Oral leukoplakia, the ongoing discussion on definition and terminology

Med Oral Patol Oral Cir Bucal. 2015 Nov 1;20 (6):e685-92. Oral leukoplakia

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Journal section: Oral Medicine and Pathology

Publication Types: Review

Oral leukoplakia, the ongoing discussion on denition and terminology

Isaäc van der Waal

VU University Medical Center (VUmc)/Academic Centre for Dentistry Amsterdam (ACTA), Department of Oral and Maxil-

lofacial Surgery and Oral Pathology, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands

Correspondence:

Department of Oral and Maxillofacial Surgery and Oral Pathology

VU University Medical Center

P.O. Box 7057

1007 MB Amsterdam

The Netherlands

I.vanderwaal@vumc.nl

Received: 17/08/2015

Accepted: 27/09/2015

Abstract

In the past decades several denitions of oral leukoplakia have been proposed, the last one, being authorized by

the World Health Organization (WHO), dating from 2005. In the present treatise an adjustment of that denition

and the 1978 WHO denition is suggested, being : “A predominantly white patch or plaque that cannot be char-

acterized clinically or pathologically as any other disorder; oral leukoplakia carries an increased risk of cancer

development either in or close to the area of the leukoplakia or elsewhere in the oral cavity or the head-and-neck

region”. Furthermore, the use of strict diagnostic criteria is recommended for predominantly white lesions for

which a causative factor has been identied, e.g. smokers’ lesion, frictional lesion and dental restoration associat-

ed lesion. A nal diagnosis of such leukoplakic lesions can only be made in retrospect after successful elimination

of the causative factor within a somewhat arbitrarily chosen period of 4-8 weeks. It seems questionable to exclude

“frictional keratosis” and “alveolar ridge keratosis” from the category of leukoplakia as has been suggested in

the literature. Finally, brief attention has been paid to some histopathological issues that may cause confusion in

establishing a nal diagnosis of leukoplakia.

Key words: Oral leukoplakia, potentially malignant oral disorders, denition.

van der Waal I. Oral leukoplakia, the ongoing discussion on denition and

terminology. Med Oral Patol Oral Cir Bucal. 2015 Nov 1;20 (6):e685-92.

http://www.medicinaoral.com/medoralfree01/v20i6/medoralv20i6p685.pdf

Article Number: 21007 http://www.medicinaoral.com/

eMail: [email protected]

Indexed in:

Science Citation Index Expanded

Journal Citation Reports

Index Medicus, MEDLINE, PubMed

Scopus, Embase and Emcare

Indice Médico Español

doi:10.4317/medoral.21007

http://dx.doi.org/doi:10.4317/medoral.21007

Introduction

1. The denition and terminology of oral leukoplakia

and leukoplakialike (“leukoplakic”) lesions and dis-

orders of the oral mucosa is the subject of discussion

in the literature for many decades. This discussion is

mainly focused on clinical aspects, but is partly related

to some histopathological aspects as well. In this trea-

tise the various denitions of oral leukoplakia will be

discussed, resulting in a suggestion for a slight adjust-

ment of the 2005 WHO denition. Furthermore, some

leukoplakic lesions will be discussed that may cause

some confusion as whether or not to exclude them from

the category of leukoplakia; examples are “alveolar

ridge keratosis” and “frictional keratosis”.

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Denition

2.1 The various WHO denitions and suggestion for an

adjusted denition

In 1978, oral leukoplakia has been dened by the World

Health Organization (WHO) as: ‘A white patch or plaque

that cannot be characterized clinically or pathologically

as any other disease’ (1). In an explanatory note it has

been explicitly stated that the term leukoplakia is unre-

lated to the absence or presence of epithelial dysplasia.

In a monograph by the WHO, published in 1997, the

phrase: ‘any other denable disease’ was replaced by

‘any other denable lesion’ (2). No justication has been

provided for this change.

