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J Oral Pathol Med. 2019;00:1–8. wileyonlinelibrary.com/journal/jop
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© 2019 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
1 | INTRODUCTION
Oral squamous cell carcinoma (OSCC) is commonly preceded by
oral potentially malignant disorders (OPMDs), which include a va-
riety of mucosal lesions such as oral lichen planus (OLP), oral li-
chenoid lesions (OLL) and oral lichenoid dysplasia (OLD). Diagnosis
of these lichenoid conditions can be challenging, as their clinical and
histopathological features overlap with each other and a number of
other conditions.
The World Health Organization (WHO) developed widely
used clinical and histopathological criteria for OLP in 1978, which
were modified by van der Meij and van der Waal in 2003.1,2 These
modified criteria sought to improve the correlation of clinical and
histopathological features of OLP and emphasised the importance
Received:5June2019
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Accepted:5June2019
DOI : 10.1111 /jo p.12 90 4
SPECIAL ISSUE ARTICLE
Oral lichenoid dysplasia and not oral lichen planus undergoes
malignant transformation at high rates
Kate Shearston1 | Behrooz Fateh1 | Shixiong Tai1 | Dzikamai Hove1 |
Camile S. Farah1,2
1UWADentalSchool,U niversityofWestern
Australia,Nedlands,WesternAu stral ia,
Australia
2AustralianCentreforOr alOncol ogy
Research&Educat ion,Nedlands,Western
Australia,Australia
Correspondence
CamileS.Farah,AustralianCent reforOral
OncologyResearch&Educ ation,N edlands,
WA,6009,Australia.
Email: camile@oralmedpath.com.au
Abstract
Objectives: Oral potentially malignant disorders (OPMD) include a variety of mucosal
lesions such as oral lichen planus (OLP), oral lichenoid lesions (OLL) and oral lichenoid
dysplasia (OLD). Their rate of malignant transformation ranges from 0% to 34% and is
dependent on OPMD type, lesion site and a range of risk factors. This study seeks to
determine the proportion of oral lichenoid conditions that transform into oral squa-
mouscellcarcinoma(OSCC)inanAustralianpopulation.
Methods: The study is a retrospective audit of patients from a private oral medicine
clinic, diagnosed with OLP, OLL or OLD using clinical and histopathological data be-
tween 2006and2014.Patientswerecross‐matched with CancerRegistrydatafor
OSCC, and the rate and time to malignant transformation determined.
Results: OLP and OLL patients displayed a low risk of malignant transformation;
0.49%(1/206)forOLPand0%(0/31)forOLL.Incontrast,OLDpatients,allofwhom
presented clinicallyasOLP,wereatmuchhigherriskwith6.81%(3/44)developing
OSCCoveranaveragetimeof4.6years(±2.4SD).Ratesofsmokingandalcoholcon-
sumption were no higher in OLD patients compared to others.
Conclusions: Compared with other oral lichenoid conditions, OLD lesions are at a
particularly high risk of malignant transformation and should be managed based on
the presence of dysplasia and not the lichenoid inflammator y infiltrate. OLP demon-
strates a relatively low rate of malignant transformation. Diagnostic histopathology
is important for discriminating OLP from OLD.
KEYWORDS
Australia,malignanttransformation,orallichenplanus,orallichenoiddysplasia,orallichenoid
lesion, oral squamous cell carcinoma
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SHEARSTON ET A l.
