ARTICLE IN PRESS

Oral Oncology xxx (2008) xxxxxx

Contents lists available at ScienceDirect

Oral Oncology
journal homepage: http://intl.elsevierhealth.com/journals/oron/

Review

Potentially malignant disorders of the oral and oropharyngeal mucosa;

terminology, classication and present concepts of management
Isac van der Waal *
VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxillofacial Surgery/Pathology,
P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

a r t i c l e

i n f o

Available online xxxx

Keywords:
Oral leukoplakia
Oral lichen planus
Actinic cheilitis
Submucous brosis
Potentially malignant oral disorders

s u m m a r y
In a recently held WHO workshop it has been recommended to abandon the distinction between potentially malignant lesions and potentially malignant conditions and to use the term potentially malignant
disorders instead. Of these disorders, leukoplakia and erythroplakia are the most common ones. These
diagnoses are still dened by exclusion of other known white or red lesions. In spite of tremendous progress in the eld of molecular biology there is yet no single marker that reliably enables to predict malignant transformation in an individual patient. The general advice is to excise or laser any oral of
oropharyngeal leukoplakia/erythroplakia, if feasible, irrespective of the presence or absence of dysplasia.
Nevertheless, it is actually unknown whether such removal truly prevents the possible development of a
squamous cell carcinoma.
At present, oral lichen planus seems to be accepted in the literature as being a potentially malignant disorder, although the risk of malignant transformation is lower than in leukoplakia. There are no means to
prevent such event. The efcacy of follow-up of oral lichen planus is questionable. Finally, brief attention
has been paid to oral submucous brosis, actinic cheilitis, some inherited cancer syndromes and immunodeciency in relation to cancer predisposition.
2008 Elsevier Ltd. All rights reserved.

Introduction
In a World Health Organization (WHO) Workshop, held in 2005,
the terminology, denitions and classication of oral lesions with a
predisposition to malignant transformation have been discussed.
The term potentially malignant was preferred above premalignant or precancerous;1 furthermore, it has been recommended
to abandon the traditional distinction between potentially malignant lesions and potentially malignant conditions and to use the
term potentially malignant disorders instead.
In this treatise, attention will be mainly paid to leukoplakia and
erythroplakia. Furthermore, lichen planus and submucous brosis
will be discussed, as well as a number of miscellaneous potentially
malignant disorders.
Leukoplakia
Denition and terminology
Leukoplakia is at present dened as A white plaque of questionable risk having excluded (other) known diseases or disorders
* Tel.: +31 20 444 4039; fax: +31 20 444 4046.
E-mail address: i.vanderwaal@vumc.nl

that carry no increased risk for cancer.1 Examples of white

or predominantly white diseases of the oral mucosa that
carry no increased risk for cancer development are shown in
Table 1.
The term leukoplakia can be used at different levels of certainty
(C-factor) as a clinical term only (C1 or C2) or as a clinicopathological term (C3 or C4), as shown in Table 2.
Epidemiology and etiology
The estimated reported prevalence of oral leukoplakia, worldwide, is approximately 2%.2 However, when viewed in relation to
an annual malignant transformation rate of 1%, this prevalence gure would result in development of oral cancer in 20 per 100,000
populations per year. Obviously, this cancer incidence gure, based
on malignant transformation of oral leukoplakia alone is much too
high. Probably, the prevalence of oral leukoplakia has to be set at a
more realistic gure of less than 0.5%. There are some geographical
differences with regard to the gender distribution.
Leukoplakia is six times more common among smokers than
among non-smokers.3 Alcohol is an independent risk factor,
regardless of beverage type or drinking pattern.4 There are conicting results of studies related to the possible role of human papillomavirus infection.57

1368-8375/$ - see front matter 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.oraloncology.2008.05.016

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
2

I. van der Waal / Oral Oncology xxx (2008) xxxxxx

Table 1
The most common white or predominantly white benign diseases of the oral mucosa
and their main diagnostic criteria
Lesion

Main diagnostic criteria

Aspirin burn
Candidiasis, pseudomembranous

History of local application of aspirin tablets

Clinical aspect (pseudomembranes, often
symmetrical pattern)

Candidiasis, hyperplastica
Frictional lesion
Hairy leukoplakia
Leukoedema
Linea alba
Lupus erythematosus
Morsicatio (habitual chewing or
biting of the cheek, tongue, lips)
Papilloma and allied lesions
Syphilis, secondary (mucous
patches)
Tobacco-induced lesionsb
Smokers palate (nicotinic
stomatitis)
Snuff induced lesion
White sponge nevus

Presence of mechanical irritation (e.g. habit

of vigorous toothbrushing)
Clinical aspect (incl. bilateral localization on
the tongue); histopathology (incl. EBV)
Clinical aspect (incl. symmetrical pattern)
Clinical aspect (incl. location on the line of
occlusion in the cheek mucosa)
History of skin lesions; clinical appearance
(incl. bilateral pattern); histopathology
History of habitual chewing or biting;
clinical aspects
Clinical aspect; histopathology
Clinical aspect; demonstration of T.
pallidum; serology
Clinical aspect; history of smoking
Clinical aspect; site were snuff is placed
Family history; clinical aspect (often
symmetrical pattern)

a
There is no consensus in the literature as whether to recognize a hyperplastic
subtype of oral candidiasis: some prefer to refer to these lesions as Candida-associated leukoplakia.
b
Palatal lesions in reverse smokers are considered potential malignant disorders.

