Leukoplakia

322 Journal of Dental Education Volume 65, No. 4

Tobacco Use and Oral LeukoplakiaJoln Bnczy, D.Sc.; Zeno Gintner, Ph.D.; Csaba Dombi, Ph.D.Abstract: The increase in cancer mortality throughout the world justifies the study of its causes and development. Hungary has

the highest mortality rate from oropharyngeal cancer out of forty-six countries. Tobacco use is implicated in the development of

oral cancer, and oral leukoplakia as well. The aim of the study was to give an overview of the connection between tobacco use and

oral leukoplakia, considering the epidemiologic patterns of tobacco habits, the prevalence of smoking in oral leukoplakia, and the

effect of smoking on clinically healthy oral mucosa with special respect to central Europe and Hungary. In the data, strong

evidence has been found for the role of smoking in the development of both oral cancer and oral leukoplakia. Epidemiologic

patterns of cigarette smoking show a steep increase in central European countries. Cross-sectional studies show a higher

prevalence rate of leukoplakia among smokers, with a dose-response relationship between tobacco use and oral leukoplakia, and

intervention studies show a regression of the lesion after stopping the smoking habit.

Dr. Bnczy is Professor Emeritus at the Department of Oral Biology, Dr.Gintner is research associate at the Department of

Prosthetic Dentistry, Semmelweis University, Budapest; Dr. Dombi is lecturer at the Department for Education, Semmelweis

University, Budapest. Direct correspondence and requests for reprints to: Dr. Joln Bnczy, Department of Oral Biology,

Semmelweis University Budapest, Nagyvrad tr 4, H-1089 Budapest, Hungary; 36-1-303-2436 phone/fax;

[email protected] e-mail.

Keywords: oral leukoplakia, oral cancer, tobacco, smoking, cigarette consumption, central Europe

Cancer is a major cause of disease and death

throughout the world.1 Recent data that com-

pare death rates in forty-six countries show

Hungary with the highest rate among males and the

second highest rate among females, followed by

France, Croatia, Slovenia, and Romania (see Tables

1 and 2).2 Oropharyngeal cancer is the fifth most

common cancer worldwide in men and the seventh

in women, but there are marked geographical varia-

tions.3 In males, the highest mortality rates are found

in Hungary (11.1) and Czechoslovakia (7.9), with

decreasing rates in the other seven central European

countries investigated. Among females the highest

mortality rate was also reported from Hungary (1.5),

with little difference from the rates of the other cen-

tral European countries.4 The death rate from oral

cancer has increased more than fivefold since the

early 1960s, due mainly to a rapid increase of tongue

cancer in males.5

Tobacco and alcohol use as well as diet have

been implicated in the large increase in oral cancer

mortality.6 Of these, tobacco use and alcohol are iden-

tified as major risk factors,2 but interaction and/or

summation of all factors may play a role (see the

article by Dr. Newell Johnson in this issue for a fur-

ther discussion of this).

Oral leukoplakia frequently precedes oral can-

cer and has similar etiologic factors. To investigate

the relationship between tobacco use and oral leuko-

plakia, as well as the role of tobacco use in the ma-

lignant transformation of oral leukoplakia in the

European and, specifically, the central European and

Hungarian context, the following points will be dis-

cussed:

Epidemiologic patterns of tobacco habits,

prevalence of oral leukoplakia,

prevalence of smoking and oral leukoplakia,

Table 1. Age-adjusted rates for oral cancer (per100,000 population) for selected sites for forty-sixcountries, 1992-95

Sites Male Female

Lung and bronchus 84.0 (1) 17.9 (5)Colorectal 32.0 (2) 19.0 (1)Breast - 23.9 (8)Stomach 22.1 (14) 5.0 (8)Oral cavity and pharynx 18.5 (1) 2.4 (1)Prostate 16.5 (16) -Leukemia 7.2 (2) 4.7 (1)Uterus - 11.3 (8)All sites 265.0 (1) 138.0 (2)

Note: Figures in parentheses are the rank for Hungary.3

Table 2. Age-adjusted death rates (per 100,000population) for cancer of the oral cavity and pharynxin the top ten of 46 countries3

Country Male (rank) Female (rank)

Hungary 18.5 (1) 2.4 (1)France 12.0 (2) 1.3 (7)Croatia 11.7 (3) 1.1 (17)Slovenia 11.2 (4) 0.9 (34)Romania 11.1 (5) 1.0 (24)Ukraine 9.6 (6) 0.9 (29)Russian Federation 9.2 (7) 1.0 (22)Estonia 9.0 (8) 1.1 (14)Belarus 8.8 (9) 0.7 (40)Lithuania 8.3 (10) 0.9 (32)

April 2001 Journal of Dental Education 323

effect of smoking on clinically healthy oral mu-

cosa, and

evaluation of the data and conclusions.

