TABLE I.-Continued Study Sample Methods Observations Comments Grew and Paulson. 1983 kont.) o ?o?*???o examination conducted of soft and hard oral tissues. o 26% of smoke less tobacco users had site specific gingival recession. o Lesions graded o Users with according to a lesions had scale developed longer use and by Ax&ll et al. higher daily (1976) and mcdi- exposure than fied by Greer users without and Pouleon. lesions. Teeth . `. found no evidence of tobacco associated dental ties." o No evidence of occlusal or in&al abrasion. o OnecaseOf cenical erosion. o Smokeless tobacco associated periodontal degeneration defined. o Did not assess the interrelation- ship of smoke less tobacco, cigarettes, and alcohol. Greer et al.. 1986 Salivary Glands o 45 smokeless o Cross-sectional o Of 18 tissue mbscco users design . Authors suggest samples with (43 males and 2 that the degree females); 15 sub- o Lesions graded salivary glands, of salivary gland jects in each by classification 4 demonstrated fibrosis. degan- developed by sialadeuitis and goup known as erative change, Grem and degenerative and sialadenitis juvenih, young Paulson. 1983. Changes. may be aas& adulta. and ated with geriat.liC. o ?????*?? ?*o? o A routine pattern of tobacco brand . Ages 13.74 lesions classified according to cllronic instead of a Y-. sialadenitis was generaJizd scheme. response awed o ??*???? not shown for Colorado. o Histomorpho any of the three by all tobacco. logical methods age groups. used on tissue Specimens. o Four patients (age3 21. 25. 50 * No statistical and 66) showed analysis either mild, conducted. moderate, or severs salivary gland fibrosis. 101 TABLE l.-Continued Study Sample Methods Observations Comments Hirsch et al.. 1982 LWk0phkid MUcosal Pathology o 50 male habitual o Cross-sectional snuff dippers. o Interpretation of o Dose considera- design. histomorphologi- tions were made o 41.3.year mean o Subjects Cal and histo chemical results and confounding age hmge 15-84 classified on a variables con- Years). four-degree scale demonstrated sidered. of lesion severity that the oral o ?????*? o Differences in (developed by mucosaf reaction AxdI et al., to snuff-induced brand of tobacco used were taken 1976); biopsies hyperplasia in were taken. the basal cell into account. o Histomorpho layers. logical and his. . Lethal damage tochemical was found in methods con- surface layers. ducted on sub o Duration of use jects' tissue and daily expo snecimens. sure to smoke o Tobacco and alcohol use histories ascertained from a questionnaire. less tobacco were shown to affect the severity of the leukoplakia. o Dysplasia could not be predicted by using sug gested CIinical degree of lesion classification. o Tissue speci. o Statistical mans from 74% analysis con- of patients ducted: oneway included salivary analysis of vari- glands. ante and multi- ple comparisons using the Scheffe method. Salivary Glands o The salivary glands and ex- cretory ducts showed degener- ative changes of a more severe nature than found in the sur- face epithelium. o 42% of salivary glands demon- strated siafaden- itis and degsner- ative changes. o Weak oxidative enzyme activi- ties noted in acinic cells in salivary glands with sialadenitis and degenera- tive changes. o Some signs of metabolic atypia noted. o Markedl degen- erative c k nges seen in salivary glands associ- ated with the more severely, clinicdy classi- fied lesions. o Degenerative changes not spe- cificdy defined by authors. o Authors state that variations in degenerative changes of salivary glands may lx bemuse of differences in brands of snuff and snuff- dipping habits, 102 TABLE l.-Continued Study Sample Methods Observations comments Jungell and Mahnstr6m. 1985 o 441 military recruits. o Ages 17-19 yf%X% o Finland. o 48 (11%) were snuff users. o l&9-year mean age (range 17-2 1 years). o Cross-sectional design o ???????**???? administered to ascertain to bacco product use and drinking habits and fre quency of dental care. o ?o?*???o ?????*?? tion conducted. o Biopsies taken of 21 snuff users with lesions. . Besting and stimulated @ar- affin served as the stimulator) salivary excre tions measured. o Statistical a&y- sis conducted t-test. o 10 nonusers of snuff also mea sured for sali- vary excretions. salivary Glands o Resting salivary flow of snuff users was signif- icantly higher than that of nonusers. o ?????o???? ??o????? ?o?? was higher, but not significantly, among snuff users than among controls. o There was no difference in buffering capacity be tween the two groups. o Authors inter- pret difference in resting salivary flowtobea reaction to the presence of the local irritant snuff. Modk et al.. GighI and 1980 Period0ntal o 232 school ClIiIM 119 males, 113 females. o 13.5 years mean age. o 11% of males were regdsr snuff users. o Sweden. o ????????????*?o design. o ?*????????? about tobacco product use his- tory and oral hygiene prac- tices. o ???*???????? dental indices used t.0 measure changes in oral hygiene and periodontal conditions. o Dental caries assessed clini- cally and radio graphically. o Statistical analyses con- ducted cross tabulations, mul- tiple regression, and student's t-test. o TheUseOfSmlff demonstrated a significant relation to gingi- vitis after con- trolling for plaque. o Effects of snuff on the gingival tissue included both location of the snuff and as a predictor of gingivitis in general. o Authors state snuff use may influence gingi val tissue directly result- ing in gingivitis. o Examiners blind to reqmse3 from iuterview. 103 TABLE l.-Continued Study Sample Methods Observations Comments Offenbacher and Weathers, 1985 o 565 m&s from 5 schools. o 13.8.year mean age (range lo-17 years). o 75 (13.3%) smokeless tobacco users. o ???????? L4?UkOjlhkid MUcosal Pathology o Cross-sectional design. o Frequency of occurrence of o Questio rmaire used to obtain history of tobac- co product "se, dental visits, and social history. o Intraoral exami- soft .g ele\ !Pri Eke vi ; tissue hology was aificantly rated in users gqJfgkF 11 lesions). nation conducted using some stan- o No attributable dardized indices. risk for mucosal o Statistical anafy pathology in smokeless ses included: chi tobacco users square, odds who were free of ~ZilkJJt&~, gingivitis. S o Control group Used. Giagival and PeriodOIltal o No relationship between smoke less tobacco use and the preva- lence of gingivitis. o Prevalence of gingival reces- sion signifi- cantly elevated in smokeless tobacco users. o A si fYnificant attrr "table risk exists for gingi- val recession m smokeless tobacco users. Teeth o Smokeless to bacco users with gingivitis had si,gnificantly greater caries arevalence corn pared with non- users without gingivitis. o Prevalence of caries was signif- icantly greater in users wth gingi- vitis who used both snuff and chewing tobacco cornoared with nonusers with gingivitis or those who were gingivitis free. o Soft tissue pzs not o Method of selecting schools for subject ascertainment not described. o ??*???*??*? variables considered. o Smokeless to baCCOUSeis viewed as a co factor with the presence of gin givitis in pro- moting gingivaf recesskon. o No dinhI defi. nitions provided for the assess- ment of gingiti- tis or gingival recession. 104 TABLE I.--continued Study Sample Methods Observations Comment43 Peacock et al., 1960 o 1,338 employees of local textile miu. o North Carolina. o Cross-sectional design o ?