Vol. 126 No.
4 October 2018
AAOM clinical practice statement subject: leukoplakia
Ivan J. Stojanov, DMD,a,b and Sook-Bin Woo, DMD MMScc,d
PURPOSE
The American Academy of Oral Medicine (AAOM)
affirms that oral leukoplakia is a condition with malig-
nant potential and is the most common precursor to oral
squamous cell carcinoma (SCCa). Its identification re-
quires a thorough history and clinical examination, and
warrants clinicopathologic correlation. Definitive diag-
nosis and appropriate management of patients with
leukoplakia is necessary in an attempt to reduce the in-
cidence and mortality rates of SCCa.
METHODS
This statement is based on a review of the current
literature related to leukoplakia. A PubMed search
was conducted using the terms ‘leukoplakia,’
‘erythroleukoplakia’ and ‘proliferative verrucous leuko-
plakia.’ Expert opinions and best current practices were
relied upon when direct evidence was not available.
BACKGROUND
Leukoplakia of the oral cavity is a specific disease entity
notable for being the most common precursor lesion to
The authors have received no financial support in the preparation of
this statement and have no conflicts of interest to declare.
The American Academy of Oral Medicine (AAOM) affirms that oral leu-
koplakia is a condition with malignant potential and is the most common
precursor to oral squamous cell carcinoma (SCCa). Leukoplakia may
present as a homogeneous white plaque, often with sharply demarcated
borders, or with variably fissured, verrucous/nodular, or erythematous com-
ponents. Biopsy may show epithelial dysplasia or hyperkeratosis in the
absence of dysplasia, particularly in homogeneously thin leukoplakia. Clini-
copathologic correlation is critical for diagnosis and management.
Management includes observation with surveillance biopsies, removal,
patient education and lifetime follow-up.
This Clinical Practice Statement was developed as an educational tool
based on expert consensus of the AAOM leadership. Readers are en-
couraged to consider the recommendations in the context of their specific
clinical situation and consult, when appropriate, other sources of clin-
ical, scientific, or regulatory information prior to making a treatment
decision.
a
Department of Oral and Maxillofacial Medicine and Diagnostic
Sciences, Case Western Reserve University School of Dental Medicine,
Cleveland, OH 44106.
b
Department of Pathology, Case Western Reserve University School
of Medicine, Cleveland, OH 44106.
c
Department of Oral Medicine, Infection, and Immunity, Harvard School
of Dental Medicine, Boston, MA 02115.
d
Division of Oral Medicine and Dentistry, Brigham and Women’s
Hospital, Boston, MA 02115.
Received for publication Feb 8, 2018; returned for revision May 11,
2018; accepted for publication Jun 12, 2018.
2212-4403/$ - see front matter
https://doi.org/10.1016/j.oooo.2018.06.006
squamous cell carcinoma (SCCa). Leukoplakia is con-
sidered a clinical term denoting a white or sometimes
red/white plaque; it cannot be classified clinically or his-
topathologically as another known white lesion and
excludes frictional keratoses (also white). Its annual ma-
lignant transformation rate has been estimated to be
between 1-3%.1,2 Reported overall malignant transfor-
mation rates have varied tremendously from 0.36%-
34.0%, with a trend towards higher rates amongst studies
with longer periods of follow-up.3 The true natural history
of leukoplakia is difficult to ascertain due to the impact
of surgical intervention on disease course.
Leukoplakia is associated with smoking tobacco
and alcohol use and is characteristically a disease of
older males (approximately 3:1 M:F ratio). Human
papillomavirus is associated with only a very small per-
centage of cases.4 Leukoplakia may present on any oral
mucosal surface and is associated with the highest in-
cidence of malignant transformation when occurring on
nonkeratinized sites including the ventral tongue, floor
of mouth, and soft palate.
Leukoplakia has a spectrum of appearance, and can
be most confidently recognized clinically when present-
ing as a solitary white plaque with sharply-demarcated
borders.5 Leukoplakia may be homogeneous, verrucous/
nodular, or partially erythematous (erythroleukoplakia/
speckled leukoplakia). Some studies have shown an
association between the duration of a leukoplakia, the
presence of these verrucous/nodular and erythematous
features, the size and increased rates of malignant
transformation.3,6-10
Proliferative (verrucous) leukoplakia, a much less
common presentation of leukoplakia, presents as mul-
tifocal or extensive solitary involvement of the oral
mucosa by white plaques that may have any of the
aforementioned clinical features. Its presentation is
often but not invariably verrucous. This disease has a
predilection for females and nontobacco users and
most frequently involves the gingiva/alveolar mucosa
and buccal mucosa. Its annual malignant transforma-
tion rate is estimated at 6-16% and overall malignant
transformation rate is at least 64%.11,12 This condition
is demographically, clinically and prognostically differ-
ent from solitary leukoplakia, although an unanswered
question remains whether the higher malignant trans-
formation rates simply reflect increased leukoplakia
surface area involvement.
