- Email: [email protected]
An epidemiologic study of oral cancer in a statewide network
Am J Otolaryngol 7:200-208, 1986
An Epidemiologic Study of Oral Cancer in a Statewide Network THERESAB. YOUNG, PH.D., CHARLESN. FORD, M.D., AND JAMES H. BRANDENBURG, M.D. A case-control study was conducted to investigate the risks of male and female oral, oropharyngeal, and hypopharyngeal cancer associated with poor oral health, mouthwash use, occupation, histories of tobacco and alcohol use, and other factors. Data were collected from all newly diagnosed patients entered into the Wisconsin Head and Neck Cancer Network over an 18-month period (N = 623). The prevalence of painful or ill-fitting dentures was significantly higher among males and females with oral cavity cancer. Relative risks for painful dentures were 5.97 (males) and 1.60 (females); for i~l-fitting dentures, the relative risks were 3.15 (males) and 2.15 (females). For males, high relative risks of oropharyngeal cancer were also found to be associated with these indicators of poor dentition. Other indicators of poor oral health, including toothbrushing frequency and prevalence of broken teeth, were not associated with oral cancer. Mouthwash use was not found to carry a risk of oral cavity, oropharyngeal, or hypopharyngeal cancer. The risks of upper aerodigestive cancers with smoking and alcohol were confirmed for males, and lifetime use patterns were explored. Notable sex differences in exposure to alcohol and tobacco were found. There was little evidence that past alcohol use was related to female oral cancer.
Because of their anatomic location and function, tissues of the upper aerodigestive tract are subject to diverse exposures to both known and potential carcinogens. In addition to food- and air-borne substances, the oral cavity is vulnerable to pharmaceuticals, oral hygiene products, and dental procedures and preparations that include x-rays, bonding materials, and metals. Other factors include physical trauma, direct contact with the envi r onm ent (including intimate contact with o t h e r persons), and substances habitually chewed or held in the mouth. Based on evidence from several studies, tobacco and alcohol use appear to be the most important etiologic factors. 1-4 In view of the vast array of potentially carcinogenic exposures of the oral cavity, there exists the p o s s i b i l i t y of o t h e r factors' acting synergistically with tobacco and alcohol or contributing additional risk. Some studies have been conducted that indicate risk is associated with nutritional deficiencies, poor
dentition, m o u t h w a s h use, viruses, and occ u p a tions i n v o l v i n g m e t a l s , t e x t i l e s , a n d a s b e s tos.a-a This case-control investigation was desig n e d to explore the characteristics of oral cance r patients including subjects with lesions of the oral cavity, oropharynx, and h y p o p h a r y n x . T he data were d e r i v e d from t he W i s c o n s i n H e a d a n d Neck Cancer Network, 9 w h i c h was established as a program to improve the m a n a g e m e n t a n d outcome of patients w i t h h e a d and neck cancer. The Network comprises 12 hospitals and 22 active physician members contributing to a comprehensive centralized data base. Over a fouryear period, 91 per cent of all cases of head a n d neck cancer (N = 1,560) seen at N e t w o r k hospitals w e r e e n t e r e d i nt o t h e p r o g r a m . T h i s number represents approximately 80 per c e n t of all cases statewide. As part of the project, detailed data on smoking, alcohol use, o c c u p a tional exposures, soci oeconom i c status, oral hygiene, and other factors were obtained fro m all subjects r e c r u i t e d into the proj ect d u r i n g the first 18 months.
Received August 19, 1985, from the Department of Preventive Medicine (Dr. Young) and the Department of Surgery, Division of Otolaryngology-Headand Neck Surgery, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans' Hospital (Drs. Ford and Brandenburg), M~disnnWisconsin. Acceptedfor publication October 28, 1985. Address reprint requests to Dr. Young:Department of Preventive Medicine, University of Wisconsin-Madison, 504 Walnut St., Madison, W[ 53705,
METHODS
Study Design Because the Network project was restricted to patients with cancer of some head or neck site,
200
YOUNC ET AL. no data on i n d i v i d u a l s w i t h o u t h e a d / n e c k cancer were available for comparison. For this case-control investigation, the "case" group c o m p r i s e d three subsets: oral cavity cancer cases, oropharyngeal cancer cases, and hypopharyngeal cancer cases. Two basic control groups are used: 1) patients with cancer of head and neck sites not thought to be related to tobacco use, i n c l u d i n g s a l i v a r y gland, nasopharynx and paranasai sinus sites, and 2) patients w i t h c a n c e r of the l a r y n x , a k n o w n smoking-related cancer site. Since head and neck cancers are thought to have some etiologic factors in c o m m o n , p r e v i o u s r e t r o s p e c t i v e studies of oral cancer have used hospitalized controls with illnesses other than cancer or controis with cancer of sites other than head/neck. There are advantages, however, in using . . . . and control groups from the same serio" tients were uniformly recruited into tt with no distinction as to case or con thereby m i n i m i z i n g any differences ae~ween case and control groups caused by selection procedures. In retrospective studies, there is often concern that patients are influenced by their cancer diagnosis to recall past exposures in a different manner from controls. The potential for recall bias is minimized when bath cases and controls share a diagnosis of head/neck cancer. Given that the controls are more similar to the cases, this analytic design allows a more rigorous test of potential risk factors for specific head/neck cancer sites. It is of additional interest to compare the degree of exposure to shared risk factors, such as tobacco and alcohol use, across s p e c i f i c h e a d / n e c k cancer site groups. For this investigation, 639 patients were interviewed by their attending physicians and were asked to complete an eight-page questionnaire with the assistance of Network personnel. Data were collected on sociodemographics, including education, s t a n d a r d of living, marital status, ethnic status and religion, family history, occupational history and exposures, diet, current and past use of tobacco and alcohol, regular dental hygiene, and condition of natural and artificial teeth. All neoplasms were histologically confirmed. S i x t e e n p a t i e n t s w i t h primary neoplasms of multiple sites were excluded from this analysis, resulting in a sample of 623 cases and controls. Variables to investigate risk factors were created from the interview and questionnaire database and were analyzed using a medical statistics software system2 ° Odds ratios are used to
express the magnitude of association between oral, oropharyngeal, or hypopharyngeal cancer and some of the factors under investigation. The odds ratio is an estimate of relative risk and conveys the likelihood of having the disease if there is (or was) exposure to the particular factor under investigation, compared w i t h the likelihood of having the disease if the exposure is (or was) not present. 11
Sample Description The distribution of the sample by sex and age for each cancer site group is given in Table 1. The mean ages of the case and control groups are 63.2 and 61.5, respectively. The mean age of each site group does not deviate more than four years from the total group mean, w i t h the exception of the nasopharyngeal group, for which the mean is ten years lower than the total group mean. Overall, there is no statistically significant difference in the age distribution by cancer site group. Consequently, the sample was not conditioned on age. Age was, however, investigated as a potential confounding factor for specific associations, The sex ratios for each site indicate that males predominate most in the oral cavity, oropharyngeal, hypopharyngeal, and lar, yngeal cancer site groups. This pattern is consistent with previous findings. 12,1a
RESULTS
Sociodemographic Factors Variables for standard of living (five increments from low to high), educational attainment (seven increments from "no formal schooling" to "beyond college degree"}, and marital status (married, single, divorced, w i d o w e d , or separated) were examined. The cancer site groups did not differ significantly on standard of living for any past or present time period or on educational attainment, Among males, oropharyngeal cancer patients were least likely to be married. The prevalence of divorce for this site group was two to three times greater than other site groups. Although the pattern of marital status was similar for female cancer site groups, the deviation from the expected was not statistically significant.
