Diagnosis of oral lichen planus: a position paper of the ......2017/02/01 · Diagnosis of oral lichen planus: a position paper of the American Academy of Oral and Maxillofacial Pathology

Diagnosis of oral lichen planus: a position paper of theAmerican Academy of Oral and Maxillofacial Pathology

Yi-Shing Lisa Cheng, DDS, MS, PhD,a Alan Gould, DDS, MS,b Zoya Kurago, DDS, PhD,c John Fantasia, DDS,d

and Susan Muller, DMD, MSe

Texas A&M University College of Dentistry, Dallas, TX, USA, Louisville Oral Pathology Laboratory, Louisville, KY, USA, Augusta University,

Augusta, GA, USA, Hofstra North Shore-Long Island Jewish Health System, New Hyde Park, NY, USA, and Atlanta Oral Pathology, Decatur, GA,

USA

Despite being one of the most common oral mucosal diseases and recognized as early as 1866, oral lichen planus

(OLP) is still a disease without a clear etiology or pathogenesis, and with uncertain premalignant potential. More research is

urgently needed; however, the research material must be based on an accurate diagnosis. Accurate identification of OLP is

often challenging, mandating inclusion of clinico-pathological correlation in the diagnostic process. This article summarizes

current knowledge regarding OLP, discusses the challenges of making an accurate diagnosis, and proposes a new set of

diagnostic criteria upon which to base future research studies. A checklist is also recommended for clinicians to provide

specific information to pathologists when submitting biopsy material. The diagnostic process of OLP requires continued

clinical follow-up after initial biopsy, because OLP mimics can manifest, necessitating an additional biopsy for direct

immunofluorescence study and/or histopathological evaluation in order to reach a final diagnosis. (Oral Surg Oral Med Oral

Pathol Oral Radiol 2016;122:332-354)

Perhaps no disease in the field of oral pathology and

medicine has generated more discussion and been asso-

ciated with more controversy than oral lichen planus

(OLP). Although much effort has been invested in clin-

ical, pathologic, and basic science research studies,

inconsistent results and diverse opinions still leave many

questions unanswered regarding etiology, pathogenesis,

and premalignant potential. While this fact obviously

points to the need for more research on OLP, any useful

investigations must be based on an accurate diagnosis.

However, a reliable diagnosis of OLP has proven chal-

lenging for a few reasons (as shall be explained later in

this article), and significant disagreements concerning

its diagnosis continue to be found among pathologists

and clinicians. Therefore, the main purposes of this

article are to discuss the challenges in making the diag-

nosis of OLP and to propose a new set of diagnostic

criteria by adding additional elements to the existing

modified WHO criteria proposed by Van der Meij and

van der Waal.1 A brief review of the current knowledge

about OLP is included as background. As we

emphasize clinicopathologic correlation in making

the diagnosis of OLP, we also recommend that a

checklist encompassing all important, relevant, clinical

information be provided to pathologists, together with

the biopsy, to aid in establishing an accurate diagnosis.

OVERVIEW OF OLP AND ITS COMPLEXITIESHistorical backgroundThe initial clinical description of lichen planus (LP) is

generally attributed to FerdinandRitter vonHebra, who in

1860 termed the condition “lichen ruber planus.”2 The

clinical definition was refined through the work of

Erasmus Wilson and Moritz Kaposi, with the former

being the first to simplify the name to “lichen planus.”

Wilson offered the first published description of oral

lichen planus (OLP) in 1866, noting a white papular

eruption of the tongue and buccal and mandibular labial

mucosa in a 56-year-old female.3 This was followed by

his report in 1869 of 50 additional patients with OLP.4

Characterization of white striations in cutaneous LP was

provided by Louis Wickham in 1895.2,5 It is useful to

recognize that from the time of its initial identification,

OLP was discussed, studied, and diagnosed for 40 years

entirely as a clinical disorder without any histopathologic

characterization, as microscopic features would not be

delineated until the work of William Dubreuilh in 1906.4

Efforts to identify keyclinical and histopathologic criteria,

and to design a valid method of clinicopathologic

correlation to ensure accurate diagnosis of OLP, have

been both challenging and elusive, occupying the

efforts of numerous investigators for over a century.

