Special Topic: Potentially premalignant oral epithelial lesions (PPOEL)

Vol. 125 No. 6 June 2018

Historical perspective and nomenclature of potentially

malignant or potentially premalignant oral epithelial lesions
with emphasis on leukoplakia—some suggestions for
modifications
Isaäc van der Waal, DDS, PhD

Of the potentially (pre)maligant oral epithelial lesions, leukoplakia is the most common. A brief overview of the various defini-
tions of leukoplakia that have been used in the past is presented here. A proposal has been made to modify the current definition.
Clinically, for decades, leukoplakias have been divided into homogeneous and nonhomogeneous leukoplakias and further into
different subtypes. A proposal has been made to slightly rearrange these subtypes. Furthermore, attention has been paid to a
number of keratotic lesions that have been reported in the literature. It is expected that the increasing knowledge on carcino-
genesis, including various genetic aspects, will be reflected in the definition of oral potentially (pre)malignant lesions in the near
future. (Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:577–581)

Of the potentially (pre)malignant oral epithelial lesions,
leukoplakia, being a predominantly white lesion, is the
most common one. The term leukoplakia was intro-
duced in 1877 by Schwimmer, a Hungarian
dermatologist.1 Entirely red lesions, erythroplakias, are
much less common than leukoplakias but carry a much
higher risk of malignant transformation. The discus-
sion on whether or not oral lichen planus is a potentially
(pre)malignant disorder is ongoing. Therefore, this entity
will not be discussed here.
For a long time, the adjectives premalignant and pre-
cancerous have been used to designate an increased risk
of malignant transformation of leukoplakias. A precan-
cerous lesion has been defined as a morphologically
altered tissue in which cancer is more likely to occur com-
pared with its apparently normal counterpart, whereas
a precancerous condition has been defined as a gener-
alized state associated with a significantly increased risk
of cancer.2 However, no odds ratios that would define
“more likely” and “significantly increased” have been pro-
vided by previous studies. Currently, preference is given
to the term potentially (pre)malignant instead of the terms
premalignant and precancerous. At present, this quali-
fication is also used for fields of epithelial cells in the
mucosa that are not visible clinically, harboring one or
more cancer-associated genetic alterations, such as loss
of 17 p (TP53) or 9 p (CDKN2 A encoding p16 Ink4 A).3,4
Several attempts have been made in the past to provide
a definition of leukoplakia, partly for scientific
purposes and partly for use in the everyday practice. In
1968, Pindborg et al. defined oral leukoplakia as a white
patch or plaque, not less than 5 mm in diameter, which
could not be removed by rubbing and which could not
be classified as any other diagnosable disease.5 It was
noted that the use of the term leukoplakia does not carry
any histologic connotation. In 1978, the term was rede-
fined by the World Health Organization (WHO) as a white
patch or plaque that cannot be characterized clinically
or pathologically as any other disease.6 The reasons for
excluding the criteria of size and whether or not the lesion
could be removed by rubbing have not been made explicit.
At an international seminar held in 1983, the 1978
WHO definition of leukoplakia was slightly modified by
the additional description that leukoplakia is not asso-
ciated with any physical or chemical causative agent
except the use of tobacco.7 As a result, 2 types of leu-
koplakia were introduced: tobacco-associated leukoplakia
and non–tobacco-associated (idiopathic or crypto-
genic) leukoplakia. At yet another symposium, held in
1994, the 1978 WHO definition was left more or less
unchanged.8 However, a proposal was made to apply a
provisional clinical diagnosis of leukoplakia in case of
only a single oral examination and that a definitive di-
agnosis of leukoplakia should be based on the result of
elimination of suspected etiologic factors, if any—and,
in case of a persistent or an idiopathic lesion, as re-
vealed on histopathologic examination.

VU University Medical Center (VUmc)/Academic Centre for Dentistry

Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery
and Oral Pathology, Amsterdam, The Netherlands.
Received for publication Aug 1, 2017; returned for revision Oct 27,
2017; accepted for publication Nov 8, 2017.
© 2017 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
https://doi.org/10.1016/j.oooo.2017.11.023
Statement of Clinical Relevance
Oral leukoplakia is an important potentially (pre)ma-
lignant lesion. Proper use of the definition and
terminology related to leukoplakia and leukoplakia-
like lesions is of great importance for both clinical and
research purposes.

