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Cigarette Smoking and the Risks of Basal Cell Carcinoma and Squamous Cell Carcinoma

Open ArchivePublished:April 14, 2017DOI:https://doi.org/10.1016/j.jid.2017.03.027
      Sunlight is the principal environmental risk factor for keratinocyte cancers, but other carcinogens have also been implicated, including tobacco smoke. Findings have been conflicting, however. We investigated associations between cigarette smoking and incidence of basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) in QSkin, a prospective study of skin cancer (N = 43,794). Smoking history was self-reported at baseline; newly diagnosed BCCs and SCCs were ascertained through data linkage and verified by histopathology reports. We restricted analyses to white participants who at baseline reported no past history of skin cancer excisions and no more than five destructively treated actinic skin lesions. We fitted Cox proportional hazards models, adjusted for known confounders. Compared with never smokers, current smokers had significantly lower risks of BCC (hazard ratio = 0.6; 95% confidence interval = 0.4–0.9) but significantly higher risks of SCC (hazard ratio = 2.3; 95% confidence interval = 1.5–3.6). Former smokers had similar risks for BCC and SCC as never smokers. Among smokers, we observed no dose-response trends with duration of smoking, intensity, or time since quitting. On further analysis, current smokers had fewer skin examinations and procedures than never smokers, suggesting greater opportunities for detection among never smokers. Strengths include large sample size, prospective design, and virtually complete follow-up; however, histologic details were missing for a proportion of excised tumors. In conclusion, current smokers had a lower incidence of BCC (possibly because of detection bias) but higher rates of SCC.

      Abbreviations:

      BCC (basal cell carcinoma), CI (confidence interval), HR (hazard ratio), KC (keratinocyte carcinoma), SCC (squamous cell carcinoma)

      Introduction

      Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively named keratinocyte carcinomas (KCs), are the most common malignancies worldwide (
      • Cakir B.O.
      • Adamson P.
      • Cingi C.
      Epidemiology and economic burden of nonmelanoma skin cancer.
      ). Although UVR exposure is established as the major causal factor for KCs, the role of smoking, which is the strongest modifiable risk factor for many human cancers (
      • El Ghissassi F.
      • Baan R.
      • Straif K.
      • Grosse Y.
      • Secretan B.
      • Bouvard V.
      • et al.
      A review of human carcinogens—part D: radiation.
      ), is not yet understood. New evidence continues to expand the list of tobacco-related cancers; however, the potential role of cigarette smoking in relation to cutaneous malignancies remains inconclusive, with previous epidemiological studies reporting both positive and negative associations.
      Two meta-analyses reported pooled estimates of the association between smoking and the risk of KCs and drew different conclusions. The first reported that ever smokers of both sexes had slightly increased risks of both BCC and SCC compared with never smokers (
      • Song F.
      • Qureshi A.A.
      • Gao X.
      • Li T.
      • Han J.
      Smoking and risk of skin cancer: a prospective analysis and a meta-analysis.
      ). The second concluded that smoking increases the risk of SCC but not BCC (
      • Leonardi-Bee J.
      • Ellison T.
      • Bath-Hextall F.
      Smoking and the risk of nonmelanoma skin cancer: systematic review and meta-analysis.
      ). More recently, the findings from a 16-year prospective study of 1,621 adults residing in Nambour, Queensland, Australia were published, reporting a nonsignificant inverse association between current smoking and BCC compared with never smokers (
      • Hughes M.C.
      • Olsen C.M.
      • Williams G.M.
      • Green A.C.
      A prospective study of cigarette smoking and basal cell carcinoma.
      ) but no association with SCC (
      • McBride P.
      • Olsen C.M.
      • Green A.C.
      Tobacco smoking and cutaneous squamous cell carcinoma: a 16-year longitudinal population-based study.
      ).
      Possible reasons for the inconsistencies between previous studies include using different approaches to analyze smoking exposure (ever vs. never, current vs. former vs. never), failure to account for various dimensions of smoking history (e.g., duration, intensity), inadequate control of potential confounding factors, and loss to follow-up in prospective studies. In addition, most studies have not explored other potential sources of bias, such as detection biases that appear to underlie BCC surveillance in high-incidence populations (
      • Valery P.C.
      • Neale R.
      • Williams G.
      • Pandeya N.
      • Siller G.
      • Green A.
      The effect of skin examination surveys on the incidence of basal cell carcinoma in a Queensland community sample: a 10-year longitudinal study.
      ).
      Given the uncertainty of these associations, we sought to investigate the relationship between cigarette smoking and risk of BCC and SCC using data from a large, population-based cohort study that captured detailed information at baseline on phenotype, sun exposure, and medical history, in addition to other items necessary to explore potential detection biases.

      Results

      Baseline demographic characteristics of the study cohort according to smoking status are presented in Table 1. Overall, 10% and 35% of the study cohort were current and ex-smokers, respectively; data for smoking status were missing for 61 people. Current smokers were younger (mean age = 53 years vs. 54 years, respectively), more likely to be men (46% vs. 37%, respectively), less likely to have private health insurance (39% vs. 73%, respectively) and less likely to hold a university degree (13% vs. 33%, respectively) than never smokers. Current smokers were also less likely than never smokers to report having undergone destructive treatments for actinic skin lesions or skin cancers (P < 0.001) and were less likely to have had their skin checked by a doctor before baseline.
      Table 1Baseline characteristics of 18,828 QSkin study participants, overall and stratified by smoking status
      Numbers may not sum to total because of missing data.
      ParameterSmoking StatusChi-Square

