Journal of Dentistry Indonesia

Volume 30 Number 2 Article 1

8-31-2023

Oral Leukoplakia: Diagnosis And Management Revisited

Isaäc van der Waal
VU medical center Amsterdam, Amsterdam, Netherlands, [email protected]

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Recommended Citation
van der Waal, I. Oral Leukoplakia: Diagnosis And Management Revisited. J Dent Indones. 2023;30(2):
73-80

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Journal of Dentistry Indonesia 2023, Vol. 30, No. 2, 73-80
doi: 10.14693/jdi.v30i2.1507

LITERATURE REVIEW

Oral Leukoplakia: Diagnosis And Management Revisited

Isaäc van der Waal*

VU medical center Amsterdam, Amsterdam, Netherlands
*Correspondence e-mail to: [email protected]

ABSTRACT
The definition of oral leukoplakia has not much changed during the past five decades and is still a definition by
exclusion of ‘known’ lesions. Therefore, a diagnosis of leukoplakia is not always a straightforward one for the
clinicians and, to some extent, also for the pathologists. The traditional clinical classification in homogeneous
and nonhomogeneous leukoplakia may just be simplified into leukoplakia (thin and thick/verrucous) and
erythroleukoplakia. In spite of numerous reported predictive molecular and genetic parameters of malignant
transformation, the presence and grade of epithelial dysplasia as assessed by histopathological examination is still
the most important one. Of the various treatment modalities, surgery and CO2 laser evaporation are still the most
common ones. Treatment may delay or prevent recurrence, but does not seem to prevent malignant transformation
or the occurrence of cancer development elsewhere in the mouth or the head and neck region or beyond. There is
a strong need for randomized prospective studies and uniform reporting of treatment results.

Key words: diagnosis, management, oral leukoplakia, potentially malignant disorder of the oral mucosa,
premalignant oral diseases
How to cite this article: van der Waal I. Oral leukoplakia: diagnosis and management revisited. J Dent In-
dones. 2023;30(2): 73-80

INTRODUCTION

Leukoplakia is the most common potentially malignant not always occur within or close to the leukoplakia but
lesion or disorder of the oral mucosa. The adjectives also may arise in other parts of the mouth or elsewhere
‘potentially malignant’, ‘premalignant’, ‘potentially in the head-and-neck region and even in the esophagus,
premalignant and ‘precancerous’ are all synonyms and there is some merit in considering leukoplakia a
indicate an increased risk of malignant transformation. disorder rather than a lesion.
Unfortunately, ‘increased risk’ has not been specified
in the literature. The present, somewhat simplified, The reported prevalence of oral leukoplakia varies
definition reads: ‘a potentially malignant, predominantly between 1%-3%. Oral leukoplakia usually occurs above
white lesion or disorder of the oral mucosa, having the age of 30-40 years. In some parts of the world there
excluded well-defined (‘known’) predominantly white is a strong male preference. Tobacco habits and, in
lesions or disorders’.1 Several notes should be added to some parts of the world, betel quid use with or without
this definition: 1) a diagnosis of leukoplakia is primarily smokeless tobacco, are the most important etiological
based on clinical features and does not necessarily factors. However, in some cases no etiologic factors
require histopathological examination as a routine, 2) can be identified. Leukoplakia may occur in every
if biopsied or excised, the histopathological findings are part of the mouth; the sites of preference may differ
not pathognomonic; epithelial dysplasia may or may not in various parts of the world. Symptoms may or may
be present, 3) absence of epithelial dysplasia does not not be present.
preclude potential malignant behaviour, 4) in case of
an underlying squamous cell carcinoma or verrucous The reported annual malignant transformation rate
carcinoma, the clinical term leukoplakia is replaced by varies widely but an estimated rate in the range of a
the respective diagnosis, and 5) since a malignancy may few percent seems a reasonable one.2

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Table 1. Some well-defined (‘known’) predominantly white lesions or disorders that should be excluded from a diagnosis of
leukoplakia.