ity of dysplasia is based on architectural disturbance accompanied

by cytological atypia. The WHO 2005 classication recognizes ve
histopathological stages in epithelial precursor lesions (Table 3).11
The criteria used for diagnosing dysplasia are shown in Table 4. It
should be emphasized that dysplasia is a spectrum and that no criteria exist to precisely divide this spectrum into mild, moderate
and severe categories. Furthermore, there may be a substantial
interobserver and intraobserver variation in the histopathological
assessment of the presence and severity of epithelial dysplasia.1214 Perhaps a better consensus can be reached by modifying
the WHO ve tier system into a binary one, recognizing low-risk
versus high-risk lesions.15 It has been suggested that an AgNOR
cut-point may be helpful to distinguish mild and moderate dysplasia.16 In Table 5 two other grading systems the Squamous Intraepithelial Neoplasia (SIN) system and the Ljubljana classication of
Squamous Intraepithelial Lesions (SIL) are shown. Occasionally,
koilocytic changes in dysplastic lesions (koilocytic dysplasia)
can be observed, apparently related to the presence of intermediate and high-risk human papillomavirus; the clinical signicance
and potential for malignant transformation is as yet unclear.7 Yet
another subtype of dysplasia is lichenoid dysplasia (see discussion on lichen planus).
Occasionally, a diagnosis of verrucous carcinoma, carcinoma
in situ or invasive squamous cell carcinoma is made in the clinical
presentation of leukoplakia; in such event the histopathological
diagnosis replaces the clinical diagnosis of leukoplakia. It is well

Table 3
Histopathological stages in epithelial precursor lesions11
1

Squamous
hyperplasia

Mild dysplasia

Moderate
dysplasia

Severe
dysplasia

Carcinoma
in situ

Table 2
Certainty (C)-factor of a diagnosis of oral leukoplakia
C1
C2

C3
C4

Evidence from a single visit, applying inspection and palpation as the only
diagnostic means (provisional clinical diagnosis)
Evidence obtained by a negative result of elimination of suspected etiologic
factors, e.g. mechanical irritation, during a follow-up period of 24 weeks or
in the absence of any suspected etiological factors (denitive clinical
diagnosis)
As C2, but complemented by incisional biopsy (provisional histopathological
diagnosis)
Evidence following excision and pathological examination of the resected
specimen (denitive histopathological diagnosis)

Clinical aspects
Leukoplakia may affect any site of the oral and oropharyngeal
cavity. Clinically, leukoplakia can be subdivided in a homogeneous
type (at, thin, uniform white in colour) and a non-homogeneous
type. The non-homogeneous type has been dened as a whiteand-red lesion (erythroleukoplakia), that may be either irregularly at (speckled) or nodular. Verrucous leukoplakia is yet another type of non-homogeneous leukoplakia. Although verrucous
leukoplakia usually has a uniform white appearance, its verrucous
texture is the distinguishing feature from homogeneous (at) leukoplakia. Verrucous leukoplakia is clinically indistinguishable from
the clinical aspect of verrucous carcinoma. Proliferative verrucous
leukoplakia (PVL) is a subtype of verrucous leukoplakia,8 being
characterized by multifocal presentation, resistance to treatment
and a high rate of malignant transformation.9,10 PVL seems more
prevalent among elderly women. There may or may not be a history of tobacco use.
Histopathological aspects
Histopathologically, a distinction can be made between dysplastic and non-dysplastic leukoplakia. The assessment and sever-

This may be in the spinous layer (acanthosis) and/or in

the basal/parabasal cell layers (basal cell hyperplasia);
the architecture shows regular stratication without
cellular atypia
The architectural disturbance is limited to the lower
third of the epithelium accompanied by cytological
atypia
The architectural disturbance extends into the middle
third of the epithelium; consideration of the degree of
cytological atypia may require upgrading
The architectural disturbance involves more than two
thirds of the epithelium; architectural disturbance into
the middle third of the epithelium with sufcient
cytologic atypia is upgraded from moderate to severe
dysplasia
Full thickness or almost full thickness architectural
disturbance in the viable cell layers accompanied by
pronounced cytological atypia

Table 4
Criteria used for diagnosing dysplasia11
Architecture
Irregular epithelial stratication
Loss of polarity of basal cells
Drop-shaped rete ridges
Increased number of mitotic gures
Abnormal supercial mitoses
Premature keratinization in single cells (dyskeratosis)
Keratin pearls within rete pegs
Cytology
Abnormal variation in nuclear size (anisonucleosis)
Abnormal variation in nuclear shape (nuclear pleomorphism)
Abnormal variation in cell size (anisocytosis)
Abnormal variation in cell shape (cellular pleomorphism)
Increased nuclear-cytoplasmic ratio
Increased nuclear size
Atypical mitotic gures
Increased number and size of nucleoli
Hyperchromasia

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
I. van der Waal / Oral Oncology xxx (2008) xxxxxx
Table 5
Classication schemes that histologically categorize precursor and related lesions
WHO 2005)11
WHO
classication
Squamous cell
hyperplasia
Mild dysplasia
Moderate
dysplasia
Severe
dysplasia
Carcinoma
in situ

Squamous
intraepithelial neoplasia
(SIN)

Ljubljana classication squamous

intraepithelial lesions (SIN)
Squamous cell (simple) hyperplasia

SIN 1
SIN 2

Basal/parabasal cell hyperplasiaa

Atypical hyperplasiab

SIN 3c

Atypical hyperplasiab

SIN 3c

Carcinoma in situ

a
Basal/parabasal cell hyperplasia may histologically resemble mild dysplasia, but
the former is conceptually a benign lesion and the latter the lower grade of precursor lesions.
b
Risky epithelium. The analogy to moderate and severe dysplasia is
approximate.
c
The advocates of SIN combine severe dysplasia and carcinoma in situ.