The histopathologic assessment of leukoplakia has
been an area of controversy for some time and has
hindered further understanding of this disease. The
331

332 Stojanov and Woo
challenges have included development of a universally
acceptable grading scheme (whether three-tiered with
mild, moderate and severe or two-tiered with low-
grade and high-grade) that has high interobserver
reliability, reproducibility, and strong correlation with
prognosis. Furthermore, the diagnosis of hyperkera-
totic lesions that show no dysplastic phenotype has yet
to be fully addressed. Approximately 26-40% of
leukoplakias show dysplasia while the remainder show
hyperkeratosis alone, previously referred to as ‘kerato-
sis of unknown significance.’13,14 The concept that
hyperkeratosis may precede histopathologically identi-
fiable epithelial dysplasia, and ultimately invasive SCCa,
in the evolution of leukoplakia is a critical one to grasp,
both for clinicians and pathologists. The importance of
this subset of leukoplakias is substantiated by older
studies reporting malignant transformation occurring
in 3.6-30% of ‘benign hyperkeratosis’ and the fact that
this histopathologic appearance is seen in early biop-
sies of proliferative (verrucous) leukoplakia, with dysplasia
and invasive carcinoma developing on follow-up.1,6,15,16
Mutational profiling of this and other dysplasias is
needed to evaluate whether this particular pattern of
hyperkeratosis indeed represents the earliest dysplasia
phenotype.
Considering that leukoplakias may exhibit hyperkera-
tosis with no dysplasia and that hyperkeratosis alone is
also seen in other conditions with no malignant poten-
tial (frictional keratoses such as morsicatio mucosae
oris and benign alveolar ridge keratosis17,18), communi-
cation between the clinician and pathologist is essential
in identifying and managing leukoplakia at its earliest
stage of presentation. Sending a clinical photograph of
any keratotic lesion to the pathologist can only improve
the probability of optimal patient management. Some
keratotic lesions may nevertheless remain difficult to
classify as leukoplakias or benign mimickers (‘kerato-
sis of unknown significance’) and should be followed
carefully.
Much has been published on the predictive value of
dysplasia in the malignant transformation of leukopla-
kia, with some studies showing an association with
increasing grades of dysplasia but others not.1,9,19 Such
discordance is not entirely unexpected considering current
paradigms in carcinogenesis, in particular the fact that
genetically unstable lesions (malignancies and
premalignancies) may not necessarily acquire genomic
alterations in a predictable timeframe.20 And, of course,
accurate grading of dysplasia is contingent on adequate
sampling.21 With this in mind, the presence of dyspla-
sia may be viewed as just as important if not more so
than the particular grade. Indeed, cumulative experi-
ence shows that carcinoma arises from all grades of
dysplasia.8,22 Molecular markers such as loss of hetero-
zygosity on 4q, 9p and 17p may possibly refine
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October 2018
stratification of dysplasia into higher and lower risk of
malignant transformation in the future.23,24
Leukoplakia management options currently include
observation, surgery, laser excision, cryotherapy and
photodynamic therapy, combined with life-time
follow-up.25-27 Studies have shown that leukoplakias tend
to recur in almost one-third of cases when removed by
surgery or laser. Whether these are true recurrences or
progression of residual disease if margins are not free
of dysplasia is often not documented. While older studies
show that removal of leukoplakia does not affect pro-
gression to SCCa, newer studies show that there is
significantly less progression to SCCa if lesions are
widely excised.28-30 Indications for observation include
large size and multifocality, anatomic limitations, and
patient factors. A recent Cochrane review concluded
that interventions such as beta-carotene and carot-
enoids, non-steroidal anti-inflammatory drugs, herbal
extracts such as tea and raspberry gel, topical bleomycin
and Bowman-Birk inhibitor had little to no effect
on resolving leukoplakia or reducing malignant
transformation.31
Clinicians may look to the management of precursor
lesions of other organ systems with similar malignant po-
tential for guidance. Actinic keratosis of the skin
progresses to squamous cell carcinoma at an annual rate
of 0.1-0.6% and is routinely removed by cryotherapy,
topical chemotherapy or other conservative methods to
prevent the development of SCCa.32-34 Less than 5% of
colorectal adenomatous polyps progress to colorectal car-
cinoma, yet prophylactic removal of colonic polyps has
led to a profound decrease in colorectal cancer inci-
dence and provides the basis for colonoscopic
screening.35-37 High-grade cervical intraepithelial neo-
plasia (CIN II/III) progresses to carcinoma in at least 12%
of cases and these patients are routinely treated with cone
excision or loop electrosurgical excision procedure to
reduce cervical carcinoma incidence. CIN I does not pro-
gress to invasive carcinoma without first progressing to
CIN II/III and patients may elect for observation or
removal.38
Adjunctive techniques, such as optical adjuncts (eg.
tissue autofluorescence) or vital staining have been ad-
vocated to facilitate the management of leukoplakia by
experts (and not primary clinicians), and may be useful
for biopsy site selection, mapping for surgical excision,
or for long-term surveillance. However, their utility as
a screening technique is currently hampered by high
sensitivity and low specificity, with many false positive
results and occasional false negatives.39,40 Given that
the oral cavity is an anatomic site amenable to direct
and easy visual examination, thorough clinical exami-
nation informed by a working understanding of the
etiologies and clinical presentations of keratotic lesions
remains essential.
