Oral lichen planus and oral lichenoid lesions: diagnostic and

therapeutic considerations
Ibtisam Al-Hashimi, BDS, PhD,a
Mark Schifter, BDS, MDSc, MSnD ACSed, MomRcsed FFD RCSI (Oral Med) FRMEDs (Oral Med),b
Peter B. Lockhart, DDS,c David Wray, MD, BDS, MBChB, FDS RCPS, FDS RCSEd, FMed Sci,d
Michael Brennan, DDS, MHS,e Cesar A. Migliorati, DDS, MS, PhD,f Tony Axll, DDS, PhD,g
Alison J. Bruce, MBChB,h William Carpenter, DDS, MS,i Ellen Eisenberg, DMD,j
Joel B. Epstein, DMD, MSD,k Palle Holmstrup, DDS, PhD,l Mats Jontell, DDS, PhD,m
Francina Lozada-Nur, DDS, MS, MPH,n Raj Nair, BDS, MSc, PhD (Sol),o
Bud Silverman, MAS, DDS,p Kobkan Thongprasom, DDS, MSc,q
Martin Thornhill, MBBS, BDS, PhD,r Saman Warnakulasuriya, BDS, PhD,s and
Isac van der Waal, DDS, PhDt, Houston, TX, Sydney, Australia, Charlotte, NC, Glasgow,
Scotland, Fort Lauderdale, FL, Halmstad, Sweden, Rochester, MN, San Francisco, CA, Farmington,
CT, Chicago, IL, Copenhagen, Denmark, Goteborg, Sweden, Queensland, Australia, Bangkok,
Thailand, Sheffield, UK, London, UK, and Amsterdam, the Netherlands
BAYLOR COLLEGE OF DENTISTRY, UNIVERSITY OF SYDNEY, CAROLINAS MEDICAL CENTER, UNIVERSITY
OF GLASGOW, NOVA SOUTHEASTERN UNIVERSITY, COUNTY HOSPITAL, MAYO CLINIC, UNIVERSITY OF
CONNECTICUT HEALTH CENTER, CHICAGO CANCER CENTER, UNIVERSITY OF COPENHAGEN,
SAHLGRENSKA ACADEMY, UNIVERSITY OF CALIFORNIA SAN FRANCISCO, GRIFFITH UNIVERSITY
CHULALONGKORN UNIVERSITY, UNIVERSITY OF SHEFFIELD, UNIVERSITY OF LONDON, VU UNIVERSITY
MEDICAL CENTRE/ACADEMIC CENTRE FOR DENTISTRY AMSTERDAM

Several therapeutic agents have been investigated for the treatment of oral lichen planus (OLP). Among these
are corticosteroids, retinoids, cyclosporine, and phototherapy, in addition to other treatment modalities. A systematic
review of clinical trials showed that particularly topical corticosteroids are often effective in the management of
symptomatic OLP lichen planus. Systemic corticosteroids should be only considered for severe widespread OLP and
for lichen planus involving other mucocutaneous sites. Because of the ongoing controversy in the literature about the
possible premalignant character of OLP, periodic follow-up is recommended.
There is a spectrum of oral lichen planuslike (lichenoid) lesions that may confuse the differential diagnosis.
These include lichenoid contact lesions, lichenoid drug reactions and lichenoid lesions of graft-versus-host disease. In regard
to the approach to oral lichenoid contact lesions the value of patch testing remains controversial. Confirmation of the
diagnosis of an oral lichenoid drug reaction may be difficult, since empiric withdrawal of the suspected drug and/or its
substitution by an alternative agent may be complicated. Oral lichenoid lesions of graft-versus-host disease (OLL-GVHD) are
recognized to have an association with malignancy. Local therapy for these lesions rests in topical agents, predominantly
corticosteroids. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl 1):S25.e1-S25.e12)

Director of Salivary Dysfunction Clinic, Baylor College of Dentistry.

Head of Department, University of Sydney, Westymend Centre for
Oral Health, Westmend Hospital, Sydney, Australia.
c
Chairman, Department of Oral Medicine, Carolinas Medical Center.
d
Department of Oral Medicine, University of Glasgow, Glasgow,
Scotland.
e
Oral Medicine Program Director, Carolinas Medical Center.
f
Professor, NOVA Southeastern University, College of Dental Medicine.
g
County Hospital, Halmstad, Sweden.
h
Consultant, Department of Dermatology, Mayo Clinic, Rochester;
Assistant Professor, Mayo College of Medicine, Mayo Clinic.
i
Consultant in Oral Pathology, School of Dentistry.
j
Professor, Oral Heal and Diagnostic Sciences and Division Head,
University of Connecticut Health Center.
k
Professor and Head of Oral Medicine, College of Dentistry, Chicago
Cancer Center.
l
Professor and Chairman, University of Copenhagen, School of Dentistry, Copenhagen, Denmark.
b

Professor, Sahlgrenska Academy, Goteborg, Sweden.

Professor of Clinical Oral Medicine, University of California, San
Francisco.
o
Senior Lecturer in Oral Medicine, Griffith University, Gold Coast,
Queensland, Australia.
p
University of California, San Francisco.
q
Professor, Oral Medicine Department, Chulalongkorn University,
Bangkok, Thailand.
r
Chair, Oral Medicine, University of Sheffield, School of Clinical
Dentistry, Sheffield, UK.
s
Professor of Oral Medicine and Experimental Oral Pathology, University of London, Guys, Kings and St. Thomas Dental Institute,
London, UK.
t
Head, Professor of Oral Pathology, VU University Medical Centre
(Vumc)/Academic Centre for Dentistry Amsterdam (ACTA), Amsterdam, Netherlands.
1079-2104/$ - see front matter
2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2006.11.001
n

S25.e1

S25.e2

Al-Hashimi et al.

Lichen planus is a chronic systemic disease of established immune-mediated pathogenesis. It commonly

involves the mucosa of the oral cavity, but can involve
other sites, namely the skin, the vulvar and vaginal
mucosa, the glans penis, the scalp (resulting in alopecia), and the nails. The reported prevalence rates of oral
lichen planus (OLP) vary from 0.5% to 2.2% of the
population. The typical age of presentation is between
30 and 60 years, and it is more frequently seen in
women.
Lichen planus commonly affects the oral mucosa,
most often in the absence of skin lesions. Mucosal
lesions are usually multiple and almost always have a
bilateral, symmetrical distribution. They commonly
take the form of minute white papules that gradually
enlarge and coalesce to form either a reticular, annular,
or plaque-like pattern. A characteristic feature is the
presence of slender white lines (Wickhams striae) radiating from the papules. In the reticular form there is
a lacelike network of slightly raised gray-white lines,
often interspersed with papules or rings. The plaquelike form may be difficult to distinguish from leukoplakia. In some patients the lesions are erythematous or
frankly ulcerated. Oral lesions of lichen planus may
also include bullae, but these are rare.1 These different
forms may merge or coexist in the same patient. The
gingivae are commonly the site of erythematous/erosive OLP.
The clinical features alone may be sufficiently diagnostic, particularly when presenting in the classic
reticular form. The evidence regarding the need and
value of biopsy for histological confirmation of the
diagnosis is not definitive. Studies have shown variability in both interobserver and intraobserver reliability in
the clinicopathological assessment of OLP.2 Because
OLP is a chronic disorder that often requires long-term
treatment and monitoring, biopsy would be prudent
clinical practice, particularly when the disease does not
present with its typical manifestations, or when there is
concern of dysplasia or malignancy. The term lichenoid dysplasia is used by some pathologists to describe
a dysplastic surface epithelium accompanied by a bandlike lymphocytic infiltrate in the subjacent lamina propria. These findings are indicative of a premalignant
process; they should not be misconstrued as lichen
planus with dysplastic features.3
The value and need for other investigations, such as
screening for chronic liver disease and hepatitis C
(HCV), in the routine assessment of a patient with OLP
is controversial.4-6 Examination by a dermatologist or
gynecologist should be considered, depending on the
presenting signs and symptoms.
The elimination of precipitating or provoking factors
is an important initial step in the management of symp-

