American Association of Oral and Maxillofacial Surgeons

Position Paper

Oral Mucosal Dysplasia
Eric R. Carlson, DMD, MD, EdM, FACS
Deepak Kademani, DMD, MD, FACS
Brent B. Ward, DDS, MD, FACS
Daniel Oreadi, DMD, FACS
Oral potentially malignant disorders (OPMDs) of
the oral mucosa include leukoplakia, erythroplakia,
erythroleukoplakia, lichen planus and oral lichenoid lesions– each with varying incidences of dysplastic disease at thetime of presentation and each with observed incidences ofmalignant transformation over time. The primary goal ofthe management of dysplasia, therefore, includes its early
detection and treatment prior to malignant transformation.
The recognition and management of these OPMDs andan understanding of their potential progression to oral
squamous cell carcinoma will reduce the morbidity andmortality associated with these lesions with expedientand properly executed treatment strategies that will havea positive effect on patient survival. It is the purpose ofthis position paper to discuss oral mucosal dysplasia interms of its nomenclature, epidemiology, types, natural
history and treatment to acquaint clinicians regarding thetiming of biopsy, type of biopsy and follow-up of patientswith these lesions of the oral mucosa. This position paper
represents a synthesis of existing literature on this topic
with the intention of closing gaps in our understandingof oral mucosal dysplasia while also stimulating new
thinking to guide clinicians in the proper diagnosis andmanagement of OPMDs. The fifth edition of the World
Health Organization classification of head and neck tumors
published in 2022 represents new information regarding
this topic and a construct for this position paper.
In 2005, the World Health Organization (WHO) introduced
the term potentially premalignant oral epithelial lesion(PPOEL). It is important today to differentiate PPOEL(that represents a broad term to define a wide variety ofclinical lesions) from oral epithelial dysplasia (OED),a term that should be reserved specifically for lesions
with microscopic evidence of dysplasia.1 Unfortunately,
PAGE 1 Oral Mucosal Dysplasia

the nomenclature is not universally consistent, and theterms PPOEL and dysplasia have frequently been usedinterchangeably in the past, thereby creating confusionin the international literature. The 2017 WHO definitionof oral potentially malignant disorders is a group of
conditions that have clinical presentations that carry arisk of cancer development in the oral cavity, whether
in a clinically definable precursor lesion or in clinicallynormal mucosa.2 In 2023, OPMDs encompass lesions that
include leukoplakia, erythroplakia, erythroleukoplakia,
lichen planus and oral lichenoid lesions. The primary
goal of management of oral mucosal dysplasia, therefore,
includes its early detection, concerted surveillance asappropriate and treatment as required prior to malignant
transformation. The recognition and management ofthese OPMDs and an understanding of their potential
progression to oral squamous cell carcinoma (OSCC) will
reduce the morbidity and mortality associated with theselesions with expedient and proper treatment that will havea positive effect on patient survival.
There has been marginal improvement in the fiveyear survival rate of patients with OSCC treated withmultimodality contemporary therapy over the last 30
years. Current survival rates for all stages of OSCC
range from 50 to 55 percent.3,4 The emphasis of early
detection, diagnosis and treatment of premalignant lesions
is primarily directed to prevent their transformation to
OSCC. Early detection is pivotal to increasing the fiveyear survival rate because it is directly correlated withstage de-escalation of the lesion at initial presentation. It
is important to understand that progression to OSCC is
not a singular event but a gradual process of genetic andhistologic changes that leads to malignant transformation.
The current oral cancer progression model resultsfrom genetic changes leading to the accumulationand progression of molecular damage translating toa functional and/or phenotypic change of the normal
oral mucosa. This molecular damage often includes
inactivation of tumor suppressor genes, most notably
p53 and p16, loss of heterozygosity (LOH) at the 3p and
9p locations, and unregulated expression of regulatorymolecules such as epidermal growth factor.5,6,7 Subclinicalchanges may accumulate sufficiently to become clinically
and/or microscopically apparent as a phenotypicallydistinct lesion from the remaining oral mucosa. These
entities include oral dysplasia, carcinoma in situ (CIS),
and frank invasive carcinoma. It is the purpose of thisposition paper to inform the clinician about the diagnosis
and management of oral mucosal dysplasia as well as its
epidemiology, type, management and outcomes. To thisend, a PubMed search was conducted with the searchterms oral mucosal dysplasia, OPMDs, leukoplakia,
erythroplakia and erythroleukoplakia to identify publishedliterature regarding these search terms. A review of
relevant published literature from 2012 to 2022 resulted
in 35 papers deemed to provide reasonable evidence
and appropriate for final review. This literature review
permitted members of the AAOMS Committee on Oral,
Head and Neck Oncologic and Reconstructive Surgery
the opportunity to create a position paper represented bya synthesis of evidence and consensus expert opinion
regarding the diagnosis and treatment of oral mucosal
dysplasia.

