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Oral Mucosal Lesions Found in Smokeless Tobacco Users
A R T I C L E S
T he risk fo r oral m ucosal lesions associated w ith use o f sm okeless tobacco a m o n g 1,109 professional baseball players during spring tra in in g in 1988 was investigated. L e u k o p la k ia was very strongly associated w ith use o f sm okeless tobacco in this p o p u la tio n o f healthy y o u n g m en. O f the 423 current sm okeless tobacco users, 196 had le u ko p la kia com pared to seven o f the 493 nonusers (O R = 60.0, 95% C l = 40.5-88.8). T h e a m o u n t o f sm okeless tobacco used (in hours per day th a t sm okeless tobacco was held in the m o u th ), recency o f sm okeless tobacco use (hours since last use), type (sn u ff versus chew ing tobacco), a n d brand o f s n u ff used were significa n tly associated w ith risk fo r leu ko p la kic lesions a m o n g sm okeless tobacco users. N inety-eight leu ko p la kic areas in 92 subjects were biopsied and ex a m in ed m icroscopically. A ll lesions were benign, b ut one specim en h a d m ild ep ith elia l dysplasia. T h e long-term significance o f leu ko p la kia in sm okeless tobacco users a n d their relation to oral cancer is n o t clear.
Oral mucosal lesions found in smokeless tobacco users D. G rady, M D , M P H ; J. G reene, D M D , M PH ; T . E. D a n iels, DDS; V. L . Ernster, P hD ; P . B. R ob ertson , D D S , MS; W . H a u ck , PhD ; D . G reensp an, BDS; J. G reen sp an , BD S, P h D , FR C Path; S. S ilv erm an Jr., M A, D D S
se of smokeless tobacco (chew ing tobacco an d snuff) has been asso cia te d w ith o ra l m u c o sal lesions ,1-8 and some of these lesions may e v e n tu a lly beco m e m a l i g n a n t .69 T h e recent increase in the prevalence of use of smokeless tobacco in the U nited States 10 co u ld lead to in c re a sin g incidences of oral cancer .3 O ral m ucosal lesions occur at the site of p lacem en t of the to b a cc o 121112 an d prelim inary evidence suggests th a t lesions are associated w ith d u ratio n and am o u n t of smokeless tobacco use .211128 However, m a n y of th e s tu d ie s of o ra l m u c o sa l lesio n s in sm okeless tobacco users are d iffic u lt to in te rp re t b ecause they did not incorporate clear clinical diagnostic c r ite r ia for o ra l le sio n s, b io c h e m ic a l validation of smokeless tobacco use status, ap p ro p riate control groups, or assessment of potential co nfounding variables such as cigarette sm oking an d alcohol con
U
sum ption. At present, we do n o t know exactly how sm okeless tobacco causes o ra l m ucosal lesio n s or w h ich g ro u p s of users are m ost susceptible. T h e effect of recency of use, ty p e, a n d b ra n d of sm o k e le ss to b a cc o u sed , a n d age a t in itia tio n has n o t been addressed. A vail able in fo rm a tio n does n o t allow us to accurately predict histological appearance a t b io p sy o r to e s tim a te m a lig n a n t transform ation potential. We e x a m in e d p ro fe s s io n a l b aseb a ll players d u rin g sp rin g tra in in g in 1988 to determ ine the risk for oral m ucosal lesions in smokeless tobacco users com pared w ith nonusers, co n tro llin g for age, race, cigarette sm oking, alcohol use, and d en tal hygiene. S m okeless tobacco use status was carefully assessed to determ ine th e effect of a m o u n t, d u r a tio n , an d recency of sm okeless tobacco use, type an d b ra n d used, a n d age at in itia tio n of smokeless tobacco use o n risk for oral
lesio n s. A ll p la y ers w ith le sio n s were o ffe re d o r a l b io p s y to d e te rm in e th e prevalence of h isto p ath o lo g ic ab n o rm al ities am o n g smokeless tobacco users w ith leukoplakia. Methods D u rin g sp rin g train in g , we studied 1,109 mem bers of the m ajo r an d m in o r league pro fessio n al baseball team s: C alifo rn ia Angels, C hicago Cubs, Cleveland Indians, M ilw aukee Brewers, O ak lan d A thletics, San Francisco G iants, an d Seattle M ari ners. Subjects com pleted a q uestionnaire th a t in c lu d e d d e m o g ra p h ic d a ta a n d in f o r m a tio n o n e d u c a tio n , c ig a re tte s m o k in g , a lc o h o l c o n s u m p tio n , a n d d e n ta l h y g ie n e . D eta ile d in f o rm a tio n con cern in g patterns of smokeless tobacco u se w as a s c e rta in e d , in c lu d in g th e am o u n t (hours per day smokeless tobacco was held in the m outh), d u ratio n (years JADA, Vol. 121, July 1990 ■ 117
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since first use), and recency (hours since last used), age at in itiatio n of use, type (sn u ff versus c h e w in g to b acco ), a n d brand. T h e sprin g train in g schedule required that the study be conducted in geograph ic a lly s e p a ra te te am f a c ilitie s a n d be lim ited to about 20 m inutes per subject. T h e r e f o r e , th e e v a lu a tio n s w ere p e r fo rm ed by seven e x a m in a tio n g ro u p s. Each g ro u p consisted of personnel from the U niversity of C alifornia San Francisco in c lu d in g a dentist w ho perform ed the e x a m in a tio n , a d e n ta l h y g ie n is t w h o reco rd ed the resu lts, an d tw o research assistants w ho obtain ed other in fo rm a tio n . B efore th e s ta r t of the stu d y , e x a m in a tio n g r o u p s w ere e x ten siv ely tra in e d to e s ta b lish u n ifo rm ity in a ll p ro ced u res. C lin ic a l slides an d e x a m in atio n of patients w ith a variety of oral m u c o sa l c h a n g e s served to e s ta b lis h agreem ent am ong exam iners for descrip tio n , c la s s ific a tio n , a n d g r a d in g of m u c o sa l le sio n s. D iffe re n ce s betw een exam iners were discussed a n d resolved, an d th e process w as rep e ate d u n til at le ast 90% a g re e m e n t b etw een any tw o e x a m in e rs w as a c h ie v e d for a ll m easurem ents. Subjects were ex am in ed at the seven sp rin g train in g cam ps in a m obile dental v an o r w ith use of p o r ta b le d e n ta l eq u ip m en t (chair, light, air compressor). A m o u th m irro r, to n g u e blade, a n d 2x 2 -in g au ze w ere used d u r in g the ex am ination. Before entering the exam in a tio n are a, each su b je ct th o ro u g h ly rin se d h is m o u th tw ice w ith w ater to rem ove any signs of sm okeless tobacco use. Subjects were also asked not to reveal th e ir sm o k e le ss to b a c c o use sta tu s to the exam iner or recorder. All oral m ucosal surfaces were carefully inspected. If any w hite or red lesion of the oral m u c o sa w as d e te c te d , th e e x a m in e r c la ssifie d th e le sio n as le u k o p la k i a / ery th ro p lak ia—w hich is any w hite lesion th a t d id n o t ru b off a n d w as n o t identifiable clinically as som e other w hite lesion, o r any red lesion not identifiable c lin ic a lly as som e o th e r red lesion or a lesion th a t included b oth red and w hite changes; and other w hite lesion—w hich is an y w h ite lesion th a t was clinically id e n tif ia b le . T h is c a te g o ry in c lu d e s frictional keratoses in c lu d in g interdental h yperkeratosis (a lin ear w hite lesion at the interdental line on the buccal mucosa, p re su m a b ly cau sed by ir r ita tio n from th e te e th ), ch eek b iti n g (an ir re g u la r w h ite to red le sio n in th e area of the interdental line, presum ably caused by 118 ■ JADA, Vol. 121, July 1990
the h ab it of sucking an d b itin g on the cheeks) an d re tro m o la r h y p e rk e ra to sis (a w hite lesion in the retrom olar trigone, presum ably caused by irrita tio n of the retrom olar area d u rin g m astication). Any lesion classified as le u k o p la k ia / ery th ro p lak ia was subsequently defined by size in m illim eters; lo c atio n in the m o u th ; c o lo r (n o rm a l, w h ite , red , o r red an d white); texture (sm ooth, g ran u lar, a n d co rru g ate d ); c o n to u r (raised , flat, or cratered); a n d degree of severity on a scale from 1 to 4 (1 = no or only slight color chan g e w ith a tex tu re change; 2 = c o lo r a n d te x tu re c h a n g e , b u t n o thickening; 3 = color an d texture change w ith m ild to m oderate th ick en in g ; 4 = no norm al color, severe texture change, a n d heavy th ic k e n in g (F ig 1-5). Since few o f th e le u k o p la k ic /e r y th r o p la k ic le sio n s c o n ta in e d an y red c o lo r, they are su b se q u e n tly referred to as le u k o plakia. B ased o n se lf-re p o rte d sm o k eless tobacco use, subjects were classified as nonusers (subjects w ho h ad never used sm o k e le ss to b a c c o , o r w h o h a d used smokeless tobacco in the past b u t never m o re fre q u e n tly th a n o n ce a m o n th ); fo rm e r u se rs (su b je c ts w h o h a d used sm o k e le ss to b a cc o m o re th a n o n c e a m o n th in the past b ut w ho had n o t used w ith in the previous m onth); an d users (su b jec ts w h o used sm okeless tobacco m ore frequently th an once a m o n th and w ho had used smokeless tobacco w ithin th e p a s t m o n th ). U sers w ere f u r th e r s e p a ra te d in to th o se w h o h a d u sed smokeless tobacco w ith in the past m o n th b u t n o t w ith in the past week, an d those w ho had used w ith in the past week. Serum co tin in e and thiocyanate were m easured for biochem ical v alid atio n of self-reported smokeless tobacco use. T h e se ru m c o tin in e level is e le v a te d in cigarette smokers an d users of smokeless tobacco, w h ile th io c y a n a te is elevated only in cigarette smokers. Elevated serum cotinine in the presence of norm al serum thiocyanate was considered biochem ical evidence of smokeless tobacco use. U sing this criterio n , only 5% of subjects w ho reported that they did n ot use smokeless tob acco w ere classified b io c h e m ic a lly as users. As blood was n ot available for 22% of subjects, an d because self-reported use was h ig h ly ac cu rate, use sta tu s is reported based on self-report only. S u b je c ts id e n tif ie d a ll sm o k eless tobacco products that they used, the site w h ere they u s u a lly h e ld th e to b acco , a n d th e typ e a n d b ra n d . A m o u n t of smokeless tobacco use was determ ined
Fig 1 ■ Normal oral mucosa.
Fig 3 ■ Degree 2 oral leukoplakia.
Fig 4 ■ Degree 3 oral leukoplakia.
Fig 5 ■ Degree 4 oral leukoplakia.