recognized, that (proliferative) verrucous leukoplakia may show a

spectrum of histopathological changes, ranging from hyperkeratosis with or without dysplasia to verrucous hyperplasia and verrucous carcinoma. Some authors consider verrucous hyperplasia an
early stage of verrucous carcinoma,17 while others do make a distinction between verrucous hyperplasia and verrucous
carcinoma.18
Malignant transformation
In a study from India, an annual malignant transformation rate
of 0.3% have been reported.19 In studies from Western countries
somewhat higher gures have been mentioned; an annual malignant transformation rate of approximately 1% is probably a reasonable average gure for all types of leukoplakia together. It is well
appreciated that this gure is much higher for non-homogeneous
types,20 including proliferative verrucous leukoplakia. The latter
probably nearly always transforms into verrucous carcinoma or
squamous cell carcinoma and may do so in a protracted course
of over 1015 years. Malignancies may develop within the site of
pre-existing leukoplakia, but may also occur elsewhere in the oral
cavity or the upper aerodigestive tract.
The commonly recognized factors that statistically carry an increased risk of malignant transformation into a squamous cell carcinoma are listed in Table 6. Of these risk factors, the presence of
epithelial dysplasia often correlating with a clinical non-homogeneous, erythroleukoplakic subtype is in general regarded the
most important indicator of malignant potential. Nevertheless, it
should be recognized that some dysplastic lesions may remain
clinically unchanged or may even show complete regression.19 Furthermore, carcinomatous transformation may also take place in
non-dysplastic leukoplakia.20 In fact, genetic changes, particularly
at chromosomes 3, have been demonstrated in the majority of keratotic, non-dysplastic lesions.21
Table 6
Reported risk factors of statistical signicance for malignant transformation of
leukoplakia, listed in an at random order (not applicable in the individual patient)









Female gender
Long duration of leukoplakia
Leukoplakia in non-smokers (idiopathic leukoplakia)
Location on the tongue and/or oor of the mouth
Size > 200 mm2
Non-homogeneous type
Presence of C. albican
Presence of epithelial dysplasia

Although the presence of Candida albicans has been mentioned

as a risk factor,22 it is remarkable that this microorganism seems to
be particularly present in leukoplakias at the commissures of the
mouth and at the dorsum of the tongue, while these sites are rarely
involved in cancer development. In several studies from the Western world, the borders of the tongue and the oor of the mouth
have been mentioned as high-risk sites, while this is not the case
in India.19 In a study from Denmark also size was shown to be of
importance, particularly when exceeding 200 mm2.20
In spite of tremendous progress in the eld of molecular biology, there is as yet no single marker or set of markers that reliably
enables to predict malignant transformation of leukoplakia in an
individual patient with leukoplakia,11,23 perhaps with the exception of expression of podoplanin24 suprabasal expression of
p53,25 angiogenesis,26 the presence of high-risk HPV types, such
as HPV 16,27 the immunohistochemically expression patterns of
cyclin D1, p27 and p63,28 or the expression of cytokeratin 8.29
The use of non-invasive genetic tests, using exfoliated or brushed
cells of lesional tissue,3032 or molecular markers from saliva33,34
may prove to be a step forward in the search for relevant prognostic markers.
Management
A owchart for the management of leukoplakia has been presented in Table 7. In the presence of possible etiological factors,
including tobacco habits,35 an observation period of not more than
a somewhat arbitrarily chosen 24 weeks seems acceptable to observe a possible regression after elimination of such factors. Of
course, it is well appreciated that complete regression may take
much more time. On the other hand, one would not like to postpone a biopsy for a too long time in case a biopsy has not been taken already at the rst visit. In patients with multifocal or
widespread leukoplakia multiple biopsies (eld mapping), if
needed using general anesthesia, should be considered.36 Particularly in case of a non-homogeneous leukoplakia an incisional
biopsy may not be representative.37,38 In small leukoplakias, e.g.
<23 cm, an excisional biopsy may be considered.
The diagnostic value of oral brush cytology is still a subject of
controversy;3941 this technique may have value as a screening
tool, but histopathologic examination is at present still the gold
standard for diagnostic purposes. This is also true for the use of
toluidine blue.4244 Nevertheless, toluidine blue may be useful in
identifying potentially malignant disorders as a risk of progression
to squamous cell carcinoma.45 Optical spectroscopy may become
an attractive non-invasive diagnostic tool to identify dysplasia.46
This also applies to direct uorescence visualization,47,48 and to visual assessment of oral cavity luminescence following a chemical
reaction, i.e. chemiluminescence.49
The reason to treat leukoplakia may be the presence of symptoms and an attempt to prevent malignant transformation. Reasons not to treat may consist of a large extent or a diffuse
pattern of the lesion. Furthermore, patients factors, such as a poor
general condition, may hinder optimal treatment. Although there
is no scientic evidence that treatment, of whatever modality,
truly prevents the possible future development of a squamous cell
carcinoma,50 it seems safe practice to actively treat leukoplakias,
irrespective of the absence or presence of epithelial dysplasia.51
Apart from surgical excision, various treatment modalities are
available such as cryosurgery, laser surgery (including evaporation),52,53 administration of retinoids, either topically or systemically,5456 mouthwash therapy containing an attenuated
adenovirus57,58 and photodynamic therapy.59 The most commonly
used treatment modalities consist of surgical excision or laser therapy. The width of the margin that should be taken into account has
never been discussed in detail; probably most clinicians will

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
4

I. van der Waal / Oral Oncology xxx (2008) xxxxxx

Table 7
Management of leukoplakia

LEUKOPLAKIA
(Provisional clinical diagnosis C1*)

Elimination of possible cause(s), including tobacco habits

(2-4 weeks to observe the result)

Good response

No possible cause(s)
(Definitive clinical diagnosis: C2)

No response
(Definitive clinical diagnosis C2)

Biopsy

Histopathologically proven diagnosis

(By exclusion of "other known lesions": C3 or C4)

Known lesion
Management accordingly

Non-dysplastic leukoplakia

Dysplastic leukoplakia

Treatment (if feasible, e.g. < 2-3 cm)

Follow-up in both treated
and untreated patients
at intervals of 6 months; lifelong (?)