Epidemiology
Oral mucosal dysplasia is a condition that is commonly
evaluated and treated by oral and maxillofacial surgeons
and other medical and dental specialists. It is estimatedthe international incidence of oral dysplasia is 2.5 percentof the population with high-risk groups being as high as
10 percent.8,9 The recognition and management of oral
dysplastic lesions is critical to mitigate progression tomalignancy. In 2020, oral cancer accounted for 377,713
new cases and 177,757 deaths reported worldwide.10
Patients with OSCC are typically males aged greater than
40 years with a history of regular exposure to etiologicalrisk factors such as tobacco products, alcohol, or betel
quid; however, younger patients with lower cumulative
tobacco or alcohol exposure are increasingly presenting
with OSCC or oropharyngeal squamous cell carcinoma.
These early-onset OSCCs or oropharyngeal squamouscell carcinomas located at the base of the tongue, tonsils,
and oropharynx are most frequently associated with thehuman papillomavirus infection. Alcohol and tobacco
have a synergistic effect with heavy alcohol consumption
and tobacco use having 38 times the risk of developing
oral cancer compared to those who refrain from both.5,11
Current trends show an increase in the incidence of oral
cancer among several populations, including younger
patients below the age of 40 years regardless of an increasein knowledge about etiological risk factors for OSCC.
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Position Paper
Despite technological advances in cancer therapies,
the five-year survival rate for oral cancer remains atapproximately 50 percent for most populations and has
not changed significantly for the past three decades.9,12
Squamous cell carcinoma is often preceded by lesions suchas leukoplakia or erythroplakia that have the potential tobe dysplastic and progress to malignancy. The primaryobjective to improve patient prognosis is through early
detection of these lesions. Detecting dysplastic changes
at an early stage allows for active intervention before
lesions progress to malignancy. Current practices for thedetection of malignant or potentially malignant lesions
involve a conventional oral examination (COE) with visualand tactile examination, with leukoplakic or erythroplakic
lesions considered suspicious for OED or OSCC.
Induration and fixation are tactile signs that might suggest
oral malignancy. To confirm clinical findings, patientsare usually referred to a specialist for biopsy of lesions
for a definitive diagnosis and management. A biopsy isconsidered the gold standard for the diagnosis of dysplasia
as it allows for a thorough evaluation of the epithelial
architecture of the lesion.
Observation of oral lesions without biopsy may be inselected situations is appropriate. It should be recognizedthat premalignant or malignant changes can often be
subtle and overlooked even with meticulous follow-up.
Histological changes indicative of dysplasia can be foundin clinically normal mucosa. The advantage for biopsy oflesions that persist over time is the ability to definitively
match a clinical diagnosis with histopathology. It is areality that patients do present with late-stage OSCC who
have been followed closely. While screening programs
to identify malignant lesions have been trialed, theircost-effectiveness in the general population is uncertain
and the onus has fallen on primary care providers toscreen patients for such lesions. In the United States, it
is currently recommended that patients undergo annual
screening for oral and head and neck cancer.3,5 Of concern,a meta-analysis has indicated that a COE, while having
a relatively high sensitivity at 93 percent, has a poor
specificity at 31 percent and cannot reliably differentiate
between benign and dysplastic lesions.13 Several benign
conditions mimic oral malignancies and in converse
dysplasia may be found in clinically normal mucosa.

Types of dysplasia
OED is a collective term for lesions of the oral mucosathat possess changes in color, histology, and molecularcharacteristics compared to surrounding oral soft tissues.
From a clinical perspective, OED can be described as
white (leukoplakia), red (erythroplakia), or mixed red
and white (erythroleukoplakia). Leukoplakia (Figure 1)
is defined as a white plaque of equivocal risk, whereby
other known diseases or disorders are excluded that areassociated with no increased risk of cancer.2 Therein,
the evaluation of a white lesion of the oral cavity andthe proclamation of the term leukoplakia requiresthat otherwise innocuous lesions are excluded in thelesion's differential diagnosis including those thatare developmental (hereditary benign intraepithelial
dyskeratosis), reactive (hairy tongue, leukoedema,smokeless tobacco keratosis), infectious (candidiasis, oral
hairy leukoplakia), immune-mediated and autoimmune(idiopathic lichen planus, chronic graft vs host disease,migratory glossitis) and metabolic (uremic stomatitis).
Aside from its mere white color, leukoplakia issubcategorized as either homogenous or nonhomogenous.
Homogenous leukoplakia is most frequently welldemarcated and fissured, while nonhomogenous
leukoplakia is most commonly verrucous or nodular.2
The estimated international prevalence of leukoplakia is
2 percent.14 Leukoplakia does not designate the presenceor absence of any specific grade of dysplasia as theterm represents a clinical definition and is not linked toany specific microscopic pattern.14,15 Stated differently,
leukoplakia can be dysplastic or nondysplastic in terms of
its histologic character.
Erythroplakia (Figure 2) is defined as a “fiery red patchthat cannot be characterized clinically or pathologicallyas any other definable disease.”14 Rather than a patch, theclinical presentation of erythroplakia is a symptomatic
flat or occasionally depressed change of the mucosa suchthat erythroplasia might be a more appropriate term.14 The
prevalence of erythroplakia varies between 0.02 percent
and 0.83 percent, and it occurs primarily in middle-aged
and elderly people.16
Histologically, erythroplakia typically demonstrates atleast moderate or severe dysplasia, or CIS, and the vast
majority of erythroplakic lesions will undergo malignant
transformation.14,16 Erythroleukoplakia (Figure 3) is avariant of nonhomogenous leukoplakia. These lesions
are mixed red and white lesions and are often referred
to as speckled leukoplakia. In a sample of 684 cases oforal premalignant epithelial disorders, Pires et al17 found
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Position Paper
that leukoplakia represented 82 percent of the sample(564 cases), erythroleukoplakia, referred to as speckled
leukoplakia, represented 6 percent of the sample (42cases), and pure erythroplakias were not found in thesample.
Proliferative verrucous leukoplakia is another variantof nonhomogenous leukoplakia and is characterized
by unremitting, multifocal and progressive disease at asingle site or at contiguous sites in the oral mucosa thatare refractory to conventional treatment. Proliferative
verrucous leukoplakia may not only possess the classic
verrucous and nodular pattern, typical of nonhomogenous
leukoplakia, but may also possess the homogenous fissured
and erythroplakic patterns such that the more accurate
and inclusive term, proliferative leukoplakia has been
proposed.18 A comparison of solitary leukoplakia andproliferative leukoplakia is noted in Table 1.
Numerous molecular factors have been associatedwith the malignant transformation of oral leukoplakia.
These include DNA methylation, LOH, cytokeratin
expression, DNA aneuploidy, matrix metalloproteinase-9
positivity and survivin positivity.19 In most studies, thepresence and grade of dysplastic change represents theprimary risk factor for malignant transformation ofleukoplakia, although 3p and/or 9p LOH are the mostsignificant predictors of progression. Most cancers
possess dysregulated activation of a few cancer pathways,
including WNT/β-catenin, PI3K/AKT/mTOR, JAK/STAT,RAS/RAF/MAPK, or TGFβ.20
Dysplasia of the oral mucosa has historically been gradedas mild (Figure 4), moderate (Figure 5), severe (Figure 6),
and CIS (Figure 7). Odell et al20 indicated that all OED
grading systems represent artificial constructs that are
subjective estimates of a spectrum of changes. Gradingof OED therefore exists as a highly contentious practiceand international consensus is difficult to obtain due
to varying grading schemes in different regions of theworld.21 The fifth edition of WHO classification of headand neck tumors published in 2022 maintains the threetiered OED grading system, although it is emphasizedthat defining oral mucosal dysplasia by thirds of the oral
epithelium oversimplifies its complexity.21 For example,