In 2002, it has been recommended to make a distinction

between a provisional clinical diagnosis of oral leuko-

plakia and a denitive one (Table 1) (3). A provisional

diagnosis was made when a lesion at the initial clinical

examination could not be clearly diagnosed as either leu-

koplakia or any other disease. In case of a provisional

clinical diagnosis, Certainty factor 1 was assigned (Ta-

ble 2). A denitive clinical diagnosis of leukoplakia was

made after unsuccessful elimination of suspected etio-

logical factors or in the absence of such factors, assigning

Certainty factor 2. Certainty factor 3 was assigned when

histopathological examination of an incisional biopsy did

not show the presence of any other diseases. In case of an

excisional biopsy or surgical excision, performed after an

incisional biopsy, Certainty factor 4 was assigned based

on histopathological examination of the surgical speci-

men (Fig. 1). It goes without saying that in epidemiologi-

cal studies a Certainty factor 1, based on a single oral

examination, is acceptable, while in scientic studies,

e.g. comparing different treatment results, Certainty fac-

tor 4 will be required, if feasible. Apparently, the recom-

mendation to use a Certainty factor has not been widely

accepted in the recent literature (4), although the use of

such factor is common practice in cancer registries.

In 2005, the denition of oral leukoplakia has been

changed at a WHO supported meeting into: ‘A white

plaque of questionable risk having excluded (other)

known diseases or disorders that carry no increased risk

for cancer’ (5). During the latter meeting it has deliber-

ately been decided to consider leukoplakia a potentially

malignant- premalignant and precancerous are equiva-

lent adjectives- disease and not a lesion since it is well

known that cancer development not always occurs in or

close to the leukoplakia but may also occur at other sites

in the oral cavity or the head-and-neck region.

DIAGNOSIS OF ORAL LEUKOPLAKIA

(Provisional clinical diagnosis, C 1*)

Consider the taking of a biopsy, particularly in case of symptoms No possible cause(s)

(Definitive clinical diagnosis, C 2)

In the absence of dysplasia

Elimination of possible cause(s), such as mechanical irritation, amalgam restoration

in direct contact with the white lesion, fungal infection, and tobacco habits

(maximum 4-8 weeks to observe the result)

No response Biopsy

(Definitive clinical diagnosis, C 2)

Good response Definitive clinicopathological diagnosis

C 3 (in case of incisional biopsy only

C 4 (in case of excisional biopsy or surgical

excision after an incisional biopsy

Definable lesion Non-dysplastic leukoplakia Dysplastic leukoplakia Definable lesion

* C=Certainty factor (see table 2)

Table 1. Diagnosis of oral leukoplakia.

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Although various international meetings on the sub-

ject of oral leukoplakia have been held between 1978

(WHO) and 2005 (WHO) no substantial changes in the

denition of leukoplakia have resulted from these meet-

ings.

In the sixties of the past century a minimum size of 5

mm was required before being allowed to use the term

leukoplakia (6). There seems no strong reason to re-

introduce a minimum size, since cancer devopment

may also take place in very small leukoplakias. Another

part of previous denitions of leukoplakia has been the

requirement of a non-removable nature of the white le-

sion, apparently mainly meant to separate pseudomem-

branous candidiasis from leukoplakia. The adjectives

“non-removable” or “non-scrapable” seem, indeed, to

have some practical value, but there is no strong reason

to include these in the denition.

The advantage of the 2005 WHO denition above the

one from 1978 is its statement about the behaviour of

oral leukoplakia (“questionable risk”). Unfortunately, in

both WHO denitions (1978 and 2005) the diagnosis of

leukoplakia is one by exclusion (of other “known dis-

eases or disorders”). A list of these “known diseases”

is depicted in table 3. Some of these diseases will be

briey commented upon (see ad 3). Many, if not most,

of the listed entities may be easy to distinguish from

leukoplakia by an experienced clinician, either based on

the history or based on the clinical appearance, but this

may not be the case for the less experienced clinician,

being either a dentist, an oral and maxillofacial surgeon,

an otolaryngologist or a dermatologist. Furthermore, it

does not seem realistic to expect family doctors to be

knowledgable in this eld, since probably in most parts

of the world little attention is paid to oral diseases dur-

ing the medical curriculum. One may even discuss at

what level dentists-general practitioners should be edu-

cated in the diagnosis and management of the numerous

lesions and disorders of the oral mucosa .