Known lesion
Management accordingly

Treatment (if feasible, e.g. < 2-3 cm)

Follow-up in both treated
and untreated patients
at intervals of 3 months; lifelong (?)

* C = certainty factor

include a margin of just a few millimetres, although it is conceivable and actually demonstrated that nuclear changes in the epithelium are present well beyond clinically visible leukoplakia. This
phenomenon most likely explains the risk of local recurrence and
the development of new leukoplakias. Recurrence rates vary in various papers from almost zero up to 30%.53,60,61 There are no scientic data available about the possible value of follow-up and the
optimal intervals after treatment of leukoplakia; nevertheless,
some suggestions have been provided in Table 7.

of the leukoplakia as follows: no change (stable disease), partial

regression (>50%), complete regression, and progressive disease
(>25%).63 The most suitable criterium to measure such changes
seems, indeed, to be the size of the leukoplakia and not so much
the whiteness and/or the texture of the lesion (Table 9). In case
of monitoring the lesion by one or more biopsies during followup, the possible change in the histopathological ndings could then
be reected in the staging system shown in Table 8.
Erythroplakia

Uniform reporting; classication and staging system

In order to promote uniform reporting, the use of a classication
and staging system is recommended in which the size and the histopathological features are taken into account (Table 8). In addition, gender, age at the time of diagnosis, any etiologic factors, if
identied, and the oral or oropharyngeal subsite(s) should be recorded. The system presented in Table 8 has been slightly modied
from a previously reported proposal;62 it has not been validated
yet.
The recording of treatment results should be standardized as
much as possible, including the length of the follow-up intervals
and the total length of follow-up. After surgical excision (including
laser surgery or evaporation) recurrences are not uncommon.
When the recurrence is at the site of the primary lesion, the term
recurrence seems justied, indeed, irrespective of the time span
between the excision and the recurrence. When the recurrence
develops at a distinct different oral subsite, it seems appropriate
to refer to such lesion as a new leukoplakia.
In case of non-surgical treatment or observation, the ndings
should be expressed as a percentage related to the original size

Erythroplakia is dened as A ery red patch that cannot be

characterized clinically or pathologically as any other denable
disease.64 The clinical appearance may be at or even depressed
with a smooth or granular surface. In case of a mixture of red
and white changes such lesion is usually categorized as non-homogeneous leukoplakia (erythroleukoplakia). Tobacco and alcohol
use are considered important etiologic factors. The possible role
of C. albicans is at present still unclear.
Prevalence gures of erythroplakia are only available from studies performed in South- and Southeast Asia and vary between
0.02% and 0.83%.65 Erythroplakia mainly occurs in the middle aged
and the elderly. There is no distinct gender preference. Any site of
the oral and oropharyngeal cavity may become involved, usually in
a solitary fashion. This solitary presentation is often helpful in clinically distinguishing erythroplakia from erosive lichen planus, lupus erythematosus and erythematous candidiasis, since these
lesions occur almost always in a bilateral, more ore less symmetrical pattern.
Histopathologically, erythroplakia commonly shows at least
some degree of dysplasia and often even carcinoma in situ or

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
I. van der Waal / Oral Oncology xxx (2008) xxxxxx

Table 8
Classication and staging system for oral leukoplakias (OL-system)

Lichen planus

L (size of the leukoplakia)

L1
L2
L3
LX

There is an ongoing debate in the literature whether patients

with oral lichen planus (OLP) carry an increased risk of developing a squamous cell carcinomas. Nevertheless, there is a tendency
to accept that there is.6770 The reported annual malignant transformation rate is usually well below 1%. Apparently, such event
may occur in all clinical types of OLP.71 Unfortunately, the issue
of malignant transformation in OLP is blurred by the often present lack of clinicopathologic correlation in the diagnosis.72,73 Furthermore, there is the somewhat confusing histopathological
term lichenoid dysplasia,74 probably mainly used in case of a
bandlike lymphocytic inltrate underneath dysplastic epithelium.
When one accepts that oral lichen planus may transform into a
squamous cell carcinoma, then it is conceivable that in such
event dysplastic changes may occur, justifying the use of the
term lichenoid dysplasia. However, based on personal experience
there is rarely clinical evidence for pre-existing lichen planus in
case of lichenoid dysplasia; this has also been conrmed by
others.75
There are no possibilities to truly prevent malignant transformation of oral lichen planus. The efcacy of continuous followup of oral lichen planus patients is questionable,68 although such
follow-up has been recommended by various authors.7679

P (pathology)
P0
P1
P2
Px
OL-staging system
Stage I
Stage II
Stage III
Stage IV

Size
Size
Size
Size

of single or multiple leukoplakias together <2 cm

of single or multiple leukoplakias together 24 cm
of single or multiple leukoplakias together >4 cm
not specied

No epithelial dysplasia (includes no or perhaps mild

epithelial dysplasia)
Mild or moderate epithelial dysplasia
Severe epithelial dysplasia
Absence or presence of epithelial dysplasia not specied
in the pathology report
L1P0
L2P0
L3P0 or L1L2P1
L3P1, any L P2

General rules of the OL-staging system

1. If there is doubt concerning the correct L category to which a particular case
should be allotted, than the lower (i.e. less advanced) category should be chosen. This will also be reected in the stage grouping.
2. In case of multiple biopsies of single leukoplakia or biopsies taken from multiple leukoplakias the highest pathological score of the various biopsies should be
used.
3. For reporting purposes the oral subsite according to the ICD-DA should be mentioned (World Health Organisation, International Classication of Diseases.
Tenth Revision. Application to Dentistry and Stomatology, ICD-DA, Geneva,
1992).