Lesion or disease Main diagnostic criteria

Aspirin burn (including other types of chemical burns) History of prolonged application of aspirin tablets or other
chemical agents
Candidiasis, hyperplastic Somewhat questionable entity; some authors refer to this
lesion as candida-associated leukoplakia
Hairy leukoplakia Usually bilateral on the borders of the tongue; histopathology
(A rather unfortunate term, because 1) it is a well known is diagnostic, particularly by the immunohistochemical
entity, and 2) the lesion is not premalignant) presence of EBV.
Keratotic lesions (include reversed smoking keratosis and Different etiologies and various clinical presentations; in
tobacco pouch keratosis); it is an issue of debate whether or some cases the taking of a biopsy is indicated.
not frictional keratosis and alveolar ridge keratosis to exclude
from a diagnosis of leukoplakia
Lesion caused by prolonged, direct contact of the oral mucosa Disappearance of the lesion within an arbitrarily chosen
with an amalgam restoration or other dental restorations; period of 2-3 months after removal of the restoration; the
often referred to as a lichenoid lesion taking of a pretreatment biopsy should be considered.
Leukodema Primarily a clinical diagnosis of a veil-like aspect of the
buccal mucosa, bilaterally; tends to disappear when stretched.
Occurs almost exclusively in dark-skinned people.

Lichen planus and lichenoid lesion Often a clinical diagnosis; occasionally difficult to distinguish
from leukoplakia, particularly in nonreticular subtypes of
lichen planus. A biopsy may be helpful.
Morsicatio History of habitual chewing or biting. Clinical aspect of
irregular whitish-yellowish flakes. Often bilateral. A biopsy
is rarely indicated.
Skin graft, e.g. after vestibuloplasty History of a previous graft
Snuff dipper’s lesion See keratotic lesions (tobacco pouch keratosis)
Syphilis, secondary (“mucous patches”) Medical history; clinical aspect. Demonstration of T.
pallidum; serology.
White sponge nevus May occur on a young age; often family history. The clinical
aspect is more or less diagnostic. Occasionally, a biopsy may
be helpful.

EXCLUSION OF WELI-DEFINED (‘KNOWN’) CLINICAL CLASSIFICATION

LESIONS FROM A DIAGNOSIS OF
LEUKOPLAKIA Leukoplakia, erythroleukoplakia, erythroplakia
Traditionally, a clinical classification has been used,
It is well recognized that the definition of oral leukoplakia consisting of homogeneous leukoplakia (thin, flat or
is one by exclusion of well-defined (‘known’) white wrinkled) and nonhomogeneous leukoplakia (thick,
lesions or disorders. Therefore, a diagnosis of verrucous leukoplakia or leukoplakia intermingled
leukoplakia strongly depends on the experience of the with red areas, often referred to as erythroleukoplakia).
clinicians and, to a lesser degree, of the pathologists It seems appropriate to abandon the adjectives
(Table 1). ‘homogeneous’ and ‘nonhomogeneous’ and, instead,
to recognize 1) leukoplakia, being a predominantly
Nonreticular lichen planus and hyperplastic candidiasis white lesion or disorder, irrespective of the texture,
may be difficult to separate from leukoplakia both being either thin or thick/verrucous (Figure 1), and
clinically and histopathologically. An issue of debate 2) erythroleukoplakia, in case of a mixture of white
is the question whether frictional keratosis and alveolar and red changes of the oral mucosa (Figure 2). With
ridge keratosis are benign lesions, that should be regard to management guidelines it seems relevant to
excluded from a diagnosis of leukoplakia.3,4 Based on identify a) thin, and b) thick/verrucous leukoplakia,
a preliminary study, using clinical pictures, application although it is well acknowledged that the distinction
of texture analysis on leukoplakic lesions has shown to between thin, thick and verrucous can not be accurately
be a promising diagnostic method.5 A somewhat similar described. In case of erythroleukoplakia, subtyping
observation has been reported in another study using in erosive, granular and speckled, does not seem to
machine learning.6 be relevant. At the end of the spectrum of leukoplakia

