Case–control study of oropharyngeal cancer

Cancer Detection and Prevention 30 (2006) 152–157 www.elsevier.com/locate/cdp

Case–control study of oropharyngeal cancer Hristina D. Vlajinac MD, PhDa,*, Jelena M. Marinkovic MD, PhDb, Sandra B. Sipetic MD, PhDa, Dragoslava M. Andrejic MD, Mr Scc, Benko J. Adanja MD, PhDa, Svetlana L. Stosic-Divjak MD, PhDc a

Institute of Epidemiology, School of Medicine, Belgrade University, Visˇegradska 26, 11000 Belgrade, Serbia and Montenegro b Institute for Social Medicine, Statistics and Health Research, School of Medicine, Belgrade, University, Belgrade, Serbia and Montenegro c Institute of Otorynolaryngology and Maxillofacial Surgery, Clinical Centre of Serbia, Belgrade, Serbia and Montenegro Accepted 13 February 2006

Abstract Background: In order to test some hypotheses of risk factors for oropharyngeal cancer (neoplasm of base of tongue, palate and tonsils) matched case–control study was conducted in Belgrade, Serbia and Montenegro, during the period 1998–2000. Methods: Study comprised 100 incidence cases with oropharyngeal cancer and 100 controls with some non-malignant diseases of head and neck. Results: According to multivariate analysis, ever smoking, interaction between smoking and alcohol consumption, and occupational exposure to wood dust were found to be independent risk factors for oropharyngeal cancer (odds ratio—OR = 5.10 95% confidence intervals—95% CI = 1.70–15.27, OR = 2.61 95% CI = 1.54–4.41, and OR = 4.16 95% CI = 1.45–11.91, respectively). Conclusion: The results of the present study are in line with other authors, findings showing that smoking and alcohol consumption are the main risk factors for oropharyngeal cancer. The effect of occupational exposure to wood dust warrants further investigation. # 2006 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. Keywords: Oropharyngeal cancer; Risk factors; Case–control study; Wood dust; Family history; Smoking; Alcohol; Occupational; Herpes simplex virus (HSV); Human papilloma virus (HPV)

1. Introduction Cancer of the mouth and pharynx is the fifth most common incident cancer and the seventh most common cause of death from cancers throughout the world [1]. During the period 1996–1999, in Serbia without provinces (Central Serbia without Vojvodina and Metohia) average annual incidence rate of cancer of the mouth and pharynx (Institute of Public Health of Serbia, unpublished data) standardized according to age distribution of ‘‘world population’’, was 5.16 per 100 000 for men, and 1.56 per * Corresponding author at: Institute of Epidemiology, School of Medicine, Belgrade University, Visˇegradska 26, 11000 Belgrade, Serbia and Montenegro. Tel.: +381 11 361 57 80; fax: +381 11 361 57 68. E-mail address: [email protected] (H.D. Vlajinac).

100 000 for women. During the same period average annual standardised mortality rates were 1.34/100 000 in men, and 0.18/100 000 in women [2]. Among all malignant diseases malignant tumors of the mouth and pharynx were the tenth most common cause of death in men, and the ninth most common cause of death in women. Established causes of mouth and pharyngeal cancer are smoking, chewing of tobacco and chewing of betel quid [1,3,4]. The evidence that alcohol increases the risk of this cancer is convincing [5,6], as well as the evidence that diet high in vegetables and fruit decreases the risk of these malignant diseases [1,7]. With the exception of the herbal infusion mate, the regular drinking of which possibly increases risk, the evidence of the effect of some other environmental factors on the occurrence of these malignant tumors are either inconsistent or rare to make a judgement possible.

0361-090X/$30.00 # 2006 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.cdp.2006.02.001

H.D. Vlajinac et al. / Cancer Detection and Prevention 30 (2006) 152–157

The aim of the present study was to test some hypotheses of risk factors for oropharyngeal malignant tumors (neoplasm of base of tongue, palate and tonsils).