A combination of the 1978 and the 2005 WHO de-

nitions of oral leukoplakia may result in the following

text: “A predominantly white patch or plaque that can-

not be characterized clinically or pathologically as any

other disorder; oral leukoplakia carries an increased risk

of cancer development either in or close to the area of

leukoplakia or elsewhere in the oral cavity or the head-

and-neck region”.

2.2 What is a signicant increased risk of cancer de-

velopment?

In dening a potentially malignant disorder it is usu-

ally stated that there is “signicant increased risk” of

cancer development, without specifying “signicant”.

When the incidence- number of new patients per year-

of oral cancer is set at a low 2:100,000 population and

the annual malignant transformation rate of leukoplakia

at 2:100 (irrespective of the discussion whether or not

treatment of leukoplakia reduces the risk of malignant

transformation) there is a thousandfold risk in leukopla-

kia patients to develop cancer in comparison with pa-

tients not having leucoplakia. Probably, a thousandfold

increased risk is perceived, particularly by patients, as

being signicant.

Discussion on some “other known diseases and

disorders” that may have a leukoplakic appear-

ance

-3.1 Alveolar ridge “keratosis”

A few papers have been devoted to “alveolar ridge kera-

tosis” (7,8). Apparently, the supposed cause of the lesion

is chronic frictional (masticatory) trauma to the max-

Evidence from a single visit, applying inspection and palpation as the only diagnosis means (Provisional clinical

diagnosis), including a clinical picture of the lesion.

Evidence obtained by a negative result of elimination of suspected etiologic factors, e.g. mechanical irritation, during a

follow-up period of 6 weeks (Definitive clinical diagnosis)

As C

, but complemented by pretreatment incisional biopsy in which, histopathologically, no definable lesion is

observed (Histopathologically supported diagnosis)

Evidence following surgery and pathologically examination of the resected specimen

Table 2. Certainty (C)-factor of a diagnosis of oral leukoplakia.3.

Fig. 1. Leukoplakia (or "benign alveolar ridge keratosis"?) in both

sides of the maxilla in a patient who never smoked and has not been

wearing a partial denture.

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illary and mandibular alveolar ridges. Histopathologi-

cally, almost of all these lesions show hyperkeratosis

without epithelial dysplasia. The suggestion has been

made in both previous papers to remove this lesion

from oral leukoplakia, mainly based on the assumption

that malignant transformation is extremely rare (Fig. 1).

There are not many follow-up studies that focused on

leukoplakia of the alveolar ridges only. Therefore, there

is some reluctance to accept the suggestion to remove

this lesion from leukoplakia.

In one paper on this subject it was noted that alveolar

ridge keratosis resembles chronic lichen simplex of the

skin, apparently being caused by chronic frictional in-

jury (8). Therefore, the authors suggested the somewhat

confusing term “oral lichen simplex chronicus” as a

synonym.

There may be some overlap with the reported frictional

keratosis of the facial (buccal) attached gingiva to be

discussed in 3.3

-3.2 Candidiasis, hyperplastic type

There is some room for discussion, both clinically and

histopathologically, about the diagnosis of hyperplas-

tic candidiasis versus Candida-associated leukoplakia,

particularly if located at the commissures of the lips, the

hard palate and the dorsal surface of the tongue. If such

lesions disappear after antifungal treatment within an

arbritarily chosen period of 4-8 weeks there is no jus-

tication to call such lesions leukoplakias any longer.

Table 3. Denable white diseases and disorders that may have a leukoplakic appearance.