Epidemiology and clinical featuresThe prevalence of LP is estimated at 0.22% to 5%

worldwide,6 and the incidence of OLP is estimated at

aDepartment of Diagnostic Sciences, Texas A&M University College

of Dentistry, Dallas, TX, USA.bLouisville Oral Pathology Laboratory, Louisville, KY, USA.cDepartment of Oral Health and Diagnostic Sciences, College of

Dental Medicine, Augusta University, Augusta, GA, USA.dDepartment of Dental Medicine, Hofstra North Shore-Long Island

Jewish Health System, New Hyde Park, NY, USA.eProfessor Emeritus, Emory University School of Medicine, Atlanta,

GA; Atlanta Oral Pathology, Decatur, GA, USA.

Received for publication Feb 18, 2016; returned for revision May 3,

2016; accepted for publication May 11, 2016.

� 2016 Published by Elsevier Inc.

2212-4403/$ - see front matter

http://dx.doi.org/10.1016/j.oooo.2016.05.004

332

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up to 2.2%.7 Patients with cutaneous LP are estimated

to exhibit oral disease expression in up to 60% of

cases.7,8 However, only a minority of OLP patients,

approximately 15%, develop cutaneous lesions.9-11

Aside from oral and cutaneous disease expression,

additional characteristic anatomic distributions of LP

are recognized (e.g., peno-gingival syndrome, vulvo-

vaginal-gingival syndrome). LP in the genitalia occurs

in approximately 20% of patients with OLP, and con-

current oral and esophageal LP is also observed.8 Scalp

lesions with alopecia, and disease expression in nails,

glans penis, and conjunctivae are recognized.12

OLP most often occurs in persons 30 to 80 years of

age, with a greater prevalence in females.2,6,8,13

Although OLP is rare in children,14 a recent report

described 316 pediatric patients with LP (ages

0-14 years), representing 18.76% of all patients

attending an LP clinic, and 18% of this childhood LP

population were reported to have oral involvement.15

Interestingly, a slight male predominance was noted

in pediatric LP cases.15 Approximately two-thirds of

patients with OLP experience discomfort.8 Symptom

intensity is variable and expressed in some cases only

upon contact with spicy or acidic foods. Spontaneous

symptoms are also described. A sense of mucosal

roughness, reduced mucosal flexibility, and limited

opening of the mouth are noted. Significant negative

impact on quality of life is emphasized.6,7

Characteristic clinical features of OLP include

well-defined looping and intersecting white lines or

striae on a background of minimal to substantial

erythema (Figure 1A).2,6,8,12,13 A roughly symmetric

distribution is typical, commonly affecting the buccal

mucosa, gingiva, and tongue. Six patterns of clinical

expression of OLP are recognizeddnamely: reticular,

atrophic, erosive, papular, plaque, and bullous

(see Figures 1A-F).6,16 When OLP affects gingiva, it

often presents as desquamative gingivitis, which can be

indistinguishable clinically from some OLP mimics

(see “Challenges in Diagnosis of OLP”). The preva-

lence of a reticular pattern appears to diminish with

increased duration of disease. Plaque-type lesions have

been reported more commonly in cigarette smokers,

with lesion persistence unaffected by tobacco cessa-

tion.17 In dark-skinned individuals, a pigmented retic-

ular pattern is sometimes seen (Figure 1G).

Histopathologic features and directimmunofluorescence findingsMicroscopic features of OLP include hyper-

parakeratosis, hyperorthokeratosis, and combinations of

the two; cytoid (Civatte) bodies18; basal cell hydropic

change; and a band-like chiefly lymphocytic infiltrate

in the lamina propria.19 This pattern of inflammatory

change has been termed “interface mucositis,” which

is also encountered in oral lesions of lupus

erythematosus and in additional oral lichenoid

conditions.20,21 Figures 2A-C depict characteristic

histopathologic alterations in a case clinically

presenting with the reticular pattern. Additional

findings include saw-tooth rete ridges, atrophy, acan-

thosis, a homogeneous eosinophilic deposit at the

epithelium-connective tissue junction, and ulceration.

