L eu ko ed em a of the oral m ucosa
This report concerns itself with the first two of
Roy T. Durocher, DD S, P itts b u rg h
Roger Thalman, D M D
Giuseppe Fiore-Donno, M D, D M D , G eneva,
S w itz e rla n d
A n e x tre m e ly h ig h in c id e n c e o f le u k o e d e m a o f th e
o ra l m u c o s a w a s fo u n d c lin ic a lly in th is s tu d y o f
430 p a tie n ts . L e u k o e d e m a o n th e b u c c a l m u c o s a
w a s c lin ic a lly o b s e rv e d in 400 p a tie n ts , a n d a ls o
on th e la b ia l m u c o s a in 131 p a tie n ts . In m o s t p a ­
tie n ts b u c c a l in v o lv e m e n t w a s b ila te ra l. In te n s ity
o f th e e x a m in a tio n la m p p ro v e d to be a c ritic a l
fa c to r in th e id e n tific a tio n o f m ild fo rm s o f le u k o ­
e d e m a . B e c a u s e o f th e h ig h in c id e n c e o f le u k o ­
e d e m a fo u n d in th e s tu d y s a m p le , th e p o s s ib ility
th a t it is a v a ria tio n o f n o rm a l s h o u ld be c o n s id ­
ere d.
In 1953, Sanstead and L ow e1 reported on an in­
teresting phenomenon that they had observed in
the buccal mucosa o f 43% o f the white and 90%
of the black patients of 646 individuals in a psy­
chiatric hospital. These investigators described
what they saw as “ a generalized, whitish gray
lesion” ; the biopsy specimens o f the lesions re­
vealed intracellular edema and epithelial hyper­
plasia. They further said that “ the mucosa ap­
peared edematous” and “ the degree of involve­
ment ranged from a filmy opalescence to a whit-
ish-gray or ‘waterlogged’ appearance” and that
the condition was asymptomatic. They termed
the lesion leukoedema.
A 1954 study by Sandstead and co-workers,
reported by others2 in 1968, indicated that the
condition was diagnosed in 45% of the patients
'in a hospital population of 1,017; there was a
much higher incidence o f the condition among
black patients than among white patients. Others
have reported on leukoedema, but mostly it has
been mentioned as only one finding among
others in general epidemiological surveys of the
oral cavity.3'8
Our objectives were to conduct a systematic
study of the clinical incidence of leukoedema,
to analyze its possible correlation with several
factors, and .to investigate its histochemistry.
those three activities.
D iagnostic crite ria
We made a clinical diagnosis of leukoedema of
the buccal mucosa when these characteristics
were observable. The lesion was diffuse, whit­
ish to whitish-gray, frequently folded into wrin­
kles or whitish streaks, and asymptomatic (Fig
1). At times, however, the wrinkles and streaks
were absent, but a filmy opalescence was pres­
ent and continued to obliterate, at least in part,
the fine vascular network usually observed in
the nonkeratinized portions o f the oral mucosa.
Unless the mucosa is heavily wrinkled, the whit­
ishness or whitish-grayness can be made to dis­
appear by stretching the tissue. A s the stretched
mucosa is relaxed, the original opalescence re­
turns. H owever, if the opalescence is heavy,
the film may not disappear com pletely. In in­
stances of doubt at first glance, extremely fine
whitish streaks can be caused to appear if the
mucosa is gently compressed on itself. The sur­
face is soft to the touch and cannot be scraped
off without surgical manipulation. (The last cri­
terion does not seem to agree with observations
of some other investigators.5'7)
These criteria were necessarily modified in
the examination o f nonbuccal sites o f the oral
mucosa. So that the mucosa o f the upper lip
could be seen with the patient in the standard­
ized position to be described, a turning back of
the lip and, thus, a stretching o f the mucosa was
necessary. A t other sites, it was impossible to
manipulate the mucosa. Consequently, at non­
buccal sites clinical diagnosis was made only
on the basis of the filmy opalescense with or
without streaking; otherwise, the lesions were
typical o f those seen in the buccal mucosa.
■ Clinical examination: Two dental operator­
ies were used. The various positions o f each
chair were adjusted and calibrated so that pa­
tients were positioned as similarly as possible.
The back was about at a 45° angle to the seat and
the headrest was adjusted so that the head and
neck were in a straight line with the upper part
o f the patient’s body. The only variable in each
chair was the height o f the headrest which was
JADA, Vol. 85, Novem ber 1972 ■ 1105
adjusted to accommodate the height of each in­
dividual.