*????????? about tobacco product use and given an oral examination. Leukopw MUcosal Pathology o Highly signifi- cant relation- ships between chronic snuff and tobacco use and oral leukoplakia development found for all age groups and for both sexes. . Examiners blind to interview rmponma. o 90% of employees had either poorly fitting complete dentures or only few and rxrious teeth o Many employees have had the habit since they were 3 years old. Pot&on et al, 1984 o 445 subjects: 52% females, 47% males . 56 (12.6%) smokeless to hacco "Sal3 (all -W. o 16.7-year mean age Irange 14-19 Y-L . Rurd Colorado. o Cross-sectional d@P. o ???????**???? ????*??????? (same as one usedinGrmx and Paulson. 1983). o ?o?*???o ?????? nation conducted oforalhardand soft tissues. o ?????*? ???? by classification developed by GWSIld Poufson. 1963. o Of 56 smokeless t,htwco users, 35 (63%) had lesions of the hard or soft timues. o 33 (58.9%) smokeless tobac- co users had mu- cosal alterations. o Mucod lesions were found in area of quid placement. o Duration of use and length of daily exposure were factors in the development of lesions. o Multiple lesions in&same subject reported Giivd and Paiodontal o Of 56 smokeless tobacco users. 15 (27%) had site specific gingival recession: 2 users had periodontal lesions only; 13 had both mucosal lesions and periodontal destruction. . Examiners blind to responsea on q"estionnaire. o Definitions of CIiuical states provided. o ????????*??? *??o???? *?? ???????? o Ahistoryofcon- folmdmg vari- ables obtained. Effects of variables not addressed statisticauy o Periodontal degeneration defined. . Effects of con founding vari- ables not addressed statistically. 105 TABLE Z.-Summary of Selected Case Report&i Study NUlUk Product Duration country of users Age Ueed of use Ffndings Archard E&r 1972 Chl-kte", Amlstro"g, and McDaniel. 1979 Christen, McDaniel. and Doran, 1979 Frithiof et al.. 1983 Hoge and Kirkham. 1983 Pindborg and Poutson. 1962 Pindborg and Re".Wlp, 1963 Zitterbart. Marlin, and Christen, 1983 USA USA USA USA De-k De-k USA 3 1 14 21 1 7 12 1 31 42 60 S"Uff Snuff S"Uff 11 years 20 years 50 years 36 Snuff 13 years 18-22 Snuff, 6 months chewing to tobacco 9 years 31-79 Snuff 1060 years 21121 with snuff- induced lesions local- idtoareawhere snuff was held; 2/21 with observable gingival retraction. 20 S"Uff lY- Gingival recession and hyperkeratosis found where t.obam was habitually placed. Not reported S"Uff 20-30 years 4/7 bad whitish mucous membrane with a delicately folded appearance at site of snuff placement. 3483 Snuff 20-50 years 12112 with mucous membrane that was "whitish, sometimes yellowish-brown, dry appearance with a very delicately folded or finely grooved surface." 36 Chewing tobacco 24 years Gingival recession, "smokeless tobacco users lesion," and abraded occlusal sur- faces of posterior teeth found where tobacco was habitually placed. A homogeneous eosin- opbilic submucoszd deposit above the "linor salivary glands did not initiate a" in- flammatoryrespo"= nor support the possi- bility that the deposits were amyloid. Gingival rcsession, clinical leukoplakia, period0"td bone loss, and tooth abrasion found where tobacco was habitually placed. 8114 with clinically detectable gin&al recession; 9114 with clinical leukoplakia; 11114 with erythema- tou.9 soft tissue changes where te bacco or snuff was habitually held. 106 THE EFFECTS OF SMOKELESS TOBACCO USE ON ORAL LEUKOPLAKWMUCOSAL PATHOLOGY AND THE TRANSFORMATION OF ORAL SOFT TISSUES Oral LeukoplakiaMucosal Pathology Background and Deftitions Various oral soft tissue effects of smokeless tobacco use have been relxxted in the literature. These effects include oral leukoplakia/mucosal pathology. The actual terms used and the definitions employed to describe these conditions vary widely from study to study (table 3). The World Health Organization (WHO) defines oral leukoplakia as a white patch or plaque that cannot be characterized clinically or pathologically as any other disease (1). The mucosal pathology that is found in smoke less tobacco users also has been referred to as hyperkeratosis, an oral mucosal lesion that exhibits an abnormal whitish (keratinized) appear- ance clinically. The authors' terms are employed when a specific study's findings are described. However, in the discussion portion of the report, the general terms of oral leukoplakialmucosal pathology are used. The association between smokeless tobacco use and oral leukoplakia/ mucosal pathology has been moderately studied. The WHO has stated that tobaux is an etiologic agent for the formation of oral leukoplakia (1). This association was n&firmed at an International Seminar on Oral Leu- koplalda and Associated Lesions Related to Tobacco Habits (21. In a re view of the effects of tobacco habits other than smoking, the use of smoke less tobacco/snuff was associated with the presence of leukoplakia (3). Studies in the United States Six studies have addressed the prevalence of oral leukoplakia/muco sal pathology in smokeless tobacco/snuff users (49). In two of these studies, blindness of the examiners toward the tobacco habits of the subjects was maintained, and oral tissue findings in smokeless tobacco users and nonusers were compared (7,9). Three of these studies investi- gated adults (4@ and three investigated adolescents (7,9). In addition, several case reports have described oral leukoplakialmucosal pathology findings in smokeless tobacco users (1@13). Highlights of these studies and reports are summarized below. Offenbacher and Weathers investigated the oral tissue effects of smokeless tobacco use in adolescent males from the greater metropoli- tan area of Atlanta, Georgia (9). They used oral examinations and self- administered questio maims on tobacco use. Of the 565 males who were examined, 75 (13.3 percent) used smokeless tobacco. The difference in the prevalence of mucosal pathology in smokeless tobacco users (22.7 percent) was statistically significant compared with that of nonusers (4.7 percent); however, the authors did not provide specific diagnostic 107 TABLE 3.-Variations in Terms Used and Definitions Provided for LeukoplakiaMwoeal Pathology Associated With Smokeless Tobacco Use by Studies Cited Study Term(s) Used Definition(s) Provided Comment.9 Ax6U 1976 Christ.S?n. Armstrong, and McDaniel, 1979 christen, McDaniel, and Doran, 1979 Frithiof et al., 1983 Greer and Paulson. 1983 Hirsch, Heyden, and Thilander, 1982 Snuff- dipper's lesion. Clinical leukoplakia. Leukoplakia. Snuff- induced lesion. Oral mucosal lesions (alterations) associated with the use of smokeless tobacco. Snuff- induced lesions. A fourcategory classifi- cation scheme based on tissue color, wrinkhng. and thickening was used. "Implies only the clinical feature of a white patch or plaque on the oral mucosa which will not rub off and which cannot be characterized clinically or histologically as any other specific disease." "Implies only the clinical feature of a white plaque on themucosa.. .I' "Tissue changes in the oral mucosa" that are due to snuff use. These lesions were defined by a modification of a clinical grading method developed by Axdl et al. 1976. These lesions were defined by the grading method developed by Ax&l et al., 1976. The authors believe that this is a well-defined irritation that excludes it from the diagnosis of leukoplakia. The authors cite the WHO 1978 and Waldron and Shafer 1975 references (l&I The authors cite the Waldron and Shafer 1960 reference (48). The authors cite the WHO 1978 reference for the definition of let&o plakia and state that "since the snuff-induced lesion, with its typical clinical pattern and its specific etiology, obvi- ously constitutes a definite diagnostic entity, the term `leukoplakia' is avoided. I' In addition, lesions were classified by their texture, contour, and color. - 108 TABLE 3.