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Table 1
■ D istribution of study subjects
by d em o g ra p h ic and o th e r c h a ra c te ristics (N = 1,109). N*
Percent
Age (years) <20 20-24 25-29 30-34 35-39 >40
95 562 286 79 39 40
8.6 51.0 26.0 7.2 3.5 3.6
Race White Hispanic Black Asian
753 181 157 16
68.0 16.4 14.2 1.4
Educational level Elementary school Some high school H igh school graduate Some college College graduate
29 43 203 543 246
2.7 4.0 19.1 51.0 23.1
Cigarette sm oking Never smoked Former smoker Current smoker
956 100 44
86.9 9.1 4.0
Alcohol consum ptionf Nondrinker 1-13 drinks/week 14-20 drinks/week > 20 drinks/week
253 773 56 27
22.8 69.7 5.0 2.4
Frequency of teeth cleaning at a dental office Every 6 months Every year Every 2 years Rarely or never
317 445 195 141
28.9 40.5 17.8 12.8
Frequency of flossing Daily Weekly M onthly Rarely or never
359 387 154 204
32.5 35.1 13.9 18.5
Frequency of brushing teeth Daily 1,101 Weekly 2 Rarely or never 2
99.6 0.2 0.2
* Totals in each category may differ bet ause of missing values. f A nondrinker is a player who drinks no alcohol or
who has drunk fewer than ten drinks in the past year.
by the n u m b e r of snuff or p o u ch es of chew ing tobacco used per week. T hose w ho usually used one type of smokeless tobacco occasionally used the other type. T h u s, the n um ber of hours that smokeless tobacco was held in the m outh per day was calcu lated as a co m b in ed m easure of intensity of use. Recency of use was d e te rm in e d as h o u r s sin c e sm o k e le ss tobacco was last used. In analyses based on n um ber of sub jects, those w ith m ore th an one leukoplakic lesion were classified by the lesion of the highest degree lesion. T h e effects
of smokeless tobacco use, am o u n t, d u ra tion, recency, age at in itia tio n of use, and type and b rand used on the occur rence of le u k o p la k ic areas an d o n the severity of lesions w ere assessed u sin g odds ratios (OR), 95% confidence intervals (Cl), and separate x 2 tests of significance. W hen the incidence of a disease is rare, the O R closely approxim ates the relative risk . A lth o u g h th e d isease of in te re st in our study (leukoplakia) was n ot rare, O R were used as th e m easu re of asso ciation to perm it m u ltiv a ria te analysis u sin g logistic regression to co n tro l for p o ten tial confounders. In this case, the O R are a valid m easure of association, b u t overestim ate the relative risk. A m u ltip le logistic regression m odel was used to adju st for the effects of age, race, cigarette sm oking, alcohol use, and d e n ta l h y g ie n e p ra c tic e s o n th e a sso c ia tio n of ea c h v a r ia b le o f in te re s t ( d u ra tio n , a m o u n t, age a t in it ia t io n , recency, type, brand) w ith the occurrence of leukoplakic lesions in users com pared w ith n o nusers. In su b se q u en t analyses c o n fin e d to sm o k e le ss to b a c c o u sers, u n iv a ria te O R s fo r le u k o p la k ia were c a lc u la te d fo r d u r a tio n (p er y ear of smokeless tobacco use), am o u n t (per hour ST held in the m o u th per day), age at in itiatio n (per year of age w hen smokeless tobacco was first used), recency (per hour since la st usage) a n d ty p e /b ra n d used (each b ra n d c o m p a re d to a ll u sers of ch ew in g tobacco). A m u ltip le lo g istic re g re ssio n m o d e l w as th e n u sed to determ ine the in dependent effect of each of these variables on risk of leukoplakia, a d ju s tin g fo r th e effects of a ll of the other variables. In analyses confined to users w ith leukoplakia, u n iv ariate ORs for severity of lesio n (m ild = degree 1 or 2 versus severe = degree 3 or 4) were c a lc u la te d for d u r a tio n , a m o u n t, age a t in itia tio n , recency, an d ty p e /b ra n d used. A m u ltip le logistic regression model
w as th e n used to d e te rm in e th e in d e pendent effect of each of these variables o n sev erity of le u k o p la k ia , a d ju s tin g for the effects of all of the other variables. Results T h e d is tr ib u tio n of th e 1,109 s tu d y subjects by d em o g rap h ic characteristics, e d u c a tio n a l le v el, c ig a re tte s m o k in g , alcohol co n su m p tio n , an d dental hygiene p ra c tic e s is sh o w n in T a b le 1. B ased on self-report, there were 493 smokeless tobacco nonusers (45%), 138 form er users (13%), an d 463 users (42%). A m o n g the users, 423 were w ithin-w eek users (39%), an d 40 w ere w ith in -m o n th users (4%). T h e m a jo r ity of w ith in -w e e k u se rs reported use w ith in the past day. As the n u m b e r o f fo rm e r u se rs a n d w ith in m o n th users was sm all a n d sim ila r to n u m b e rs o f n o n u s e rs , a ll s u b s e q u e n t analyses are based o n a co m p ariso n of n o n u s e rs (N = 493) a n d c u r r e n t u sers (N = 423 w ith in -w e e k u se rs). A m o n g c u rre n t u sers, th e average d u r a tio n of use was 6.4 years (SD = 4.2 years), the average tim e th a t tobacco was k ep t in the m o u th each day was 1.6 h ours (SD = 2.1 h o u rs), the tim e sin ce sm okeless to b a cc o w as la st u sed w as 17.8 h o u rs (SD = 33.5 hours), an d the age at in itia tio n of use was 17.7 years (SD = 3.7 years). All oral m ucosal ab n o rm a lities id e n tified am ong nonusers an d cu rren t users are presented in T ab le 2. A m ong sm oke less to b acco u sers, risk w as in c re a se d only for leukoplakic lesions, an d further analyses were confined to lesions in this categ o ry . T h e re w ere 214 le u k o p la k ic areas in 196 of the 423 cu rren t users and eight leu k o p lak ic areas in seven of the 493 nonusers (OR = 60.0, 95% C l = 40.588 . 8 ). T h is in c re a s e in ris k re m a in e d after ad ju stm en t for age, race, cigarette sm o k in g , a lc o h o l c o n s u m p tio n , a n d dental hygiene (adjusted O R = 66.0, 95%
Table 2 ■ Num ber* of oral mucosal lesions by sm okeless tobacco use status. Oral lesion sf Leukoplakia/ erythroplakia Degree I Degree 2 Degree 3 Degree 4 Other white lesions
Nonuser (N = 493)
Former user (N = 138)
W ithin m onth (N = 40)
W ithin week (N = 423)
8
3
2
214
6 2
2 1 0 0 11
2 0 0 0 3
85 105 21 2 20
0 0 52
* Numbers of lesions include m ultiple lesions in some subjects. + I .eukoplakia/erythroplakia and other white lesions are defined in the text.
Gradv-Others : ORAL MUCOSAL LESIONS IN SMOKELESS TOBACCO USERS ■ 119
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Table 3 ■ Location of leukoplakic lesions on oral mucosa. Location Anterior alveolar/labial R ight anterior alveolar/buccal R ight posterior alveolar/buccal Left anterior alveolar/buccal Leit posterior alveolar/buccal T otal area
Mandible (%)
Maxilla
42 7 12 18 15 94
1.8 0.4 1.3 0.4 2.1 6.0
(%)
Table 4 ■ Leukoplakic lesions in curren t sm okeless tob acco users by am o un t used. Subjects with lesions/total subjects
With lesion (%)
Odds ratios§
43/118 72/104 51/61
36.4 69.2 83.6
39.8 156.2 354.1
17.3-91.7 66.5-367.1 129.2-970.2
C hew f (pouches/w k) < 1 pouch 2-3 pouches > 4 pouches
5 /4 0 4/24 5/15
12.5 16.7 33.3
8.5 12.3 30.8
3.0-32.9 3.8-51.3 9.4-128.3
Hours in m outh/day+ > 0-0.5 > 0 .5 -1 .0 > 1.0-1.5 > 1.5-2.0 > 2.0-4.0 > 4 .0
26/106 39/91 30/56 27/40 35/56 26/31
24.8 42.8 53.6 67.5 62.5 83.8
22.6 52.1 80.1 144.2 115.7 361.0
9.5-53.7 22.2-122.3 32.2-199.5 53.2-390.9 46.0-290.8 107.3-1215.2
Snuff* (cans/w k) < 1 can 2-3 cans 4 cans
95% confidence intervals
* Subjects who usually use snuff, t Subjects who usually use chewing tobacco. £ H ours in m o u th /d ay = (num ber of cans or pouches used per w eek—num ber of dips or chews per can or p o u c h —n um ber of m in u tes each d ip or chew is usually held in th e m o u th ) -r 420 (60 m in u tes per h o u r— 7 days per week). § Odds ratios calculated with number of smokeless tobacco nonusers with leukoplakia as referent.
Table 5 ■ Leukoplakic lesions in current sm okeless tobacco users by duration, recency, and age of initiation of sm okeless tobacco use. Subjects with lesions/total subjects
% with lesions
OR*
95% CI
Duration £ 3 years 4-6 years 7-9 years > 10 years
34/105 79/152 39/74 42/84
32.4 52.0 52.7 50.0
33.2 75.1 77.4 69.4
14.2-77.9 33.4-169.1 32.3-185.5 29.4-164.1
T im e since last used > 24 hrs > 12-24 hrs > 1-12 hrs < 1 hr
11/59 22/97 65/118 81/109
18.6 22.7 55.1 74.3
15.9 20.4 85.2 200.8
5.9-42.9 8.4-49.3 37.1-195.2 84.9-475.1
5/14 34/78 134/275 19/47 4 /9
35.7 43.6 48.7 40.4 44.4
38.6 53.6 66.0 47.1 55.5
10.3-144.9 22.5-128.1 30.2-144.3 18.3-121.4 12.2-251.9
Age at initiation '■ 10 years 11-15 years 16-20 years 21-25 years > 25 years
* Odds ratios calculated with number ol smokeless tobacco nonusers with leukoplakia as referent.