Oral submucous brosis

Table 9
Reporting of treatment results of oral leukoplakia: a proposal63












Age at the time of rst admission

Gender
Etiologic factors, if present
Type of treatment
Surgical (incl. CO2)
Non-surgical
Chemo-prevention
Observation only
Response rate (in case of non-surgical treatment or observation without
treatment)
No response (stable disease)
Partial response (>50% reduction in size, but not complete)
Complete response
Progressive disease (>25% increase in size or the appearance of a new
lesion)
Recurrence
Leukoplakia at the same subsite, irrespective of time interval
New primary
Leukoplakia at a distinctly different subsite
Malignant transformation
Malignant event in the head-and-neck region, outside the oral cavity
Malignant event outside the head-and-neck region
Length of follow-up

invasive carcinoma.66 Probably by far the majority of erythroplakias will undergo malignant transformation. There are not enough
documented series that would allow to calculate a reliable annual
malignant transformation rate.
In general, erythroplakia needs to be treated because of its highrisk of malignant transformation. Besides, most erythroplakias are
symptomatic. Surgery, either by cold knife or by laser, is the recommended treatment modality. As for excision of leukoplakia, no
guidelines are available with regard to the width of the surgical
margins. There are no data from the literature about the recurrence
rate after excision of erythroplakias.

The occurrence of oral submucous brosis (OSF) is more or less

restricted to Southeast Asia, although a number of cases have been
reported in other parts of the world, such as South Africa, Greece
and the United Kingdom. The disease is most likely caused by
the habit of chewing areca and betel quid or substitute.80
Clinically, OSF is characterized by a burning sensation, blanching and stiffening of the oral mucosa and oropharynx, and trismus.
In advanced stages vertical brous bands appear in the cheeks, faucial pillars, and encircle the lips. Through an as yet unknown process, brosis and hyalinization occur in the lamina propria, which
results in atrophy of the overlying epithelium. The atrophic epithelium apparently predisposes to the development of a squamous
cell carcinoma in the presence of carcinogens. In a long-term follow-up study the annual malignant transformation rate was
approximately 0.5%.81

Some miscellaneous potentially malignant disorders

Actinic cheilitis
Actinic cheilitis is a clinical term for an ulcerative, sometimes
crust-forming lesion of the mucosa of part or entire vermilion border of the lower lip. The histopathologic spectrum varies from
hyperkeratosis with or without epithelial dysplasia to early squamous cell carcinoma in the presence of basophilic changes in the
lamina propria. There may be a marked inammatory cell inltrate
present. The disease mainly occurs in elderly men. There are no
incidence gures available from the literature. Depending on the
clinical signs and symptoms, and the result of a biopsy, treatment
usually consists of supercial surgical excision (lip shave) or
CO2-laser evaporation.82 The advantage of surgical excision is the
availability of a specimen for histopathologic examination. If
CO2-laser is used, a pretreatment biopsy should be taken. Other
treatment modalities such as photodynamic therapy, seem less
effective.83 There are no follow-studies of untreated actinic cheilitis that would allow to present annual malignant transformation
rates.