--contiuued Study lkrm(s) Used Definition(s) Provided Comments Hoge and Kirkham, 1983 Moore, Bissinger, and ProehL 1952 Oral leukoplakia. Offenbacher Mucosal and pathology, Weathers, soft tissue 1985 pathology. Peacock, Greenberg, and Brawley, 1960 Pindborg and Poulson, 1962 Pindborg and Renstrup, 1963 Poulson, Lindenrnuth, and Greer, 1984 Zitterbart, Generalized Marlin, and smokeless Christen, tobacco 1983 users lesion. Hyper- keratotic- appearing tissue. Leukoplakia. Leukoplakia. Snuff- induced leukoplakia. Oral mucosal lesions (alterations) associated with the use of smokeless tdacco. No definition is provided, although the authors dis- cuss the "formation of a hyperkeratotic zone in the region of the `snuff pouch' where the tobacco is habitually held." No definition provided. No definitions provided. "A pearly white plaque on the mucous membrane which could not be scraped off with a tongue blade." No definition provided. No definition provided. The clinical appearance of these lesions was defined by a grading method developed by Greer and Poulson, 1983. No definition provided. The authors cite the Shafer, Hine, and Levy 1969 reference 149). The pathological findings identified by the investi- gators included morsica- tio, ulcer, keratosisileuko plakia, vesiculobullous, petechiae, abscess, erythema. mucocele, and pericoronitis. The investigators described the mucous membrane as having a slightly whitish, deli- cately folded appearance. The investigators de scribed the leukoplakias as "slightly whitish, some times yellowish-brown. dry appearance with a very delicately folded or finely grooved surface." Alterations in texture, color, and contour of the mucosal lesions also were identified. The lesion was described clinically as "peculiarly wrinkled and thickened." 109 criteria in this assessment. The range of mucosal pathologic findings in- cluded such conditions as morsicatio (cheek biter's lesion), ulcer, kera- tosisileukoplakia, vesiculobullous, petechiae, abscess, erythema, mucocele, and pericoronitis. Although 50 percent of the smokeless tobacco users with mucosal pathology had keratosisfleukoplakia com- pared with 3.8 percent of the nonusers with mucosal pathology, the authors did not identify the locations of the mucosal pathologies. Peacock, Greenberg, and Brawley reported a significant relationship between chronic tobacco use and the presence of oral leukoplakia* in a study of 1,388 textile mill workers in North Carolina (5). The 362 employees who reported using smokeless tobacco had a significantly higher prevalence of leukoplakia (34 percent) than did the 457 nonusers (7.4 percent). In addition, the authors noted a direct leukoplakia and age effect. In a study conducted in Denver, Colorado, Greer and Poulson exam- ined 1,119 teenagers in grades 9 to 12 to assess the relationship between oral tissue alterations and the use of smokeless tobacco (7). Smokeless tobacco was used by 117 (10.5 percent) of these teenagers. Of these, 42.7 percent had oral mucosal lesions? in the area of tobacco placement. Forty-six percent of the teenagers with mucosal lesions also had con- comitant periodontal tissue degeneration.$ Poulson, Lindenmuth, and Greer examined a sample of 445 teenagers in five rural Colorado towns to assess the relationship betwen oral tissue alterations and smokeless tobacco use (8). Smokeless tobacco was used by 56 (12.6 percent) of the teenagers. Of these, 58.9 percent had oral mucosal lesions in the area of habitual tobacco placement. Concom- itant periodontal degeneration was noted in 39.4 percent of those with oral mucosal lesions. Contrasting the results of rural versus urban adolescent smokeless tobacco users, Poulson, Lindenmuth, and Greer suggested that the duration of use may be critical in the development of "oral lesions" (8j.s Those adolescents with oral lesions used smokeless tobacco longer (an average of 3.3 years in the rural and urban groups) than those without lesions in both the rural and urban groups (2.3 years and 2.2 years, respectively). In addition, the authors noted similar effects of different levels of smokeless tobacco use in daily exposure. Users with oral le sions were exposed 205 minutes per day in the rural group and 177 minutes per day in the urban group compared with users with no oral le sions (110 minutes and 53 minutes, respectively). Also, more than twice * Leukoplakia was defined as a "pearly white plaque on the mwous membrane nhlch could not be scraped off wth a tongue blade. t The authors used a mod~ficatmn of the classificatmn method that u'as developed by .&&I et al. that Identifies the oral mucosal lesion> according to color. wrinkling. and thickening 1141. $ The authors define this degeneratmn as "site-specific gm@val recession wth apical migration of the gingwa to or beyond the cementwnamel ~unctmn. with OF wthout clmical evidence of inflammation." $ The term "oral lesmn~' used here includes penodonral tissue degeneratmn and oral mucosal lesions. 110 as many marked oral mucosal lesions were identified in the rural population as in the urban population. Smith et al. examin ed a population of 15,500 snuff users by cytologi- cal, histological, and visual means fs). Of these users, 1,751 (11.3 per- cent) demonstrated oral mucous membrane changes. Although no defi- nitions were provided, these changes were described as "cloudy or gray glistening" areas having "wrinkled appearance(s)" and presenting "white or red granular appearance(s)." The authors reported that when snuff was withdrawn, the tissue returned to normal appearance. Moore, Bissinger, and Proehl investigated the relationship between tobacco use and oral cancer in male patients age 50 years and older who attended the General lnmor Clinic in Minneapolis, Minnesota (4). The authors noted that a significant number of the patients who manifested oral leukoplakia (18 of 23-78.3 percent) used smokeless tobacco. A to bacco user in this study was defined as a person who used the tobacco product for 20 or more years. Apparently, some of these 23 patients were also pipe, cigar, or cigarette smokers, although the exact number was not specified. The authors indicated that the most severe patches of leukoplakia were seen in patients who chewed "strong" tobacco and over a longer duration (no quantification reported). In most instances in which patients had stopped using smokeless tobacco, leukoplakia disappeared. Several case reports (table 2) have described oral leukoplakiaimucosal pathology at the site of smokeless tobacco/snuff placement (1013). These cases represent males of various ages with differing years of smokeless tobacco/snuff use. Hoge and Kirkham reported that in one patient, withdrawal of snuff resulted in a reversal of the hyperkeratotic lesions (12). Studies in Scandinavia Studies of