Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study

doi:10.1016/j.jaad.2018.06.014

Journal of the American Academy of Dermatology

Volume 80, Issue 2, February 2019, Pages 460-465.e9

https://doi.org/10.1016/j.jaad.2018.06.014 Get rights and content

Background

Hydrochlorothiazide use has been associated with markedly increased risk for squamous cell carcinoma. No previous studies have investigated the association between hydrochlorothiazide use and the risk for Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST).

Objective

To examine the association between hydrochlorothiazide use and the risk for MCC and MAST.

Methods

Using Danish nationwide health registries, we identified all patients with incident MCC or MAST during 2004-2015 and matched the cases individually to cancer-free population controls by risk set sampling. Using conditional logistic regression, we estimated the odds ratios (ORs) and confidence intervals (CIs) associated with cumulative use of hydrochlorothiazide.

Results

The adjusted ORs for MCC and MAST associated with high use (≥50,000 mg) of hydrochlorothiazide was 2.3 (95% CI 1.1-4.8) and 3.6 (95% CI 1.9-7.0), respectively, which increased to 3.3 (95% CI 1.3-8.3) and 5.6 (95% CI 2.4-13.3), respectively, with highest use (≥100,000 mg). We found no increased risk for these tumors in analyses of drugs with similar indications as hydrochlorothiazide, except there was a tendency toward an increased risk for MCC associated with the use of furosemide (OR 1.9, 95% CI 0.9-4.0).

Limitations

No data on sun exposure was available.

Conclusion

Hydrochlorothiazide use is associated with an increased risk for MCC and MAST.

Section snippets

Methods

We performed a nested case-control study, similarly to our recent studies,4, 5, 6 on the basis of the nationwide Danish demographic and health registries (Supplementary Appendix; available at http://www.jaad.org).

From the Danish Cancer Registry,¹⁶ we identified patients (cases) with a histologically verified primary diagnosis of Merkel cell carcinoma or malignant adnexal skin tumor during January 1, 2004-December 31, 2015 (study period). Supplemental Table I (available at http://www.jaad.org)

Results

We included 97 patients with Merkel cell carcinoma and 132 with malignant adnexal skin tumors (Fig 1) matched to 1857 and 2620 population controls, respectively. Baseline characteristics were similar between patients with malignant adnexal skin tumors and controls (Table I); however, Merkel cell carcinoma patients had higher numbers of comorbidities and drug use, in particular of the photosensitizing drugs macrolides and aminoquinolines, and had a higher level of education compared with their

Discussion

In this large nationwide population-based study, we found a 2.3-fold increased risk for Merkel cell carcinoma and a 3.6-fold increased risk for malignant adnexal skin tumors associated with high use of hydrochlorothiazide.

Epidemiologic studies of risk factors of these rare skin tumors are scarce. The use of nationwide Danish registries enabled the identification of cases and controls with low risk for selection bias. Case diagnoses were histologically verified, further enhancing validity. We

References (23)

S. Gopinath et al.
Characteristics and survival of patients with eccrine carcinoma: a cohort study
J Am Acad Dermatol
(2016)
S.N. Robinson et al.
Photosensitizing agents and the risk of non-melanoma skin cancer: a population-based case–control study
J Invest Dermatol
(2013)
B.D. Lemos et al.
Pathologic nodal evaluation improves prognostic accuracy in Merkel cell carcinoma: analysis of 5823 cases as the basis of the first consensus staging system
J Am Acad Dermatol
(2010)
Y.R. Wang
Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States
Arch Intern Med
(2007)
Q. Gu et al.
Trends in Antihypertensive medication use and blood pressure control among United States adults with hypertension clinical perspective
Circulation
(2012)
D. Moore
e. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management
Drug Saf
(2002)
A. Pottegård et al.
Association of hydrochlorothiazide use and risk of malignant melanoma
JAMA Intern Med
(2018)
A. Pottegård et al.
Hydrochlorothiazide use is strongly associated with risk of lip cancer
J Intern Med
(2017)
S.A. Pedersen et al.
Hydrochlorothiazide use and risk of nonmelanoma skin cancer: a nationwide case-control study from Denmark
J Am Acad Dermatol
(2017)
R.W. Miller et al.
Merkel Cell carcinoma and melanoma: etiological similarities and differences
Cancer Epidemiol Biomarkers Prev
(1999)

J.P. Robertson et al.

