ORAL LEUKOPLAKIA

J.J. Sdubba
Department of Dental Medicine, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, New York 11040

ABSTRACT: Leukoplakia has evolved as a clinico-pathologic concept over many years, with the current clinical designation
being accepted worldwide. Reflective of the biology of leukoplakia is the concept of cellular atypia and epithelial dysplasia.
Adding to a better understanding of leukoplakia in general has been the definition of relevant clinical subsets which, in some
cases, includes etiology (snuff), while in other cases a verrucous clinical appearance will suggest a more aggressive anticipat-
ed behavior pattern. Tobacco usage, in many of its forms, remains the prime etiologic factor; however, other considerations
also apply. More recently, the potential etiologic role of Candida albicans has been stressed, as well as its possible role in car-
cinogenesis. So-called oral hairy leukoplakia has been defined in relation to a possible Epstein-Barr viral infection, usually in
the immunosuppressed patient. Other viruses, human papilloma virus in particular, have been implicated in leukoplakia, while
genetic alterations involving tumor suppressor elements (p53) have also been investigated. Finally, the management of this
common condition remains a variable and includes local, topical, and systemic therapies such as anti-oxidants, carotenoids,
and retinoids.

Keywords. Leukoplakia, transformation, tobacco, p53, therapy.

Introduction which show microscopic evidence of dysplasia extend

from 3.7% (Mehta et al, 1971) to 28.7% (Banoczy and

T he World Health Organization (1978) has defined oral

leukoplakia as a white patch or plaque which cannot
otherwise be characterized clinically or pathologically as
any other disease. From an historical perspective, this
was an important statement in that it removed the des-
ignation of leukoplakia from the histopathologist to the
clinician, resulting in leukoplakia being a clinical term
only, without an attendant histological diagnosis or con-
notation. Historically, many pathologists and clinicians
used the term leukoplakia synonymously with micro-
scopic alteration, chiefly that of epithelial dysplasia or
carcinoma.
Leukoplakia has been studied for many years and is
commonly agreed upon as representing the most com-
mon pre-malignant oral mucosal lesion. There are wide
variations concerning the frequency of malignant trans-
formation. Confusion exists concerning not only the ter-
minology used to describe various white lesions which
arise in the oral cavity, but also their biology. Studies will
often indicate rates of "malignant transformation", while
other studies deal with the development of dysplasia
within leukoplakia. Thus, transformation may mean the
development of cancer or the development of pre-inva-
sive cancer characterized by various levels or degrees of
dysplasia. Separation of these two considerations is
important. Ranges of the percentage of leukoplakias
Csiba, 1976). A recent review by Bouquot and Whitaker
(1994) noted that Sir James Paget, in 1851, was aware of
the cancer-forming potential of what we today consider
to represent leukoplakia, reporting on this entity as
leukokeratosis and smoker's patch. Oral leukoplakia was
first and fully described in the second half of the 19th
century by the Hungarian dermatologist, Schwimmer
(1877). Over the ensuing decades, oral leukoplakia has
been recognized and established as a definitively pre-
cancerous lesion, often serving as the harbinger for the
development of oral cancer, its importance lying in the
general morbidity and high mortality rates associated
with invasive cancer. In general, a pre-malignant lesion
may be defined as a morphologically altered tissue in
which cancer is more likely to develop when compared
with its apparently normal counterpart (WHO, 1973).
The concept of leukoplakia representing a pre-can-
cerous state was strengthened by the identification of
dysplastic change, if not early invasive cancer, when large
numbers of leukoplakia specimens were studied. In
those studies (Pindborg et al, 1963; Waldron and Shafer,
1975; Bouquot and Gorlin, 1986), a range of dysplasia,
carcinoma in situ, and carcinoma from 17% to 25% was
found in leukoplakias from all oral sites. In examinations
of specific clinical subtypes or presentations of leuko-
plakia with variable ranges of transformation rates, fig-