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CI = 43.6-100.0). Most of the lesions were lo c a te d in th e m a n d ib u la r la b ia l a n d buccal gutter, w ith 42% in the an terio r m a n d ib u la r are a (T a b le 3). O f th e le u k o p lak ic lesions noted on e x a m in a tio n , 60% w ere lo c ate d a t sites in th e m o u th w h ere s u b je c ts r e p o r te d th a t smokeless tobacco was held. A m o n g u sers, risk fo r le u k o p la k ia in c re a se d w ith in c re a s in g a m o u n t o f to b acco used (T a b le 4). A m o n g u su a l snuff users, 36% w ho used one or fewer cans per week had leu k o p lak ic lesions, co m p ared w ith 69% of those w h o used two to three cans per week, an d 84% of those w ho used fo u r or m ore cans per week. T h e increased risk for leukoplakia am o n g usual chew ing tobacco users also increased w ith a m o u n t used, a lth o u g h the absolute risk was less th an for usual snuff users. Risk for leukoplakia increased d ram atically w ith in creasin g h o u rs per day th at smokeless tobacco was kept in th e m o u th . O f the su b je cts w h o h e ld to b acco in the m o u th for a h a lf-h o u r per day, 25% had leukoplakia, com pared w ith 84% w ho held it in the m o u th for 4 or m ore hours per day (T able 4). Risk for le u k o p la k ia in creased as d u r a tio n of u se exceeded 3 years, b u t d id n o t in c re ase fu rth e r w ith lo n g e r d u r a tio n o f u se (T a b le 5). T h e p r o p o r ti o n of su b je c ts w ith le u k o p la k ia d ec reased progressively as the tim e since tobacco w as last used becam e longer. O f those w ho had used smokeless tobacco w ith in th e la st h o u r , 63% h a d le u k o p la k ia , co m p ared w ith 23% of th o se w h o h ad n o t used for more th an 24 h ours (Table 5). T h e r e w as n o in c re a s e d ris k fo r le u k o p lak ia associated w ith earlier age at in itiatio n of the h ab it (Table 5). A lth o u g h in fo rm a tio n w as g ath ered concerning 19 different smokeless tobacco p ro d u c ts , th re e sn u ffs (C o p e n h a g e n , Skoal, an d H aw ken) an d two ch ew in g to b a c c o s (R e d m a n a n d L ev i G a r re tt) accounted for the m ajority of p ro d u cts used (Table 6). T h e risk for leukoplakia am o n g snuff users (O R = 87 com pared w ith n o n u sers) was m u ch h ig h e r th a n for users of chew ing tobacco (O R = 1 5 c o m p a re d w ith n o n u se rs). U sers o f C openhagen and Skoal were at very h ig h risk (O R for C openhagen use = 1 1 1 , for Skoal use = 81 com pared w ith nonusers), w h ile users of H aw k en were at low est risk of a n y p r o d u c t u sed (O R = 4 c o m p ared w ith n o n u sers). A d ju stm e n t for age, race, cigarette sm oking, alcohol c o n s u m p tio n , an d d e n ta l h y g ie n e d id n o t s ig n ific a n tly c h a n g e an y of th e findings reported.
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C o m p a r is o n s of sm o k e le ss to b a c c o users w ith lesions to users w ith o u t lesions are s h o w n in T a b le 7. In u n iv a r ia te a n a ly se s, th e risk fo r le u k o p la k ia increased sig n ific an tly w ith in c reasin g d u ratio n of use (O R = 1.06 for each year of d u ratio n of use) and increasing am o u n t used (O R = 1.74 for each h o u r per day held in the m o u th ). R isk sig n ific an tly decreased as th e tim e since sm okeless to b a c c o w as la st h e ld in th e m o u th increased (O R = 0.96 for each h o u r since last held in the m outh). T h ere was no increased risk for leukoplakia for earlier ag e at in itia tio n of the h a b it. As risk for leukoplakia am ong chew ing tobacco users was low a n d h o m o g e n eo u s, this gro u p was used as the referent for analyses of risk am o n g users of vario u s bran d s of sn u ff. R isk fo r le u k o p la k ia w as sig n ific an tly increased am o n g users of C openhagen (O R = 7.61 com pared w ith chew ing tobacco users) and Skoal (O R = 5.63 com pared w ith chew ing tobacco users). Com pared w ith users of chew ing tobacco, H aw ken users were on ly 22% as likely to have leukoplakic lesions. T o determ ine the in dependent effects of duration, am ount, recency, and type/ b rand used, m u ltip le logistic regression a n a ly sis w as p e rfo rm e d in c lu d in g all of these v aria b les in the m odel. A fter a d ju stm e n t for the effects of the other v a ria b le s , d u r a tio n of use a n d age at in i t i a t i o n w ere n o t in d e p e n d e n t risk factors for leukoplakia. T h e am o u n t used w as in d e p e n d e n tly a n d s ig n ific a n tly associated w ith risk for leukoplakia (OR = 1.55 for each h o u r held in the m outh). Persons w ho held tobacco in the m outh for 4 hours per day had an O R 5.8 times hig h er th an users w ho held tobacco in the m outh only 1 h o u r per day (O R for 4 hours per day of use = 1.554). Recency of use w as also in d e p e n d e n tly a n d significantly associated w ith leukoplakia (OR = 0.98 per h o u r since last use). O R for persons who had not used smokeless to b a cc o for 24 h o u rs w ere o n ly 0.62 c o m p a re d w ith th o se w h o h a d used w ithin the last hour (OR = 0.9824). Use of C openhagen and Skoal was indepen dently and significantly associated w ith le u k o p la k ia . T h e odds of h av in g le u koplakia in C openhagen users were 6.0 times higher and in Skoal users 4.2 times h ig h e r th an in chew ing tobacco users. H aw ken was less likely than any product used to cause leukoplakia. A lthough the finding was not statistically significant, alter ad ju stm e n t for o th e r variables of use, the O R for H aw ken users com pared with chew ing tobacco users was 0.28.
Table 6 ■ L e u k o p la k ie le s io n s in c u r re n t s m o k e le s s to b a c c o u s e rs by ty p e and brand o f sm okeless tobacco usually used. Subjects with lesions/total subjects
With lesions
(%)
ORJ
95% Cl
Snuff totals* Copenhagen Skoal Hawken Others
169/304 131/213 34/63 1/19 3/9
55.6 61.3 54.0 5.3 40.0
86.9 110.9 81.4 3.9 34.7
39.9-189.5 50.1-245.8 33.2-199.4 0.5-33.0 7.2-167.5
Chew totals'! Redman Levi-Garrett Other
15/87 6/37 8/42 1/8
17.0 16.2 19.4 11.1
14.5 13.4 16.3 9.9
5.7-56.7 4.3-42.4 5.6-47.7 1.1-91.7
* Subjects who usually used snuff, t Subjects who usually used chewing tobacco. X Odds ratios calculated with number of smokeless tobacco nonusers with leukoplakia as referent.
Table 7 ■ L o g is tic re g re s s io n a n a ly s is o f le u k o p la k ia s in c u rre n t s m o k e le s s tobacco users by d uration, am ount used, age a t initia tio n , tim e since last use, and type/brand used.
Variable
Risk per
OR*
Adjusted ORt
CIJ
Duration
Year of smokeless tobacco use H our/day smokeless tobacco use Year since smokeless tobacco first tried Hour since smokeless tobacco last used
1.06§
0.99
0.92-1.06
174§
1.55§
1.22-1.96
1.01
1.04
0.96-1.12
0.95§
0.98§
0.96-0.99
7.61 § 5.63§ 0.27 2.40
6.00§ 4 .10§ 0.29 0.72
2.99-12.05 1.72-9.76 0.03-3.16 0.08-6.83
Amount Initiation Recency Type brand Copenhagen Skoal Hawken Other snuff
Referent is users of chew ing tobacco
* Univariate OR from logistic regression model where outcome = leukoplakia (present or absent) and only one predic tor variable as noted. t M ultivariate OR from logistic regression model where outcome = leukoplakia (present or absent) and all variables in the table included as predictors. | 95% confidence interval for the adjusted OR. § P < 0.05.
In clu d in g age, race, cigarette sm oking, alcohol consum ption, and dental hygiene in the m ultivariate m odel d id n ot alter the findings. A nalyses of u sers w ith le u k o p la k ia rev ealed a s ig n ific a n t in c re a se in th e p e rc e n t of severe le sio n s (d eg ree 3 o r 4) w ith in c re a s in g a m o u n t of use, d u ratio n of use, shorter tim e since last use, an d in users of snuff, p a rtic u la rly C openhagen or Skoal (Table 8). Severity of leu k o p lak ic lesions d id n o t vary by age, race, c ig a re tte s m o k in g , a lc o h o l consum ption, or dental hygiene practices. M ultiple logistic regression analysis was perform ed to determ ine the independent effect of these v ariab les on severity of lesions. N o ch ew in g tobacco user h ad a severe lesion, so th at there was no
adequate com parison g ro u p for the snuff u sers. T h u s , th e m u ltiv a r ia te m o d e l in c lu d e d o n ly a m o u n t, d u r a tio n , a n d recen cy . In th is a n a ly s is , a m o u n t of sm o k e le ss to b a c c o u se d w as th e o n ly in d e p e n d e n t p r e d ic to r o f th e sev erity of the lesion (OR = 1.22, 95% C l = 1.011.49). N in ety -eig h t leu k o p lak ic areas in 92 subjects were biopsied an d then exam ined h is t o p a th o lo g ic a lly . T h e r e w as c lo se c o r r e la tio n b etw e en th e a m o u n t of hyperkeratosis observed m icroscopically an d the clinical degree of the lesion (P = 0.001). All lesions were benign, b u t one specim en had m ild ep ith elial d ysplasia (p e rc e n t w ith d y s p la s ia = 1%, 95% C l = 0%-4%). T h is le s io n w as c lin ic a lly classified degree 1, an d occurred in a
Grady-Others : ORAL MUCOSAL LESIONS IN SMOKELESS TOBACCO USERS ■ 121
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Table 8 ■ S e v e rity o f le u k o p la k ia by age at in itia tio n o f s m o k e le s s to b a c c o use, a m o u n t, d u ra tio n and recen cy of sm okeless to b a cc o use and typ e /b ra n d of sm okeless tobacco used. T otal lesions
Degree (%) 1 or 2
Degree (%) 3 or 4
Age at initiation* 1= 10 years 11-15 years 16-20 years 21-25 years > 25 years
5 34 134 19 4
80.0 91.2 88.1 89.5 75.0
20.0 8.8 11.9 10.5 25.0
A m ou n tf > 0-0.5 hours > 0 .5 -1 .0 hours > 1.0-1.5 hours > 1.5-2.0 hours > 2.0-4.0 hours > 4 hours
26 39 30 27 35 26
100.0 97.4 90.0 77.8 88.6 73.1
0.0 2.6 10.0 22.2 11.4 26.9
Duration^ < 3 years 4-6 years 7-9 years > 10 years
34 79 39 42
91.2 88.6 92.3 81.0
8.8 11.4 7.7 19.0
Recency§ < 1 hour > 1-12 hours > 12-24 hours > 24 hours
81 65 22 11
82.7 90.8 95.4 100.0
17.3 9.2 4.6 0.0
169 131 34 1 3 15 6 8 1
87.0 86.3 91.2 100.0 66.7 100.0 100.0 100.0 100.0
13.0 13.7 8.8 0.0 33.3 0.0 0.0 0.0 0.0
Type/brand Snuff Copenhagen Skoal Hawken Other snuff C hew ing tobacco Redman Levi-Garrett Other chew
* Age at which smokeless tobacco was first used, t Hours per day any smokeless tobacco product was helc in the mouth. X Years of smokeless tobacco use. § Hours since smokeless tobacco last used.