Epidemiologic Patterns ofTobacco Habits

Among the developed countries, tobacco is

considered responsible for 24 percent of all male

deaths and 7 percent of female deaths in eastern Eu-

ropean countries, with the figure rising to over 40

percent for males in certain of these countries.7 Al-

though tobacco control campaigns have decreased

tobacco consumption in North America and in some

northern European countries over the past twenty to

thirty years,8 this has not occurred in eastern and

southern Europe. According to recent statistics of the

World Health Organization,9 Poland, Greece, and

Hungary have the highest per capita cigarette con-

sumption, and this rate has increased over the last

two decades (Table 3). In 1991, Hungary ranked

forty-second in smoking prevalence with 40 percent

smoking among men and 27 percent among

women.8,9 These data are reflected in the high mor-

tality rate of all cancers, including oropharyngeal

cancer, in the central European countries where oral

cancer and leukoplakia represent some of the most

frequent tobacco-associated diseases.10

Prevalence of OralLeukoplakia

According to well-documented epidemiologic

data from different countries over the last thirty years,

the prevalence of oral leukoplakia varies between 1.1

and 11.7 percent, with a mean value of 2.9 percent.11-19

This range reflects assessments made on the basis of

different definitions of oral leukoplakia,20-22 which

can result in different prevalence rates. Epidemio-

logic surveys in Hungary report a prevalence between

0.57 and 3.6 percent (Table 4). In terms of gender,

the prevalence of oral leukoplakia in these studies

was between 1 and 7 percent in men and 0.17 and

1.5 percent in women.

Table 3. Per capita cigarette consumption of the top ten consuming countries from 1990 to 1992 among 111 countries9

1970-72 Rank 1980-82 Rank 1990-92 Rank

Poland 3,010 11 3,400 6 3,620 1Greece 2,640 16 3,440 4 3,590 2Hungary 2,940 13 3,320 7 3,260 3Japan 2,950 12 3,430 5 3,240 4Republic of Korea 2,370 20 2,750 15 3,010 5Switzerland 3,700 2 3,060 10 2,910 6Iceland 2,940 14 3,230 9 2,860 7The Netherlands 3,150 6 3,290 8 2,820 8Yugoslavia 2,330 21 3,030 12 2,800 9Australia 3,410 4 3,440 3 2,710 10

Table 4. The prevalence of oral leukoplakia in Hungarian population samples

Men Women All examined personsAuthor Year Population n leukoplakia percent n leukoplakia percent n leukoplakia percent

Bruszt23 1962 Adults in 2,713 122 7 2,817 8 0.27 5,613 130 3.67 villages

Bnczy et al.24 1969 X-ray lung 7,548 79 1 8,784 15 0.17 16,332 94 0.57screening

Sonkodi and Tth25 1974 Textile 679 47 6.92 1,145 4 0.35 2,124 51 2.4workers

Bnczy and Rig26 1991 X-ray lung 3,358 73 2.14 4,462 31 0.69 7,820 104 1.3screening

Dombi et al.5 1996 X-ray lung 2,131 123 5.8 2,903 44 1.5 5,034 167 3.3screening


Smoking and the Prevalence ofOral Leukoplakia

Early descriptive studies (performed mainly in

India and Denmark) have shown that the frequency

of oral leukoplakia among smokers is so high that,

in the absence of controls, the habit could be consid-

ered as causative. Thus, Renstrup27 found that among

ninety leukoplakia patients, twenty-three were smok-

ers (25.5 percent). Pindborg, Roed-Petersen, and

Renstrup28 showed that among 345 Danish females

with oral leukoplakia, 32.3 percent were cheroot

smokers. Roed-Petersen and Pindborg29 in a Danish

sample of 450 leukoplakias found that thirty-two (7.1

percent) were exclusively male snuff users (Table 5).