Oral Hygiene Several variables based on questionnaire data concerning toothbrushing, m o u t h w a s h use, and
Volume 7 Number 3 May 1986
201
EPIDEMIOLOGIC S T U D Y OF O R A L C A N C E R
TABLE 1. CANCER SITE Cases Oral Oropharynx Hypopharynx Controls Cancers not related to tobacco Salivary gland Paranasal sinus Nasopharynx Tobacco-related cancer Larynx All Cases All controls Total
Sample of Cases and Controls
NO. OF MALES
NO. OF FEMALES
TOTAL
SEX RATIO
M E A N ACE ~(YEARS)
150 59 29
52 19 8
202 78 37
2,9 3.1 3.6
63.5 62.5 64.4
48 17 5
45 8 4
93 25 9
1,1 2.1 1.3
58.6 65.4 51,9
160 238 230 468
19 79 76 155
179 317 306 623
8.4 3,02 3,03 3.02
63.0 63,2 61.5 62.6
dentition were examined. No statistically signifi c a n t d i f f e r e n c e s r e g a r d i n g f r e q u e n c y of brushing teeth, rated on a scale ranging from rarely to three or more times per day, were found. Mouthwash use was classified according to responses to the inquiry into what brand mouthwash, if any, they had usually used prior to any manifestation of head/neck cancer. Patients indicating a commercial brand of m o u t h w a s h were classified as users, and those using no mouthwash or home preparations of baking soda or salt water were classified as nonusers. The data do not support a positive association between oral cancer a n d use of c o m m e r c i a l mouthwashes. Among males, there was little difference in the percentage of users by cancer site group, and among females, the oral, oropharyngeal, and hypopharyngeal site groups had the lowest percentage of users. Because mouthwash use m a y be a consequence of s m o k i n g a n d drinking habits, both of which are risk factors
for some head/neck cancer sites, it is important to assess the risk of m o u t h w a s h use while controlling for the c o n f o u n d i n g effects of the tobacco and alcohol exposures. Odds ratios indicating the relative risk of oral cancer associated with m o u t h w a s h use are presented in Table 2. It can be seen that for all sex, smoking, and alcohol use categories, there is no evidence of any risk of oral cavity, hypopharyngeal, or oropharyngeal cancer because of m o u t h w a s h use. All odds ratio estimates are close to 1.00, with 95 per cent c o n f i d e n c e intervals t h a t i n c l u d e 1.00, indicating that the odds of h a v i n g oral cancer for m o u t h w a s h users is the same as that for nonusers. Although no individual site group showed a significantly higher prevalence of dental appliances, including full and partial dentures and bridges, a higher percentage of females reported having some type of d e n t a l appliances [50 to 87.5 per cent of individual cancer site groups) compared with males (40.8 to 65.6 per cent of
TABLE 2. Relative Risks of Oral, Orapharyngeal and Hypopharyngeal Cancers Associated with Commercial Mouthwash Use TOBACCO/ALcOHOL USE SUBGROUPS
American Journal of
Otolaryngolagy
Males Smokers Nonsmokers Drinkers Nondrinkers All males Females Smokers Nonsmokers Drinkers Nondrinkers All females
ORAL CANCER ODDS RATIO (95% C[) 0.90 2.63 1.01 0,97 1.02
(0.58, 1.38) (0,50, 13.731 (0.66, 1,57) (0.18, 5.37) (0.67, 1.56)
OROPHARYNGEAL AND HYPOPHARYNGEAL CANCER ODDS RATIO (950/0 CI) 0.80 0.45, 1,42) 0.91 0.55, 1.49) 0,91 0.55, 1.50) 0.96 0.52,
1,50)
0.59 (0,23, 0.41 (0.12, 0.55 (0,24,
1.50) 1.43) 1.26)
0.48 0,17, 1,41) 1,50 0.15, 14,94) 0.54 0,20, 1,46)
0.52 (0.25,
1.10)
0.55 0,22,
1.40)
YOUNG ET AL.
TABLE 3. Relative Risk of Oral and Oropharyngeal Cancer Associated with Ill-fitting and Painful Dentures SITE GROUP
RISKFACTOR
Oral Cancer Odds Ratio (95% CI)
Oropharyngeal Cancer Odds Ratio (95% CI)
5.97 (2.34, 15,22) 1.60 [0.39, 6.59)
5.50 (1.72, 17.58) 0.41 (0.02, 8.00)
3.15 (1,48, 2.15 f0.65,
4.36 (1.81, 10.51) 1.53 (0.27, 8.70)
Dentures that hurt Males Females Dentures that are loose or ill-fitting Males Females
individual cancer site groups). For both males and females, having broken teeth was not independent of cancer site group (P ~< 0.05). The highest prevalence of broken teeth was reported by females with cancer of the larynx (31.6 per cent), whereas those with oral and oropharyngeal cancer were among the groups with the lowest prevalence (3.8 to 10.5 per cent). Variables for ill-fitting and for painful dentures were significantly associated with having oral cancer. Both male and female oral cancer site groups and the male oropharyngeal cancer site group had the highest percentage of patients reporting that their dentures did not fit and/or hurt. Odds ratios to express the relative risk associated with these variables are given in Table 3. Males with painful dentures were nearly six times as likely to have oral cavity cancer as males with dentures that did not hurt. Similarly, the odds ratio for ill-fitting dentures indicates a relative risk of 3.15 for male oral cavity cancer. Significant odds ratios for male oropharyngeal cancer were also found. Odds ratios indicating a risk for female oral cancer with loose, ill-fitting, and painful dentures were found, but the broad confidence intervals preclude statistical significance. Female oropharyngeal cancer was not associated with these denture conditions. Patients were asked whether they often got sores in their mouths, prior to manifestation of head/neck cancer, and the responses were used to indicate the prevalence of previous oral lesions. For males, there was little difference in the prevalence of oral lesions among cancer site groups (<7 per cent). Females in general reported a higher prevalence of oral lesions than males. Prevalence was slightly greater for the o r a l , a n d o r o p h a r y n g e a l female c a n c e r site groups (17 and 21 per cent), compared with the other groups (~13 per cent), with the exception of the nasopharyngeal group (25 per cent), but the difference was not statistically significant.
6.70) 7,09)
Occupation Responses providing information on the patients' first permanent job, current job, and job of longest duration were c o d e d according to 1970 Census categories of 1) type of occupation and 2) type of industry. Specific jobs in industries involving wood, metal, chemicals, automobile manufacture, and pulp and paper production were investigated. Of particular interest were pulp mills, a major industry in Wisconsin. Sulfuric acid, used in some pulping processes, has been associated with cancer of the larynx. 14 Other information on occupational exposures included self-reported exposures to radiation, dust, and chemicals or fumes. No statistically significant assomanons were found for oral cancer cases and any occupation or industry variable, but some trends for other cancer sites were seen. For males, 17 p e r cent of the salivary cancer site group reported farming as the job they had the longest, compared with 3 to 11 per cent of the other cancer site groups. Longest job in industries involved with wood manufacture was reported by 20 per cent of the nasopharyngeal cancer group and 6 per cent of the paranasal sinus cancer group, whereas less than 2 per cent of any other site group reported wood-related jobs. From 4 to 6 per cent of all groups reported employment in pulp and paper mills. For males and females, the oral and oropharyngeal cancer case groups reported the least exposure to dust, chemicals, and fumes. Exposure to dust or dust in combination with chemicals and fumes was at least twice as prevalent for patients with nasopharyngeal cancer. For males, 60 per cent of the nasopharyngeal cancer patients reported a job involving this type of exposure for their job of longest duration as well as current job, as compared with 20 to 30 per cent of any other site group. Among females with no-
Volume 7 Number 3 May 1986 203
EPIDEMIOLOGICSTUDYOF ORALCANCER TABLE 4.
Recent Cigarette Smoking CONTROLS CASES
Oral Females* None <1 pack/day 11/2-2 p a c k s / d a y >2 p a c k s / d a y Total Malest None <1 pack/day 11/2-2 p a c k s / d a y >2 packs/day Total
Orapharyngeal No. (%)
No.
C%)
24 15 10 3 52
(46) (29) (19) (6) --
7 9 1 2 19
(37) (47) (5) (ii) --
43 52 38 17 150
(29) (35) (25) (11) --
8 19 22 10 59
(14) (32) (37) (17) --
Hypapharyngeal No. (%) 3 2 3
0
(37) (25) (37)
(0)
Laryngeal No. (%) 3 5 8
(16) (26) (42)
3
(16)
Salivary, Nasapharyngeal, ParanasolS i n u s No. (%) 37 17 2
1
(65} (30) (4)
(2)
8
--
19
--
57
--
5 13 9
(17) (44) (31)
29 55 59
(18) (34) [37)
28 22 12
(40) (39) (17)
17
(~1)
2 29
(7) --
160
--
8 70
(4) --
* P = 0.004. t P : 0.00B.