of utilising both when at tempting a diagnosis. Importantly, this
model excludes any lesion with evidence of dysplasia from their
definition of OLP and uses the definition of OLL to encompass
cases where there is discordance between clinical and histologi-
cal assessment. This varies from the model previously proposed
by Krutchkoff and Eisenberg, which uses the controversial term
oral “lichenoid dysplasia” to describe lesions which include both
histopathological features of OLP and dysplasia.3 A recent posi-
tionpaper from theAmericanAcademy ofOral andMaxillofacial
Pathology(AAOMP)madefurthermodificationstothediagnostic
criteria.4
Oral lichenoid lesions share many similarities with OLP, and in
fact, some authors have argued they are a continuum of the same
condition.5 They may share clinical and histological features; how-
ever, the major distinction between OLL and OLP is the underlying
aetiology. OLLs can be caused by dental materials, an array of drugs,
graft vs host disease or have an unclassified causative agent. OLLs
tend to display a unilateral distribution compared with OLP, which is
typically bilateral and symmetrical, and can be resolved by identify-
ing and eliminating (where possible) the causative agent, in contrast
to OLP.5
The WHO considers OLP to be a potentially malignant condi-
tion, however, the rate at which patients with OLP undergo ma-
lignant transformation varies considerably in the literature.6 The
reported rate of MT across different studies ranges from 0% to
5.4%.7-1 9Arece n tsys t e m a ticr e v iew c a l c ula t e dac o m b ined M Trat e
of 1.4% with an annual transformation rate of 0. 2% 20 which was
comparable with other recent meta-analyses which obtained com-
bined values of 1.09% 21 and 1.1%, respectively.22 Interestingly,
when a sub-group analysis was per formed utilising only studies
adhering to the updated 2003 WHO criteria, which specifically ex-
cludeslesions withdysplasia,Aghbari etal22 obtained an MT rate
of 0.9%. This highlights the importance of lesion classification, as
grade of dysplasia has been correlated with MT risk, and studies
that consider that OLP can include dysplasia may have artificially
high rates.23
The goal of the present study was to assess the rate of malig-
nant transformation of OLP and other oral lichenoid conditions in
an Austr alian cohor t and to investigat e the impact of pat ient risk
factors on this process. This has not previously been carried out in
anAustr alianpopul ationandhasthepotentia ltoshapethemanage-
ment of OLP and related conditions by providing a greater under-
standingoftheriskofMTinAustralianpatients.
2 | MATERIALS AND METHODS
The study is a retrospective audit of patients from a private oral medi-
cineclinicinQueenslandAustralia,diagnosedwithOLP,OLLorOLD
between2006 and 2014, and followedfora minimumof1.5years.
The study was conducted in accordance with human ethics guide-
linesapp rovedby th eU ni ve rsityofWes te rnAu str al ia'sH um anEt hi cs
Committee(RA/4/20/4028).PublicHealthActapprovalwasobtained
from the Queensland Government to access C ancer Registry data
(RD007425). Patient records were searched to identify cases of OLP,
OLL and OLD then cross-matched with oral cancer records from the
Queensl and Cancer Reg istry, which inc luded data fro m 2006 until
the end of 2015.
The OLP group included patient s with a clinical and histopatho-
logical diagnosis of OLP and excluded the following:
• Anypatientswithclinical and histopathological signs ofOLLini-
tiated by an identifiable cause such as a hypersensitivity reaction
to mechanical irritation.
• Anypatientwithotherpotentiallymalignantdisordersorthatex-
hibited biopsy proven dysplasia.
• AnypatientwithouttheinitialhistopathologicaldiagnosisofOLP
and development of OSCC during a follow-up period.
• Any patientwith a diagnosis of OLP concomitant with OSCC at
thefirst visit,ordeveloping OSCC within6monthsoftheinitial
OLP lesion.
The OLL group included lesions with lichenoid inflammation that were
not characteristic of OLP, or clinical lichenoid lesions with evidence of
a specific causative agent (eg hypersensitivity reaction or proven drug
reaction).
The OLD group included any lesion displaying oral epithelial dys-
plasia (OED) on a background of OLP or with an associated lichenoid
infiltrate on histopathology.
Patient files of all those who developed OSCC were reviewed by
an oral medicine specialist (CSF), and the original nature and site of
the lesion confirmed. Pathology slides were reviewed independently
by three oral pathologists according to the WHO,24 and consensus
obtained on presence and grade of dysplasia and the lichenoid in-
filtrate. Time to malignant transformation was calculated from the
biopsy date of the original lesion to the time of development of
malignancy. To assess the influence of time, patients were divided
into two groups; namely those with <5 years follow-up and those
>5 years follow-up.