Mehta et al.,30 in a survey of 50,915 Indian villagers,

found a prevalence of oral leukoplakia between 0.2

and 4.9 percent and that intraoral locations varied

depending upon the chewing and smoking habits in-

volved.

In four Hungarian studies, prevalence of smok-

ing was as high as 82.0-100 percent in leukoplakia

patients (Table 5). In the cross-sectional study by

Dombi et al.,5 88 percent of leukoplakia patients were

active smokers, 9 percent had quit, and only 3 per-

cent had never smoked; corresponding percentages

in the total sample were 31 percent, 22 percent, and

47 percent, respectively.

Cross-sectional studies indicate the risk for oral

leukoplakia between smokers and nonsmokers. Table

6 shows the prevalence of oral leukoplakia from stud-

ies in India, the United States, Cuba, and China, as

well as Hungary. The smoking habits in India show a

varying association with locally prevailing tobacco

habits, i.e., chewing, smoking, and mixed habits

(chewing betel quid and bidi smoking). All habits

were associated with the onset of oral leukoplakia,

and the prevalence was considerably higher among

the tobacco-using groups than the non-users.

In Hungary, cigarette-smoking predominates,

apart from some rare pipe-smoking. Among the stud-

ies presented in Table 6, Bruszt23 mentions that al-

most all of the leukoplakia cases were smokers, but

no numerical values are given. Only two studies re-

port on the distribution of leukoplakia cases accord-

ing to smoking habits. Banoczy and Rigo26 quote the

prevalence of leukoplakia among smokers as 3.73

and among nonsmokers as 0.26. In the study by

Dombi et al.,5 these percentages were 6.03 and 0.22

respectively.

The dose-response relationship between to-

bacco and oral leukoplakia has been assessed in sev-

eral studies.34 Among 104 leukoplakia patients,

Banoczy and Rigo26 found that 13.5 percent did not

smoke, 9.6 percent smoked one to ten cigarettes per

day, and 76.9 percent smoked ten or more cigarettes

per day. In a case-control study from Kenya,36 the

highest relative risk of leukoplakia was for smoking

both unprocessed tobacco and cigarettes. In Downers

study12 of 292 individuals among which there was a

2.9 percent prevalence of oral leukoplakia, there was

a significantly increased risk (odds ratio of 3.43) for

heavy smoking (>20 cigarettes/day). Winn19 similarly

found a significant correlation between the preva-

lence of leukoplakia and the amount of snuff use in

1,109 adult baseball players (see also Winns article

in this issue).

Evidence from TobaccoIntervention Studies

A decrease in the prevalence of oral leukoplakia

after smoking cessation has been observed in many

studies, confirming an etiological role (Table 7). In

a study following the elimination of etiological fac-

tors, but mainly smoking, Banoczy39 reported that

43.2 percent of oral leukoplakias resolved. In Roed-

Petersens study,43 smoking cessation for at least one

year caused resolution of leukoplakia in 58.3 per-

cent of the cases. Gupta et al.44 found that after a

cessation intervention among 36,000 Indian tobacco

users, the five-year age-adjusted incidence rate of

leukoplakia was four to six times lower among both

men and women than the nonintervention group. In

a recent study of 3,051 male U.S. military trainees,

among the 302 individuals using smokeless tobacco,

39.3 percent had leukoplakia compared to 1.5 per-

cent among non-users. After six weeks of tobacco

cessation, 97.5 percent of leukoplakic lesions showed

complete resolution clinically.45

Table 5. The proportion of smokers among leuko-plakia patients in European studies

Leukoplakia GroupAuthor Year n percent of smokers

Renstrup27 1958 90 25.5 percentBruszt23 1962 130 ~100 percentPindborg et al.28 1972 365 32.3 percent

(cheroots)Roed-Petersen, 1973 450 7.1 percent (snuff)

Pindborg29Sonkodi and Tth25 1974 51 82.3 percentBnczy and Rig26 1991 104 86.5 percentDombi5 1996 167 97 percent