sm o k eless tobacco u se r w h o h ad used o n e -h a lf can of C o p e n h ag e n snuff p er day for 3 years. Discussion L eu k o p lak ic /ery th ro p lak ic lesions were very s tr o n g ly a s so c ia te d w ith use of sm o k eless to b a cc o in th is p o p u la tio n of h ealth y y o u n g m en. A m ong current sm o k e le ss to b a cc o u se rs, 46.3% h a d leu koplakia (O R = 60 for users com pared w ith nonusers). O ther investigators13'8'11' 13 have noted an increased risk for oral m ucosal lesions in users, alth o u g h none had controlled for the com bined effects of the p o te n tia l co n fo u n d in g variables in c lu d e d h ere. T h e e le v a te d O R fo r leu k o p lak ia in o u r p o p u la tio n are strik ingly high. Some previous studies have n o t ex am ined a control g ro u p of n o n 122 ■ JADA, Vol. 121, July 1990
u s e rs ,11’13 o r th ey h av e n o t re p o r te d findings in the nonusers .2'12 O ffenbacher a n d W eathers 3 fo u n d an O R of 6, an d W olfe a n d C a rlo s 8 fo u n d a n O R of 9 for oral m ucosal lesions in users co m pared w ith nonusers. T h e m uch higher O R for le u k o p lak ia in o u r study p o p ulatio n m ig h t be a result of differences in the p o p u latio n s studied. Both O ffen b a c h e r a n d W e a th e rs 3 a n d W o lfe a n d C a rlo s 8 stu d ie d a d o le sc e n ts w h o m ay have used smokeless tobacco for a shorter tim e, o r used a sm a lle r a m o u n t th a n the y o u n g to m id d le-ag ed m en in o u r study. In additio n , o u r exam iners were h ighly trained, a n d subtle lesions were recorded. A m o u n t of sm o k eless to b acco used, recency of use, type, an d b ran d of snuff used were sig n ifican tly associated w ith risk for leukoplakia am o n g users. O ther
investigators have suggested an increase ris k fo r o ra l le sio n s b e c a u se o f th e increasing am o u n t of smokeless tobacco used ,2'81112 b u t the im portance of recency of use and brand used has not been noted. We decided to investigate the independent effect of recency of use because, d u rin g p ilo t stu d ies, su b je cts n o te d th a t o ral lesions occurred if they used for a short tim e o r b rie fly in c re a se d th e a m o u n t of use, an d disappeared if they q u it briefly or reduced use. Recency is independently associated w ith le u k o p lak ia, even after a d ju s tm e n t for a m o u n t a n d d u ra tio n , suggesting that lesions result from sh o rt term m u c o sal in ju ry a n d m ay resolve quickly w ith term ination of use. A m ong subjects w ith leukoplakia w ho returned several days after the in itia l ex am in atio n for oral biopsy, some lesions h ad resolved. S urprisingly, after ad ju stm en t for am o u n t an d recency, d u ratio n was n o t ind ep en d e n tly asso cia te d w ith th e o cc u rre n ce of leu koplakia am ong smokeless tobacco users. T h e ap p aren t increase in risk for leu k o p lak ia in subjects w ith long d u ra tio n of use w as th e r e s u lt o f th e fact th at these subjects used m ore smokeless tobacco m ore recently. O ther investigators may have no ted increased risk for oral lesions in users of lo n g d u ratio n because no m u ltiv ariate analysis was perform ed to c o n tro l for a m o u n t a n d recency of use .2'8'11'12 S nuff was m u ch m ore stro n g ly asso ciated w ith le u k o p la k ia th a n ch ew in g tobacco. T h is is of p a rtic u la r co n cern as use of snuff is increasing am o n g young m en an d snuff is m ore strongly associated w ith oral cancer th an chew ing tobacco .10 Users of C openhagen and Skoal, the two m ost com m only used snuffs, were four to six tim es m ore likely to have leukop la k ic lesio n s co m p ared w ith users of chew ing tobacco. N ot all snuffs appear to be m ore likely to cause leu k o p lak ia th a n c h e w in g tobacco. O n ly o n e leukoplakic lesion was detected am ong the 19 u sers of H a w k e n (th e th ir d m o st com m on snuff used). T h e reason for these differences is unclear, b u t may be related to d iffe re n c e s in p H o r c o n te n t of carcinogens, nicotine, o r oth er substances contained in smokeless tobacco products. A ccording to data reported by H offm an an d o th e r s , 14 C o p e n h a g e n a n d S k o al c o n ta in m o re v o la tile n itr o s a m in e s , tobacco specific n itro sam in es, benzo(a)p y ren e , p o lo n iu m , n itr a te , a lk a lo id s , le ad , a n d c a d m iu m c o m p a re d w ith H aw k en . T h e p H of C o p e n h ag e n an d Skoal is 7.8 w ith a m oisture content of 50% an d 51% respectively, com pared w ith
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a pH of 6.0 and a moisture content of 20% for Hawken.14 Further investigation is needed to determine which com ponents m ight increase the risk for leukoplakia. Severity of leukoplakic areas increased w ith in creasing am ou n t of sm okeless tobacco used and appear to be more severe in snuff users. Hirsch and others11 studied 50 male users aged 15-84 with oral lesions and reported that lesion severity increased w ith age of the user, duration of use, and am ount used, but no m ultivariate m ethods were used to con trol for the effects of other parameters of use. Wolfe and Carlos8 did not find any relationship between parameters of use and lesion severity.
Sin ce acceptance o f th is m a n u scrip t, w e have obtained similar data on 1,050 subjects during spring tr a in in g in 1989. D u r in g th is e x a m in a tio n , w e inquired about seasonal use of sm okeless tobacco. Sm okeless tobacco w as reported to be used only or mostly during baseball season by 203 of the 397 users. T o determ ine the im p act o f season al use, w e repeated the analyses presented in th is paper on the 1989 data including seasonal use as a variable. T h e resu lts w ere e ss e n tia lly the sam e as those presented in the report.
T h is study w as supported by G rant no. 5 P01 DE08547-02 from the N ational Institute for Dental Research. T he informed consent of all hum an subjects who p a rticip a ted in th e e x p e rim e n ta l in v e stig a tio n reported or described in this manuscript was obtained after the nature o f the p roced u re and p o ssib le discomforts and risks had been explained fully.
Summary An increased risk for oral cancer in lon g term snuff users has been reported10’15’16 and our study clearly shows that smoke less tobacco is strongly associated with oral leukoplakia. L euk oplakic lesion s in smokeless tobacco users are common and w ould be of trem endous m edical and public health concern if m any of these lesion s were destined to becom e malignant. However, leukoplakic lesions seem to occur rapidly w ith sm okeless tobacco use, may resolve quickly w ith cessation, and are not strongly related to duration. T h e sig n ifica n ce o f le u koplakia in smokeless tobacco users and its relation to oral cancer is not clear, particularly if the h abit is con tin u ed or if the le u k o p la k ic le sio n p ersists. Mutagenesis and carcinogenesis may be related to long-term use or to certain com ponents of tobacco, but at present we cannot accurately d istin g u ish dysp lastic from benign lesion s clin ically, and we do not understand the factors that m ight cause benign oral m ucosal lesions to become malignant.
T h e authors thank the m an agem en t, trainers, players, coaches, and medical staff of the follow ing p r o fe ssio n a l b a seb all team s: C a lifo r n ia A n gels, C h ica g o C ubs, C lev ela n d In d ia n s, M ilw aukee Brewers, Oakland Athletics, San Francisco Giants, and Seattle M ariners, and ja n a M urray, R N , for her assistance. Dr. Grady is assistant c lin ic a l professor, epide m io lo g y and m edicine, School of M edicine, U n i versity o f C a lifo rn ia, San Francisco; Dr. G reene is professor and dean, School of Dentistry, University of California, San Francisco; Dr. Daniels is professor of oral pathology, School of Dentistry; Dr. Ernster is professor an d ch air o f E p id e m io lo g y , S ch o o l o f M edicine; Dr. R obertson is professor, S ch ool o f Dentistry, University of California, San Francisco, and dean, School of Dentistry, University of British Colum bia; Dr. Hauck is professor o f biostatistics, School o f M edicine, U niversity of California, San Francisco; Dr. D. G reenspan is c lin ic a l professor o f oral m edicine, Sch ool o f D entistry, U niversity o f California, San Francisco; and Dr. J. Greenspan is professor and chair o f oral m e d ic in e, S ch o o l of Dentistry, University of Calfornia, San Francisco. Address requests for reprints to Dr. Grady, Veterans Administration Medical Center (111A1), 4150 Clement St, San Francisco, 94121. 1. Axell T , Mornstad H , Sundstrom B. The relation o f the c lin ic a l p ictu re to the h is to p a th o lo g y o f sn u ff d ip p er’s le sio n s in a S w ed ish p o p u la tio n . J Oral Pathol 1976;5:229-36. 2. Greer RO Jr, Poulson TC. Oral tissue alterations
associated w ith th e u se o f sm ok eless tob acco by teen-agers. O ral S u rg O ral M ed O ral P a th o l 1983;56:275-84. 3. Offenbacher S, Weathers DR. Effects of smoke less tobacco on the periodontal m ucosal and caries status of adolescent males. J Oral Pathol 1985;14:16981. 4. Pindborg JJ, Reibel J, Roed-Petersen R, Mehta FS. T obacco-indu ced changes in oral leu k op lak ic epithelium . Cancer 1980;45:2230-6. 5. P in d b o r g JJ , R e n stru p G. S tu d ies in oral leukoplakia II. Effect of snuff on oral epithelium . Acta Derm Venereol 1963;43:271-6. 6. Roed-Peterson B, Pindborg JJ. A study of Danish s n u ff-in d u c ed oral le u k o p la k ia . J O ral P a th o l 1973;2:301-13. 7. Sm ith JF, M incer H A , H op k in s KP, B ell J. Snuff-dipper’s lesion. A cytological and pathological stu d y in a large p o p u la tio n . A rch O to la r y n g o l 1970;92:450-6. 8. W olfe M D, Carlos JP. Oral health effects of smokeless tobacco use in Navajo Indian adolescents. Com m unity Dent Oral E pidem iol 1987;15:230-5. 9. Mehta FS, G upta PC, Pindborg JJ. C hew ing and sm ok in g habits in relation to precancer and oral cancer. J Cancer Res C lin O ncol 1981;99:359. 10. Advisory Com m ittee to the Surgeon General. T h e H e a lth C o n seq u e n c es o f U s in g S m ok eless Tobacco. Bethesda, MD: US Department of H ealth and H u m a n S ervices, P u b lic H e a lth Service, 1986;NIH publication no. 86-2874. 11. Hirsch JM, H eyden G, T hilander H. A clinical, h is to m o r p h o lo g ic a l and h isto c h e m ic a l study on snuff-ind uced le sio n s o f varying severity. J Oral Pathol 1982;11:387-98. 12. Poulson T C , L indenm uth JE, Greer R O Jr. A com parison of the use of sm okeless tobacco in rural and urban teenagers. CA 1984;34:248-61. 13. Christen AG, M cDaniel RK, Doran JE. Snuff dip ping and tobacco chew ing in a group of Texas college athletes. T ex Dent J 1979;97:6-10. 14. H offm an D , Adam s JD , L isk D , F isenne I, B runnem ann KD. T o x ic and carcin ogen ic agents in dry an d m o is t sn u ff. J N a tl C ancer Inst 1987;79:1281-6. 15. W orld H e a lth O r g a n iz a tio n In te r n a tio n a l Agency for Research and Cancer. Volum e 37: IARC M onographs on the Evaluation of the carcinogenic risk of chem icals to humans: tobacco habits other than smoking; betel q u id and areca nu t chew ing, and some related nitrosamines. Lyon: World Health Organization, 1985. 16. W in n D M , B lot W J, Shy CM, P ick le LW , T o le d o A, Fraum eni JF. S n u ff d ip p in g and oral cancer am ong w om en in the southern U nited States. N Engl J Med 1981;304:745-9.