smokeless tobacco from Scandinavia have investigated the prevalence of oral 1eukopWmucosal pathology in users (X-19). Axell found 1,444 smokeless tobacco users (predominantly men) in the 20,333 Swedes who were examin ed for soft tissue lesions (la. Of these users, 116 (8 percent) had "snuff-dipper's lesion" (see table 3 for definitions). The prevalence of oral leukoplakia among the total study population was 3.6 percent. Hirsch, Heyden, and Thilander f18) graded oral mucosal lesions on an established four-point scale (14) and correlated these findings with the snuff habits in 50 Swedes ages 15 to 84 years who used snuff routinely. Younger patients were found to have lower degrees of pathologic changes, while a significant predominance of older patients was noted with higher degrees. The authors reported that patients with oral mucosal lesions of the highest degree had used snuff an average of 34.7 years compared with the 9.2- to 13.6-year average for patients with lower degrees of pathologic changes. They also noted that patients with high degrees of pathologic changes dipped twice as long per day (an 111 average of 10.1 and 10.6 hours per day) as patients withlower degrees of pathologic changes (5.2 and 6.5 hours per day, respectively). Although these patients reported multiple tobacco habits, the authors stated that no differences in clinical grading were found between patients who used snuff only and those who used snuff and other tobacco products. In addition, several case reports have described oral leukoplakial mucosal pathology (table 2). In Sweden, Frithiof et al. examined 21 male snuff users ages 31 to 79 years (19). All had snuff-induced lesions that were localized to the area in the oral cavity where the tobacco was held. Similarly, leukoplakia lesions were found at the site of snuff place ment in all 12 male users of snuff ages 39 to 83 years in a study in Den- mark (15). In this latter study, 3 weeks after one of the patients discon- tinued snuff use, the clinical appearance of the mucous membrane had returned to normal. In another report, four of seven Danish male users of snuff exhibited leukoplakia at the site of snuff placement (16). Discussion The studies from the United States and Scandinavia demonstrate that oral leukoplakialmucosal pathology is associated with smokeless tobacco/snuff use. In two studies, a higher prevalence of oral leuko plakia/mucosal pathology was found in users compared with nonusers of smokeless tobacco-22.7 percent compared with 4.7 percent (9) and 34.0 percent compared with 7.4 percent (5). In all of these studies, be tween 8 and 59 percent of smokeless tobacco/snuff users were found to have oral leukoplakialmucosal pathology. It appears that the oral leukoplakialmucosal pathology noted in smokeless tobacco/snuff users is found commonly at the habitual site of tobacco/snuff placement. Using a similar grading classification for snuff-induced lesions (7,14), all of the mucosal pathology that was noted in four studies was at the site of habitual tobacco placement (7,8,17,18). Similarly, the majority of the oral leukoplakia/mucosal pathology that was described in the case reports was found where the tobacco/snuff was usually placed. The duration of use (in years) and daily exposure (in hours or minutes) to smokeless tobacco appear to be critical in the development and sever- ity of oral leukoplakiafmucosal pathology. Three studies using similar approaches to the definition of oral 1eukoplakAmuco.A pathology and to the measurement of exposure noted this effect (7,418). Only two studies were designed to study the concomitant findings of oral leukoplakia/mucosal pathology and other tissue changes. The authors reported that 39.4 (8) and 46.0 (7) percent, respectively, of smokeless tobacco users with oral leukoplakia/mucosal pathology also had periodontal tissue degeneration (gingival recession). These oral soft tissue changes also were found at the site of habitual tobacco placement. In several studies where individuals had stopped smokeless tobacco use, the oral leukoplakia/mucosal pathology disappeared (4,6,12,15). 112 Background and Defiitions The previous section that discussed smokeless tobaccoinduced leu- koplakia noted that clinically observable changes in soft tissue mor- phology do occur as a result of smokeless tobacco use. Smokeless tobaccoassociated lesions that have been traditionally classified as leu- koplakias (white lesions) offer varying clinical degrees of differentiation and may persist or progress with continued smokeless tobacco use. Additionally, some leukoplakias have been observed to resolve clinically upon the cessation of smokeless tobacco use. This section of the report addresses the transformation of oral soft tissues. It discusses the poten- tial for smokeless tobaccoinduced lesions to regress, persist, or continue to progress to lesions with higher mahgnant potential or to malignancy. There are varying clinical and histologic definitions in the scientific literature related to tobaccoinduced changes (transformation) of oral soft tissues. The following definitions represent those most frequently encountered. It will be noted when significant variation of these defini- tions occurs in studies cited: o Oral leukoplakia-a white patch or plaque that cannot be charac- terized clinically or pathologically as any other disease (1). o Snuff dipper's leukoplakia-a leukoplakia associated with the use of smokeless tobacco. These are further characterized as to differ- ing morphologic forms. o Erythroplakia-a lesion present as a bright red patch or plaque that cannot be characterized clinically or pathologically as any other condition, such as carcinoma or infection. o FVecancerous condition-a generalized state that is associated with an increased risk of cancer based on epidemiologic or histo logic evidence. o Precancerous lesion-a morphologically altered tissue in which cancer is more likely to occur than in its apparently n0rma.l counterpart. o Acanthosis-an increased thickness of the spinous cell layer of the epithelium. o Hyperkeratosis-an increased thickness of the keratinized layer of the epithelium. o Hyperparakeratosis-an increased thickness of a normally para- keratotic layer of the epithelium, i.e., surface cells with retained nuclei. o Hyperorthokeratosis-an incrased thickness of a normally kera- totic layer of the epithelium, i.e., surface cells without retained nuclei. 113 o Chevron keratinization-a keratinization pattern typified by verti- cal streaks of parakeratinization that extend to the epitheliaI sur- face and create surface irregularities by extensions of the outer sur- face layer. o Dysplasia-abnormal tissue development characterized by vary- ing numbers and degrees of morphologic cell changes that reflect grades of severity. o Dysplastic changes include the following - Pleomorphism in the size and shape of cells and their nuclei. - Abnormal numbers of cells undergoing mitotic activity (discrep ancy in maturation). - Atypical mitotic cells. - Cytoplasmic atypicalities (altered nuclear to cytoplasmic ratio). - Hyperchromasia. - Irregular nuclear borders. - Basal cell hyperplasia. - Loss of polarity. o Carcinoma in situ-a significant number of dysplastic epithelial cdl changes that extend from the basal layer to the surface layer without violation of the basement membrane. o Verrucous carcinoma-a clinically verruciform cancer of epithelial tissue that tends to be slowly and locally invasive with a metasta- sis and mortality potential that is lower than classic squamous cell carcinomas. The cells are well differentiated. o Squamous cell carcinoma-a cancer of the stratified squamous epi- thelium that has varying clinical appearances, is invasive, extends beyond the basement membrane, and has a great potential for metastasis. Evidence of the relationship between smokeless tobacco use and the transformation of oral soft tissues is represented by the following 1. Clinical reports describing tobacco habits of persons with graded oral lesions. 