6(2):147-160 (1995) Crit Rev Oral Biol Med 147


Figure 1. An early leukoplakia with minimal verrucous features
is multifocal and well-delineated and is arising at the junction of
the attached and alveolar gingival mucosa.
ures as high as 36% have been reported (Silverman et al.,
1984), while, when leukoplakias in general were consid-
ered, the range of transformation in large studies has
been reported from less than 3% to 17.5%% (Table 1).
When coupling these statistics of transformation rates
and their relationship to invasive cancer to the reported
statistic by Bouquot and Gorlin (1986), which states that
only 25% of leukoplakias are ever biopsied, clinicians
must be aware of the clinical features, biological quali-
ties, and behavioral characteristics of such lesions as
well as their relationship to the overall health and well-
being of their patient population.
Epidemiology
The prevalence of leukoplakia in various populations
shows a wide range. In India, between 0.2 and 4.9% of the
population over 15 years of age was found to have leuko-
plakia (Mehta et al, 1969, 1972a,b). In a Swedish study,
Axell (1976) reported a prevalence of 3.6%, while in
Hungary, the prevalence of leukoplakia varied between
0.6 and 3.6% of the adult population, as reported by
Banoczy and Sugar (1972). A broader summary of the
investigations concerning prevalence demonstrates fig-
ures ranging from 1 to 5% (Gerry et al, 1952; Atkinson et
al, 1964; Pindborg et al, 1965a,b, 1966, 1968; Mehrotra,
1969; Mehta etal, 1969, 1972a; Silverman etal, 1976; Lay
et al, 1982; Rodriguez et al, 1983; Bouquot and Gorlin,
1986; Reichart et al, 1987). Of interest is the examination
of the annual incidence of leukoplakia in those who do
not use tobacco (0.6 per 1,000) vs. those who use betel
148 Crit Rev Oral Biol Ued
quid (1.3 per 100,000). In smokers, this rises to an inci-
dence of 4.2, while an incidence of 8.9 has been reported
among those who smoke and also use smokeless tobac-
co (Mehta, 1972b).
In a 10-year population-based study, more than
30,000 individuals 15 years of age or older were studied
by Gupta et al in 1980. These individuals were from three
areas of India, with an average of 10,000 individuals
forming random samples from these three separate com-
munities. They were followed annually and examined in
a house-to-house survey manner. The annual incidence
per 1000 men ranged from 1.1 to 2.4, while in women in
the same geographical areas the incidence ranged from
0.2 to 0.03. Where reverse smoking was practiced, the
incidence of white patches on the palate was 6.3 per 1000
men and 11.2 among women. Of greatest importance in
this particular study was that tobacco use in one form or
another was the most common variable relative to the
development of leukoplakia.
Estimation of trends relative to the occurrence of
leukoplakia over time are provided by many of the above-
mentioned studies and offer an overview relative to risk
factors for leukoplakia as well as prevalence and inci-
dence rates. Documentation of exposure to known risk
factors is important so that, over time, such mucosal
changes can be interpreted and applied directly to out-
come.
The gender distribution of leukoplakia varies widely
from one survey to another. Such differences in distribu-
tion have been attributed to variability in tobacco habits
(R0ed-Petersen et al, 1972). In a study in the United
States, Waldron and Shafer (1975) demonstrated an
increased frequency of leukoplakia in women between
1961 and 1975, with the suggestion that this increased
frequency may reflect changes in smoking habits during
the period of observation.
The greatest emphasis has been directed toward
tobacco as the major etiologic agent in the development
of leukoplakia (Pindborg et al, 1977, 1980). Several stud-
ies have shown a paradoxical relationship between the
development of leukoplakia and non-smoking status. In
fact, Einhorn and Wersall (1967) have noted that the fre-
quency of malignant tumors developing within pre-exist-
ing leukoplakia in non-smokers was eight times that
noted in tobacco users with leukoplakia. A similar,
although less strongly biased, conclusion was noted by
Silverman and Rosen (1968). The relationship of the
absence of this particular risk factor and development of
carcinoma is unclear but may reflect fundamental alter-
ations within keratinocyte maturation and differentiation
in the non-risk group, while in smokers or users of tobac-
co in other forms, a certain degree of reversibility may be
a consideration.
Topical placement of tobacco—such as in the form
of chewing, snuff dipping, or other forms of tobacco-con-
6(2):147-160 (1995)
 taining preparation—onto the oral mucous mem-
brane will produce clinical and microscopically evi-
dent alterations in the form of snuff dipper's kerato-
sis or snuff dipper's leukoplakia. In one recent study,
epithelial dysplasia was noted in 2.9% of cases and
other oral lesions in up to 13% of cases (Kaugars et
al, 1992). A study of high school students who use
smokeless tobacco revealed 50 of 117 (42.7%) with
oral lesions (Greer and Poulson, 1983). Amateur
and professional athletes who regularly use some
form of smokeless tobacco had oral lesions ranging
from 13% in high school athletes (Creath et al, 1991)
to between 34% and 53% in professional baseball
players (Daniels et al, 1989; Grady et al, 1990;
Robertson et al, 1991; Wisniewski et al, 1991).
Separation of snuff users from users of chewing
tobacco may be a valid exercise, in that while
Greene et al (1989) reported oral lesions (including
leukoplakia) in 55% of subjects, only 14% of chewing
tobacco users showed evidence of such lesions.
Whether this difference in the risk of oral lesion
development in relation to the form of smokeless
tobacco is related to specific constituents of the
preparation or to the manner and duration of tobac-
co placement remains unclear.
Anatomical distribution and transition time for
development of oral mucosal changes varies with
the form of smokeless tobacco used. With use of
snuff, the location of such changes, including hyper-
keratosis with or without epithelial dysplasia, was in
the buccal vestibule under the area of contact with
the snuff product. Kaugars et al. (1992) noted a mini-
mum of 2190 hours of smokeless tobacco use prior
to diagnosis of a hyperkeratotic lesion, while devel-
opment of epithelial dysplasia was noted at 7300
hours of exposure. When actual duration of habit is
translated to hours of contact time, hyperkeratosis
Figures 2 and 3. Proliterative verrucous leukoplakia lesions demonstrate
may be noted at a minimum of two years, while for coalescence, with a thickened warty surface configuration.
epithelial dysplasia to develop, a minimum transi-
tion of 6.6 years is necessary. Previously published
studies indicate that mucosal lesions, including
leukoplakias, may require 10 or more years to devel-
op in a minority of users of smokeless tobacco, while 40 focal and smooth or homogeneous to "pumice-like", with
more years may be necessary for carcinoma to develop an associated low risk of malignant transformation.
(Winn et al, 1981; McGuirt, 1983; Kaugars et al, 1991, Other lesions may be heterogeneous or non-homoge-
1992). Finally, the study by Winn et al. (1981) noted that neous (speckled, erosive, ulcerative, verrucous), which
the relative risk of carcinoma developing in altered may be interspersed with red or atrophic areas and are
mucosa (gingiva and buccal mucosa) of females chroni- associated with a higher risk of dysplasia and malignant
cally using snuff is 50-fold compared with that of a non- transformation (Eveson, 1983; Williams, 1990; Wright,
user control population, although the rate of such trans- 1994). Also to be appreciated is the dynamic quality
formation is low. within the group of leukoplakias, with transitions from
one clinical form to another commonly noted.
Forms of Leukoplakia With such a shift from a homogeneous to a non-
The range of clinically altered oral mucosa involved by homogeneous form, re-biopsy is mandatory. Histologic
leukoplakia is broadly presented. Many lesions may be analysis and comparison between homogeneous and