577
ORAL AND MAXILLOFACIAL PATHOLOGY
578 van der Waal
PRESENT DEFINITION AND CLASSIFICATION
OF ORAL LEUKOPLAKIA AND
ERYTHROPLAKIA
Definition
In 2005, in another WHO-guided conference on the def-
inition and terminology related to leukoplakia and
leukoplakia-like (leukoplakic) lesions, the 1978 WHO def-
inition was amended as follows: “The term leukoplakia
should be used to recognize white plaques of question-
able risk having excluded (other) known diseases or
disorders that carry no increased risk for cancer.”9 It was
added that leukoplakia is primarily a clinical term and
has no specific histology. In Table I, a series of well-
defined, known lesions or disorders that should be
differentiated from leukoplakia is presented.
The definition of erythroplakia, that is, a fiery red patch
that can not be characterized as any other definable
disease, has remained unchanged over the years.9
Table I. Well-defined predominantly white lesions or diseases that should be excluded from leukoplakia
Lesion or disease
Aspirin burn (including other types of chemical burns)
Candidiasis, hyperplastic
Cinnamon-induced contact stomatitis
Glassblower’s white patch
Hairy leukoplakia
Keratotic lesions (include reversed smoking keratosis,
sublingual keratosis, alveolar ridge keratosis,
frictional keratosis, sanguinaria-associated keratosis,
tobacco pouch keratosis, and keratosis of unknown
significance)
Lesion caused by prolonged, direct contact of the oral
mucosa with an amalgam restoration or other dental
restorations; often listed as a lichenoid lesion
Leukodema
Lichen planus and lichenoid lesion
Linea alba
Lupus erythematosus
Morsicatio
Papilloma and allied lesions (e.g., condyloma
acuminatum, multifocal epithelial hyperplasia and
verruca vulgaris)
Reversed smoking–induced palatal lesion
Skin graft (e.g., after vestibuloplasty)
Smoker’s palate (“stomatitis nicotina”)
Snuff dipper’s lesion
Syphilis, secondary (“mucous patches”)
White sponge nevus
Slightly modified from Warnakulasuriya et al.9
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June 2018
Clinical classification of leukoplakia
In the 1960s, a 3-tier clinical classification of leukopla-
kia was proposed: (1) simple leukoplakia, (2) verrucous
leukoplakia, and (3) erosive leukoplakia.10 In the 1978
WHO classification a 2-tier clinical classification was
recommended—homogeneous and nonhomogeneous
leukoplakia.6 The distinction between homogeneous and
nonhomogeneous leukoplakia has been shown in most
studies to be of statistical significance with regard to the
prediction of malignant transformation, which is higher
for the nonhomogeneous type.
Homogeneous leukoplakia. Some apply the term
homogeneous leukoplakia only for leukoplakias that
are thin and flat,8 whereas others also recognize a
thick type of homogeneous leukoplakia. In addition,
subvariants of homogeneous leukoplakia have been
reported, such as velvet-like and pumice stone–like
types.
Main diagnostic criteria
History of prolonged application of aspirin tablets or other chemical agents.
Somewhat questionable entity; some refer to this lesion as candida-associated
leukoplakia.
Identification of the frequent use of chewing gums and also of some toothpastes that
contain a high concentrate of cinnamon; a biopsy may be helpful.
Mainly located in the buccal mucosa; disappears within a few weeks after cessation of
glassblowing.
Usually bilateral on the borders of the tongue; histopathology is important, including
the immunohistochemical demonstration of the presence of Epstein-Barr virus.
Different etiologies and various clinical presentations; in many cases, biopsy is
indicated.
Some of the keratotic lesions carry an increased risk of malignant transformation.
Disappearance of the lesion within an arbitrarily chosen period of 2 to 4 weeks after
removal of the restoration; pretreatment biopsy is recommended.
Clinical diagnosis of a veil-like aspect of the buccal mucosa, bilaterally; tends to
disappear when stretched. Occurs almost exclusively in dark-skinned people.
Often a clinical diagnosis; occasionally difficult to distinguish from leukoplakia. A
biopsy may be helpful.
Clinical diagnosis; almost always bilateral on the line of occlusion.