there are instances where OED is limited to the lower
third of the epithelium, yet severe dysplasia is diagnosed
due to numerous architectural and cytologic featuresthat upgrade the dysplasia (Table 2). The designation of
CIS was merged with severe dysplasia in the 2017 WHOclassification due to the inability to differentiate these typesof dysplasia on histologic grounds as well as the inability
to differentiate their risk of malignant transformation.20,21
Despite great controversy associated with the gradingof OED, these designations possess clinical utility andtherefore remain the standard regarding management of
OED.20Subjectivity in histological interpretation and gradingof dysplasia remains a challenge with the 3-tier methodof classification of mild dysplasia, moderate dysplasia,
and severe dysplasia/CIS. Substantial differences in theinterpretations of OED have historically existed among
oral and maxillofacial pathologists.22 Compounding
the confusion of grading is the unpredictability of thedevelopment of invasive carcinoma from all gradesof dysplasia.23 There are many variables involved inmetabolic soft tissue changes, including but not limited tomolecular alterations, features of histologic atypia, coexistence of other disease states such as herpes simplex
virus, and chromosomal derangements. As many ofthese entities often coexist with dysplastic change, it isextremely difficult if not impossible to determine with any
degree of certainty the likelihood of progression of OED.
A binary (two-stage) system of OED grading, lowgrade and high-grade, has recently come into use inmany centers. It is based on the appearance of several
cytologically identifiable cellular changes seen in OED.
Various studies have concluded that this method is easily
reproducible with better interobserver agreements whencompared to the present three-tier classification system in
use today. These visual changes can then be scored and thedysplasia can be graded as either high-grade or low-grade.
While the treatment algorithm proposed in this paper
continues to use the more standard three-tier classification
system of dysplasia, it is acknowledged that the binary
staging system also has utility in the management oforal mucosal dysplasia. In fact, the combination of both
systems could be of great value to the clinician in planning
treatment and follow-up of patients with oral mucosal
dysplasia.
Human papillomavirus (HPV)-associated dysplasia of
the oral mucosa has gained significant attention due toits distinction from conventional OED. HPV-associateddysplasia is mostly seen in males (M:F = 6:1) and with a
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Position Paper
peak incidence in the sixth decade.21 The ventral/lateral
tongue and floor of mouth are most affected, although thegingiva and buccal mucosa also can be affected. These
dysplastic lesions usually present as a flat and welldemarcated white-to-red patch that is indistinguishable
from other types of oral leukoplakia. Distinguishinghistologic findings of HPV-associated oral dysplasia are
noted in Table 3.
Lichen planus of the oral mucosa is a chronic inflammatory
autoimmune disease that is characteristically identified
by lacy white lesions with or without erosive or atrophic
areas. The disease has been estimated to affect 1.32 percentof the European population and the disease increases in its
incidence after the age of 40 years.24 Gonzalez-Moles etal25 performed a systematic review and meta-analysis ofstudies investigating the risk of malignant transformationof oral lichen planus and identified a cancer incidence of
1.14 percent among these cases. The fifth edition of the
WHO classification of head and neck tumors continues
to designate oral lichen planus as an OPMD, yet authors
report that this designation was a contentious issue.21
Furthermore, numerous publications have refined theclinical and microscopic features or oral lichenoid lesions
to distinguish them from oral lichen planus; however, these
distinctions were believed to be insufficient to remove oral
lichen planus as a potentially malignant disorder. OSCC
arising from lichen planus has been reported to be distinct
related to their clinical characteristics and outcomes withhigher rates of survival but also higher rates of relapse.26

Summary of available evidence
An annual rate of malignant transformation for all typesof leukoplakia collectively is estimated at 1 percent.14
According to van der Wall,14 risk factors for malignant
transformation include leukoplakia in nonsmokers,
nonhomogeneous type, long duration of the leukoplakic
lesion, female gender, the presence of epithelial dysplasia,
and size more than 200 m2. The various clinicalpresentations for oral leukoplakia permit discretionon the part of the clinician regarding the performanceof an incisional biopsy. Small, innocuous-appearing
homogenous leukoplakic lesions might be subjected toclinical follow-up, while larger and multifocal lesions