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Volume 126, Number 4
CLINICAL PRACTICE STATEMENT
1. The AAOM recognizes that:
A. Leukoplakia is a potentially malignant disease of
oral mucosal epithelium.
B. Leukoplakia is the most common precursor lesion
to oral SCCa, with which it shares tobacco/
alcohol use as a risk factor. Other risk factors
include immunocompromise, chewing areca nut,
and history of previous malignancy.
C. The annual malignant transformation rate of leu-
koplakia is at least 1-3%.
D. The clinical appearance of leukoplakia is variable:
i. Homogeneous leukoplakia is usually a sharply
demarcated white (keratotic) plaque, some-
times with fissuring.
ii. Nonhomogeneous leukoplakia may have
verrucous/nodular or erythematous compo-
nents. This form of leukoplakia is associated with
a higher rate of malignant transformation as is
larger size.
E. Leukoplakias are dynamic and evolving lesions
in which:
i. Approximately 60% show hyperkeratosis and/
or parakeratosis in the absence of dysplasia
at time of baseline biopsy, and such cases can
subsequently develop dysplasia and, even
carcinoma.
ii. Approximately 40% of leukoplakias show dys-
plasia, carcinoma-in-situ or invasive SCCa at
time of biopsy
1. Mild dysplasia comprises the largest pro-
portion of this population.
iii. Multiple biopsies should be performed for non-
homogenous or extensive lesions to identify
the most severe pathology (ie highest grade
of dysplasia, carcinoma-in-situ or invasive
SCCa).
iv. Lesions that show moderate or severe dyspla-
sia are more like to undergo malignant
transformation.
F. Clinical features are critical in discriminating
between and managing frictional keratoses and
leukoplakias.
i. When biopsied, both conditions may show hy-
perkeratosis and/or parakeratosis without
dysplasia; frictional keratoses tend to be poorly
demarcated and will resolve with resolution
of the source of trauma, but may also recur
if there is a parafunctional habit.
G. Proliferative (verrucous) leukoplakia is an un-
common, multifocal or extensive presentation of
leukoplakia with an overall malignant transfor-
mation rate of at least 60%.
Stojanov and Woo 333
2. The AAOM thus recommends that:
A. Clinicopathologic correlation is necessary in
the diagnosis of leukoplakia (particularly
the homogeneous variant) and proliferative
(verrucous) leukoplakia which tends to exhibit
only hyperkeratosis and/or parakeratosis on
biopsy:
i. The clinician should send a clinical image to
the pathologist to assist in making this clinico-
pathologic correlation.
ii. If a pathology report only states hyperkera-
tosis or parakeratosis with no further comment,
the clinician must consider frictional/reactive
keratosis and leukoplakia in the differential
diagnosis.
B. The various options for treatment of leukoplakia
should be discussed with the patient, from careful
follow-up to removal. Treatment at this time is con-
troversial with some advocating follow-up even
for severe dysplasia and others advocating removal
for all grades of dysplasia.
i. Patients should be offered the option of com-
plete removal especially for moderate and
severe dysplasia with submission of tissue to
pathology. Mild epithelial dysplasia can be
removed or followed but this too depends on
the clinical appearance of the lesion (e.g. non-
homogenous lesions carry higher risk) and
accessibility.
1. Treatment options include surgical exci-
sion, laser excision, cryotherapy and
photodynamic therapy.
ii. Recurrence suggests persistent or aggressive
disease to be treated by wider re-excision if
feasible and clinically appropriate.
C. If a decision is made to monitor lesions with sur-
veillance biopsies when appropriate, optimal
follow-up periods are 3-6 months.
i. Clinical features worrisome for evolving
dysplasia or carcinoma include increased kera-
tosis; verrucous, nodular, or erythematous
components; induration or ulceration and these
should be biopsied for histopathologic
examination.
D. Patients should be educated regarding the nature
and prognosis of this condition and its variants,
and be provided written information.
i. Risk reduction strategies, such as tobacco,
alcohol and areca nut habit cessation, should
be advocated and implemented whenever
possible.
ii. Diets rich in fresh fruits and vegetables should
be advocated and implemented whenever
possible.
iii. Patients should be followed indefinitely.

334 Stojanov and Woo
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