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
6

I. van der Waal / Oral Oncology xxx (2008) xxxxxx

Some inherited cancer syndromes

In xeroderma pigmentosum and Fanconis anemia there is an
increased incidence of malignancies, including oral cancer. 84
Immunodeciency
In immunodepressed patients, e.g. due to the prolonged use of
immunosuppressive drugs after solid organ transplants, there is
an increased risk of cancer, particularly of the lower lip.85 In patients who underwent a liver transplant there was no increased
prevalence of oral or oropharyngeal cancer.86 There has been a report of an immunosuppressed liver transplant recipient in whom
oral leukoplakia rapidly progressed to carcinoma.87
Particularly in the era before HAART therapy, but also more recently, a number of HIV-infected patients with oral cancer have
been reported.88 Furthermore, oral cancer have been reported in
patients suffering from chronic Graft Versus Host Disease after
stem cell transplantation.89
Conict of interest statement
None declared.
References
1. Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and
classication of potentially malignant disorders of the oral mucosa. J Oral
Pathol Med 2007;36:57580.
2. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review.
Oral Oncol 2003;39:77080.
3. Baric JM, Alman JE, Feldman RS, Chauncey HH. Inuence of cigarette, pipe, and
cigar smoking, removable partial dentures, and age on oral leukoplakia. Oral
Surg Oral Med Oral Pathol 1982;54:4249.
4. Maserejian NN, Joshipura KJ, Rosner BA, Giovannucci E, Zavras AI. Prospective
study of alcohol consumption and risk of oral premalignant lesions in men.
Cancer Epidemiol Biomarkers Prev 2006;15:77481.
5. Bagan JV, Jimenez Y, Murillo J, et al. Lack of association between proliferative
verrucous leukoplakia and human papillomavirus infection. J Oral Maxillofac
Surg 2007;65:469.
6. Campisi G, Giovannelli L, Arico P, et al. HPV DNA in clinically different variants
of oral leukoplakia and lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2004;98:70511.
7. Fornatora M, Jones AC, Kerpel S, Freedman P. Human papillomavirus-associated
oral epithelial dysplasia (koilocytic dysplasia). An entity of unknown biologic
potential. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;82:4756.
8. Hansen LS, Olson JA, Silverman Jr S. Proliferative verrucous leukoplakia. A longterm study of thirty patients. Oral Surg Oral Med Oral Pathol 1985;60:28598.
9. Cabay RJ, Morton TH, Epstein JB. Proliferative verrucous leukoplakia and its
progression to oral carcinoma: a review of the literature. J Oral Pathol Med
2007;36:25561.
10. van der Waal I, Reichart PA. Oral proliferative verrucous leukoplakia revisited.
Oral Oncol, in press, doi:10.1016/j.oraloncology.2007.09.010.
11. Barnes L, Eveson JW, Reichart PA, Sidransky D. World Health Organization
classication of tumours. Pathology and genetics. Head and neck tumours.
World Health Organization; 2005.
12. Abbey LM, Kaugars GE, Gunsolley JC, et al. Intraexaminer and interexaminer
reliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1995;80:18891.
13. Karabulut A, Reibel J, Therkildsen MH, Praetorius F, Nielsen HW, Dabelsteen E.
Observer variability in the histologic assessment of oral premalignant lesions. J
Oral Pathol Med 1995;24:198200.
14. Kujan O, Khattab A, Oliver RJ, Roberts SA, Thakker N, Sloan P. Why oral
histopathology suffers inter-observer variability on grading oral epithelial
dysplasia: an attempt to understand the sources of variation. Oral Oncol
2007;43:22431.
15. Kujan O, Oliver RJ, Khattab A, Roberts SA, Thakker N, Sloan P. Evaluation of a
new binary system of grading oral epithelial dysplasia for prediction of
malignant transformation. Oral Oncol 2006;42:98793.
16. Chattopadhyay A, Ray JG. AgNOR cut-point to distinguish mild and moderate
epithelial dysplasia. J Oral Pathol Med 2008;37:7882.
17. Murrah VA, Batsakis JG. Proliferative verrucous leukoplakia and verrucous
hyperplasia. Ann Otol Rhinol Laryngol 1994;103:6603.
18. Shear M, Pindborg JJ. Verrucous hyperplasia of the oral mucosa. Cancer
1980;46:185562.
19. Gupta PC, Mehta FS, Daftary DK, et al. Incidence rates of oral cancer and natural
history of oral precancerous lesions in a 10-year follow-up study of Indian
villagers. Community Dent Oral Epidemiol 1980;8:283333.

20. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment outcome of

oral premalignant lesions. Oral Oncol 2006;42:46174.
21. Schwarz S, Bier J, Driemel O. Losses of 3p14 and 9p21 as shown by uorescence
in situ hybridization are early events in tumorigenesis of oral squamous cell
carcinoma and already occur in simple keratosis. Cytom A 2008;73A:
30511.
22. Field EA, Field JK, Martin MV. Does Candida have a role in oral epithelial
neoplasia? J Med Vet Mycol 1989;27:27794.
23. Brennan M, Migliorati CA, Lockhart PB, et al. Management of oral epithelial
dysplasia: a review. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2007;103(Suppl. 1):S19.
24. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, et al. Podoplanin: a novel
marker for oral cancer risk in patients with oral premalignancy. J Clin Oncol
2008;26:35460.
25. Vora HH, Trivedi TI, Shukla SN, Shah NG, Goswami JV, Shah PM. p53 expression
in leukoplakia and carcinoma of the tongue. Int J Biol Markers 2006;21:7480.
26. Johnstone S, Logan RM. Expression of vascular endothelial growth factor (VEGF)
in normal oral mucosa, oral dysplasia and oral squamous cell carcinoma. Int J
Oral Maxillofac Surg 2007;36:2636.
27. Luo CW, Roan CH, Liu CJ. Human papillomaviruses in oral squamous cell
carcinoma and pre-cancerous lesions detected by PCR-based gene-chip array.
Int J Oral Maxillofac Surg 2007;36:1538.
28. Kovesi G, Szende B. Prognostic value of cyclin D1, p27, and p63 in oral
leukoplakia. J Oral Pathol Med 2006;35:2747.
29. Gires O, Mack B, Rauch J, Matthias C. CK8 correlates with malignancy in
leukoplakia and carcinomas of the head and neck. Biochem Biophys Res Commun
2006;343:2529.
30. Furrer VE, Benitez MB, Furnes M, Lanfranchi HE, Modesti NM. Biopsy vs.
supercial scraping: detection of human papillomavirus 6, 11, 16, and 18 in
potentially malignant and malignant oral lesions. J Oral Pathol Med
2006;35:33844.
31. Bremmer JF, Braakhuis BJM, Ruijter-Schippers HJ, et al. A noninvasive genetic
screening test to detect oral precancerous lesions. Laboratory Invest
2005;85:14818.
32. Smith EM, Ritchie JM, Summersgill KF, et al. Human papillomavirus in oral
exfoliated cells and risk of head and neck cancer. J Nat Cancer Inst
2004;96:44955.
33. Brailo V, Vucicevic-Boras V, Cekic-Arambasin A, Alajbeg IZ, Milenovic A, Lukac J.
The signicance of salivary interleukin 6 and tumor necrosis factor alpha in
patients with oral leukoplakia. Oral Oncol 2006;42:3703.
34. Rhodus NL, Ho V, Miller CS, Myers S, Ondrey F. NF-kappaB dependent cytokine
levels in saliva of patients with oral preneoplastic lesions and oral squamous
cell carcinoma. Cancer Detect Prev 2005;29:425.
35. Poate TWJ, Warnakulasuriya S. Effective management of smoking in an oral
dysplasia clinic in London. Oral Dis 2006;12:226.
36. Thomson PJ, Hamadah O. Cancerisation within the oral cavity: the use of eld
mapping biopsies in clinical management. Oral Oncol 2007;43:206.
37. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant lesions: Is a
biopsy reliable? J Oral Pathol Med 2007;36:2626.
38. Lee JJ, Hung HC, Cheng SJ, et al. Factors associated with underdiagnosis from
incisional biopsy of oral leukoplakic lesions. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2007;104:21725.
39. Kujan O, Desai M, Sargent A, Bailey A, Turner A, Sloan P. Potential applications
of oral brush cytology with liquid-based technology: results from a cohort of
normal oral mucosa. Oral Oncol 2006;42:8108.
40. Greenberg MS. The brush controversy. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2002;93:2178.
41. Scheifele C, Schmidt-Westhausen AM, Dietrich T, Reichart PA. The sensitivity
and specicity of the OralCDx technique: evaluation of 103 cases. Oral Oncol
2004;40:8248.
42. Gandolfo S, Pentenero M, Broccoletti R, Pagano M, Carrozzo M, Scully C.
Toluidine blue uptake in potentially malignant oral lesions in vivo: clinical and
histological assessment. Oral Oncol 2006;42:8995.
43. Epstein JB, Zhang L, Poh C, Nakamura H, Berean K, Rosin M. Increased allelic loss
in toluidine blue-positive oral premalignant lesions. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2003;95:4550.
44. Zhang L, Williams M, Poh CF, et al. Toluidine blue staining identies high-risk
primary oral premalignant lesions with poor outcome. Cancer Res
2005;65:801721.
45. Epstein JB, Sciubba J, Silverman S, Sroussi HY. Utility of toluidine blue in oral
premalignant lesions and squamous cell carcinoma: continuing research and
implications for clinical practice. Head Neck 2007;29:94858.
46. Sharwani A, Jerjes W, Salih V, et al. Assessment of oral premalignancy using
elastic scattering spectroscopy. Oral Oncol 2006;42:3439.
47. Poh CF, Zhang L, Anderson DW, et al. Fluorescence visualization detection of
eld alterations in tumor margins of oral cancer patients. Clin Cancer Res
2006;12:671622.
48. Westra WH, Sidransky D. Fluorescence visualization in oral neoplasia: shedding
light on an old problem. Clin Cancer Res 2006;12:65947.
49. Epstein JB, Gorsky M, Lonky S, Silverman Jr S, Epstein JD, Bride M. The efcacy
of oral luminoscopy (ViziLite) in visualizing oral mucosal lesions. Spec Care
Dentist 2006;26:1714.
50. Lodi G, Sardella A, Bez C, Demarosi F, Carrassi A. Interventions for treating oral
leukoplakia (Review). Cochrane Database Syst Rev(4):CD001829.
51. Tradati N, Grigolat R, Calabrese L, et al. Oral leukoplakias: To treat or not? Oral
Oncol 1997;33:31721.

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016

ARTICLE IN PRESS
I. van der Waal / Oral Oncology xxx (2008) xxxxxx
52. Chandu A, Smith ACH. The use of CO2 laser in the treatment of oral white
patches: outcomes and factors affecting recurrence. Int J Oral Maxillofac Surg
2005;34:396400.
53. van der Hem PS, Nauta JM, van der Wal JE, Roodenburg JL. The results of CO2
laser surgery in patients with oral leukoplakia: a 25 year follow up. Oral Oncol
2005;41:317.
54. Chiesa F, Tradati N, Grigolato R, et al. Randomized trial of fenretinide (4-HPR) to
prevent recurrences, new localizations and carcinomas in patients operated on
for oral leukoplakia: long-term results. Int J Cancer 2005;115:6259.
55. Mulshine JL, Atkinson JC, Greer RO, et al. Randomized, double-blind, placebocontrolled phase IIB trial of the cyclooxygenase inhibitor ketorolac as an oral
rinse in oropharyngeal leukoplakia. Clin Cancer Res 2004;10:156573.
56. Sood S, Shiff SJ, Yang CS, Chen X. Selection of topically applied non-steroidal
anti-inammatory drugs for oral cancer chemoprevention. Oral Oncol
2005;41:5627.
57. Rudin CM, Cohen EEW, Papadimitrakopoulou VA, et al. An attenuated
adenovirus, ONYX-015, as mouthwash therapy for premalignant oral
dysplasia. J Clin Oncol 2003;21:454652.
58. Gaballah K, Hills A, Curiel D, Hallden G, Harrison P, Partridge M. Lysis of
dysplastic but not normal oral keratinocytes and tissue-engineered
epithelia with conditionally replicating adenoviruses. Cancer Res 2007;67:
728494.
59. Kvaal SI, Warloe T. Photodynamic treatment of oral lesions. J Environ Pathol
Toxicol Oncol 2007;26:12733.
60. Ishii J, Fujita K, Komori T. Laser surgery as a treatment for oral leukoplakia. Oral
Oncol 2003;39:75969.
61. Vedtofte P, Holmstrup P, Hjorting-Hansen E, Pindborg JJ. Surgical treatment of
premalignant lesions of the oral mucosa. Int J Oral Maxillofac Surg
1987;16:65664.
62. van der Waal I, Axell T. Oral leukoplakia: a proposal for uniform reporting. Oral
Oncol 2002;38:5216.
63. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer
treatment. Cancer 1981;47:20714.
64. Pindborg JJ, Reichart PA, Smith CJ, van der Waal I. Histological typing of cancer
and precancer of the oral mucosa. International histological classication of
tumours. World Health Organization; 1997.
65. Reichart PA, Philipsen HP. Oral erythroplakia. A review. Oral Oncol
2005;41:55161.
66. Shafer WG, Waldron CA. Erythroplakia of the oral cavity. Cancer
1975;36:10218.
67. Hsue SS, Wang WC, Chen CH, Lin CC, Chen YK, Lin LM. Malignant
transformation in 1458 patients with potentially malignant oral mucosal
disorders: a follow-up study based in a Taiwanese hospital. J Oral Pathol Med
2007;36:259.
68. Mattsson U, Jontell M, Holmstrup P. Oral lichen planus and malignant
transformation: Is a recall of patients justied? Crit Rev Oral Biol Med
2002;13:3906.
69. Roosaar A, Yin L, Sandborgh-Englund G, Nyren O, Axell T. On the natural course
of oral lichen lesions in a Swedish population-based sample. J Oral Pathol Med
2006;35:25761.
70. van der Meij EH, Mast H, van der Waal I. The possible premalignant character of
oral lichen planus and oral lichenoid lesions: a prospective ve-year follow-up
study of 192 patients. Oral Oncol 2007;43:7428.