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THE ROLE OF THE BIOPSY IN THE DIAGNOSIS

OF LEUKOPLAKIA

A diagnosis of leukoplakia may often be made on the

clinical appearance alone. There is not much room
for the use of adjunctive diagnostic tests other than a
biopsy,11 although some promising preliminary results
Figure 1. Leukoplakia of the right (a) and left (b) buccal have been reported on the use of colcoscopy to detect
mucosa; cave verrucous carcinoma. dysplastic changes.12,13

A biopsy of an asymptomatic predominantly white

lesion may be indicated when the clinical differential
diagnosis includes a ‘known’ lesions or condition, as
has been shown in Table 1. In a proven flat, otherwise
asymptomatic leukoplakia, the taking of one or
more biopsies is not mandatory for establishing the
diagnosis. Nevertheless, a biopsy may be taken in
such circumstances for reassurance of the patient or on
the request by the patient, or because of medicolegal
reasons, particularly when treatment will consist of
CO2 laser evaporation where no surgical specimen will
Figure 2. Erythroleukoplakia of the tongue.
become available.

and erythroleukoplakia one recognizes an entirely red In case of thick or verrucous leukoplakia or in the
lesion, being referred to as erythroplakia. The risk of presence of induration, a biopsy is indicated to rule
malignant transformation of erythroplakia is much out verrucous carcinoma or squamous cell carcinoma.
higher than in leukoplakia and erythroleukoplakia. Erythroleukoplakias should always be biopsied. It
Because of its rather rare occurrence, this entity will should be no surprise that a biopsy of an (erythro)
not be discussed here any futher. leukoplakic lesion may not be representative.14

In general, leukoplakias are asymptomatic otherwise HISTOPATHOLOGICAL ASPECTS

and are often not dysplastic, as will be discussed later.
On the other hand, erythroleukoplakias are usually As has been mentioned before, a diagnosis of
symptomatic, such as a burning sensation, and usually leukoplakia may be based on clinical aspects alone.
show epithelial dysplasia or even carcinoma (in situ) at If a biopsy or a surgical specimen is available, the
histopathological examination. histopathological features of leukoplakia may vary
from hyperorthokeratosis or hyperparakeratosis
Proliferative verrucous leukoplakia (Figure 3) to various grades of epithelial dysplasia
A rather confusing subject relates to a diagnosis of (Figure 4). The absence of epithelial dysplasia does
‘Proliferative verrucous leukoplakia’ (PVL), introduced not preclude a diagnosis of leukoplakia. Based on
as a separate subtype of oral leukoplakia in 1985.7 histopathological features, a few authors distinguish
Ever since, various modifications of the diagnosis three types of keratosis: 1) reactive, e.g. frictional
and terminologies of PVL have been proposed, such keratosis, 2) dysplastic/malignant, and 3) keratosis of
as ‘proliferative multifocal leukoplakia’, ‘lichenoid unknown significance.15
proliferative leukoplakia’, ‘proliferative leukoplakia’
and ‘proliferative erythroleukoplakia’. Not surprisingly, Epithelial dysplasia (ED) is based on cytological
much confusion on this issue may arise between and abnormalities and/or architectural ones. Reported
among clinicians and pathologists.8 Most recently, subtypes include, a.o., adenoid ED,16 koilocytic ED,17
PVL has been defined as ‘an oral potentially malignant and lichenoid ED, the use of the latter subtype being
disorder that presents in the form of multifocal white discouraged.18 The clinical relevance of these subtypes
plaques, which have expanded throughout its evolution, is unknown.
persistent and resistant to treatment, which is diagnosed
in people in the second half of life, although it probably Various grading systems of ED have been reported
begins in earlier stages, and which has a very high risk in the literature.19-21 Most systems recognize mild,
of developing into oral cancer’.9 One may consider to moderate and severe ED. The histopathological
abandon the term PVL due to the lack of reproducible assessment of ED and the absence or presence and its
clinical and histopathological criteria and to classify grade, carries a high degree of intra- and interobserver
the hitherto reported cases of PVL as examples of variation.22 The application of articial intelligence may
widespread/multifocal verrucous leukoplakias.10 be helpful to obtain a reproducible histopathological

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Table 2. Predictive, statistically relevant, factors of

malignant transformation (listed in arbitrarily order).