sopharyngeal cancer or paranasal sinus cancer, 25 per cent were occupationally exposed to dusts, compared with 0 to 12.5 per cent of any other site group. Tobacco
American JournaJ
of Otalaryngology 204
The risk of oral, hypopharyngeal, oropharyngeal, and laryngeal cancer associated with tobacco use has been well established, s,ls Similarly, smoking is not considered a risk factor for salivary gland, nasopharyngeal, and paranasal sinus cancers, and the smoking habits of patients with these cancers can be assumed to parallel the general populationJ 6 The goal of this analysis of tobacco risk was to explore patterns of tobacco use. For this, the salivary, nasopharyngeal, and paranasal sinus cancer site groups were combined for comparison with each of the oral, hypopharyngeal, and oropharyngeal, and laryngeal site groups. Previous studies of oral and upper airway cancers have detailed the risk of cigarette smoking, with exposure quantified by packs per day, years of smoking, and packyears. In this analysis, a new look is taken at smoking habits by comparing daily tobacco use at several age periods prior to cancer diagnosis, to see whether a particular type of smoker is at higher risk for developing an oral, oropharyngeal, and hypopharyngeal cancer or laryngeal cancer later in life. Detailed histories of tobacco use, i n c l u d i n g cigarette, p i p e , a n d cigar smoking, snuff, and chewing tobacco, were examined. Use of a tobacco product other than cigarettes was rare for females (<1 per cent). Among
males, 3.5 per cent had ever u s e d snuff or chewed tobacco regularly, 12 per cent smoked cigars, and 9.5 per cent smoked a pipe. There were no statistically significant differences between cancer site groups on these users of tobacco. There was a statistically significant difference between cancer site groups on amount of current cigarette smoking, for both males and females (Table 4). The proportion of smokers was least in both male and female control groups and greatest in the laryngeal cancer group for females and in the oropharyngeal, h y p o p h a r y n geal, and laryngeal cancer groups for males. Of the oral, oropharyngeal, and hypopharyngeal sites, the oral cavity group had a smaller proportion of smokers, b u t a m o n g the males, the smokers in the oral cavity site groups tended to smoke as h e a v i l y as t h o s e in the other two groups. Data on cigarette smoking for three time periods for each patient (under the age of 20 years, from age 30 to 40 years, and from age 40 to 50 years) were analyzed. Data for the period of 20 to 30 years of age were very similar to those of the "under age 20" period, and data on age period of 50 to 60 years and beyond were not comparable because of the exclusion of patients under the age of 60 years. For both males and females, the control group (salivary, paranasal sinus, and nasopharyngeal cancer site groups combined) had the smallest proportion of smokers at any age, as expected. Although the pattern was similar for m a l e s a n d f e m a l e s , t h e d i f f e r e n c e in the smoking histories by cancer site group was statistically significant for females for the last age period only. The laryngeal and hypopharyngeal
YOUNGET AL. site groups had the greatest proportion of patients who smoked before they were 20 years old. A higher percentage of the male and female oral, oropharyngea[, hypopharyngea], and laryngeal cancer site groups were in the category of smoking at least one pack of cigarettes daily at that age. For subsequent time periods, while controls t e n d e d to decrease the a m o u n t of smoking, individuals in the other cancer site groups increased their daily cigarette smoking. Overall, the laryngeal and hypopharyngeal site groups appear to have histories of the heaviest smoking. Alcohol The lifetime pattern approach was also used to investigate alcohol consumption. Various categories of beer and liquor weekly intake were used to investigate alcohol exposure, because the distributions differed by sex and type of alcohol. Specifically, the range of alcohol consumption was much greater for males, and for both sexes, the range of daily consumption was greater for beer as compared with liquor. Like tobacco, alcohol has not been considered to be a risk factor for salivary, paranasal, and nasopharyngeal cancers, and these site groups were combined into one control group. 16 For females, laryngeal a n d oropharyngeal cancer patients tended to be the heaviest beer drinkers. Laryngeal, hypopharyngeal, and oral cancer patients tended to be the heaviest consumers of liquor. Between 15 and 25 per cent of these site groups reported consuming over 15 shots or mixed drinks per week, compared with none in the control group. The small number of heavy-drinking females in any site group, however, was notable. Although these data translate into high odds ratios for alcohol use among the oral, laryngeal, hypopharyngeal, and oropharyngoal site groups, the risk estimates are not statistically significant, and further analyses, including stratification by smoking status, are not presented. Both current beer and liquor consumption were significantly related to cancer site group for males. There was little difference in the proportion of site groups consuming no beer, but there were marked differences in the distribution by amount of beer consumed per week. The oropharyngeal and hypopharyngeal site groups h a d the largest percentage of heaviest beer drinking, followed by the oral cavity site group. The pattern was somewhat different for liquor,
TABLE 5. Relative Risk of Heavy Alcohol Consumption and Smoking for Male Oral, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancer
ODDSRATIOS Oropharyngeal and Oral Hypopharyngeal Laryngeal
Beer (>40 cans or bottles/week} 0 cigarettes/day 0.23 1-20 cigarettes/day 1.39 21-40 cigarettes/day 2.70 >40 cigarettes/day 4.30 Liquor (>20 shots or mixed drinks/week/ 0 cigarettes/day 2.01 1-20 cigarettes/day 8.55 21-40 cigarettes/day 0.50 >40 cigarettes/day 4.30
8.78 4.32 2.81 5.40
4.64 1.62 0.77 15.90
1.90 3.53 2.80 2.17
2.10 8.08 3.20 8.o5
where the control group had the largest proportion of men who drank no liquor. Additionally, the oropharyngeal, laryngeal, and oral cavity site groups showed the heaviest drinking. Odds ratios, given in Table 5, show an increasing risk for heavy (20 to 40 cans or bottles per week) and heaviest (over 40 cans or bottles per week) beer drinking. Odds ratios for the heaviest category were markedly higher than the heavy category, particularly for the oral site group and the orepharyngeal and hypopharyngeal site groups combined. Beer and liquor weekly consumption for females over three time periods (under age 20, age 30 to 40, and age 40 to 50) does not support a hypothesis that past use of beer and liquor contribute to oral dancer risk for females. The past drinking habits of the oral, oropharyngeal, and hypopharyngeal site groups indicate little exposure and do not differ from the drinking habits of the control group. In contrast, a higher proportion of the laryngeal cases began drinking beer at an early age. Over all time periods, the laryngeal group reported more beer consumption daily than any of the other site groups. Male alcohol-use histories showed that for both beer and liquor consumption, use under the age of 20 did not differ significantly from that expected under the null hypothesis of no association between cancer site group and alcohol. There was little difference in the amount of beer consumed by site group for this age period. For liquor, however, a trend toward heavier consumption for the oral, oropharyngoal, hypopharyngeal, and laryngeal sites can be discerned. The trend is significant for the next
American JournaJ of Otolaryngology
205
EPIDEMIOLOGIC STUDY OF ORAL CANCER
two age periods for both beer and liquor use. All groups s h o w an increase in some alcohol cons u m p t i o n after the age of 20, as expected. However, after the age of 30, the control group shows little t e n d e n c y t o w a r d increased alcohol cons u m p t i o n as c o m p a r e d w i t h the o t h e r site groups, p a r t i c u l a r l y the h y p o p h a r y n g e a l and oropharyngeal groups. Heaviest drinking is a discriminator b e t w e e n control and other site groups, with none of the controls reporting more than 40 cans/bottles of beer per week or more than 20 shots of l i q u o r or m i x e d drinks per week.
Concurrent smoking a n d alcohol use has been investigated as an interactive risk factor for oral, oropharyngeal, and hypopharyngeal and laryngeal cancers, a H e a v y smoking w i t h heavy alcohol use has been s h o w n to carry a higher risk that w o u l d be expected from the additive risk of both factors. Odds ratios for beer and liquor use by c i g a r e t t e - s m o k i n g categories are given in Table 5 for males. For every level of cigarette smoking, there is a positive risk associated with heavy drinking for the oropharyngea] and hypopharyngeal cancer site groups, relative to the control group. Thus, regardless of the smoking status, alcohol exerts an i n d e p e n d e n t risk for these sites. These odds ratios are lower than the o d d s r a t i o s o b t a i n e d p r i o r to stratifying on smoking habits. This change in magnitude reflects the c o n f o u n d i n g effect of t o b a c c o use, w h e r e b y tobacco u s e carries a cancer risk for these sites and is also associated with alcohol use.
A l t h o u g h there are inconsistencies, alcohol also appears to exert an i n d e p e n d e n t risk for oral cancer and laryngeal cancer. For males who smoke u p to one pack of cigarettes per day, there is little or no oral cancer risk associated with heavy beer drinking, but there is a substantial risk associated with h e a v y liquor drinking. Because t h e o d d s ratios a s s o c i a t e d w i t h h e a v y d r i n k i n g do n o t c o n s i s t e n t l y i n c r e a s e w i t h smoking level, it is not possible to make inferences about an additional risk due to the joint o c c u r r e n c e of h e a v y s m o k i n g a n d h e a v y drinking. P r o p e r i n v e s t i g a t i o n of this topic, which has been p r e v i o u s l y addressed in depth, 1 necessitates larger sample sizes in all smoking/ drinking categories, than were available for this study. American Journal of OtoJaryngology
206
DISCUSSION Several studies have reported inverse relationships b e t w e e n oral, pharyngeal, and laryn-
geal cancers and s o c i o e c o n o m i c status, indicated p r i m a r i l y by i n c o m e or e d u c a t i o n , but these findings remain largely unexplained. ~7 Socioeconomic status is a c o m p l e x variable that may be a surrogate for n u m e r o u s factors, including health care, nutrition, occupation, lifestyle, smoking, and drinking. The correlations of some of these factors, particularly alcohol and smoking, with socioeconomic status, however, are inconsistent or have changed over time. No difference in socioeconomic status a m o n g the cancer site groups was seen in the present study. The control group, c o m p o s e d mainly of patients with salivary gland cancer, did not have a higher income or education level than the oral, hypopharyngeal, oropharyngeal, or laryngeal site groups. It is likely that the lack of e x p e c t e d higher income and education level of the control group, relative to the other groups, is because of the higher proportion of farmers found in the salivary gland cancer site group. An individual in a farm-based "low socioeconomic status" category is unlikely to share the same lifestyle and characteristics that are indicated by a non-farmbased " l o w s o c i o e c o n o m i c status" category. These findings suggest that the underlying direct factors responsible for previously reported inverse relationships between income or education and oral cancer are not captured if u r b a n farm differences exist and are net accounted for. The results of this s t u d y indicate that oral cancer patients differ most from other head-andneck cancer patients in the prevalence of painful a n d ill-fitting dental a p p l i a n c e s . Other indicators of p o o r oral health, i n c l u d i n g t o o t h brushing frequency, did not differentiate the oral cancer patients from the other site groups. Although poor oral health has often been linked to oral cancer in texts and review articles, the evidence has m a i n l y b e e n b a s e d on case re. ports, a,16 There has been little speculation on the etiologic role of poor oral health in oral cancer. It has been suggested that trauma or irritation to oral tissue provides an easier portal of entry for a viral or chemical carcinogen. Indirectly, poor oral health may be correlated with tobacco use, alcohol use, and lower socioeconomic status, all of which have been associated with risk of oral cancer. In this study, however, the variables for dental irritation, toothbrushing frequency, and other indicators of oral health were not associated with either smoking or alcohol use. Furthermore, no relationship b e t w e e n s o c i o e c o n o m i c status and oral cancer was e v i d e n t in these data. It is possible that the finding of an association
YOUNG ET AL.