Compared to cutaneous disease, oral lesions less often

exhibit saw-tooth rete ridges and more frequently

exhibit atrophy.4,6 Biopsy specimens of OLP may show

melanosis and melanin incontinence with associated

melanophages, particularly in individuals with dark

complexions (Figure 2D). Melanin incontinence is not

specific to OLP, and is encountered in a wide range

of inflammatory disorders sharing a lichenoid

inflammatory process.22

Direct immunofluorescence (DIF) is a diagnostic

adjunct that may be employed to help support a diag-

nosis of OLP. For example, DIF is often necessary to

differentiate OLP from autoimmune blistering diseases

that typically present as desquamative gingivitis (see

“Challenges in Diagnosis of OLP”).23,24 Deposition of

fibrinogen in a shaggy pattern along the basement

membrane zone (BMZ) in the absence of immuno-

globulin (except for cytoid bodies, which are coated by

immunoglobulin)25 and complement is the

characteristic immunofluorescence pattern found in

OLP.12 However, fibrinogen at the basement

membrane has been reported in premalignant and

malignant oral lesions,26 indicating that this finding is

not specific for OLP (see “Challenges in Diagnosis of

OLP”). DIF requires submission of fresh tissue for

frozen sections or tissue placed in an appropriate

transport medium (Michel’s solution). DIF adds cost

to the diagnostic process, but may be necessary in

situations where available clinical and pathologic

information are insufficient to support a definitive

diagnosis of OLP. Indirect immunofluorescence (IIF)

is negative and not a useful technique in diagnosis

of OLP.

Etiology and pathogenesisThe etiology of OLP is unknown, and its clinical course

suggests that OLP and cutaneous LP may encompass

differences in respective pathogenesis mechanisms. A

number of potential triggers and contributing factors in

OLP have been proposed, including: 1) local and sys-

temic inducers of cell-mediated hypersensitivity; 2)

stress; 3) autoimmune response to epithelial antigens;

and 4) microorganisms.27 Hypersensitivity responses

generally align with lichenoid mucositis, such as

those seen with local reactions to dental restorative

OOOO ORIGINAL ARTICLE

Volume 122, Number 3 Cheng et al. 333


Fig. 1. Clinical patterns of OLP. A, Reticular. B, Atrophic. C, Erosive. D, Papular (in area close to the retractor, image courtesy of

Dr. John Wright). E, Plaque (image courtesy of Dr. Gil Selkin). F, Bullous. G, In dark-skinned individuals, pigmentation can be

seen associated with the reticular pattern. OLP, oral lichen planus.

ORAL AND MAXILLOFACIAL PATHOLOGY OOOO

334 Cheng et al. September 2016


materials or flavoring agents, or adverse responses to

systemic medications.21,28-31 The role of psychologi-

cal stress is unclear, as the cause and effect relationship

between stress and onset of OLP has not been estab-

lished.32-34 Definitive evidence for autoimmunity in

OLP has not been demonstrated, although a number of

studies point to dysregulated immune responses, which

allow for the possibility of autoimmunity.35-37 Several

microbial agents have been investigated for their

possible role in OLP, of which hepatitis C virus has

thus far emerged as the only microorganism with a

convincing association, and that only in some

geographic regions.27,38-42 Autoimmunity leads the list

of proposed theories for hepatitis C virus-associated

OLP, but a mechanism has yet to be determined.

Evidence collected from patients with OLP, primar-

ily with erosive or reticular forms of the disorder,

indicate mainly a type 1 immune response leading to

damage of oral mucosal surface epithelium.43-48 This

response involves participation of plasmacytoid and

myeloid dendritic cells,49-51 CD4þ and CD8þ

T cells,44,52-55 natural killer cells,50 and mast cells,52,56

and is dominated by soluble factors characteristic of

type 1 responses (interferons, interleukin-12, tumor

necrosis factor alpha, and other factors), without

apparent contributions by B lymphocytes and anti-

bodies. Important studies of other mucosal factors, such

as the oral microflora and receptors that control anti-

microbial responses, are currently in their early

stages.57-61 Whether the destruction of keratinocytes in

OLP occurs due to autoreactivity or as a bystander

effect (i.e., due to a dysregulated response to an exog-

enous antigen) has not been resolved. A more detailed

account of the current views on etiology and patho-

genesis of OLP is described elsewhere.62-64

ManagementAppropriate management of patients with OLP has

been explored in several recently published compre-

hensive reviews.2,8,13 The importance of patient edu-

cation before treatment is emphasized.2 The patient

should be advised that therapy is not curative but is

directed at controlling inflammation and reducing the

associated symptoms. As response to therapy is often

delayed and continuous maintenance is necessary, it is

Fig. 2. Histopathologic features of the reticular form of OLP. A, Oral mucosal stratified squamous epithelium exhibits a thickened

surface layer of parakeratin, saw-tooth rete ridge morphology, a thin eosinophilic band adjacent to the basal cell layer, and a dense

band-like chronic inflammatory cell infiltrate in the superficial lamina propria (H&E stain, original magnification �100). B, A

dense predominantly lymphocytic infiltrate is situated in the lamina propria abutting oral mucosal stratified squamous epithelium.