might warrant incisional biopsy at the time of consultation.
An expedient incisional biopsy of an erythroplakic lesion
is typically indicated due to the likelihood of highgrade dysplasia or frank carcinoma being present in anerythroplakic lesion, as well as the high rate of malignant
transformation of these lesions over time.
Evren et al19 reported a retrospective study of 170 patientswith leukoplakia of the oral mucosa, including 117 womenand 53 men. The age range of these patients was 26 to
98 years with a mean of 59 years. Ninety one patients(54 percent) presented with a homogenous leukoplakia,
while 79 patients presented with a nonhomogenous
leukoplakia that was described as erythroplakia, nodular
or verrucous. The tongue accounted for 59 sites ofleukoplakia and the floor of mouth accounted for 27 sitesthat collectively were designated by the authors as highrisk after analysis while all remaining anatomic sites ofleukoplakia were categorized as low risk. Ninety-one
patients underwent observation as initial treatment, while
69 patients underwent excision of their leukoplakia.
Malignant transformation of the leukoplakia to squamouscell carcinoma occurred in 39 of 170 (22.9 percent)patients. After exclusion of the first year, in which no
malignant transformation occurred, the annual malignant
transformation rate remained relatively stable between 4.5
percent and 6.3 percent annually over the 11 years of thestudy. These data indicate the need to provide long-term,and possibly, life-time clinical surveillance of patientswith oral leukoplakia because the rate of malignant
transformation remains clinically significant over time.
Furthermore, the authors and their panel recommend theneed to provide a new biopsy of oral leukoplakia whenclinical change is demonstrated.
Aguirre-Urizar et al27 performed a systematic review
and meta-analysis of malignant transformation of oral
leukoplakia. Twenty four studies were selected thatreported a total of 16,604 patients. The rate of malignant
transformation ranged from 1.1 to 40.8 percent. Following
meta-analysis, the pooled proportion of malignant
transformation was 9.8 percent. The time from firstdiagnosis of leukoplakia to the onset of carcinoma wasdetermined in 10 studies and ranged from 1.8 to 5.1 years.
The clinical type of leukoplakia that transformed into
squamous cell carcinoma was determined in 13 studies.
Two-thirds of 525 lesions that underwent malignant
transformation were nonhomogenous leukoplakia andone-third of the 525 lesions were homogenous leukoplakia.
The meta-analysis showed a 4.06-fold increased riskof malignant transformation for nonhomogeneous
leukoplakia (95% confidence interval [CI]: 1.39 to 11.89).
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Position Paper
In terms of grade of the dysplasia of the leukoplakic lesion,
the presence of dysplasia showed a 23.8-fold increased
risk of malignant transformation (95% CI: 9.5 to 38.2).
Furthermore, high-grade dysplasia demonstrated a 4.90fold increased risk of malignant transformation comparedto low-risk epithelial dysplasia (95% CI: 3.02 to 7.96).
Gilvetti, et al28 provided a retrospective review of theoutcomes of 95 patients with high-grade dysplasiaof the oral mucosa. In all cases, the lesions appeared
as homogenous or nonhomogenous leukoplakia(erythroleukoplakia, verrucous, nodular or other exophytic
features) or erythroplakia. For inclusion in the study, ahistopathologic diagnosis of severe dysplasia was required,but cases of moderate dysplasia were included if they
showed sufficient cytologic and/or architectural atypia tobe regarded as high-grade dysplasia. Seventeen patients(17.8 percent) developed a squamous cell carcinoma at
the same site as the high-grade dysplasia, with a meantime for malignant transformation of 50 months. None of
the 20 patients underwent malignant transformation who
had high-grade dysplasia who were originally diagnosed
with moderate dysplasia. The authors reported that somepatients with high-grade dysplasia of the oral mucosa
may develop recurrence and/or malignant transformationof their lesions eight to 10 years following effective
excisional biopsy such that these patients also should
undergo indefinite clinical surveillance. A young age(50 years or less) at the time of diagnosis, homogenous
appearance of the lesion, and complete excision of thelesion with negative margins improved the patient's
prognosis.
Wang et al29 reviewed 5,071 patients, 4,299 males
and 772 females, with OPMDs over a 10-year period.
These disorders included 186 patients with dysplastic
oral submucous fibrosis, 957 patients with epithelial
dysplasia, 869 patients with verrucous hyperplasia, and1,684 patients with hyperkeratosis/epithelial hyperplasia.
Malignant transformation was noted in nine of 186 patientswith dysplastic oral submucous fibrosis and 63 of the957 patients with epithelial dysplasia. Sixty-one of the949 patients (6.43 percent) with mild epithelial dysplasia
progressed to cancer, six of the 108 patients (5.56
percent) with moderate epithelial dysplasia progressedto cancer, and five of the 86 patients (5.81 percent) withsevere epithelial dysplasia progressed to oral cancer. Of
particular interest is that 49 of the 1,684 patients withbenign epithelial hyperplasia/hyperkeratosis experienced
malignant transformation to 37 squamous cell carcinomas
and 12 verrucous carcinomas.
Gonzalez-Moles et al24 have provided a critical review
of 89 published papers in the international literaturethat specifically comment on the potential for malignant
transformation of oral lichen planus. Their meta-analysis
indicated a rate of malignant transformation of 2.28
percent, and the authors therefore proclaimed lichen
planus as a potentially malignant disorder. The authors
also proposed to establish recommendations to researchersand clinicians regarding the criteria for performing futurestudies whose results will be scientifically valid. The
samples should be representative of the general population
including patients derived from hospitals, dental schools
and private offices. The authors pointed out that the
primary confounding factor in the study of the malignant
transformation of oral lichen planus is the lack of widely
accepted diagnostic criteria of lichen planus. Their clinicaldiagnostic criteria included the presence of white reticularlesions at any location of the oral mucosa without therequirement for symmetry or bilaterality. Exclusion criteria
were intimate contact of the lesion with dental restorative
materials, lesions in close temporal relationship with theuse of a drug, the history of organ transplantation, and thepresence of skin lesions or systemic disorders suggestiveof lupus erythematosus.24

Treatment of dysplasia
The status of evidence related to the treatment of oral
leukoplakia and dysplasia is summarized by a 2016
Cochrane review.30 “Surgical interventions, including
laser therapy and cryotherapy, have never been studied
by means of a randomized controlled trial (RCT) that
included a no treatment or placebo arm.” Most trials
in the Cochrane review were chemoprevention rather
than surgical intervention, with none of these trials
demonstrating value that would suggest broad application.
The available data for evidence-based decision-making
related to surgical therapies are therefore extremely limited
and significant controversy exists regarding treatment
protocols.31,32,33 The views expressed in this section are
therefore based primarily on consensus expert opinion
related to this disease process noting that the authors of
this position paper have significant individual and vast
collective experience. The concepts suggested should beconsidered as general gestalt that requires application to
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Position Paper
the specific clinical situation of each patient. In no way
are the authors’ recommendations intended to create astandard of care related to any specific patient condition.
In addition, given the lack of unambiguous evidence,
it is important that patients be given the opportunity
for shared decision-making related to their care sincemultiple modalities, including observation remain viable
alternatives in many cases, especially in cases of persistentand recurrent disease. It is also acknowledged that somepatients present with an unresectable burden of diseaseor disease that is technically resectable, but for which
the morbidity associated with resection may not warrant
treatment. Furthermore, the algorithms do not intend toaddress all clinical situations surrounding the surgicaltreatment of dysplasia, for example, whether or not to“chase” surgical margins of dysplasia beyond the treatmentof clinical disease. Finally, patients should be made awarethat recurrence even after successful treatment is commonand no treatment, including surgical interventions, hasbeen scientifically proven to prevent progression to cancer;
thus, careful follow-up with providers trained in COE iswarranted.
While limited in magnitude, some evidence exists thattreatment of dysplasia is in fact cancer protective. In a
recent retrospective study of 120 patients with high-grade
OED, the malignant transformation rate was 28.6 percent
in untreated patients and 12.3 percent in patients who
underwent treatment using scalpel excision, laser excision,or laser ablation.28 Older age, nonhomogenous clinicalappearance and incomplete excision all demonstrated aworse prognosis.28 A prior study of 118 patients withsevere dysplasia reached similar conclusions where
treated patients had a risk of transformation of 6 percent
compared to 29 percent in untreated patients (P = .004).
Likewise, a retrospective study of 136 patients of all
grades of dysplasia demonstrated a significant reduction inmalignant transformation rate with both scalpel excisionand laser ablation.34 These data are collectively stronger,
but in contrast to the report by Holmstrup et al,9 noting
a higher transformation rate to cancer in patients who
underwent intervention for their premalignant lesions. As
mentioned previously, none of these studies were RCTs
and conclusions are therefore limited. Nevertheless, thedata serve a basis for the reasonable recommendations

