Leukoplakia-A Diagnostic and Management Algorithmjorigids.com/co_editor/upload/1506486637PIIS0278239116310205.pdf · plaques of the oral mucosa and particularly the buccal mucosa

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Leukoplakia—A Diagnostic andManagement 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 clinicalpresentation 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.

� 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 evidentfrom 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 itbe 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

ed from Department of Oral Medicine, Infection and

ity, Harvard School of Dental Medicine, Boston, MA.

ociate Surgeon, Division of Oral Medicine and Dentistry,

m and Women’s Hospital, Boston; Instructor.

sociate Surgeon, Division of Oral Medicine and Dentistry,

m and Women’s Hospital, Boston; Associate Professor.

flict of Interest Disclosures: None of the authors

ny relevant financial relationship(s) with a commercial

t.

723

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 thefollowing reasons:

1) Excess production of keratin as a response to

injury (eg, friction or biting)

2) Excess production of keratin intrinsically from

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:

[email protected]

Received October 3 2016

Accepted October 18 2016

� 2016 American Association of Oral and Maxillofacial Surgeons

0278-2391/16/31020-5

http://dx.doi.org/10.1016/j.joms.2016.10.012

Delta:1_given name

Delta:1_surname

mailto:[email protected]

http://dx.doi.org/10.1016/j.joms.2016.10.012

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724 LEUKOPLAKIA MANAGEMENT

benign keratotic diseases (eg, genodermatoses)

or from dysplasia

3) Thickening of the epithelium (acanthosis)

4) Damage to epithelial cells from direct and identi-

fiable contact injury

As noted earlier, these changes can occur because ofgenetic 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 clinicianto 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

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.

to accurately diagnose and differentiate reactive or in-

flammatory keratotic conditions from leukoplakias

because of the precancerous nature of the latter,

which requires close follow-up or complete removal.

White Lesions in Genetic Diseases andGenodermatoses

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 conjunctivawithout 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 epithelialcells (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.

FIGURE 1. Leukoedema of the right buccal mucosa.


2017.

FIGURE 3. Benign alveolar ridge keratosis of the right mandibularridge.


2017.

VILLA AND WOO 725

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 onthe 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 abenign 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 andgagging (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.


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 usuallysuccessful. 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, whichis 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 theleft border of the tongue.


2017.

FIGURE 5. Hairy tongue.


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 orwhitish 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 andbuccal mucosa.


2017.

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 immunosuppressiveagents). 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 whiteplaques 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. Denturesshould 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.


2017.

FIGURE8. Oral lichen planus with classic reticular white lesions ofthe right buccal mucosa.


2017.

VILLA AND WOO 727

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 todysplastic 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. Lesionsmight 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 (classicand most common), atrophic, erosive, papular, pla-

que, and bullous, have been described, this is not uni-

versally accepted.34 The 3most 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 lesionbecause 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

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 definedas 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

FIGURE 9. Leukoplakia of the left ventral tongue.


2017. FIGURE 11. Proliferative verrucous leukoplakia of the left buccalmucosa.


2017.

Table 2. MAIN DIFFERENCES BETWEEN LOCALIZEDLEUKOPLAKIA AND PROLIFERATIVE LEUKOPLAKIA

Localized Leukoplakia Proliferative Leukoplakia

Mostly in men Mostly in women

Strong association with Weak association with


or induration always should be submitted for biopsy

examination.

Proliferative verrucous leukoplakia (PVL) is consid-ered a form of nonhomogeneous leukoplakia by the

WHO. It is more common in women, with fewer

than 45% of cases being associated with a tobacco

habit. PVL is usually multifocal or affects contiguous

areas and is characterized by relentless progression

and spread, with the gingiva being the most frequently

affected site.40-42 Most cases of PVL are

nonhomogeneous with a verrucous or nodular orerythroleukoplakia-like appearance (Fig 11).43 Similar

to erythroleukoplakia, the erythroleukoplakia form of

PVL can be misdiagnosed as lichen planus because it is

multifocal and bilateral. Multiple biopsy examinations

show no evidence of cytologic dysplasia but often

exhibit verrucous hyperplasia, hyperkeratosis, or para-

keratosis with epithelial atrophy or KUS. There are

many differences between localized leukoplakias (byfar the more common) and PVL and these are pre-

FIGURE 10. Erythroleukoplakia of the left ventral tongue.


2017.

sented in Table 2. Because of these differences, it

might be more useful to consider PVL a separate entityrather than a form of nonhomogeneous leukoplakia.

EPIDEMIOLOGY

Most data on the prevalence and incidence of leuko-

plakia are based on old retrospective and hospital-

based studies. The definition of leukoplakia differs

across the studies, making it difficult to compare the

cigarette smoking smoking

Single site, usually ventral

tongue, floor of mouth

Multifocal

�40% are dysplasia or SCC

at time of first biopsy

examination

<10% show dysplasia or

SCC at time of first

biopsy examination,

mostly atypical

verrucous hyperplasia

or KUS

Malignant transformation

3-15% overall


70-100% overall


1-3% per year


10% per year

Easy to ablate or excise

because localized

Difficult to treat because

multifocal

Abbreviations: KUS, keratosis of unknown significance; SCC,squamous cell carcinoma.


2017.

VILLA AND WOO 729

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

leukoplakiawas present in 2.9% of 23,616white 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 isthat 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

‘‘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 KUSwhen 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 alterationsthat 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 isdriven 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,

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

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

FIGURE 13. Actinic keratosis of the lower lip.


2017.

VILLA AND WOO 731

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 prevalenceis likely an overestimation or could represent HPVunas-

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 Althoughthe 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 goldstandard, 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 ofmoderate or severeepithelial 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 ofmild dysplasia in reality could repre-

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

FIGURE 14. Keratosis of unknown significance of the left tongue.


2017.


management. Treatment (surgery, radiation, or chemo-

therapy) is dependent on the stage.103,104

White lesionswith 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 arelikely 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 noclinical evidenceof

obvious pathogenesis and the lesion has sharply demar-

catedmargins, this should be followed carefully, period-

ically reinvestigated by biopsy examination, or excised

or ablated depending on the clinical context. Lesionslarger than 200 mm2 should be re-evaluated every

3months and re-evaluated by biopsy examination every

6 to 12 months; patients with lesions smaller than

200mm2shouldbe followedupevery3monthswithpe-

riodic biopsy examinations depending on the circum-

stances.48 This study reiterates the early finding that

large leukoplakias with a histopathologic diagnosis of

‘‘benignkeratosis’’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’’

shouldbe followedevery3months,withexcisionof 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-

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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Gelband H, Jha P, Sankaranarayanan R, et al (eds): Cancer: Dis-ease Control Priorities Volume 3.Washington, DC. Available at:https://www.ncbi.nlm.nih.gov/books/NBK343649/. AccessedDecember 13, 2016























































































































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Leukoplakia-A Diagnostic and Management Algorithmjorigids.com/co_editor/upload/1506486637PIIS0278239116310205.pdf · plaques of the oral mucosa and particularly the buccal mucosa