Epidemiology of Merkel cell carcinoma in New Zealand: a population-based study

Br J Dermatol

(2015)

Cited by (40)

Hydrochlorothiazide increases risk of nonmelanoma skin cancer in an elderly Japanese cohort with hypertension: The Shizuoka study
2023, JAAD International
Hydrochlorothiazide (HCT), a widely used hypertensive drug, has photocarcinogenic potential, leading to concerns about the development of nonmelanoma skin cancers (SCs) after intake. Despite substantial numbers of observational studies, the results remain inconsistent especially among Asian countries.
To assess the incidence of nonmelanoma SCs in hypertensive Japanese HCT users compared with nonusers.
A population-based, cohort nested, propensity score-matched study was conducted using the Shizuoka Kokuho database. All participants were patients aged ≥60 years. Hazard ratios for SC incidence were calculated in the matched cohorts using the propensity scores of potential confounders, sex, age category, comorbidities, and administration of methotrexate, cyclosporin, and statins.
The risk of SC was higher in HCT users than in nonusers (hazard ratio, 1.58; 95% confidence interval, 1.04-2.40), with preferential sun-exposed location and a tendency to develop squamous cell carcinoma, but not basal cell carcinoma or Bowen disease.
No additional information was available from other than medical records. The data were confined to a Japanese population.
HCT use increases the risk of SC in Japanese patients with hypertension and a dark skin type, highlighting the increased risk of SC among HCT users in the aging society worldwide.
The use of specific antihypertensive medication and skin cancer risk: A systematic review of the literature and meta-analysis
2023, Vascular Pharmacology
The use of hydrochlorothiazide has recently been linked to skin cancer in observational studies. This may be explained by its photosensitizing properties, but photosensitivity has also been reported for other antihypertensive drugs. We conducted a systematic review and meta-analysis to compare skin cancer risk among antihypertensive drug classes and individual blood pressure lowering drugs.
We searched Medline, Embase, Cochrane and the Web of Science and included studies that investigated the association between antihypertensive medication exposure and non-melanoma skin cancer (NMSC) or cutaneous malignant melanoma (CMM). We combined the extracted odds ratios (OR) using a random effects model.
We included 42 studies with a total of 16,670,045 subjects. Diuretics, in particular hydrochlorothiazide, were examined most frequently. Only 2 studies provided information about antihypertensive co-medication. Exposure to diuretics (OR 1.27 [1.09–1.47]) and calcium channel blockers (OR 1.06 [1.04–1.09]) was associated with an increased risk for NMSC. The increased risk for NMSC was only observed in case control studies and studies that did not correct for sun exposure, skin phototype or smoking. Studies that did correct for covariates as well as cohort studies did not show a significantly increased risk for NMSC. Egger's test revealed a significant publication bias for the subgroup of diuretics, hydrochlorothiazide and case-control studies concerning NMSC (p < 0.001).
The available studies investigating the potential skin cancer risk that is associated with antihypertensive medication have significant shortcomings. Also, a significant publication bias is present. We found no increased skin cancer risk when analyzing cohort studies or studies that corrected for important covariates. (PROSPERO (CRD42020138908)).
What Dermatologists Should Know About Thiazides
2022, Actas Dermo-Sifiliograficas
La hidroclorotiazida (HCTZ) y otros diuréticos tiazídicos son fármacos que se han empleado desde hace décadas para el tratamiento de la hipertensión arterial, la insuficiencia cardíaca o la enfermedad renal crónica. Las tiazidas se han asociado con reacciones de fotosensibilidad, siendo heterogéneas en cuanto a manifestación clínica y tiempo de recuperación, y en las cuales, el fototest, el fotoparche y la biopsia cutánea nos pueden ser útiles en el diagnóstico. En relación con estos fármacos, en los últimos años se ha evidenciado también un mayor riesgo dosis-dependiente de desarrollar determinados tipos de cáncer cutáneo en pacientes tratados de forma crónica con HCTZ. En esta revisión se comentan, asimismo, otros efectos adversos menos habituales o reconocidos de los diuréticos tiazídicos reportados de forma aislada en la literatura.
Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been linked to photosensitivity with heterogeneous clinical manifestations and recovery times. Diagnosis can be aided by phototesting, photopatch testing, and skin biopsy. Long-term use of hydrochlorothiazide has been linked to an increased dose-dependent risk of certain types of skin cancer in recent years. In this review, we also look at other less common or lesser-known adverse effects of thiazide diuretics that have been described in isolated reports.
[Translated article] What Dermatologists Should Know About Thiazides
2022, Actas Dermo-Sifiliograficas
Hydrochlorothiazide and other thiazide diuretics have been used for decades to treat high blood pressure, heart failure, and chronic kidney disease. Thiazides have been linked to photosensitivity with heterogeneous clinical manifestations and recovery times. Diagnosis can be aided by phototesting, photopatch testing, and skin biopsy. Long-term use of hydrochlorothiazide has been linked to an increased dose-dependent risk of certain types of skin cancer in recent years. In this review, we also look at other less common or lesser-known adverse effects of thiazide diuretics that have been described in isolated reports.
La hidroclorotiazida (HCTZ) y otros diuréticos tiazídicos son fármacos que se han empleado desde hace décadas para el tratamiento de la hipertensión arterial, la insuficiencia cardíaca o la enfermedad renal crónica. Las tiazidas se han asociado con reacciones de fotosensibilidad, siendo heterogéneas en cuanto a manifestación clínica y tiempo de recuperación, y en las cuales, el fototest, el fotoparche y la biopsia cutánea nos pueden ser útiles en el diagnóstico. En relación con estos fármacos, en los últimos años se ha evidenciado también un mayor riesgo dosis-dependiente de desarrollar determinados tipos de cáncer cutáneo en pacientes tratados de forma crónica con hidroclorotiazida. En esta revisión se comentan, asimismo, otros efectos adversos menos habituales o reconocidos de los diuréticos tiazídicos reportados de forma aislada en la literatura.
Diagnosis and treatment of arterial hypertension 2021
2022, Kidney International
Citation Excerpt :
In the past decades, repeatedly, potential side effects of antihypertensive medication regarding cancer were assumed, which however could not be confirmed afterward.62 Very recently, several observational studies highlighted an increased risk of several types of skin cancer with the use of thiazide diuretics.63–66 Although there is no evidence to suggest that thiazide diuretics and in particular HCT per se are causing skin cancer, its photosensitizing properties may enhance the detrimental effects of sun exposure, and potentially the risk of developing several skin cancers.
In the last 4 years, several evidence-based, national, and international guidelines on the management of arterial hypertension have been published, mostly with concordant recommendations, but in some aspects with discordant opinions. This in-depth review takes these guidelines into account but also addresses several new data of interest. Although being somewhat obvious and simple, accurate blood pressure (BP) measurement with validated devices is the cornerstone of the diagnosis of hypertension, but out-of-office BP measurements are of crucial importance as well. Simplified antihypertensive drug treatment such as single-pill combinations enhances the adherence to medication and speeds up the process of getting into the BP target range, a goal not so far adequately respected. Recommended (single-pill) combination therapy includes diuretics as part of the first step of antihypertensive therapy, and updated analysis does not provide evidence to exclude diuretics from this first step because of the recently discussed potential risk of increasing cancer incidence. Target BP goals need to be individualized, according to comorbidities, hypertension-mediated organ damage, coexistence of cardiovascular risk factors (including age), frailty in older patients, and individual tolerability. There are also concordant recommendations in the guidelines that an office BP between 120 and 140 mm Hg systolic and between 70 and 80 mm Hg diastolic should be achieved. The BP target of Kidney Disease: Improving Global Outcomes for hypertensive patients with chronic kidney disease are not applicable for clinical practice because they heavily rely on 1 study that used a study-specific, nontransferable BP measurement technique and excluded the most common cause of chronic kidney disease, namely, diabetic nephropathy. Actual data even from a prospective trial on chronotherapy have to be disregarded, and antihypertensive medication should not be routinely dosed at bedtime. Rigorously conducted trials justify the revival of renal denervation for treatment of (at least, but not only) uncontrolled and treatment-resistant hypertension.
Reply to “Comment on ‘Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case–control study from Denmark’”
2021, Journal of the American Academy of Dermatology

