PATHOLOGY

Leukoplakia—A Diagnostic and

Management Algorithm
Alessandro Villa, DDS, PhD, MPH,* and Sook Bin Woo, DMD, MMScy

Oral white lesions are frequently encountered in daily practice. Most white lesions are benign (eg, reactive
keratoses or keratoses from inflammatory conditions) and the diagnosis is usually evident from the clinical
presentation and histopathology. Leukoplakia is a common condition characterized by an increased risk
for malignant transformation. Histopathology of leukoplakia can disclose hyperkeratosis with dysplasia
or carcinoma or hyperkeratosis or parakeratosis without dysplasia. Treatment depends on demographic,
social, clinical, and histopathologic factors. This review focuses on the diagnosis and management of oral
leukoplakia.
Ó 2016 American Association of Oral and Maxillofacial Surgeons
J Oral Maxillofac Surg 75:723-734, 2017

Oral white lesions, including leukoplakias, are
commonly encountered in daily practice by oral health
care providers, especially oral and maxillofacial sur-
geons. They are often investigated by biopsy examina-
tion to rule out the presence of dysplastic changes or
cancer. Most white lesions are benign frictional kerato-
ses or keratoses from inflammatory conditions (eg,
lichen planus) and the diagnosis is usually evident
from the histopathology.1,2 Leukoplakia is the term
used for a white lesion that is precancerous and is
defined by the World Health Organization (WHO) as
‘‘a white plaque of questionable risk having excluded
(other) known diseases or disorders that carry no
increased risk for cancer.’’3 It is one of several poten-
tially malignant oral lesions, including erythroplakia
and submucous fibrosis. As such, it is essential that it
be recognized because of its premalignant potential
and managed accordingly and differently from other
white lesions. There continues to be confusion on
the use of the term leukoplakia, especially on how
to manage leukoplakia in a patient whose diagnosis
shows ‘‘hyperkeratosis with no evidence of dysplasia.’’
There also is no consensus on management or ‘‘best
practice’’ guidelines for the management and treat-
ment of dysplastic lesions, much less leukoplakias
without dysplasia.4
The objectives of this article were:
1) To review common non-leukoplakia white
lesions
2) Define leukoplakia and proliferative leukoplakia
and the prevalence of dysplasia or carcinoma in
these 2 conditions
3) Update the reader on the current concept that
dysplasia is caused by driver mutations that are
unlikely to be reversible
4) Introduce the concept of ‘‘keratosis of unknown
significance’’ (KUS) and offer a treatment algo-
rithm for the management of leukoplakia with
or without dysplasia
Not all white keratotic lesions on the oral mucosa
are leukoplakias, as noted in the WHO definition.
The oral mucosa becomes white for the
following reasons:
1) Excess production of keratin as a response to
injury (eg, friction or biting)
2) Excess production of keratin intrinsically from

Received from Department of Oral Medicine, Infection and
Immunity, Harvard School of Dental Medicine, Boston, MA.
*Associate Surgeon, Division of Oral Medicine and Dentistry,
Brigham and Women’s Hospital, Boston; Instructor.
yAssociate Surgeon, Division of Oral Medicine and Dentistry,
Brigham and Women’s Hospital, Boston; Associate Professor.
Conflict of Interest Disclosures: None of the authors
have any relevant financial relationship(s) with a commercial
interest.
Address correspondence and reprint requests to Dr Villa: Division
of Oral Medicine and Dentistry, Brigham and Women’s Hospital,
1620 Tremont Street, Suite BC-3-028, Boston, MA 02120; e-mail:
avilla@partners.org
Received October 3 2016
Accepted October 18 2016
Ó 2016 American Association of Oral and Maxillofacial Surgeons
0278-2391/16/31020-5
http://dx.doi.org/10.1016/j.joms.2016.10.012

723
724 LEUKOPLAKIA MANAGEMENT

benign keratotic diseases (eg, genodermatoses) to accurately diagnose and differentiate reactive or in-
or from dysplasia flammatory keratotic conditions from leukoplakias
because of the precancerous nature of the latter,
3) Thickening of the epithelium (acanthosis) which requires close follow-up or complete removal.