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March 2007

tomatic OLP. Patient education and the undertaking of

active measures to resolve or minimize mechanical
trauma from dental procedures, sharp cusps, rough dental restorations, and ill-fitting prostheses, or chemical
trauma from acidic, spicy, or strongly flavored foods
and beverages should be encouraged and can lead to
symptomatic improvement, or, more rarely, resolution
of the disease.4,7 The accumulation of bacterial plaque,
often as a result of the discomfort associated with oral
hygiene procedures in patients with gingival involvement, may also exacerbate the condition. The use of
alternative oral hygiene measures, including the use of
alcohol-free chlorhexidine gluconate mouth rinses, may
be helpful in such cases.7-9
Psychosocial interventions and support are also
thought to be of importance, given the long-term
chronic nature and associated discomfort of symptomatic OLP. There is limited and conflicting evidence that
psychological factors, particularly acute stress and/or
anxiety, contribute to the pathogenesis of OLP.10-13
There is an ongoing controversy in the literature as to
whether OLP is associated with an increased risk of
malignant transformation.14-17 The alleged annual malignant transformation rate for OLP is between 0.2%
and 0.5%. Patients should be encouraged to avoid or
discontinue habits such as excessive tobacco and alcohol use that are likely to increase the risk of malignant
transformation. Long-term monitoring may be problematic as this is resource intensive. At a minimum,
annual monitoring of OLP is recommended.18,19
There are various lesions that resemble lichen planus
both clinically and histopathologically. Usually, these
lesions are referred to as lichenoid lesions. Oral lichenoid lesions encompass several clinical settings20:
(1) Oral lichenoid contact lesions (OLCL) as a result of
allergic contact stomatitis (delayed immune mediated
hypersensitivity). They are seen in direct topographic
relationship to dental restorative materials, most commonly amalgam, or other contacted agents, e.g., cinnamon. (2) Oral lichenoid drug reactions (OLDR), wherein
oral and/or cutaneous lesions arise in temporal association
with the taking of certain medications, e.g., oral hypoglycemic agents, angiotensin-converting enzyme inhibitors, and nonsteroidal anti-inflammatory agents; previously, such lesions were seen in conjunction with the
widespread use of gold salts and penicillamine for the
management of rheumatoid arthritis. (3) Oral lichenoid
lesions of graft-versus-host disease (OLL-GVHD) in
patients with acute, or more commonly, chronic graftversus-host disease (cGVHD).
Clinically, oral lichenoid lesions may present with a
range of different features that include asymptomatic
white reticular striae and plaques, to painful erythematous, eroded, or ulcerated lesions. Histopathologically,

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Volume 103, Number 3, Suppl 1

oral lichenoid lesions are often characterized by a lichenoid tissue reaction in which 2 key features are
noted: (1) a bandlike lymphohistiocytic infiltrate that
fills the lamina propria; and (2) liquefactive degeneration of basal keratinocytes. These reactions may be the
result of several diverse possible triggers, but all likely
share a common pathologic process, that of immunemediated damage to the oral epithelial basal cells.
QUESTION TO BE ADDRESSED
One of the goals of the World Workshop of Oral
Medicine IV has been to present the results of a systematic
review of the literature on the management of symptomatic oral lichen planus and oral lichenoid lesions.
REVIEW OUTCOME AND RECOMMENDATIONS
Oral lichen planus
In a systematic review of the literature on treatment
of symptomatic OLP, 25 studies were identified. Nine
studies were randomized clinical trials (RCTs) and
these were also included in the Cochrane review by
Chan et al. in 2005.21 The present review is not limited
to placebo-controlled trials. Most of the published trials
are observational and are not always prospective. Several therapies have been tried for treatment of OLP,
most of them are aimed at symptomatic relief rather
than treatment of the disease. Studies that use the same
class of medication often use different dosages and/or
different formulations, which complicate direct comparison. The outcome measures are generally subjective, using visual analogue scores for the symptoms
and, as in a study by Thongprasom et al.,22 clinical
scores for the lesions.
Four main classes of medical interventions were
identified. These include corticosteroids, retinoids, calcineurin inhibitors (cyclosporin and tacrolimus) either
delivered topically or systemically, and ultraviolet
(UV) phototherapy.
Corticosteroids. Corticosteroids were investigated
in 12 trials.23-34 Of these, 4 were placebo controlled.23,24,26,27 Altogether 300 individuals were examined in the studies, 20 to 60 individuals per study,
and 8 to 25 individuals per group. Most studies were
not focused on investigating the value of corticosteroids in the treatment of OLP per se but compared the
effectiveness of different formulations, different classes
of corticosteroid, different strengths of topical steroids,
and different frequency of application.
The specific medications included in the review are
fluocinonide, fluocinolone acetonide, triamcinolone acetonide, clobetasol propionate, fluticasone propionate, and
betamethasone valerate/sodium phosphate for topical therapy, with dosages ranging from 0.025%, 0.1%, and 0.5%,
and the frequency of application varying from 2, 3, and

Al-Hashimi et al. S25.e3

4 times a day. The average duration of the studies was

between 4 and 8 weeks, except for 1, which was for 6
months.32 Carbone et al.s32 study compared systemic
plus topical versus topical alone; they did not find a
difference in the outcome between systemic and topical
corticosteroids.
Systemic corticosteroids were used in 1 trial: prednisone 50 mg a day, for up to 60 days.32 Indeed, there
is a paucity of well-designed trials regarding the value
of systemic corticosteroids, and none, to date has used
a dosage based on the patients weight. Their role
would appear to be limited to 3 main clinical indications: (1) OLP that initially presented with very severe
and/or widespread ulceration and erythema; (2) treatment of resistant/recalcitrant OLP, or (3) treatment of
resistant/recalcitrant lichen planus involving multiple
sites, including the oral cavity. Short courses or bursts
of high-dose corticosteroids, such as prednisone, at 0.5
to 1.0 mg per kg of the patients body weight, per day
until a therapeutic response has been achieved, followed by rapid tapering of the corticosteroids has been
shown to be effective in other symptomatic autoimmune diseases, and may reduce some of the significant
adverse effects seen with chronic high-dose administration of corticosteroids. For patients needing longterm systemic corticosteroid therapy, the patient
should be monitored for potential comorbidities such
as hypertension, diabetes mellitus, gastric or peptic
ulceration, bone mineral density loss, and cataract
formation. In such patients, there is a need for corticosteroid-sparing agents, but their efficacy in the
treatment of OLP still awaits substantive testing.
Not all studies with corticosteroids reported side
effects. When reported, oral candidiasis was the most
frequent side effect. Side effects were more prevalent
with systemic corticosteroids than topical agents. The
overall conclusion suggests that corticosteroids are effective in the management of OLP. Topical agents are
unlikely to cause serious side effects. There is no study
determining if adhesive vehicles are better than mouth
rinses. However, empirical evidence seems to suggest
that mouth rinses are of value in patients with widespread symptomatic OLP, where the lesions are not
easily accessible to the placement of ointments or gels.
The evidence also suggests that higher potency corticosteroids, such as clobetasol are probably more
effective.
A summary of the evidence basis for the value of
topical steroids in the treatment of OLP is presented in
Table I.
Retinoids. Seven studies were identified that dealt
with the use of retinoids for the treatment of oral lichen
planus.35-41 Of the latter, 2 were included in the Cochrane review.35,36 A total of 183 individuals partici-

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Al-Hashimi et al.