of surgical treatment based on patient and clinical lesion
factors.
As histopathology is a prominent consideration in a
proposed decision-making process, it should be noted that
controversy exists regarding the reliably of histopathology
related to multiple factors, including those in control ofboth surgeons and pathologists. From a surgical standpoint,
incisional biopsy may not be representative of the mostaggressive location of any given lesion and multiple
biopsies of larger lesions are certainly a reasonable but
not required consideration. In addition, concordanceof histopathologic reads by pathologists has shown
significant variability in the literature.9 As such, while therecommendations below use mild, moderate and severe
dysplasia, it is acknowledged that some investigators haveadvocated for a two-grade system of low-grade and highgrade dysplasia.
Decision-making for treatment of dysplasia consistsof the combination of patient, clinical lesion andhistopathologic factors in a shared decision-making
model where patients understand potential risks andbenefits. It is again emphasized that all patients should be
informed that progression despite treatment occurs, andrecurrence is common such that long-term – and, at times,
lifelong – follow-up is indicated. While some patients
present with truly unresectable disease or unresectable
due to morbidity, in many circumstances a justifiable andbeneficial role for surgery exists. Surgery for dysplasia
has two distinct forms, either excision or ablation.
Excision refers to removal of a lesion with the generationof a specimen for pathologic assessment. On the other
hand, ablation involves vaporization of the lesion,
typically with a C02 laser, and does not produce tissue
for a histologic assessment. Therein, three procedures
may be performed, including scalpel excision, laser
ablation and laser excision. Scalpel excision and laser
excision of oral mucosal dysplasia incorporate a linear
margin surrounding the lesion, the magnitude of which
is based on the discretion of the surgeon as well as thegrade of the dysplastic lesion. Both procedures provide
tissue for thorough lesion diagnosis, assignment of themost advanced grade of dysplasia and complete margin
assessment. There are no reliable data at present for
distinguishing outcomes between the laser excision andscalpel excision. Laser ablation, as occurs with a carbon
dioxide laser, does not provide tissue to a pathologist for a
microscopic diagnosis of the lesion or margin assessment,
and therefore requires the surgeon's judgment regarding
the appropriateness of ablation of any oral mucosal lesion
without first performing an incisional biopsy. The authors
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Position Paperof this paper do not recommend the use of laser ablation
for high-grade dysplasia, including severe or CIS of theoral mucosa that has been diagnosed on incisional biopsy,
or any lesion that is clinically suspicious for malignant
transformation. Specimens from laser excision may beassessed for margins; however, cauterization createscomplexity in histopathologic interpretation of thosemargins, especially for the smaller excisions and smaller
margins for dysplastic lesions compared to the 1.0-1.5 cm
margins routinely taken for cancer. Margin assessment
is important in cases where surgeons and patients plan
to continue excision beyond the clinical lesion forhistopathologic evidence of disease either on frozen or
permanent sections. It is important to recognize thatdifficulty can exist for interpreting dysplasia and its precise
grade on frozen sections.
Treatment of oral mucosal dysplasia is multidimensionaland based on individual patient and lesion characteristics
and clinical observation. Many patients ultimately require
surgery with effective provider communication and shareddecision-making with patients representing the hallmark oftreatment. Comprehensive and flexible treatment planningis especially important given that oral mucosal dysplasia
is a disease process that is unpredictable, frequently
unremitting or recurrent, and whose treatment can resultin significant morbidity, with the ultimate outcome
being progression to cancer regardless of treatment. For
simplicity, patient and clinical lesion features are combinedwith histopathology as the primary consideration in thealgorithm presented (Figure 8). Table 4 outlines general
high-risk features for consideration in both patientsand clinical lesions. Our treatment algorithm proposes
treatment combining the two features with variable
treatment options based on availability as well as surgeon
and patient shared decision-making.

Follow-up of patients with
dysplasia of the oral mucosa
The follow-up of patients with oral mucosal dysplasia
is dependent on clinician preferences as standardized
guidelines on the recommended surveillance of thesepatients do not exist. This notwithstanding, clinical followup of patients should be frequent, particularly in patientswith severe dysplasia/CIS for concern for malignant
transformation. The potential for all grades of dysplasia toundergo malignant transformation should not be dismissed.
Clinical surveillance should be based on the site of thelesion, the grade of dysplasia, and the patient's presenceor absence of risk factors. In the final analysis, long-term
follow-up of patients with oral mucosal dysplasia, andpossible lifelong follow-up, can certainly be justified withprinciples of self-examination reviewed with the patient at
each follow-up visit.34,35 Follow-up may appropriately bedelegated to any provider adequately trained in COE.

Research regarding
oral mucosal dysplasia
As more questions than answers currently exist in theunderstanding of etiology, progression, treatment andprevention of OED, ongoing research is critical. Whilewhat is included below is not applicable to current practiceand only briefly summarized, it is intended to point readers
toward areas of research that may impact the future
understanding and inform future treatments.

