Critique 187: Alcohol and squamous cell carcinoma of the skin — 14 June 2016

Siiskonen S, Han J, Li T, Cho E, Nijsten T, Qureshi A, Alcohol intake is associated with increased risk of squamous cell carcinoma of the skin: three US prospective cohort studies.  Nutrition and Cancer 2016;68:545-553.

Authors’ Abstract

The association between alcohol intake and cutaneous squamous cell carcinoma (cSCC) is unclear. We studied the association between alcohol intake and incident invasive cSCC in three cohorts of women and men with repeated assessments of alcohol intake in the US.  Information on alcohol intake was collected repeatedly during follow-up.  Cumulative average of alcohol intakes was used.  Multivariable Cox proportional hazards models with time-dependent exposure were used to estimate relative risks (RRs) and 95% confidence intervals, followed by a meta-analysis.

During a follow-up of 4,234,416 person-years, 2,938 cSCC were identified. Alcohol intake was associated with an increased risk of cSCC with a dose-response relationship.  Each additional drink (12.8 gram of alcohol) per day was associated with a 22% increased risk of cSCC (RR 1.22, 95% confidence interval: 1.13-1.31).  White wine consumption of >/= 5 times/wk was associated with an increased risk of cSCC (RR 1.31, 95% confidence interval: 1.09-1.59).  We found no increased risk of cSCC with other alcoholic beverages.  The population-attributable risk associated with alcohol intake of >/= 20 grams/d was 3% of cSCCs.

In conclusion, alcohol intake was associated with an elevated risk of cSCC. Among alcoholic beverages, white wine was associated with cSCC.

Forum Comments

All types of cancer of the skin are known to be strongly associated with ultra-violet light exposure. A report from the Nurses’ Health Study and the Health Professionals Study in 2015 reported that cutaneous basal cell carcinoma was increased in both men and women by alcohol consumption (Wu et al), with suggestions that this association may somehow be due to sun exposure.  Numerous studies have shown that excessive sun exposure increases the risk of melanoma, and alcohol intake has been shown to be significantly related to sun exposure (Mukamal).  However, data are inconsistent as to a possible specific association between alcohol and the second most common type of skin cancer, squamous cell cancer (Freedman et al, Fung et al, Jensen et al).

Further background on the topic: In a recent overview of the association of wine consumption with skin cancers, Forum member Stockley noted the following: “From a review of five papers that had assessed a role for wine consumption on certain skin cancers, there appeared to be no relationship between red wine and malignant melanomas but potentially a linear dose-response relationship with white wine in one study (Kubo et al).  Another study saw a relationship with wine per se (Bendetti et al).  Concerning basal cell carcinomas, one study reported an increased risk associated with wine consumption (Fung et al), while another reported an increased risk for white wine consumers but a decreased risk for red wine consumers (Ansems et al).  Gender differences were also observed but not consistently.  There was no observed increased risk between wine and squamous cell carcinoma when there was no past history of skin cancer but an increase when there was a past history of skin cancer (Rota et al).

“Thus, the limited number of observational studies on the risk of skin cancers associated with wine consumption provides no clear conclusions. Similarly, although a meta-analysis of 16 observational studies on alcohol consumption per se suggests that alcohol consumption may be positively associated with the risk of skin cancers, the study also concludes that residual confounding by sun exposure cannot be excluded and the results should be considered cautiously (Rota et al).”

The present large analysis combines data from the two Nurses’ Health Study cohorts (women) and the Health Professionals Study (men) to evaluate the association between cumulative assessments of alcohol intake and the development of cutaneous squamous cell cancer (cSCC). The investigators had several measures related to sun exposure and sunburns to include as confounders in their analyses; follow up extended up to 19 years.