Illumination was provided by a Ritter dental
overhead light, model J, with lamp number
141160. This unit provides an adjustment for
light intensity. The intensity was calibrated for
each o f the two lamps at 32,000 lux at a distance
of 61.5 cm from the center of the lamp shield to
a point on the patient’s upper lip overlying the
notch inferior to the anterior nasal spine. This
distance was maintained for each patient.
Two standard no. 4 dental mirrors were used
to examine the oral cavity. Stretching and re­
laxation of the buccal and labial mucosa were
accomplished by the use of the mirrors or fin­
gers, or both. The submaxillary glands were pal­
pated.
A specially designed form was used to record
the findings o f the clinical examination of the
lips, tongue, floor of the mouth, submaxillary
glands, hard and soft palates, uvula, tonsils,
glosso- and pharyngopalatine walls, posterior
oropharyngeal wall, edentulous ridges, alveolar
mucosa, gingiva, metallic restorations, labial
mucosa, and buccal mucosa. The absence or
presence of prostheses was documented also.
Leukoedema was recorded as being adjacent to
natural teeth, prostheses, edentulous spaces, or
a combination of these. The name of the exam­
iner was noted.
The clinical examinations were conducted by
two of us, one examiner in each of the two oper-
atories. Negative and doubtful clinical impres­
sions relative to leukoedema were confirmed by
a second examiner.
■ H istologic review: Incisional biopsy speci­
mens were taken for definitive diagnostic pur­
poses if both investigators had doubtful clinical
impressions o f the region. In some instances,
tissue of buccal mucosa clinically judged by
both clinicians to be free of leukoedema was.
submitted for histologic review also.
Biopsies were performed with a 0.5-cm round
punch instrument and a scalpel to free the base
o f the specimen. Local anesthesia was infiltrat­
ed in regions away from the site of the tissue to
be removed. The specimen was placed, with the
epithelial surface downward, on coarse filter
paper and immediately immersed, with the con­
nective tissue surface downward, in a bottle
containing a 10% Formalin fixative. (The speci­
men was placed on the bottom of the bottle.)
Sections were stained with hematoxylin and
eosin.
1106 ■ JADA, Vol. 85, November 1972
Fig 1 ■ A rrow s outline more prom inent area of leukoedema.
■ Interexaminer reliability: These steps were
taken before the study to establish reliability be­
tween examiners.
Single biopsy specimens were taken from the
buccal mucosa o f each of three persons for
whom a clinical diagnosis of leukoedema had
been made by the investigator having the most
clinical experience with leukoedema. A review
of the sections revealed the presence of epi­
thelial intracellular edema. This was accepted,
in accordance with the Sanstead and Lowe
study, as a confirmation of the clinical impres­
sion.
The principal investigator double-checked
clinically the second investigator’s clinical diag­
noses of leukoedema in five patients who had
the typical whitish-gray wrinkling or streaks.
The second investigator then was required
to agree, without previous knowledge, with the
first on a mixture of normal and abnormal find­
ings in several other patients.
Biopsies were performed in two additional
patients who were thought after clinical exam­
ination to be free of leukoedema and in one other
patient whose condition was in doubt—inasmuch
as there was a faint filmy opalescence, but no
wrinkles or streaks. (The specimen from the lat­
ter patient proved to show epithelial intracellu­
lar edema as did one of the first two specimens
thought to be normal clinically. The section
from the third patient exhibited only an occa­
sional cell containing a space, and therefore, it
was judged to be representative of normal tis­
sue.)
Table ■ The d istrib u tio n of find in gs at various sites.
Site No. cases % cases
Buccal mucosa 400
Unilateral 14
Bilateral 386
Labial mucosa 131
Uvula 42
Tongue 6 1.5
Other 9 2.5
A t the completion of the study, we tried to de­
termine if any actual differences in performance
existed between the two examiners in the iden­
tification o f leukoedema. A 2 x 2 chi-square test
was performed on the clinical findings in the
study sample. The results showed no statistical
difference.
■ Sam ple selection: During April, May, and
June 1971, 430 patients (more than 15 years old)
were examined immediately after, and in the
order of, their registration at the polyclinic of
the section o f dental medicine o f the Faculty of
Medicine, University o f Geneva. Children were
excluded because registration and care of this
group of patients is provided in another clinic.
Oral findings for all o f the patients were record­
ed.