Quantitative tissue phenotyping
Of potential future value in predicting malignant
transformation of oral mucosal dysplasia is the use ofquantitative tissue phenotype.36,37 The gradual developmentof genomic instability of cells predicts changes inphenotype that can distinguish malignant cells fromnormal cells. Changes can occasionally be detectedwith hematoxylin and eosin-stained tissue. A subset ofpremalignant cells at risk for malignant transformation
might be phenotypically distinct. To this end, quantitative
tissue pathology permits the profiling of numerous
microscopic characteristics at the cellular and subcellularlevels that are not apparent at the conventional microscopic
level.36 Guillaud et al37 studied the utility of quantitative
tissue phenotype as measured by high-resolution
image analysis to predict malignant transformation of
hyperplasia, mild and moderate dysplasia, and severe
dysplasia and CIS. A nuclear phenotype score (NPS) wasestablished as an aggregate of five nuclear morphometriccharacteristics that distinguished 4,027 normal nuclei in
29 normal oral mucosal biopsy specimens from 4,298
abnormal nuclei in 30 specimens of squamous cell
carcinoma. These five features included the maximum
radius of the nucleus (Max_radius), the amount of thenuclear boundary explained by 3 lobes (Harm003_fft), therelative spatial distribution of high and low absorbancevariations in the nucleus (Fractal_area1), the presenceof a dark nucleus with light areas of a light nucleus with
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Position Paper
dark areas (Absorbance_skewness), and the fraction of thenuclear diameter one can travel prior to an intensity change(Long90_runs). A cell-by-cell phenotypic analysis was
performed whereby a score was assigned to each nucleus
indicating similarity to normal or cancer cells in 10 regionsof interest within each tissue sample. The NPS represented
the weighed sum of the 10 regions. An NPS with a value of
1 corresponded to a tissue sample with 100 percent normal
cells, while an NPS with a value of 10 corresponded
to a tissue sample with 100 percent cancer-like cells.
The NPS was defined for 69 cases of oral premalignant
lesions. A significant increase in NPS was noted in casesof severe dysplasia and CIS compared to hyperplasia,
mild dysplasia and moderate dysplasia. Within the formergroup, an elevated NPS was significantly correlated withthe presence of high-risk LOH patterns. In addition, there
was a statistically significant difference between casesof hyperplasia, mild dysplasia, and moderate dysplasiathat progressed to cancer compared to those that did not
progress to cancer. The authors selected a cutoff valueof 4.5 for the NPS to distinguish those cases that would
undergo malignant transformation versus those cases thatwould not progress. Cases with an NPS more than 4.5
had a 10-fold increase in progression to cancer within five
years.

Prevention of malignant transformationof oral mucosal dysplasia
Chemoprevention represents a strategy that delays,
reverses or prevents the development of invasive cancerfrom premalignant disease. Numerous compounds andpharmacologic agents have been administered and studied
to determine their ability to interfere with progressionof dysplasia to invasive cancer of the oral cavity. These
entities are antimutagens, including desmutagens andbioantimutagens; N-acetyl-L-cysteine; topical bleomycin;
polyphenols such as green tea extract and curcumin;
antiproliferatives such as retinoids, carotenoids, andnonsteroidal anti-inflammatory drugs; and ligands ofperoxisome proliferator-activated receptor gamma.38
McCarthy et al39 reviewed early-phase trials in the
chemoprevention of oral cancer in terms of their evidence
and methodology. They point out that no trial has realized
uniform acceptance due to toxicity or lack of efficacy, aswell as problems related to the study's size and end points.
A common problem is that studies do not properly selectthe patients at high risk for progression of dysplasia toinvasive cancer versus those patients with nonprogressive
disease.38 Lodi et al30 reviewed 14 RCTs involving 909
patients undergoing medical and other treatments for oral
mucosal leukoplakia in terms of preventing its progression
to invasive cancer. The development of invasive cancer,
clinical resolution of the leukoplakia and improvementof histologic features were assessed with three treatment
interventions: topical bleomycin versus placebo, systemic
beta carotene versus placebo, and systemic vitamin A
versus placebo. None of these treatments were effective
in preventing the development of invasive cancer asmeasured up to two years for beta carotene and vitamin
A, and up to seven years for topical bleomycin therapy.
Most treatments caused side effects of varying severity in ahigh proportion of participants. While no chemoprevention
protocols are currently advocated, a new RCT “Metformin
for the Prevention of Oral Cancer in Patients with Oral
Leukoplakia or Erythroplakia” is underway and enrolling
subjects.

Position Paper
In the final analysis, there are currently no validated
mechanisms to prevent the progression of oral mucosal
dysplasia to cancer. Surgical intervention remains
unstudied in a randomized prospective clinical trial thatwould have the power to delineate its benefits. This
position paper is intended to assist clinicians with available
evidence and expert opinion to best serve the significant
numbers of patients impacted by this complex disease
process.

Acknowledgments
The authors recognize the contributions of Dr J. Michael
McCoy regarding histopathological analysis of oral
mucosal dysplasia.

Figures and Tables

Figure 1

Figure 1. An example of homogenous leukoplakia of the left buccal mucosa. The histopathology
pertaining to incisional biopsy of this lesion identified verrucous carcinoma.
PAGE 9 Oral Mucosal Dysplasia

Figure 2

Position Paper

Figure 2. An example of erythroplakia of the left palatal mucosa. The histopathology pertaining
to incisional biopsy of this lesion identified microinvasive squamous cell carcinoma.

Figure 3

Figure 3. An example of erythroleukoplakia of the right ventral tongue. The histopathology
pertaining to incisional biopsy of this lesion identified invasive squamous cell carcinoma.
PAGE 10 Oral Mucosal Dysplasia

Position Paper
Figure 4

Figure 4. Mild dysplasia of the oral mucosa based on the classic three-tier system. With theminimal number of ominous cytologic changes seen, including the lack of abnormal variation in
nuclear size and shape, this is an example of low-grade dysplasia using the binary system. Suchan example of mild dysplasia might be observed under specific circumstances rather than excised(Figure courtesy of Kitrina Cordell, DDS, MS).

PAGE 11 Oral Mucosal Dysplasia

Position Paper
Figure 5

Figure 5. Moderate dysplasia of the oral mucosa. With the blunted and budding rete ridges, as well
as atypical mitotic figures and abnormal variation in cell size and shape (arrows), this dysplasia istermed high-grade using the binary system. While some cases of moderate dysplasia are observed,
the high-grade nature of this histopathology dictates excision of this lesion (Figure courtesy of
Kitrina Cordell, DDS, MS).

PAGE 12 Oral Mucosal Dysplasia

Position Paper
Figure 6

Figure 6. Severe dysplasia of the oral mucosa. Severe dysplasia and carcinoma in situ are usedinterchangeably based on the WHO 2017 and 2022 classifications. The classification equivalence
supports treatment recommendations as severe dysplasia and CIS are treated identically with wide
local excision. (Figure courtesy of Kitrina Cordell, DDS, MS).