2. Material and methods Case–control study was conducted in Belgrade during the period 1998–2000. Case group comprised 100 consecutive patients diagnosed for the first time as oropharyngeal neoplasm cases (neoplasm of base of tongue – codes CO1, neoplasm of palate – CO5.1, C05.2, CO5.8, CO5.9, and neoplasm of tonsils – CO9.1, CO9.8, according to International Classification of Disease and Related Health Problems, 10th revision) at the Institute of Otorynolaryngology and maxillofacial surgery, Clinical Centre of Serbia, Belgrade. In all cases diagnosis was histologically confirmed. Control group consisted of 100 subjects chosen among patients treated during the same period for some nonmalignant diseases of head and neck, the most frequently nasopharyngitis, sinusitis, rhinitis and pharyngitis. Cases and controls were individually matched according to age (2 years), sex and place of residence.

153

All participants were interviewed by one physician. A structural questionnaire was used. Data were collected on: basic demographic and anthropometrical characteristics, occupational exposure to various chemicals, dust and some other agents, habits (smoking and consumption of alcohol and coffee), personal and family history. Data about smoking (current and former) comprised average number of cigarettes smoked per day by participants, as well as how long participants smoked. Current smokers were defined as individuals who smoked in the previous 12 months and included those who quit within the past year. Former smokers were defined as those who had quit more than a year earlier. For alcohol consumption (ever drinking) data about type of beverages and their average weekly consumption were obtained. It was assumed that alcohol content in the beverages was as follows: 30% in brandy, 40% in hard liquor, 12% in wine, and 3.5% in beer. The total dose of alcohol consumption for each participant was calculated by adding all the individual beverages weighted according to their alcohol content. The cut-off for categories of alcohol consumption was chosen according to sample distribution as well as defined critical values (of greatest significance). Occupational exposure was assessed by asking the participants whether

Table 1 Smoking habits of cases with oropharyngeal cancer and their controls

Non-smokers Former smokers Current smokers

Cases (n = 100), no.

Controls (n = 100), no.

Odds ratio (95% confidence intervals) a

5 36 59

36 27 37

1.00 5.71 (2.05–15.87) 6.85 (2.16–21.77)

Cases (n = 59), no.

Controls (n = 37), no.

Odds ratio (95% confidence intervals) a

7 24 6

1 0.76 (0.39–1.46) 1.22 (0.73–2.44)

10 17 32

14 14 9

1 1.81 (1.11-2.93) 2.72 (1.52-4.86)

Cases (n = 36), no. (%)

Controls (n = 27), no. (%)

Odds ratio (95% confidence intervals) a

5 16 6

1 0.79 (0.13-4.75) 1.34 (0.55-3.29)

19 6 2

1 3.70 (0.96-14.31) 3.53 (1.32-9.46)

Current smokers Number of cigarettes smoked per day 14 15 15–24 39 25+ 5 p-Value for trend > 0.05 Years of smoking 29 30–39 40+ p-Value for trend < 0.01

Former smokers Number of cigarettes smoked per day 14 3 15–24 20 25+ 13 p-Value for trend > 0.05 Years of smoking 29 30–39 40+

13 11 12

p-Value for trend < 0.01 a

Adjusted for education, BMI, alcohol consumption and family history of oropharyngeal cancers.

154

H.D. Vlajinac et al. / Cancer Detection and Prevention 30 (2006) 152–157

Cases were more frequently current smokers ( p < 0.001) and former smokers ( p < 0.001) in comparison with controls and smoked for a longer period of time ( p < 0.01 for current smokers and p < 0.05 for ex-smokers who smoked 40+ years). p-Values for tend was <0.01 for both current and former smokers. Differences between cases and controls in the average number of cigarettes smoked per day were not statistically significant. (Table 1). In comparison with controls, cases more frequently consumed alcohol ( p < 0.05). The total dose of alcohol consumed was significantly higher in cases then controls, both when alcohol consumption was analysed as continuous variable ( p < 0.01), and when various quantities of alcohol consumption were compared ( p < 0.0001 for weekly consumption >1.75 dl, for test of trend p < 0.05) (Table 2). Out of

they have ever been exposed to the items listed. Some data about diet were also obtained from all participants, but they are not presented in this paper. In the analysis of data, conditional univariate and multivariate logistic regressions were used.