Often a clinical diagnosis; almost always cutaneous involvement as well.
Histopathology and direct immunofluorescence may be helpful.
History of habitual chewing or biting. Clinical aspect of irregular whitish-yellowish
flakes. Often bilateral.
Clinical aspect; medical history. A biopsy, including human papillomavirus typing,
may be helpful.
May mimic leukoplakia or erythroplakia; carries a high risk of malignant
transformation.
History of a previous graft.
Usually a clinical diagnosis. Rarely becomes malignant. Regresses after cessation of
the smoking habit.
See keratotic lesions (tobacco pouch keratosis).
Medical history; clinical aspect. Demonstration of Treponema pallidum; serology.
Young age; often family history. The clinical aspect is more or less diagnostic.
Occasionally a biopsy may be helpful.
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Volume 125, Number 6
Nonhomogeneous leukoplakia. Nonhomogeneous leu-
koplakia has been subdivided into a mixed red-and-
white type (erythroleukoplakia) and a verrucous type.
Erythroleukoplakias may be subdivided into speckled,
granular, and nodular types.
Although having a homogeneous white color, verru-
cous (wart-like) leukoplakia has been classified as a
subtype of nonhomogeneous leukoplakia.8 In cases of
widespread verrucous leukoplakia, the term prolifera-
tive verrucous leukoplakia (PVL) is often used.11 Apart
from being widespread, PVL also has a strong tenden-
cy to recur after treatment. In the past, the terms florid
oral papillomatosis12 and verrucous hyperplasia have been
used for this clinical presentation.13
PRELEUKOPLAKIA, KERATOSES
Preleukoplakia
There have been some reports in the literature on
preleukoplakia, thought of as a precursor stage of leu-
koplakia and decribed as a gray or grayish-white area
with indistinct borders blending into the adjacent normal
mucosa.14,15 This term may perhaps be applied to flat
changes of the mucosa that are not white enough to
qualify for the term leukoplakia.
Keratoses
The use of the term keratosis for a number of oral white
lesions is somewhat confusing. In fact, keratosis is pri-
marily a histologic term, used in cases of
hyperorthokeratosis or hyperparakeratosis. In a study by
Payne, it was shown that thickening of the keratin layer
per se or the overall thickness of the epithelium actual-
ly may not be the primary factor in causing an intraoral
lesion to appear white.16 Nevertheless, the term kerato-
sis is quite commonly used by clinicians and researchers
to describe an oral white plaque, whether based on biopsy
findings or not.
In some parts of South India and occasionally in other
parts of the world, reversed smoking is practiced, causing
often initially white changes of the palatal mucosa. The
whitish changes have been referred to as reversed smoking
keratosis.17 These palatal lesions have a high risk of ma-
lignant transformation. Because they are regarded as a
well-defined, known entity, they are excluded from the
common category of leukoplakia.
Sublingual keratosis refers to widespread whitish
changes of the floor of the mouth, the ventral aspect of
the tongue, and the lingual mucosa. A study from the
United Kingdom emphasized the high risk of malig-
nant transformation in that particular subsite of the oral
cavity.18 There is, at present, no justification for the use
of the term sublingual keratosis instead of leukoplakia.
A few papers have been published on alveolar ridge
keratosis.19,20 Apparently, the supposed cause of the lesion
is chronic frictional (masticatory) trauma to the maxil-
REVIEW ARTICLE
van der Waal 579
lary and mandibular alveolar ridges, particularly in the
retromolar pad and edentulous parts of the ridges. His-
topathologically, almost of all these lesions show
hyperkeratosis without epithelial dysplasia. The authors
recommended that this lesion be removed from the cat-
egory of oral leukoplakia because of its low risk of
malignant transformation and to use the term benign al-
veolar ridge keratosis instead.
The term frictional keratosis has been used for white
lesions that are supposedly caused by friction—that is,
vigorous brushing of teeth. The suggestion to remove this
lesion from the category of leukoplakia21 seems some-
what questionable. If the lesion disappears after
elimination of the suggested causative habit, there should
be no objection to the use of the term frictional. However,
in persistent cases, the role of friction remains uncer-
tain. In such cases, a diagnosis of leukoplakia seems
preferable.