2. Followup (cohort) studies of tissue changes, including trans- formation to malignancy, among patients with leukoplakia. 3. Casecontrol studies or case series of oral cancer describing con- comitant leukoplakia. A review of the evidence in each of these study areas follows: Clinical Reports of Oral Lesions in Association With Smokeless Tobacco Use Hirsch, Heyden, and Thilander (18) graded oral snuff-induced mucosal lesions in 50 patients on a four-point scale according to criteria developed by Ax&l (14): 114 o Degree 1: A superficial lesion with a color similar to the surround- ing mucosa, slight wrinkhng, and no obvious thickening. o Degree 2: A superficial whitish or yellowish lesion with wrinkhng and no obvious thickening. o Degree 3: A whitish-yellowish to brown lesion with wrinkhng, intervening furrows of normal mucosal color, and obvi- ous thickening. o Degree 4: A marked whiteyellowish to brown lesion with heavy wrinkhng, intervening deep and reddened furrows, and heavy thickening. Snuff habits and drinking habits of the patients were obtained from questionnaires. Patients in the degree 4 category had been snuff dippers significantly longer than the rest of the patients. Also, patients in de grees 3 and 4 dipped approximately twice as long per day as did pa- tients in degrees 1 and 2. The daily exposure to snuff was significantly longer in degree 4 (10.6 hours) than in degrees 1 (5.2 hours) and 2 (6.5 hours). When total exposure was compared between the four clinical groups taking into account hours of use per day as well as years of use, significant differences were found. In this study, no significant differences could be found with regard to clinical grading and histologicai appearances between patients with multiple habits (snuff, smoking, and drinking) and those who only used snuff. The four clinical degrees of lesions exhibited an agedependent ef- fect with younger patients usually found in clinical degrees 1,2, and 3 and a significant predo minance of older patients noted in degree 4. Degree 4 lesions included an increased number of mitotic figures, edema, and slight to moderate mflammation compared with the other three degrees. Eighteen percent of the patients exhibited slight epithe lial dysplasia, and lesions with slight epithelial dysplasia were found in all categories. Patients in the dysplastic group had been snuff dippers longer on average (23.9 years) as compared with those without dyspla- sia (19.5 years). No case of moderate or severe dysplasia was noted. (The authors referenced the WHO Collaborating Center for Oral Precancer- ous Lesions as the definition for dysplasia (l).) AxelI, M&n&ad, and Sundstrom obtained biopsies of the oral mucosal lesions of 114 male dippers ages 20 to 88 years from a sample of 1,200 Swedish snuff dippers (14). Clinically, lesions were graded (degrees 1 through 4) based on color and morphology. Lesions of higher clinical degrees were associated with greater daily exposure to snuff in terms of hours and grams of exposure. All but one of the biopsies showed increased epithelial thickness. The outer layers appeared vacua lated with occasional remnants of cell nuclei. Lesions in degrees 3 and 4 had more pronounced surface layers. Acanthosis was evident in all of the clinical groups. None of the biopsies showed changes that were interpreted as cellular atypia or epithelial dysplasia. The cessation of 115 snuff dipping for a few days was reported to result in clinical regression of the lesions with loss of the vacuolated layer. Greer et al. reviewed clinically and histologically examined smokeless tobacc&nduced leukoplakias from 45 patients ages 13 to 74 years @O), following criteria that were previously established by Greer and Poulson (7/ as adapted from Ax&lL The vast majority of the mucosal lesions were corrugated, white, and raised. No evaluations for an inter- relationship between smokeless tobacco use, smoking, and alcohol use and clinical or histologic tissue changea were attempted. Histologic examinations for specific changes were reported. Dark celI keratino cytes characterized by a strong affinity for basic dyes and by electron density of their cytoplasm and nucleus and suggested as dedifferenti- ated precursors of a neoplastic keratinocyte were found in 17 of 45 cases. However, their presence was unrelated to the clinical degree of the lesion. While they have also been observed in leukoplakias that are associated with smoking (or other causes), the control group of nontobaccoinduced hyperkeratoses demonstrated dark cell keratinocytes in only 3 of 45 rxses. Chevron keratinization of the epithelial layer representing altered cellular maturation was present in 42 of 45 smoke+ tobaccoinduced leukoplakias but in only 4 of 45 control leukoplakia cases. Koilocytotic changea appearing as vacuolated epithelial cells that may obscure the cytoplasm or appear with pyknotic nuclei, which are often associated with inclusion of viral particles in epithelial cells, were present in 27 of 45 smokeless tobaccoinduced leukoplakias. In the entire sample of 45 cases, only 1 case of dysplasia (described as occuing in a long-term smokeless tobacco user) was identified Three of the following characteristics had to be present for a lesion to be characterized as dysplastic: o Loss of celIular polarity. o Basal cell hyperplasia. o Altered nuclearlcytoplasmic ratios. o Anaplasia. o Dyskeratosis. o Atypical mitoses. Because the dysplasia case also involved the use of alcohol and smok- ing, it is not possible to attribute its appearance solely to smokeless tobacco use. In a study of 21 Finnish military recruits ages 17 to 21 years, mucosal lesions corresponded to the site of snuff placement and included the alveolar and labial mucosa to varying degrees (21). The duration and in- tensity of snuff use for this specific group could not be determined from the study. Epithelial hyperplasia and acanthosis were universally found under the light microscope. Hyperorthokeratinization was noted in 12 cases, hyperparakeratinization in 9 cases, and Chevron-type keratiniza- 116 tion in 1 case. One case of mild epithelial dysplasia was noted that in- cluded atypical and increased mitoses and loss of basal cell polarity. The authors concluded that this suggests a positive relation between snuff dipping and malignant changes. Van Wyk biopsied 25 snuff-induced lesions from Bantu smokeless tobacco users whose lesions had existed from a few weeks to 40 years (22). Comparison biopsies were also taken from healthy parts of the mucosa in the users, from healthy mucosa in nonusers, and from other white lesions and squamous carcinomas. From the biopsies obtained from snuff users, 18 cases of acanthosis, 23 