between irritation or poorly fitting dentures and oral cancer is noncausal. Even though questions on oral healthy were directed to the time before disease, preclinical stages of oral cancer may have caused greater oral sensitivity. However, because of the large odds ratios estimated, it is unlikely that the entire measured risk can be so explained. Some assurance that the disease is not responsible for the association is that the prevalence of oral lesions was not significantly greater for either the male or female oral cancer site groups. Among the few past epidemiologic studies of oral cancer that have investigated oral health, the following indicators of poor oral health have been significantly, but not consistently, associated w i t h oral cancer: c o n d i t i o n of teeth (carious, septic, broken, etc.), complete or partial absence, age of becoming edentulous, hygiene practices, and irritation caused by sharp teeth or dentures. 2.a Causal interpretations are difficult because some of the oral health conditions may be concurrent or subsequent to the onset of carcinogenesis. It is likely that differences in the operational definitions and the sources of information for the indicators used account for some of the lack of agreement. Furthermore, these studies, as well as the current study, were not designed primarily to test a hypothesis of oral cancer and poor dentition. Collectively, the results to date do provide the rationale for a future study to be undertaken with the objective of testing a model of oral cancer and poor oral health. Data on exposure might be collected from previous dental records as well as current assessment. M o u t h w a s h use has been recently investigated as a risk factor for oral cancer. Commercial mouthwash usually contains alcohol, an established risk factor, as well as dyes and other chemicals. 18 Small risks have been found, particularly for females and nonsmokers. 8,7 The authors of these studies stressed that this exposure is not likely to account for a substantial amount of oral cancer, but since the populations studied were normally at low risk for development of oral cancer, they thought the possible association merited further investigation. Several n o n c a u s a l e x p l a n a t i o n s for these findings have been offered, including mouthwash use as a response to unpleasant tastes or odors possibly present in various states, including the preclinical stage, of oral cancer. 1~ Mouthwash use has also been suggested as a compensation for poor oral hygiene, halitosis associated with poor dentition, or chronic can-
didal infection, 19 which m a y be associated with oral cancer risk. In our study, oral cancer patients did not have a higher prevalence of m o u t h w a s h use compared with controls. This result persisted after stratification on sex, smoking, and alcohol use. Information was solicited on usual mouthwash use prior to disease, but no informalion on years of use, strength of m o u t h w a s h used, or frequency of use were collected. It is possible that the variable used was not sensitive enough to detect a small risk. In addition, the data do not support concerns that oral cancer patients may have a higher prevalence of mouthwash use because of the disease or other possible oral cancer risk factors. Since no information on duration was collected, individuals who began m o u t h w a s h use as a result of precancerous oral conditions could not be discerned. Consequently, these data would be particularly vulnerable to a bias toward finding a positive association. Furthermore, no correlation was found between m o u t h w a s h use and indicators of poor health, smoking, or alcohol use. Oral, oropharyngeal, hypopharyngeal, and laryngeal cancers were s i g n i f i c a n t l y associated with cigarette smoking, as expected. For both males and females, the oral cancer group had the lowest risk associated with cigarette smoking of the above smoking-related cancer site groups. A lower proportion of both oral site groups were currently smoking, and the oral cancer smokers did not smoke as heavily as the other smokingrelated cancer site groups. For both males and females, those who begin smoking at an early age appear to be at highest risk of developing hypopharyngeal or laryngeal cancer. Increased amount of daily smoking later in life appears to be associated w i t h oral and o r o p h a r y n g e a l cancer as well. Female hypopharyngeal and laryngeal cancer site groups had smoking histories that were similar to the corresponding male site groups. In contrast, females with oral and oropharyngeal cancer had smoking histories t h a t i n d i c a t e d much less exposure than the c o r r e s p o n d i n g males. It is not clear w h y a sex difference in the risk associated with tobacco occurs for these two sites and not for the hypopharyngeal and laryngeal sites. Perhaps other factors are operant for females, such as poor nutrition and iron deficiency. The role of anemia is particularly interesting because of the k n o w n female preponderance of P l u m m e r - V i n s o n syndrome. A striking difference was seen between male and female alcohol exposures. Female histories
Volume 7 Number 3 May 1986 207
EPIDEMIOLOGIC STUDY OF ORAL CANCER
i n d i c a t e d m u c h lighter e x p o s u r e , c o m p a r e d with males, to both beer and liquor. Although the female oral, oropharyngeal, hypopharyngeal, and laryngeal groups reported heavier current alcohol use than the control group, the differences were small. The female laryngeal cancer group had the most extensive drinking histories, including the heaviest beer drinking. There was little e v i d e n c e for an association b e t w e e n female oral c a n c e r a n d alcohol. Although the female oral cancer site group had the greatest proportion of those currently drinking liquor on a weekly basis, the majority of females with oral cancer did not drink at all. Furthermore, the drinking histories do not distinguish the oral cancer cases from the other females. Similar results were f o u n d in the few epidemiologic studies of oral cancer that have included females. In general, the high risks associated with a l c o h o l use that are seen for male oral cancer are not found for females. 2,s,2° Although oral cancer has been considered to be a predominantly male disease, there is indication that the male-to-female ratio is decreasing, lz This change is thought to parallel increased female smoking and drinking. The results of this study, however, suggest that the past alcohol use is not a major risk factor for female oral cancer. For males, drinking at an early age does not appear to contribute to oral cancer. Males with oral cancer can be characterized by heavy beer and liquor drinking after the age of 40 years. Particularly high risks of oral, oropharyngeal, and h y p o p h a r y n g e a l cancer were associated with current heavy b e e r d r i n k i n g . Acknowledgments. T h e h e l p of K a t h l e e n Rebstock, project coordinator, Russell Spry, computer programmer, on the Wisconsin Head and Neck Cancer N e t w o r k , a n d J e r o m e H. K l o t z for s t a t i s t i c a l s u p p o r t is gratefully acknowledged. References 1. Rothman K, Keller A: The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. ] Chronic Dis 25:711-716, 1972
American Journal of Otolaryngology 208
2. Wynder EL, Bross, IJ, Feldman RM: A study of the etiological factors in c a n c e r of the m o u t h . Cancer 10:1300-1323, 1957 3. Graham S, Dayal K, Rohrer MA, et ah Dentition, diet, tobacco and alcohol in the e p i d e m i o l o g y of oral cancer. JNCI 59:1611-1618, 1977 4. Blot WJ, Fraumeni JF: Geographic patterns of oral cancer in the U n i t e d States: e t i o l o g i c a l i m p l i c a t i o n s . J Chronic Dis 30:745-757, 1977. 5. Winn DM, Ziegler RG, Pickle LW, et ah Diet in the etiology of oral and pharyngeal cancer among women from the southern United States. Cancer Res 44:12161222, 1984 6. Blott WJ, W i n n DM, F r a u m e n i IF: Oral cancer and mouthwash. JNC! 70:251-253, 1983 7. Wynder EL, Kabat G, Rosenberg S, et ah Oral cancer and mouthwash use. JNC[ 70:255-260, 1983 8. Shillitoe EJ, Creenspan D, Greenspan IS, et ah Neutralizing antibody to herpes simplex virus type 1 in patients with oral cancer. Cancer 49:2315-2320, 1982 9. Ford CN, Rebstoek KE, Brandenburg JH: Lessons from the Network and the next steps: the Wisconsin Head and Neck Cancer Network, in Engstrom PF, Anderson PN, Mortenson LE (eds): Advances in Cancer Control: Research and Development. N e w York, Alan Liss [nc., 1983, pp. 279-290 10. BMDP Statistical Software. Berkeley, University of Callfornia Press, 1981 11. Fleiss JL: Statistical Methods for Rates and Proportions. New York, John Wiley and Sons, 1973, pp 4 3 - 5 0 12. McGuirt WF: Head and neck cancer i n - w o m e n - - a changing profile. Laryngoscope 93'.106-107, 1983 13. Young FL, Pollack ES: The incidence of cancer in the U.S., in Schottenfeld D, Fraumeni IF (ads): Cancer Epi d e m i o l o g y and P r e v e n t i o n . P h i l a d e l p h i a , WB Saunders, 1982, pp 138-165 14. Soskolne CL, Zeighami EA, Hanis NM, et ah Laryngeal cancer and occupational exposure to sulfuric acid. Am J Epidomiol 120:358-368, 1984 15. Keane WM, Atkins JP, Wetmore R, et ah Epidemiology of head and neck cancer. Laryngoscope 91:2037-2045, 1981 16. Decker J, Goldstein JC: Risk factors in head and neck cancer. Mod Intell 306:1151-1155, 1982 17. Ernster VL, Seivin S, Sacks ST, et al: Major histologic types of cancers of the gum and mouth, esophagus, larynx, and lung by sex a n d income level, ]NCI 69:773-776, 1982 18, Eveson JW: Oral premalignancy, Cancer Surveys 2:412424, 1983 19. Newcombe RG: Oral Cancer and mouthwash use (letterJ. JNCI 71:1103-1105, 1983 20. Feldman JG, Hazan M: A case-control investigation of alcohol, tobacco, and diet in head and neck cancer. Prey Med 4:444-463, 1975
An Epidemiologic Study of Oral Cancer in a Statewide Network THERESAB. YOUNG, PH.D., CHARLESN. FORD, M.D., AND JAMES H. BRANDENBURG, M.D. A case-control study was conducted to investigate the risks of male and female oral, oropharyngeal, and hypopharyngeal cancer associated with poor oral health, mouthwash use, occupation, histories of tobacco and alcohol use, and other factors. Data were collected from all newly diagnosed patients entered into the Wisconsin Head and Neck Cancer Network over an 18-month period (N = 623). The prevalence of painful or ill-fitting dentures was significantly higher among males and females with oral cavity cancer. Relative risks for painful dentures were 5.97 (males) and 1.60 (females); for i~l-fitting dentures, the relative risks were 3.15 (males) and 2.15 (females). For males, high relative risks of oropharyngeal cancer were also found to be associated with these indicators of poor dentition. Other indicators of poor oral health, including toothbrushing frequency and prevalence of broken teeth, were not associated with oral cancer. Mouthwash use was not found to carry a risk of oral cavity, oropharyngeal, or hypopharyngeal cancer. The risks of upper aerodigestive cancers with smoking and alcohol were confirmed for males, and lifetime use patterns were explored. Notable sex differences in exposure to alcohol and tobacco were found. There was little evidence that past alcohol use was related to female oral cancer.