Lesion Main diagnostic criteria

Alveolar ridge "keratosis" * Primarily a clinical diagnosis of a flat, white aspect of the mucosa of an edentulous part of the alveolar

ridge; may overlap Frictional "keratosis"

Aspirin burn History of prolonged local application of aspirin tablets (paracetamol may cause similar changes)

Candidasis, pseudomembranous Clinical aspect (pseudomembranous, often symmetrical pattern)

hyperplastic* Somewhat questionable entity; some refer to this lesion as candida associated leukoplakia

Darier-White diseases Associated with lesions of the skin and the nails; rather typical histopathology

Frictional "keratosis"* Disappearance of the lesion within an arbitrarily chosen period of 4-8 weeks after elimination of the

suspected mechanical irritation (e.g. habit of vigorous toothbrushing); therefore, it is a retrospective

diagnosis only

Geographic tongue Primarily a clinical diagnosis; characterized by a wandering pattern in time

Glassblowers lesion Occurs only in glassblowers; disappears within a few weeks after cessation of glassblowing

Hairy leukoplakia* Clinical aspect (bilateral localization on the borders of the tongue); histopathology (incl. EBV)

Lesion caused by a dental restoration (often amalgam)* Disappearance of the anatomically closely related (amalgam) restoration within an arbitrarily chosen

period of 4-8 weeks after its replacement; therefore, it is a retrospective diagnosis only

Leukoedema Clinical diagnosis (incl. symmetrical pattern) of a veil-like aspect of the buccal mucosa

Lichen planus, reticular type and erythematous type Primarily a clinical diagnosis (incl. symmetrical pattern); histopathology is not diagnostic by its own

Linea alba Clinical aspect (located on the line of occlusion in the cheek mucosa; almost always bilateral)

Lupus erythematosus Primarily a clinical diagnosis (incl. symmetrical pattern); almost always cutaneous involvement as well.

Histopathology is not diagnostic by its own

Morsicatio (habitual chewing or biting of the cheek, tongue, lips) History of habitual chewing or biting; clinical aspects

Papilloma and allied lesions, e.g. condyloma acuminatum, Clinical aspect; medical history; HPV typing of a biopsy may be helpful.

multifocal epithelial hyperplasia, squamous papilloma,

verruca vulgaris

Skin graft, e.g. after a vestibuloplasty History of a previous skin graft

Smokers' lesion* Disappearance of the lesion within an arbitrarily chosen period of 4-8 weeks after cessation of the

tobacco habits; therefore, it is a retrospective diagnosis only

Smokers' palate ('stomatitis nicotinica') Clinical aspect; history of smoking

Syphilis, secondary ('mucous patches') Clinical aspect; demonstration of T. pallidum; serology

Verrucous hyperplasia and verrucous carcinoma Primarily histopathological entities

White sponge nevus Family history; clinical aspect (often symmetrical pattern)

*These entities will be briey discussed in the text.

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However, in case of persistence, it seems safe practice

to consider a diagnosis of Candida-associated leukopla-

kia.

-3.3 Frictional “keratosis”

Another possible reversible white lesion is the frictional

lesion caused by mechanical irritation, e.g. vigorously

brushing of the teeth (Fig. 2). This lesion is sometimes

Fig. 2. Leukoplakia (or "frictional keratosis"?) in a 57-year-old wom-

an.

referred to as “frictional keratosis”. The term “lesion” is

preferred because “keratosis” is actually a histopatho-

logical term. There may be some overlap with the pre-

viously discussed alveolar ridge keratosis (see ad 3.1).

The suggestion to remove this lesion- particularly when

located on the buccal attached gingiva- from the cat-

egory of leukoplakia seems rather questionable (9). A

nal diagnosis of frictional lesion can only be applied to

cases where the lesion has disappeared after elimination

of the possible mechanical cause- provided that there

are no symptoms that would require to immediately bi-

opsy the lesion- , within a somewhat arbitrarily chosen

period of no more than 4-8 weeks. In other words, a de-

nitive diagnosis of frictional lesion can only be made

in retrospect.