3. Results The majority of cases were men (89 subjects). The median age of cases was 59 (age range 39–79), and the median age of controls was 59 (age range 37–79). Cases and controls did not differ in their education and occupation. Most of cases and controls were married, but a number of widowed people were greater among controls ( p < 0.05). Table 2 Alcohol consumption by cases with oropharyngeal cancer and their controls

Consumption of alcoholic beverages No Yes Average weekly alcohol consumption in dl (median) Average weekly alcohol consumption in dl 0 1.75 >1.75

Cases (n = 100)

Controls (n = 100)

Odds ratio (95% confidence intervals)a

19 81

33 67

1 1.52 (0.70–3.29)

1.54

0.75

1.35 (1.05–1.74) b

19 39 42

33 37 30

1 1.55 (0.72–3.35) 1.98 (1.28–3.05)

16 50 15

17 40 10

1 1.26 (0.87–1.82) 1.50 (0.73–3.00)

p-Value for trend < 0.05 Duration of alcohol consumption (years) <19 20–39 40+ p-Value for trend > 0.05 Cases (n = 66) Alcohol brand and average weekly consumption Brandy—number of small glasses (0.5 dl) 4 7 5–9 59 Cases (n = 15) Alcohol brand and average weekly consumption Hard liquor—number of small glasses (0.5 dl) 4 2 5–9 13 Cases (n = 22) Alcohol brand and average weekly consumption Wine—number of glasses (2.0 dl) 8 16 9+ 6 Cases (n = 37) Alcohol brand and average weekly consumption Beer—number of bottles (5.0 dl) 8 10 9+ 27 a b

Controls (n = 44)

Odds ratio (95% confidence intervals)a

13 31

1 1.41 (1.09–1.83)

Controls (n = 7)

Odds ratio (95% confidence intervals)a

4 3

1 2.58 (1.12–5.95

Controls (n = 16)

Odds ratio (95% confidence intervals)a

13 3

1 0.81 (0.47–1.40)

Controls (n = 32)

Odds ratio (95% confidence intervals)a

16 16

1 1.19 (0.79–1.79)

Adjusted for education, BMI, smoking and family history of oropharyngeal cancers. When alcohol consumption was used as continuous variable.

H.D. Vlajinac et al. / Cancer Detection and Prevention 30 (2006) 152–157

155

Table 3 Specific occupational exposure of cases with oropharyngeal cancer and their controls

Table 5 Factors related to oropharyngeal cancer—multivariate logistic regression analysis

Specific exposure

Cases (n = 100), no.

Controls (n = 100), no.

Odds ratio (95%) confidence intervalsa

Variable

Multivariate logistic regression analysisa OR (95% CI)

High temperature Low temperature High humidity Dry air Coal dust Cement dust Aniline dyes Wood dust Metal dust Chemical dust or smoke Nickel and chromium Mortar Formaldehyde

49 56 52 57 16 16 11 22 23 24

52 56 45 73 14 12 7 12 30 30

0.51 0.82 1.04 0.30 0.88 1.58 1.41 2.33 0.57 0.71

Ever smoking Occupational exposure to dry air Occupational exposure to wood dust Dental diseases (other than caries) HSV infection Smoking  alcohol consumption

5.10 0.15 4.16 0.12 0.22 2.61

6

5

1.33 (0.30–5.90)

16 8

11 2

1.68 (0.57–4.97) 4.48 (0.63–31.63)

(0.12–2.09) (0.42–1.58) (0.53–2.05) (0.14–0.64) (0.36–2.14) (0.58–4.33) (0.44–4.44) (0.96–5.66) (0.27–1.18) (0.34–1.48)

a Adjusted for education, BMI, smoking, alcohol consumption and family history of oropharyngeal cancers.

alcoholic beverages cases consumed greater quantity of brandy ( p < 0.05), hard liquor ( p < 0.05) and beer ( p = 0.052) in comparison with controls. Cases and controls did not differ in the duration of alcohol consumption. Cases and controls did not differ in the frequency, quantity or duration of coffee consumption. Concerning special occupational exposure (Table 3), cases were more frequently exposed to wood dust ( p < 0.1), and controls were more frequently exposed to dry air ( p < 0.05). Out of diseases and operations in previous history (Table 4), other dental diseases and herpes simplex virus (HSV) infections were more frequently reported by controls ( p < 0.1 and 0.05, respectively). Cases and controls did not significantly differ in family history of oropharyngeal cancer (odds ratio = 2.04, 95% confidence intervals = 0.36–11.40) and family history of other malignant diseases (odds ratio = 1.41, 95% confidence intervals = 0.69–2.90). Table 4 Diseases and operations in personal history of cases with oropharyngeal cancer and their controls Personal history

Cases (n = 100), no.