Because of their anatomic location and function, tissues of the upper aerodigestive tract are subject to diverse exposures to both known and potential carcinogens. In addition to food- and air-borne substances, the oral cavity is vulnerable to pharmaceuticals, oral hygiene products, and dental procedures and preparations that include x-rays, bonding materials, and metals. Other factors include physical trauma, direct contact with the envi r onm ent (including intimate contact with o t h e r persons), and substances habitually chewed or held in the mouth. Based on evidence from several studies, tobacco and alcohol use appear to be the most important etiologic factors. 1-4 In view of the vast array of potentially carcinogenic exposures of the oral cavity, there exists the p o s s i b i l i t y of o t h e r factors' acting synergistically with tobacco and alcohol or contributing additional risk. Some studies have been conducted that indicate risk is associated with nutritional deficiencies, poor
dentition, m o u t h w a s h use, viruses, and occ u p a tions i n v o l v i n g m e t a l s , t e x t i l e s , a n d a s b e s tos.a-a This case-control investigation was desig n e d to explore the characteristics of oral cance r patients including subjects with lesions of the oral cavity, oropharynx, and h y p o p h a r y n x . T he data were d e r i v e d from t he W i s c o n s i n H e a d a n d Neck Cancer Network, 9 w h i c h was established as a program to improve the m a n a g e m e n t a n d outcome of patients w i t h h e a d and neck cancer. The Network comprises 12 hospitals and 22 active physician members contributing to a comprehensive centralized data base. Over a fouryear period, 91 per cent of all cases of head a n d neck cancer (N = 1,560) seen at N e t w o r k hospitals w e r e e n t e r e d i nt o t h e p r o g r a m . T h i s number represents approximately 80 per c e n t of all cases statewide. As part of the project, detailed data on smoking, alcohol use, o c c u p a tional exposures, soci oeconom i c status, oral hygiene, and other factors were obtained fro m all subjects r e c r u i t e d into the proj ect d u r i n g the first 18 months.
Received August 19, 1985, from the Department of Preventive Medicine (Dr. Young) and the Department of Surgery, Division of Otolaryngology-Headand Neck Surgery, University of Wisconsin-Madison, and William S. Middleton Memorial Veterans' Hospital (Drs. Ford and Brandenburg), M~disnnWisconsin. Acceptedfor publication October 28, 1985. Address reprint requests to Dr. Young:Department of Preventive Medicine, University of Wisconsin-Madison, 504 Walnut St., Madison, W[ 53705,
METHODS
Study Design Because the Network project was restricted to patients with cancer of some head or neck site,
200
YOUNC ET AL. no data on i n d i v i d u a l s w i t h o u t h e a d / n e c k cancer were available for comparison. For this case-control investigation, the "case" group c o m p r i s e d three subsets: oral cavity cancer cases, oropharyngeal cancer cases, and hypopharyngeal cancer cases. Two basic control groups are used: 1) patients with cancer of head and neck sites not thought to be related to tobacco use, i n c l u d i n g s a l i v a r y gland, nasopharynx and paranasai sinus sites, and 2) patients w i t h c a n c e r of the l a r y n x , a k n o w n smoking-related cancer site. Since head and neck cancers are thought to have some etiologic factors in c o m m o n , p r e v i o u s r e t r o s p e c t i v e studies of oral cancer have used hospitalized controls with illnesses other than cancer or controis with cancer of sites other than head/neck. There are advantages, however, in using . . . . and control groups from the same serio" tients were uniformly recruited into tt with no distinction as to case or con thereby m i n i m i z i n g any differences ae~ween case and control groups caused by selection procedures. In retrospective studies, there is often concern that patients are influenced by their cancer diagnosis to recall past exposures in a different manner from controls. The potential for recall bias is minimized when bath cases and controls share a diagnosis of head/neck cancer. Given that the controls are more similar to the cases, this analytic design allows a more rigorous test of potential risk factors for specific head/neck cancer sites. It is of additional interest to compare the degree of exposure to shared risk factors, such as tobacco and alcohol use, across s p e c i f i c h e a d / n e c k cancer site groups. For this investigation, 639 patients were interviewed by their attending physicians and were asked to complete an eight-page questionnaire with the assistance of Network personnel. Data were collected on sociodemographics, including education, s t a n d a r d of living, marital status, ethnic status and religion, family history, occupational history and exposures, diet, current and past use of tobacco and alcohol, regular dental hygiene, and condition of natural and artificial teeth. All neoplasms were histologically confirmed. S i x t e e n p a t i e n t s w i t h primary neoplasms of multiple sites were excluded from this analysis, resulting in a sample of 623 cases and controls. Variables to investigate risk factors were created from the interview and questionnaire database and were analyzed using a medical statistics software system2 ° Odds ratios are used to
express the magnitude of association between oral, oropharyngeal, or hypopharyngeal cancer and some of the factors under investigation. The odds ratio is an estimate of relative risk and conveys the likelihood of having the disease if there is (or was) exposure to the particular factor under investigation, compared w i t h the likelihood of having the disease if the exposure is (or was) not present. 11
Sample Description The distribution of the sample by sex and age for each cancer site group is given in Table 1. The mean ages of the case and control groups are 63.2 and 61.5, respectively. The mean age of each site group does not deviate more than four years from the total group mean, w i t h the exception of the nasopharyngeal group, for which the mean is ten years lower than the total group mean. Overall, there is no statistically significant difference in the age distribution by cancer site group. Consequently, the sample was not conditioned on age. Age was, however, investigated as a potential confounding factor for specific associations, The sex ratios for each site indicate that males predominate most in the oral cavity, oropharyngeal, hypopharyngeal, and lar, yngeal cancer site groups. This pattern is consistent with previous findings. 12,1a
RESULTS
Sociodemographic Factors Variables for standard of living (five increments from low to high), educational attainment (seven increments from "no formal schooling" to "beyond college degree"}, and marital status (married, single, divorced, w i d o w e d , or separated) were examined. The cancer site groups did not differ significantly on standard of living for any past or present time period or on educational attainment, Among males, oropharyngeal cancer patients were least likely to be married. The prevalence of divorce for this site group was two to three times greater than other site groups. Although the pattern of marital status was similar for female cancer site groups, the deviation from the expected was not statistically significant.