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Grady-Others : ORAL MUCOSAL LESIONS IN SMOKELESS TOBACCO USERS ■ 123
T he risk fo r oral m ucosal lesions associated w ith use o f sm okeless tobacco a m o n g 1,109 professional baseball players during spring tra in in g in 1988 was investigated. L e u k o p la k ia was very strongly associated w ith use o f sm okeless tobacco in this p o p u la tio n o f healthy y o u n g m en. O f the 423 current sm okeless tobacco users, 196 had le u ko p la kia com pared to seven o f the 493 nonusers (O R = 60.0, 95% C l = 40.5-88.8). T h e a m o u n t o f sm okeless tobacco used (in hours per day th a t sm okeless tobacco was held in the m o u th ), recency o f sm okeless tobacco use (hours since last use), type (sn u ff versus chew ing tobacco), a n d brand o f s n u ff used were significa n tly associated w ith risk fo r leu ko p la kic lesions a m o n g sm okeless tobacco users. N inety-eight leu ko p la kic areas in 92 subjects were biopsied and ex a m in ed m icroscopically. A ll lesions were benign, b ut one specim en h a d m ild ep ith elia l dysplasia. T h e long-term significance o f leu ko p la kia in sm okeless tobacco users a n d their relation to oral cancer is n o t clear.
Oral mucosal lesions found in smokeless tobacco users D. G rady, M D , M P H ; J. G reene, D M D , M PH ; T . E. D a n iels, DDS; V. L . Ernster, P hD ; P . B. R ob ertson , D D S , MS; W . H a u ck , PhD ; D . G reensp an, BDS; J. G reen sp an , BD S, P h D , FR C Path; S. S ilv erm an Jr., M A, D D S
se of smokeless tobacco (chew ing tobacco an d snuff) has been asso cia te d w ith o ra l m u c o sal lesions ,1-8 and some of these lesions may e v e n tu a lly beco m e m a l i g n a n t .69 T h e recent increase in the prevalence of use of smokeless tobacco in the U nited States 10 co u ld lead to in c re a sin g incidences of oral cancer .3 O ral m ucosal lesions occur at the site of p lacem en t of the to b a cc o 121112 an d prelim inary evidence suggests th a t lesions are associated w ith d u ratio n and am o u n t of smokeless tobacco use .211128 However, m a n y of th e s tu d ie s of o ra l m u c o sa l lesio n s in sm okeless tobacco users are d iffic u lt to in te rp re t b ecause they did not incorporate clear clinical diagnostic c r ite r ia for o ra l le sio n s, b io c h e m ic a l validation of smokeless tobacco use status, ap p ro p riate control groups, or assessment of potential co nfounding variables such as cigarette sm oking an d alcohol con
U
sum ption. At present, we do n o t know exactly how sm okeless tobacco causes o ra l m ucosal lesio n s or w h ich g ro u p s of users are m ost susceptible. T h e effect of recency of use, ty p e, a n d b ra n d of sm o k e le ss to b a cc o u sed , a n d age a t in itia tio n has n o t been addressed. A vail able in fo rm a tio n does n o t allow us to accurately predict histological appearance a t b io p sy o r to e s tim a te m a lig n a n t transform ation potential. We e x a m in e d p ro fe s s io n a l b aseb a ll players d u rin g sp rin g tra in in g in 1988 to determ ine the risk for oral m ucosal lesions in smokeless tobacco users com pared w ith nonusers, co n tro llin g for age, race, cigarette sm oking, alcohol use, and d en tal hygiene. S m okeless tobacco use status was carefully assessed to determ ine th e effect of a m o u n t, d u r a tio n , an d recency of sm okeless tobacco use, type an d b ra n d used, a n d age at in itia tio n of smokeless tobacco use o n risk for oral
lesio n s. A ll p la y ers w ith le sio n s were o ffe re d o r a l b io p s y to d e te rm in e th e prevalence of h isto p ath o lo g ic ab n o rm al ities am o n g smokeless tobacco users w ith leukoplakia. Methods D u rin g sp rin g train in g , we studied 1,109 mem bers of the m ajo r an d m in o r league pro fessio n al baseball team s: C alifo rn ia Angels, C hicago Cubs, Cleveland Indians, M ilw aukee Brewers, O ak lan d A thletics, San Francisco G iants, an d Seattle M ari ners. Subjects com pleted a q uestionnaire th a t in c lu d e d d e m o g ra p h ic d a ta a n d in f o r m a tio n o n e d u c a tio n , c ig a re tte s m o k in g , a lc o h o l c o n s u m p tio n , a n d d e n ta l h y g ie n e . D eta ile d in f o rm a tio n con cern in g patterns of smokeless tobacco u se w as a s c e rta in e d , in c lu d in g th e am o u n t (hours per day smokeless tobacco was held in the m outh), d u ratio n (years JADA, Vol. 121, July 1990 ■ 117
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since first use), and recency (hours since last used), age at in itiatio n of use, type (sn u ff versus c h e w in g to b acco ), a n d brand. T h e sprin g train in g schedule required that the study be conducted in geograph ic a lly s e p a ra te te am f a c ilitie s a n d be lim ited to about 20 m inutes per subject. T h e r e f o r e , th e e v a lu a tio n s w ere p e r fo rm ed by seven e x a m in a tio n g ro u p s. Each g ro u p consisted of personnel from the U niversity of C alifornia San Francisco in c lu d in g a dentist w ho perform ed the e x a m in a tio n , a d e n ta l h y g ie n is t w h o reco rd ed the resu lts, an d tw o research assistants w ho obtain ed other in fo rm a tio n . B efore th e s ta r t of the stu d y , e x a m in a tio n g r o u p s w ere e x ten siv ely tra in e d to e s ta b lish u n ifo rm ity in a ll p ro ced u res. C lin ic a l slides an d e x a m in atio n of patients w ith a variety of oral m u c o sa l c h a n g e s served to e s ta b lis h agreem ent am ong exam iners for descrip tio n , c la s s ific a tio n , a n d g r a d in g of m u c o sa l le sio n s. D iffe re n ce s betw een exam iners were discussed a n d resolved, an d th e process w as rep e ate d u n til at le ast 90% a g re e m e n t b etw een any tw o e x a m in e rs w as a c h ie v e d for a ll m easurem ents. Subjects were ex am in ed at the seven sp rin g train in g cam ps in a m obile dental v an o r w ith use of p o r ta b le d e n ta l eq u ip m en t (chair, light, air compressor). A m o u th m irro r, to n g u e blade, a n d 2x 2 -in g au ze w ere used d u r in g the ex am ination. Before entering the exam in a tio n are a, each su b je ct th o ro u g h ly rin se d h is m o u th tw ice w ith w ater to rem ove any signs of sm okeless tobacco use. Subjects were also asked not to reveal th e ir sm o k e le ss to b a c c o use sta tu s to the exam iner or recorder. All oral m ucosal surfaces were carefully inspected. If any w hite or red lesion of the oral m u c o sa w as d e te c te d , th e e x a m in e r c la ssifie d th e le sio n as le u k o p la k i a / ery th ro p lak ia—w hich is any w hite lesion th a t d id n o t ru b off a n d w as n o t identifiable clinically as som e other w hite lesion, o r any red lesion not identifiable c lin ic a lly as som e o th e r red lesion or a lesion th a t included b oth red and w hite changes; and other w hite lesion—w hich is an y w h ite lesion th a t was clinically id e n tif ia b le . T h is c a te g o ry in c lu d e s frictional keratoses in c lu d in g interdental h yperkeratosis (a lin ear w hite lesion at the interdental line on the buccal mucosa, p re su m a b ly cau sed by ir r ita tio n from th e te e th ), ch eek b iti n g (an ir re g u la r w h ite to red le sio n in th e area of the interdental line, presum ably caused by 118 ■ JADA, Vol. 121, July 1990
the h ab it of sucking an d b itin g on the cheeks) an d re tro m o la r h y p e rk e ra to sis (a w hite lesion in the retrom olar trigone, presum ably caused by irrita tio n of the retrom olar area d u rin g m astication). Any lesion classified as le u k o p la k ia / ery th ro p lak ia was subsequently defined by size in m illim eters; lo c atio n in the m o u th ; c o lo r (n o rm a l, w h ite , red , o r red an d white); texture (sm ooth, g ran u lar, a n d co rru g ate d ); c o n to u r (raised , flat, or cratered); a n d degree of severity on a scale from 1 to 4 (1 = no or only slight color chan g e w ith a tex tu re change; 2 = c o lo r a n d te x tu re c h a n g e , b u t n o thickening; 3 = color an d texture change w ith m ild to m oderate th ick en in g ; 4 = no norm al color, severe texture change, a n d heavy th ic k e n in g (F ig 1-5). Since few o f th e le u k o p la k ic /e r y th r o p la k ic le sio n s c o n ta in e d an y red c o lo r, they are su b se q u e n tly referred to as le u k o plakia. B ased o n se lf-re p o rte d sm o k eless tobacco use, subjects were classified as nonusers (subjects w ho h ad never used sm o k e le ss to b a c c o , o r w h o h a d used smokeless tobacco in the past b u t never m o re fre q u e n tly th a n o n ce a m o n th ); fo rm e r u se rs (su b je c ts w h o h a d used sm o k e le ss to b a cc o m o re th a n o n c e a m o n th in the past b ut w ho had n o t used w ith in the previous m onth); an d users (su b jec ts w h o used sm okeless tobacco m ore frequently th an once a m o n th and w ho had used smokeless tobacco w ithin th e p a s t m o n th ). U sers w ere f u r th e r s e p a ra te d in to th o se w h o h a d u sed smokeless tobacco w ith in the past m o n th b u t n o t w ith in the past week, an d those w ho had used w ith in the past week. Serum co tin in e and thiocyanate were m easured for biochem ical v alid atio n of self-reported smokeless tobacco use. T h e se ru m c o tin in e level is e le v a te d in cigarette smokers an d users of smokeless tobacco, w h ile th io c y a n a te is elevated only in cigarette smokers. Elevated serum cotinine in the presence of norm al serum thiocyanate was considered biochem ical evidence of smokeless tobacco use. U sing this criterio n , only 5% of subjects w ho reported that they did n ot use smokeless tob acco w ere classified b io c h e m ic a lly as users. As blood was n ot available for 22% of subjects, an d because self-reported use was h ig h ly ac cu rate, use sta tu s is reported based on self-report only. S u b je c ts id e n tif ie d a ll sm o k eless tobacco products that they used, the site w h ere they u s u a lly h e ld th e to b acco , a n d th e typ e a n d b ra n d . A m o u n t of smokeless tobacco use was determ ined
Fig 1 ■ Normal oral mucosa.
Fig 3 ■ Degree 2 oral leukoplakia.
Fig 4 ■ Degree 3 oral leukoplakia.
Fig 5 ■ Degree 4 oral leukoplakia.