cases of parakeratosis, 5 cases of keratosis, and 4 cases with numerous mitotic figures, plea morphism, hyperchromatism, and an irregular basal cell layer were noted. Additionally, 11 showed a disrupted appearance of the basement membrane. Those not associated with inflammation were considered possibly to be premalignant. Epithelium featuring these characteristics has been referred to by some as "disquiet epithelium." Contrarily, the author stated that "the impression is gained that no relationship exists between oral malignancy and the use of snuff." This was based on the widespread use of snuff but the occurrence of only one case of alveolar or sulcular cancer (not in a snuff user) in the hospital during this study. Several investigators have described connective tissue changes in snuff-induced lesions. A hyalinized, eosinophilic material that occurs well below the epithelium and around the minor salivary glands or in a plane that is generally parallel to the epithelial surface has been reported by Pindborg et al. (16), Archard et al. (23), Axell et al. (14), and Greer et al. (20). The exact nature of and underlying explanation for the finding are not clear. Additionally, the role of such a histologic finding in the development or progression of premalignant or malignant lesions has not been identified. Cohort Studies Several investigations have followed persons with oral lesions for subsequent health outcomes. Smith reported the lo-year followup results on a group of patients with smokeless tobacco-induced leuko plakias (24). In the original study, oral cytologies were performed on 1,751 patients presenting with leukoplakias out of 15,500 snuff users (6). Results of the oral cytology e xamination consistently indicated only benign hyperkeratoses. * Biopsies were made of 157 leukoplakic lesions. However, no objective criteria for lesions selected for biopsy were of- fered. None of the biopsies showed changes consistent with dyskera- tosis or malignancy. These patients were followed with repeat cytology smears for 5.5 years. No additional significant mucosal changes were * The use of oral c of a high rate of fa E tology for detecring dysplastic changes in leukoplakic lesmns is less than satisfactory because e negative findmgs. The hy rkeratinized nature of leuko lakic lesions renders them resistant to the oral cytology scraping technique. CeUu r missed m/. r changes in deeper layers o P the epithehum would thus likely be 117 reported. In a subsequent 4.5-year followup (10 years total followup), periodic biopsies were done on 128 of the 157 patients who had originally received biopsies (24). The authors reported no dyskeratosis or carci- nomas in the followup study. The method of followup was not specified. Significant numbers of patients were lost, and the clinicel and histologic diagnostic criteria were not fully described. A prospective study of oral cancer among persons with oral leuko plakia or other possible precancerous lesions was conducted in the Emakulum district, Kerala State, India, as part of a lo-year followup to a much larger study of 50,915 adults in 5 rural districts of India (26). Among those individuals who had been diagnosed as having a leuko plakia during the original survey, there was a malignant transforma- tion rate of 9.711,OOO per year for those who only chewed tobacco. For those who both smoked and chewed, the rate was 5/1,000 per year, while no malignancies were reported for individuals with or without tobacco habits who had not had a previous oral lesion The transformation rates among those with lesions were much higher than rates reported in the United States or European studies. While these results are not directly comparable to United States or European studies since the tobacco chewed in India is a variable mixture of betel leaf, areca nut, slake lime, and coarse tobacco, they suggest that the persons with leukoplakia are at increased risk of oral cancer. Specific clinical morphotypes of leukoplakia demonstrated varying potentials for malignant transfor- mation: homogeneous, 2.27 percent; speckled, 21.4 percent; and ulcer- ated, zero percent. In a small study of English coal miners, 8 of 22 patients with leuko plakia who chewed tobacco were followed for 5 years (27). Five of the eight cases showed no advance in the lesions, and two showed regres- sion. The author does not specify whether these were clinical or histo logic determinations or whether the smokeless tobacco habit persisted in all cases. One lesion that had been regarded as benign showed some hyperorthokeratosis and acanthosis of the epithelium but with no more than "minor epithelial atypia." The clinical appearance of this lesion was reported to have regressed initially over an intermediate 2-year period despite continuance of the habit of tobacco chewing and smok- ing. Subsequent followup over a 2-year period indicated that the lesion had progressed to an exophytic squamous cell carcinoma. The site of the lesion was where the patient had held tobacco for 30 years. While the malignant transformation rate in the group of chewing tobacco- associated leukoplakias was 12.5 percent, the small numbers and high dropout rate limit the significance of the finding. Of significance was the unpredictable course of the malignant lesion, initially regressing and then transforming into a squamous cell carcinoma. In a Danish study, 32 patients with snuff-induced leukoplakias from a group of 450 patients with leukoplakia were observed for a median time of 4.1 years (28). Each patient had also used alcohol, with 17 per- 118 cent claiming daily use. Thirty-three biopsies demonstrated hyperplas- tic epithelium with hyperparakeratosis in 87 percent of the cases; haIf showed vacuolated cells. One initial case of epithelial dysplasia was found, and one carcinoma was found to develop from a nondyskeratotic leukoplakia over the followup period. This represents a rate of premalig- nant or malignant transformation of 6.2 percent for either dysplasia or carcinoma. In comparing the rate of development of dysplasia and car- cinoma from snuff-induced leukoplakias to nonsnuff-induced leuko plakias, the authors found no statistically significant differences. How- ever, the rate of transformation in both groups was higher than would be expected in individuals without leukoplakic mucosa. In an earlier report on a small sample of 12 white male snuff-using leukoplakia patients (use from 20 to 50 years), Pindborg and Renstrup did not find any malignant transformation (15). Biopsies were taken from sites where the snuff was held. All 12 showed unkeratinized hyper- plasia of the epithelium with a few deep streaks of parakeratosis and downgrowth and broadening of the rete pegs with the outer layers of cells being vacuolated and large. The authors state that snuff-induced leukoplakias are easily reversible. Based on the limited size of this sam- ple, definitive conclusions could not be made. Oral Lesions Concomitant With Oral Cancer Thme hundred and thirty-three patients with cancers of the buccal cav- ity and pharynx from the Robert Winship Memorial Clinic in Atlanta, Georgia, were compared with three control groups: a group with dis- eases of the mouth other than cancer or with no diseases; a group with cancer of sites other than the mouth, pharynx, or larynx; and a group without cancer and whose mouths