Table I. Evidence basis for the value of topical corticosteroids in the treatment of oral lichen planus (OLP)
Intervention:
Class/method:

Clobetasol propionate 0.05%

Ointment
Applied twice daily, for 2 months

Indications:
Intervention:
Class/method:

Considered the treatment of choice for symptomatic atrophic/erosive OLP

Clobetasol propionate 0.025%
Ointment
Applied twice daily, for first month, then, once daily for the second
month

Classification*
____ Class I
__ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
__ Class IIA
____ Class IIB

Level of Evidence
____ A
__ B
____ C

____ Class III

Indications:
Intervention:
Class/method:

Considered the treatment of choice for symptomatic atrophic/erosive OLP

Triamcinolone acetonide 0.1%
Mixed with orabase
Applied 3 times daily, until symptoms improve

Indications:
Intervention:
Class/method:

First topical steroid for the treatment of localized and/or initially

symptomatic OLP
Triamcinolone acetonide 0.1%
Mouthwash
Rinse for 4 weeks

Indications:
Intervention:
Class/method:

Useful for generalized lesions of symptomatic OLP

Fluocinonide 0.05%

Applied 3 times daily for first 2 months, then twice, and then once daily
Indications:
Intervention:
Class/method:

Useful in chronic symptomatic atrophic/erosive OLP

Fluocinolone acetonide 0.1%
In orabase
Applied 4 times daily for 1 month

Indications:
Intervention:
Class/method:

Useful in symptomatic OLP who failed to respond to other medications

Betamethasone sodium phosphate
Mouth rinse 0.5 mg/10 mL water
Held in the mouth for 3 minutes, 4 times daily

Indications:
Intervention:
Class/method:

Useful in the short-term treatment of symptomatic atrophic/erosive OLP

Hydrocortisone hemisuccinate mouthwash

Used as a mouthwash for 2 weeks

Indications:
Intervention:
Class/method:

Useful for symptomatic OLP in areas difficult to apply ointments/creams

Fluticasone propionate 50 g
Aqueous solution
Apply 2 puffs to lesion, 4 times daily

Indications:

Short-term treatment of symptomatic erosive/ulcerative OLP

*Class I - Treatment is useful and effective.

Class IIA - Weight of evidence/opinion is in favor of usefulness.
Class IIB - Usefulness is less well established.
Class III - Treatment is not useful and may be harmful.
Level of evidence: A - Data derived from multiple randomized clinical trials (RCT).
B - Data derived from a single RCT, or nonrandomized studies.
C - Consensus opinion of experts.

Classification
__Class I
____ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
__ Class I
____ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
__ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
__ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
____ Class IIA
____ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
____ Class IIA
__ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

Classification
____ Class I
____ Class IIA
__ Class IIB
____ Class III

Level of Evidence
____ A
__ B
____ C

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Volume 103, Number 3, Suppl 1

pated in the studies. Four of the studies examined the

effect of different concentration and frequency of application of topical retinoids (0.05%, 0.1%, 0.18%,
used 2-4 times a day). Only 1 study examined systemic
use of retinoids, 25 mg 3 times per day.35 The duration
of the studies ranged between 4 and 12 weeks. They all
reported improvement, but less than with corticosteroids when these were used for comparison. Based on a
histopathologic follow-up study,37 reticular OLP responded better than less keratinized lesions, but only 1
in 6 lesions showed complete healing over an 8-week
period. The overall outcome suggests that retinoids are
potentially effective in the treatment of OLP, but probably inferior to topical corticosteroids. The most common reported side effect was a transient burning
sensation.
Systemic retinoids are associated with a number of
serious adverse effects that would prohibit their routine
use for the management of OLP, and include elevated/
deranged transaminase levels, hyper-lipidemia, cheilitis, dermatoxerosis, alopecia, and dystrophic nail formation. Retinoids are teratogenic and therefore their
use in women of childbearing age would be contraindicated.
Calcineurin inhibitors. Cyclosporine: a total 64 individuals were examined in 4 studies.42-45 Three studies
used a 500-mg rinse 1 or 3 times a day.42,44,45 Two
studies examined cyclosporine mouth rinse 500 mg 3
times daily,42,45 and in the study by Harpenau et al.44 a
single dose of 500 mg a day was used. The Sieg et al.45
study was single-blinded, whereas the Eisen et al.42
study was double-blinded and placebo controlled.
Gaeta et al.43 used 128 mg in adhesive gel 3 times
daily. In all of the studies, the side effects were minimal, and mainly consisted of a transient burning sensation. The results of all of the studies showed a marked
improvement in the oral symptoms. However, cyclosporine mouth rinse was not significantly better than
1% triamcinolone paste.45
Tacrolimus and pimecrolimus are newer calcineurin
inhibitors, with an improved safety profile in comparison with cyclosporine, for the prevention of rejection
in organ transplant recipients and graft-versus-host Disease (GVHD) in allogeneic hematopoeitic stem-cell
transplant recipients. Only a limited number of studies
have been published.46-50 However, there is a Food and
Drug Administration (FDA) Black Box warning attached to the use of these agents because of a theoretical increased risk of malignancy (squamous cell carcinoma and lymphoma) in patients using topical
tacrolimus/pimecrolimus for cutaneous psoriasis. In a
recent case report of a patient with oral lichen planus,
the topical use of tacrolimus 0.1% was suggested to be
the cause of the development of a squamous cell car-

Al-Hashimi et al. S25.e5

cinoma of the tongue.51 Therefore, the use of these

agents should be restricted and patients should be made
aware of these concerns.
Phototherapy. There has been 1 study of the benefits
of phototherapy using psoralen ultraviolet A light
(PUVA),52 in which 18 individuals were randomized
based on side; the contralateral side served as control.
The total treatment was 16.5 J/cm2 UV radiation, given
in 12 sessions, 2 to 3 days apart with 0.6 mg/kg methoxypsoralen (puvamet) per visit. Fourteen of the 16
patients had side effects, of which 2 had such severe
adverse reactions they had to withdraw. Nine patients
had a marked improvement. The authors suggested
using topical psoralens to avoid side effects seen with
systemic administration. This study was included in the
Cochrane review.
UV light has a known oncogenic potential. Therefore, its use for OLP should be seriously questioned.5,53-56
Other and/or steroid-sparing systemic medications. There are only a limited number of indications
for the use of steroid-sparing systemic medications:
(1) symptomatic OLP, or (2) symptomatic LP involving
other sites outside the oral cavity as well that are
resistant to topical therapies. There is only limited
evidence in support of a restricted number of potentially useful agents:
(1) Lysosomotropic amines (the antimalarials chloroquine and hydroxychloroquine)57,58 have proven
their value in the management of the autoimmune
diseases rheumatoid arthritis and lupus erythematosus. Hydroxychloroquine, at doses of 200 to 400
mg daily, has also been shown to be effective for
OLP; however, this was an open trial of only 30
patients.58 Further, it is not always effective, and it
may take several months for improvement to occur.
Hydroxychloroquine is not a completely harmless
drug and before instituting therapy it is advised that
baseline visual acuity testing is performed and repeated every 6 to 12 months to check for ocular
toxicity. UV (sun) lightinitiated lichenoid cutaneous reactions have also been reported with this
agent, as have haematological abnormalities and
deranged liver function tests. Therefore, regular
monitoring of patients complete blood count and
liver function tests are warranted. Preexisting retinopathy, psoriasis, and porphyria represent known
contraindications to the use of hydroxychloroquine.
(2) Azathioprine has been reportedly successful as a
steroid-sparing agent for cutaneous lichen planus, and there is limited published evidence suggesting it may have a similar role in recalcitrant
OLP.59-63 In general, the initial dose should be

S25.e6

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March 2007

Al-Hashimi et al.