The authors conclude that there is a positive association between alcohol intake and cSCC, with up to 3% of such cancers in the population being related to the intake of ≥20 g/day of alcohol. For specific beverages, and using continuous rather than categorical estimates of alcohol in a meta-analysis (based on all three cohorts), the only statistically significant increase in risk of cSCC was for subjects reporting ≥ 5 drinks/week of white wine.  The overall RR was < 1.0 for non-light beer and red wine, 1.08 for liquor, 1.10 for white wine, and 1.14 for light beer.  However, there were differences in the associations between each type of beverage and cancer among the different cohorts (e.g., a stronger increase was seen for liquor in the original Nurses’ Study cohort).

Forum review of a previous study on the topic from the Women’s Health Initiative (WHI), and specific comments by Dr. Arthur Klatsky: The Forum previously had reviewed a publication from the WHI relating alcohol to skin cancer (Kubo et al).  That study reported a higher hazard of malignant melanoma (MM) (HR 1.64) and non-melanoma skin cancers (NMSC) (HR 1.23) for drinkers of 7 or more drinks/week, compared with non-drinkers.  In a review by our Forum of that paper (available at www.bu.edu/alcohol-forum/critique-129), members noted that there were large decreases in the estimates of the HRs related to alcohol consumption when adjustments were made for sun exposure and other known confounders, and raised the possibility that there may be residual confounding from sun exposure affecting the results.

Forum member Klatsky noted at that time: “Several decades of follow-up data from the Kaiser-Permanente study, with more than 300,000 subjects and more than 1,000 cases of malignant melanoma, had found that among persons preferring wine, the HR for melanoma at 3+ drinks per day was 1.7 (95% CI 1.2-2.5), while it was 1.2, 1.3, and 1.1 in persons with preference for liquor, beer, and no beverage type. However, at 1-2 drinks per day, wine drinkers had a HR of 0.9.”  Klatsky stated at the time: “So maybe too much should not be made of the beverage type data in these analyses.  However, the association with alcohol seems statistically solid.”

The Forum noted at the time a previous study by Mukamal (2006) on the relation of alcohol consumption with sun exposure. It was based on data from 300,000 subjects participating in a risk factor surveillance survey, and stated: “Approximately 33.5% of respondents reported a sunburn within the past year.  Heavier average alcohol use and binge drinking were both positively associated with prevalence and number of sunburns within the past year.  The adjusted odds ratios for prevalence and number of sunburns among binge drinkers were 1.39 (1.31-1.48) and 1.29 (1.20-1.38), respectively.”  Forum member Klatsky wondered  at the time whether “possible confounding by sun is not only an artifact of SES and tropical vacations, but whether heavy imbibers at the beach may fall asleep when exposed or simply do not notice their sunburn until it is severe.”

Upon reviewing the present paper, Forum member Klatsky added: “It really is beginning to look as if there is an empiric relationship between alcohol and increased risk of several skin cancer types. Interestingly, smoking is related to lower risk, especially for melanoma.  The smoking association may be more likely to have a biological association.  The only type of skin cancer we have looked at is melanoma (Klatsky et al, 2015); the most relevant paragraph from that text: ‘While there are previous reports of possible increased risk of melanoma in drinkers (Rota et al), the association of drinking with increased risk of melanoma in this analysis is noteworthy for its strength in both heavy and light drinkers.  We have presented data (Klatsky et al, 2013) showing that the alcohol-associated risk is similar for men and women. In another of our reports (Tran et al) and several other papers (e.g., Song et al), smoking is inversely related to melanoma, so residual confounding by smoking is not a plausible explanation for the association with alcohol. A noteworthy feature in our melanoma analyses is that the alcohol association is stronger for non-invasive than invasive disease, suggesting earlier diagnosis in drinkers.  Earlier diagnosis could, in turn, be related to higher socio-economic status and more recreational sun exposure. Among light-moderate drinkers wine preponderance is related to increased melanoma risk, another possible indicator of higher socio-economic status.  We hope that further work by others will help to sort out the alcohol/.smoking/melanoma puzzle.’”