PAGE 13 Oral Mucosal Dysplasia

Position Paper
Figure 7

Figure 7. Carcinoma in situ of the oral mucosa. Carcinoma in situ is no longer the preferred termin grading OED and is replaced with the term severe dysplasia. This notwithstanding, cytologic
differences are appreciated between this example of CIS that demonstrates abnormal variationin nuclear size and shape, abnormal variations in cell size, and atypical mitotic figures (arrows),
and Figure 6 that demonstrates severe dysplasia without a similar magnitude of cellular atypia(Figure courtesy of Kitrina Cordell, DDS, MS).

PAGE 14 Oral Mucosal Dysplasia

Position Paper
Figure 8

Mild (Low)Moderate (Intermediate)

Patient and clinical risk factors

Patient and clinical risk factors

Low

Observe

ModerateHigh• Observe• Observe• Laser
ablation• Laser
ablation• Laser or
scalpelexcisionLong-term follow-up

Laser orscalpelexcision

Moderate

Low• Laser
ablation• Laser or
scalpelexcision• Laser or
scalpelexcisionLong-term follow-up

Figure 8: Algorithm for treatment of dysplasia of the oral mucosa

PAGE 15 Oral Mucosal Dysplasia

Severe/CIS (High)High

Laser orscalpelexcision

Laser orscalpelexcisionLong-term follow-up

Position Paper
Table 1Distinguishing features of solitary vs. proliferative leukoplakia of the oral mucosa
Parameter

Solitary leukoplakia

Proliferative leukoplakia

GenderMostly men 2-3.5 : 1

Mostly women 2.5-5 : 1

Smoking history

Common (> 60%)

Uncommon (< 30%)

Number of sites

Solitary

Multiple

Most common sites

Lateral/ventral tongue
and floor of mouth

Gingiva and buccal mucosa

Malignant transformation

8 – 22%70 – 100%

Management

Amenable to surgical excision

Serial biopsies due to recurrence andpredilection to malignant transformation

Adapted from: Woo SB: Oral epithelial dysplasia and premalignancy. Head and Neck Pathology 13: 423-39, 2019

Table 2

Architectural and cytologic features of oral epithelial dysplasia (WHO 2022)
Architectural features

Cytologic features

Altered keratin pattern for oral subsite

Abnormal variation in nuclear size

Verrucous or papillary architecture

Abnormal variation in nuclear shape

Extension of changes along minor gland ducts

Abnormal variation in cell size

Sharply defined margin to changes

Abnormal variation in cell shape

Multiple different patterns of dysplasia

Increased nuclear:cytoplasmic ratio

Multifocal or skip lesions

Atypical mitotic figures

Expanded proliferative compartment

Increased number and size of nucleoli

Basal cell clustering/nestingSingle cell keratinization
Apoptotic mitoses
Increased nuclear size

Adapted from: Woo SB: Oral epithelial dysplasia and premalignancy. Head and Neck Pathology 13:423-39, 2019; and Muller S, Tilakaratne WM:
Update from the fifth Edition of the World Health Organization Classification of Head and Neck Tumors: Tumours of the Oral Cavity and Mobile
Tongue. Head and Neck Pathology, 2022.
PAGE 16 Oral Mucosal Dysplasia

Position Paper
Table 3

Histologic features of HPV-associated oral dysplasia
Half to Full Thickness of Epithelium Affected
Replacement of most of epithelial thickness by cells of basaloid or lower prickle cell morphology
Loss of demarcation between basal, prickle cell, and maturing compartments
Acanthosis
Increased suprabasilar mitoses
Scattered isolated markedly atypical cells at all levels including apoptotic cells, apoptotic mitoses, multinucleated cells,
and grossly atypical cells with karyorrhexis.
Tendency to vertical orientation of basal and prickle cells
Preserved basal layer of small cuboidal almost normal cells
Brightly eosinophilic parakeratinized surface
Folded epithelial architecture
Focal koilocytic change/vacuolation near surface layer typical of replicative HPV infection
Intense positive reaction for p16 immunoexpression
Positive DNA or RNA in situ hybridization for HPV
Adapted from: Odell E, Kujan O, Warnakulasuriya S, Sloan P: Oral epithelial dysplasia: recognition, grading, and clinical significance.
Oral Diseases 27: 1947-76, 2021.

Table 4High-risk features for oral mucosal dysplasia
Patient Characteristics

Lesion Characteristics• Older age (> 60 years)• Tobacco/Alcohol consumption• Multiple lesions (PVL)• Diagnosis of lichen planus• Unable to engage in routine follow-up• Erythroleukoplakia or erythroplakia• Size exceeding 200 mm• Location• Nonhomogenous• Ill-defined margins

PAGE 17 Oral Mucosal Dysplasia

References
1.

Liviu Feller JL, Lemmer J. Oral squamous cell carcinoma
epidemiology, clinical presentation and treatment. J Cancer Ther
3:263-268, 2012.

2.

Woo SB. Oral epithelial dysplasia and premalignancy. Head andNeck Pathology 13:423-439, 2019.

3.

Rethman MP, Carpenter W, Cohen EE et al. Evidence-based
clinical recommendations regarding screening for oral squamouscell carcinomas. American Dental Association Council on
Scientific Affairs Expert Panel on Screening for Oral Squamous
Cell Carcinomas. J Am Dent Assoc 141:509-520, 2010.

4.

5.

Speight PM, Khurram SA, Kujan O. Oral potentially malignant
disorders: Risk of progression to malignancy. Oral Surg Oral Med
Oral Pathol Oral Radiol. 125:612-627, 2018.
Chaturvedi AK, Udaltsova N, Engels EA et al. Oral Leukoplakia
and Risk of Progression to Oral Cancer: A Population-Based
Cohort Study. J Natl Cancer Inst 112:1047-1054, 2020.

6.

Smith J, Rattay T, McConkey C et al. Biomarkers in dysplasia of
the oral cavity: A systematic review. Oral Oncol 45:647-653, 2009.

7.

Mishra R. Biomarkers of oral premalignant epithelial lesions forclinical application. Oral Oncol 48:578-584, 2012.

8.

Gillenwater A, Papadimitrakopoulou V, Richards-Kortum R. Oral
premalignancy: New methods of detection and treatment. Curr
Oncol Rep 8:146-154, 2006.

9.