Role of Smoking in MalignantTransformation of OralLeukoplakia

The studies cited above mostly provide evi-

dence of the role of smoking in the development of

oral leukoplakia. However, there is also strong evi-

dence of a relationship between tobacco use and the

development of oral cancer, although it is not clear

whether smoking promotes the development of can-

cer from oral leukoplakia. Earlier studies have

showed an increased risk of malignant transforma-

tion of oral leukoplakia among nonsmokers. Einhorn

and Wersall37 cite an eightfold risk in Sweden, and

Roed-Petersen38 a fivefold risk in Denmark. In

Banoczys study,39,40 87 percent of individuals with

leukoplakia smoked, but only 77 percent of those

developing carcinoma smoked. Silverman and Rozen

in 196841 followed 117 leukoplakia patients for up to

eleven years, but found no difference in the propor-

tion of smokers among leukoplakia or carcinoma

patients. Later, in 1984 Silverman, Gorsky, and

Lozada reported an extremely high malignant trans-

formation of 17.5 percent in a follow-up of 257 un-

treated patients with oral leukoplakia, but found that

while there were 73 percent smokers in the leuko-

plakia group, there were only 47 percent in the group

developing carcinoma.42 However, as relatively few

leukoplakias transform into cancer, it is difficult to

determine the role of tobacco in this process.

Effect of Smoking onClinically Healthy OralMucosa

Several investigators have studied the question

of whether the structure of the clinically healthy oral

mucosa shows any alterations in smokers. Banoczy46

reported on the results of cytological examination of

oral smears in 100 healthy, male and female smok-

ers and nonsmokers. Evaluation of the keratiniza-

tion pattern revealed a significant increase in kerati-

nized cells in the epithelium of the tongue and hard

palate of both male and female smokers, when com-

pared with nonsmokers. Meyer, Rubinstein, and

Medak47 took smears of ten clinically normal regions

from ninety-nine subjects and found that smoking

affected keratinocytes differently in different regions,

depending on the extent of direct exposure to smoke.

The initial changes were more marked in

nonkeratinized than in keratinized regions and, in-

terestingly, were in the direction of a less differenti-

ated cell type. The results of both studies point to

cellular alterations preceding the clinical changes.

ConclusionsStudies of the role of smoking in the develop-

ment of oral leukoplakia all point to similar conclu-

sions.48 There is strong evidence that

both oral cancer and oral leukoplakia can be in-

duced and promoted by tobacco;

cigarette smoking shows a steep increase in the

central European countries, and in these countries

the incidence and mortality from oropharyngeal

Table 6. The prevalence of oral leukoplakia among smokers and nonsmokers

Non-smokers Smokers All examined personsAuthor Year n leukoplakia percent n leukoplakia percent n leukoplakia percent

Pindborg et al.31 1967 6,669 2 0.03 3,301 326 9.9 10,000 328 3.2Mehta et al.32 1969 674 - - 2,851 208 7.3 3,785 208 5.5Roed-Petersen et al.33 1972 5,530 10 0.2 4,452 281 6.3 9,982 291 2.9Baric et al.34 1982 443 17 3.8 482 110 22.8 925 127 13.7Rosabal-Lopez et al.35 1985 110 - - 199 38 19.1 309 38 12.2Fang et al.13 1986 86,637 2,101 2.4 47,855 11,975 25.0 137,492 14,076 10.5Bnczy and Rig26 1991 5,410 14 0.26 2,410 90 3.73 7,820 104 1.3Dombi et al.5 1996 2,350 5 0.22 2,684 162 60.3 5,034 167 3.3

Table 7. Intervention studies

Resolution ofleukoplakia

after smokingcessation

Author Year ( percent) Time period

Bnczy38 1977 43.2 9.8 years (mean)Roed-Petersen43 1982 58.3 1 yearGupta et al.44 1986 50-60 5 yearsChad Martin et al45 1999 97.5 6 weeks (snuff)


cancer ranks among the highest in the world for

both men and women;

the proportion of tobacco users (both smoking and

smokeless tobacco) among individuals with leu-

koplakia is high, and a relationship is evident be-

tween the tobacco habit and the anatomical

location of the leukoplakia;

cross-sectional studies show a higher prevalence

of leukoplakia among smokers than among non-

smokers;

a dose-response relationship exists between to-

bacco use and oral leukoplakia; and

intervention studies show a regression of oral leu-

koplakia after tobacco cessation.

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Documents

Leukoplakia