4) Damage to epithelial cells from direct and identi-
fiable contact injury
As noted earlier, these changes can occur because of
genetic dyskeratotic disease (eg, Cannon white
sponge nevus, a very rare condition), immune-
mediated disease (eg, lichen planus), bite trauma,
and oncogenic mutations (leukoplakia with dysplasia).
Table 1 lists such conditions.
Taking a careful history and clinical and histopatho-
logic examinations of all such white lesions by an oral
and maxillofacial pathologist will enable the clinician
to arrive at a final diagnosis. It is extremely important
Table 1. WHITE LESIONS OF THE ORAL CAVITY
Developmental Cannon white sponge nevus
Hereditary benign
intraepithelial dyskeratosis
Other congenital
genodermatoses (eg,
pachyonychia congenita)
Reactive or frictional Leukoedema
Contact desquamation
Frictional keratosis: MMO,
BARK
Hairy tongue
Associated with tobacco use:
nicotinic stomatitis,
smokeless tobacco keratosis
Infectious Candidiasis
Hairy leukoplakia (associated
with EBV)
Immune mediated Lichen planus
Lichenoid lesions
Benign migratory glossitis
Autoimmune Lupus erythematosus
Chronic graft-vs-host disease
Metabolic Uremic stomatitis
Palifermin-associated
hyperkeratosis
Malignant and OPMD Keratosis of unknown
significance
Dysplastic leukoplakia
SCC
Verrucous carcinoma
White Lesions in Genetic Diseases and
Genodermatoses
These are extremely uncommon and all have spe-
cific and distinctive histopathologic features. Cannon
white sponge nevus presents as diffuse bilateral white
plaques of the oral mucosa and particularly the buccal
mucosa and tongue and could involve esophageal
and genital mucosa, but not the skin.5,6 Similarly,
hereditary benign intraepithelial dyskeratosis
presents as bilateral thick white plaques of the oral
mucosa and as gelatinous plaques of the conjunctiva
without involvement of the skin.7,8 Pachyonychia
congenita also results in oral plaques but always with
the presence of thickened skin lesions, and
dyskeratosis congenita causes leukoplakias and oral
cancer at a young age.9,10
White Lesions Caused by Local Injury
Lesions in this category include leukoedema, fric-
tional keratoses, and contact injury, such as keeping
mildly caustic substances for long periods at 1 site
(eg, smokeless tobacco or chewing gum).
Leukoedema occurs in up to 90% of the population
and can occur after exposure to mildly irritating sub-
stances (eg, mouthwash, toothpaste, and tobacco or
marijuana smoke).11,12 It presents as delicate gray-
white lacy lines on the buccal mucosa or ventral
tongue that disappear with stretching of the mucosa
and histopathology shows only edema of epithelial
cells (Fig 1). These are rarely submitted for biopsy ex-
amination because they are readily recognized and no
treatment is necessary except for stopping the habit.

Abbreviations: BARK, benign alveolar ridge keratosis; EBV,

Epstein-Barr virus; MMO, morsicatio mucosae oris; OPMD,
oral potentially malignant disorders; SCC, squamous cell car-
cinoma.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
FIGURE 1. Leukoedema of the right buccal mucosa.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
VILLA AND WOO
Common frictional keratoses are morsicatio
mucosae oris (MMO) and benign alveolar ridge kera-
tosis (BARK).13,14 MMO is a usually self-induced and
manifests as white plaques and papules with poorly
demarcated ‘‘fading’’ margins. Affected sites are those
that are easily traumatized by teeth, such as the lower
lip mucosa, lateroventral tongue, and buccal mucosa
(Fig 2). Patients are usually unaware of this parafunc-
tional habit, especially if the habit is nocturnal. Con-
stant trauma to the edentulous alveolar ridge is
commonly seen on the retromolar pad and under-
neath ill-fitting dentures and manifests as BARK
(Fig 3). These 2 common traumatic factitial keratoses
constitute approximately 75% of all biopsy results of
white lesions and have distinct and readily recog-
nized histopathologic features and the diagnosis on
the pathology report should be ‘‘benign frictional
keratosis’’ or terminology to that effect.1,13,14 Such
frictional keratoses also are commonly seen in a
ringlike configuration around traumatic ulcers
(Fig 4). Biopsy examination establishes the frictional
or factitial nature of the condition and patients only
require reassurance.