approximately 1.0 mg/kg/d (50 to 100 mg) gradually increasing in increments of 0.5 mg/kg/d over
several weeks, if necessary up to a maximum dose
of 2 mg/kg/d. If no improvement occurs in the
patients condition within 3 months, the azathioprine should be ceased. On observation of a therapeutic response, consideration should be given to
reducing the maintenance dosage to the lowest
level compatible with maintenance of that response
and the individual patient response, particularly
hematological tolerance. Before starting azathioprine, a thiopurine methyltransferase (TPMT) assay should be performed to determine the potential
risk of the patient suffering marrow aplasia. All
potential xanthine oxidase inhibitors, of which allopurinol is the commonest and most potent example, need to be ceased and patients warned against
the taking of these medications as they act as potent
agonists of azathioprine, increasing the risk of marrow aplasia. Close monitoring of the patients full
blood count is essential (ideally weekly), in the first
8 weeks of therapy, or with any change in the dose,
as azathioprine has been associated with a doserelated, generally reversible, depression of bone
marrow function, most frequently expressed as leukopenia, specifically agranulocytosis, but also
sometimes as anemia and/or thrombocytopenia.
The blood count frequency may be reduced later in
therapy, but it is recommended that complete full
blood count is repeated at least 3 times monthly.
(3) There are no proper trials to support the use mycophenolate mofetil as a steroid-sparing agent in
recalcitrant OLP or widespread LP.57,64,65 However, mycophenolate has shown promise as an alternative to azathioprine as an immunomodulatory
agent with a better safety profile in the management
of graft rejection in organ transplant recipients, and
GVHD, and therefore may be a candidate for use in
recalcitrant OLP.57
Conclusions on current therapies of symptomatic
oral lichen planus. There is a distinct lack of randomized placebo-controlled trials that examine the efficacy
of various drugs treatments for OLP. The published
trials generally included small study populations and
lack proper documentation, which made it difficult to
accurately measure the outcome. Only limited therapies
were tested in randomized, placebo-controlled clinical
trials and they are not confirmed. Therefore, at present,
recommendations for the treatment of OLP are based
mainly on clinical experience.
Oral lichenoid lesions
Oral lichenoid contact lesions. Oral lichenoid contact lesions (OLCLs) are seen in direct topographic

Table II. Diagnostic criteria for oral lichenoid contact

lesions
Diagnostic feature
1

Clinical presentation

Histopathology

Results of patch testing

Results of covering/
replacement of
suspected causative
restorative material

Commentary
A direct topographic relationship
between the suspected
causative restorative material
and the lesion
Not always required, except for
exclusion of malignancy
Patch testing can assist in
determining what alternative
materials to use
Coverage/removal of the
suspected causative restorative
material(s) should result in
resolution of the lesion,
thereby establishing the
diagnosis

relationship to an offending agent. This reaction is most

often attributable to dental restorative materials, most
commonly amalgam.66-68 With the removal and replacement of the putative causative material, the majority of such OLCLs resolve within several months.
Contact of the oral mucosa to select dental restorative
materials, particularly mercury-containing amalgam,
appears to be able to induce a sensitivity response
resulting in immune-mediated damage of the basal epithelial keratinocytes.
Clinically and histologically, OLCL may be indistinguishable from OLP. However, the distinguishing feature of OLCL is the lesions direct topographic relationship to the suspected causative agent.66-75 Typical
sites include the lateral borders of the tongue and the
buccal mucosa, sites that have a direct anatomical relationship (i.e., direct contact) with the filling/dental
restoration(s) or another offending contact agent
(e.g., cinnamon). In OLP lesions, ulcerative areas
may also be found in close contact with dental materials. The difference is the extent of the lesions. In
OLCL, lesions are limited to such contacts, whereas
in OLP the lesions may affect oral mucosal sites not
in contact with restorations, the gingivae, or other
mucocutaneous sites, e.g., skin or vulvo-vaginal mucosa.66,72 A list of the main diagnostic criteria for
OLCL is mentioned in Table II. The duration of the
contact between the oral mucosa and the putative
causative material is likely an important factor in the
development of OLCL.
The evidence regarding the need and value of a
biopsy for histological confirmation of the diagnosis of
OLCL is not definitive, particularly as regards differentiating OLP from OLCL. A recent study confirmed

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Volume 103, Number 3, Suppl 1

the difficulty of distinguishing the 2 conditions on

histological features alone.20 Biopsy should be considered when the disease does not present with typical
manifestations.76
The value of cutaneous patch testing of a battery of
dental restorative materials, normally conducted on the
forearm or back of test subjects, remains controversial.47,52,67-70,74,77-79 Uncertainty remains with regard
to which mercurial/amalgam compounds or salts to use
in skin patch testing, distinguishing sensitivity from
irritant responses, how long test materials should remain in contact with the skin (72 hours, 96 hours, 7
days, 14 days, or even longer), and the value of skin
patch testing in identifying true OLCL. Furthermore,
there is debate about the validity of extrapolating skin
reactions to mucosal responses. Nonetheless, skin patch
testing might be helpful to the clinician particularly in
the determination of suitable replacement material
(those to which the patient has not demonstrated a
reaction).
The most recent review of the current literature regarding OLCLs was undertaken by Issa et al. in 2004,74
but notably, this was restricted to those lichenoid contact lesions related to mercury-containing amalgam fillings and only covered studies published up to 2000.
Nineteen studies met the inclusion criteria, but the
authors noted these were of variable quality. There
have been 3 other recent major studies published.20,66,69
There were no randomized controlled studies. Of the 22
studies, 17 were cohort studies and 5 were case controlled. The suspected causative filling material was
overwhelmingly mercury-containing amalgam. There
were also isolated case reports of lichenoid contact
lesions to the copper component of amalgam, as well as
to gold, porcelain, composite, and glass ionomer cement.71,73 In the studies by Thornhill et al.,20,66 the
combination of a positive patch test and a strong
clinical association between the lesions and amalgam
restorations was an excellent predictor of lesion improvement following amalgam replacement (with an
NNT 1.1 [the number of patients with a positive
result that would need to be treated to result in 1
successful treatment outcome]) and was a better predictor than either a positive patch test alone (NNT
2) or a strong clinical association alone (NNT
1.46). However, an earlier study by Ostman et al.79
did not find patch testing of value.
There are several case reports and cases within substantive trials in which spontaneous resolution of the
OLCLs has occurred without removal/replacement of
suspected filling material. OLCLs in rare cases may be
inherently precancerous.76
Oral lichenoid drug reactions. Oral lichenoid drug
reactions (OLDR) in contrast to cutaneous lichenoid

Al-Hashimi et al. S25.e7

drug reactions are uncommon. More recently, the literature has been replete with case reports and a few
limited studies of oral lichenoid drug reactions to angiotensin-converting enzyme (ACE) inhibitors and
nonsteroidal anti-inflammatory drugs (NSAIDs). However, oral hypoglycemic drugs, penicillamine, and gold
have also been frequently implicated. There are no
clear or distinct clinical or histological features that
reliably distinguish OLDR from oral lichen planus or
other lichenoid lesions.7,8,53,57,80 Drug reactions may
occur anytime, even years after the introduction of the
drug.81
The most reliable means of diagnosing a lichenoid
drug reaction is to note resolution of the reaction after
the suspected inciting drug is withdrawn, and to determine whether the reaction recurs when the patient is
rechallenged with the same drug. This is both impractical (since such reactions may take months to resolve)
and potentially dangerous. Therefore, confirmation of
the diagnosis of OLDR remains problematic. Unsurprisingly, there are no evidence-based studies regarding
OLDR.
Oral lichenoid lesion(s) of graft-versus-host disease
(OLL-GVHD). GVHD is a major complication that
arises in recipients of allogeneic hematopoietic stemcell or bone marrow transplantation. Although the etiopathogenesis of GVHD is not fully understood, it appears to be due to donor T-lymphocytes reaction to
minor histocompatibility tissue antigen expression by
recipient cells. GVHD is divided into acute, that is
occurring within 100 days after transplantation, or
chronic, appearing more than 100 days after transplantation. Acute GVHD affects predominantly 3 specific
organ systems: the skin, the liver, and the gastrointestinal tract (GIT), including the oral cavity. In chronic
GVHD (cGVHD) a greater number of organs tend to be
involved, and oral involvement, including salivary
glands, is more prevalent. Clinically and histologically
OLL-GVHD may be indistinguishable from OLP.64,82
Therefore, treatments successful in oral GVHD may be
applicable to the management of OLP. Also of interest
is the natural history of OLL-GVHD. Previous studies
suggest that GVHD and concomitant immunosuppressive therapy may increase the risk for solid cancers,
particularly squamous-cell carcinomas (SCCs) of the
oral cavity and skin.83-86 This would indicate that OLLGVHD, like OLP, is a condition associated with risk of
malignant transformation.
GVHD is a common complication of allogeneic hematopoietic stem-cell transplantation, despite aggressive prophylaxis. Depending on the source of the stem
cells, OLL-GVHD affects up to 70% of peripheral stem
cell recipients, as opposed to only 53% of patients who
receive bone marrow derived stem cells. The overall

