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