Hairy (coated) tongue is included because it is a
benign retention keratosis caused by decreased exfo-
liation of keratin and the development of elongated
filiform papillae (‘‘hairs’’). The tongue dorsum pre-
sents with a white, coated, or hairy appearance
(Fig 5).15 It can become pigmented from intrinsic
bacteria or food (hence, the ‘‘black hairy tongue’’). Pa-
tients also might complain of sticky and mucinous
saliva with an associated pasty, metallic taste and
gagging (when the coating is localized in the poste-
rior third of the tongue). The most common cause
of this condition is dehydration and hyposalivation.
This is seen in patients who have had recent illness
(often associated with antibiotic therapy), use of
FIGURE 2. Morsicatio mucosae oris of the right buccal mucosa.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
725
FIGURE 3. Benign alveolar ridge keratosis of the right mandibular
ridge.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
alcohol-containing rinses, and smoking. Conditions
that cause dry mouth, such as polypharmacy, chronic
anxiety, radiotherapy, and Sj€ ogren syndrome, also
result in hairy tongue. This condition also is seen in
patients with poor diet with consumption of mainly
soft foods (common in hospitalized patients). Hairy
tongue can be misdiagnosed for candidiasis, although
treatment with antifungal medications is not usually
successful. An oral candida culture is not helpful
because 20 to 30% of patients are carriers for
Candida albicans.16 Management strategies include
hydration, improving the diet, discontinuation of de-
hydrating mouthwashes (eg, alcohol-containing
rinses), smoking cessation, or gentle brushing of
the tongue 2 to 3 times a day. Anecdotal evidence
suggests that eating a food such as pineapple, which
is not only acidic but also contains the enzyme
bromelain, also helps this condition.
Smokeless tobacco can be inhaled, chewed, or
smoked. In South Asia, it is often mixed with areca
FIGURE 4. Traumatic ulcer with a ringlike frictional keratosis of the
left border of the tongue.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
726
FIGURE 5. Hairy tongue.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
nut, betel leaf, slaked lime, and spices (paan or gutka)
and these preparations are strongly associated with
submucous fibrosis,17 a fibrotic precancerous condi-
tion that appears marble white and leathery but is
not keratotic. American moist or dry snuff has a higher
level of tobacco-associated nitrosamines than Swedish
snuff.18 Ethiopian toombak has the highest concentra-
tion of nitrosamines.19,20 Qat (or khat; it contains
cathinone, an alkaloid chemical with psychoactive
effects) chewing is a common habit in Southern
Arabia and Eastern Africa and has been associated
with leukoplakia with a low risk of malignant
transformation.21,22 Smokeless tobacco keratoses or
lesions are caused by contact with caustic agents
within the tobacco. Lesions are usually grayish or
whitish with poorly defined margins with fissures
and wrinkles where the tobacco is placed. Early
lesions are usually reversible and resolve with
discontinuation of the habit (Fig 6). Leukoplakia can
develop over time and these generally have well-
FIGURE 6. Smokeless tobacco keratosis of the left vestibule and
buccal mucosa.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
LEUKOPLAKIA MANAGEMENT
defined margins and should be submitted for biopsy
examination to rule out dysplasia.23,24
White Lesions Caused by Infections
Oral candidiasis is the most common opportunistic
fungal infection; it is usually caused by C albicans, a
commensal present in 20 to 30% of patients.16 Oral
lesions occur when the normal flora is altered (as
in patients with hyposalivation, who wear dentures,
who smoke, or who are on immunosuppressive
agents). Additional contributing factors include ane-
mia, diabetes mellitus, endocrine dysfunction, immu-
nosuppression (eg, acquired immunodeficiency
syndrome or human immunodeficiency virus
[HIV]), antibiotic use, infancy, and advanced age.
Candidiasis also can develop overlying dysplastic le-
sions.25 Pseudomembranous candidiasis is the most
common form and is characterized by thick white
plaques and papules that can be rubbed off, often
leaving a raw, bleeding surface (Fig 7). Other forms
include erythematous and hyperplastic candidiasis.
The latter is a rare chronic variant that manifests as
white plaques that cannot be rubbed off, mimicking
leukoplakia.