Position Paper
17. Pires FR, Barreto MEZ, Nunes JGR et al. oral potentiallymalignant disorders: Clinical-pathological study of 684 cases
diagnosed in a Brazilian population. Med Oral Patol Oral Cir Bucal
25:e84-88, 2020.
18. Villa A, Menon RS, Kerr AR et al. Proliferative leukoplakia:
Proposed new clinical diagnostic criteria. Oral Dis 24:749-760,
2018.
19. Evren I, Brouns ER, Wils LJ et al. Annual malignant
transformation rate of oral leukoplakia remains consistent: A longterm follow-up study. Oral Oncol 110:105014, 2020.
20. Odell E, Kujan O, Warnakulasuriya S, Sloan P. Oral epithelial
dysplasia: Recognition, grading and clinical significance. Oral Dis
27:1947-1976, 2021.
21. Muller S, Tilakaratne WM. Update from the 5th Edition of theWorld Health Organization Classification of Head and Neck
Tumours: Tumours of the Oral Cavity and Mobile Tongue. Headand Neck Pathol 16:54-62, 2022.
22. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant
lesions: Is a biopsy reliable? J Oral Pathol Med 36:262-266, 2007.

Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Long-term treatment
outcome of oral premalignant lesions. Oral Oncol 42:461-474,
2006.

23. Saito T, Sugiura C, Hirai A, et al. Development of squamous cell
carcinoma from pre-existent oral leukoplakia: With respect totreatment modality. Int J Oral Maxillofac Surg 30: 49-53, 2001.

10. Sung H, Ferlay J, Siegel RL. Global cancer statistics 2020:
GLOBOCAN estimates of incidence and mortality worldwide for
36 cancers in 185 countries. CA Cancer J Clin 71:209-249, 2021.

24. Gonzalez-Moles M, Ramos-Garcia P, Warnakulasuriya S.
An appraisal of highest quality studies reporting malignant
transformation of oral lichen planus based on a systematic review.
Oral Dis 27:1908-1918, 2021.

11. Awadallah M, Idle M, Patel K, Kademani D. Management updateof potentially premalignant oral epithelial lesions. Oral Surg Oral
Med Oral Pathol Oral Radiol 125:628-636, 2018.
12. Amagasa T, Yamashiro M, Uzawa N. Oral premalignant lesions:
From a clinical perspective. Int J Clin Oncol 16:5-14, 2011.
13. Watabe Y, Nomura T, Onda T, et al. Malignant transformationof oral leukoplakia with a focus on low-grade dysplasia. J Oral
Maxillofac Surg Med Pathol 28:26-29, 2016.
14. van der Waal I. Potentially malignant disorders of the oral andoropharyngeal mucosa; present concepts of management. Oral
Oncol 46:423-425, 2010.
15. Abati S, Bramati C, Bondi et al. Oral cancer and precancer: A
narrative review on the relevance of early diagnosis. Int J Environ
Res Public Health 17:9160, 2020.
16. van der Waal I. Potentially malignant disorders of the oral andoropharyngeal mucosa; terminology, classification, and present
concepts of management. Oral Oncol 45:317-323, 2009.
PAGE 18 Oral Mucosal Dysplasia

25. Gonzalez-Moles MA, Ruiz-Avila I, Gonzalez-Ruiz L, et al.
Malignant transformation risk of oral lichen planus: A systematic
review and comprehensive meta-analysis. Oral Oncol 96:121-130,
2019.
26. Best DL, Herzog C, Powell C, et al. Oral lichen planus-associatedoral cavity squamous cell carcinoma is associated with improved
survival and increased risk of recurrence. J Oral Maxillofac Surg
78:1193-1202, 2020.
27. Aguirre-Urizar JM, de Mendoza ILI, Warnakulasuriya S.
Malignant transformation of oral leukoplakia: Systematic review
and meta-analysis of the last 5 years. Oral Dis 27:1881-1895, 2021.
28. Gilvetti C, Soneji C, Bisase B, Barrett AW. Recurrence andmalignant transformation rates of high grade oral epithelial
dysplasia over a 10 year follow up period and the influenceof surgical intervention, size of excision biopsy and marginal
clearance in a UK regional maxillofacial surgery unit. Oral Oncol
121:105462, 2021.

29. Wang YY, Tail YH, Want WC et al. malignant transformation in
5071 southern Taiwanese patients with potentially malignant oral
mucosal disorders. BMC Oral health 14:99, 2014.
30. Lodi G, Franchini R, Warnakulasuriya S et al. Interventions fortreating oral leukoplakia to prevent oral cancer. Cochrane Database
Syst Rev 7:CD001829, 2016.
31. Zhang L, Lubpairee T, Laronde DM, Rosin MP. Should severe
epithelial dysplasia be treated? Oral Oncol 60:125-129, 2016.
32. van der Waal I. Oral leukoplakia, the ongoing discussion on
definition and terminology. Med Oral Patol Oral Cir Bucal
20:e685-692, 2015.
33. Tradati N, Grigolat R, Calabrese L et al. Oral leukoplakias: To treat
or not? Oral Oncol 33:317-321, 1997.
34. Arnaoutakis D, Bishop J, Westra W, Califano JA. Recurrence
patterns and management of oral cavity premalignant lesions. Oral
Oncol 49:814-817, 2013.
35. Wetzel SL, Wollenberg J. Oral potentially malignant disorders.
Dent Clin N Am. 64:25-37, 2020.
36. Crawford M, Johnson EH, Liu KYP, et al. On the cutting edgeof oral cancer prevention: Finding risk-predictive markers in
precancerous lesions by longitudinal studies. Cells 11:1033, 2022.
37. Guillaud M, Zhang L, Poh C, et al. Potential use of quantitative
tissue phenotype to predict malignant risk for oral premalignant
lesions. Cancer Res. 68:3099-3107, 2008.
38. Tsai JY, Dillon JK. Chemoprevention in oral cancer In: Kademani
D. (ed): Improving Outcomes in Oral Cancer. A Clinical andTranslational Update. Springer Nature, chapter 2:13-22, 2020.
39. McCarthy C, Fedele S, Ottensmeier C, Shaw RJ. Early-phaseinterventional trials in oral cancer prevention. Cancers (Basel)
13:3845, 2021.

© 2023 American Association of Oral and Maxillofacial
Surgeons. No portion of this publication may be used or
reproduced without the express written consent of theAmerican Association of Oral and Maxillofacial Surgeons.
PAGE 19 Oral Mucosal Dysplasia

Position Paper