6(2):147-160 (1995) Crit Rev Oral Biol Ued 149

 Eversole and Papanicolaou, 1983; Gaillard et al,
1983; Hansen et al, 1985). Some authors regard ver-
rucous hyperplasia as an early form of verrucous
carcinoma (Slootweg and Muller, 1983), although
the characteristic feature of a blunted epithelial
front pushing into the underlying lamina propria,
characteristic of verrucous carcinoma, is absent in
verrucous hyperplasia. Leukoplakia with significant
dysplastic features at its first appearance must not
be placed into the verrucous or proliferative verru-
cous leukoplakia category, but rather, diagnosed
specifically as a dysplastic process.
Shear and Pindborg (1980) unified the previ-
ously defined term, verrucous leukoplakia (Adkins
and Monpour, 1976), by defining verrucous hyper-
plasia as a separate histologic subset within the
leukoplakia family of clinically defined lesions.
Others, however, believe that verrucous hyperplasia
Figure 4. Smooth or homogeneous leukoplakia along the ventral tongue (Fig. 1), while descriptive, should not be accorded
surface with ill-defined margins. This lesion has developed slowly over the status of a separate clinico-pathologic entity
several years in the absence of symptoms. (Hansen et al, 1985). Supporting this view is the
histopathologic overlap noted among verrucous
hyperplasia, verrucous leukoplakia, verrucous carci-
TABLE 1 noma, and oral florid papillomatosis. Supporting
this contention is the fact that it is at times difficult
Malignant Transformation Rates in Oral Leukoplakia to distinguish clinically between verrucous hyper-
(selected studies) plasia and verrucous carcinoma. A preponderance
of both entities has been noted in elderly females,
Study Country n % transformation with the buccal mucosa and mandibular gingiva
and alveolar ridge being the most common location
Gupta et al. (1980) India 410 2.2 for verrucous carcinoma. Both lesions tend to
Einhorn and Wersall (1967) Sweden 782 4.0 involve large broad areas of mucosa with well-
Silverman and Rosen (1968) USA 117 6.0 defined margins. Elongated, sharp, highly kera-
Banoczy(1977) Hungary 670 6.0 tinized warty or verrucous white processes are pre-
Silverman et al. (1984) USA 257 17.5
sent clinically. In addition, a second pattern, con-
sisting of polypoid, less heavily keratinized aggre-
gates forming blunt exophytic processes, may be
non-homogeneous forms of leukoplakia correlates with present. Absent at the microscopic level in verrucous
increasing levels and frequency of dysplasia as the level hyperplasia are the endophytic epithelial extensions into
of clinical heterogeneity increases (Pindborg et al, 1963; the lamina propria. In analyses of 36 cases of verrucous
Mehta et al, 1969; Banoczy, 1977; Shear and Pindborg, hyperplasia with associated leukoplakia, 66% exhibited
1980). epithelial dysplasia, 29% were associated with verrucous
An important additional consideration in the evalu- carcinoma, and 10% were found juxtaposed to squamous
ation of oral leukoplakia is the location or anatomical cell carcinoma. Analyzing these data, Shear and
site of the lesion and its relation to the risk of dysplasia Pindborg (1980) concluded that a pre-cancerous conno-
or malignancy (Table 2). The floor of the mouth and ven- tation could be attributed to verrucous hyperplasia and
tral surface of the tongue are of greatest concern, with a that, with time, it could transform or progress to squa-
demonstrated risk of 43% noted at initial biopsy by mous or verrucous carcinoma. Slootweg and Muller
Waldron and Shafer (1975). (1983) studied 27 patients with verrucous lesions of the
Leukoplakias with verrucous or verruciform micro- oral mucosa with endophytic or exophytic growth pat-
scopic patterns are well-recognized and -accepted. Terms terns. Co-existing or separately occurring carcinoma or
used to describe these microscopic alterations include epithelial dysplasia was present in 63% of cases, with the
verrucous hyperplasia, verrucous leukoplakia, oral florid conclusion being that verrucous hyperplasia is a precur-
papillomatosis, and proliferative verrucous leukoplakia sor of carcinoma.
(Wechsler and Fisher, 1962; Shear and Pindborg, 1980; Still another form of leukoplakia, proliferative verru-