Treatment consists of topical and systemic anti-
fungal agents. The most commonly used topical med-
ications include nystatin suspension (100,000 U/mL)
swished in the mouth 4 to 5 times a day and clotrima-
zole troches (10 mg) dissolved in the mouth 4 to 5
times a day for 7 to 10 days. Systemic therapy with flu-
conazole 100 to 200 mg/day for 7 days is very effective
because of its ease of use, although it interacts with
many commonly used medications, such as warfarin,
codeine, midazolam, phenytoin, and statins. Dentures
should be soaked in 3% sodium hypochlorite diluted in
water (1:10) or chlorhexidine di-gluconate 0.12% over-
night and not worn overnight.26
FIGURE 7. Pseudomembranous candidiasis of the hard palate.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
VILLA AND WOO
Oral hairy leukoplakia (OHL) is a condition associ-
ated with Epstein-Barr virus that is seen mostly in
immunocompromised patients, in particular those
with HIV and a low CD4+ T-cell count and those after
undergoing organ transplantation, although it also
can be seen in healthy older individuals likely from im-
munosenescence.27,28 In this condition, the term
leukoplakia is not related to malignancy or to
dysplastic changes. OHL usually presents with
asymptomatic white plaques with vertical lines on
the lateral border of the tongue often secondarily
infected with Candida species or bacterial
colonization.29 The virus enters the epithelium from
the lymphocytes of the peripheral blood and prolifer-
ates within the epithelial cells.30 A diagnosis of OHL
mandates ruling out immunosuppression. Lesions
might resolve with initiation of antiretroviral therapy
or the decrease of immunosuppressants in patients af-
ter organ transplantation. Use of valacyclovir has been
shown to decrease the recurrence of disease in 67% of
affected individuals.31 Some patients respond well to a
combination of 5% acyclovir or 1% penciclovir cream
or ointment and 25% podophyllin resin.32
Immune-Mediated Keratotic Lesions
Oral lichen planus (OLP) is an immuno-mediated
chronic condition present in 1 to 2% of the population,
usually middle-age women.33 Of note, 10 to 15% of pa-
tients with OLP have cutaneous lesions. OLP can be
idiopathic or secondary to local or systemic conditions
and in particular to ingestion of medications such as
antihypertensive and hypoglycemic agents.
Oral lesions are typically symmetric and bilateral
and there is controversy regarding the clinical types.
Although 6 distinct forms, namely reticular (classic
and most common), atrophic, erosive, papular, pla-
que, and bullous, have been described, this is not uni-
versally accepted.34 The 3 most recognizable forms are
reticular, erosive or erythematous, and ulcerative.34
Bullous (rarely seen), atrophic, and erosive forms are
likely better considered 1 clinical entity because they
present 1 spectrum of disease and the most common
appearance is an erythematous or erosive lesion
because of ruptured bullae or thin, atrophic red-
appearing mucosa. The reticular form is characterized
by classic white (keratotic) reticular lesions (Wickham
striae; Fig 8). The plaque type of lichen planus when
occurring as a single lesion is not readily distinguish-
able from a leukoplakia. Lupus erythematous and
chronic graft-versus-host disease are 2 conditions
that can clinically resemble OLP.35 Biopsy and histo-
pathologic examinations are usually indicated when
the presentation is not typical (eg, lack of reticulations
or unilateral presentation). Treatment includes topical
corticosteroids (eg, 0.05% fluocinonide or clobetasol
727
FIGURE 8. Oral lichen planus with classic reticular white lesions of
the right buccal mucosa.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
gel) and 0.1% tacrolimus ointment; for refractory
cases, treatment includes systemic corticosteroids
and other immunosuppressive agents (in particular,
hydroxychloroquine). Malignant transformation can
occur in 1.1% (range, 0.0 to 3.5%) of cases, although
some of these cases could represent malignant trans-
formation of erythroleukoplakia rather than of OLP, if
lesions are unilateral and red and white.36
Leukoplakia
Leukoplakia is a potentially malignant lesion defined
as a ‘‘white plaque of questionable risk having
excluded (other) known diseases or disorders that
carry no increased risk for cancer’’ (eg, frictional kera-
toses).3 Leukoplakia is a clinical term only; its defini-
tion is usually modified after a histopathologic
evaluation. For example, a clinical impression of leu-
koplakia at biopsy examination might show candidi-
asis, bite keratosis, or lichen planus.
