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Contemplating the association of hydrochlorothiazide to nonmelanoma skin cancer raises my blood pressure

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By Warren R. Heymann, MD
March 29, 2018

Photosensitivity secondary to hydrochlorothiazide (HCTZ) use. Well-demarcated erythema on sun-exposed region of the forearm of this patient who was taking HCTZ.
Credit: JAAD

If you asked me to name the most important cutaneous adverse reactions to the thiazide diuretic hydrochlorothiazide (HCTZ), my immediate response would be a photolichenoid eruption and subacute cutaneous lupus. (1,2) Non-melanoma skin cancer (NMSC) would not have been mentioned—increasing data suggests that it should.

As Pedersen et al. note, HCTZ is one of the most frequently used diuretic and antihypertensive drugs in the United States and Western Europe. (3) It is a known photosensitizer. Because of prior reports linking HCTZ to lip cancer, the authors examined the association of HCTZ and the risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The authors identified patients with NMSC from the Danish Cancer Registry (2004-2012). Controls were matched 1:20 by age and sex. Cumulative hydrochlorothiazide use was assessed. Using conditional logistic regression, they calculated odds ratios (ORs) for BCC and SCC associated with hydrochlorothiazide use. A high use of hydrochlorothiazide (≥50,000 mg) was associated with ORs of 1.29 for BCC and 3.98 for SCC. A clear dose-response relationship between hydrochlorothiazide use and both BCC and SCC was noted; the highest cumulative dose category (≥200,000 mg of HCTZ) had ORs of 1.54 and 7.38 for BCC and SCC, respectively. Use of other diuretics (including furosemide, which also has a sulfa moiety) and antihypertensives was not associated with NMSC. Patients under age 50 had the highest ORs, which further supports the association. The authors concluded that HCTZ use is associated with a substantially increased risk of NMSC, especially SCC.

In their search of EMBASE and MEDLINE, Cognetta et al. found 3 studies demonstrating an increased risk of SCC or lip cancer. Using HCTZ for more than 5 years was associated with the highest risk. (4)

In a study of 58,213 white patients, of whom 2291 had BCCs, a significantly increased risk of BCC associated with diuretic use (hazard ratio 1.22) was found. Interestingly, this was noted in overweight and obese patients, suggesting that those patients may have required higher dosages for a longer duration. (5) Unfortunately, there was no breakdown of which diuretics were used.

Not all authors have reached the same conclusions.

Gandini et al. performed a meta-analysis to determine which antihypertensive drugs might be associated with skin cancer. They found that calcium channel blocker (CCB) users were at increased NMSC risk with a summary relative risk (SRR) of 1.14, and beta-blocker users were at increased risk of developing cutaneous melanoma (SRR) 1.21 (melanoma risk is worthy of a separate discussion). There was no association among the use of thiazide diuretics, angiotensin converting enzyme inhibitors (ACEI), or angiotensin receptor blockers (ARB) and skin cancer risk. The authors concluded that family doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and beta-blockers, and instruct them to perform periodic skin self-examination. (6)

Although these are conflicting data, if you accept the proposition that HCTZ is associated with NMSC, the proposed mechanism for the drug to cause cancer is UV-induced dissociation of its chlorine substituent, leading to free radical formation and DNA damage. (4)

I asked Dr. Daniel Hyman, head of General Internal Medicine at Cooper Medical School of Rowan University, to read the article by Pedersen et al. He said, “I was aware of the photosensitivity aspect of HCTZ but not the association with NMSC. The present guidelines recommend first-line pharmacologic treatment choices for HTN being thiazides, ARBs, ACEI, or CCB. I think the majority of us are going with ACEI now unless there is a contraindication. I will generally use HCTZ as an add-on later if control is inadequate. I will use HCTZ more often in African American patients. I would be curious whether HCTZ increases risk in AA pts. After reading this article, I will likely prescribe thiazides less in first-line treatment of HTN.” The latest guidelines have recently been published. (7)

Two outstanding internists at Cooper, Drs. Nancy Beggs and Rosemarie Leuzzi, agreed with Dr. Hyman’s assessment.

Point to Remember: Recent studies suggest that long-term exposure to HCTZ increases the risk of NMSC, especially SCC.

1. Johnston GA, Coulson IH. Thiazide-induced lichenoid photosensitivity. Clin Exp Dermatol. 2002;27(8):670-672.

2. Lowe G, Henderson CL, Grau RH, Hansen CB, Sontheimer RD. A systematic review of drug-induced subacute cutaneous lupus. Br J Dermatol. 2011;164(3):465-472.

3. Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S, Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: a nationwide case-control study from Denmark. J Am Acad Dermatol. 2018;78(4):673-681.

4. Cognetta AB Jr, Wolfe CM, Heinrichs E. Hydrochlorothiazide use and skin cancer: a Mohs surgeon’s concerns. Dermatol Surg. 2016;42(9):1107-1109.

5. McDonald E, Freedman DM, Alexander BH, et al. Prescription diuretic use and risk of basal cell carcinoma in the nationwide U.S. radiologic technologists cohort. Cancer Epidemiol Biomarkers Prev. 2014;23(8):1539-1545.

6. Gandini S, Palli D, Spadola G, et al. Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis. Crit Rev Oncol Hematol. 2018;122:1-9.

7. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127-e248.

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