S25.e8

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March 2007

Al-Hashimi et al.

incidence, regardless of stem-cell source, is 85%.82,87

OLL-GVHD contributes to patient morbidity in its own
right, but it may also serve as an indicator of active
GVHD involvement of critical organs such as the GIT,
liver, and lung.
Acute OLL-GVHD is often painful, being erythematous, ulcerated, or presenting with marked desquamation. Chronic OLL-GVHD predominantly presents as
keratotic white striae or plaques, with areas of erythema, erosion, or ulceration.82 The clinical features
alone are often sufficiently diagnostic, provided that
they are present in the setting of a patient who has been
a recipient of an allogeneic haematopoietic stem-cell
transplantation. Histological confirmation of OLLGVHD is indicated (1) in the absence of signs/symptoms of involvement of other systems or organs, or
when investigations of such other sites provide only
negative or nonspecific results; and (2) in cases of
atypical clinical presentation to exclude dysplasia/malignancy, especially as part of clinical monitoring of
patients with long-standing chronic disease.
A most up-to-date review of the various therapies for
OLL-GVHD has been published by Imanguli and colleagues.87 This review highlighted the issues in attempting to use an evidence-based approach to the
management of OLL-GVHD. Given that GVHD is
often a multiorgan disease, systemic therapy is indicated. Few if any studies specifically assess what the
effect is, if any, on oral GVHD. High-dose systemic
corticosteroids remain the mainstay of treatment for
GVHD. This is usually supplemented by one of the
calcineurin inhibitors, traditionally cyclosporine. However, more recent studies using systemic tacrolimus or
sirolimus are being reported. One study showed that in
8 patients with oral cGVHD (of a total of 19), 3 had
complete resolution and 5 a partial response to systemic
sirolimus.88 Extracorporeal photopheresis (ECP) employs the external aphaeresis of the patients mononuclear cells (thereby including the highly immunoreactive T cells), which are then sensitised to UV-A light by
the addition of 8-metoxypsoralen, and then returned to
the patient. It is particularly effective for cutaneous
cGVHD, as DallAmico et al.89 showed with 59 patients with oral cGVHD, of whom 63% responded.
Thalidomide has been evaluated in 1 study of 15 patients with only oral cGVHD, but its side effects required frequent cessation of the drug, and the overall
response was only 24%.90
Local therapies for oral cGVHD rely on topical agents,
predominantly corticosteroids. Success has been reported
with topical budesonide,91 dexamethasone mouthrinse,56
cyclosporine,92 and azathioprine.93,94 Topical tacrolimus
holds the most promise,95 but concerns about its oncogenic potential have been raised, which may limit its

future use. Local phototherapy with UV-A light plus the

use of topical or systemic leukocyte-sensitising psoralen is
of concern because of the oncogenic potential of ultraviolet light.5,53-56 Application of low-level laser has shown
anecdotal success.96
Given that GVHD often will involve multiple systems or organs, treatment for OLL-GVHD is usually
integral part of the systemic management. Treatment
specific and solely for OLL-GVHD is indicated as a
supplement to systemic therapy, particularly if intensifying the systemic immunosuppressive therapy can be
avoided. Unfortunately, to date there are few wellcontrolled trials of systemic therapy for GVHD that
have explicitly assessed the effect or benefits on OLLGVHD, and even more infrequent has been the assessment of therapies, local (topical) or systemic, specifically for OLL-GVHD.
In essence, the information regarding therapies for OLP
are applicable for OLL-GVHD, with the exception that
there have been no reports of the use of retinoids (systemic or topical) for OLL-GVHD and only a very limited
number of case reports regarding the use of retinoids in
cutaneous and ocular GVHD.97-99
In several of studies it was recognized that patients
with OLL-GVHD are at a statistically increased risk of
developing OSCC as compared with the general population.83-86 Therefore, long-term monitoring OLLGVHD is indicated. Surveillance for opportunistic infections presenting in the oral cavity is also warranted
for those patients on active immunosuppressive therapy
for GVHD.
SUMMARY
Current state
Oral lichen planus.

Biopsy and histological confirmation in cases of OLP

is recommended where there is uncertainty about the
diagnosis or where the lesions are clinically atypical
(to exclude the presence of dysplasia or malignancy).
Routine HCV testing of patients with OLP is not
indicated.
Topical corticosteroids (/ topical antimycotics)
are the first-line treatment; currently, there is insufficient evidence regarding different dosages, formulations, or modes of delivery of topical steroids (e.g.,
paste, spray, mouthwash) to make an evidence-based
recommendation about which is best.
Systemic corticosteroids (/ topical antimycotics)
are the first-line treatment only for severe, widespread OLP and for lichen planus involving other
mucocutaneous sites (e.g., vaginal/vulval LP) recalcitrant/resistant to topical therapies.

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Topical retinoids should be considered only as second-line therapy for OLP; systemic retinoids are not
recommended.
Topical calcineurin inhibitors should be considered
only as second-line therapy (see footnote).
UV light irradiation (PUVA) is not recommended for
OLP because of its oncogenic potential.
Hydroxychloroquine and azathioprine are useful as
steroid-sparing agents in systemic corticosteroidresponsive OLP, or widespread LP with oral involvement. Caution is indicated with these agents because
of the risk of retinal damage and marrow aplasia,
respectively.
Mycophenolate mofetil cannot be recommended at
this time because, as yet, there is insufficient evidence to support its use for the treatment of OLP.
At present, there is no concensus about the possible
premalignant character of OLP; nevertheless, monitoring is recommended, at least annually.

Al-Hashimi et al. S25.e9

Footnote:

Oral lichenoid lesions: Oral lichenoid contact lesions

(OLCL).

Histological confirmation of OLCL is recommended

in cases that are clinically atypical (to exclude the
presence of dysplasia or malignancy). Note: histopathology alone cannot reliably distinguish between
OLP and OLCL.
Skin patch testing of putative causative material and
any materials likely to be used as a substitute (gold,
composite, glass ionomer cement, and acrylic) may
be helpful in selected cases; readings need to be
taken at Days 3, 7, and 14, or even later to avoid
missing delayed reactions.
Treatment consists of removal/replacement/coverage
of restorations that are in direct physical contact with
mucosal lesions and that are thought to be playing a
causative role.

Oral lichenoid lesions: Oral lichenoid drug reactions

(OLDR).

A diagnosis of OLDR may be difficult to establish

because (1) of the lack of specific clinical and/or
histopathological features that distinguish OLDR
from OLP, (2) it may be hazardous to replace or
withdraw the offending drug, and (3) it may take
several months before a clinical change can be observed after the withdrawal of the offending drug.

Oral lichenoid lesions: Oral lichenoid lesions in graft

versus host disease (OLL-GVHD).

Histological confirmation of OLL-GVHD is indicated (1) in the absence of signs/symptoms of involvement of other systems or organs, or when investigations of such other sites provide only negative

or nonspecific results; and (2) in the case of atypical

clinical presentation to exclude dysplasia/malignancy, especially as part of clinical monitoring of
patients with long-standing chronic disease.
First-line treatment: topical corticosteroids (/ topical antimycotics) as an adjunct to systemic therapy
or for isolated lesions.
Second-line treatment: topical calcineurin inhibitors
as an adjunct to systemic therapy or for isolated
lesions (see footnote).
PUVA is not recommended for OLL-GVHD because
of its oncogenic potential.