3 | RESULTS
Atotalof281patientswerereviewed,with206casesdiagnosedas
OLP, 31 cases as OLL and 4 4 cases as OLD (Table 1).
Females predominated in all three groups ( Table 2). The mean age
was comparable bet ween groups, with the majority of patients in the
50-70 year age range (Figure 1). The buccal mucosa was the most
common site for all patient groups, although in the OLP group the gin-
giva was the next most common, followed by the tongue. The second
most common site in both the OLL and OLD groups was the tongue,
followed by the gingiva . 47% of OLP patient s presented with lesions at
multiple sites compared with only 23% of those with OLL lesions and
31% with OLD lesions. The OLL group had a substantially higher rate
of past or present smoking (38.7%), compared with the OLP and OLD
groupswhichdisplayedsimilarrates(22.3%and26.7%,respectively).
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SHEAR STON ET A l.
Asimilarpatternwasseenwithalcoholconsumption,whereOLLpa-
tients had the highest rates (12.9%), followed by OLD and OLP (9.1
and 8.7%, respectively). The prevalence of diabetes was highest in the
OLP group (7.8%), lower in the OLD group (2.2%) and absent in the
OLLgroup.Steroidtherapywasusedin60%oftheoverallcohort.
FortheOLPcases,56ofthesewerefollowedfor<5yearswhile
the remaining 150 had greater than 5 years follow-up. Only 1 patient
diagnosed with OLP underwent malignant transformation to OSCC
at the same site as their original lesion (Table 3). Time to malignant
transformation was 4.8 years, which generated an MT rate of 1.8%;
andaMTof 0.49% overall.None ofthe31cases classified asOLL
underwent MT in the time-frame observed. Of the 44 OLD cases, 14
had <5 years follow-up and the remaining 30 had more than 5 years
of follow-up. Of the OLD cases, 3 patients developed an OSCC at
the same site as their original lesion, with an average malignant
transformationtimeof4.6±2.4SD(Table3).ThisgeneratedanMT
rateof6.81%,whichequatedto7.1%(1/14)inthe<5‐yearfollow‐up
groupand6.7%(2/30)inthe>5‐yearfollow‐upgroup.
Patients who developed OSCC were all female and ranged in age
from 60 to 76with an average ageof 68(67.61± 7.7)at diagnosis
(Table3),whichwasindicativeoftheoverallpatientprofile.Noneof
these patients reported smoking and regular alcohol consumption.
One patient was diabetic, whilst another suffered from rheumatoid
arthritis and was on systemic immunosuppressive medication. Two
patients (40%) had no contributory medical history. The tongue was
the site of the tumour in 50% of patient s, followed by the alveolar
ridge and gingiva (25%) and the buccal mucosa (25%). The primary
lesion was dysplastic in 75% of patients, with the majorit y being
moderate(Figure2).Allpatients whodevelopedOSCCunderwent
incisional biopsy of their initial lesion, with wide surgical excision
being undertaken in all patients.
4 | DISCUSSION
Within ourcohortofOLP patients, only 1/206patient underwent
malignant transformation, generating an overall MT rate of 0.49%
which is within the range of 0%-5.4% established in the literature,
but somewhat lower than the rates c alculated in recent meta-analy-
ses of approximately 1.1%-1.4%.2 0-2 2
The MT rate in our cohort is consistent with studies per-
formed in the Czech Republic, Malaysia, Iran, Turkey, Sweden,
Taiwan, Thailand and China where MT rates ranged from 0% to
0.7%.10 ,14-19,25 Other studies from the Netherlands, Italy, UK,
Spain and A rgentina sh owed higher rat es ranging f rom 1.85% to
4.5%.7‐9,11‐13,26, 27
Factors which increase the risk of MT in OLP patients include
smoking and infection with the hepatitis C virus, although this has
been investigated in only a few studies.22 Lesions on the tongue
and female patients are also at higher risk of MT.20 While the exac t
mechanisms by which OLP undergoes malignant transformation
have not yet been determined, it is thought that chronic immune
stimulation and inflammation can cause growth signal dysregulation
TABLE 1 Patient cohort and malignant transformation rates
All patients Patients with <5 y follow‐up Patients with >5 y follow‐up
No. of
patients
No. patients
undergoing MT
Rate of
MT (%)
Mean Time
to MT (y)
No. of
patients
No. patients
undergoing MT
Rate of MT
(%)
Mean Time
to MT (y)
No. of
patients
No. patients
undergoing MT
Rate of
MT (%)
Mean time
to MT (y)
OLP 206 10.49 4.8±0SD 56 11.8 4.8 150 0 0 NA
OLL 31 0 0 NA 7 0 0 NA 24 0 0 NA
OLD 44 36.81 4.6±2.4SD 14 17. 1 1.9 30 26.7 5.9±0.8SD
Abbreviations:OLP,orallichenplanus;OLL ,orallichenoidlesions;OLD,orallichenoiddysplasia.