      P-Value
      Total (N = 18,828)Never (n = 10,222)Former (n = 6,675)Current (n = 1,870)
      n (%)n (%)n (%)n (%)
      Age in years at entry (mean, SD)54.2 (8.2)53.8 (8.2)55.3 (8.2)52.8 (7.6)<0.001
      P-value for significant difference using Ryan-Einot-Gabriel-Welsch multiple range test.
      Age group in years
       40–496,535 (34.7)3,771 (36.9)1,965 (29.5)772 (41.3)<0.001
       40–597,134 (37.9)3,797 (37.2)2,574 (38.6)733 (39.2)
       60–695,159 (27.4)2,654 (25.9)2,126 (31.9)365 (19.5)
      Sex
       Female10,983 (58.3)6,472 (63.3)3,472 (52.1)1,007 (53.6)<0.001
       Male7,845 (41.7)3,750 (36.7)3,193 (47.9)873 (46.4)
      Further education
       No school certificate1,315 (7.5)524 (5.4)542 (8.8)244 (14.5)<0.001
       School certificate2,607 (14.8)1,351 (13.9)949 (15.4)298 (17.6)
       Higher school3,470 (19.7)1,872 (19.3)1,197 (19.4)386 (22.9)
       Trade/certificate/diploma5,434 (30.8)2,743 (28.2)2,133 (34.5)541 (32.0)
       University degree4,808 (27.3)3,224 (33.2)1,359 (22.9)219 (12.9)
      Private health insurance
       No6,442 (34.3)2,798 (27.5)2,474 (37.3)1,141 (60.9)<0.001
       Yes12,324 (65.7)7,393 (72.5)4,168 (62.7)732 (39.1)
      Skin color
       Fair9,981 (53.3)5,584 (54.9)3,445 (51.9)923 (49.4)<0.001
       Medium7,054 (37.7)3,746 (36.9)2,569 (38.7)715 (38.3)
       Olive/dark1,688 (9.0)833 (8.2)619 (9.3)229 (12.3)
      Eye color
       Blue/grey6,886 (37.0)3,720 (36.8)2,445 (37.2)695 (37.4)0.68
       Green/hazel7,137 (38.4)3,932 (38.9)2,480 (37.8)706 (38.0)
       Brown/black4,573 (24.6)2,460 (24.3)1,642 (24.98)457 (24.6)
      Hair color
       Dark brown/black8,372 (44.70)4,603 (45.3)2,952 (44.5)789 (42.2)0.01
       Light brown7,106 (37.9)3,833 (37.7)2,545 (38.4)704 (37.7)
       Blonde2,602 (13.9)1,366 (13.4)924 (13.9)304 (16.3)
       Red/auburn658 (3.5)371 (3.6)214 (3.2)73 (3.9)
      Burning tendency
       No burns2,066 (11.0)967 (9.5)777 (11.7)313 (16.7)<0.001
       Burns a little8,874 (47.4)4,704 (46.2)3,228 (48.7)908 (48.5)
       Burns moderately5,853 (31.2)3,338 (32.8)2,002 (30.2)500 (26.7)
       Burns badly1,947 (10.4)1,171 (11.5)621 (9.4)150 (8.0)
      Tanning tendency
       No tan702 (3.8)420 (4.1)210 (3.2)70 (3.8)<0.001
       Tan lightly3,205 (17.1)1,963 (19.3)937 (14.1)300 (16.1)
       Tan moderately9,755 (52.1)5,379 (52.9)3,477 (52.5)870 (46.6)
       Tan deeply5,066 (27.0)2,411 (23.7)2,005 (30.3)626 (33.6)
      Freckles at age 21 years (face)
       None9,981 (53.2)5,169 (50.8)3,732 (56.2)1,041 (55.6)<0.001
       A few5,726 (30.5)3,274 (32.2)1,889 (28.4)544 (29.0)
       Some2,320 (12.4)1,325 (13.0)786 (11.7)217 (11.6)
       Many720 (3.8)404 (4.0)244 (3.7)71 (3.8)
      Sunburns as a child
       Never4,178 (24.3)2,311 (24.7)1,427 (23.7)428 (24.8)<0.001
       1–58,086 (47.1)4,469 (47.7)2,809 (46.6)785 (45.6)
       6–102,761 (16.1)1,517 (16.2)982 (16.3)254 (14.7)
       11+2,155 (12.5)1,073 (11.5)815 (13.5)256 (14.9)
      AKs/skin cancers destructively treated before baseline
       None13,322 (62.7)7,065 (61.0)4,718 (62.3)1,501 (74.2)<0.001
       1-55,506 (25.9)3,157 (27.3)1,947 (25.7)379 (18.7)
       6 +2,413 (11.4)13,59 (11.7)906 (12.0)144 (7.1)
      Abbreviations: AK, actinic keratoses; SD, standard deviation.
      1 Numbers may not sum to total because of missing data.
      2 P-value for significant difference using Ryan-Einot-Gabriel-Welsch multiple range test.
      During a median follow-up period of 3.0 years, 640 participants developed at least one histologically confirmed BCC, and 193 developed at least one histologically confirmed invasive SCC. In addition, there were 316 participants with a Medicare claim for at least one KC event for whom no confirmatory histopathological reports were obtained. BCCs occurred mainly on the head/neck (48%), with 35% occurring on the trunk and 17% on the limbs, whereas most SCCs occurred on the limbs (47%) and head/neck (42%), with 11% on the trunk. Compared with never smokers, current smokers at baseline had significantly lower risks of developing BCC (hazard ratio [HR] = 0.64, 95% confidence interval [CI] = 0.44–0.93); ex-smoking was not significantly associated (Table 2). We observed no significant linear trend in risk of BCC with increasing smoking intensity or duration (P trend = 0.06 and 0.11, respectively) among smokers. Because individuals with a past history of actinic skin damage have markedly higher risks of subsequent KC (
      • Whiteman D.C.
      • Thompson B.S.
      • Thrift A.P.
      • Hughes M.C.