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Table 1
■ D istribution of study subjects
by d em o g ra p h ic and o th e r c h a ra c te ristics (N = 1,109). N*
Percent
Age (years) <20 20-24 25-29 30-34 35-39 >40
95 562 286 79 39 40
8.6 51.0 26.0 7.2 3.5 3.6
Race White Hispanic Black Asian
753 181 157 16
68.0 16.4 14.2 1.4
Educational level Elementary school Some high school H igh school graduate Some college College graduate
29 43 203 543 246
2.7 4.0 19.1 51.0 23.1
Cigarette sm oking Never smoked Former smoker Current smoker
956 100 44
86.9 9.1 4.0
Alcohol consum ptionf Nondrinker 1-13 drinks/week 14-20 drinks/week > 20 drinks/week
253 773 56 27
22.8 69.7 5.0 2.4
Frequency of teeth cleaning at a dental office Every 6 months Every year Every 2 years Rarely or never
317 445 195 141
28.9 40.5 17.8 12.8
Frequency of flossing Daily Weekly M onthly Rarely or never
359 387 154 204
32.5 35.1 13.9 18.5
Frequency of brushing teeth Daily 1,101 Weekly 2 Rarely or never 2
99.6 0.2 0.2
* Totals in each category may differ bet ause of missing values. f A nondrinker is a player who drinks no alcohol or
who has drunk fewer than ten drinks in the past year.
by the n u m b e r of snuff or p o u ch es of chew ing tobacco used per week. T hose w ho usually used one type of smokeless tobacco occasionally used the other type. T h u s, the n um ber of hours that smokeless tobacco was held in the m outh per day was calcu lated as a co m b in ed m easure of intensity of use. Recency of use was d e te rm in e d as h o u r s sin c e sm o k e le ss tobacco was last used. In analyses based on n um ber of sub jects, those w ith m ore th an one leukoplakic lesion were classified by the lesion of the highest degree lesion. T h e effects
of smokeless tobacco use, am o u n t, d u ra tion, recency, age at in itia tio n of use, and type and b rand used on the occur rence of le u k o p la k ic areas an d o n the severity of lesions w ere assessed u sin g odds ratios (OR), 95% confidence intervals (Cl), and separate x 2 tests of significance. W hen the incidence of a disease is rare, the O R closely approxim ates the relative risk . A lth o u g h th e d isease of in te re st in our study (leukoplakia) was n ot rare, O R were used as th e m easu re of asso ciation to perm it m u ltiv a ria te analysis u sin g logistic regression to co n tro l for p o ten tial confounders. In this case, the O R are a valid m easure of association, b u t overestim ate the relative risk. A m u ltip le logistic regression m odel was used to adju st for the effects of age, race, cigarette sm oking, alcohol use, and d e n ta l h y g ie n e p ra c tic e s o n th e a sso c ia tio n of ea c h v a r ia b le o f in te re s t ( d u ra tio n , a m o u n t, age a t in it ia t io n , recency, type, brand) w ith the occurrence of leukoplakic lesions in users com pared w ith n o nusers. In su b se q u en t analyses c o n fin e d to sm o k e le ss to b a c c o u sers, u n iv a ria te O R s fo r le u k o p la k ia were c a lc u la te d fo r d u r a tio n (p er y ear of smokeless tobacco use), am o u n t (per hour ST held in the m o u th per day), age at in itiatio n (per year of age w hen smokeless tobacco was first used), recency (per hour since la st usage) a n d ty p e /b ra n d used (each b ra n d c o m p a re d to a ll u sers of ch ew in g tobacco). A m u ltip le lo g istic re g re ssio n m o d e l w as th e n u sed to determ ine the in dependent effect of each of these variables on risk of leukoplakia, a d ju s tin g fo r th e effects of a ll of the other variables. In analyses confined to users w ith leukoplakia, u n iv ariate ORs for severity of lesio n (m ild = degree 1 or 2 versus severe = degree 3 or 4) were c a lc u la te d for d u r a tio n , a m o u n t, age a t in itia tio n , recency, an d ty p e /b ra n d used. A m u ltip le logistic regression model
w as th e n used to d e te rm in e th e in d e pendent effect of each of these variables o n sev erity of le u k o p la k ia , a d ju s tin g for the effects of all of the other variables. Results T h e d is tr ib u tio n of th e 1,109 s tu d y subjects by d em o g rap h ic characteristics, e d u c a tio n a l le v el, c ig a re tte s m o k in g , alcohol co n su m p tio n , an d dental hygiene p ra c tic e s is sh o w n in T a b le 1. B ased on self-report, there were 493 smokeless tobacco nonusers (45%), 138 form er users (13%), an d 463 users (42%). A m o n g the users, 423 were w ithin-w eek users (39%), an d 40 w ere w ith in -m o n th users (4%). T h e m a jo r ity of w ith in -w e e k u se rs reported use w ith in the past day. As the n u m b e r o f fo rm e r u se rs a n d w ith in m o n th users was sm all a n d sim ila r to n u m b e rs o f n o n u s e rs , a ll s u b s e q u e n t analyses are based o n a co m p ariso n of n o n u s e rs (N = 493) a n d c u r r e n t u sers (N = 423 w ith in -w e e k u se rs). A m o n g c u rre n t u sers, th e average d u r a tio n of use was 6.4 years (SD = 4.2 years), the average tim e th a t tobacco was k ep t in the m o u th each day was 1.6 h ours (SD = 2.1 h o u rs), the tim e sin ce sm okeless to b a cc o w as la st u sed w as 17.8 h o u rs (SD = 33.5 hours), an d the age at in itia tio n of use was 17.7 years (SD = 3.7 years). All oral m ucosal ab n o rm a lities id e n tified am ong nonusers an d cu rren t users are presented in T ab le 2. A m ong sm oke less to b acco u sers, risk w as in c re a se d only for leukoplakic lesions, an d further analyses were confined to lesions in this categ o ry . T h e re w ere 214 le u k o p la k ic areas in 196 of the 423 cu rren t users and eight leu k o p lak ic areas in seven of the 493 nonusers (OR = 60.0, 95% C l = 40.588 . 8 ). T h is in c re a s e in ris k re m a in e d after ad ju stm en t for age, race, cigarette sm o k in g , a lc o h o l c o n s u m p tio n , a n d dental hygiene (adjusted O R = 66.0, 95%
Table 2 ■ Num ber* of oral mucosal lesions by sm okeless tobacco use status. Oral lesion sf Leukoplakia/ erythroplakia Degree I Degree 2 Degree 3 Degree 4 Other white lesions
Nonuser (N = 493)
Former user (N = 138)
W ithin m onth (N = 40)
W ithin week (N = 423)
8
3
2
214
6 2
2 1 0 0 11
2 0 0 0 3
85 105 21 2 20
0 0 52
* Numbers of lesions include m ultiple lesions in some subjects. + I .eukoplakia/erythroplakia and other white lesions are defined in the text.
Gradv-Others : ORAL MUCOSAL LESIONS IN SMOKELESS TOBACCO USERS ■ 119
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Table 3 ■ Location of leukoplakic lesions on oral mucosa. Location Anterior alveolar/labial R ight anterior alveolar/buccal R ight posterior alveolar/buccal Left anterior alveolar/buccal Leit posterior alveolar/buccal T otal area
Mandible (%)
Maxilla
42 7 12 18 15 94
1.8 0.4 1.3 0.4 2.1 6.0
(%)
Table 4 ■ Leukoplakic lesions in curren t sm okeless tob acco users by am o un t used. Subjects with lesions/total subjects
With lesion (%)
Odds ratios§
43/118 72/104 51/61
36.4 69.2 83.6
39.8 156.2 354.1
17.3-91.7 66.5-367.1 129.2-970.2
C hew f (pouches/w k) < 1 pouch 2-3 pouches > 4 pouches
5 /4 0 4/24 5/15
12.5 16.7 33.3
8.5 12.3 30.8
3.0-32.9 3.8-51.3 9.4-128.3
Hours in m outh/day+ > 0-0.5 > 0 .5 -1 .0 > 1.0-1.5 > 1.5-2.0 > 2.0-4.0 > 4 .0
26/106 39/91 30/56 27/40 35/56 26/31
24.8 42.8 53.6 67.5 62.5 83.8
22.6 52.1 80.1 144.2 115.7 361.0
9.5-53.7 22.2-122.3 32.2-199.5 53.2-390.9 46.0-290.8 107.3-1215.2
Snuff* (cans/w k) < 1 can 2-3 cans 4 cans
95% confidence intervals
* Subjects who usually use snuff, t Subjects who usually use chewing tobacco. £ H ours in m o u th /d ay = (num ber of cans or pouches used per w eek—num ber of dips or chews per can or p o u c h —n um ber of m in u tes each d ip or chew is usually held in th e m o u th ) -r 420 (60 m in u tes per h o u r— 7 days per week). § Odds ratios calculated with number of smokeless tobacco nonusers with leukoplakia as referent.
Table 5 ■ Leukoplakic lesions in current sm okeless tobacco users by duration, recency, and age of initiation of sm okeless tobacco use. Subjects with lesions/total subjects
% with lesions
OR*
95% CI
Duration £ 3 years 4-6 years 7-9 years > 10 years
34/105 79/152 39/74 42/84
32.4 52.0 52.7 50.0
33.2 75.1 77.4 69.4
14.2-77.9 33.4-169.1 32.3-185.5 29.4-164.1
T im e since last used > 24 hrs > 12-24 hrs > 1-12 hrs < 1 hr
11/59 22/97 65/118 81/109
18.6 22.7 55.1 74.3
15.9 20.4 85.2 200.8
5.9-42.9 8.4-49.3 37.1-195.2 84.9-475.1
5/14 34/78 134/275 19/47 4 /9
35.7 43.6 48.7 40.4 44.4
38.6 53.6 66.0 47.1 55.5
10.3-144.9 22.5-128.1 30.2-144.3 18.3-121.4 12.2-251.9
Age at initiation '■ 10 years 11-15 years 16-20 years 21-25 years > 25 years
* Odds ratios calculated with number ol smokeless tobacco nonusers with leukoplakia as referent.