-3.4 Hairy leukoplakia

The term hairy leukoplakia is a misnomer- but well ac-

cepted in the literature- for various reasons, being 1) it

is a well described entity, particularly by the immuno-

histochemical demonstration of EBV DNA in the koilo-

cytic epithelial cells of a biopsy specimen, 2) it is not a

potentially malignant disorder, and 3) the clinical aspect

is not always “hairy”. Admittedly, it is difcult to come

up with a better term (10).

-3.5 Restoration associated lesion

A somewhat similar approach as discussed above with

regard to frictional lesions is valid in case of a provision-

al diagnosis of a “contact lesion”, supposedly caused by

direct prolonged contact by large amalgam restorations,

particularly in case of a buccal or lingual extension. A

nal diagnosis of amalgam associated lesion should

only be applied when the lesion has disappeared after

replacement or removal of the amalgam restoration-

provided that there are no symptoms that would require

to immediately biopsy the lesion- , within a somewhat

arbitrarily chosen period of no more than 4-8 weeks.

Therefore, a denitive diagnosis of amalgam associated

lesion can only be made in retrospect.

-3.6 Smokers’ lesion versus tobacco associated leuko-

plakia

It is well known that leukoplakia in patients with to-

bacco habits might be reversible if patients give up their

smoking habits (11). In the absence of symptoms, be-

ing a strong indication for an immediate biopsy in order

to exclude the presence of severe epithelial dysplasia

or even squamous cell carcinoma, the patient should

be advised to give up the tobacco habit. If successful

and if the white lesion regresses within a somewhat ar-

bitrarily chosen period of no more than 4-8 weeks the

provisional clinical diagnosis of such lesion should, in

retrospect, be changed into “smokers’ lesion”. When the

patient is not able or willing to give up the tobacco habit

and in case of persistence of the leukoplakia, the term

“tobacco-associated leukoplakia” can be applied, irre-

spective of the relevance of such designation.

Clinical classication of leukoplakia with em-

phasis on (proliferative) verrucous leukoplakia.

4 1. Traditionally, two major clinical types of leukopla-

kia are recognized, being the homogeneous and the non-

homogeneous type respectively. The signicance of this

classication is the assumption that there is a correla-

tion between the clinical type and the risk of malignant

transformation, the non-homogeneous type carrying a

higher risk. In some studies there is such correlation

while in other studies there is not.

The homogeneous type is characterized by a thin, at

and homogeneous whitish appearance (Fig. 3). The

non-homogeneous type is subdived in a variety of sub-

types, such as speckled or erythematous (white and red

changes), also referred to as erythroleukoplakia (Fig.

4), nodular (Fig. 5) and verrucous (Fig. 6). Particularly

the verrucous type is probably quite often misdiag-

nosed by clinicians because of its homogeneous white

appearance and its often homogeneous (verrucous) tex-

ture. There are actually no strict criteria how to make

a distinction clinically between verrucous leukoplakia

and verrucous carcinoma.

Another confusing type is the proliferative verrucous

leukoplakia (PVL), as being introduced in the literature

by Hansen et al. (12). In the original publication PVL

has been characterized as a slow-growing, persistent,

and irreversible lesion, resistant to all forms of therapy

as recurrence is the rule. PVL may start as a simple

keratosis at one end to invasive carcinoma at the other.

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In fact, a diagnosis of PVL can only be made in retro-

spect. In several of such cases the initial lesion may just

be a solitary homogeneous or non-homogeneous leuko-

plakia (13). Unfortunately, in many scientic reports on

PVL just multifocality and involvement of the gingiva

seem to have been used as diagnostic criteria without

paying attention to the history of the disease.

Some histopathological areas of confusion

-5.1 The assessment of epithelial dysplasia

It is well recognized that the assessment of the presence

and degree of epithelial dysplasia carries a substantial

degree subjectivity, reected in a distinct intra- and in-

terobserver variation (14-16). Unfortunately, in spite of

numerous attempts, as being suggested in the literature,

there is no international consensus on this issue.