      • Muranushi C.
      • Neale R.E.
      • et al.
      A model to predict the risk of keratinocyte carcinomas.
      ), which may modify any association between smoking and KC risk, we also performed analyses stratified by past history of treatment for actinic skin lesions (no lesions, n = 13,322 vs. one to five lesions, n = 5,506). Among those with no past history of destructive treatments for skin lesions, current smoking had a nonsignificant but inverse association with BCC compared with never smoking (HR = 0.85; 95% CI = 0.54–1.33). Among those with one to five skin lesions, however, the risks of BCC were significantly lower among current smokers compared with never smokers (HR = 0.43, 95% CI = 0.21–0.88). The interaction between smoking status and history of destructive treatments for skin lesions did not reach statistical significance, however.
      Table 2The association between different dimensions of smoking and basal cell carcinoma, stratified by self-reported history of destructive treatments for skin lesions before baseline
      Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure. Never smoker was the reference category for all analyses. P-trend values do not include reference group (P-value for the exact Cochran-Armitage trend test).
      ParameterTotal (N = 18,828)No Destructive Treatments for Skin Lesions Before Baseline (n = 13,322)One to Five Destructive Treatments for Skin Lesions Before Baseline (n = 5,506)
      Case/Person-YearsHR (95% CI)Cases/Person-YearsHR (95% CI)Cases/Person-YearsHR (95% CI)
      Smoking status
      One person with basal cell carcinoma had missing smoking status.
       Never smoker384/30,1991.00187/21,0031.00197/9,1961.00
       Ever smoker255/25,2590.81 (0.68–0.97)142/18,4470.87 (0.68–1.12)113/6,8130.79 (0.61–1.03)
      Ex-smoker217/19,6840.85 (0.71–1.03)112/14,0050.88 (0.68–1.14)105/5,6800.86 (0.66–1.12)
      Current smoker38/5,5750.64 (0.44–0.93)30/4,4420.85 (0.54–1.33)8/1,1330.43 (0.21–0.88)
      P-value<0.001<0.0010.075
      Age in years when started smoking
       Never384/30,1991.00187/21,0031.00197/9,1961.00
       <1529/3,3030.85 (0.56–1.26)15/2,5280.81 (0.46–1.41)14/7750.97 (0.54–1.76)
       15–1671/7,4570.78 (0.58–1.03)37/5,4620.79 (0.53–1.17)34/1,9940.79 (0.53–1.21)
       >16151/14,2680.83 (0.68–1.03)87/10,2690.93 (0.70–1.24)64/3,9990.77 (0.56–1.05)
      P-trend0.9420.5030.449
      Duration of smoking in years
       Never384/30,1991.00187/21,0031.00197/9,1961.00
       ≤1070/5,4411.05 (0.79–1.38)34/3,6271.09 (0.73–1.62)36/1,8140.97 (0.66–1.43)
       11–2049/6,0630.66 (0.47–0.91)23/4,3770.59 (0.37–0.95)26/1,6860.75 (0.48–1.18)
       21–3066/5,9460.90 (0.67–1.22)36/4,5560.97 (0.65–1.44)30/1,3890.92 (0.58–1.45)
       >3066/7,5140.71 (0.53–0.96)46/5,6500.90 (0.62–1.31)20/1,8640.54 (0.33–0.91)
      P-trend0.1150.9760.064
      Intensity of smoking (cigarettes/day)
       Never384/30,1991.00187/21,0031.00197/91961.00
       ≤1090/7,9030.98 (0.76–1.25)45/5,6611.01 (0.71–1.43)45/22420.99 (0.69–1.41)
       11–2098/10,1170.76 (0.59–0.98)59/7,4110.86 (0.61–1.20)39/2,7060.70 (0.47–1.02)
       21–3045/4,6100.75 (0.52–1.06)21/3,3860.66 (0.39–1.10)24/1,2280.88 (0.54–1.43)
       >3019/2,0980.59 (0.34–1.04)15/1,6290.93 (0.51–1.70)4/4700.13 (0.01–0.97)
      P-trend0.0640.5050.972
      Pack-years of smoking
       Never384/30,1991.00187/21,0031.00197/9,1961.00
       ≤1090/8,0590.93 (0.72–1.19)43/5,6190.93 (0.64–1.32)47/2,4400.93 (0.65–1.32)
       11–2061/5,6190.92 (0.69–1.24)29/4,0690.89 (0.58–1.35)32/1,5500.99 (0.66–1.49)
       21–3033/4,1170.66 (0.44–0.98)22/3,1040.81 (0.49–1.34)11/1,0140.53 (0.27–1.04)
       >3064/6,6920.70 (0.51–0.96)43/5,1030.87 (0.58–1.28)21/1,5890.56 (0.33–0.97)
      P-trend0.0750.7650.985
      Years since quitting (past smokers)
       Never384/30,1991.00187/21,0031.00197/9,1961.00
       ≤1047/5,2970.82 (0.59–1.14)26/4,0810.80 (0.51–1.26)21/1,2150.95 (0.58–1.53)
       11–2056/5,3870.83 (0.61–1.14)33/3,9461.01 (0.68–1.52)23/1,4410.66 (0.39–1.10)
       21–3065/5,5460.88 (0.66–1.19)27/3,8560.74 (0.47–1.17)38/1,6901.04 (0.70–1.54)
       >3048/3,3550.86 (0.61–1.23)25/2,0390.98 (0.60–1.61)23/1,3160.76 (0.46–1.25)
      P-trend0.5460.7090.958
      Abbreviations: CI, confidence interval; HR, hazard ratio.
      1 Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure. Never smoker was the reference category for all analyses. P-trend values do not include reference group (P-value for the exact Cochran-Armitage trend test).