Topical calcineurin inhibitors such as topical tacrolimus and pimecrolimus may perform better than topical cyclosporine; however, the evidence base for
their use in OLP and the different oral lichenoid
lesions is weak at present. Furthermore, clinicians
considering their use should be aware of the FDAs
Black Box warning about the possibility of an
increased risk of malignancy (squamous cell carcinoma and lymphoma) in patients using topical tacrolimus or pimecrolimus.

Future research directions

Future studies should contain definitions of the clinical descriptors used in the study (e.g., erythematous,
erosive, atrophic, or ulcerative) with a representative
photograph, and how such mucosal changes were
measured and monitored.100-102
Information should be provided about the duration of
the disease, past treatment, any comorbidity, and
whether histopathological examination has been performed.
The multiplicity of reports of different therapies for
OLP highlights the complexity of treatment for this
often-recalcitrant disease. For instance, in a recent
publication, topical clobetasol was shown to be more
effective than cyclosporine in inducing clinical improvement, whereas clobetasol caused more side effects than cyclosporine.103
Combination therapies or rotational therapeutic approaches may prove to be superior to monotherapy
for both disease control and limitation of side effects.
In view of concerns about the possibly premalignant
character of OLP, lifelong monitoring of patients is
advised.
In the future, molecular markers that are useful in
establishing the diagnosis or in predicting future malignant transformation of oral lichen planus and lichenoid lesions may become available.

S25.e10

Al-Hashimi et al.

REFERENCES
1. WHO Collaborating Centre for Oral Precancerous Lesions.
Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol
1978;46:518-39.
2. Van der Meij EH, Van der Waal I. Lack of clinicopathologic
correlation in the diagnosis of oral lichen planus based on the
presently available diagnostic criteria and suggestions for modification. J Oral Pathol Med 2003;32:507-12.
3. Eisenberg E. Clinical controversies in oral and maxillofacial
surgery: part one. Oral lichen planus: a benign lesion. J Oral
Maxillofac Surg 2000;58:1278-85.
4. Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB,
Thongprasom K. Current controversies in oral lichen planus:
report of an international consensus meeting. Part 1. Viral
infections and etiopathogenesis. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2005;100:40-51.
5. Lodi G, Scully, C, Carrozzo M, Griffiths M, Sugerman PB,
Thongprasom K. Current controversies in oral lichen planus:
report of an international consensus meeting. Part 2. Clinical
management and malignant transformation. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2005;100:164-78.
6. Chainani-Wu N, Lozada-Nur F, Terrault N. Hepatitis C and oral
lichen planus. A review of the literature. Oral Surg Oral Med
Oral Pathol Oral Radiol Endod 2004;98:171-83.
7. Eisen D, Carrozzo M, Bagan Sebastian JV, Thongprasom K.
Number V. Oral lichen planus clinical features and management. Oral Dis 2005;11:338-49.
8. Eisen D. Evaluating and treating patients with oral lichen planus. Dermatol Ther 2002;15:206-17.
9. Holmstrup P, Schiotz AW, Westergaard J. Effect of dental
plaque control on gingival lichen planus. Oral Surg Oral Med
Oral Pathol 1990;69:585-90.
10. Chaudhary S. Pyschosocial stressors in oral lichen planus. Aust
Dent J 2004;49:192-5.
11. Koray M, Dulger O, Ak G, Horasanli S, Ucok A, Tanyeri H,
et al. The evaluation of anxiety and salivary cortisol levels in
patients with oral lichen planus. Oral Dis 2003;9:298-301.
12. Picardi A, Abeni D. Stressful life events and skin diseases:
disentangling evidence from the myth. Pyschother Psychosom
2001;70:118-36.
13. Rojo-Moreno JL, Bagan JV, Rojo-Moreno J, Donat JS, Millan
MA, Jimenez Y. Psychologic factors and oral lichen planus. A
psychometric evaluation of 100 cases. Oral Surg Oral Med Oral
Pathol Oral Radiol Endodont 1998;86:687-91.
14. Silverman S Jr, Gorsky M, Lozada-Nur F. A prospective follow-up study of 570 patients with oral lichen planus: persistance, remission and malignant association. Oral Surg Oral Med
Oral Pathol 1985;60:30-4.
15. Van der Meij EH, Schepman KP, Van der Waal I. The possible
premalignant character of oral lichen planus and oral lichenoid
lesions: a prospective study. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2003;96:164-71.
16. Eisen D. The clinical features, malignant potential, and systemic associations of oral lichen planus: a study of 723 patients.
J Am Acad Dermatol 2002;46:207-14.
17. Gandolfo S, Richiardi L, Carrozzo M, Broccoletti R, Carbone
M, Pagano M, et al. Risk of oral squamous cell carcinoma in
402 patients with oral lichen planus: a follow-up study in an
Italian population. Oral Oncol 2004;40:77-83.
18. Mignogna MD, Lo Muzio L, Lo Russo L, Fedele S, Ruoppo E,
Bucci E. Clinical guidelines in early detection of oral squamous
cell carcinoma arising in oral lichen planus: a 5-year experience. Oral Oncol 2001;37:262-7.

OOOOE
March 2007
19. Wu NC, Silverman S Jr, Lozada-Nur F, Mayer P, Watson JJ.
Oral lichen planus. Patient profile, disease progression and
treatment responses. J Am Dent Assoc 2001;132:901-9.
20. Thornhill MH, Sankar V, Xu X-J, Barrett AW, High AS, Odell
EW, et al. The role of histopathological characteristics in distinguishing amalgam-associated oral lichenoid reactions and
oral lichen planus. J Oral Pathol Med 2006;35:233-40.
21. Chan ES, Thornhill M, Zakrzewska J. Interventions for treating
oral lichen planus: review. The Cochrane Library 2005;4:1-21.
22. Thongprasom K, Luangjarmekorn L, Sererat T, Taweesap W.
Relative efficacy of fluocinolone acetonide compared with triamcinolone acetonide in treatment of oral lichen planus. J Oral
Pathol Med 1992;21:456-8.
23. Tyldesley WR, Harding SM. Betamethasone valerate aerosol in
the treatment of oral lichen planus. Br J Dermatol 1977;96:659-62.
24. Vote AB, Schulten EA, Langendijk PN, Kostense PJ, van der
Waal I. Fluocinonide in an adhesive base for treatment of oral
lichen planus. A double-blind, placebo-controlled clinical
study. Oral Surg Oral Med Oral Pathol 1993;75:181-5.
25. Thongprasom K, Luengvisut P, Wongwatanakij A, Boonjatturus C. Clinical evaluation in treatment of oral lichen planus
with topical fluocinolone acetonide: a 2 year follow-up. J Oral
Pathol Med 2003;32:315-22.
26. Carbone M, Conrotto D, Carrozzo M, Broccoletti R, Gandolfo
S, Scully C. Topical corticosteroids in association with miconazole and chlorhexidine in the long-term management of atrophic-erosive oral lichen planus: a placebo-controlled and comparative study between clobetasol and fluocinonide. Oral Dis
1999;5:44-9.
27. Lozada-Nur F, Miranda C, Maleski R. A double blind clinical
trial on the efficacy and toxicity of clobetasol ointment on
Orabase and fluocinonide ointment in Orabase for the treatment
of chronic oral inflammatory diseases. Oral Surg Oral Med Oral
Pathol 1994;77:598-604.
28. Sardella A, Demarosi F, Oltolina A, Rimondini L, Carrassi A.
Efficacy of topical mesalazine compared with clobetasol propionate in treatment of symptomatic oral lichen planus. Oral Dis
1998;4:25-9.
29. Buajeeb W, Pobrurksa C, Kravaphan P. Efficacy of fluocinolone acetonide gel in the treatment of oral lichen planus. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:42-5.
30. Lo Muzio L, della Valle A, Mignogna MD, Pannone G, Bucci
P, Bucci E, et al. The treatment of oral aphthous ulceration or
erosive lichen planus with topical clobetasol propionate in three
preparations: a clinical and pilot study on 54 patients. J Oral
Pathol Med 2001;30:611-7.
31. Hegarty AM, Hodgson TA, Lewsey JD, Porter SR. Fluticasone propionate spray and betamethasone sodium phosphate
mouthrinse: a randomized crossover study for the treatment
of symptomatic oral lichen planus. J Am Acad Dermatol
2002;47:271-9.
32. Carbone M, Goss E, Carrozzo M, Castellano S, Conrotto D,
Broccoletti R, et al. Systemic and topical corticosteroid treatment in oral lichen planus: a comparative study with long-term
follow-up. J Oral Pathol Med 2003;32:323-9.
33. Campisi G, Giandalia G, De Caro V, Di Liberto C, Arico P,
Giannola LI. A new delivery system of clobetasol-17-propionate (lipid loaded microspheres 0.025%) compared with conventional formulation (lipophilic ointment in a hydrophilic
phase (0.025%) in topical treatment of atrophic/erosive oral
lichen planus. A Phase IV, randomized, observer-blinded, parallel group clinical trial. Br J Dermatol 2004;150:984-90.
34. Ungphaiboon S, Nittayanata W, Vuddhakul V, Maneenuan D,
Kietthubthew S, Wongpoowarak W, et al. Formulation and