CLINICAL FINDINGS
Clinically, leukoplakias are divided into homoge-
nous and nonhomogeneous lesions.37,38 The
homogeneous type is usually a thin, flat, and uniform
white plaque with at least 1 area that is well
demarcated with or without fissuring (Fig 9). Nonho-
mogeneous leukoplakia is characterized by the pres-
ence of speckled or erythroplakic and nodular or
verrucous areas.39 Erythroleukoplakia can be misdiag-
nosed as OLP because of its white and red compo-
nents. However, other clinical signs can guide the
clinician to the correct diagnosis: erythroleukoplakia
does not possess the typical white reticular changes
and it is usually unilateral with associated well-
demarcated white plaques (Fig 10). Areas of firmness
728 LEUKOPLAKIA MANAGEMENT

FIGURE 9. Leukoplakia of the left ventral tongue.

Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017. FIGURE 11. Proliferative verrucous leukoplakia of the left buccal
mucosa.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
or induration always should be submitted for biopsy 2017.
examination.
Proliferative verrucous leukoplakia (PVL) is consid-
sented in Table 2. Because of these differences, it
ered a form of nonhomogeneous leukoplakia by the
might be more useful to consider PVL a separate entity
WHO. It is more common in women, with fewer
rather than a form of nonhomogeneous leukoplakia.
than 45% of cases being associated with a tobacco
habit. PVL is usually multifocal or affects contiguous
areas and is characterized by relentless progression EPIDEMIOLOGY
and spread, with the gingiva being the most frequently Most data on the prevalence and incidence of leuko-
affected site.40-42 Most cases of PVL are plakia are based on old retrospective and hospital-
nonhomogeneous with a verrucous or nodular or based studies. The definition of leukoplakia differs
erythroleukoplakia-like appearance (Fig 11).43 Similar across the studies, making it difficult to compare the
to erythroleukoplakia, the erythroleukoplakia form of
PVL can be misdiagnosed as lichen planus because it is
multifocal and bilateral. Multiple biopsy examinations Table 2. MAIN DIFFERENCES BETWEEN LOCALIZED
show no evidence of cytologic dysplasia but often LEUKOPLAKIA AND PROLIFERATIVE LEUKOPLAKIA
exhibit verrucous hyperplasia, hyperkeratosis, or para-
Localized Leukoplakia Proliferative Leukoplakia
keratosis with epithelial atrophy or KUS. There are
many differences between localized leukoplakias (by
Mostly in men Mostly in women
far the more common) and PVL and these are pre- Strong association with Weak association with
cigarette smoking smoking
Single site, usually ventral Multifocal
tongue, floor of mouth
40% are dysplasia or SCC <10% show dysplasia or
at time of first biopsy SCC at time of first
examination biopsy examination,
mostly atypical
verrucous hyperplasia
or KUS
Malignant transformation Malignant transformation
3-15% overall 70-100% overall
Malignant transformation Malignant transformation
1-3% per year 10% per year
Easy to ablate or excise Difficult to treat because
because localized multifocal

Abbreviations: KUS, keratosis of unknown significance; SCC,

FIGURE 10. Erythroleukoplakia of the left ventral tongue. squamous cell carcinoma.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017. 2017.
VILLA AND WOO
true prevalence and incidence. Some older studies
used the 1978 WHO definition for leukoplakia, which
did not exclude frictional keratoses.44 The pooled
prevalence estimated for oral leukoplakia was 1.49%
(95% confidence interval [CI], 1.42-1.56) to 2.60%
(95% CI, 1.72-2.74).45 In 1967, Pindborg et al46 con-
ducted a large prospective study (N = 10,000) in India
and found that 3.28% of patients (n = 328) had leuko-
plakia. Similarly, Mehta et al47 in 1969 reported a prev-
alence of leukoplakia from 0.2 to 4.9% in 50,915 adult
villagers. This higher incidence could be related to the
widespread use of areca nut in India leading to devel-
opment of leukoplakia. In 1986, Bouquot2 found that
leukoplakia was present in 2.9% of 23,616 white adults
in the United States. The male-to-female ratio depends
on the geographic distribution of the disease. In gen-
eral, leukoplakia is more frequent in older individuals.