Hydropic degeneration in basal cells is apparent. Dissolution of the basement membrane is also seen (H&E stain, original

magnification �250). C, Lymphocyte-mediated injury of oral mucosal stratified squamous epithelium, with keratinocyte apoptosis

represented as a colloid (Civatte) body (arrow, H&E stain, original magnification �400). D, Melanosis and melanin incontinence

with associated melanophages can sometimes be found, especially in biopsies from individuals with dark complexions (insert,

H&E stain, original magnification �250). OLP, oral lichen planus; H&E, hematoxylin and eosin.




best that patients are prepared for prolonged periods of

treatment. Because variation in patient response to

specific therapies is well recognized, patients should

be warned that sequential use of several treatment

regimens may be necessary before effective symptom

control is achieved. Patients also should be advised of

possible linkages of OLP to development of oral

cancer, although this aspect of OLP remains

controversial (more discussion in “Controversy

regarding malignant transformation”). This knowledge

will aid in developing, accepting, and implementing a

long-term patient monitoring plan.

The potential for clinicopathologic mimicry of OLP

is significant, and the patient should be made aware of

this before initiation of therapy (more discussion in

“Challenges in Diagnosis of OLP”). It must be made

clear that although the presence of oral cancer and

epithelial dysplasia are ruled out based on histopatho-

logic findings, continued clinical follow up is still

necessary, not only for adequate control of disease, but

also for appropriate management of changes that may

occur either in response to OLP-specific treatment or in

the context of other systemic disorders managed with

medications. Confidence in diagnostic validity is most

often achieved through patient clinical observation over

time, noting responses to therapies and sequential

evaluation of oral mucosal status. For example, a

pattern of clinical presentation and histopathologic data

may fulfill the criteria for OLP, and early patient clin-

ical response to conventional topical therapy may

appear to substantiate this diagnosis. However, failure

to maintain acceptable control of OLP after continued

initial and subsequent alternative therapies would

mandate additional patient evaluation and testing (e.g.,

DIF and IIF studies, rheumatologic evaluation, and

patch testing). Positive findings in this process would

likely identify a lichenoid clinicopathologic mimic

(e.g., chronic ulcerative stomatitis, lichen planus pem-

phigoids, lupus erythematosus, paraneoplastic

pemphigus, contact hypersensitivity), permitting initia-

tion of a more appropriate patient management strategy.

The process of patient evaluation, initiation of treat-

ment, assessment of clinical response, and selection of

alternative and ultimately effective treatment protocols

may require months to years. Both the patient and the

clinician should be prepared for this process.

A wide variety of therapies are described for control

of OLP, including topical, locally injected, and

systemic corticosteroids2,7,8,12,13; doxycycline; topical

retinoids2,8,9; topical calcineurin inhibitors65;

hydroxychloroquine; azathioprine; mycophenolate

mofetil; methotrexate; dapsone; thalidomide;

phototherapy2; biological agents (e.g., efalizumab,

etanercept, alefacept, rituximab)66; topical aloe vera;

and oral curcuminoids.67 The validity of selection

among treatment options is hampered by the paucity

of relevant published placebo-controlled double-blind

studies, and the absence of consensus-based objective

measures of disease activity. Attention to maintenance

of good oral hygiene,2,8,12,68 detection and control of

candida species infection,69 as well as assessment and

management of salivary gland hypofunction70 are

required for successful therapeutic outcomes.

Controversy regarding malignant transformationEver since the first known clinical report about

malignant transformation in OLP was published in the

medical literature in 1924,71 there has been an

unresolved controversy regarding whether OLP

should be considered a premalignant condition. For

the purposes of this article, a brief overview of this

controversy is described below. Readers interested in

detailed discussions of the malignant potential of

OLP are encouraged to read the several excellent

published reviews.27,72-76

The reported OLP malignant transformation rates

vary from 0.4% to 12.5%,27,72-77 with an overall

average rate of 1.09% cited in a recent meta-analysis

and systematic review of 7,806 patients in 16

studies.72 For this reason, in 2005 the World Health

Organization (WHO) in their Global Oral Health

Program designated OLP a premalignant condition.78

Many OLP studies have investigated molecular events

and mechanisms involved in carcinogenesis, such as

telomerase activity, cytogenetic abnormalities,

expression of p53, MDM2, p21, SUMO-1, PCNA,

argyrophilic nucleolar organizer regions (AgNOR),

Ki-67, Bcl-2, BAX, and loss of heterozygosity at the

tumor suppressor gene loci.79-96 However, the results of

these studies have not shown evidence of premalignant

potential as convincing, consistent, or conclusive as that

characterizing epithelial dysplasia. Therefore, the

controversy regarding the premalignant nature of OLP

remains unresolved.