      2 One person with basal cell carcinoma had missing smoking status.
      We conducted further stratified analyses to evaluate other potential instances of effect modification (Figures 1 and 2). We found that the association between current smoking and BCC differed by body site, with lower risks observed for BCC occurring on the trunk and limbs compared with the head/neck (Figure 1). Stratification by self-reported history of skin checks by a doctor in the past 3 years showed a significant inverse association between current smoking and BCC in people who reported one or more skin checks but a null association in people who reported never having their skin checked (Table 3 and Figure 1). None of the interactions described above (i.e., by body site of BCC or history of skin checks by a doctor) reached statistical significance, however. We found no differences in risk of BCC by sex, age, skin color, tanning tendency, freckles at age 21 years, or having a skin biopsy during follow-up.
      Figure 1
      Figure 1Results of stratified analyses on the association between current smoking at baseline and risk of basal cell carcinoma. The square represents the HR of the association between current smoking and risk of basal cell carcinoma, and the lines represent the 95% confidence intervals of the association. CI, confidence interval; HR, hazard ratio.
      Figure 2
      Figure 2Results of stratified analyses on the association between current smoking at baseline and risk of squamous cell carcinoma. The square represents the HR of the association between current smoking and risk of basal cell carcinoma, and the lines represent the 95% confidence intervals of the association. The upper range of the confidence interval for some strata was too large and was truncated while trying to keep the same scale. CI, confidence interval; HR, hazard ratio.
      Table 3Smoking status and risk of basal cell carcinoma and squamous cell carcinoma, stratified by self-reported history of skin checks by a doctor (yes/no) in the past 3 years
      Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure.
      ParameterSkin Never Checked by a DoctorSkin Ever Checked by a Doctor
      BCCSCCBCCSCC
      CasesHR (95% CI)CasesHR (95% CI)CasesHR (95% CI)CasesHR (95% CI)
      Smoking status among people with fewer than five destructive treatments for skin lesions before baseline
       Never smoker1011.00271.002831.00591.00
       Former smoker640.83 (0.58–1.18)271.05 (0.55–1.83)1530.88 (0.71–1.10)461.07 (0.70–1.64)
       Current smoker190.99 (0.57–1.72)162.77 (1.37–5.68)190.49 (0.29–0.84)182.08 (1.14–3.79)
      Smoking status among people with no history of destructive treatments for skin lesions before baseline
       Never smoker611.00191.001261.00261.00
       Former smoker460.97 (0.63–1.50)170.82 (0.39–1.74)660.83 (0.59–1.26)251.33 (0.71–2.47)
       Current smoker161.16 (0.62–2.20)132.61 (1.15–5.91)140.66 (0.34–1.27)112.24 (0.95–5.28)
      Abbreviations: BCC, basal cell carcinoma; CI, confidence interval; HR, hazard ratio; SCC, squamous cell carcinoma.
      1 Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure.
      We found that current smokers at baseline had significantly higher SCC incidence compared with never smokers (HR = 2.30, 95% CI = 1.46–3.62) (Table 4), and the risks remained significantly elevated after adjusting for the independent effects of duration and intensity (see Supplementary Table S1 online). Unlike BCC, the risks of SCC associated with smoking varied only modestly according to self-reported history of destructive treatments for skin lesions. The association between current smoking and SCC varied slightly according to self-reported history of skin checks, and consistent with the pattern seen for BCC, risk of SCC was lower among people with a history of skin checks (Table 3 and Figure 2). Stratified analyses by body site showed a significantly increased risk of SCC on the limbs but not on the trunk or head/neck among current smokers (Figure 2). Again, the interaction terms did not reach statistical significance. Sensitivity analyses including intraepithelial carcinoma/keratoacanthoma as SCC cases did not result in any material difference to the associations we observed between smoking status and SCC (see Supplementary Table S2 online).
      Table 4The association between different dimensions of smoking and squamous cell carcinoma, stratified by self-reported history of destructive treatments for skin lesions at baseline
      Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, cumulative sun exposure. Never smoker was the reference category for all analyses. P-trend values do not include reference group (P-value for the exact Cochran-Armitage trend test).
      ParameterTotal (N = 18,828)No Destructive Treatments for Skin Lesions Before Baseline (n = 13,322)One to Five Destructive Treatments for Skin Lesions Before Baseline (n = 5,506)
      Cases/Person-YearsHR (95% CI)Cases/Person-YearsHR (95% CI)Cases/Person-YearsHR (95% CI)
      Smoking status
       Never smoker86/30,6541.0045/21,2241.0041/9,4301.00
       Ever smoker107/25,4801.26 (0.92–1.73)66/18,5421.36 (0.88–2.09)41/6,9381.20 (0.75–1.92)
      Ex-smoker73/19,8891.05 (0.74–1.48)42/14,0861.10 (0.68–1.77)31/5,8031.03 (0.62–1.71)
      Current smoker34/5,5912.30 (1.46–3.62)24/4,4562.49 (1.38–4.47)10/1,1352.21 (1.07–4.56)
      P-value<0.001<0.0010.001
      Age in years when started smoking
       Never86/30,6541.0045/21,2241.0041/9,4301.00
       <1512/3,3220.98 (0.48–1.98)5/2,5380.55 (0.16–1.80)7/7841.70 (0.69–4.10)
       15–1636/7,5051.42 (0.92–2.18)23/5,4711.70 (0.96–3.00)13/2,0331.17 (0.59–2.32)
       >1659/14,4161.26 (0.87–1.18)38/10,3401.41 (0.86–2.30)21/4,0761.14 (0.66–1.97)
      P-trend0.6640.2400.438
      Duration of smoking in years
       Never86/30,6541.0045/21,2241.0041/9,4301.00
       ≤1016/5,5181.12 (0.64–1.95)8/3,6591.25 (0.58–2.70)8/1,8580.96 (0.42–2.16)
       11–2017/6,1090.87 (0.49–1.56)10/4,3940.94 (0.43–2.02)7/1,7150.79 (0.33–1.90)
       21–3023/6,0151.24 (0.74–2.09)15/4,5851.37 (0.69–2.71)8/1,4301.18 (0.51–2.67)
       >3050/7,5381.60 (1.07–2.40)33/5,6621.74 (1.01–2.98)17/1,8761.61 (0.88–2.97)
      P-trend0.1170.2390.219
      Intensity of smoking in cigarettes/day
       Never86/30,6541.0045/21,2241.0041/9,4301.00
       ≤1032/7,9821.51 (0.98–2.32)20/5,6881.73 (0.97–3.09)12/2,2941.32 (0.69–2.54)
       11–2035/10,2121.04 (0.67–1.60)19/7,4671.04 (0.57–1.89)16/2,7451.08 (0.58–2.04)
       21–3019/4,6571.03 (0.57–1.84)14/3,3911.22 (0.58–2.56)5/1,2650.82 (0.32–2.13)
       >3016/2,1031.32 (0.67–2.61)10/1,6361.25 (0.51–3.04)6/4671.76 (0.61–5.07)
      P-trend0.5460.8970.897
      Pack-years of smoking
       Never86/30,6541.0045/21,2241.0041/9,4301.00
       ≤1025/8,1501.15 (0.71–1.85)14/5,6541.26 (0.65–2.42)11/2,4961.03 (0.51–2.08)
       11–2021/5,6791.32 (0.80–2.18)15/4,0871.81 (0.97–3.35)6/1,5920.82 (0.34–1.95)
       21–3014/4,1491.04 (0.55–1.97)8/3,1241.06 (0.44–2.53)6/1,0251.12 (0.43–2.87)
       >3041/6,7311.24 (0.79–1.94)26/5,1231.16 (0.62–2.15)15/1,6091.51 (0.78–2.93)
      P-trend0.9530.5050.367
      Years since quitting, ex-smokers
       Never86/30,6541.0045/21,2241.0041/9,4301.00
       ≤1016/5,3371.08 (0.59–1.96)11/4,0951.19 (0.54–2.58)5/1,2421.09 (0.42–2.81)
       11-2012/5,4550.62 (0.31–1.25)6/3,9830.50 (0.17–1.41)6/1,4720.79 (0.31–2.05)
       21-3026/5,6151.34 (0.83–2.17)15/3,8761.35 (0.70–2.62)11/1,7401.33 (0.65–2.69)
       >3018/3,3820.96 (0.54–1.70)10/2,0481.16 (0.54–2.46)8/1,3330.77 (0.32–1.86)
      P-trend0.6640.5970.975
      Abbreviations: CI, confidence interval; HR, hazard ratio.
      1 Models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, cumulative sun exposure. Never smoker was the reference category for all analyses. P-trend values do not include reference group (P-value for the exact Cochran-Armitage trend test).
      We found no evidence of dose-response effects for any of the continuous measures of smoking with respect to BCC or SCC once the qualitative effect of smoking was incorporated in the model (see Supplementary Table S1). Furthermore, using nonlinear terms of smoking measures did not improve the model fit (data not shown).
      Finally, we conducted sensitivity analyses to test the possible effects of missing pathology data on the association between smoking and risks of BCC and SCC. The directions of association were unchanged, although the magnitude varied depending on whether we assigned all participants with missing pathology data as BCC cases (adjusted HR, current vs. never smoker = 0.84; 95% CI = 0.63–1.11) or non-cases (adjusted HR, current vs. never smoker = 0.64; 95% CI = 0.44–0.93), or else randomly assigned 75% of all participants missing pathology data as BCC cases (adjusted HR, current vs. never smoker = 0.81; 95% CI = 0.61–1.08) (see Supplementary Table S3 online). We performed similar sensitivity analysis for SCC; the positive associations between current smoking and SCC remained significant under each scenario (see Supplementary Table S3).