120
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CI = 43.6-100.0). Most of the lesions were lo c a te d in th e m a n d ib u la r la b ia l a n d buccal gutter, w ith 42% in the an terio r m a n d ib u la r are a (T a b le 3). O f th e le u k o p lak ic lesions noted on e x a m in a tio n , 60% w ere lo c ate d a t sites in th e m o u th w h ere s u b je c ts r e p o r te d th a t smokeless tobacco was held. A m o n g u sers, risk fo r le u k o p la k ia in c re a se d w ith in c re a s in g a m o u n t o f to b acco used (T a b le 4). A m o n g u su a l snuff users, 36% w ho used one or fewer cans per week had leu k o p lak ic lesions, co m p ared w ith 69% of those w h o used two to three cans per week, an d 84% of those w ho used fo u r or m ore cans per week. T h e increased risk for leukoplakia am o n g usual chew ing tobacco users also increased w ith a m o u n t used, a lth o u g h the absolute risk was less th an for usual snuff users. Risk for leukoplakia increased d ram atically w ith in creasin g h o u rs per day th at smokeless tobacco was kept in th e m o u th . O f the su b je cts w h o h e ld to b acco in the m o u th for a h a lf-h o u r per day, 25% had leukoplakia, com pared w ith 84% w ho held it in the m o u th for 4 or m ore hours per day (T able 4). Risk for le u k o p la k ia in creased as d u r a tio n of u se exceeded 3 years, b u t d id n o t in c re ase fu rth e r w ith lo n g e r d u r a tio n o f u se (T a b le 5). T h e p r o p o r ti o n of su b je c ts w ith le u k o p la k ia d ec reased progressively as the tim e since tobacco w as last used becam e longer. O f those w ho had used smokeless tobacco w ith in th e la st h o u r , 63% h a d le u k o p la k ia , co m p ared w ith 23% of th o se w h o h ad n o t used for more th an 24 h ours (Table 5). T h e r e w as n o in c re a s e d ris k fo r le u k o p lak ia associated w ith earlier age at in itiatio n of the h ab it (Table 5). A lth o u g h in fo rm a tio n w as g ath ered concerning 19 different smokeless tobacco p ro d u c ts , th re e sn u ffs (C o p e n h a g e n , Skoal, an d H aw ken) an d two ch ew in g to b a c c o s (R e d m a n a n d L ev i G a r re tt) accounted for the m ajority of p ro d u cts used (Table 6). T h e risk for leukoplakia am o n g snuff users (O R = 87 com pared w ith n o n u sers) was m u ch h ig h e r th a n for users of chew ing tobacco (O R = 1 5 c o m p a re d w ith n o n u se rs). U sers o f C openhagen and Skoal were at very h ig h risk (O R for C openhagen use = 1 1 1 , for Skoal use = 81 com pared w ith nonusers), w h ile users of H aw k en were at low est risk of a n y p r o d u c t u sed (O R = 4 c o m p ared w ith n o n u sers). A d ju stm e n t for age, race, cigarette sm oking, alcohol c o n s u m p tio n , an d d e n ta l h y g ie n e d id n o t s ig n ific a n tly c h a n g e an y of th e findings reported.
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C o m p a r is o n s of sm o k e le ss to b a c c o users w ith lesions to users w ith o u t lesions are s h o w n in T a b le 7. In u n iv a r ia te a n a ly se s, th e risk fo r le u k o p la k ia increased sig n ific an tly w ith in c reasin g d u ratio n of use (O R = 1.06 for each year of d u ratio n of use) and increasing am o u n t used (O R = 1.74 for each h o u r per day held in the m o u th ). R isk sig n ific an tly decreased as th e tim e since sm okeless to b a c c o w as la st h e ld in th e m o u th increased (O R = 0.96 for each h o u r since last held in the m outh). T h ere was no increased risk for leukoplakia for earlier ag e at in itia tio n of the h a b it. As risk for leukoplakia am ong chew ing tobacco users was low a n d h o m o g e n eo u s, this gro u p was used as the referent for analyses of risk am o n g users of vario u s bran d s of sn u ff. R isk fo r le u k o p la k ia w as sig n ific an tly increased am o n g users of C openhagen (O R = 7.61 com pared w ith chew ing tobacco users) and Skoal (O R = 5.63 com pared w ith chew ing tobacco users). Com pared w ith users of chew ing tobacco, H aw ken users were on ly 22% as likely to have leukoplakic lesions. T o determ ine the in dependent effects of duration, am ount, recency, and type/ b rand used, m u ltip le logistic regression a n a ly sis w as p e rfo rm e d in c lu d in g all of these v aria b les in the m odel. A fter a d ju stm e n t for the effects of the other v a ria b le s , d u r a tio n of use a n d age at in i t i a t i o n w ere n o t in d e p e n d e n t risk factors for leukoplakia. T h e am o u n t used w as in d e p e n d e n tly a n d s ig n ific a n tly associated w ith risk for leukoplakia (OR = 1.55 for each h o u r held in the m outh). Persons w ho held tobacco in the m outh for 4 hours per day had an O R 5.8 times hig h er th an users w ho held tobacco in the m outh only 1 h o u r per day (O R for 4 hours per day of use = 1.554). Recency of use w as also in d e p e n d e n tly a n d significantly associated w ith leukoplakia (OR = 0.98 per h o u r since last use). O R for persons who had not used smokeless to b a cc o for 24 h o u rs w ere o n ly 0.62 c o m p a re d w ith th o se w h o h a d used w ithin the last hour (OR = 0.9824). Use of C openhagen and Skoal was indepen dently and significantly associated w ith le u k o p la k ia . T h e odds of h av in g le u koplakia in C openhagen users were 6.0 times higher and in Skoal users 4.2 times h ig h e r th an in chew ing tobacco users. H aw ken was less likely than any product used to cause leukoplakia. A lthough the finding was not statistically significant, alter ad ju stm e n t for o th e r variables of use, the O R for H aw ken users com pared with chew ing tobacco users was 0.28.
Table 6 ■ L e u k o p la k ie le s io n s in c u r re n t s m o k e le s s to b a c c o u s e rs by ty p e and brand o f sm okeless tobacco usually used. Subjects with lesions/total subjects
With lesions
(%)
ORJ
95% Cl
Snuff totals* Copenhagen Skoal Hawken Others
169/304 131/213 34/63 1/19 3/9
55.6 61.3 54.0 5.3 40.0
86.9 110.9 81.4 3.9 34.7
39.9-189.5 50.1-245.8 33.2-199.4 0.5-33.0 7.2-167.5
Chew totals'! Redman Levi-Garrett Other
15/87 6/37 8/42 1/8
17.0 16.2 19.4 11.1
14.5 13.4 16.3 9.9
5.7-56.7 4.3-42.4 5.6-47.7 1.1-91.7
* Subjects who usually used snuff, t Subjects who usually used chewing tobacco. X Odds ratios calculated with number of smokeless tobacco nonusers with leukoplakia as referent.
Table 7 ■ L o g is tic re g re s s io n a n a ly s is o f le u k o p la k ia s in c u rre n t s m o k e le s s tobacco users by d uration, am ount used, age a t initia tio n , tim e since last use, and type/brand used.
Variable
Risk per
OR*
Adjusted ORt
CIJ
Duration
Year of smokeless tobacco use H our/day smokeless tobacco use Year since smokeless tobacco first tried Hour since smokeless tobacco last used
1.06§
0.99
0.92-1.06
174§
1.55§
1.22-1.96
1.01
1.04
0.96-1.12
0.95§
0.98§
0.96-0.99
7.61 § 5.63§ 0.27 2.40
6.00§ 4 .10§ 0.29 0.72
2.99-12.05 1.72-9.76 0.03-3.16 0.08-6.83
Amount Initiation Recency Type brand Copenhagen Skoal Hawken Other snuff
Referent is users of chew ing tobacco
* Univariate OR from logistic regression model where outcome = leukoplakia (present or absent) and only one predic tor variable as noted. t M ultivariate OR from logistic regression model where outcome = leukoplakia (present or absent) and all variables in the table included as predictors. | 95% confidence interval for the adjusted OR. § P < 0.05.
In clu d in g age, race, cigarette sm oking, alcohol consum ption, and dental hygiene in the m ultivariate m odel d id n ot alter the findings. A nalyses of u sers w ith le u k o p la k ia rev ealed a s ig n ific a n t in c re a se in th e p e rc e n t of severe le sio n s (d eg ree 3 o r 4) w ith in c re a s in g a m o u n t of use, d u ratio n of use, shorter tim e since last use, an d in users of snuff, p a rtic u la rly C openhagen or Skoal (Table 8). Severity of leu k o p lak ic lesions d id n o t vary by age, race, c ig a re tte s m o k in g , a lc o h o l consum ption, or dental hygiene practices. M ultiple logistic regression analysis was perform ed to determ ine the independent effect of these v ariab les on severity of lesions. N o ch ew in g tobacco user h ad a severe lesion, so th at there was no
adequate com parison g ro u p for the snuff u sers. T h u s , th e m u ltiv a r ia te m o d e l in c lu d e d o n ly a m o u n t, d u r a tio n , a n d recen cy . In th is a n a ly s is , a m o u n t of sm o k e le ss to b a c c o u se d w as th e o n ly in d e p e n d e n t p r e d ic to r o f th e sev erity of the lesion (OR = 1.22, 95% C l = 1.011.49). N in ety -eig h t leu k o p lak ic areas in 92 subjects were biopsied an d then exam ined h is t o p a th o lo g ic a lly . T h e r e w as c lo se c o r r e la tio n b etw e en th e a m o u n t of hyperkeratosis observed m icroscopically an d the clinical degree of the lesion (P = 0.001). All lesions were benign, b u t one specim en had m ild ep ith elial d ysplasia (p e rc e n t w ith d y s p la s ia = 1%, 95% C l = 0%-4%). T h is le s io n w as c lin ic a lly classified degree 1, an d occurred in a
Grady-Others : ORAL MUCOSAL LESIONS IN SMOKELESS TOBACCO USERS ■ 121
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Table 8 ■ S e v e rity o f le u k o p la k ia by age at in itia tio n o f s m o k e le s s to b a c c o use, a m o u n t, d u ra tio n and recen cy of sm okeless to b a cc o use and typ e /b ra n d of sm okeless tobacco used. T otal lesions
Degree (%) 1 or 2
Degree (%) 3 or 4
Age at initiation* 1= 10 years 11-15 years 16-20 years 21-25 years > 25 years
5 34 134 19 4
80.0 91.2 88.1 89.5 75.0
20.0 8.8 11.9 10.5 25.0
A m ou n tf > 0-0.5 hours > 0 .5 -1 .0 hours > 1.0-1.5 hours > 1.5-2.0 hours > 2.0-4.0 hours > 4 hours
26 39 30 27 35 26
100.0 97.4 90.0 77.8 88.6 73.1
0.0 2.6 10.0 22.2 11.4 26.9
Duration^ < 3 years 4-6 years 7-9 years > 10 years
34 79 39 42
91.2 88.6 92.3 81.0
8.8 11.4 7.7 19.0
Recency§ < 1 hour > 1-12 hours > 12-24 hours > 24 hours
81 65 22 11
82.7 90.8 95.4 100.0
17.3 9.2 4.6 0.0
169 131 34 1 3 15 6 8 1
87.0 86.3 91.2 100.0 66.7 100.0 100.0 100.0 100.0
13.0 13.7 8.8 0.0 33.3 0.0 0.0 0.0 0.0
Type/brand Snuff Copenhagen Skoal Hawken Other snuff C hew ing tobacco Redman Levi-Garrett Other chew
* Age at which smokeless tobacco was first used, t Hours per day any smokeless tobacco product was helc in the mouth. X Years of smokeless tobacco use. § Hours since smokeless tobacco last used.