This issue is challenging to resolve for at least the

following reasons:

1. A structured, standardized basis for reporting data

is lacking, and important clinical information and/or

histopathologic evidence are often missing in pub-

lications.72,77 In some reports the diagnosis of OLP

was made solely on the clinical presentation without

histopathologic confirmation. It is therefore difficult

or impossible to determine whether the reported

cases were accurately diagnosed as OLP, and

therefore doubts must be cast upon the validity of

outcomes and conclusions.

2. Many other oral diseases may show clinical and

microscopic features similar to those found in OLP,

including proliferative verrucous leukoplakia (more




Table I. Differential diagnosis of oral lichen planus

Pathologic condition Clinical features Histopathological features Immunofluorescent findings

OLP Multifocal, usually bilateral affecting buccal mucosa,

tongue, lips, and gingiva; can appear as desquamative

gingivitis; white reticular patches with or without

erosions and ulcerations.

Reticular form: Hyperkeratosis with basal cell degeneration,

necrosis of basal and parabasal keratinocytes, and a band-like

predominantly lymphocytic infiltrate adjacent to basal cells.

Erosive form: Sub-basal separation with basal cell degeneration;

inflammation may contain plasma cells; reactive, regenerative,

or reparative epithelial changes may be seen in these cases and,

depending on the degree of ulceration, pathologic features may

be less distinct.

DIF: Usually negative, may

see shaggy fibrinogen

deposition at BMZ and

colloid bodies.

IIF: Negative.

MMP Often presents as desquamative gingivitis; erosions and

ulcers without a reticular component; rare intact bullae;

frequently affects other oral mucosal sites, such as

buccal mucosa and palate.

Sub-basilar epithelial separation without basal cell liquefaction;

inflammation mixed and often sparse.

DIF: Linear IgG and C3 at

BMZ; less often IgA,

IgM, and fibrin.

IIF: Linear IgG and/or IgA

at BMZ (low titer); salt

split skin shows linear IgG

and/or IgA at roof or floor

of the split.

Lichen planus

pemphigoides

Combined features of lichen planus and pemphigoid

(vesicles or bullae) on oral mucosa, skin, or both.

Most often affects buccal mucosa and gingiva, although

palate, vestibule, and labial mucosa can also be involved.

Features of OLP (basal cell degeneration, thickening and dissolution

of basement membrane, band-like lymphocytic infiltrate in

superficial lamina propria), MMP (sub-basilar epithelial

separation), or both.

DIF: Same as MMP.

IIF: Immunoglobulin

(most often IgG) at BMZ.

Chronic graft-versus-

host disease

Similar to OLP; history of bone marrow transplant. Basal cell degeneration with subepithelial lymphocytic infiltrate (may

be sparse).

DIF: May be similar to OLP.

IIF: Negative.

Chronic ulcerative

stomatitis

Similar to OLP. Similar to OLP. DIF: Stratified SES-ANA

in lower third of epithelium.

IIF: SES-ANA positive.

Oral lichenoid

drug reactions

Similar to OLP; may see a temporal relationship with

offending drug, but delayed onset of more than 1 year

has been reported.

Similar to OLP but mixed inflammation, may extend into the deep

lamina propria, may show perivascular inflammation.

DIF: Similar to OLP.

IIF: Usually negative.

Oral lichenoid contact

hypersensitivity

reactions

Can be unilateral or bilateral; topographic relationship to

dental restorations, flavoring agents (Table III).

Similar to OLP but inflammation mixed; may see lymphoid follicles

in reactions to dental materials; perivascular inflammation and

scattered eosinophils; epithelial acanthosis in cinnamon reaction.

DIF: Similar to OLP.

IIF: Usually negative.

Lupus erythematosus Oral involvement in up to 25% of cases and resembles erosive

OLP; hard palate often affected; central area of ulceration

surrounded by radiating keratotic striae.