Oral Hygiene Several variables based on questionnaire data concerning toothbrushing, m o u t h w a s h use, and
Volume 7 Number 3 May 1986
201
EPIDEMIOLOGIC S T U D Y OF O R A L C A N C E R
TABLE 1. CANCER SITE Cases Oral Oropharynx Hypopharynx Controls Cancers not related to tobacco Salivary gland Paranasal sinus Nasopharynx Tobacco-related cancer Larynx All Cases All controls Total
Sample of Cases and Controls
NO. OF MALES
NO. OF FEMALES
TOTAL
SEX RATIO
M E A N ACE ~(YEARS)
150 59 29
52 19 8
202 78 37
2,9 3.1 3.6
63.5 62.5 64.4
48 17 5
45 8 4
93 25 9
1,1 2.1 1.3
58.6 65.4 51,9
160 238 230 468
19 79 76 155
179 317 306 623
8.4 3,02 3,03 3.02
63.0 63,2 61.5 62.6
dentition were examined. No statistically signifi c a n t d i f f e r e n c e s r e g a r d i n g f r e q u e n c y of brushing teeth, rated on a scale ranging from rarely to three or more times per day, were found. Mouthwash use was classified according to responses to the inquiry into what brand mouthwash, if any, they had usually used prior to any manifestation of head/neck cancer. Patients indicating a commercial brand of m o u t h w a s h were classified as users, and those using no mouthwash or home preparations of baking soda or salt water were classified as nonusers. The data do not support a positive association between oral cancer a n d use of c o m m e r c i a l mouthwashes. Among males, there was little difference in the percentage of users by cancer site group, and among females, the oral, oropharyngeal, and hypopharyngeal site groups had the lowest percentage of users. Because mouthwash use m a y be a consequence of s m o k i n g a n d drinking habits, both of which are risk factors
for some head/neck cancer sites, it is important to assess the risk of m o u t h w a s h use while controlling for the c o n f o u n d i n g effects of the tobacco and alcohol exposures. Odds ratios indicating the relative risk of oral cancer associated with m o u t h w a s h use are presented in Table 2. It can be seen that for all sex, smoking, and alcohol use categories, there is no evidence of any risk of oral cavity, hypopharyngeal, or oropharyngeal cancer because of m o u t h w a s h use. All odds ratio estimates are close to 1.00, with 95 per cent c o n f i d e n c e intervals t h a t i n c l u d e 1.00, indicating that the odds of h a v i n g oral cancer for m o u t h w a s h users is the same as that for nonusers. Although no individual site group showed a significantly higher prevalence of dental appliances, including full and partial dentures and bridges, a higher percentage of females reported having some type of d e n t a l appliances [50 to 87.5 per cent of individual cancer site groups) compared with males (40.8 to 65.6 per cent of
TABLE 2. Relative Risks of Oral, Orapharyngeal and Hypopharyngeal Cancers Associated with Commercial Mouthwash Use TOBACCO/ALcOHOL USE SUBGROUPS
American Journal of
Otolaryngolagy
Males Smokers Nonsmokers Drinkers Nondrinkers All males Females Smokers Nonsmokers Drinkers Nondrinkers All females
ORAL CANCER ODDS RATIO (95% C[) 0.90 2.63 1.01 0,97 1.02
(0.58, 1.38) (0,50, 13.731 (0.66, 1,57) (0.18, 5.37) (0.67, 1.56)
OROPHARYNGEAL AND HYPOPHARYNGEAL CANCER ODDS RATIO (950/0 CI) 0.80 0.45, 1,42) 0.91 0.55, 1.49) 0,91 0.55, 1.50) 0.96 0.52,
1,50)
0.59 (0,23, 0.41 (0.12, 0.55 (0,24,
1.50) 1.43) 1.26)
0.48 0,17, 1,41) 1,50 0.15, 14,94) 0.54 0,20, 1,46)
0.52 (0.25,
1.10)
0.55 0,22,
1.40)
YOUNG ET AL.
TABLE 3. Relative Risk of Oral and Oropharyngeal Cancer Associated with Ill-fitting and Painful Dentures SITE GROUP
RISKFACTOR
Oral Cancer Odds Ratio (95% CI)
Oropharyngeal Cancer Odds Ratio (95% CI)
5.97 (2.34, 15,22) 1.60 [0.39, 6.59)
5.50 (1.72, 17.58) 0.41 (0.02, 8.00)
3.15 (1,48, 2.15 f0.65,
4.36 (1.81, 10.51) 1.53 (0.27, 8.70)
Dentures that hurt Males Females Dentures that are loose or ill-fitting Males Females
individual cancer site groups). For both males and females, having broken teeth was not independent of cancer site group (P ~< 0.05). The highest prevalence of broken teeth was reported by females with cancer of the larynx (31.6 per cent), whereas those with oral and oropharyngeal cancer were among the groups with the lowest prevalence (3.8 to 10.5 per cent). Variables for ill-fitting and for painful dentures were significantly associated with having oral cancer. Both male and female oral cancer site groups and the male oropharyngeal cancer site group had the highest percentage of patients reporting that their dentures did not fit and/or hurt. Odds ratios to express the relative risk associated with these variables are given in Table 3. Males with painful dentures were nearly six times as likely to have oral cavity cancer as males with dentures that did not hurt. Similarly, the odds ratio for ill-fitting dentures indicates a relative risk of 3.15 for male oral cavity cancer. Significant odds ratios for male oropharyngeal cancer were also found. Odds ratios indicating a risk for female oral cancer with loose, ill-fitting, and painful dentures were found, but the broad confidence intervals preclude statistical significance. Female oropharyngeal cancer was not associated with these denture conditions. Patients were asked whether they often got sores in their mouths, prior to manifestation of head/neck cancer, and the responses were used to indicate the prevalence of previous oral lesions. For males, there was little difference in the prevalence of oral lesions among cancer site groups (<7 per cent). Females in general reported a higher prevalence of oral lesions than males. Prevalence was slightly greater for the o r a l , a n d o r o p h a r y n g e a l female c a n c e r site groups (17 and 21 per cent), compared with the other groups (~13 per cent), with the exception of the nasopharyngeal group (25 per cent), but the difference was not statistically significant.
6.70) 7,09)
Occupation Responses providing information on the patients' first permanent job, current job, and job of longest duration were c o d e d according to 1970 Census categories of 1) type of occupation and 2) type of industry. Specific jobs in industries involving wood, metal, chemicals, automobile manufacture, and pulp and paper production were investigated. Of particular interest were pulp mills, a major industry in Wisconsin. Sulfuric acid, used in some pulping processes, has been associated with cancer of the larynx. 14 Other information on occupational exposures included self-reported exposures to radiation, dust, and chemicals or fumes. No statistically significant assomanons were found for oral cancer cases and any occupation or industry variable, but some trends for other cancer sites were seen. For males, 17 p e r cent of the salivary cancer site group reported farming as the job they had the longest, compared with 3 to 11 per cent of the other cancer site groups. Longest job in industries involved with wood manufacture was reported by 20 per cent of the nasopharyngeal cancer group and 6 per cent of the paranasal sinus cancer group, whereas less than 2 per cent of any other site group reported wood-related jobs. From 4 to 6 per cent of all groups reported employment in pulp and paper mills. For males and females, the oral and oropharyngeal cancer case groups reported the least exposure to dust, chemicals, and fumes. Exposure to dust or dust in combination with chemicals and fumes was at least twice as prevalent for patients with nasopharyngeal cancer. For males, 60 per cent of the nasopharyngeal cancer patients reported a job involving this type of exposure for their job of longest duration as well as current job, as compared with 20 to 30 per cent of any other site group. Among females with no-
Volume 7 Number 3 May 1986 203
EPIDEMIOLOGICSTUDYOF ORALCANCER TABLE 4.
Recent Cigarette Smoking CONTROLS CASES
Oral Females* None <1 pack/day 11/2-2 p a c k s / d a y >2 p a c k s / d a y Total Malest None <1 pack/day 11/2-2 p a c k s / d a y >2 packs/day Total
Orapharyngeal No. (%)
No.
C%)
24 15 10 3 52
(46) (29) (19) (6) --
7 9 1 2 19
(37) (47) (5) (ii) --
43 52 38 17 150
(29) (35) (25) (11) --
8 19 22 10 59
(14) (32) (37) (17) --
Hypapharyngeal No. (%) 3 2 3
0
(37) (25) (37)
(0)
Laryngeal No. (%) 3 5 8
(16) (26) (42)
3
(16)
Salivary, Nasapharyngeal, ParanasolS i n u s No. (%) 37 17 2
1
(65} (30) (4)
(2)
8
--
19
--
57
--
5 13 9
(17) (44) (31)
29 55 59
(18) (34) [37)
28 22 12
(40) (39) (17)
17
(~1)
2 29
(7) --
160
--
8 70
(4) --
* P = 0.004. t P : 0.00B.
