Tools for Practice


#248 Hydrochlorothiazide and Squamous Cell Skin Cancer: Remember when hypertension was easy?


CLINICAL QUESTION
Does hydrochlorothiazide increase the risk of squamous cell carcinoma (SCC) of the skin? 

BOTTOM LINE
Observational data suggest an association between hydrochlorothiazide and the risk of SCC. Causation has not been proven. Risk appears to consistently increase with dose and duration (example: 5 years of use increases risk 3-4 times). Baseline incidence of SCC is <0.1% annually. The same risk has not been established with thiazide-like diuretics (like indapamide or chlorthalidone). The benefit of switching from hydrochlorothiazide to another agent should be weighed against the risk of changing medications.


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EVIDENCE
Statistically significant unless indicated. 
  • Systematic review:1 2 cohort and 7 case-control studies (395,789 patients). 
    • Association of SCC with thiazide diuretics: Odds Ratio (OR)=1.9 
      • Subgroup analysis: 
        • Hydrochlorothiazide and hydrochlorothiazide combinations consistently increased SCC risk: OR=2. 
        • Long-term HCTZ use (≥4.5 years) associated with higher SCC risk OR=3.3 
      • Limitations: potential unmeasured confounders; recall and detection bias; multiple comparisons. 
  • Largest case-control study2, not in above systematic review: 80,162 SCC cases in Denmark matched with 1,603,345 controls. 
    • Hydrochlorothiazide ≥50,000mg cumulative dose (~6 years use) associated with SCC risk: OR=4. 
    • Consistent dose-response relationship observed for SCC: OR=7.4 with hydrochlorothiazide ≥200,000mg cumulative dose (~20 years use). 
  • Hydrochlorothiazide associated with risk of SCC lip cancer3: 
    • Dose-response effect observed: OR=7.7 with ≥100,000mg cumulative dose. 
  • Another systematic review4 reported no effect with thiazides but did not include studies reporting on hydrochlorothiazide alone. 
  • Basal cell carcinoma risk very small (OR=1.2-1.3), if real.1,2 
Context: 
  • Baseline SCC risk varies with ethnicity, age, sex, and geographic location. A recent UK cohort reported an incidence of 77 cases per 100,000 people (<0.1%) per year.5 Metastatic SCC developed in 1.1-2.4% of patients with SCC.6 
  • Non-randomized studies may overestimate beneficial and harmful effects and cannot prove causation. 
  • Thiazide and thiazide-like agents reduce morbidity and mortality in randomized controlled trials and are first line therapy in hypertension.7 
  • One hypertension society recommends thiazide-like diuretics as preferred initial option for hypertension (like chlorthalidone or indapamide), although suggest continuing hydrochlorothiazide in stable patients.8 
November 25, 2019

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Author(s):

  • Braden O’Neill MD DPhil CCFP
  • Samantha Moe PharmD
  • Tina Korownyk MD CCFP

1. Shin D, Lee ES, Kim J, et al. J Clin Med Res. 2019 Apr; 11(4):247-255.

2. Pedersen SA, Gaist D, Schmidt SA, et al. J Am Acad Dermatol. 2018 Apr 1; 78(4):673-81.

3. Pottegård A, Hallas J, Olesen M, et al. J Intern Med. 2017 Oct; 282(4):322-331.

4. Gandini S, Palli D, Spadola G, et al. Crit Rev Oncol Hematol. 2018 Feb; 122:1-9.

5. Venables ZC, Nijsten T, Wong KF, et al. Br J Dermatol. 2019; 181(3):474-482.

6. Venables ZC, Autier P, Nijsten T, et al. JAMA Dermatol. 2019; 155(3):298-306.

7. Wright JM, Musini VM, Gill R. Cochrane Database Syst Rev. 2018 Apr 19; 4: CD001841.

8. Faconti L, Ferro A, Webb AJ, et al; J Hum Hypertens. 2019 Apr; 33(4):257-258.

Authors do not have any conflicts of interest to declare.