■ Survey questionnaire: A self-administered
questionnaire, available in French, Italian, or
Spanish, was used at the time of examination
to determine the possible correlation o f leuko­
edema with other factors selected on the basis
o f subjective hypotheses. It consisted of three
parts. Part one included the statistics of name,
age, race, sex, parental nationality, and occupa­
tion. Another part, permitting space for an open-
ended response, concerned the patient’s spe­
cific history o f dermatitis, allergy, hormonal
disturbance, pregnancy, diabetes, anemia, ner­
vousness, and drug use. The third section in­
cluded questions about diet and alcohol habits
and tobacco, wafer, toothpaste, and mouth­
wash usage.
Results
■ Clinical examination: Leukoedema was clin­
ically observed in 400, or 93%, of the 430 pa­
tients examined. In each instance o f a positive
observation, the lesion was present in the buc­
cal mucosa, although it was frequently present
at other sites as well. Except for 14 patients,
buccal involvement was bilateral; unilateral in­
cidence was only 3%. The lesion was observed
in the labial mucosa in 131 persons, or 32% o f
the patients. Although it was seen at times only
100
3
97
32 in the inferior labial mucosa, in no patients was
10
it seen in the superior labial mucosa only. The
uvula exhibited leukoedema in 42 patients and
the tongue in only 6. The condition was ob­
served in the floor o f the mouth in only two per­
sons. In nine patients leukoedema was observed
in the pharyngoglossopalatine sites (Table).
Several other oral changes were observed and
recorded. H owever, since any one variety o f
these was minimal in number and inasmuch as
the number of patients without leukoedema was
so small, correlations could not be made. There­
fore, listing of the additional findings is not per­
tinent to this report.
■ Survey questionnaire: Responses to the ques­
tionnaire were subjected to statistical analysis.
The ages of the patients with leukoedema ranged
from 16 to 82. O f 60 persons 21 years old or
younger who were examined, 57 had the condi­
tion, including the five patients who were age
16. The age distribution of those individuals
without leukoedema was wide, from age 19 to
76, and unclustered. Alm ost 100% of the respond­
ents listed their race as white. Sex distribution
was nearly even with respect to numbers ex­
amined and incidence o f leukoedema. The par­
ents o f the individuals were mainly of Swiss,
Italian, French, or Spanish origin.
A side from these observations, little can be
said o f the data. Again, in view o f the fact that
there were so few patients without leukoedema,
it is impossible to make any statistical compar­
isons between the groups with and without leu­
koedema. A lso, it is not possible to make com­
parisons within the leukoedema group because
data are not known on the distribution of vari­
ables, such as the percentage of the total pop­
ulation from which the study sample came who
drink alcoholic beverages or who have a history
of diabetes.
D iscussion
The high clinical incidence of leukoedema as de­
termined by this study conducted under care­
fully controlled conditions raises a question
concerning data obtained by other investigators,
although the data o f Sanstead and L ow e1 for
blacks did approach the findings o f this investi­
gation.
On the basis o f the clinical descriptions and
histologic sections reported by those investiga-
D urocher—Thalm an— Fiore-D onno: LEUKOEDEMA OF ORAL MUCOSA ■ 1107

Fig 2 ■ Buccal mucosa w ith no clinical m anifestation of leuko­
edema.
tors, we believe that they observed the same
clinical variations that we did. Sanstead and
Lowe referred to a “ bluish cast” to the leuko-
edemic mucosa among some blacks. A similar
color was observed in at least one black in the
present study. Undoubtedly, a pigmented back­
ground enhances the ease with which leuko­
edema is observed. Indeed, the optic aspect of
leukoedema is critical to the finding of this phe­
nomenon. The intensity of light and the pliabil­
ity of the mucosa are significant factors in the
establishment o f a clinical diagnosis.
In standardization of the intensity of each of
the two adjustable dental lights, quite by acci­
dent it was noticed that mild forms of leuko­
edema could be made to appear and disappear
clinically by manipulation of the intensity. Fur­
thermore, in instances in which the clinical ob­
servations about the presence of a change were
in doubt, it was frequently possible for the in­
vestigator to bring about fine whitish folds or
streaks by gently compressing the mucosa on
1108 • JADA, Vol. 85, November 1972
itself. Moreover, doubtful and negative clinical
observations did not necessarily rule out the
possibility of the presence of intracellular ede­
ma, either observable only through microscopic
examination or manifested clinically under con­
ditions other than those described for this par­
ticular study.