150 Crit Rev Oral Biol Med 6(2):147-160(1995)

 cous leukoplakia (Figs. 2 and 3), has been defined
by Hansen and colleagues (1985). Associated with a
strong risk of carcinoma development, this condi-
tion begins as a simple hyperkeratosis which
spreads and merges with multiple foci of similar
quality. Progress is slow, but when measured over
20 years or longer, this specific form of leukoplakia
is irreversible, slowly becomes verrucous in nature,
proliferative, and is persistent and progressive. The
concept of proliferative verrucous leukoplakia per-
mits the view that this diagnosis may at any time
represent a continuum of one disease condition
with variable clinical and histopathologic expres-
sion. The microscopic expression of lesions which
were clinically papillary to verrucal may range from
minimally verruciform and keratotic to heavily kera-
totic and verrucous.
Conceptually and pragmatically, the prolifera-
tive verrucous leukoplakia spectrum includes the
term oral florid papillomatosis, an aggressive and
proliferative process. This former term has pro-
duced great confusion in the past, with a seemingly
benign connotation. However, in retrospect, some
believe that these should be categorized as verru-
cous carcinomas (Grinspan and Abulafia, 1979;
Takagi and Ishikawa, 1982).
A degree of caution must be exercised concern-
ing the evolution of clinically homogeneous leuko-
plakia (Fig. 4) to proliferative verrucous leukoplakia.
While the latter condition arises in homogeneous
leukoplakia, in only a minority of cases is that evo-
lution seen (Figs. 5 and 6). Likewise, one must not
assume that the spectrum of proliferative verrucous
leukoplakia includes all cases of verrucous carcino-
ma, verrucous hyperplasia, and squamous cell car-
cinoma (Hansen et al., 1985), although the distinc-
tion between proliferative verrucous leukoplakia
and other entities such as verrucous hyperplasia is Figures 5 and 6. A homogeneous but thickened leukoplakia was untreat-
not always clear clinically or histologically. ed for many years (Fig. 5). The same area in Fig. 6 after nearly a decade
Involvement of Candida albicans in the etiology or of neglect, which, wnen biopsied, demonstrated moderate to severe
progression of leukoplakic lesions remains contro- epithelial dysplasia.
versial. Candida-associated leukoplakia is often
ulcerated or of the non-homogeneous type (R0ed-
Petersen et al, 1970). The term "candidal leuko-
plakia" has been suggested to emphasize the possible open question.
participatory or co-factor role of this organism in leuko- The argument that candidal participation in transfor-
plakia (Cawson and Lehner, 1968). Pindborg (1994) mation of some cases of leukoplakia is possible is based
states that most if not all non-homogeneous forms of on the work concerning those biotypes of Candida albicans
leukoplakia are the seat of a candidal infection. Proper associated with leukoplakias (Scully et al., 1994). lepsen
use of antifungal therapy may result in a shift from high- and Winther (1965), Krogh eta/. (1987), and Krogh (1990)
er-risk nodular or speckled leukoplakia to lower-risk have demonstrated higher nitrosation potentials of can-
homogeneous leukoplakia (Holmstrup and Besserman, didal organisms isolated from non-homogeneous leuko-
1983). While the epithelium may be superficially invaded plakias when compared with homogeneous forms.
by the yeast organisms, a causal relationship regarding Elaboration of nitrosamine compounds by some candi-
etiology or transformation of leukoplakia remains an dal biotypes may thus play a role in the carcinogenesis