Similar to OLP; sometimes deep perivascular inflammation. DIF: Linear band or

continuous granular IgG,

IgM, IgA, or C3 at BMZ.

IIF: Negative.

Proliferative verrucous

leukoplakia

Multifocal keratotic lesions with a predilection for the gingiva,

palate, and tongue in elderly females; erosive lesions can

occur, mimicking erosive OLP.

Varies, but one pattern may exhibit a lichenoid appearance with a

band-like inflammatory cell infiltrate, saw-tooth rete ridges, and

inflammatory cell transmigration through the epithelium;

hyperchromatic, pleomorphic nuclei with varying degrees of

cytologic atypia may be present.

DIF: May show fibrinogen

deposition along BMZ

IIF: Unknown.

(continued on next page)

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discussion in “Challenges in Diagnosis of OLP”).

In fact, it is not uncommon to see microscopic

lichenoid features in dysplasia and oral squamous

cell carcinoma (OSCC).97,98 Therefore, misdiagnosis

of OLP can occur, especially when limited clinical

information is provided, or when atypical cellular

changes that are premalignant in nature are mild in

degree and/or accompanied by a lichenoid infiltrate.

3. There are currently still no widely accepted diag-

nostic criteria for OLP. Some pathologists use the

WHO criteria, which did not address a way to

distinguish or exclude epithelial dysplasia from

the OLP diagnosis.19 Application of WHO criteria

has appeared to reveal great interobserver and

intraobserver variability.99 Others use the modified

diagnostic criteria proposed by van der Meij and

van der Waal,1 in which the presence of epithelial

dysplasia precludes a diagnosis of OLP. Absence

of broad consensus in selection of diagnostic

criteria has been identified as the major obstacle to

assuring the validity of studies investigating OLP

potential for undergoing malignant transformation.73

It is clear that more research is needed to address the

complex issues concerning the potential or actual

transformation of OLP to oral cancer.

CHALLENGES IN DIAGNOSIS OF OLPThe challenges in making the diagnosis of OLP include

the following:

1. Various other disorders clinically and/or histopath-

ologically resemble OLP (Table I).

2. The histopathologic features of OLP appear to fall

on a spectrum, potentially influenced by the stage of

the disease activity at the time of the biopsy, by any

recent therapy of the condition, the clinical types

(reticular vs erosive), and/or the anatomic sites

(buccal mucosa vs gingiva).

3. Many microscopic features of OLP are not specific

for OLP and can be found in other diseases.

These challenges are discussed in detail below.

Various disorders may present with clinical and/orhistopathologic features similar to OLP (orallichenoid lesions)The terminology, classification, and diagnosis of oral

lichenoid lesions have been debated and discussed for

decades.21,28-30 Many names have been used in the

literature to signify this group of conditions, contrib-

uting to confusion surrounding terminology and

impeding progress in developing effective approaches

to diagnosis and management. The focus of this section

is on differentiating OLP from lichenoid lesions. MoreTab

leI.

Continued

Pathologic

condition

Clinicalfeatures

Histopathologicalfeatures

Immunofluorescentfindings

Oralepithelial

dysplasia

Typically

presentsas

asingle

isolatedwhiteplaque

(leukoplakia)orredplaque(erythroplakia).

Characterizedbyvariousdegreeofatypical

cellularchanges

(hyperchromatism,pleomorphism,increasednuclear/cytoplasm

ic

ratio);may

sometim

esexhibitaband-likeinflam

matory

infiltrate;however,theinflam

matory

cellinfiltrate

isoften

mixed

incelltypes.

DIF:May

show

fibrinogen,

andoccasional

C3deposition

alongBMZ.

IIF:Unknown.

OLP,orallichen

planus;

DIF,directim

munofluorescence;BMZ,basem

entmem

branezone;

IIF,indirectim

munofluorescence;MMP,mucousmem

branepem

phigoid;Ig,im

munoglobulin;SES-ANA,

squam

ousepithelium-specificantinuclearantibody.




detailed information concerning each of the conditions

discussed below is available in several previously

published articles.28,29 The following conditions can

mimic OLP both clinically and microscopically.

Mucous membrane pemphigoid. Mucous membrane

pemphigoid (MMP) is a chronic autoimmune blistering

mucocutaneous disease characterized by subepithelial

vesicles and bullae. MMP occurs in all age groups, and

is most common between the 6th and 8th decades. Any

mucosal site may be affected in MMP; however, the

oral and ocular mucosae are most commonly involved.