Factors
History of previous head and neck cancer
Increasing age
Female gender
Nontobacco associated leukoplakia
Thick/verrucous leukoplakia and erythroleukoplakia
Size of the leukoplakia > 200 mm2
Subsite (tongue; floor of mouth); in some countries the
Figure 3. In spite of some disturbed architecture one seems buccal mucosa is at risk
to be dealing with nondysplastic epithelium. Presence of C. albicans
Presence and degree of epithelial dysplasia

topical steroids, seems to be associated with malignant

transformation.30
I n one st udy, compr isi ng over 60 0 pat ient s,
erythroleukoplakia (‘nonhomogeneous’ leukoplakia)
and a size >200mm2 were shown to be the only relevant
predictors of malignant transformation, while epithelial
dysplasia was less predictive.31 In thick/verrucous
leukoplakia, often running a protracted clinical course,
there may be a highly increased risk of malignant
Figure 4. Distinct epithelial dysplasia or even carcinoma transformation. However, because of poor clinical
in situ. and histopathological definitions (see section 3.2) it is
difficult to come up with science-based conclusions. In
judgement, including the assessment of the grade of some studies, the presence of C. albicans was shown
epithelial dysplasia, if present.23 to be of importance, at least in what the authors called
‘chronic hyperplastic candidiasis’,32 while in another
There is no universal agreement on the distinction study it was not.33 Also age and female gender may
between the histopathological features of verrucous be associated with an increased risk of malignant
hyperplasia and verrucous carcinoma, which is a cause of transformation.34
confusion among and between pathologists, as has been Deep learning-based pathology image analysis may be
mentioned already.8 In case of an underlying carcinoma useful to predict cancer progression risk.35
(in situ), an (exophytic) squamous cell carcinoma or a
verrucous carcinoma, the term leukoplakia is replaced MANAGEMENT
by the respective histopathological diagnosis.
Leukoplakia
The main reason to treat leukoplakia and erythro
PREDICTORS OF MALIGNANT leukoplakia is to try to prevent malignant transformation.
TRANSFORMATION Although spontaneous regression has been reported in
screening-detected leukoplakia,36 such event seems
At the statistical level, there are numerous clinical, rather rare in patients who have been admitted for
histopathological, immunohistochemical and genetic consultation of their leukoplakia. In the decision to
predictors of future malignant transformation, none treat or not to treat, the size and the location of the
of these being reliable for use in the management of lesion, as well as the absence or presence of epithelial
an individual patient (Table 2).24-29 In most studies, dysplasia, play an important role. This also applies to
erythroleukoplakia, location on the borders of the the morbity of the treatment and patient’s factors, such
tongue and the floor of the mouth- in some parts of as physical and mental condition. In all cases, proper
the world the buccal mucosa is a site of preference- patient information should lead to a ‘shared-decison’.
and the presence of epithelial dysplasia are regarded
as ominous signs. It is well accepted, that the risk of It is well recognized that all types of leukoplakia and
malignant transformation increases with the severity of erythroleukoplakia may coexist, often requiring a
the dysplasia. Immunosupression, including the use of modified type of treatment as being outlined below.

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Furthermore, the feasibility of management protocols

very much depends on clinical skills, available
treatment facilities, financial aspects and transport
facilities for patients. Furthermore, the interest and
compliance of patients may vary widely all over the
world, even within single countries and even between
citizens and people living in rural areas.