6(2):147-160 (1995) Crit Rev Oral Bid Med 151


Figure 7. Clinically, this lesion was homogeneous and slightly thickened
Histoloqically, an increased thickness of surface keratin overlies a well
ordered, benign, stratified squamous epithelium with an evenly progres
sive maturational sequence and no evidence of cellular atypia.
process. This may occur by way of interaction with other
carcinogens or directly on oral epithelial cells.
Neoplastic initiation can then result by proto-oncogene
activation (Field eta!., 1989).
Microscopic Features
Predicting the development of carcinomatous transfor-
mation of leukoplakia has depended primarily on the
histopathologic analysis of tissue specimens.
Importantly, the majority of leukoplakias demonstrate
benign features, with hyperkeratosis being the usual
microscopic diagnosis provided (Fig. 7). In those cases
where levels of dysplasia are present, a degree of prog-
nostication can be provided (Waldron and Shafer, 1975;
Crissman and Zarbo, 1989) with some confidence
(Banoczy, 1983). Of the 3256 cases of leukoplakia histo-
logically analyzed by Waldron and Shafer (1975), mild
and moderate dysplasia were found in 12.2%, while a 6%
rate of severe dysplasia was noted. The latter was strong-
ly correlated with a non-homogeneous or speckled clini-
cal presentation. Recently, Lumerman and colleagues
(1995) expanded the diagnostic criteria of oral epithelial
dysplasia in analyzing 308 such cases which included
leukoplakia along with erythroplakia and erythroleuko-
plakia. In assessing retrieved cases where various levels
of dysplasia or carcinoma were noted in situ, they found a
rate of 16% transformation to invasive squamous cell
carcinoma within a mean follow-up period of over 33
months.
Unfortunately, these statistics included the less
common but more frequently dysplastic clinical condi-
152 Crit Rev Oral Biol Med
TABLE 2
Leukoplakia Transformation Risk by
Anatomical Site
%of %with
Site Carcinoma Dysplasia/Cancer
Floor of mouth 9 43
Tongue 7 24
Lip (vermilion) 10 24
Palate 11 19
Buccal mucosa 22 17
(Waldron & Shafer, 1975)
tion of erythroplakia. Criteria listed for the estab-
lishment of epithelial dysplasia are listed in Table 3
and include features previously established by van
der Waal (1986) and others (Lumerman et a!., 1995;
Crissman and Zarbo, 1989; Bouquot and Gnepp,
1991).
After the presence of epithelial dysplasia has
been established, its level or degree must be communi-
cated to the clinician. This remains a subjective exercise;
however, there are useful assessments which utilize a
range of dysplasia from mild to severe (Fig. 8), plus the in
situ designation indicating the most severe pre-invasive
stage of intra-epithelial neoplasia or so-called squamous
intra-epithelial neoplasia ("SIN") (Crissman and Zarbo,
1989). Importantly, the cellular alterations described
clinically within the context of the white lesion are equal-
ly applicable to any form of clinically altered oral
mucosa, and regardless of the location, the presence of
significant levels of dysplasia within any leukoplakia car-
ries the risk of progression to invasive squamous cell car-
cinoma (Crissman and Zarbo, 1989). A consideration to
be noted is the situation where a benign or non-dysplas-
tic diagnosis is made. In the presence of such a diagno-
sis, there is not necessarily a removal of all risk over
time. It merely reduces such risk for the period between
the biopsy procedure and the next follow-up visit.
Oral Hairy Leukoplakia
Oral hairy leukoplakia, the most recently defined form of
leukoplakia, represents a legitimately designated type of
white lesion. Some may dispute the use of the term
"hairy"; nevertheless, this condition has become, in near-
ly all instances, a marker of host immunosuppression,
either natural or iatrogenically induced.
Introduced by Greenspan and her colleagues (1984)
as an alteration along the lateral border of the tongue in
male homosexuals, this mucosal alteration has, until
recently, served as a clinical marker for human immunod-
6(2):147-160 (1995)
 WaaHBfr;

Figure 8. (A) Moderate epithelial dysplasia with the abnormal or atypical epithelial features confined to the lower half of the epithelium.
(B) Abnormal epithelial maturation, drop-shaped rete ridges, focal thickening of the epithelial surface, and a diffuse, minimal inflamma-
tory infiltrate in the lamina propria. (C) Severe epithelial dysplasia with nearly total thickness alterations of cell maturation, cellular dysad-
hesion, premature keratinization, and basal cell hyperplasia. Severe cellular alterations noted in (D) include nuclear hyperchromatism,
abnormal nuclear-cytoplasmic ratios, disordered cellular stratification, and nuclear fragmentation.