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SHEARSTON ET A l.
and this com bines with ox idative st ress to induce D NA damage. 21
People with diabetes have an increased risk of both pre-malignant
lesions and OSCC, and a modest association between head and neck
cancer and diabetes in ‘never‐smokers'.28 Women with diabetes
have a significantly higher relative risk than men of developing oral
ca ncer.29
Oral lichenoid lesions have been studied less extensively than
OLP in the literature, however, recent studies have recorded MT
TABLE 2 Overall patient characteristics and risk factors
Gender (% female) Mean age (y)
Alcohol con‐
sumer (%)
Past or present
smoker (%)
Grade of dysplasia (%)
Mild Moderate Severe Not specified
OLP 71.4 59.4±12.0SD 8.7 22.3 0 0 0 0
OLL 67. 7 56.6±14.3SD 12.9 38 .7 0 0 0 0
OLD 62.2 63 .7±12.8SD 9. 1 26.7 51.2 7. 0 9. 3 32.5
Abbreviations:OLP,orallichenplanus;OLL ,orallichenoidlesions;OLD,orallichenoiddysplasia.
FIGURE 1 Patient characteristics and
risk factors
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SHEAR STON ET A l.
rates of 1.2%,27 3.2% 30 and 4.4%.31 Interestingly, in two of these
studies, the rate of MT in OLL was higher than in OLP 30,31 and this
was also the case in a systematic review where the OLL MT rate was
2.43% vs 1.37% for OLP.20 Patient characteristics in the OLL group
were comparable to the OLP and OLD groups and demonstrated a
higher rate of known OSCC risk factors including smoking and alco-
hol use. This indicates that the low rate of MT cannot be explained
by risk factors in the patient population.
Oral lichenoid dysplasia cases displayed a considerably higher rate
ofMTthan eitherOLP or OLL withanoverall rateof6.81%(3/44),
equatingto7.1%inpatients followed forlessthan5 years,and6.7%
in those followed for more than 5 years. Of the OLD patient s who
transformed, none reported smoking and regular alcohol consump-
tion ,whichwaslowertha ntheoverallco hor t,whichhadr atesof26%
and 10% for smoking and alcohol consumption, respectively. In com-
parison to the OLP cohort, the OLD group had similar rates of smok-
ing and alcohol consumption and reduced rates in comparison to the
OLL group, so these risk factors cannot explain the increased MT rate.
Of the three OLD patients who transformed, one had mild OED
and two had moderate OED. This is in contrast to the overall cohort
where the majority of OLD patients displayed mild dysplasia (51.2%),
with 32% without a specified OED grade and 7.0% and 9.3%, respec-
tively, being classified as moderate or severe OED. This is consis-
tent with the literature correlating more severe grades of dysplasia
with a higher risk of MT,23 although there is not absolute consensus
on this.32 Fifty per cent of transformed lesions were on the tongue,
which is representative of the overall cohor t. The tongue and floor
of mouth have been reported to have the highest rates of malignant
transformation.32
Accurateassessmentoftheriskofvariousconditionsundergoing
MT is hampered by inconsistencies in the definitions of OLP/OLL/
OLD. Even in studies where consistent diagnostic criteria are applied,
inter-observer variability between pathologists can be substantial.1
Interestingly, of the three patient s undergoing MT on a background
of OLD, several had their initial biopsies classified as OED (ranging
from mild to severe). Our results have demonstrated an increased risk
of MT for OLD lesions compared with OLL and OLP lesions but it is
challenging to contextualise this in the literature with OLD not always
recognised as a specific subset of OPMD. For example, Thomson et
al33 investigated the MT rate of OLLs and found a transformation rate
of 1.7%, however, their definition of OLLs is analogous to the use of
OLD in the current study (although their study did include hyperkera-
tosis with lichenoid infiltrate which comprised 28% of OLL s).