OOOOE
Volume 103, Number 3, Suppl 1

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

efficacy of triamcinolone acetonide mouthwash for treating oral

lichen planus. Am J Health Syst Pharm 2005;62:485-91.
Hersle K, Mobacken H, Sloberg K, Thilander H. Severe oral
lichen planus: treatment with an aromatic retinoid (etretinate).
Br J Dermatol 1982;106:77-80.
Giustina TA, Stewart JC, Ellis CN, Regezi JA, Annesley T,
Woo TY, et al. Topical application of isotretinoin gel improves
oral lichen planus. Arch Drmatol 1986;122:534-6.
Regezi JA, Ellis CN, Stewart JC, Giustina TA. Histological
changes associated with the topical use of isotretinoin on oral
lichen planus. Oral Surg 1986;5:479-84.
Boisnic S, Branchet MC, Pascal F, Ben Slama L, Rostin M,
Szpirglas H. Topical tretinoin in the treatment of lichen planus
and leukoplakia of the mouth mucosa. A clinical evaluation.
Ann Dermatol Venereol 1994;121:459-63. French.
Buajeeb W, Kraivaphan P, Pobrurksa C. Efficacy of topical
retinoic acid compared with topical fluocinolone acetonide in
the treatment of oral lichen planus. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1997;83:21-5.
Petruzzi M, De Benedittis M, Grassi R, Cassano N, Vena G,
Serpico R. Oral lichen planus: a preliminary clinical study on
treatment with tazarotene. Oral Dis 2002;8:291-5.
Scardina GA, Messina P, Carini F, Maresi E. A randomized
trial assessing the effectiveness of different concentrations of
isotretinoin in the management of lichen planus. Int J Oral
Maxillofac Surg 2006;35:67-71.
Eisen D, Ellis CN, Duell EA, Griffiths CE, Voorhees JJ. Effect
of topical cyclosporine rinse on oral lichen planus. A doubleblind analysis. N Engl J Med 1990;323:290-4.
Gaeta GM, Serpico R, Femiano F, La Rotonda MI, Capello B,
Gombos F. Cyclosporin bioadhesive gel in the topical treatment
of erosive oral lichen planus. Int J Immunopathol Pharmacol
1994;7:125-32.
Harpenau LA, Plemons JM, Rees TD. Effectiveness of a low
dose of cyclosporine in the management of patients with oral
erosive lichen planus. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1995;80:161-7.
Sieg P, Von Domarus H, Von Zitzewitz V, Iven H, Farber L.
Topical cyclosporin in oral lichen planus: a controlled, randomized, prospective trial. Br J Dermatol 1995;132:790-4.
Olivier V, Lacour JP, Mousnier A, Garraffo R, Monteil RA,
Ortonne JP. Treatment of chronic erosive oral lichen planus
with low concentrations of topical tacrolimus. Arch Dermatol
2002;138:1335-8.
Kalikatsou F, Hodgson TA, Lewsey JD, Hegarty AM,
Murphy AG, Porter SR. Management of recalcitrant ulcerative lichen planus with topical tacrolimus. J Am Acad
Dermatol 2002;46:35-41.
Hodgson TA, Sahni N, Kaliakatsou F, Buchanan JA, Porter SR.
Long-term efficacy and safety of topical tacrolimus in the
management of ulcerative/erosive oral lichen planus. Eur J
Dermatol 2003;13:466-70.
Byrd JA, Davis MD, Bruce AJ, Drage LA, Rogers RS. Response of oral lichen planus to topical tacrolimus in 37 patients.
Arch Dermatol 2004;140:1508-12.
Swift JC, Rees TD, Plemons JM, Hallmon WW, Wright JC. The
effectiveness of 1% pimecrolimus cream in the treatment of oral
erosive lichen planus. J Periodontol 2005;76:627-35.
Becker JC, Houben R, Vetter CS, Brcker E. The carcinogenic
potential of tacrolimus ointment beyond immune suppression: a
hypothesis creating case report. BMC Cancer 2006;6:7-13.
Lundquist G, Forsgren H, Gajecki M, Emtestam L. Photochemotherapy of oral lichen planus. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 1995;79:554-8.

Al-Hashimi et al. S25.e11

53. Scully C, Eisen D, Carrozzo M. Management of oral lichen
planus. Am J Clinic Dermatol 2000;1:287-306.
54. Lindelof B, Sigurgersson B, Tegner E, Larko O, Johannesson
A, Berne B, et al. PUVA and cancer: a large scale epidemiologic study. Lancet 1991;338:91-3.
55. Bandow GD, Koo JY. Narrow-band ultraviolet B radiation: a
review of the current literature. Int J Dermatol 2004;43:555-61.
56. Wolff D, Anders V, Corio R, Horn T, Morison WL, Farmer E,
et al. Oral PUVA and topical steroids for treatment of oral
manifestations of chronic graft-vs-host disease. Photodermatol
Photoimmunol Photomed 2004;20:184-90.
57. Eisen D. The clinical manifestations and treatment of oral
lichen planus. Dermatol Clin 2003;21:79-89.
58. Eisen D. Hydroxychloroquine sulfate (Plaquenil) improves oral
lichen planus: an open trial. J Am Acad Dermatol 1993;28:609-12.
59. Klein LR, Callen JP. Azathioprine: effective steroid sparing therapy for generalized lichen planus. South Med J 1992;85:198-201.
60. Verma KK, Sirka CS, Khaitan BK. Generalized severe lichen
planus treated with azathioprine. Acta Derm Venereol
1999;79:493.
61. Silverman S Jr, Gorsky M, Lozada-Nur F, Giannotti K. A
prospective study of findings and management in 214 patients
with oral lichen planus. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 1991;72:665-70.
62. Verma KK, Sirka CS, Khaitan BK. Generalized severe lichen
planus treated with azothioprine. Acta Derm Venereol 1999;
79:493.
63. Lozada-Nur F. Prednisone and azathioprine in the treatment of
oral inflammatory mucocutaneous diseases. Oral Surg Oral Med
Oral Pathol 1981;52:257-60.
64. Basara N, Blau WI, Romer E, Rudolphi M, Bischoff M, Kirsten
D, et al. Mycophenolate mofetil for the treatment of acute and
chronic GVHD in bone marrow transplant patients. Bone Marrow Transplant 1998;22:61-5.
65. Frieling U, Bonsmann G, Schwarz T, Luger TA, Beissert S.
Treatment of severe lichen planus with mycophenolate mofetil.
J Am Acad Dermatol 2003;49:1063-6.
66. Thornhill MH, Pemberton MN, Simmons RK, Theaker ED.
Amalgam-contact hypersensitivity lesions and oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod
2003;95:291-9.
67. Laeijendecker R, Dekker SK, Burger PM, Mulder PG, Van
Joost T, Neumann MH. Oral lichen planus and allergy to dental
amalgam restorations. Arch Dermatol 2004;140:1434-8.
68. Lopez-Jornet P, Camacho-Alonso F, Gomez-Garcia F, Bermejo
Fenoll A. The clinicopathological characteristics of oral lichen
planus and its relationship with dental materials. Cont Dermat
2004;51:210-1.
69. Issa Y, Duxbury AJ, Macfarlane TV, Brunton PA. Oral lichenoid lesions related to dental restorative materials. Br J Dent
2005;198:361-6.
70. Lind PO. Oral lichenoid reactions related to composite restorations: preliminary report. Acta Odontol Scand 1988;46:63-5.
71. Blomgren J, Axell T, Sandahl O, Jontell M. Adverse reactions
in the oral mucosa associated with anterior composite restorations. J Oral Pathol Med 1996;25:311-3.
72. Dunsche A, Kstel I, Terheyden H, Springer ING, Chirstophers E,
Brasch J. Oral lichenoid reactions associated with amalgam: improvement after amalgam removal. Br J Dermatol 2003;148:70-6.
73. Larsson A, Warfvinge G. The histopathology of oral mucosal
lesions associated with amalgam or porcelain-fused-to-metal
restorations. Oral Dis 1995:1:152-8.
74. Issa Y, Brunton PA, Glenny AM, Duxbury AJ. Healing of oral
lichenoid lesions after replacing amalgam restorations: a sys-