eficiency virus infection and as a predictor of future devel-
opment of AIDS (Greenspan et al, 1987). While predomi-
nantly noted on the lateral tongue (Fig. 9), the lesion may
also be noted on the buccal or labial mucosa. Early
lesions tend to be smooth and later vertically corrugated.
They tend to become heavily folded over time. As with
leukoplakia of the classic type, it does not rub off. While
once considered to represent a unique clinical marker of
impending development of AIDS, more recent studies
have demonstrated the rare occurrence of this condition
in immunocompetent individuals (Eisenberg et al, 1992).
Histologically, the free surface is heavily parakera-
totic, with slender surface projections and corrugations
(Fig. 10). Beneath the parakeratotic layer is a band of pal-
lid "balloon cells" forming the superior portion of the
spinous layer, which is generally thickened. Within the
balloon cell nuclei, a characteristic nuclear chromatin
alteration (Fig. 11) has been noted which is characterized
by a peripheral condensation of chromatin along the
inner aspect of the nuclear membrane in a "necklace-
like" configuration (Sciubba et al., 1989). Central to this
altered chromatin pattern is an amphophilic homoge-
neous deposit which consists of viral aggregates (Fig.
12), consistent with Epstein-Barr virus (Sciubba et al,
1989; Felix et al, 1993). In the deeper layers of the epithe-
lium, there is no evidence of dysplasia, nor is there any
reported association with malignant transformation of
this form of leukoplakia over time.
Management of oral hairy leukoplakia is not neces-
sary beyond routine observation unless an esthetic con-
sideration applies. Anti-viral systemic therapy for other
aspects of HIV-related disease will often produce tempo-
rary resolution of this condition, with expected recur-
rence upon discontinuation of anti-viral therapy.
Important in the longer-term aspect of management is
the observation that, unlike routine or classic leuko-
plakia, hairy leukoplakia is not a pre-malignant lesion at
any time in its course.

6(2):147-160 (1995) Crit Rev Oral Biol Med 153


Figure 9. Oral hairy leukoplakia along the lateral tongue surface presents
with vertically corrugated striations which blend with a more homoge-
neous keratinization pattern inferiorly.
Figure 10. A low-power view of oral hairy leukoplakia demonstrates a
thick parakeratotic surface layer which overlies a stratum spinosum which
is pallid in its superficial half and generally acanthotic overall. An
absence of inflammation within the lamina propria is characteristically
noted and shown.
Human Papilloma Virus
Of the scores of human papilloma virus (HPV) subtypes
identified in a wide group of mucous membrane alter-
ations, types 6, 11, 16, 18, 31, 33, and 35 have been most
often studied. In studies utilizing DNA probe/in situ
hybridization techniques, such papilloma subtypes are
frequently present in squamous papillomas; however,
154 Crit Rev Oral Bio! Med
TABLE 3
Microscopic Components of Dysplastic
Oral Epithelium
cell and nuclear enlargement and pleomorphism
basal cell hyperplasia
hyperchromatic nuclei
enlarged prominent nucleoli
increased nuclearxytoplasmic ratio
premature, individual cell keratinization
increased mitotic index
mitoses superficial to basal layer
loss of cellular polarity
diminished cellular adhesion
bulbous/drop-shaped rete ridges
when the same methods have been applied to
studying oral pre-malignant conditions, the results
have been inconsistent (Loning et al, 1984, 1985;
Young and Min, 1991; Zeuss et al., 1991). Therefore,
whether or not HPV plays an etiologic role in the
genesis of leukoplakia or is merely a bystander/pas-
senger remains an open question.
Genetic Alterations
Phenotypically, malignant cells and tissues have
been shown to be associated with oncogene tumor-
suppressor gene alterations. The most common
genetic alteration involves the p53 tumor suppres-
sor gene in relation to human cancer (Lane and
Bechimol, 1990). While p53 protein expression is
not found in normal mucosa, Langdon and
Partridge (1992) detected the protein in nearly 80%
of squamous cell carcinoma lesions studied, thus
establishing a degree of validity for studying this
particular gene marker in relation to oral carcino-
genesis. Girod et al. (1993) studied 64 oral mucosal
white lesions defined as either leukoplakia or lichen
planus, utilizing a p53 monoclonal antibody. Over
one-fourth of such lesions contained detectable lev-
els of p53, with the grade of dysplasia correlating
with p53 phosphoprotein expression. Non-dysplas-
tic hyperplastic lesions, including a group of lichen
planus cases, also showed detectable p53 in 21% of
cases, while dysplastic lesions were positive for p53
expression in 36% of all cases. Their conclusion supports
the concept that mutation of p53 relates to increasing
levels of dysplasia and/or loss of differentiation and may
be a valid marker for oral mucosal carcinogenesis.
Supporting this is the work of Lazarus and colleagues
(1995), which noted a strong association of p53 mutation
and tobacco-related dysplasia, while dysplasias in non-
6(2):147-160(1995)
tobacco users were not associated with a similar
genetic mutation.
Extending the principle of p53 expression to
oral squamous cell carcinoma, it has been shown
that 47% of well-differentiated oral squamous cell
carcinomas expressed this marker, while 60% of
lesser differentiated and 66% of recurrent cases
demonstrated this marker (Girod et al, 1993). Most
recently, specimens obtained adjacent to head and
neck squamous cell carcinomas which were clinical-
ly normal and beyond the planned surgical margins
were analyzed. While specimens were microscopi-
cally negative or lacking in dysplastic changes, con-
sistently noted was a substantial percentage of cells
which contained the p53 mutation, as did the pri-
mary tumor (Brennan et al, 1995).