      Discussion

      We have prospectively investigated the association between smoking and the risk of developing a first BCC or SCC in a large population-based cohort while taking account of the potential confounding influence of demographic and phenotypic characteristics and sun exposure history. Overall, we found that current smokers with no prior history of any excisions for skin cancer were significantly less likely than never smokers to be diagnosed with a new BCC during follow-up but were significantly more likely to be diagnosed with a new SCC. We found no significant associations between former smoking and BCC or SCC. Unlike other cancers, for which clear dose-response relationships with increasing duration and intensity of smoking exposure have been observed (
      • van Osch F.H.
      • Jochems S.H.
      • van Schooten F.J.
      • Bryan R.T.
      • Zeegers M.P.
      Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies.
      ), we saw no trends with duration of smoking, intensity, or time since quitting in our cohort.
      Our findings of lower risk of BCC among current smokers are similar to those of previous cohort studies that reported null or inverse associations (
      • Freedman D.M.
      • Sigurdson A.
      • Doody M.M.
      • Mabuchi K.
      • Linet M.S.
      Risk of basal cell carcinoma in relation to alcohol intake and smoking.
      ,
      • Hughes M.C.
      • Olsen C.M.
      • Williams G.M.
      • Green A.C.
      A prospective study of cigarette smoking and basal cell carcinoma.
      ,
      • Song F.
      • Qureshi A.A.
      • Gao X.
      • Li T.
      • Han J.
      Smoking and risk of skin cancer: a prospective analysis and a meta-analysis.
      ). Case-control studies have been heterogeneous and reported both positive and negative associations (
      • Boyd A.S.
      • Shyr Y.
      • King Jr., L.E.
      Basal cell carcinoma in young women: an evaluation of the association of tanning bed use and smoking.
      ,
      • De Hertog S.A.
      • Wensveen C.A.
      • Bastiaens M.T.
      • Kielich C.J.
      • Berkhout M.J.
      • Westendorp R.G.
      • et al.
      Relation between smoking and skin cancer.
      ,
      • Marehbian J.
      • Colt J.S.
      • Baris D.
      • Stewart P.
      • Stukel T.A.
      • Spencer S.K.
      • et al.
      Occupation and keratinocyte cancer risk: a population-based case-control study.
      ,
      • Rollison D.E.
      • Iannacone M.R.
      • Messina J.L.
      • Glass L.F.
      • Giuliano A.R.
      • Roetzheim R.G.
      • et al.
      Case-control study of smoking and non-melanoma skin cancer.
      ). It is unlikely that the associations reported here are due to confounding, because we controlled for sun exposure and phenotypic and other skin cancer risk factors, although some analyses suggested differences according to health-promoting behaviors. When we stratified by recent history of skin checks, we saw no effect of current smoking on BCC risk among those who never had their skin checked, but we saw a significantly protective effect of current smoking among those who had undergone a skin check. Our assessment is that the inverse association between current smoking and BCC is likely explained, at least in part, by detection bias, in which never smokers who undergo regular skin checks are more likely to be diagnosed with indolent BCCs than current smokers. This fits with the baseline data presented in Table 1. Never smokers were more highly educated, more likely to have private health insurance, and more likely to have skin checks than current smokers; thus they were more likely to have health-promoting behaviors. This is consistent with previous research, which has shown that incidence of BCC varies according to the methods of surveillance (
      • Valery P.C.
      • Neale R.
      • Williams G.
      • Pandeya N.
      • Siller G.
      • Green A.
      The effect of skin examination surveys on the incidence of basal cell carcinoma in a Queensland community sample: a 10-year longitudinal study.
      ).
      In our cohort we found a strongly positive significant association between current smoking and SCC, consistent with earlier reports from the female Nurses’ Health Study (
      • Song F.
      • Qureshi A.A.
      • Gao X.
      • Li T.
      • Han J.
      Smoking and risk of skin cancer: a prospective analysis and a meta-analysis.
      ), male Health Professional Follow-Up Study (
      • Song F.
      • Qureshi A.A.
      • Gao X.
      • Li T.
      • Han J.
      Smoking and risk of skin cancer: a prospective analysis and a meta-analysis.
      ), and others (
      • De Hertog S.A.
      • Wensveen C.A.
      • Bastiaens M.T.
      • Kielich C.J.
      • Berkhout M.J.
      • Westendorp R.G.
      • et al.
      Relation between smoking and skin cancer.
      ,
      • Grodstein F.
      • Speizer F.E.
      • Hunter D.J.
      A prospective study of incident squamous cell carcinoma of the skin in the nurses' health study.
      ). The Nambour cohort in Queensland (
      • McBride P.
      • Olsen C.M.
      • Green A.C.
      Tobacco smoking and cutaneous squamous cell carcinoma: a 16-year longitudinal population-based study.
      ) and the Swedish Construction Workers cohort (
      • Odenbro A.
      • Bellocco R.
      • Boffetta P.
      • Lindelof B.
      • Adami J.
      Tobacco smoking, snuff dipping and the risk of cutaneous squamous cell carcinoma: a nationwide cohort study in Sweden.
      ) reported nonsignificant increased associations between smoking and SCC. The association may not have reached significance in the Nambour study because of the relatively small sample size, and the Swedish Construction Workers study did not control for potential confounding effects of sun exposure and phenotypic factors. Other possible sources of inconsistency across studies include using different approaches to define smoking status and failing to account for potential sources of bias (particularly detection bias). In addition, most previous studies did not analyze different dimensions of smoking, nor did they adjust for skin cancer risk factors at baseline.
      We found little evidence of confounding, because the risk estimates remained stable after adjustment and stratification. Moreover, the observed association between smoking and SCC is not likely due to information bias, because follow-up was high and our sensitivity analyses, in which we variously included participants with missing pathology data as cases or non-cases, resulted in similar risk estimates. We cannot, however, exclude the possibility of detection bias, which may have resulted in an underestimate of the effect. The risks of SCC associated with smoking were modestly lower among those who had ever had their skin checked by a doctor (HR = 2.08) than among those with no prior history of skin checks (HR = 2.77). The difference between these estimates was not statistically significant, however. Thus, although there may be some detection effect for SCC, the magnitude appears less than that observed for BCC. This accords with the known differences between BCC and SCC detection, because it has been shown previously that incidence of BCC (but not SCC) varies according to the methods of surveillance (
      • Valery P.C.
      • Neale R.
      • Williams G.
      • Pandeya N.
      • Siller G.
      • Green A.
      The effect of skin examination surveys on the incidence of basal cell carcinoma in a Queensland community sample: a 10-year longitudinal study.
      ).
      There are several possible biological mechanisms for how smoking may induce cutaneous malignancies, although none explains why the effect would be restricted to current smokers or be specific for SCC but not BCC. Although the toxic constituents of tobacco products have been reported to down-regulate gene expression of the Notch pathway (an important gene inhibiting the growth of KCs) (
      • Nicolas M.
      • Wolfer A.
      • Raj K.
      • Kummer J.A.
      • Mill P.
      • van Noort M.
      • et al.
      Notch1 functions as a tumor suppressor in mouse skin.
      ,
      • Panelos J.
      • Massi D.
      Emerging role of Notch signaling in epidermal differentiation and skin cancer.
      ), why this would differentially influence SCC and BCC development is unclear. Nicotine, the main constituent of cigarette smoke, acts systemically to suppress the immune system (
      • Sopori M.
      Effects of cigarette smoke on the immune system.
      ), which might conceivably be associated more strongly with SCC than BCC. These mechanistic explanations remain entirely speculative, however.
      A limitation of our study is reliance on self-reported exposure information and smoking history, which is potentially subject to misclassification. Arguing against this is our previous demonstration of a very high degree of repeatability for smoking measures in this cohort (
      • Morze C.J.
      • Olsen C.M.
      • Perry S.L.
      • Jackman L.M.
      • Ranieri B.A.
      • O'Brien S.M.
      • et al.
      Good test-retest reproducibility for an instrument to capture self-reported melanoma risk factors.
      ). A further limitation was the reasonably high level of missing pathology data among participants who were known to have undergone treatment for a KC. We addressed this in a series of sensitivity analyses in which participants with missing pathology data were randomly assigned various states. In none of these sensitivity analyses were our conclusions markedly altered.
      Our study has several strengths. The large sample size allowed us to restrict our analyses to participants with no prior history of treatment for any skin lesion. We captured comprehensive data at baseline on key phenotypic and exposure variables for skin cancer, which permitted careful control of confounders and reduced potential recall bias. Further strengths were the complete follow-up of skin cancer events in the cohort through data linkage and pathologic testing confirmation for most diagnoses. We were also able to conduct stratified analyses, including for health-promoting behaviors reported previously to be associated with smoking status (
      • Wheless L.
      • Ruczinski I.
      • Alani R.M.
      • Clipp S.
      • Hoffman-Bolton J.
      • Jorgensen T.J.
      • et al.
      The association between skin characteristics and skin cancer prevention behaviors.
      ). Finally, our analyses enabled the assessment of associations with a range of smoking dimensions measures independent of the effects of ever smoking.
      In conclusion, our data accord with the emerging consensus that BCC and SCC have very different associations with smoking. We found that current smoking is associated with lower risk of BCC, possibly as a result of detection bias due to lower rates of screening among smokers, although a lower risk of BCC in smokers cannot be ruled out. Because our findings for BCC may be influenced by screening practices that are specific to Queensland, our findings may not be generalizable to other populations. The significantly increased risk of SCC among current smokers we report may be causal, because the association is consistent with evidence from other cohort studies, and we have demonstrated temporality and specificity. However, because of the lack of association among ex-smokers, the lack of a dose-response relationship with intensity and duration of smoking, and no compelling biologic mechanism, we urge cautious interpretation of our findings.