The possibility of clinically undetected leuko­
edema was suggested when the biopsies were
performed to establish reliability between exam­
iners. Therefore, specimens for histologic re­
view were obtained from the buccal mucosa of
seven persons in the survey sample. In five pa­
tients, mucosa clinically judged by both exam­
iners to be free of leukoedema was found to
contain intracellular edema of sufficient degree
to be diagnosed as leukoedema by the patholo­
gist who studied the specimens without the
benefit of any clinical impression (Fig 2, 3).
These histologic findings were substantiated
later by two of us. In three of the five patients,
a biopsy on clinically normal mucosa was per­
formed because the mucosa of the opposite buc­
cal pouch was clinically judged by the two ex­
aminers to indicate leukoedema. In both of the
other two patients of the five, the buccal mucosa
was clinically normal bilaterally. In one, bilater­
al biopsies were performed and the specimen
from one side was positive. In the other indivi­
dual, buccal mucosa obtained from only one
side was subjected to microscopic examination.
This specimen also was reported to exhibit leu­
koedema. Again, in both instances the path­
ologist offered the diagnosis on the basis of in­
tracellular edema and without benefit of clini-
ical impressions. The diagnoses also were sub­

stantiated by the same two examiners. In the re­
maining two of the seven persons subjected to
biopsy, the two examiners observed leuko­
edema unilaterally in the buccal mucosa, but
they had some doubt about the clinical appear­
ance of the opposite sides. For both patients,
the results of the histologic examination were
positive for leukoedema on the sides in question
(Fig 4).
The findings from histologic examination of
these seven patients indicate the probability
that there are more instances of the intracellular
edema characteristic o f leukoedema than those
manifested by clinical signs.
Furthermore, the findings from the clinical
examinations reported in this study indicate the
likelihood of a far higher incidence of the clinical
signs of leukoedema than would be detected by
casual examination.
S u m m ary
Under controlled conditions, leukoedema of the
oral mucosa was clinically observed in 400
(93%) of 430 dental clinic patients in Geneva,
Switzerland. Tissue specimens, taken from the
clinically normal buccal sides o f the mucosa of
five of the 400 patients, were found by micro­
scopic examination to contain intracellular
edema of a degree characteristic of leukoedema.
Histologic specimens taken from two patients
of the clinically normal group revealed the same
intracellular edema.
Because of the optic phenomenon related to
the tissue alterations, the conditions under which
the clinical examination is conducted are critical
for identification of leukoedema.
It was not possible to make a statistical cor­
relation of the finding of leukoedema with other
Durocher— Thalm an— Fiore-Donno: LEUKOEDEMA OF ORAL MUCOSA ■ 1109
Fig 4 ■ P hotom icrograph revealing epithelial In­
tracellular edema in biopsy specim en obtained
from buccal mucosa of do ubtfu l clinical appear­
ance. (Arrows indicate area of qu ite high degree of
change.) Leukoedema, however, was clin ica lly o b ­
served in buccal m ucosa of opposite side.
clinical changes, vital statistics, histories, or
habits.
Because this study suggests an the extremely
high incidence of intracellular edema on the oral
mucosa, the possibility that this phenomenon is
a variation of normal must be considered. This
concept is further supported by evidence that
intracellular edema is a common finding in “ nor­
mal” vaginal m ucosa.1,9
The authors wish to acknow ledge the assistance of Dr. B. Port-
mann, pathologist at the Faculty of Medicine, University of Gene­
va, and Dr. T. Zullo o f the University of P ittsburgh School of
Dental M edicine fo r his statistical analysis.
Dr. D urocher was a visiting professor of stom atology at the
section o f dental medicine, Faculty o f M edicine, University of
Geneva, Switzerland. His current address is School of Dental
Medicine, University o f Pittsburgh, 348 Salk Hall, Pittsburgh,
15213. Dr. Thalman is assistant and Dr. Fiore-Donno is professor
and chief, o f the departm ent of stom atology and oral surgery,
University of Geneva, Switzerland.
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tosis In relation to leukoplakia of the buccal mucosa in man.
J Natl Cancer Inst 14:423 Oct 1953.
2. A rchard, H.O.; Carlson, K.P.; and Stanley, H.R. Leukoedema
o f the human oral mucosa. Oral Surg 25:717 May 1968.
3. Martin, J.L.: Buenahora, A.M.; and Bolden, T.E. Cyto-his-
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47 March 1969.
4. Hamner, J.E., and Villegas, O.L. The effect of coca leaf
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