In developing countries, leukoplakia is diagnosed be-
tween the third and fifth decades of life; in developed
countries, it is more common after 40 years of age.49
DIAGNOSIS
The diagnosis of true leukoplakia is based on a com-
bination of the patient history, clinical considerations,
and histopathology and is typically a diagnosis of
exclusion.38 Leukoplakia usually has, at least in part,
sharply demarcated margins, often with fissuring,
and it is generally distinguishable from reactive kerato-
ses, which are usually poorly demarcated lesions. Er-
ythroleukoplakia tends to be less well-demarcated.
Biopsy and histopathologic examinations remain the
gold standard for diagnosis and are important in help-
ing to exclude other keratotic lesions, as discussed
earlier.48 Management depends on the histopathologic
diagnosis and clinical presentation (see Manage-
ment section).
HISTOPATHOLOGY
A biopsy examination of oral leukoplakia can show
1) hyperkeratosis or parakeratosis with dysplasia, car-
cinoma in situ, or invasive carcinoma or 2) ‘‘benign hy-
perkeratosis’’ without dysplasia but with acanthosis,
atrophy, or inflammation (ie, KUS).1 Frictional kerato-
ses should never be included in the category of leuko-
plakia once the diagnosis is established by biopsy
examination. Oral epithelial dysplasia, carcinoma in
situ, or invasive squamous cell carcinoma (SCC) was
noted in 9 to 27% of cases of leukoplakia in studies
before 1990,50-52 whereas more recent studies have
reported 39 to 53%.1,50-57 Therefore, the corollary is
that 47 to 61% of cases exhibit hyperkeratosis or
parakeratosis without dysplasia or carcinoma and
represent KUS.
In a study by Silverman et al50 in 1984 in the United
States, 15.7% of patients (37 of 235) with a diagnosis of
729
‘‘benign hyperkeratosis’’ developed SCC; in a study
from the Netherlands in 1998, the malignant transfor-
mation of nondysplastic leukoplakias (‘‘benign hyper-
keratosis’’) occurred in 30% of patients (6/20).53 In
2006, a Taiwanese study on the malignant transforma-
tion rate observed was lower at 3.6%.54 In a recent
study by Woo et al,55 57.1% of cases of leukoplakia
were diagnosed as ‘‘benign hyperkeratosis’’ or KUS
when all frictional keratoses were excluded, with a
range of 24.3 to 61.1% in other studies (although a
different term was used).1,53-56,58 In other words,
many studies have reported on keratotic lesions that
were clinically leukoplakias, that leukoplakias clearly
not frictional in nature occur fairly often, and that
leukoplakias can transform to dysplasia and cancer
and therefore could represent genomic alterations
that might be irreversible.
When dysplasia or carcinoma in situ is considered,
the malignant transformation rate is 5 to 36%, with
higher rates in individuals who are betel leaf
chewers.50,57,59-62
In general, nonhomogeneous leukoplakias are asso-
ciated with a higher risk of development of dysplasia
or oral cancer (20 to 25%) compared with homoge-
neous cases (0.6 to 5%).49,63,64 PVL is the most
aggressive form among leukoplakias, with a
malignant transformation rate of 70 to 100% when
followed long term.41,42,65-68 The anatomic sites at
higher risk for cancer development and with a
stronger association with dysplasia are the floor of
the mouth, ventral tongue, and soft palate
(nonkeratinized areas).69,70 Large size (lesions
>200 mm2 had 5.4 times increased risk),71 female
gender (15.2 vs 1.7% in men; P < .001),70 long dura-
tion, and nonhomogeneous type (14.5 vs 3% in homo-
geneous type; P < .001)70 increase the risk of
malignant transformation.54,69,71,72 This is in keeping
with cases of PVL that occupy a large surface area
with multifocality and that show malignant
transformation in more than 70 to 100% of cases.
Biopsy examination of multiple sites of a large lesion
is essential because varying grades of dysplasia or
even invasive SCC can be present in 1 lesion, and
these can be missed in 10 to 17% of cases if only a
single biopsy specimen is taken.73,74 This further
supports the contention that hyperkeratosis or
parakeratosis without dysplasia is the first change in
this process of multistep carcinogenesis.
MOLECULAR FINDINGS
The malignant transformation of oral leukoplakia is
driven by multiple genetic or epigenetic alterations.