71. Gandolfo S, Richiardi L, Carrozzo M, et al. Risk of oral squamous cell carcinoma
in 402 patients with oral lichen planus: a follow-up study in an Italian
population. Oral Oncol 2004;40:7783.
72. van der Meij EH, van der Waal I. Lack of clinicopathologic correlation in the
diagnosis of oral lichen planus based on the presently available diagnostic
criteria and suggestions for modications. J Oral Pathol Med 2003;32:50712.
73. Larsson A, Warfvinge G. Oral lichenoid contact reactions may occasionally
transform into malignancy. Eur J Cancer Prev 2005;14:5259.
74. Krutchkoff DJ, Eisenberg E. Lichenoid dysplasia: a distinct histopathologic
entity. Oral Surg Oral Med Oral Pathol 1985;60:30815.
75. Eisenberg E. Clinical controversies in oral and maxillofacial surgery. Part one.
Oral lichen planus: a benign lesion.. J Oral Maxillofac Surg 2000;58:127885.
76. Al-Hashimi I, Schifter M, Lockhart PB, et al. Oral lichen planus and oral
lichenoid lesions: diagnostic and therapeutic considerations. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2007;103(Suppl. 1):S25.
77. Eisen D. The clinical features, malignant potential, and systemic associations of
oral lichen planus: a study of 723 patients. J Am Acad Dermatol
2002;46:20714.
78. Xue JL, Fan MW, Wang SZ, Chen XM, Li Y, Wang L. A clinical study of 674
patients with oral lichen planus in China. J Oral Pathol Med 2005;34:46772.
79. Mignogna MD, Fedele S, Lo Russo L. Dysplasia/neoplasia surveillance in oral
lichen planus patients: a description of clinical criteria adopted at a single
centre and their impact on prognosis. Oral Oncol 2006;42:81924.
80. Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral
submucous brosis: review on aetiology and pathogenesis. Oral Oncol
2006;42:5618.
81. Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant
transformation rate in oral submucous brosis over a 17-year period.
Community Dent Oral Epidemiol 1985;13:3401.
82. Satorres NM, Gargallo AJ, Gay EC. Surgical management of actinic cheilitis. Med
Oral 2001;6:20517.
83. Berking C, Herzinger T, Flaig MJ, Brenner M, Borelli C, Degitz K. The efcacy of
photodynamic therapy in actinic cheilitis of the lower lip: a prospective study
of 15 patients. Dermatol Surg 2007;33:82530.
84. Prime SS, Thakker NS, Pring M, Guest PG, Paterson IC. A review of inherited
cancer syndromes and their relevance to oral squamous cell carcinoma. Oral
Oncol 2001;37:116.
85. Visscher de JGAM, Bouwes Bavinck JN, van der Waal I. Squamous cell
carcinoma of the lower lip in renal-transplant recipients. Report of six cases.
Int J Oral Maxillofac Surg 1997;26:1203.
86. Scheifele C, Reichart PA, Hippler-Benscheidt M, Neuhaus P, Neuhaus R.
Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas
among 1515 patiens after liver transplantation. Oral Oncol 2005;41:6706.
87. Hernandez G, Arriba L, Jimenez C, et al. Rapid progression from oral leukoplakia
to carcinoma in an immunosuppressed liver transplant recipient. Oral Oncol
2003;39:8790.
88. Demopoulos BP, Vamvakas E, Ehrlich JE, Demopoulos R. Non-acquired
immunodeciency syndrome-dening malignancies in patients infected with
human immunodeciency virus. Arch Pathol Lab Med 2003;127:58992.
89. Szeto CH, Shek TW, Lie AK, Au WY, Yuen AP, Kwong YL. Squamous cell
carcinoma of the tongue complicating chronic oral mucosal graft-versus-host
disease after allogeneic hematopoietic stem cell transplantation. Am J Hematol
2004;77:2002.

Please cite this article in press as: van der Waal I, Potentially malignant disorders of the oral and oropharyngeal mucosa; ..., Oral Oncol
(2008), doi:10.1016/j.oraloncology.2008.05.016