Potential mechanisms for an association between alcohol and skin cancer. Is there residual confounding by sun exposure?  Forum member Waterhouse reflected the overall views of Forum members: “While this study no doubt shows an association between white wine consumption and cSCC, a mechanistic causal pathway is difficult to discern.  One could theorize a mechanism on the potential presence of UV-initiated DNA cross-linking substances, such as furanocoumarins.  However, such substances are not known in grapes or wine, and consuming these substances orally does not usually lead to significant levels in the skin.  (Common examples are dermal exposure to celery or limes.)   More likely, those consuming white wine in this population had a coincidental higher incidence of sun exposure or were more sensitive to UV light.”

Reviewer Thelle commented: “The causes for the increased incidence of skin cancer (in casu squamous epithelial cancer) comprise increasing age, more frequent sun-exposure and out-door activities with light clothing, solar studios, and better registration. These changes coincide with increasing alcohol consumption especially in the northern countries (Ramstedt).  Whether the observed association between alcohol and cancer represents a causal relationship cannot be determined at this stage.  It has been noted that alcohol drinkers (especially binge drinkers) have increased episodes of sunburn and a higher prevalence of skin cancer (Saladi et al), who stated: ‘We hypothesize that the combination of alcohol consumption with UV radiation can potentiate the skin carcinogenic effects through the intermediate biproducts or metabolites of alcohol, which serve as the photosensitizers, consequently enhancing the cellular damage.’  This may imply a biological interaction effect between alcohol and sun exposure, or that alcohol consumption leads to prolonged exposure time.”

Reviewer Zhang has stated: “It is easy to suggest that residual confounding may account for an association; however, if one can do a quantitative sensitivity analysis to see how likely such an effect estimate may be confounded by the residual or unknown confounders, it will be more productive and helpful for the readers. Ding & VanderWeele (2016) have recently demonstrated how to estimate residual (or unknown) confounding.  Their paper shows the magnitude of the potential confounding for various combinations of the exposure-confounder association and the confounder-outcome association.”

Zhang has applied the approach of Ding & VanderWeele to estimate the smallest true relative risk for skin cancer for varying reported levels of drinking. He noted that while the most important factor determining ultra-violet exposure is geographic (e.g., being especially high in Australia), personal risk is also affected by the prevalence of sunburn.  Using the the association between the prevalence of sunburn among moderate drinkers shown by Mukamal (2006), about 1.35 times that of abstainers, he has applied the Ding & WanderWeele formula to estimate the lower limits of the RR for alcohol consumption and cSCC.  The calculations indicate, for example, that if sun exposure increases the risk of cSCC by 1.5, the lowest “true” RR for alcohol and cSCC would be 1.18.  If the RR of sunlight exposure and risk of cancer is 3.0, then the smallest true RR of alcohol and risk of CSCC would be 1.06.  However, it is appreciated that because the authors have already included some measures of sun exposure in their multi-variable equations (and the specific changes in estimates when only these variables were added are not given in the paper), using these approaches may or may not provide very good estimates of the degree of residual confounding in the present analyses.

Other Forum members were skeptical that alcohol has much to do with the development skin cancer, considering that sun exposure is the main factor and residual confounding is a more likely cause for the reported association. Rather than suggesting, as the authors do, that “ . . . physicians may consider counseling their patients about the association between alcohol consumption and risk for cSCC,” physicians might focus more on advising patients to avoid excessive exposure to ultra-violet rays.

References from Forum Critique

Ansems TM, van der Pols JC, Hughes MC, Ibiebele T, Marks GC, Green AC. Alcohol intake and risk of skin cancer: a prospective study.  Eur J Clin Nutr 2008;62:162-170.

Benedetti A, Parent ME, Siemiatycki J. Lifetime consumption of alcoholic beverages and risk of 13 types of cancer in men: results from a case-control study in Montreal.  Cancer Detect Prev 2009;32:352-362.

Ding P, VanderWeele TJ. Sensitivity Analysis Without Assumptions.  Epidemiology 2016;27:368–377.