Controls (n = 100), no.

Odds ratio (95% confidence intervals)a

Dental caries Other dental diseases Precancerous oral lesionsb Oral ulcer Herpes simplex virus infection Tonsillectomy or adenoidectomy

45 7 2

31 23 1

1.13 (0.57–2.23) 0.25 (0.08–0.77) 1.33 (0.09–18.14)

1 6

3 18

0.50 (0.04–5.85) 0.33 (0.11–0.95)

15

13

1.38 (0.53–3.59)

a

Adjusted for education, BMI, smoking, alcohol consumption and family history of oropharyngeal cancers. b Leukoplakia, erithroplakia.

(1.70–15.27) (0.06–0.36) (1.45–11.91) (0.03–0.42) (0.07–0.72) (1.54–4.41)

a In the model were included all observed variables related, according to univariate logistic regression analysis, to oropharyngeal neoplasm at significant level of p  0.1 [ever smoking, alcohol consumption (designated as 0, for non-drinking; as 1, for drinking <1. 75 ml per day; as 2, for drinking >1.75 per day), other dental diseases, herpes simplex virus infection, occupational exposure to dry air and wood dust, and smoking  alcohol consumption].

Variables related to oropharyngeal neoplasm at significance level of p  0.10 (ever smoking, alcohol consumption, other dental diseases, herpes simplex virus infection, occupational exposure to dry air and wood dust) were included into model of multiple logistic regression analysis (Table 5). In model was also included the interaction involving smoking and alcohol consumption (smoking  alcohol). According to multivariate analysis following variables were significantly associated with oropharyngeal neoplasm: ever smoking, occupational exposure to wood dust or dry air, dental diseases (other than caries), HSV infections and smoking  alcohol consumption. When these variables were adjusted to other factors significantly related to oropharyngeal neoplasm (body mass index, frequent consumption of fatty milk and frequent consumption of rice), the results actually did not change.

4. Discussion There are no data of any previous studies on oropharyngeal cancer in this region. According to results of numerous studies from other populations, it can be concluded that established causes of mouth and pharyngeal cancer are smoking, chewing of tobacco and chewing of betel quid [1,3,4,8–10]. The risk of developing these cancers increases with the amount smoked or chewed and with the duration of the habit. The results of the present study are in agreement with the above statement. Cases were more frequently current and ex-smokers and they smoked for a longer period of time. Data from numerous studies, cohort and case–control, have shown increased risk for mouth and pharyngeal cancers with higher alcohol consumption [3,6,10,11–14] and the risk was independent of smoking [15]. These cancers are about six times more common in drinkers than in non-drinkers. The risks varied by type of alcohol beverage, being highest among those consuming hard liquor or beer rather than wine

156

H.D. Vlajinac et al. / Cancer Detection and Prevention 30 (2006) 152–157

[15–17]. The dose-response effect was also observed in term of frequency and duration [14,18,19], although not in all studies [6]. The risk of cancer of the mouth and pharynx is greatly increased among those who both drink alcohol and smoke [20–22]. In a large case–control study conducted in USA [16], risks of oral and pharyngeal cancer were increased more than 35-fold among those who consumed two or more packs of cigarettes per day and took more than four alcoholic drinks per day. However, in a large study conducted in Brazil [23] there was little statistical evidence for tobacco and alcohol interaction on cancer of the mouth. In the present study alcohol was more frequently consumed and it was consumed in greater quantity by cases than by control, the greatest difference being found for brandy and hard liquor consumption. In the present study interaction between alcohol and tobacco was also present. The risk of oropharyngeal cancer was increased among those who both drink alcohol and smoke. Exposure to wood dust was related to malignant tumors of nasal cavity, paranasal sinuses and nasopharynx [24–26]. In Maier et al. study an increased risk for head and neck cancer was also observed after exposure to wood dust [27]. Wood dust is considered as carcinogenic [29]. Exposure to wood dust may cause cellular changes in the nasal epithelium and to increase frequency of cuboidal metaplasia and dysplasia. The toxicity and mutagenicity of wood dust was found in some studies with laboratory animals and in vitro with animal or microbial cell. It is known that wood dust can be deposited in human upper and lower airways, and there are suggestions that carcinogenic effect is attributable to wood constituents or to specific chemicals used in the wood industry in order to preserve wood [28,29]. In the present study occupational exposure to wood dust was a risk factor for oropharyngeal cancer, however data are not precise enough. The actual exposure was not measured. Participants were asked whether they had ever been exposed to some occupational hazards, but they were not asked about frequency and duration of exposure (in our population until recently people seldom changed their occupation). In addition in a case–control studies there is also concern about reliability of data collected since these data are retrospective, and recall of past exposure can be incomplete and/or incorrect. However we do not expect important differences in recall between cases and controls. Since participants were not aware of the hypotheses tested, one could expect that the proportion of wrongly classified subjects was likely to be similar in compared groups, and this non-differential misclassification most frequently leads to underestimation of the effect. By all means our finding warranted further investigation of the effect of such an exposure. Negative association of oropharyngeal cancers with occupational exposure to dry air and with dental diseases (other that caries) in the present study could be explained as characteristic of controls rather than as a protective factor for oropharyngeal cancers. Controls were patients with naso-

