-embedded 6-thioguanine generates reactive oxygen species and oxidative DNA damage, producing a synergistic mutagenic effect that is highly selective for sun-exposed skin and drives keratinocyte carcinogenesis independent of the drug's immunosuppressive action. This mechanism explains the striking predilection for multiple keratinising squamous cell carcinomas on sun-exposed sites in long-term thiopurine users and underlies BAD advice on rigorous year-round photoprotection for these patients. Because the effect is mediated by 6-thioguanine incorporation and UVA activation rather than by systemic immune suppression alone, it is the single most important contributor in this scenario. Why the other options are wrong: E. Concurrent hepatic cirrhosis: cirrhosis itself is not a recognised direct risk factor for cutaneous squamous cell carcinoma and does not explain the sun-exposed distribution described. B. Age alone: age is a general risk factor for skin cancer but does not account for the marked excess risk and site-specific pattern seen with thiopurine therapy. C. TPMT deficiency: TPMT activity was explicitly normal here, and TPMT status governs myelotoxicity risk from thiopurine metabolite accumulation, not photocarcinogenesis. D. Underlying autoimmune hepatitis: autoimmune hepatitis is not independently linked to keratinocyte skin cancer; the excess risk is attributable to the drug used to treat it, not the disease itself. Key point: azathioprine's 6-thioguanine metabolite sensitises DNA specifically to UVA, causing a drug-mechanism-driven excess of sun-exposed squamous cell carcinomas that is distinct from, and more important than, general immunosuppression or TPMT status.
Reference: British Association of Dermatologists, 'Azathioprine: friend or foe?' British Journal of Dermatology 2019 (BJD 181:16-17), and BAD Guidelines for Safe and Effective Prescribing of Azathioprine 2011, https://onlinelibrary.wiley.com/doi/full/10.1111/bjd.17345