were not examined-see chapter 2 (29). The authors, citing leukoplakia as a precancerous condition, found leukoplakias "more commonly in women with low grade squamous car- cinomas arising in the mouth and with multiple cancers. Snuff dipping was frequently associated with leukoplakia and low grade cancer aris- ing in the mouth." In a case-control study in Minnesota of cancers of the alveolar ridge, floor of the mouth, and buccal mucosa, it was noted that leukoplakias and cancers of the mouth were related to the use of snuff or chewing to bacco (4). The most severe leukoplakias were reported among those who used "strong snuff" (no definition was provided) and held the quid at the same site for many years. Patients who quit using smokeless to bacco reportedly had leukoplakias disappear in most instances. A number of patients had multiple primary carcinomas that were also specific to the site of quid placement. Cancer lesions were described as having developed slowly over a period of several years, although no evidence of periodic clinical or histologic assessment was provided. McGuirt reported on 76 oral cancer patients, most with carcinomas of the alveolar ridge or buccal mucosa, identified from the tumor registry 119 at the North Carolina Baptist Hospital who had a documented history of heavy smokeless tobacco use (30). Fifty-seven of these patients used snuff and reported no cigarette, pipe smoking, or alcohol habits. The range of use was from 10 to 75 years. Leukoplakias had previously been excised in 13.9 percent of the cases, and 47 percent had associated leukoplakias at the time of surgery. The author cited "panmucosal in- sult" from smokeless tobacco use as the cause of multiple lesions and recurrences-a type of field cancerization. From histologic evaluations of oral tissue among 23 Swedish patients with anterior oral vestibular cancer who were snuff users, leukoplakic lesions were noted outside the snuff-associated tumor in 5 (31). Lake plakia and multiple carcinomas occurred together with the snuff- associated lesion in three cases. Eleven of nineteen cases assessed for presence of candida were positive. The temporal relationship between candida and carcinoma was not ascertainable, nor was the potential etiologic role of candida. Rosenfeld and Callaway examined data from records at Vanderbilt University Hospital, Nashville General Hospital, and the office of Rosenfeld for cases of squamous cell carcinoma arising in the mucous membrane of the anterior twothirds of the tongue, the floor of the mouth, the gingiva, and the buccal area (32). A total of 525 cases were examined in users and nonusers of smokeless tobacco-300 occurred on the gingiva and buccal areas. Among women with cancer of the buccal or gingival area, 90 percent had a history of snuff use. While no periodic quantitative or qualitative assessment of the natural history of the cancers is provided, the authors do offer the following clinical impres- sion of snuff-induced lesions in their study: These carcinomas arising in the inner cheek and gingiva frequently start as leukoplakia. Progressive thickening, cornification, and even- tual cauliflower-like ulcerations ensue. All stages in the progressive disease may be seen in microscopic sections from a mere slight in- crease in the keratin layer, through carcinoma in situ to invasive malignancy. Twenty-five cases of histologically confirmed buccal gingival cancer in female snuff users were identified at the University of Arkansas Medical Center from 1950 to 1959 (33). Eleven cases occurred at buccal sites, 10 gingival, and 4 buccal and gingival. The patients (ages 44 to 84 years-mean 67.5) had a smokeless tobacco habit between 20 and 50 years. The lesions corresponded to the site of habitual tobacco placement. Leukoplakia was a concomitant lesion and had been pres- ent for many years. Bepeat biopsies of lesions were made over long periods in some of the patients. Leukoplakic lesions from other parts of the mouth often showed atypia. An evolution from leukoplakia to pseudoepitheliomatous hyperplasia to early squamous cell carcinoma was found. 120 Di6cu6sion In characterizing the role of smokeless tobacco use in the clinical and histologic course of oral lesions, there are several problems. First, oral leukoplakia should be considered a dynamic changing lesion of the oral mucosa (34). Lesions retain the potential to resolve, remain static, or progress depending on a variety of factors that may be either exoge nous (e.g., smokeless tobacco use) or endogenous (e.g., natural tissue defenses and repair potential). To achieve comparability of results among investigators, a standard system for gauging epithelial dysplasia is needed. Patients then could be followed prospectively to quantify the incidence of dysplastic change, incidence of transforma- tion from a dysplastic state to a cancerous state, or in some cases transformation from an apparently benign to a cancerous state. But ethical considerations do not ahow lesions to be monitored continuously from benign states to moderate and severe dysplasias and carcinoma in situ. The next best alternative would be to provide estimates of risk for malignant transformation based on empirical and clinical observations or at least to quantify descriptively the association that smokeless tobacco-induced lesions have with other lesions or other potential etiologic factors. The body of literature on smokeless tobaccoinduced lesions and their potential for malignant transformation allows for the development of a conceptual model of the natural history of smokeless tobacco-induced lesions (figure 1). This model is a composite of various prospective, retrospective, cross-sectional, and case studies that relate to smokeless tobacco-induced lesions, It depicts progressive changes that may occur in some individuals who are habitual users of smokeless tobacco and potential outcomes that could include death or disfigure- ment for some individuals who use smokeless tobacco for several dec- ades. The data are clear that habitual smokeless tobacco use can pro duce mucosaI lesions (see leukoplakia discussion). It is also clear that where groups of patients with smokeless tobaccoinduced leukoplakias have been followed for several years, cases of cancer have been identi- fied. Finally, when considering studies of oral cancers in habitual smokeless tobacco users, there appears to be a consistent finding of leukoplakias either having been previously excised in the area of habit- ual tobacco placement or being found concurrently with and in proxim- ity to oral cancers. In comparing studies on the transformation potential of smokeless tobacco-induced leukoplakias, it is found that different criteria have been used by various investigators in defining dysplastic changes. The number and nature of criteria that are considered and that are consid- ered adequate to classify a case as dysplastic are not consistent. Addi- tionally, the degree of agreement on diagnosis based on histology and clinical history between individuals has been shown to be quite variable. Pindborg, FLeibel, and Holmstrup tested the degree to which a group of 121 FIGURE 1.