pharyngitis, sinusitis, rhinitis and pharyngitis, and exposure to dry air could favour the development of these diseases. Also, rhinosinusitis, the most frequent disease of controls, frequently originate from dental pathologic process. Paradentosis was more frequent among controls as well. Herpes simplex virus (HSV) infections were also more frequent among controls than among cases. According to the results of an antibody response test in a population based study, Starz et al. [30] suggested that HSV1 may enhance the development of oropharyngeal squamous cell carcinoma in individuals who are already at increased risk of the disease because of cigarette smoking or human papilloma virus (HPV) infection. In the present study data about HSV infections were collected from participants only through interviews. We had possibilities neither for serological investigation of HSV infections nor for diagnosis of HPV infection, which has been associated with increased risk for oropharyngeal cancers [31,32]. In addition to well-known disadvantages of case–control studies the main shortcoming of the present investigation was its insufficient power to detect risk factors with moderate or low odds ratio. The results of the present study are in line with other authors’ findings showing that smoking and alcohol consumption are the main risk factors for oropharyngeal cancer. The effect of occupational exposure to wood dust warrants further investigation.

Acknowledgement This work was supported by Ministry of Science, Technology and Development of Serbia through the contract No. 8651, 1996–2000.

References [1] Panel Group. Mouth and pharynx. In: Food, nutrition and prevention of cancer: a global perspective. Washington, DC, USA: American Institute for Cancer Research/World Cancer Research Fund, 1997:96–106. [2] Demographic statistics, 1996–1999. Belgrade, Yugoslavia: Federal Institute of Statistics, 1999. [3] Garrote LF, Herrero R, Reyes RM, Vaccarella S, Anta JL, Ferbeve L, et al. Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer 2001;85:46–54. [4] Bosetti C, Negri E, Franceschi S, Conti E, Levi F, Tomei F, et al. Risk factors for oral and pharyngeal cancer in women: a study in Italy and Switzerland. Br J Cancer 2000;82:204–7. [5] Franceschi S, Levi F, Dal Maso L, Talamini R, Conti E, Negri E, et al. Cessation of alcohol drinking and risk of cancer of the oral cavity and pharynx. Int J Cancer 2000;85:787–90. [6] Schlecht NF, Pintos J, Kowalski LP, Franco EL. Effect of type of alcoholic beverage on the risks of upper aerodigestive tract cancers in Brazil. Cancer Causes Control 2001;12:579–87. [7] Uzcudun AE, Retolaza IR, Ferna´ndez PB, Sa´nchez Herna´ndez JJ, Garcia AG, Oliver LM, et al. Nutrition and pharyngeal cancer: results from a case–control study in Spain. Head Neck 2002;24:830–40. [8] Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, et al. Oral cancer in southern India: the influence of

