Hydrochlorothiazide and Skin Cancer: Raise the Red Flag

A Photosensitizing Drug and Risk for Skin Cancer

Cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC)—collectively termed nonmelanoma skin cancers (NMSC)—are the most common human malignancies, with a growing incidence both in the United States and worldwide.^[1,2] In the United States alone, more than 700,000 new cases of cSCC are reported each year, and over 3000 deaths annually are attributable to it.^[2]

Established risk factors for NMSC include a light skin phototype, immunosuppression, family history of NMSC, and heavy ultraviolet light exposure through natural or artificial sources.^[3]

The antihypertensive drug hydrochlorothiazide (HCTZ) is a potent photosensitizer, associated with phototoxic and photoallergic skin reactions as well as drug-induced lupus.^[4] HCTZ has also been shown to enhance UVA-induced DNA damage in an experimental model^[5] and to increase the incidence of SCC of the lip up to sevenfold in a recent Danish case-control study.^[6]

Because HCTZ remains one of the most commonly prescribed diuretics in the United States and Western Europe, Pedersen and colleagues^[7] sought to explore any link between chronic thiazide use and NMSC. To accomplish this, they designed a case-control study using the Danish Cancer Registry (2004-2012) to gather 71,533 cases of BCC and 8629 cases of SCC. They cross-referenced these cases with the National Prescription Registry to determine cumulative HCTZ exposure, comparing these data with those of population controls.

Study Findings

The association between HCTZ use and NMSC was dramatic, especially for cSCC. Other findings included the following:

1. High use of HCTZ (≥ 50,000 mg) increased the odds ratios (ORs) of BCC and cSCC by 1.29 and 3.98, respectively.

2. Patients with the highest HCTZ exposure (> 200,000 mg) showed increased ORs of 1.54 (BCC) and 7.38 (SCC).

3. In support of a cause-effect relationship, HCTZ exposure and NMSC showed a dose-response relationship.

4. The proportion of skin cancers attributable to HCTZ use was 9% for cSCC and 0.6% for BCC.

5. HCTZ showed the strongest association with skin cancers on heavily sun-exposed sites such as the lower limbs (versus the trunk).

6. Younger individuals (7lt; age 50 years) showed the greatest association between HCTZ use, BCC (OR, 1.91), and cSCC (OR, 42.85).

7. No associations were found between NMSC and exposure to other antihypertensive drugs.

Viewpoint

In an earlier study,^[6] this group of investigators demonstrated a strong association between HCTZ use and SCC of the lip. Now, Pedersen and colleagues have given us compelling evidence that HCTZ use increases the risk for SCC and, to a lesser extent, BCC. Perhaps their most alarming observation was that younger individuals (< age 50 years) have a > 40-fold risk of developing SCC when compared with HCTZ-naive controls.

Due to limitations in study design, Pedersen and colleagues could not assess whether HCTZ use is linked to a more (or less) aggressive BCC or SCC histopathology. They also couldn't compare tumor behavior with respect to metastasis and mortality rates.

Nevertheless, these findings raise a huge red flag. Patients taking HCTZ should be screened for SCC and BCC, and if feasible, those with a history of skin cancer and/or risk factors (light skin phototype, immunosuppression, strong family history of skin cancer) should be offered an alternative antihypertensive agent. Future studies should also consider whether any other photosensitizing drugs pose a similar increased NMSC risk.