Treatment
Establishing the clinical diagnosis of leukoplakia, Figure 11. A seam of optically clear cells is seen below the parakeratotic
followed by histopathologic analysis, leads to con- surface layer and the stratum spinosum. Intranuclear alterations include
sideration of the appropriate clinical management peripheral margination of chromarin in a necklace-like configuration,
which should be designed according to the antici- while the cell volume is considerably expanded.
pated clinical or biologic behavior. Balancing the
lesional qualities with treatment modality and associat-
ed morbidity becomes the major clinical decision. With
such considerations in mind, a wide choice of treatments
has been used, ranging from those which are locally
directed to others which are systemic (Table 4).
In the absence of histologically demonstrated dys-
plastic changes, careful and routine follow-up observa-
tions of leukoplakia may be appropriate in conjunction
with elimination of any risk-associated behavior or
habits.
Traditional surgical modalities have included
mucosal resection by means of so-called "stripping" with
graft coverage, usually an autologous skin graft (Girard et
al, 1980). Advocates of surgical management note a
recurrence rate of 20% in pre-malignant lesions, includ-
ing erythroplakia. Surgically created defects may be man-
aged by local flap rotation, free mucosal grafts, and split-
thickness skin graft. Advantages of this form of treatment
include histological analysis of the entire lesion
(Vedtofte et al, 1987) and definition of further treatment
if necessary. Given recurrence rate statistics, ample con-
sideration must be provided for post-surgical manage-
ment strategies, including follow-up.
Alternatives to scalpel or standard excisional surgery
include cryosurgery (Graham, 1993) and use of laser
ablation. Bekke and Baart (1979) noted good results
using cryosurgery without severe scar formation or func-
tional impairment. Others have noted favorable results
with laser ablation with regard to immediate and inter-
Figure 12. A low-magnification electronmicrograph of the
mediate post-operative symptoms, including pain, superficial stratum spinosum shows cytoplasmic tonofilament
edema, hemorrhage, recurrence, and scarring (Gongloff bundles surrounding nuclei containing scattered virions and
and Gage, 1983; Horch et al, 1986; Chu et al, 1988; Flynn peripherally marginated chromatin.

