Photosensitizing Medications and Risk of Skin Cancer: A Systematic Review

Abstract

Cutaneous malignancies are highly prevalent, and photosensitizing medications may amplify carcinogenic injury beyond ultraviolet radiation. This systematic review focused on hydrochlorothiazide and tetracyclines, which are widely used agents with documented photosensitivity. A PRISMA-guided search of MEDLINE, Web of Science, Scopus, and CENTRAL (1 January 2015–30 June 2025) identified analytical human studies evaluating drug exposure and incident melanoma, basal cell carcinoma, or squamous cell carcinoma. Dual screening, duplicate data extraction, ROBINS-I/NOS/RoB 2 assessments, and random-effects meta-analysis were conducted when appropriate. Of the 1,900 records, 10 studies met the eligibility criteria. Registry-based analyses have consistently linked hydrochlorothiazide with keratinocyte cancers, particularly squamous cell carcinoma, demonstrating a cumulative dose–response; lip squamous cell carcinoma showed an especially high risk at very high exposure. A subtype signal for nodular and lentigo maligna melanoma emerged at higher cumulative doses. Prospective cohorts have indicated a modest increase in basal cell carcinoma with tetracycline use, with largely null associations for melanoma and squamous cell carcinoma. Overall, evidence supports a clinically relevant association between cumulative hydrochlorothiazide exposure and squamous cell carcinoma, whereas the association between tetracyclines and basal cell carcinoma appears weaker and context dependent. Dermatologic counseling, consideration of non-photosensitizing alternatives for high-risk patients, sustained photoprotection, and ongoing pharmacovigilance are recommended. These findings align with global regulatory and international hazard evaluations.