-A Conceptual Natural History of Oral Mucosal Changes Associated With the Use of Smokeless `Ibbacc~ Diagnostic Oral Tissue Level status Smokeless Tobacco Exposure Time A HEALTH CLINICAL Leukcplaklas Erythroplakias Smokeless Tobacco Hablt P-ooablllty Low Probabmlit\/ High D~sp~asx Changes I t t CLINICAL and De&h Powble Deatr? Highly HISTOLOGIC 01 Loss of Tissue Powble or Potent'al and Function o for Disfigurement * I Months to "ear 10+ Years 122 oral pathologists could agree on diagnoses where nine cases of epithelial dysplasia, carcinoma in situ, or initial squamous cell carcinoma were examined (35). Color photomicrographs and information on the topog- raphy of the biopsy were presented. The authors' diagnoses were based on the criteria that are described in the report from the WHO Interna- tional Collaborating Center for Oral Precancerous Lesions (1). The degree of agreement with the authors' diagnoses for the nine cases ranged between 10 and 78 percent. This could partially explain the range in prevalence and incidence of malignant transformation that is reported by various investigators. Other contributing factors in comparing studies could include differ- ent population groups in terms of age and gender and other confound- ing variables (e.g., smoking, alcohol use, and type of smokeless tobacco product used). Each of these limitations is suggestive of the type of research that is needed. THE EFFECTS OF SMOKELESS TOBACCO USE ON THE GINGIVA, PERIODONTAL TISSUE, AND SALIVARY GLANDS Background and Definitions Reports of gingivitis, gingival recession, and degenerative salivary gland changes associated with smokeless tobacco use are contained in the literature. As with the previous section on oral leukoplakia, the terms used and the definitions employed to describe gingivitis and gingival recession vary widely from study to study. `lhble 4 displays the variations found in the literature. As each study is described in the fol- lowing narrative, the authors' terms are employed. However, in the discussion portion of this report, the general terms of gingivitis and gin- gival recession are used. General definitions for these terms and for sialadenitis follow: o Gingivitis-This condition refers to clinically detectable acute or chronic mflammation, either local or general, of the gingiva. o Gingival recession-In general, this condition describes the apical migration of the gingiva with or without clinical evidence of inflammation. o Sialadenitis-Inflammation of the salivary glands. Gingival and Periodontal Tissue Studies that assess the relationship between smokeless tobacco use and gingival and periodontal tissue effects are limited. The literature consists of several cross-sectional studies in teenagers and a few case reports. 123 TABLE 4.-Variations in `krms Used and Definitions Provided for Gingivitis and Gingival Recession by Studies Cited Study Term(s) used Deftition(s) Provided Conunents Christen, Armstrong, and - McDaniel. 1979 Christen, McDaniel, and Doran. 1979 :OZYd 1983 ' Ho and I(lr ham, .f 1983 Mod&r. Lavstedt, and Ahlund, 1980 C$enbacher Weathers, 1985 Paulson. Lindenmuth, and Greer, 1984 Zitterbart, Marlin, and Christen, 1983 Gingival recession, periodontal gxket. and loss of veolar bone. Clinically detectable gingival recession. Tobaccoassociated periodontal degeneration and periodontal lesions. Gingivai recession. Gingivitisigingival inflammation. Gingivitis. Gingival recession. lbbacco-associated "Defined as site periodontal degener- ation (other terms specific gingival include periodontal recession with apical migration of the deterioration," and "localized periodon- gingiva to or beyond the cementoenamel tal degeneration junction, with or associated with the without clinical site of tobacco evidence of placement"). inflammation." Gingivitis, Gmgival recession. No definition provided. No definition provided. No definitions provided. No definitions provided. Defined as site specific gmgival recession wrth apical migration of the gingiva to or beyond the cementoenamel junction, with or without clinical evidence of inflammation." No definition provided. No definition provided. No definition provided. The tissue changes were described in zrofs by the - The authors defined the recession as having "exposed approxi- mately 5 mm of labial root surface" and having destroyed the "entire functioning border of keratinized gingiva." - - The gingival recession was "considered slight to moderate, ranging in l-4 mm apical migra- tion when present." - - The clinical findings were described for each tooth site involved. 124 Studies in the United States Three cross-sectional studies have investigated the relationship of gingival and periodontal tissue changes and smokeless tobacco use in teenagers in the United States (7-9). Offenbacher and Weathers exam- ined the effects of smokeless tobacco use on mucosal pathology, on the presence of gingivitis and gingival recession, and on dental caries status (discussed in next section) (9). Of the 75 smokeless tobacco users, the authors noted 72 percent with gingivitis and 60 percent with gingival recession. In those with gingival recession, 6.6 percent presented with recession in direct juxtaposition to the location of the tobacco place ment. The authors did not describe how many users of smokeless tobac- co had demonstrated combinations of these oral conditions. Also, no specific clinical definitions were given for the assessment of gingivitis or gingival recession, although the latter findings were described as "slight to moderate, ranging from 1 to 4 mm apical migration of gingi- val tissue." The higher prevalence of gingival recession among smoke less tobacco users (60 percent) as compared with that found in nonusers (14.1 percent) was found to be statistically significant. There were no statistically significant differences in gingivitis prevalence between smokeless tobacco users (72 percent) and nonusers (77.1 percent). Of 117 adolescent smokeless tobacco users in Denver, Colorado, Greer and Poulson noted that 25.6 percent had tobaccoassociated periodontal degeneration (7). As noted earlier, this condition was de fined as "sitespecific gingival recession with apical migration of the gingiva to or beyond the cementoenamel junction, with or without clini- cal evidence of inflammation." Concomitant mucosal lesions were noted in 76.6 percent of those who had periodontal degeneration (gingival recession). In a study of rural Colorado teenagers, Poulson, Lindenmuth, and Greer (8) described 26.8 percent of 56 smokeless tobacco users with peri- odontal degeneration (gingival recession) as defined by Greer and Poulson (7). Eighty-seven percent of these had concomitant mucosal lesions. Several case reports (table 2) describe the occurrence of gingival reces- sion and periodontal tissue destruction in individual smokeless tobacco/ snuff users (1@13). The patients in these case reports were males who ranged in age from 18 to 36 years with varying duration of the smoke less tobacco/snuff habit ranging from 1 to 24 years. Although not uni- versally found, gingival recession was usually noted, and the majority of patients presented with recession that was specific to the site where the tobacco/snuff was habitually placed. Periodontal bone loss at the site of snuff placement was described in another patient who used snuff for 13 years (10). In one patient, 3 weeks after cessation of snuff use, there was no regeneration of the lost gingi- val tissue, although, as noted earlier, the hyperkeratotic areas had dis- appeared (121 125