S25.e12

75.

76.

77.

78.

79.

80.
81.
82.
83.

84.

85.

86.

87.

88.

89.

90.

OOOOE
March 2007

Al-Hashimi et al.

tematic review. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2004;98:553-65.
Bratel J, Hakeberg M, Jontell M. Effect of replacement of
dental amalgam on oral lichenoid reactions. J Dent 1996;
24:41-5.
Larsson A, Warfvinge G. Oral lichenoid contact reactions may
occasionally transform into malignancy. Eur J Cancer Prevention 2005;14:525-9.
Skoglund A. Value of epicutaneous patch testing in patients
with oral, mucosal lesions of lichenoid character. Scand J Dent
Res 1994;102:216-22.
Koch P. Bahmer FA. Oral lesions and symptoms related to
metals used in dental restorations: a clinical, allergological, and
histologic study. J Am Acad Dermatol 1999;41:422-30.
Ostman PO, Anneroth G, Skoglund A. Amalgam-associated
oral lichenoid reactions. Clinical and histological changes after
removal of amalgam fillings. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 1996;81:459-65.
McCarten BE, McCreary CE, Healy CM. Studies of drug-induced
lichenoid reactions [guest editorial]. Oral Dis 2002;9:163-4.
McCartan BE, McCreary CE. Oral lichenoid drug eruptions.
Oral Dis 1997;3:58-63.
Woo S-B, Lee SJ, Schubert MM. Graft-vs-host-disease. Crit
Rev Oral Biol Med 1997;8:201-16.
Sato M, Tokunda N, Fukumoto T, Mano T, Sato T, Ueyama Y.
Immunohistopathological study of oral lichenoid lesions of
chronic GVHD. J Oral Pathol Med 2006;35:33-6.
Abdelsayed RA, Sumner T, Allen CM, Treadway A, Ness GM,
Penza SL. Oral precancerous and malignant lesions associated
with graft-versus-host disease: report of 2 cases. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod 2002;93:75-80.
Szeto CH, Shek TW, Lie AK, Au WY, Yuen AP, Kwong YL.
Squamous cell carcinoma of the tongue complicating chronic
oral mucosal graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Am J Hematol 2004;7:200-2.
Curtis RE, Metayer C, Rizzo JD, Socie G, Sobocinski KA,
Flowers ME, et al. Impact of chronic GVHD therapy on the
development of squamous-cell cancers after hematopoietic
stem-cell transplantation: an international case-control study.
Blood 2005;105:3802-11.
Imanguli MM, Pavletic SZ, Guadagnini J-P, Brahim JS, Atkinson JC. Chronic graft versus host disease of oral mucosa:
review of available therapies. Oral Surg Oral Med Oral Pathol
Oral Radiol Endod 2006;101:175-83.
Johnston L, Brown J, Shizuru JA, Stockerl-Goldstein KE,
Stuart MJ, Blume KG, et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow
Transplant 2005;11:47-55.
DallAmico R, Messina C. Extracorporeal photochemotherapy
for the treatment of graft-versus-host disease. Ther Apher
2002;6:296-304.
Parker P, Chao N, Nademanee A, ODonnell MR, Schmidt DM,
Snyder DS, et al. Thalidomide as salvage therapy for chronic
graft-versus-host disease. Blood 1995;86:3604-9.

91. Elad S, Or R, Garfunkel AA, Shapira MY. Budesonide: a novel

treatment for oral chronic graft versus host disease. Oral Surg
Oral Med Oral Pathol Oral Radiol Endod 2003;95:308-11.
92. Epstein J, Reece DE. Topical cyclosporin A for treatment of
oral chronic graft-versus-host disease. Bone Marrow Transplant
1994;13:81-6.
93. Epstein JB, Nantel S, Shealtch SM. Topical azathioprine in the
combined treatment of chronic oral graft-versus-host disease.
Bone Marrow Transplant 2000;25:683-7.
94. Epstein JB, Epstein MS, Nantel S. Topical azathioprine in the
treatment of immune-mediated chronic inflammatory conditions. A series of cases. Oral Surg Oral Med Oral Pathol Oral
Radiol Endod 2001;91:56-61.
95. Choi C, Nghiem P. Tacrolimus ointment in the treatment of
chronic cutaneous graft-vs-host disease: a case series of 18
patients. Arch Dermatol 2001;137:1202-6.
96. Elad S, Or R, Shapira MY, Galili D, Garfunkel AA, Bitan M,
et al. CO2 laser in oral graft-versus host disease: a pilot study.
Bone Marrow Transplant 2003;32:1031-4.
97. Murphy PT, Sivakumaran M, Fahy G. Hutchinson RM. Successful use of topical retinoic acid in severe dry eye due to
chronic graft-versus-host disease. Bone Marrow Transplant
1996;18:641-2.
98. Gryn J, Crilley P. Tretinoin for the treatment of cutaneous graftversus-host disease. Bone Marrow Transplant 1990;5:279-80.
99. Schleuning M, Stoetzer O, Waterhouse C, Schlemmer M, Ledderose G, Kolb HJ. Hematopoietic stem cell transplantation
after reduced-intensity conditioning as treatment of sickle cell
disease. Exp Hematol 2002;30:7-10.
100. Rebora A. Erosive lichen planus: what is this? [editorial].
Dermatol 2002;205:226-8.
101. Piboonniyom S-O, Treister N, Pitiphat W, Woo S-B. Scoring
system for monitoring oral lichenoid lesions: a preliminary
study. Oral Surg Oral Med Oral Pathol Oral Radial Endod
2005;99:696-703.
102. Bethke G, Reichart PA. Assessment of severity of oral lichen
planus using a new clinical index. Mund Kiefer Gesichtschir
2005;9:152-60.
103. Conrotto D, Carbone M, Carrozzo M, Arduino P, Broccoletti R,
Pentenero M, et al. Cyclosporin vs clobetasol in the topical management of atrophic and erosive oral lichen planus: a double-blind,
randomized controlled trial. Br J Dermatol 2006:154:139-45.

Reprint requests:
Isac van der Waal, DDS, PhD
Department of Oral and Maxillofacial Surgery/Oral Pathology
VU university medical centre (VUmc)/Academic Centre for
Dentistry Amsterdam (ACTA)
PO Box 7057
1007 MB Amsterdam
The Netherlands
i.vanderwaal@vumc.nl