sm o k eless tobacco u se r w h o h ad used o n e -h a lf can of C o p e n h ag e n snuff p er day for 3 years. Discussion L eu k o p lak ic /ery th ro p lak ic lesions were very s tr o n g ly a s so c ia te d w ith use of sm o k eless to b a cc o in th is p o p u la tio n of h ealth y y o u n g m en. A m ong current sm o k e le ss to b a cc o u se rs, 46.3% h a d leu koplakia (O R = 60 for users com pared w ith nonusers). O ther investigators13'8'11' 13 have noted an increased risk for oral m ucosal lesions in users, alth o u g h none had controlled for the com bined effects of the p o te n tia l co n fo u n d in g variables in c lu d e d h ere. T h e e le v a te d O R fo r leu k o p lak ia in o u r p o p u la tio n are strik ingly high. Some previous studies have n o t ex am ined a control g ro u p of n o n 122 ■ JADA, Vol. 121, July 1990
u s e rs ,11’13 o r th ey h av e n o t re p o r te d findings in the nonusers .2'12 O ffenbacher a n d W eathers 3 fo u n d an O R of 6, an d W olfe a n d C a rlo s 8 fo u n d a n O R of 9 for oral m ucosal lesions in users co m pared w ith nonusers. T h e m uch higher O R for le u k o p lak ia in o u r study p o p ulatio n m ig h t be a result of differences in the p o p u latio n s studied. Both O ffen b a c h e r a n d W e a th e rs 3 a n d W o lfe a n d C a rlo s 8 stu d ie d a d o le sc e n ts w h o m ay have used smokeless tobacco for a shorter tim e, o r used a sm a lle r a m o u n t th a n the y o u n g to m id d le-ag ed m en in o u r study. In additio n , o u r exam iners were h ighly trained, a n d subtle lesions were recorded. A m o u n t of sm o k eless to b acco used, recency of use, type, an d b ran d of snuff used were sig n ifican tly associated w ith risk for leukoplakia am o n g users. O ther
investigators have suggested an increase ris k fo r o ra l le sio n s b e c a u se o f th e increasing am o u n t of smokeless tobacco used ,2'81112 b u t the im portance of recency of use and brand used has not been noted. We decided to investigate the independent effect of recency of use because, d u rin g p ilo t stu d ies, su b je cts n o te d th a t o ral lesions occurred if they used for a short tim e o r b rie fly in c re a se d th e a m o u n t of use, an d disappeared if they q u it briefly or reduced use. Recency is independently associated w ith le u k o p lak ia, even after a d ju s tm e n t for a m o u n t a n d d u ra tio n , suggesting that lesions result from sh o rt term m u c o sal in ju ry a n d m ay resolve quickly w ith term ination of use. A m ong subjects w ith leukoplakia w ho returned several days after the in itia l ex am in atio n for oral biopsy, some lesions h ad resolved. S urprisingly, after ad ju stm en t for am o u n t an d recency, d u ratio n was n o t ind ep en d e n tly asso cia te d w ith th e o cc u rre n ce of leu koplakia am ong smokeless tobacco users. T h e ap p aren t increase in risk for leu k o p lak ia in subjects w ith long d u ra tio n of use w as th e r e s u lt o f th e fact th at these subjects used m ore smokeless tobacco m ore recently. O ther investigators may have no ted increased risk for oral lesions in users of lo n g d u ratio n because no m u ltiv ariate analysis was perform ed to c o n tro l for a m o u n t a n d recency of use .2'8'11'12 S nuff was m u ch m ore stro n g ly asso ciated w ith le u k o p la k ia th a n ch ew in g tobacco. T h is is of p a rtic u la r co n cern as use of snuff is increasing am o n g young m en an d snuff is m ore strongly associated w ith oral cancer th an chew ing tobacco .10 Users of C openhagen and Skoal, the two m ost com m only used snuffs, were four to six tim es m ore likely to have leukop la k ic lesio n s co m p ared w ith users of chew ing tobacco. N ot all snuffs appear to be m ore likely to cause leu k o p lak ia th a n c h e w in g tobacco. O n ly o n e leukoplakic lesion was detected am ong the 19 u sers of H a w k e n (th e th ir d m o st com m on snuff used). T h e reason for these differences is unclear, b u t may be related to d iffe re n c e s in p H o r c o n te n t of carcinogens, nicotine, o r oth er substances contained in smokeless tobacco products. A ccording to data reported by H offm an an d o th e r s , 14 C o p e n h a g e n a n d S k o al c o n ta in m o re v o la tile n itr o s a m in e s , tobacco specific n itro sam in es, benzo(a)p y ren e , p o lo n iu m , n itr a te , a lk a lo id s , le ad , a n d c a d m iu m c o m p a re d w ith H aw k en . T h e p H of C o p e n h ag e n an d Skoal is 7.8 w ith a m oisture content of 50% an d 51% respectively, com pared w ith
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a pH of 6.0 and a moisture content of 20% for Hawken.14 Further investigation is needed to determine which com ponents m ight increase the risk for leukoplakia. Severity of leukoplakic areas increased w ith in creasing am ou n t of sm okeless tobacco used and appear to be more severe in snuff users. Hirsch and others11 studied 50 male users aged 15-84 with oral lesions and reported that lesion severity increased w ith age of the user, duration of use, and am ount used, but no m ultivariate m ethods were used to con trol for the effects of other parameters of use. Wolfe and Carlos8 did not find any relationship between parameters of use and lesion severity.
Sin ce acceptance o f th is m a n u scrip t, w e have obtained similar data on 1,050 subjects during spring tr a in in g in 1989. D u r in g th is e x a m in a tio n , w e inquired about seasonal use of sm okeless tobacco. Sm okeless tobacco w as reported to be used only or mostly during baseball season by 203 of the 397 users. T o determ ine the im p act o f season al use, w e repeated the analyses presented in th is paper on the 1989 data including seasonal use as a variable. T h e resu lts w ere e ss e n tia lly the sam e as those presented in the report.
T h is study w as supported by G rant no. 5 P01 DE08547-02 from the N ational Institute for Dental Research. T he informed consent of all hum an subjects who p a rticip a ted in th e e x p e rim e n ta l in v e stig a tio n reported or described in this manuscript was obtained after the nature o f the p roced u re and p o ssib le discomforts and risks had been explained fully.
Summary An increased risk for oral cancer in lon g term snuff users has been reported10’15’16 and our study clearly shows that smoke less tobacco is strongly associated with oral leukoplakia. L euk oplakic lesion s in smokeless tobacco users are common and w ould be of trem endous m edical and public health concern if m any of these lesion s were destined to becom e malignant. However, leukoplakic lesions seem to occur rapidly w ith sm okeless tobacco use, may resolve quickly w ith cessation, and are not strongly related to duration. T h e sig n ifica n ce o f le u koplakia in smokeless tobacco users and its relation to oral cancer is not clear, particularly if the h abit is con tin u ed or if the le u k o p la k ic le sio n p ersists. Mutagenesis and carcinogenesis may be related to long-term use or to certain com ponents of tobacco, but at present we cannot accurately d istin g u ish dysp lastic from benign lesion s clin ically, and we do not understand the factors that m ight cause benign oral m ucosal lesions to become malignant.
T h e authors thank the m an agem en t, trainers, players, coaches, and medical staff of the follow ing p r o fe ssio n a l b a seb all team s: C a lifo r n ia A n gels, C h ica g o C ubs, C lev ela n d In d ia n s, M ilw aukee Brewers, Oakland Athletics, San Francisco Giants, and Seattle M ariners, and ja n a M urray, R N , for her assistance. Dr. Grady is assistant c lin ic a l professor, epide m io lo g y and m edicine, School of M edicine, U n i versity o f C a lifo rn ia, San Francisco; Dr. G reene is professor and dean, School of Dentistry, University of California, San Francisco; Dr. Daniels is professor of oral pathology, School of Dentistry; Dr. Ernster is professor an d ch air o f E p id e m io lo g y , S ch o o l o f M edicine; Dr. R obertson is professor, S ch ool o f Dentistry, University of California, San Francisco, and dean, School of Dentistry, University of British Colum bia; Dr. Hauck is professor o f biostatistics, School o f M edicine, U niversity of California, San Francisco; Dr. D. G reenspan is c lin ic a l professor o f oral m edicine, Sch ool o f D entistry, U niversity o f California, San Francisco; and Dr. J. Greenspan is professor and chair o f oral m e d ic in e, S ch o o l of Dentistry, University of Calfornia, San Francisco. Address requests for reprints to Dr. Grady, Veterans Administration Medical Center (111A1), 4150 Clement St, San Francisco, 94121. 1. Axell T , Mornstad H , Sundstrom B. The relation o f the c lin ic a l p ictu re to the h is to p a th o lo g y o f sn u ff d ip p er’s le sio n s in a S w ed ish p o p u la tio n . J Oral Pathol 1976;5:229-36. 2. Greer RO Jr, Poulson TC. Oral tissue alterations
associated w ith th e u se o f sm ok eless tob acco by teen-agers. O ral S u rg O ral M ed O ral P a th o l 1983;56:275-84. 3. Offenbacher S, Weathers DR. Effects of smoke less tobacco on the periodontal m ucosal and caries status of adolescent males. J Oral Pathol 1985;14:16981. 4. Pindborg JJ, Reibel J, Roed-Petersen R, Mehta FS. T obacco-indu ced changes in oral leu k op lak ic epithelium . Cancer 1980;45:2230-6. 5. P in d b o r g JJ , R e n stru p G. S tu d ies in oral leukoplakia II. Effect of snuff on oral epithelium . Acta Derm Venereol 1963;43:271-6. 6. Roed-Peterson B, Pindborg JJ. A study of Danish s n u ff-in d u c ed oral le u k o p la k ia . J O ral P a th o l 1973;2:301-13. 7. Sm ith JF, M incer H A , H op k in s KP, B ell J. Snuff-dipper’s lesion. A cytological and pathological stu d y in a large p o p u la tio n . A rch O to la r y n g o l 1970;92:450-6. 8. W olfe M D, Carlos JP. Oral health effects of smokeless tobacco use in Navajo Indian adolescents. Com m unity Dent Oral E pidem iol 1987;15:230-5. 9. Mehta FS, G upta PC, Pindborg JJ. C hew ing and sm ok in g habits in relation to precancer and oral cancer. J Cancer Res C lin O ncol 1981;99:359. 10. Advisory Com m ittee to the Surgeon General. T h e H e a lth C o n seq u e n c es o f U s in g S m ok eless Tobacco. Bethesda, MD: US Department of H ealth and H u m a n S ervices, P u b lic H e a lth Service, 1986;NIH publication no. 86-2874. 11. Hirsch JM, H eyden G, T hilander H. A clinical, h is to m o r p h o lo g ic a l and h isto c h e m ic a l study on snuff-ind uced le sio n s o f varying severity. J Oral Pathol 1982;11:387-98. 12. Poulson T C , L indenm uth JE, Greer R O Jr. A com parison of the use of sm okeless tobacco in rural and urban teenagers. CA 1984;34:248-61. 13. Christen AG, M cDaniel RK, Doran JE. Snuff dip ping and tobacco chew ing in a group of Texas college athletes. T ex Dent J 1979;97:6-10. 14. H offm an D , Adam s JD , L isk D , F isenne I, B runnem ann KD. T o x ic and carcin ogen ic agents in dry an d m o is t sn u ff. J N a tl C ancer Inst 1987;79:1281-6. 15. W orld H e a lth O r g a n iz a tio n In te r n a tio n a l Agency for Research and Cancer. Volum e 37: IARC M onographs on the Evaluation of the carcinogenic risk of chem icals to humans: tobacco habits other than smoking; betel q u id and areca nu t chew ing, and some related nitrosamines. Lyon: World Health Organization, 1985. 16. W in n D M , B lot W J, Shy CM, P ick le LW , T o le d o A, Fraum eni JF. S n u ff d ip p in g and oral cancer am ong w om en in the southern U nited States. N Engl J Med 1981;304:745-9.
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