In sanguinaria-associated keratosis, the white changes
of the oral mucosa, particularly in the maxilla, are caused
by sanguinaria, an herbal extract used in dentifrices and
mouthrinses.22 In some cases, epithelial dysplasia was ob-
served. There is no information on the potential for cancer
development in these patients.
In tobacco pouch keratosis, also referred to as snuff
dipper’s lesion, the clinical appearance may vary from
a white to a more grayish coloration of the oral mucosa
in direct contact with the tobacco product. The surface
may be somewhat wrinkled or corrugated. Histopatho-
logically, hyperkeratosis and acanthosis are the common
features. Epithelial dysplasia is rarely encountered. The
risk of malignant transformation seems to be mainly
related to the type of the chewing product.23
Some authors have distinguished 3 types of kerato-
sis: (1) reactive keratosis, (2) dysplastic/malignant
keratosis, and (3) keratosis of unknown significance.24 The
risk of possible malignant transformation of keratosis of
unknown significance is still unknown.
DISCUSSION AND SOME SUGGESTIONS FOR
MODIFICATIONS OF THE DEFINITION OF
LEUKOPLAKIA AND THE CLINICAL
CLASSIFICATION
In view of the increasing knowledge about carcinogen-
esis, including various genetic aspects, it is no surprise
that suggestions already have been made to modify the
definition of potentially (pre)malignantlesions and dis-
eases. An example is the one provided by Sarode et al.:
“It is a group of disorders of varying etiologies, usually
tobacco, characterized by mutagen associated, sponta-
neous, or hereditary alterations or mutations in the genetic
material of oral epithelial cells with or without clinical
and histomorphological alterations that may lead to oral
squamous cell carcinoma transformation.”25
ORAL AND MAXILLOFACIAL PATHOLOGY
580 van der Waal
It is well recognized that the discussion on leukoplakia
is mainly based on its appearance in patients in the Western
world. Oral leukoplakia may indeed have different char-
acteristics in other parts of the world, such as India, because
of different diets, tobacco and chewing habits, and perhaps
genetic differences. In this respect, attention should be
paid to a proposal from some authors from India for a
new classification for potentially (pre)malignant disorders.26
Interestingly, in this proposal, leukoplakia has been listed
solely as a tobacco-associated lesion.
The present definitions of leukoplakia and erythroplakia
are only slightly different from the ones that have been
used already some 50 years ago. Leukoplakia and
erythroplakia are still defined by negative description, that
is, by excluding other white and red lesions or disor-
ders, respectively. The present use of the term disorder
acknowledges the fact that malignant transformation may
occur not only at or close to the site of the leukoplakia
or erythroplakia but also elsewhere in the oral cavity in
apparently clinically normal mucosa. However, the term
lesion, instead of disease and disorder, is probably better
understood by clinicians.
The part of the present definition “… having ex-
cluded other known diseases or disorders that carry no
increased risk for cancer” is somewhat confusing because
several of the well-defined lesions listed in Table I do
have (pre)malignant potential.
In the definition of leukoplakia, one may consider in-
cluding a description that the lesion cannot be wiped as
has been the case in one of the early definitions, where
the description “… that cannot be rubbed off …” has been
included. In this way, mainly pseudomembranous can-
didiasis can be easily differentiated from leukoplakia. The
phrase “cannot be wiped” seems to be a better descrip-
tion than “cannot be rubbed off.” To the best of my
knowledge, there are no red lesions of the oral mucosa
that can be wiped. Therefore, this aspect does not have
to be mentioned in the definition of erythroplakia.
For clinical use, there is no apparent reason to include
again a minimum size (e.g., 5 mm) in the definition as
has been the case in the past. Nevertheless, there may
be some merit in including a minimum size of
leukoplakias for reporting purposes, thereby avoiding
every minute white spot of the oral mucosa being in-
cluded in the study material. Additionally, for reporting
purposes, the use of a level of certainty (C-factor) on
which the diagnosis of leukoplakia has been based, shown
in Table II, is recommended.27
Clinicians are advised to perform biopsy first before
elimination of possible etiologic factors, including tobacco
habits. This is particularly important in case of symp-
toms, although a delay of several weeks or even a month
does not seem to be relevant from a prognostic point of
view. However, patients may not appreciate such a delay.