      Methods

      Study population

      The QSkin Sun and Health Study (QSkin) comprises a cohort of 43,794 men and women aged 40 to 69 years sampled randomly from the Queensland population in 2011. Detailed information of participant recruitment has been described elsewhere (
      • Olsen C.M.
      • Green A.C.
      • Neale R.E.
      • Webb P.M.
      • Cicero R.A.
      • Jackman L.M.
      • et al.
      Cohort profile: the QSkin Sun and Health Study.
      ).
      This study was approved by the Human Research Ethics Committee of the QIMR Berghofer Medical Research Institute. Each participant provided written informed consent to take part in the study.

      Exposure assessment

      At baseline participants completed a questionnaire about demographic items, general medical history, pigmentary characteristics, history of sun exposure, sun protection behaviors, and history of skin cancer. Participants were asked, About how many separate skin cancers (but not moles or warts) have you ever had cut off your skin? and separately, About how many sunspots or skin cancers have you ever had frozen or burnt off your skin? They were also asked to report the number of times they had their skin deliberately checked by a doctor during the past 3 years. Items relating to phenotype had moderate to very high repeatability (kappa coefficients = 0.51–0.87); agreement was also very high for the questions on past surgical and nonsurgical treatments of skin cancer (weighted kappa = 0.79 and 0.83, respectively) (
      • Morze C.J.
      • Olsen C.M.
      • Perry S.L.
      • Jackman L.M.
      • Ranieri B.A.
      • O'Brien S.M.
      • et al.
      Good test-retest reproducibility for an instrument to capture self-reported melanoma risk factors.
      ). With respect to smoking, participants were asked whether they had ever smoked tobacco daily for at least 6 months. Ever smokers were then asked questions about the average number of cigarettes smoked per day while smoking, their age at initiation, and the total number of years during which they had smoked. Former smokers were asked the age at which they had stopped smoking. Repeatability for smoking status (current, former, and never smoker) was almost perfect (weighted kappa = 0.97, 95% CI = 0.92–1.00), as were other smoking parameters (
      • Morze C.J.
      • Olsen C.M.
      • Perry S.L.
      • Jackman L.M.
      • Ranieri B.A.
      • O'Brien S.M.
      • et al.
      Good test-retest reproducibility for an instrument to capture self-reported melanoma risk factors.
      ).