Studies of the MT rate of OLP in particular is challenging as it is
not always routinely biopsied, although a recent study suggests that
relying on clinical appearance alone may miss higher risk lesions.34 In
thatstudy,only65%of‘clinicalOLP’wasconfirmedonhistopathol-
ogy, and within the discordant lesions, 14% had dysplasia and 1 (3%)
was an OSCC.34AllthreeoftheOLDcasesinourcohor tthattrans-
formed were clinically characteristic of OLP, and if they had not been
biopsied may have been treated more conservatively. In our trans-
formed cohort, the patient presenting with OLP had an incisional bi-
opsy to confirm diagnosis and was then treated with topical steroids,
TABLE 3 Details of patients and lesions undergoing malignant transformation
Age at
initial
lesion
diagnosis
Age at
cancer
diagnosis
Time
to
MT
(yr) Smoker Alcohol
Contributing
medical
conditions Lesion site
Clinical
presenta‐
tion
Lesion histopathological
diagnosis
Biopsy
type
Treatment of
initial lesion
Tumour
site
Tumour
diagnosis
Patient 1 54.5 59. 8 5.3 No No None Right lateral
tongue
OLP OLD
(mild dysplasia with strong
lichenoid infiltrate)
Incisional Topical ster-
oids followed
by excision
Right
lateral
tongue
SCC,NOS
Patient 2 60.5 62.4 1.9 No No None Lower left
labial
gingiva
OLP OLD
(moderate dysplasia with
mild lichenoid infiltrate)
Incisional Excision Lower
left
gingiva
SCC,NOS
Patient 3 65.7 72.2 6.5 No No Rheumatoid
arthritis
Right lateral
tongue
OLP OLD
(moderate dysplasia with
sparse lichenoid infiltrate
in patches)
Incisional Topical ster-
oids, laser
ablation,
excision
Right
lateral
tongue
SCC,NOS
Patient 4a71.6 76. 0 4.4 No No Diabetes Left bucc al
mucosa
OLP OLP Incisional Topical
steroids
Left
buccal
mucosa
SCC,NOS
aDetails obtained from clinical notes and chart review. Clinical photographs and histopathological slides were not available for assessment.
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SHEARSTON ET A l.
however we have no records of subsequent biopsies or treatment
after the initial visit, prior to the report of OSCC. OLD lesions were
frequently treated with surgical excision to remove the dysplastic
tissue but this is not always possible if lesions are multifocal. Of our
OLD patients who underwent MT, all three had the dysplastic lesion
surgically excised, despite suffering from OLP elsewhere in the oral
cavity.
To increase the value and applicability of future audit studies,
we would recommend (as others have previously) that only samples
with histopathological confirmation are included and that the recent
AAOMP di agnostic cri teria be used to id entify OLP, as it and the
van der Waal criteria before it specifically rule out the presence of
dysplasia.1,4 Unfortunately, the definitions for OLL and OLD (or OED
with lichenoid features) are less clear, which is problematic given the
relatively high rates of lesions that present with both dysplasia and
lichenoidfeatures. A clear understandingofhowlesionsdisplaying
both dysplasia and lichenoid features should be classified is required,
particularly as these are apparently at higher risk of MT than OLL or
OLP. We would also recommend multiple pathologists assess each
sample to reduce intra-observer variability.