Thin, otherwise asymptomatic leukoplakia

In case of suspected mechanical irritation or a possibly
amalgam related lesion in an otherwise asymptomatic,
thin white lesion, one may await the result of the
elimination of such lesions for an arbritarily chosen
Figure 5. (Erythro?)leukoplakia of the tongue, ‘selectively’
period of 6-8 weeks. A similar period may be being excised.
observed for the result of cessation of tobacco habits,
if applicable. In leukoplakias at the commissures, short
term, e.g. two weeks, topical antifungal treatment
should be considered in an attempt to reduce the size of
the leukoplakia or to downstage erythroleukoplakia.37
No long-term results have been reported.

In the absence of possible causes, management may

consist of observation, even without taking a biopsy
or active treatment, such as surgical removal, laser
excision or CO2 laser evaporation. In case of removal,
a margin of at least five millimeters in all directions
is recommended, if feasible. An important advantage
of surgical removal or laser excision is the availability
of a surgical specimen for thorough histopathological Figure 6. (Erythro?)leukoplakia of the floor of the mouth (a);
examination. four months after CO2 laser evaporation (b); one year later
development of a squamous cell carcinoma on the left side (c).
Thick/verrucous, otherwise asymptomatic leukoplakia
In case of thick or verrucous leukoplakia or in the
presence of induration, an incisional or, in case of a TREATMENT RESULTS
small lesion, an excisional biopsy with a margin of at
least five millimeter, if feasible, is indicated to rule The outcome of whatever treatment remains uncertain.40
out verrucous carcinoma or squamous cell carcinoma. Recurrences and development of new leukoplakias
In the latter case, additional oncologic work-up and elsewhere in the oral cavity may arise in a matter of
management will be required. In widespread or months or years (Figure 6). Such events can most likely
multiple thick/verrucous, otherwise asymptomatic be explained by the concept of field cancerization. Wider
leukoplakia, observation or surgical excision may excisions or wider CO2 laser evaporation may reduce or
be considered, if feasible, with or without being delay local recurrences,41,42 but do not decrease the risk
combined with nonsurgical treatments, such as anti- of cancer development.43 In a large study from Sweden,
inflammatory drugs, carotenoids, lycopene, vitamins some 50 years ago, the statement has alreay been made
(A, C, E), bleomycin, methotrexate and photodynamic that “there is no evidence that the incidence of oral
therapy. One may also consider laser excision or CO2 carcinoma can be diminished by surgical removal”.44
laser evaporation in one more sessions; another option Nevertheless, surgical removal was advised mainly for
consists of photodynamic therapy.38 Also intravenous obtaining a more accurate histopathologic diagnosis
administration of methotrexate may be useful, than based on a biopsy specimen alone. Cessation of
particularly in elderly patients.39 tobacco habits has been reported to reduce the number
of unfavorable events after surgical treatment.45 Some
Erythroleukoplakia and symptomatic leukoplakia authors have raised the question whether surgery may
Erythroleukoplakias and symptomatic leukoplakia, actually be a cancer promotional stimulus.46 To the best
being either thin or thick/verrucous, should be of my knowledge this subject has not been elaborated
removed, preferably by surgical excision in order in other publications.
to obtain a surgical specimen for histopathological
examination. In Figure 5 an example is shown of a Unfortunately, there is a lack of uniform reporting of
selective excision of a clinical suspicious leukoplakia treatment results.47-49
of the tongue without an attempt to remove the entire
lesion.

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FOLLOW-UP 5. Jurczyszyn K, Gedrange T, Kozakiewicz M.

Theoretical background to automated diagnosing
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up, lifelong, at intervals of 3-6 months, depending on Healthc Eng. 2020; 2020:8831161.
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authors suggested to limit the follow-up to five years.50 Nunez MC. Early detection of oral potentially
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7. Hansen LS, Olson JA, Silverman S Jr. Proliferative
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straightforward one. The traditional clinical Bilodeau EA, Bhattacharyya I, Lewis JS Jr,
classification in homogeneous and nonhomogeneous Lai J, Wright JM, Bishop JA, Leon ME, Islam
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(Received April 5, 2023; Accepted July 7, 2023)

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