      Follow-up

      Participants were followed up for the first occurrence of histologically confirmed invasive SCC or BCC through record linkage to health databases. We first linked the dataset to the Australian national health insurance scheme (Medicare) to identify participants who had received treatment for skin cancer, including biopsies and excisions. We then linked this list of treated participants to data held by the pathology laboratories servicing the Queensland population to obtain detailed histology reports for the skin lesions so identified. All pathology reports were reviewed and coded by qualified investigators.
      BCC and SCC endpoints were recorded from the date of consent through to June 30, 2014. We excluded lip SCCs from our analyses (n = 51), because these lesions have a different etiology that cutaneous SCCs (
      • Perea-Milla Lopez E.
      • Minarro-Del Moral R.M.
      • Martinez-Garcia C.
      • Zanetti R.
      • Rosso S.
      • Serrano S.
      • et al.
      Lifestyles, environmental and phenotypic factors associated with lip cancer: a case-control study in southern Spain.
      ). People with common low-grade lesions such as keratoacanthoma, intraepidermal carcinoma, Bowen’s disease, which individually have a very small risk of progressing to SCC (
      • Weedon D.D.
      • Malo J.
      • Brooks D.
      • Williamson R.
      Squamous cell carcinoma arising in keratoacanthoma: a neglected phenomenon in the elderly.
      ,
      • Zalaudek I.
      • Giacomel J.
      • Schmid K.
      • Bondino S.
      • Rosendahl C.
      • Cavicchini S.
      • et al.
      Dermatoscopy of facial actinic keratosis, intraepidermal carcinoma, and invasive squamous cell carcinoma: a progression model.
      ), were included in the non-case group in our primary analyses; however, we also included them in the SCC case group in sensitivity analyses. We obtained mortality data for the cohort through linkage with the National Death Index that records the date and cause of all deaths occurring in Australia.

      Statistical analysis

      The aims of the analyses were to quantify the association between smoking and risk of first incident BCC or SCC. We restricted our analysis to white participants who met the following inclusion criteria: (i) no reported past history of excisions for skin cancer, (ii) no more than five sunspots or skin cancers (hereafter referred to as actinic skin lesions) treated by freezing or burning reported, and (iii) no record of melanoma in the Queensland Cancer Registry at time of recruitment. The final sample for analysis numbered 18,828 participants (see Supplementary Figure S1 online).
      We used Cox proportional hazards regression analysis to examine the association between various measures of smoking and risk of first BCC or first invasive SCC. We calculated each person’s follow-up duration as the time from the date of consent up until either the date of first histologically confirmed BCC or invasive SCC, or the date of death, or the end of follow-up (June 30, 2014), whichever occurred first. In our primary analysis, we excluded those participants who had a Medicare claim for at least one KC event but for whom no confirmatory histopathological reports were obtained (termed missing pathology cases). We performed three sets of sensitivity analyses by firstly assigning those with missing pathology data as non-cases, secondly assigning them as cases, and finally by randomly assigning 75% of participants with missing pathology data as BCC cases and 25% as SCC cases (based on the BCC-to-SCC ratio of 3:1 observed in our data).
      We modeled BCC and SCC separately. We first analyzed the association between smoking status (never, ex-, and current smoker) and risk of incident BCC or incident SCC. Potential confounders included self-reported factors from the baseline questionnaire and other factors identified through record linkage to health databases. Using the DAGitty program (
      • Textor J.
      • Hardt J.
      • Knuppel S.
      DAGitty: a graphical tool for analyzing causal diagrams.
      ), we constructed directed acyclic graphs to identify a minimum sufficient adjustment set of confounding factors to estimate the total effect of smoking on BCC or SCC. Our final models were adjusted for age, sex, private health insurance, education status, natural skin color, tanning ability, number of freckles, history of sunburn as a child, and cumulative sun exposure.
      Because smoking is a multidimensional exposure, statistical models that examine only the association between smoking status and health outcome, and that fail to consider important contributors to total smoking exposure, have been deemed inefficient (
      • Thomas D.C.
      Models for exposure-time-response relationships with applications to cancer epidemiology.
      ). Therefore, we also investigated possible effects of smoking duration and intensity and time since quitting. We first used a standard approach in which never smokers were included as the reference category and continuous measures of smoking were categorized into ordinal categories at their approximate quartile cut-points. The tests for linear trend for ordinal categorical variables (restricted to ever smokers) were assessed by assigning a median value to each category and modeling as continuous variables in the model.
      To further assess possible effects of smoking intensity, duration, and time since quitting independently of the effects of ever smoking, we fitted models that included a term for smoking status (current/never smoker) and a term for the centered (rescaled to the mean) continuous measures of either duration or intensity of smoking (
      • Leffondre K.
      • Abrahamowicz M.
      • Siemiatycki J.
      • Rachet B.
      Modeling smoking history: a comparison of different approaches.
      ). This approach avoids multicollinearity. We also assessed potential nonlinear associations with dose by fitting generalized additive models with smoothed functions for the continuous measures of duration and intensity of smoking. We used SAS 9.4 software (SAS Institute, Cary, NC) for all statistical analyses except generalized additive models, which were conducted using R software.

      ORCID

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      This work was supported by a program grant from the National Health and Medical Research Council (NHMRC) of Australia (grant number 552429). DCW and REN are supported by NHMRC Research Fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

      Supplementary Material

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      Linked Article

      • Smokers versus Smoking: Is There Detection Bias for Keratinocyte Carcinomas?
        Journal of Investigative DermatologyVol. 137Issue 8
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          Dusingize et al. used a prospective observational cohort study to demonstrate a decreased risk of basal cell carcinoma and an increased risk of squamous cell carcinoma among smokers. This association disappeared after stratifying for skin screening visits, demonstrating the important role of detection bias. In the absence of randomized clinical trials, well-designed and critically analyzed observational studies can provide similarly valuable evidence.
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