Oral leukoplakia can share some of the same driver-
gene mutations observed in cancer and carry similar
chromosomal instability, such as DNA aneuploidy,
730
FIGURE 12. Diagnosis and management of leukoplakia. KUS, keratosis of unknown significance; PVL, proliferative verrucous leukoplakia;
SCC, squamous cell carcinoma.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg 2017.
loss of heterozygosity, and telomerase dysfunction,
which have been linked with tumor initiation and ma-
lignant transformation.75-77 DNA hypermethylation at
specific loci (eg, CDH1, CDKN2A, and MGMT) also
has been detected in oral dysplastic lesions and
cancers, in addition to altered expression of miRNAs
(eg, miR-345, miR-21, and miR-18b), which are associ-
ated with the initiation and progression of oral precan-
cerous lesions.78-80 Specifically, aberrant expression of
p53, p16INK4a,81-83 and mutations of genes on 3p, 9p,
and 17 (especially TP53) can be associated with
increased cancer risk.84
Current evidence suggests that the development of
preinvasive dysplastic to invasive cancer, based on
models established at other sites (eg, cervical cancer
LEUKOPLAKIA MANAGEMENT
and melanoma), involves the stepwise accumulation
of genetic alterations until the development of inva-
sion.85 The 3 steps that lead to cancer include a break-
through phase, an expansion phase, and an invasive
phase.85 During the breakthrough phase, a cell de-
velops a driver-gene mutation and begins to divide
abnormally. Lesional tissue (presumably such as leuko-
plakia) becomes clinically visible after several years. In
the expansion phase, an additional driver-gene muta-
tion occurs to give rise to the cancerous growth. Dur-
ing the invasive phase, the tumor invades the
surrounding tissues.
Oral dysplasias should conceptually be considered
neoplasms located within the epithelium, similar to
cervical dysplasia, which is termed cervical
VILLA AND WOO
intraepithelial neoplasm. To this end, the term oral
intraepithelial neoplasia has been suggested for oral
dysplasias.86,87 Dysplasia is indeed associated with a
high rate of malignant transformation and this new
nomenclature could help prompt clinicians to
manage such patients differently.
CANCER RISK
The risk of malignant transformation for oral leuko-
plakia depends on risk factors and histopathologic and
clinical characteristics.
In general, the risk factors for developing oral leuko-
plakia are similar to those reported for oral cancer and
include tobacco smoking (especially for localized leuko-
plakias), heavy alcohol consumption, areca nut use, ul-
traviolet light exposure for lip lesions, and old age.
However, other factors, such as prolonged immunosup-
pression, a history of cancer, and a family history of can-
cer, are just as important but less well recognized.
Although human papillomavirus (HPV) has been noted
in 25% of oral epithelial dysplasias by polymerase chain
reaction, this is an oversensitive test and this prevalence
is likely an overestimation or could represent HPV unas-
sociated with carcinogenesis.88 HPV-associated oral
dysplasia is a specific and uncommon histopathologic
form of oral epithelial dysplasia that presents as leuko-
plakia and is associated with high-risk HPV in 100% of
cases using more specific in situ hybridization studies
and malignant transformation occurs in 10% of cases.86
ADJUNCTIVE SCREENING AIDS
Adjunctive screening aids include 1) vital staining
with toluidine blue, 2) brush biopsy examination, 3)
devices based on autofluorescence, 4) devices based
on chemiluminescence, and 5) biomarker assessment
(from saliva, serum, or exfoliated cells).89,90 Although
the visualization adjuncts are portable tools for
clinicians and easy to use, their utility remains
controversial primarily because of high sensitivity
but low specificity.91,92 In other words, most
adjunctive tests tend to show false positive results
and this is likely because reactive and inflammatory
lesions can show similar changes as dysplasia. Even
with a biopsy examination, the current gold
standard, reactive epithelial atypia might be difficult
to distinguish from early mild dysplasia.
Management
White lesions with a histopathologic diagnosis of
dysplasia or carcinoma in situ should be excised with
clear margins, especially for cases of moderate or severe
epithelial dysplasia93 (Fig 12). Of note, some cases of
dysplasia (particularly mild dysplasia) have been re-
ported to regress over time. However, it has been shown
that several cases of mild dysplasia in reality could repre-
731
FIGURE 13. Actinic keratosis of the lower lip.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
sent reactive epithelial atypia from trauma and therefore
regression and recurrence would be expected.37
Reported recurrence after surgical treatment ranges
from 0 to 35%.50,61,71,94,95 Such recurrent lesions
should be excised with 2- to 3-mm margins. Even
without recurrence, patients should be monitored
every 3 to 6 months for the lifetime of the patient.
