Is there a correlation between hydrochlorothiazide (HCTZ) and an increased risk of skin cancer?

Hydrochlorothiazide and Skin Cancer Risk

Yes, there is a well-established correlation between hydrochlorothiazide (HCTZ) use and an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), with the risk being dose-dependent and predominantly affecting white patients taking high cumulative doses. 1

Evidence from FDA Drug Label

The FDA label for HCTZ explicitly warns that hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, with the increased risk predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. 1

• In the overall population, the increased risk was approximately 1 additional SCC case per 16,000 patients per year. 1
• For white patients taking a cumulative dose of ≥50,000 mg, the risk increase was approximately 1 additional SCC case for every 6,700 patients per year. 1
• The FDA label also notes photosensitivity as a known hypersensitivity reaction to HCTZ. 1

Mechanism and Clinical Context

HCTZ causes photosensitivity through its photosensitizing properties, which can trigger exaggerated sunburn reactions, dermatitis, and lichenoid eruptions when patients are exposed to ultraviolet radiation. 2 This photosensitizing effect is the likely mechanism underlying the increased skin cancer risk, particularly with prolonged sun exposure.

Type of Skin Cancer Risk

The evidence consistently shows:

• Squamous cell carcinoma (SCC): Clearly increased risk with HCTZ use, particularly with longer duration and higher cumulative doses. 1, 3, 4
• Basal cell carcinoma (BCC): No consistent association demonstrated across studies. 5, 4
• Melanoma: Some evidence suggests increased risk with longer duration and higher cumulative doses, though this is less consistent than for SCC. 3

Dose-Response Relationship

The risk increases with both duration of use and cumulative dose:

• Risk becomes significant with ≥10 years of use (HR: 1.12; 95% CI: 1.03-1.21). 3
• Risk substantially increases with cumulative doses ≥100,000 mg (HR: 1.49; 95% CI: 1.27-1.76). 3
• The highest risk is observed in patients with cumulative doses ≥50,000 mg, particularly in white patients. 1

Population-Specific Considerations

The skin cancer risk appears to be race-dependent:

• White/Caucasian populations: Clearly elevated risk of SCC with HCTZ use. 1, 3, 4
• Asian populations: Multiple studies from Taiwan show no significant association between HCTZ and skin cancer risk, suggesting this may be a safer option in Asian patients. 5, 6

Clinical Recommendations for Patients on HCTZ

All patients taking HCTZ should receive counseling about skin cancer risk and sun protection measures:

• Patients should seek shade when outside, particularly around midday, as ultraviolet radiation exposure varies by time of day, season, geographical location, and altitude. 2
• Patients should wear protective clothing covering as much of the body as possible, along with sunglasses and broad-brimmed hats. 2
• Broad-spectrum sunscreens with SPF 30 or higher are recommended for all sun-exposed areas. 2
• Patients should be aware that radiation can be stronger when reflected by water, sand, or snow. 2

Monitoring and Screening

Patients on long-term HCTZ therapy (>1 year) require regular dermatologic surveillance:

• Annual dermatologic examination of sun-exposed areas is recommended for patients at increased risk, including those with previous non-melanoma skin cancers or prolonged HCTZ exposure. 2
• Patients should be instructed to report any suspicious lesions immediately, particularly those that bleed, are painful, grow significantly, or become protuberant. 2
• Complete annual skin examinations should be performed for patients who have been exposed to HCTZ for extended periods. 2

Alternative Thiazide Diuretics

Bendroflumethiazide (BFT) may be a safer alternative for patients at increased risk of skin cancer, as it was not meaningfully associated with the risk of any type of skin cancer in long-term use. 4 This provides a practical alternative for patients requiring thiazide diuretic therapy who have elevated skin cancer risk.

Common Pitfalls to Avoid

• Do not dismiss photosensitivity complaints in patients on HCTZ, as this is a warning sign of the drug's photosensitizing effects. 2
• Do not assume all thiazide diuretics carry equal skin cancer risk—the evidence is strongest for HCTZ specifically. 4
• Do not neglect to document sun protection counseling in patients starting HCTZ, particularly white patients who will be on long-term therapy. 2
• Do not overlook the cumulative dose when assessing risk—patients on lower daily doses but prolonged therapy can still accumulate high-risk cumulative doses. 1, 3