6(2):147-160 (1995) Crit Rev Oral Bio! Med 155

TABLE 4
Leukoplakia: Treatment Options
cessation of tobacco use/observation
surgical excision with or without grafting
cryosurgery
laser ablation
antifungal (candida-associated leukoplakia)
chemoprevention
—retinoids
—vitamins (A,C,E)
—carotenoids
—other
photodynamic therapy
topical therapy
—bleomycin
—vitamin A acid
et al, 1988; Roodenburg et al, 1991; Gendelman et al,
1993). Emphasis must be directed to the site of biopsy
selection, with treatment often being more empirical
than logical (Poswillo, 1975), although more recently
more biologically valid therapies such as systemic
modalities have been introduced.
Systemic approaches include use of vitamins, anti-
oxidants, and vitamin congeners. Additionally, a com-
bined parenteral and locally applied treatment modality
in the form of photodynamic therapy has been advanced
(Gluckman et al, 1986; Grant et al, 1993). In this form of
management, systemic administration of an hematopor-
phyrin compound is followed by photo-irradiation with a
specific form of laser energy by surface illumination.
Advantages of this type of treatment include inactivation
of clinically subtle or undetectable alteration, sparing of
normal tissue, minimal morbidity, and its use as an
adjunctive tool to more traditional modalities.
Candida-associated leukoplakias (speckled leuko-
plakia) may respond to topical agents including imida-
zoles (Ramanathan et al, 1985). When present in an
immunocompromised person, such candidal lesions
may require use of more toxic drugs such as ampho-
tericin B (Garber, 1994). A response should be recorded
prior to defining further management considerations in
each case. The anti-candidal treatment strategy is also
helpful in ruling out a possible fungal etiology for lesions
which clinically must be differentiated from oral hairy
leukoplakia. Improved treatment outcomes may be real-
ized with concomitant elimination of smoking, since this
can often be a compromising factor.
Topical approaches to management have included
application of bleomycin (Malmstrom et al, 1988; Wong et
al, 1989), with clinical results being evident at three
months post-application. Results indicate a slower
156 Crit Rev Oral Biol Ued
recurrence after an initial response when compared with
surgical management. Topically applied vitamin A acid
has been shown to be effective in producing involution of
snuff-induced leukoplakia (Raque et al, 1975).
In an attempt to neutralize or inactivate genotoxicity
of reactive oxygen species, blocking formation of reactive
metabolic and carcinogen-DNA adducts, and inhibiting
mutagenic events, Stich and Anders (1989) have advo-
cated the use of various chemopreventive agents.
Chemoprevention, in the context of upper aerodigestive
tract cancers, has been defined as the interventional use
of chemical agents such as minor dietary constituents
and Pharmaceuticals to halt or slow the carcinogenic
process before invasion (Kelloff et al, 1993). Such agents
include vitamin A, 13-cis-retinoic acid, fenretinide, beta-
carotene, retinol, alpha-tocopherol, and N-acetyl-1-cys-
teine (Stich et al, 1991; Chiesa et al, 1992; DeVries and
DeFlora, 1993; Kaugars et al, 1993; Fountzilas, 1994;
Huber and Hong, 1994). Response rates of leukoplakias
and reduction of transformation to primary squamous
cell carcinomas by 13-cis-retinoic acid have been noted
(Huber and Hong, 1994; Toma et al, 1994). While results
are encouraging, considerable toxicity is associated with
this particular retinoid, with 33% of patients in one study
not completing a 12-month course of post-cancer treat-
ment which included retinoids (Bolla et al, 1994).
Compliance issues and concerns regarding use of
retinoids revolve around side-effects, including retinoid-
associated increases in serum cholesterol and triglyc-
eride levels, cheilitis, zerosis, and conjunctivitis, among
others. There is no proven and generally safe retinoid
currently free of undesirable side-effects. A recent letter
(Kaugars and Silverman, 1995) underscores this point,
stating that their short-term observations were less opti-
mistic than those of previous studies (Hong et al, 1986;
Lippman et al, 1990; Lippman and Hong, 1992), and that
they cannot recommend use of 13-cis-retinoic acid for
control of oral leukoplakia because of side-effects.
Garewal (1994) has presented a similar agreement
regarding this retinoid, favoring the use of beta-carotene
and anti-oxidants to control cases of oral leukoplakia.
Evaluation of extrachromosomal DNA fragments,
micronuclei, can serve as a quantifiable indicator of DNA
injury and can serve as an intermediate marker of chemo-
preventive agent efficacy (Benner et al, 1993; Beenken et
al, 1994). Also included as biomarkers are proliferating
cell nuclear antigen (PCNA), TGF-beta, EGFR, and
retinoid receptors (Benner et al, 1992).
Conclusion and Summary
Leukoplakia maintains a major and increasingly better
understood role in oral mucosal pathology which began
to be better clarified subsequent to development of a
uniformly agreed upon definition of the term. Over time,
an appreciation of the various clinical forms and presen-
6(2):147-160 (1995)
tations of this condition has led to finer levels of prog-
nostication depending upon site, appearance, and clini-
cal qualities. Homogeneous forms of this disease,
involving the buccal mucosa, for example, carry a vastly
different anticipated behavioral quality when compared
with a speckled leukoplakia involving the floor of the
mouth. Proliferative verrucous leukoplakia has become
associated with a usually protracted and often irre-
versible clinical course which carries a very high risk of
malignant transformation. Tobacco usage over several
years remains a major etiologic factor—in particular,
smoking tobacco—although chewing and other forms of
smokeless tobacco are proven causes of mucosal alter-
ations as well.
More recently, tumor suppressor gene alterations—
in particular the p53 gene and its product—have been
identified as a prognostic and behavioral indicator. In
addition, a widening array of biomarkers is being identi-
fied which reflect DNA or genetic damage and may also
serve as end-point indicators of repair secondary to use
of chemopreventive agents, the currently most widely
used form being the vitamin A analog, 13-cis retinoic
acid. Similar agents currently in clinical trial as well as
dietary components, such as naturally occurring anti-oxi-
dants, offer great promise in the non-surgical manage-
ment of this long-recognized and important oral mucos-
al disease.
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