sopharyngeal cancer or paranasal sinus cancer, 25 per cent were occupationally exposed to dusts, compared with 0 to 12.5 per cent of any other site group. Tobacco
American JournaJ
of Otalaryngology 204
The risk of oral, hypopharyngeal, oropharyngeal, and laryngeal cancer associated with tobacco use has been well established, s,ls Similarly, smoking is not considered a risk factor for salivary gland, nasopharyngeal, and paranasal sinus cancers, and the smoking habits of patients with these cancers can be assumed to parallel the general populationJ 6 The goal of this analysis of tobacco risk was to explore patterns of tobacco use. For this, the salivary, nasopharyngeal, and paranasal sinus cancer site groups were combined for comparison with each of the oral, hypopharyngeal, and oropharyngeal, and laryngeal site groups. Previous studies of oral and upper airway cancers have detailed the risk of cigarette smoking, with exposure quantified by packs per day, years of smoking, and packyears. In this analysis, a new look is taken at smoking habits by comparing daily tobacco use at several age periods prior to cancer diagnosis, to see whether a particular type of smoker is at higher risk for developing an oral, oropharyngeal, and hypopharyngeal cancer or laryngeal cancer later in life. Detailed histories of tobacco use, i n c l u d i n g cigarette, p i p e , a n d cigar smoking, snuff, and chewing tobacco, were examined. Use of a tobacco product other than cigarettes was rare for females (<1 per cent). Among
males, 3.5 per cent had ever u s e d snuff or chewed tobacco regularly, 12 per cent smoked cigars, and 9.5 per cent smoked a pipe. There were no statistically significant differences between cancer site groups on these users of tobacco. There was a statistically significant difference between cancer site groups on amount of current cigarette smoking, for both males and females (Table 4). The proportion of smokers was least in both male and female control groups and greatest in the laryngeal cancer group for females and in the oropharyngeal, h y p o p h a r y n geal, and laryngeal cancer groups for males. Of the oral, oropharyngeal, and hypopharyngeal sites, the oral cavity group had a smaller proportion of smokers, b u t a m o n g the males, the smokers in the oral cavity site groups tended to smoke as h e a v i l y as t h o s e in the other two groups. Data on cigarette smoking for three time periods for each patient (under the age of 20 years, from age 30 to 40 years, and from age 40 to 50 years) were analyzed. Data for the period of 20 to 30 years of age were very similar to those of the "under age 20" period, and data on age period of 50 to 60 years and beyond were not comparable because of the exclusion of patients under the age of 60 years. For both males and females, the control group (salivary, paranasal sinus, and nasopharyngeal cancer site groups combined) had the smallest proportion of smokers at any age, as expected. Although the pattern was similar for m a l e s a n d f e m a l e s , t h e d i f f e r e n c e in the smoking histories by cancer site group was statistically significant for females for the last age period only. The laryngeal and hypopharyngeal
YOUNGET AL. site groups had the greatest proportion of patients who smoked before they were 20 years old. A higher percentage of the male and female oral, oropharyngea[, hypopharyngea], and laryngeal cancer site groups were in the category of smoking at least one pack of cigarettes daily at that age. For subsequent time periods, while controls t e n d e d to decrease the a m o u n t of smoking, individuals in the other cancer site groups increased their daily cigarette smoking. Overall, the laryngeal and hypopharyngeal site groups appear to have histories of the heaviest smoking. Alcohol The lifetime pattern approach was also used to investigate alcohol consumption. Various categories of beer and liquor weekly intake were used to investigate alcohol exposure, because the distributions differed by sex and type of alcohol. Specifically, the range of alcohol consumption was much greater for males, and for both sexes, the range of daily consumption was greater for beer as compared with liquor. Like tobacco, alcohol has not been considered to be a risk factor for salivary, paranasal, and nasopharyngeal cancers, and these site groups were combined into one control group. 16 For females, laryngeal a n d oropharyngeal cancer patients tended to be the heaviest beer drinkers. Laryngeal, hypopharyngeal, and oral cancer patients tended to be the heaviest consumers of liquor. Between 15 and 25 per cent of these site groups reported consuming over 15 shots or mixed drinks per week, compared with none in the control group. The small number of heavy-drinking females in any site group, however, was notable. Although these data translate into high odds ratios for alcohol use among the oral, laryngeal, hypopharyngeal, and oropharyngoal site groups, the risk estimates are not statistically significant, and further analyses, including stratification by smoking status, are not presented. Both current beer and liquor consumption were significantly related to cancer site group for males. There was little difference in the proportion of site groups consuming no beer, but there were marked differences in the distribution by amount of beer consumed per week. The oropharyngeal and hypopharyngeal site groups h a d the largest percentage of heaviest beer drinking, followed by the oral cavity site group. The pattern was somewhat different for liquor,
TABLE 5. Relative Risk of Heavy Alcohol Consumption and Smoking for Male Oral, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancer
ODDSRATIOS Oropharyngeal and Oral Hypopharyngeal Laryngeal
Beer (>40 cans or bottles/week} 0 cigarettes/day 0.23 1-20 cigarettes/day 1.39 21-40 cigarettes/day 2.70 >40 cigarettes/day 4.30 Liquor (>20 shots or mixed drinks/week/ 0 cigarettes/day 2.01 1-20 cigarettes/day 8.55 21-40 cigarettes/day 0.50 >40 cigarettes/day 4.30
8.78 4.32 2.81 5.40
4.64 1.62 0.77 15.90
1.90 3.53 2.80 2.17
2.10 8.08 3.20 8.o5
where the control group had the largest proportion of men who drank no liquor. Additionally, the oropharyngeal, laryngeal, and oral cavity site groups showed the heaviest drinking. Odds ratios, given in Table 5, show an increasing risk for heavy (20 to 40 cans or bottles per week) and heaviest (over 40 cans or bottles per week) beer drinking. Odds ratios for the heaviest category were markedly higher than the heavy category, particularly for the oral site group and the orepharyngeal and hypopharyngeal site groups combined. Beer and liquor weekly consumption for females over three time periods (under age 20, age 30 to 40, and age 40 to 50) does not support a hypothesis that past use of beer and liquor contribute to oral dancer risk for females. The past drinking habits of the oral, oropharyngeal, and hypopharyngeal site groups indicate little exposure and do not differ from the drinking habits of the control group. In contrast, a higher proportion of the laryngeal cases began drinking beer at an early age. Over all time periods, the laryngeal group reported more beer consumption daily than any of the other site groups. Male alcohol-use histories showed that for both beer and liquor consumption, use under the age of 20 did not differ significantly from that expected under the null hypothesis of no association between cancer site group and alcohol. There was little difference in the amount of beer consumed by site group for this age period. For liquor, however, a trend toward heavier consumption for the oral, oropharyngoal, hypopharyngeal, and laryngeal sites can be discerned. The trend is significant for the next
American JournaJ of Otolaryngology
205
EPIDEMIOLOGIC STUDY OF ORAL CANCER
two age periods for both beer and liquor use. All groups s h o w an increase in some alcohol cons u m p t i o n after the age of 20, as expected. However, after the age of 30, the control group shows little t e n d e n c y t o w a r d increased alcohol cons u m p t i o n as c o m p a r e d w i t h the o t h e r site groups, p a r t i c u l a r l y the h y p o p h a r y n g e a l and oropharyngeal groups. Heaviest drinking is a discriminator b e t w e e n control and other site groups, with none of the controls reporting more than 40 cans/bottles of beer per week or more than 20 shots of l i q u o r or m i x e d drinks per week.
Concurrent smoking a n d alcohol use has been investigated as an interactive risk factor for oral, oropharyngeal, and hypopharyngeal and laryngeal cancers, a H e a v y smoking w i t h heavy alcohol use has been s h o w n to carry a higher risk that w o u l d be expected from the additive risk of both factors. Odds ratios for beer and liquor use by c i g a r e t t e - s m o k i n g categories are given in Table 5 for males. For every level of cigarette smoking, there is a positive risk associated with heavy drinking for the oropharyngea] and hypopharyngeal cancer site groups, relative to the control group. Thus, regardless of the smoking status, alcohol exerts an i n d e p e n d e n t risk for these sites. These odds ratios are lower than the o d d s r a t i o s o b t a i n e d p r i o r to stratifying on smoking habits. This change in magnitude reflects the c o n f o u n d i n g effect of t o b a c c o use, w h e r e b y tobacco u s e carries a cancer risk for these sites and is also associated with alcohol use.
A l t h o u g h there are inconsistencies, alcohol also appears to exert an i n d e p e n d e n t risk for oral cancer and laryngeal cancer. For males who smoke u p to one pack of cigarettes per day, there is little or no oral cancer risk associated with heavy beer drinking, but there is a substantial risk associated with h e a v y liquor drinking. Because t h e o d d s ratios a s s o c i a t e d w i t h h e a v y d r i n k i n g do n o t c o n s i s t e n t l y i n c r e a s e w i t h smoking level, it is not possible to make inferences about an additional risk due to the joint o c c u r r e n c e of h e a v y s m o k i n g a n d h e a v y drinking. P r o p e r i n v e s t i g a t i o n of this topic, which has been p r e v i o u s l y addressed in depth, 1 necessitates larger sample sizes in all smoking/ drinking categories, than were available for this study. American Journal of OtoJaryngology
206
DISCUSSION Several studies have reported inverse relationships b e t w e e n oral, pharyngeal, and laryn-
geal cancers and s o c i o e c o n o m i c status, indicated p r i m a r i l y by i n c o m e or e d u c a t i o n , but these findings remain largely unexplained. ~7 Socioeconomic status is a c o m p l e x variable that may be a surrogate for n u m e r o u s factors, including health care, nutrition, occupation, lifestyle, smoking, and drinking. The correlations of some of these factors, particularly alcohol and smoking, with socioeconomic status, however, are inconsistent or have changed over time. No difference in socioeconomic status a m o n g the cancer site groups was seen in the present study. The control group, c o m p o s e d mainly of patients with salivary gland cancer, did not have a higher income or education level than the oral, hypopharyngeal, oropharyngeal, or laryngeal site groups. It is likely that the lack of e x p e c t e d higher income and education level of the control group, relative to the other groups, is because of the higher proportion of farmers found in the salivary gland cancer site group. An individual in a farm-based "low socioeconomic status" category is unlikely to share the same lifestyle and characteristics that are indicated by a non-farmbased " l o w s o c i o e c o n o m i c status" category. These findings suggest that the underlying direct factors responsible for previously reported inverse relationships between income or education and oral cancer are not captured if u r b a n farm differences exist and are net accounted for. The results of this s t u d y indicate that oral cancer patients differ most from other head-andneck cancer patients in the prevalence of painful a n d ill-fitting dental a p p l i a n c e s . Other indicators of p o o r oral health, i n c l u d i n g t o o t h brushing frequency, did not differentiate the oral cancer patients from the other site groups. Although poor oral health has often been linked to oral cancer in texts and review articles, the evidence has m a i n l y b e e n b a s e d on case re. ports, a,16 There has been little speculation on the etiologic role of poor oral health in oral cancer. It has been suggested that trauma or irritation to oral tissue provides an easier portal of entry for a viral or chemical carcinogen. Indirectly, poor oral health may be correlated with tobacco use, alcohol use, and lower socioeconomic status, all of which have been associated with risk of oral cancer. In this study, however, the variables for dental irritation, toothbrushing frequency, and other indicators of oral health were not associated with either smoking or alcohol use. Furthermore, no relationship b e t w e e n s o c i o e c o n o m i c status and oral cancer was e v i d e n t in these data. It is possible that the finding of an association
YOUNG ET AL.