FIGURE 2 Representativeclinical(A ,
C, E) and correlating histopathological
(B,D,F)presentationsofPatient1(A,B),
Patient 2 (C, D), and Patient 3 (E, F) who
underwent malignant transformation
and for whom clinical photographs and
histopathological slides were available for
assessment
(A) (B)
(C) (D)
(E) (F)
FIGURE 3 Potential models for oral
lichenoid dysplasia development
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SHEAR STON ET A l.
Fundamental to determining appropriate treatment is under-
standing the underlying biology of these dif ferent oral conditions.
AmajorquestionregardingOLDlesionsiswhether theyareadis-
tinct histopathological entity or part of a continuum by which OED
lesions gain inflammatory features, or OLP lesions gain dysplastic
features (Figure 3). The first theory, proposed by Krutchkoff and
Eisenberg in 1985 posits that OLD lesions are a distinct group that
arise de novo a nd are at a high risk of MT.3 The second theory argues
that the dysplastic change occurring in OED stimulates an immune
response, thus adding an inflammatory component to the lesion.35
The third theory suggests that OLD is an interim stage that OLP
progresses through on its path to MT and that OLP lesions gain
dysplastic features in response to the chronic inflammation caused
by O L P. 36 The mechanism by which OLP undergoes MT is not well
described but it has certainly been suggested that mucosal inflam-
mation present in OLP could drive malignant transformation.37
Interestingly, lichenoid inflammation alone may contribute to
MT. Goodson et al38 reviewed 1248 OSCCs and found that only
5.8%arosefromdocumentedOPMDs(similar rateof6% inCowan
et al39) and whilst 43% were classified as dysplasia or carcinoma in
situ, 33% were classified as hyperkeratosis with lichenoid inflam-
mation. Histologic al evidence of inflammation in cases of dysplasia
or OSCC are relatively common, with rates of 20%-30% of lesions
displaying lichenoid features.21,40 Inflammation has certainly been
identified as a contributing factor to carcinogenesis, being added to
the Hallmarks of Cancer in 2011, and having clear examples in oe-
sophageal and colon cancer.41
Loss of heterozygosity (LOH) at 9p21, 3p or 17p in pre-malig-
nant lesions has been used as a predictor for MT, with OPMDs being
stratified into low and high-risk groups based on LOH at one or more
sites.42-44Bythisrationalet heriskofMTinOLPislow,withonly6%
displaying LOH compared with mild dysplasia (40%) and even hyper-
plasia (14%). Interestingly OLD displayed an even higher rate of LOH
than classic OED (54%).45,4 6
There are several limitations in our study which may under-
estimate the overall rate of MT due to several fac tors. Firstly, the
number of cases reported is small, the study is retrospective in de-
sign, and from one clinic. Secondly, any patients who moved out
of Queensland and subsequently developed OSCC would not be
included in the Queensland Cancer Registry and therefore would
not be included in our follow-up data. Thirdly, given that it may take
5-7 years to undergo malignant transformation, there are some pa-
tients who may develop OSCC in the future but have not yet reached
thatstageatpresent. Afollow‐upstudycouldaddress theseissues
to confirm o ur MT rates, w hile confirm ation in anot her Austra lian
cohort would also be beneficial.
In conclusion, our audit does not find that OLP undergoes malig-
nant transformation at a subst antial rate, but it does find that OLD
lesions are at high risk for malignant progression. What cannot be
delineated in the present study is whether OLD lesions outlined here
are an interim stage through which OLP progresses to malignancy.
Future studies utilising next-generation sequencing to investigate
the molecular relationship between OLP, OLD, OED and OSCC are
essential if we are to confirm this, and acquire the capacity to accu-
rately identify patients at higher risk of malignant transformation.
ACKNOWLEDGEMENTS
TheauthorsthankNormanFirthandOmarKujanforreviewofslides.
ORCID
Camile S. Farah https://orcid.org/0000‐0002‐1642‐6204
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How to cite this article: Shearston K, Fateh B, Tai S, Hove D,
Farah CS. Oral lichenoid dysplasia and not oral lichen planus
undergoes malignant transformation at high rates. J Oral
Pathol Med. 2019;00:1–8. https : //doi.org/10.1111/j op.129 04