Oral MMP can clinically mimic erosive OLP when

presenting as desquamative gingivitis (Figure 3A).

Gingiva is involved in more than 60% of cases of

oral MMP. The buccal mucosa, palate, alveolar ridge,

tongue, and lower lip may also be involved. A

positive Nikolsky sign is commonly seen in MMP,

but may also be encountered in the bullous form of

OLP. Due to frequent minor trauma to the oral

mucosa, intact vesicles or blisters are not often seen

in oral MMP. Postinflammatory atrophy can mimic

the atrophic form of OLP.100

The histopathology of MMP classically shows

subepithelial clefting similar to erosive OLP, with

specimens usually showing the epithelium detached

from the lamina propria (Figure 3B). Biopsies of

epithelium which are cleanly detached from the

underlying lamina propria or do not contain any

connective tissue should cause a pathologist to

suspect MMP. In contrast to OLP, the basal epithelial

cells affected by MMP do not exhibit hydropic

degeneration or colloid bodies.28,29 The patchy and

variable subepithelial inflammatory infiltrate found in

MMP consists of a mixed population of lymphocytes,

plasma cells, and scattered eosinophils. The micro-

scopic appearance of erosive OLP and MMP can

overlap greatly, and a definitive diagnosis of MMP

requires DIF.

The majority of patients with MMP (80%-100%) will

have continuous linear deposits of immunoglobulin (Ig)

G, IgM, or IgA, and complement (C3) along the BMZ

on DIF,100 distinguishing MMP from OLP (Figure 3C).

Most MMP patients do not show detectable circulating

antibodies with IIF; however, use of a salt-split skin

substrate can increase IIF sensitivity, and the circulating

antibody binding site(s) can be localized either at the

roof or the floor of the split, depending on the specific

distribution of autoantigens of MMP in the BMZ.101-103

Serologic tests, using immunoblot and enzyme-linked

Fig. 3. MMP presenting as desquamative gingivitis similar to the atrophic form of OLP. A, The blisters often collapse leaving

necrotic areas (arrows). This is one of the most common clinical presentations of MMP but can also be seen in pemphigus vulgaris

and OLP. B, Histopathologic features of MMP, showing characteristic subepithelial clefting (H&E stain, original

magnification �250). Unlike OLP, the basal cells are intact and the superficial lamina propria contains a sparse to moderate

inflammatory cell infiltrate consisting of lymphocytes and plasma cells. C, DIF of perilesional tissue from a patient with MMP

demonstrates a continuous linear band of IgG at the BMZ. MMP, mucous membrane pemphigoid; OLP, oral lichen planus; H&E,

hematoxylin and eosin; DIF, direct immunofluorescence; BMZ, basement membrane zone.




immunosorbent assay (ELISA), have recently been

reported to assist immunologic subtyping in the

MMP diagnosis.103

Lichen planus pemphigoides. Lichen planus pem-

phigoides (LPP), a member of the pemphigoid family, is

a rare mucocutaneous blistering disease that shows

clinical and histopathological features of LP and pem-

phigoid (bullous pemphigoid or MMP).102,104 It can

occur in both adults and children.105 In contrast toMMP,

whichmost often occurs later in life (between the 6th and

8th decades), LPP in adults occurs most commonly

between the 5th and 6th decades, and the male to

female ratio is 4 to 5.104 LPP always arises in LP, and

the time from development of LP lesions to

vesiculobullous lesions of LPP varies from

concomitant to 17 years,106 with a mean duration of

8.3 months.104 The onset of LPP in some cases

has been linked to medications (angiotensin converting

enzyme inhibitors, statins),104,105,107-109 Chinese herbal

medicine,110 psoralen-ultraviolet A therapy,111 and viral

infection (varicella zoster virus).112 Association with

internal malignancies also has been reported.113

About 24% of LPP patients have oral lesions,104 and

oral LPP without any skin or other mucosal

involvement has been reported.106,114 A total of 27

cases of LPP with oral involvement were reviewed

recently.106 Oral LPP most often affects buccal mucosa

and gingiva, and presents with typical OLP features

(multifocal white striations, papules, plaques with

erosion or ulceration, or desquamative gingivitis) with

or without vesicles or bullae.106 These clinical features

are indistinguishable from LP. Although LPP may

affect oral sites, such as the palate, vestibule, and labial

mucosa, interestingly, it rarely affects the tongue.106

Histopathologically, LPP shows features of LP,

MMP, or both. DIF shows the same findings as those

seen in MMP (linear deposition of immunoglobulins,

most often IgG, and C3 at BMZ). IIF showed immu-

noglobulins deposited at BMZ in 81% (47/58) of the

cases cited in a recent literature review.104 The

autoantigens found in LPP so far are BP180 and

BP230.104 The diagnosis of LPP is based on clinical,

histopathologic, and immunofluorescence studies. DIF

is essential for the diagnosis.