In case of disappearance of a leukoplakic lesion within
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June 2018
Table II. Certainty (C)-factor of a diagnosis of oral
leukoplakia
C1 Evidence from a single visit, applying inspection and palpation as
the only diagnosis means (provisional clinical diagnosis),
including a clinical picture of the lesion.
C2 Evidence obtained by a negative result of elimination of
suspected etiologic factors, e.g., mechanical irritation, during a
follow-up period of 2 to 4 weeks (definitive clinical diagnosis)
C3 Evidence obtained by a pretreatment incisional biopsy in which,
histopathologically, no definable lesion is observed
(histopathologically supported diagnosis)
C4 Evidence based on findings from surgery and pathologic
examination of the resected specimen (histopathologically proven
diagnosis)
From van der Waal.27
a somewhat arbitrarily chosen period of 2 to 4 weeks after
elimination of a mechanical cause, the diagnosis of fric-
tional lesion or frictional keratosis seems appropriate. For
the same reason, one may apply the term smoker’s lesion
in case of disappearance of a leukoplakic lesion after ces-
sation of the tobacco habit. However, most authors prefer
to refer to such lesion as tobacco-associated leukoplakia.
For pathologists it is important to know that absence
of epithelial dysplasia not a diagnosis of oral leukopla-
kia should not remark in the histopathologic report that
leukoplakia that is not potentially (pre)malignant. Of
course, clinicians should know that absence of dyspla-
sia does not preclude potential (pre)malignant .
The various clinical subcategories of leukoplakia are
probably too complex, not only at the expert level but
even more so for use by dentists and oral and maxillo-
facial surgeons. Therefore, one may consider simplifying
this classification. Homogeneous leukoplakia might then
perhaps be defined as a white lesion that has a homo-
geneous, predominantly white or grayish-white color and
which may vary in thickness and texture. As a result, the
clinical presentation may range from thin, smooth,
wrinkled, and corrugated to thick and/or verrucous, thus
including proliferative verrucous leukoplakia. It is, in fact,
unknown whether the verrucous morphology, rather than
its large, widespread presentation, is the main predict-
ing factor of malignant transformation in PVL.28
The term nonhomogeneous leukoplakia might be re-
stricted to the mixed white-and-red presentations
(erythroleukoplakias), recognizing that the texture may
vary from flat and smooth to speckled, granular, or
nodular. It should be emphasized that clinical subdivi-
sion into homogeneous and nonhomogeneous leukoplakias
has, statistically, some predictive value with regard to the
risk of malignant transformation but that this subdivi-
sion is not reliable for use in the individual patient.
It seems logical to adjust the definition of erythroplakia
in accordance with the proposed modifications to the def-
inition of leukoplakia. Clinicians should know that all
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Volume 125, Number 6
Table III. Proposed modifications of the definitions
and clinical classification of leukoplakia and
erythroplakia
Definitions
Leukoplakia: A predominantly white lesion of the oral mucosa that
cannot be wiped; other, well-defined predominantly white lesions
have been excluded clinically, histopathologically, or by the use of
other diagnostic aids
Erythroplakia: A red lesion of the oral mucosa; other, well-defined
red lesions have been excluded clinically, histopathologically or
by the use of other diagnostic aids
Clinical classification of leukoplakia
Homogeneous: Homogeneous white color; the thickness and texture
may vary from thin, smooth, wrinkled, and corrugated to thick
and/or verrucous
Nonhomogeneous: Mixed white-and-red appearance
(“erythroleukoplakia”); the surface may vary from smooth to
speckled, granular, or nodular
Note: Leukoplakia is primarily a clinical term and has no specific his-
tology; absence of epithelial dysplasia does not preclude a diagnosis
of oral leukoplakia and does not rule out potential malignant or po-
tentially premalignant character of the lesion.
erythroplakias carry a high risk of malignant transfor-
mation, if not being malignant already at the patient’s
first visit.
The proposed modifications of the definitions and the
clinical classification of leukoplakia and erythroplakia
are presented in Table III.
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Reprint requests:
Isaäc van der Waal, DDS, PhD
VU University Medical Center (VUmc)/Academic Centre for
Dentistry Amsterdam (ACTA)
Department of Oral and Maxillofacial Surgery and Oral Pathology
P.O. Box 7057, 1007 MB
Amsterdam
The Netherlands
i.vanderwaal@hotmail.com