Probably some pathologists will deny a diagnosis of

leukoplakia in the absence of epithelial dysplasia, what

is not in accordance with the recommendations from

the “dental” literature.

-5.2 Lichenoid dysplasia

In 1985 the supposedly distinct entity of lichenoid dys-

plasia has been introduced in the literature (17). The

use of of this term is discouraged since it, erroneously,

may suggest dysplastic changes occurring in oral li-

chen planus. Probably a number of the reported cases

of malignant transformation of lichen planus are caused

by forementioned confusing terminology, while cases

of leukoplakia with a lichenoid appearance histopatho-

logically, mainly consisting of a subepithelial bandlike

inltrate, may have erroneously been reclassied as li-

chen planus.

-5.3 Verrucous hyperplasia versus verrucous carcino-

Fig. 3. Homogeneous (at and thin) leukoplakia in a 53-year-old

man.

Fig. 4. Non-homogeneous (white and red changes, also referred to as

erythroleukoplakia) in an 88-year-old woman.

Fig. 5. Non-homogeneous, nodular, leukoplakia in a 61-year-old

man.

Fig. 6. Non-homogeneous, verrucous leukoplakia. In spite of a ho-

mogeneous white appearance and a homogeneous verrucous texture,

this lesion should not be called homogeneous leukoplakia

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Several papers have been published about the his-

topathological difference between verrucous hyper-

plasia and verrucous carcinoma, still leaving room for

discussion (18,19). In daily practice it is difcult, if not

impossible, to make this distinction in a reproducible

way. Besides, one may question the clinical relevance of

the distinction between these two entities since for both

lesions (surgical) removal is recommended. A pitfall is

that some pathologists may describe these epithelial

changes as being benign, while the behavior of such le-

sions actually is unpredictable.

Discussion and Conclusions

It is well appreciated that a number of aspects of the

presently discussed denition and terminology may not

be equally valid in all parts of the world. A classica-

tion of potentially malignant disorders has been pro-

posed in 2011 from India (20). Apparently, this classi-

cation is not limited to leukoplakia, but also includes

entities such as lichen planus, oral submucous brosis,

nutritional deciencies and some inherited cancer syn-

dromes.

The recommendation is made to modify the present

2005 WHO denition of oral leukoplakia, amongst oth-

ers by adding explicitly the requirement of histopatho-

logic examination in order to obtain a denitive clin-

icopathological diagnosis. As a result, the following

denition is proposed: “A predominantly white patch

or plaque that cannot be characterized clinically or

pathologically as any other disorder; oral leukoplakia

carries an increased risk of cancer development either

in the area of the leukoplakia or elsewhere in the oral

cavity or the head-and-neck region”.

Furthermore, the use of strict diagnostic criteria is rec-

ommended for predominantly white lesions or diseases

for which a possible causative factor has been identied,

e.g. smokers’ lesion, frictional lesion and dental resto-

ration associated lesion. An observation of 4-8 weeks

after removal of the suggested cause seems a practical

one and seems also safe practice, particularly in case of

an asymptomatic leukoplakic disorder. In this respect

one should realize that at the rst visit of a patient with

oral leukoplakia a squamous cell carcinoma may be

present already and one would not run the risk of ob-

serving such event for a period of more than 4-8 weeks.

Even such period is already a long one in case of a sq-

uamous cell carcinoma, a carcinoma in situ or severe

epithelial dysplasia. However, it should be emphasized,

that the presence of such changes is nearly always as-

sociated with symptoms. Therefore, in the presence of

symptoms a biopsy is strongly recommended before

elimination of possibly causative factors and observa-

tion of the result of such elimination.

As is true for almost all pathologies proper communica-

tion between clinicians and pathologists is important,

particularly in the eld of oral potentially malignant

disorders. For instance, some pathologists will deny

a diagnosis of leukoplakia in the absence of epithelial

dysplasia. Also the use of the term “lichenoid dysplasia”

may be the subject of confusion between pathologists

and clinicians.

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Conict of interest

None declared