Freedman DM, Sigurdson A, Doody MM, Mabuchi K, Linet MS. Risk of basal cell carcinoma in relation to alcohol intake and smoking. Cancer Epidemiol Biomarkers Prev 2003;12:1540–1543.

Fung TT, Hunter DJ, Spiegelman D, Colditz GA, Rimm EB, Willett WC. Intake of alcohol and alcoholic beverages and the risk of basal cell carcinoma of the skin.  Cancer Epidemiol Biomarkers Prev 2002;11:1119-1122.

Jensen A, Birch-Johansen F, Olesen AB, Christensen J, Tjonneland A, Kjaer SK. Intake of Alcohol May Modify the Risk for Non-Melanoma Skin Cancer: Results of a Large Danish Prospective Cohort Study. J Invest Dermatol 2012;132:2718–2726.

Klatsky A, Li Y, Tran HN, Armstrong MA, Udaltsova N, Friedman GD. Alcohol drinking, smoking, and risk of melanoma.  European Journal of Cancer 2013;49:Supplement 2 (abstract no. 1409).

Klatsky AL, Li Y, Tran HN, Baer D, Udaltsova N, Armstrong, MA, Friedman GD. Alcohol intake, beverage choice and cancer: a cohort study in a large Kaiser-Permanente population. Perm J 2015;19:28-34. doi: 10.7812/TPP/14-189.

Kubo J,T Henderson MT, Desai M, Wactawski-Wende J, Stefanick ML, Tang JY. Alcohol consumption and risk of melanoma and non-melanoma skin cancer in the Women’s Health Initiative. Cancer Causes Control 2014;25:1-10.

Mukamal KJ. Alcohol consumption and self-reported sunburn: a cross-sectional, population-based survey.  J Am Acad Dermatol 2006;55:584-589.

Ramstedt M. How much alcohol do you buy? A comparison of self-reported alcohol purchases with actual sales.  Addiction 2010;105:649-654. doi: 10.1111/j.1360-0443.2009.02839.x.

Rota M, Pasquali E, Bellocco R, Bagnardi V, Scotti L, Islami F, Negri E, Boffetta P, Pelucchi C, Corrao G, La Vecchia C. Alcohol drinking and cutaneous melanoma risk: a systematic review and dose-risk meta-analysis. Br J Dermatol 2014;170:1021-1028.

Saladi RN, Nektalova T, Fox JL. Induction of skin carcinogenicity by alcohol and ultraviolet light.  Clinical and Experimental Dermatology 2009;35:7–11.

Song F, Qureshi AA, Gao X, Li T, Han J.  Smoking and risk of skin cancer: a prospective analysis and a meta-analysis. Int J Epidemiol 2012;41:1694-1705. doi: 10.1093/ije/dys146.

Tran, HN, Udaltsova N, Li Y, Klatsky AL. Invasive versus noninvasive melanoma: Are there clues about smoking and drinking relationships?  Am J  Epidemiol 2014;177: abstract 6337.

Wu S, Li WQ, Qureshi AA, Cho E. Alcohol consumption and risk of cutaneous basal cell carcinoma in women and men: 3 prospective cohort studies. Am J Clin Nutr 2015;102:1158-1166. doi: 10.3945/ajcn.115.115196.

Forum Summary

Skin cancers, whether melanoma, basal cell, or squamous cell, are all increased by ultra-violet rays of the sun, and such cancers are much more common in areas of the world with more sun exposure. Further, the risk of such cancers is higher among individuals reporting excessive tanning (either from the sun or from tanning salons).  The present study was undertaken to judge the relation between alcohol consumption and the risk of cutaneous squamous cell carcinoma (cSCC), an association that is unclear from earlier research.  Determining the relation between alcohol and skin cancer is made difficult by the fact that excessive sun exposure has been shown to be greater among consumers of alcohol than among abstainers, thus the potential for confounding.