Other proposed treatments are topical medical
agents, systemic medical treatment, removal of risk
factors, combined treatment, or the ‘‘watchful wait-
ing’’ approach.37,96,97 A recent systematic review on
the use of carbon dioxide laser for management of
leukoplakia showed that the laser technique was
reliable and reproducible with low morbidity.
However, rates of recurrence and malignant
transformation rates varied from 0 to 15%.98 Vohra
et al99 systematically reviewed studies on photody-
namic therapy (PDT) for management of leukoplakia,
erythroplakia, and their variants. When leukoplakia
was considered, results showed complete, partial, or
no response to PDT in 27 to 90%, 5 to 48%, and 4 to
25% of oral lesions, respectively. The recurrence rate
ranged from 10 to 25%. Actinic keratosis (sun-induced
dysplasia) of the lip vermilion can be treated success-
fully with topical 5-fluorouracil (5-FU) twice a day for
2 to 4 weeks (2 vs 5% cream) or with topical imiqui-
mod 5% cream 2 to 3 times per week for up to
4 months100,101 (Fig 13). Results are more consistent
with 5-FU. Medical treatments with b-carotene, bleo-
mycin, vitamin A, tea, and ketorolac have had no effect
on malignant transformation rates, and there are no
randomized control trials using surgery as the main
modality of treatment to assess this outcome.102 Older
frail patients could be placed on long-term follow-up,
whereas it might be more appropriate to remove le-
sions in younger patients.
Patients with leukoplakias and a histopathologic
diagnosis of SCC should be referred to the head and
neck oncology team for further evaluation and
732
FIGURE 14. Keratosis of unknown significance of the left tongue.
Villa and Woo. Leukoplakia Management. J Oral Maxillofac Surg
2017.
management. Treatment (surgery, radiation, or chemo-
therapy) is dependent on the stage.103,104
White lesions with a histopathologic diagnosis of ‘ hy-
perkeratosis with no dysplasia’’ or KUS should be reas-
sessed clinically to rule out a frictional keratosis and to
evaluate for the feasibility of complete removal (Fig
14). Focal lesions with poorly demarcated margins are
likely frictional and might require a yearly follow-up
with a biopsy examination only if progressive, if nodular
or verrucous or red areas develop, or if there is evidence
of induration. However, if there is no clinical evidence of
obvious pathogenesis and the lesion has sharply demar-
cated margins, this should be followed carefully, period-
ically reinvestigated by biopsy examination, or excised
or ablated depending on the clinical context. Lesions
larger than 200 mm2 should be re-evaluated every
3 months and re-evaluated by biopsy examination every
6 to 12 months; patients with lesions smaller than
200 mm2 should be followed up every 3 months with pe-
riodic biopsy examinations depending on the circum-
stances.48 This study reiterates the early finding that
large leukoplakias with a histopathologic diagnosis of
‘ benign keratosis’’ might represent very early dysplasias.
Even if not dysplastic, clinicians can consider conserva-
tive or narrow excision (especially if the etiology is un-
clear or in younger patients). Multifocal white lesions
with a diagnosis of ‘ hyperkeratosis with no dysplasia’’
should be followed every 3 months, with excision of ver-
rucous or nodular areas.
Conclusions and Future Directions
1) Oral white lesions are common, but true leukopla-
kia has substantial potential to develop into cancer.
2) Clinical features of leukoplakia, including partial
demarcation, fissuring, and large size, and demo-
LEUKOPLAKIA MANAGEMENT
graphic information and social history guide the
clinician in recognizing high-risk lesions; this is
particularly true for PVL.
3) Histopathologic examination is vitally important
for the management of leukoplakia. Dysplastic
lesions or carcinoma in situ should be excised
with clear margins.
4) Leukoplakias with a histopathologic diagnosis of
‘‘benign keratosis’’ could represent very early
dysplasias and should be treated as a potentially
malignant disorder.
5) Prospective, multicenter studies and genome-
wide sequencing are necessary to better under-
stand the natural history of oral cancer and to
identify potential biomarkers for early detection.
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