H.D. Vlajinac et al. / Cancer Detection and Prevention 30 (2006) 152–157

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 2002;98:440–5. Dikshit RP, Kanhere S. Tobacco habits and risk of lung, oropharyngeal and oral cavity cancer: a population-based case–control study in Bhopal, India. Int J Epidemiol 2000;29:609–14. Brown LM, Gridley G, Diehl SR, Winn DM, Harty LC, Otero EB, et al. Family cancer history and susceptibility to oral carcinoma in Puerto Rico. Cancer 2001;92:2102–8. Chyou P, Nomura AM, Stemmermann GN. Diet, alcohol, smoking and cancer of the upper aerodigestive tract: a prospective study among Hawaii Japanese man. Int J Cancer 1995;60:616–21. Sanderson RJ, de Boer MF, Damhuis RA, Meeuwis CA, Knegt PP. The influence of alcohol and smoking on the incidence of oral and oropharyngeal cancer in women. Clin Otolaryngol 1997;22:444–8. Duvoux C, Delacroix I, Richardet JP, Roudot-Thoraval F, Metreau MJ, Fagniez PL, et al. Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 1999;67:418–21. Fioretti F, Bosetti C, Tavani A, Franceschi S, La Vecchia C. Risk factors for oral and pharyngeal cancer in never smokers. Oral Oncol 1999;35:375–8. Tuyns AJ, Esteve J, Raymond L, Berrino F, Benhamou E, Blanchet F, et al. Cancer of the larynx/hypopharynx, tobacco and alcohol. IARC International case–control study in Turin and Varese (Italy), Zaragoza and Navarra (Spain), Geneva (Switzerland) and Calvados (France). Int J Cancer 1988;41:483–91. Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282–7. Grønbaek M, Becker U, Johansen D, Tønnesen H, Jensen G, Sørensen TI. Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. BMJ 1998;317:844–7. Schildt EB, Eriksson M, Hardell L, Magnuson A. Oral snuff, smoking habits and alcohol consumption in relation to oral cancer in a Swedish case–control study. Int J Cancer 1998;77:341–6. Rao DN, Ganesh B, Rao RS, Desai PB. Risk assessment of tobacco, alcohol and diet in oral cancer—a case–control study. Int J Cancer 1994;58:469–73. Franceschi S, Levi F, La Vecchia C, Conti E, Maso L, Barzan L, et al. Comparison of the effect of smoking and alcohol drinking between oral and pharyngeal cancer. Int J Cancer 1999;83:1–4.

157

[21] Lissowska J, Pilarska A, Pilarski P, Samolczyk-Wanyura D, Piekarczyk J, Bardlin-Mikollajczak P, et al. Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland. Eur J Cancer Prev 2003;12:25–33. [22] Castellsague X, Quintana MJ, Martinez MC, Nieto A, Sanchez MJ, Juan A, et al. The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis. Int J Cancer 2004;108:741–9. [23] Schlecht NF, Franco EL, Pintos J, Negassa A, Kowalski LP, Oliveria BV, et al. Interaction between tobacco and alcohol consumption and the risk of cancers of the upper aero-digestive tract in Brazil. Am J Epidemiol 1999;150:1129–37. [24] Gaillard J. Le cancer proffessional ethomoido-nasal chez les travaillers du bis. J Francais D’oto-rhino-laryngologie 1984;33:491–3. [25] Boffetta P, Kogevinas M, Simonato L, Wilbourn J, Saracci R. Current perspectives on occupational cancer risk. Int J Occup Environ Health 1995;1:315–25. [26] Hildesheim A, Dosemeci M, Chan CC, Chen CJ, Cheng YJ, Hsu MM, et al. Occupational exposure to wood, formaldehyde, and solvents and risk of nasopharyngeal carcinoma. Cancer Epidemiol Biomarkers Prev 2001;10:1145–53. [27] Maier H, Dietz A, Gewelke U, Heller WD. Occupational exposure to hazardous substances and risk of cancer in the area of the mouth cavity, oropharynx, hypopharynx and larynx. A case–control study. Laryngorhinootologie 1991;70:93–8. [28] IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Wood dust and formaldehyde. IARC monographs on the evaluation of carcinogenic risks to humans, vol 62. Lyon: World Health Organization, International Agency for Research on Cancer; 1995 . [29] Hardell L, Axelson O, Rappe S. Nasal cancer and chlorophenols. Lancet 1983;1:1167. [30] Starr JR, Daling JR, Fitzgibbons ED, Madeleine MM, Ashley R, Galloway DA, et al. Serologic evidence of herpes simplex virus 1 infection and oropharyngeal cancer risk. Cancer Res 2001;61:8459–64. [31] Dahlstrom KR, Adler-Storthz K, Etzel C, Liu Z, Dillon L, El-Naggar A, et al. Human papillomavirus type 16 infection and squamous cell carcinoma of the head and neck in never-smokers: a matched pair analysis. Clin Cancer Res 2003;9:2620–6. [32] Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003;95:1772–83.