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: Funding sources: Supported by a grant from the Danish Cancer Society (grant R72-A4417) and the Danish Council of Independent Research (grant 4004-00234B). The funding source had no role in the design of the study, data analysis, or interpretation of the results.

: Conflicts of interest: Dr Gaist received honoraria from AstraZeneca (Sweden) for participating as a coinvestigator in a research project outside this work. Dr Pottegård has participated in research projects unrelated to the present study using grants provided by LEO Pharma (manufacturer of bendroflumethiazide) to the institution where he was employed. The remaining authors disclose no relevant conflicts of interest.

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Original articleHydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study

Background

Objective

Methods

Results

Limitations

Conclusion

Section snippets

Methods

Results

Discussion

J Am Acad Dermatol

J Invest Dermatol

J Am Acad Dermatol

Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States

Arch Intern Med

Trends in Antihypertensive medication use and blood pressure control among United States adults with hypertension clinical perspective

Circulation

e. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management

Drug Saf

Association of hydrochlorothiazide use and risk of malignant melanoma

JAMA Intern Med

Hydrochlorothiazide use is strongly associated with risk of lip cancer

J Intern Med

Hydrochlorothiazide use and risk of nonmelanoma skin cancer: a nationwide case-control study from Denmark

J Am Acad Dermatol

Merkel Cell carcinoma and melanoma: etiological similarities and differences

Cancer Epidemiol Biomarkers Prev

Epidemiology of Merkel cell carcinoma in New Zealand: a population-based study

Br J Dermatol

Original article
Hydrochlorothiazide use and risk for Merkel cell carcinoma and malignant adnexal skin tumors: A nationwide case-control study