We found that the commonly used photosensitizing antihypertensive drugs, HCTZ, HCTZ/TR, and nifedipine were associated with increased risk of lip cancer. Risk appeared to increase with increasing duration of use and was not explained by confounding by cigarette smoking. Non-photosensizing atenolol, when used alone, was not associated with increased risk. Findings for lisinopril, a photosensitizer, were equivocal.
Lip cancer includes malignant neoplasms of the vermilion border, commissure, and labial mucosa but excludes cancers originating on the skin of the lip 2, 14
. The histology is predominantly squamous cell and most occur on the lower lip 2
. Based on SEER data, the overall age-adjusted incidence in the USA in 2003–2007 was low, 0.7/100,000 per year, and the incidence in men (1.2) was four times that in women (0.3) 15
. The relative protection of women has been linked to less engagement in outdoor occupations and use of lipstick and other lip-coatings 16–18
. Incidence in SEER was eight-fold higher in whites (0.8) than blacks (0.1). In fact, the incidence in black women was not calculated because there were fewer than 16 cases in the five-year interval 15
. We did not find published incidence data for other ethnicities. Lip cancer is usually detected and treated early and as a result, regional metastases occur in only 5–7% of cases and distant metastases in only 0.5–2.0% 19
The protection afforded by darker pigmentation and this cancer’s more frequent occurrence on the lower lip correspond with the main known risk factor, prolonged sun exposure 2,18
. Although pipe smoking was believed to be a risk factor in the past, it has become quite infrequent in our setting and findings concerning cigarette smoking have varied considerably and have been considered inconclusive 2, 20, 21
. Our data confirmed current cigarette smoking as a risk factor. We did not expect former smokers to have a reduced risk and can only speculate that this finding was due to chance or that persons who quit smoking also have relatively low sun exposure or some other protective characteristic. Also confirming cigarette smoking as a risk factor was that in our screening study1
the only other drug associated with lip cancer beside HCTZ and nifedipine was nicotine, mostly in skin patch form, which was prescribed as an aid to discontinuing smoking.
When we narrowed our focus to the susceptible group of non-Hispanic whites, we lost a disproportionate number of control subjects, which led to the mean age at index date of the controls being 2.4 years higher than that of the cases. Before the exclusions, the mean ages were virtually identical (cases 66.95, controls 66.84 years). This age discrepancy did not bias our results or require further adjustment because conditional logistic regression analysis bases the odds ratio on the findings within each case-plus-matched-controls risk set where the ages were matched within one year.
We were not able to adjust for sun exposure, the most important lip cancer risk factor along with relative lack of pigmentation of the lips. However, it does not seem likely that users of the antihypertensive drugs associated with lip cancer experience a great deal more sun exposure than nonusers or than users of atenolol. To account for the two- to four-fold associations observed for at least five years use of HCTZ, HCTZ/TR and nifedipine, a much greater than two- to four-fold difference in carcinogenic sun exposure would be required 22
. Aside from a few self- or case-reports (http://www.ehealthme.com/ds/atenolol/photosensitivity+reaction
) the absence of a scientifically established association of atenolol alone with lip cancer adds specificity to these findings and suggests that hypertension, the condition being treated, is not responsible. There may also have been uncontrolled confounding based on different characteristics of patients related to which drug was prescribed for them. Again these differences would have to be quite strongly related to risk of lip cancer to account for the associations that we observed.
Thiazide diuretics, triamterene, some ACE inhibitors and lisinopril are photosensitizing drugs 3, 4, 23–25
. Photosensitizing drugs are believed to absorb energy from ultraviolet and/or visible light causing release of electrons. This leads to the generation of reactive oxygen intermediates and free radicals which damage DNA and other components of skin cells and produce an inflammatory response 24,25
. The causation of squamous cell skin cancer by the treatment of psoriasis with repeated exposures to photosensitizing psoralen and ultraviolet radiation (PUVA) 26
and the association of HCTZ and other antihypertensive drugs with risk of squamous cell skin cancer 27
both support the biological plausibility of an increased risk of lip cancer due to photosensitizing antihypertensive drugs. However, another study 28
surprisingly found more evidence for an association of short-term than long-term use of photosensitizing drugs with skin cancer.
We were not able to include basal cell and squamous cell skin cancers in this study because these diagnoses have not been recorded in our cancer registry. Melanoma is also related to sun exposure, but none of the antihypertensive drugs studied screened positive for an association with this cancer in our screening study1
. Melanoma has been more strongly associated with intermittent exposures, especially those producing sunburn, than with chronic exposure, so the timing of use of photosensitizing drugs could be an important consideration 29
In the study that brought our attention to antihypertensive drugs and lip cancer our screening criteria for drug/cancer associations of interest were: odds ratio for three or more prescriptions of at least 1.5 and greater than odds ratio for one prescription, as a rough indicator of dose-response, and p <0.011
. HCTZ and nifedipine met these criteria but lisinopril did not since its odds ratio was 1.36 (p=0.004) and the odds ratio for one prescription was 1.38. The findings regarding lisinopril in the present study were also weaker in that the clear positive association became only of borderline statistical significance when subjects who received other antihypertensive drugs were excluded.
One of the main reasons for the analysis of single drug exposures was the unexpected finding of a positive association five or more years of use of atenolol with lip cancer. These proved to be attributable to the associated use of the other antihypertensive drugs.
Because lip cancer is a relatively infrequent form of cancer, it is not surprising that associations with antihypertensive drugs have not been observed in large clinical trials of their efficacy. For example, 33,357 patients, mean age 66.9 years, were followed up for a mean 4.9 years in the ALLHAT study 30
About half were not non-Hispanic white and about half were women who have a lower incidence of lip cancer than white men. However, if all 33,357 were white males age 65–69 whose overall annual incidence of oropharyngeal cancer in 2003–2007 was 55.1/100,000 person-years, of which 8 percent were lip cancers15
, approximately 7 lip cancers would have been expected during follow-up in all three treatment groups combined.
Although the relatively high odds ratios, the evidence for specificity and the known biological mechanism are consistent with a causal relationship, causality cannot usually be established by a single observational study such as ours. Further investigations are needed to confirm and characterize relationships between photosensitizing antihypertensive drugs and lip cancer.
Search of the clinical literature revealed considerable attention to the effects of photosensitivity on the skin 25, 31,32
, some attention on its effects on the eye 33,34
, but little or no attention directed toward the lips except for a listing of a few lip sunscreens in the review by Ting et al 35
Antihypertensive drugs are commonly prescribed 36
and most are photosensitizing as are many other commonly prescribed drugs 3,4
. Lip cancer is rare and an increased risk of developing it is generally outweighed by the benefits of drugs that are effective for other conditions. However, physicians prescribing photosensitizing drugs should ascertain whether patients are at high risk of lip cancer by virtue of fair skin and long-term sun exposure and discuss lip protection with them. Although not yet confirmed by clinical trials, likely preventive measures are simple: a hat with sufficiently wide brim to shade the lips and lip sunscreens.