between irritation or poorly fitting dentures and oral cancer is noncausal. Even though questions on oral healthy were directed to the time before disease, preclinical stages of oral cancer may have caused greater oral sensitivity. However, because of the large odds ratios estimated, it is unlikely that the entire measured risk can be so explained. Some assurance that the disease is not responsible for the association is that the prevalence of oral lesions was not significantly greater for either the male or female oral cancer site groups. Among the few past epidemiologic studies of oral cancer that have investigated oral health, the following indicators of poor oral health have been significantly, but not consistently, associated w i t h oral cancer: c o n d i t i o n of teeth (carious, septic, broken, etc.), complete or partial absence, age of becoming edentulous, hygiene practices, and irritation caused by sharp teeth or dentures. 2.a Causal interpretations are difficult because some of the oral health conditions may be concurrent or subsequent to the onset of carcinogenesis. It is likely that differences in the operational definitions and the sources of information for the indicators used account for some of the lack of agreement. Furthermore, these studies, as well as the current study, were not designed primarily to test a hypothesis of oral cancer and poor dentition. Collectively, the results to date do provide the rationale for a future study to be undertaken with the objective of testing a model of oral cancer and poor oral health. Data on exposure might be collected from previous dental records as well as current assessment. M o u t h w a s h use has been recently investigated as a risk factor for oral cancer. Commercial mouthwash usually contains alcohol, an established risk factor, as well as dyes and other chemicals. 18 Small risks have been found, particularly for females and nonsmokers. 8,7 The authors of these studies stressed that this exposure is not likely to account for a substantial amount of oral cancer, but since the populations studied were normally at low risk for development of oral cancer, they thought the possible association merited further investigation. Several n o n c a u s a l e x p l a n a t i o n s for these findings have been offered, including mouthwash use as a response to unpleasant tastes or odors possibly present in various states, including the preclinical stage, of oral cancer. 1~ Mouthwash use has also been suggested as a compensation for poor oral hygiene, halitosis associated with poor dentition, or chronic can-
didal infection, 19 which m a y be associated with oral cancer risk. In our study, oral cancer patients did not have a higher prevalence of m o u t h w a s h use compared with controls. This result persisted after stratification on sex, smoking, and alcohol use. Information was solicited on usual mouthwash use prior to disease, but no informalion on years of use, strength of m o u t h w a s h used, or frequency of use were collected. It is possible that the variable used was not sensitive enough to detect a small risk. In addition, the data do not support concerns that oral cancer patients may have a higher prevalence of mouthwash use because of the disease or other possible oral cancer risk factors. Since no information on duration was collected, individuals who began m o u t h w a s h use as a result of precancerous oral conditions could not be discerned. Consequently, these data would be particularly vulnerable to a bias toward finding a positive association. Furthermore, no correlation was found between m o u t h w a s h use and indicators of poor health, smoking, or alcohol use. Oral, oropharyngeal, hypopharyngeal, and laryngeal cancers were s i g n i f i c a n t l y associated with cigarette smoking, as expected. For both males and females, the oral cancer group had the lowest risk associated with cigarette smoking of the above smoking-related cancer site groups. A lower proportion of both oral site groups were currently smoking, and the oral cancer smokers did not smoke as heavily as the other smokingrelated cancer site groups. For both males and females, those who begin smoking at an early age appear to be at highest risk of developing hypopharyngeal or laryngeal cancer. Increased amount of daily smoking later in life appears to be associated w i t h oral and o r o p h a r y n g e a l cancer as well. Female hypopharyngeal and laryngeal cancer site groups had smoking histories that were similar to the corresponding male site groups. In contrast, females with oral and oropharyngeal cancer had smoking histories t h a t i n d i c a t e d much less exposure than the c o r r e s p o n d i n g males. It is not clear w h y a sex difference in the risk associated with tobacco occurs for these two sites and not for the hypopharyngeal and laryngeal sites. Perhaps other factors are operant for females, such as poor nutrition and iron deficiency. The role of anemia is particularly interesting because of the k n o w n female preponderance of P l u m m e r - V i n s o n syndrome. A striking difference was seen between male and female alcohol exposures. Female histories
Volume 7 Number 3 May 1986 207
EPIDEMIOLOGIC STUDY OF ORAL CANCER
i n d i c a t e d m u c h lighter e x p o s u r e , c o m p a r e d with males, to both beer and liquor. Although the female oral, oropharyngeal, hypopharyngeal, and laryngeal groups reported heavier current alcohol use than the control group, the differences were small. The female laryngeal cancer group had the most extensive drinking histories, including the heaviest beer drinking. There was little e v i d e n c e for an association b e t w e e n female oral c a n c e r a n d alcohol. Although the female oral cancer site group had the greatest proportion of those currently drinking liquor on a weekly basis, the majority of females with oral cancer did not drink at all. Furthermore, the drinking histories do not distinguish the oral cancer cases from the other females. Similar results were f o u n d in the few epidemiologic studies of oral cancer that have included females. In general, the high risks associated with a l c o h o l use that are seen for male oral cancer are not found for females. 2,s,2° Although oral cancer has been considered to be a predominantly male disease, there is indication that the male-to-female ratio is decreasing, lz This change is thought to parallel increased female smoking and drinking. The results of this study, however, suggest that the past alcohol use is not a major risk factor for female oral cancer. For males, drinking at an early age does not appear to contribute to oral cancer. Males with oral cancer can be characterized by heavy beer and liquor drinking after the age of 40 years. Particularly high risks of oral, oropharyngeal, and h y p o p h a r y n g e a l cancer were associated with current heavy b e e r d r i n k i n g . Acknowledgments. T h e h e l p of K a t h l e e n Rebstock, project coordinator, Russell Spry, computer programmer, on the Wisconsin Head and Neck Cancer N e t w o r k , a n d J e r o m e H. K l o t z for s t a t i s t i c a l s u p p o r t is gratefully acknowledged. References 1. Rothman K, Keller A: The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. ] Chronic Dis 25:711-716, 1972
American Journal of Otolaryngology 208
2. Wynder EL, Bross, IJ, Feldman RM: A study of the etiological factors in c a n c e r of the m o u t h . Cancer 10:1300-1323, 1957 3. Graham S, Dayal K, Rohrer MA, et ah Dentition, diet, tobacco and alcohol in the e p i d e m i o l o g y of oral cancer. JNCI 59:1611-1618, 1977 4. Blot WJ, Fraumeni JF: Geographic patterns of oral cancer in the U n i t e d States: e t i o l o g i c a l i m p l i c a t i o n s . J Chronic Dis 30:745-757, 1977. 5. Winn DM, Ziegler RG, Pickle LW, et ah Diet in the etiology of oral and pharyngeal cancer among women from the southern United States. Cancer Res 44:12161222, 1984 6. Blott WJ, W i n n DM, F r a u m e n i IF: Oral cancer and mouthwash. JNC! 70:251-253, 1983 7. Wynder EL, Kabat G, Rosenberg S, et ah Oral cancer and mouthwash use. JNC[ 70:255-260, 1983 8. Shillitoe EJ, Creenspan D, Greenspan IS, et ah Neutralizing antibody to herpes simplex virus type 1 in patients with oral cancer. Cancer 49:2315-2320, 1982 9. Ford CN, Rebstoek KE, Brandenburg JH: Lessons from the Network and the next steps: the Wisconsin Head and Neck Cancer Network, in Engstrom PF, Anderson PN, Mortenson LE (eds): Advances in Cancer Control: Research and Development. N e w York, Alan Liss [nc., 1983, pp. 279-290 10. BMDP Statistical Software. Berkeley, University of Callfornia Press, 1981 11. Fleiss JL: Statistical Methods for Rates and Proportions. New York, John Wiley and Sons, 1973, pp 4 3 - 5 0 12. McGuirt WF: Head and neck cancer i n - w o m e n - - a changing profile. Laryngoscope 93'.106-107, 1983 13. Young FL, Pollack ES: The incidence of cancer in the U.S., in Schottenfeld D, Fraumeni IF (ads): Cancer Epi d e m i o l o g y and P r e v e n t i o n . P h i l a d e l p h i a , WB Saunders, 1982, pp 138-165 14. Soskolne CL, Zeighami EA, Hanis NM, et ah Laryngeal cancer and occupational exposure to sulfuric acid. Am J Epidomiol 120:358-368, 1984 15. Keane WM, Atkins JP, Wetmore R, et ah Epidemiology of head and neck cancer. Laryngoscope 91:2037-2045, 1981 16. Decker J, Goldstein JC: Risk factors in head and neck cancer. Mod Intell 306:1151-1155, 1982 17. Ernster VL, Seivin S, Sacks ST, et al: Major histologic types of cancers of the gum and mouth, esophagus, larynx, and lung by sex a n d income level, ]NCI 69:773-776, 1982 18, Eveson JW: Oral premalignancy, Cancer Surveys 2:412424, 1983 19. Newcombe RG: Oral Cancer and mouthwash use (letterJ. JNCI 71:1103-1105, 1983 20. Feldman JG, Hazan M: A case-control investigation of alcohol, tobacco, and diet in head and neck cancer. Prey Med 4:444-463, 1975