In the present analyses, combined data from three cohorts of subjects in the US, who had repeated assessments of alcohol intake over many years, were evaluated tor the relation of alcohol to the development of verified cSCC. Subjects included women in two cohorts of the Nurses’ Health Study and men in the Health Professionals’ Follow-up Study.  Among subjects providing a total of more than 4 million person-years of follow up, 2,938 cases of cSCC were identified.

The results varied somewhat among the different cohorts, but in the meta-analysis of the three studies using continuous measures of alcohol, there was an increase in risk of cSCC with alcohol intake. Among women, there was a steep increase in risk of cancer for low levels of intake (up to 5 grams of alcohol/day, slightly less than ½ of a typical drink), then a gradual increase in risk thereafter, whereas among men there was more of a gradual increase in risk with larger reported alcohol intake.

Overall, the authors report an increase in risk per typical drink per day of 22% for invasive cSCC and 14% for in situ cSCC. In beverage-specific analyses, white wine consumption of >/= 5 times/week was associated with an increased risk of cSCC (RR 1.31, 95% confidence interval: 1.09-1.59), but an increased risk of cSCC was not seen for other alcoholic beverages.  The population-attributable risk associated with alcohol intake of ≥ 20 grams/day (about 1 ½ typical drinks) was 3% of cSCCs.

Forum members considered that the analyses were well done, and the results of the study are consistent with increases in risk associated with alcohol consumption for other types of skin cancer. Given that sun exposure is by far the primary risk factor for skin cancer, and consumers of alcohol tend to have greater number of sunburns (also shown in this study), it is always difficult to determine if residual confounding by sun exposure is playing a role.  The authors of this paper attempted to adjust for sun exposure by including in their analyses the typical exposure values in the area of the world where the subjects resided, by recording the frequency that subjects reported 5 or more severe sunburns, and several other measures.  As expected, there were reductions in the estimated RR for invasive cSCC when going from age-adjusted RR (1.34) to multivariable-adjusted estimates (1.22) of risk.  However, the magnitude of decrease in risk estimates when only those adjustments for sun-exposure were added to the equation cannot be determined from the data presented.

Forum reviewers consider that these analyses support results from many previous studies and indicate that consumers of alcohol have a greater risk than non-drinkers of all types of skin cancer. Attempts to judge how much of this association may be due to residual confounding related to sun exposure are less than conclusive.  Various hypotheses have been raised for possible interactions between sun exposure and alcohol, but currently there are no experimental data to test these theories.  While the authors conclude that “physicians may consider counseling their patients about the association between alcohol consumption and risk for cSCC,” it might be more advantageous for physicians to focus more on the much greater protection against this disease that would occur if they were able to limit their patient’s exposure to ultra-violet radiation.

Reference: Siiskonen S, Han J, Li T, Cho E, Nijsten T, Qureshi A,  Alcohol intake is associated with increased risk of squamous cell carcinoma of the skin: three US prospective cohort studies.  Nutrition and Cancer 2016;68:545-553.

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Comments on the present critique were provided by the following members of the International Scientific Forum on Alcohol Research:

R. Curtis Ellison, MD, Professor of Medicine & Public Health, Boston University School of Medicine, Boston, MA, USA

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

Ulrich Keil, MD, PhD, Professor Emeritus, Institute of Epidemiology & Social Medicine, University of Muenster, Germany

Arthur Klatsky, MD, Dept. of Cardiology, Kaiser Permanente Medical Center, Oakland, CA, USA

Dominique Lanzmann-Petithory, MD, PhD, Nutrition Geriatrics, Hôpital Emile Roux, APHP Paris, Limeil-Brévannes, France

Fulvio Mattivi, MSc, Head of the Department of Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, in San Michele all’Adige, Italy

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA; Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia, Australia

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Dag S. Thelle, MD, PhD, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Norway; Section for Epidemiology and Social Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA

Yuqing Zhang, MD, DSc, Clinical Epidemiology, Boston University School of Medicine, Boston, MA, USA