Hydrochlorothiazide Substantially Increases Risk of Squamous Cell Carcinoma in a Dose-Dependent Manner
Hydrochlorothiazide (HCTZ) increases the risk of squamous cell carcinoma (SCC) approximately 4-fold at cumulative doses ≥50,000 mg, with risk escalating to 7-fold at doses ≥200,000 mg. 1, 2
Magnitude of Risk by Cumulative Dose
The FDA drug label and highest-quality epidemiologic data establish clear dose-response relationships:
- High cumulative use (≥50,000 mg): Odds ratio (OR) 3.98 (95% CI 3.68-4.31) for SCC 2
- Very high cumulative use (≥200,000 mg): OR 7.38 (95% CI 6.32-8.60) for SCC 2
- Long-term use (>10 years): Hazard ratio (HR) 3.70 (95% CI 1.77-7.73) for SCC 3
- Duration 5-10 years: HR 2.10 (95% CI 1.20-3.67) for SCC 3
The FDA Sentinel System data quantifies absolute risk: approximately 1 additional SCC case per 16,000 patients per year in the overall population, increasing to 1 additional SCC case per 6,700 patients per year in white patients taking cumulative doses ≥50,000 mg. 1
Site-Specific Risk: Lip Cancer
HCTZ demonstrates particularly strong association with lip SCC:
- Ever-use: OR 2.1 (95% CI 1.7-2.6) 4
- High use (≥25,000 mg): OR 3.9 (95% CI 3.0-4.9) 4
- Highest dose (≥100,000 mg): OR 7.7 (95% CI 5.7-10.5) 4
- Population attributable risk: 11% of lip SCC cases attributed to HCTZ use 4
Risk for Other Skin Cancers
The evidence diverges for basal cell carcinoma (BCC) and melanoma:
Basal Cell Carcinoma:
- Modest association at high doses: OR 1.29 (95% CI 1.23-1.35) for ≥50,000 mg 2
- Meta-analysis shows marginal increase: OR 1.19 (95% CI 1.02-1.38) 5
- UK cohort study found no association: HR 1.01 (95% CI 0.91-1.13) 3
Melanoma:
- No consistent association: HR 0.82 (95% CI 0.63-1.08) 3
- Meta-analysis shows marginal increase: OR 1.14 (95% CI 1.01-1.29) 5
Comparison with Other Thiazide Diuretics
Bendroflumethiazide shows no meaningful association with skin cancer, making it a safer alternative for patients at increased SCC risk. 6
Indapamide demonstrates increased melanoma risk (IRR 1.43,95% CI 1.35-1.50) but not SCC or BCC. 6
Other non-HCTZ diuretics and antihypertensives show no association with nonmelanoma skin cancer. 2, 4
Mechanism and Clinical Context
HCTZ is photosensitizing, which explains the dose-dependent relationship and predominance of SCC in sun-exposed areas. 2, 4 The latency period between exposure and cancer development means risk assessment requires evaluation of cumulative lifetime dose, not just current use. 3
Critical Clinical Pitfalls
- Do not assume all thiazides carry equal risk: The SCC association is specific to HCTZ, not a class effect. 6
- White patients face disproportionate risk: The absolute risk increase is substantially higher in white patients. 1
- Cumulative dose matters more than daily dose: A patient taking 25 mg daily for 5.5 years reaches the 50,000 mg threshold where risk substantially increases. 2
- The association is strongest for SCC, not BCC or melanoma: Do not conflate these distinct cancer types when counseling patients. 2, 3