Because LPP is a disease arising in LP, it is not

surprising that a patient could be diagnosed first as OLP

(based on clinical, histopathologic, and DIF findings),

then the disease evolves into LPP, and the diagnosis of

LPP is established later by repeated biopsy during the

follow-up period for treatment purposes.106 LPP is an

example demonstrating that the diagnostic process of

LP does not end after an initial biopsy with a

confirmed diagnosis of LP, a concept that is

emphasized in this article.

Chronic graft-versus-host disease. Oral cavity man-

ifestations of chronic graft-versus-host disease

(cGVHD) after allogeneic bone marrow transplantation

can be seen in up to 80% of graft recipients.28,115

cGVHD, a major cause of morbidity and mortality in

this patient population, exhibits a median onset of

6 months post-transplantation. cGVHD has a more

variable clinical presentation than OLP, and may

manifest with involvement of skin, eyes, liver, respi-

ratory, and gastrointestinal tracts.116 Lichenoid lesions

in cGVHD may be distributed throughout the oral

cavity, including the palate, an uncommon site for

OLP.117,118 Lesions of cGVHD can present as lacy

reticulations, thickened plaques, or erosions mimicking

OLP (Figure 4A).

The microscopic features of cGVHD and OLP also

overlap and require clinical correlation for diag-

nosis.21,29,117,118 Basal cell degeneration and colloid

bodies may be present (Figure 4B). The lymphocytic

infiltrate in the subjacent connective tissue often is

not as intense as in OLP and may contain a few

plasma cells and eosinophils. Due to the varied

clinical presentations, the diagnosis of cGVHD is

based on the clinical and microscopic findings. DIF

findings may be similar to OLP, and IIF is negative.30

Chronic ulcerative stomatitis. Chronic ulcerative

stomatitis (CUS), a rare mucocutaneous disease, pre-

sents with chronic oral ulcerations and may occasion-

ally involve cutaneous sites.119-121 The incidence of

CUS is unknown, and only 50 cases have been reported

to date in the English language literature since its first

description in 1990.21,30,122,123 The demographic char-

acteristics of CUS are virtually identical to OLP, with

female predilection and onset in the 5th and 6th decades

of life. Oral findings are also indistinguishable from

erosive OLP and MMP. Any anatomic sites in the oral

cavity may be affected, with expression most

commonly on the gingiva, tongue, and buccal mucosa,

and less commonly on the palate, lower lip, and lingual

gingiva. Gingival involvement is expressed as desqua-

mative gingivitis with erosion and ulceration

(Figure 5A).30,119,121 White striations at the periphery

of the erosions, similar to erosive OLP, also have

been described.

Histopathologic features of CUS vary depending on

biopsy site. Often, the features are indistinguishable

from those encountered in OLP: atrophic epithelium

with saw-tooth rete ridges, basal cell liquefaction, and a

dense band-like inflammatory cell infiltrate composed

chiefly of lymphocytes.21,121,123 However, ulcerative

lesions may exhibit nonspecific features with a mixed

inflammatory cell infiltrate.

The diagnosis of CUS requires DIF evaluation of

perilesional tissue, demonstrating the presence of IgG




antibodies in the nuclei of basal and parabasal epithelial

cells in a speckled and/or granular pattern.119,120,123

This characteristic finding on DIF is known as the

stratified epithelium specific-antinuclear antibody

(SES-ANA) pattern (Figure 5B).120 A shaggy linear

band of fibrinogen is sometimes identified in the

BMZ, but this DIF finding is not specific for

CUS, and indeed is also seen in OLP. However,

tangential orientation of tissue sections may render

interpretation of IgG localization problematic.

Autoimmune diseases, such as lupus erythematosus,

scleroderma, CREST syndrome (calcinosis, Raynaud’s

phenomenon, esophageal involvement, sclerodactyly,

and telangiectasia), and mixed connective tissue

disease, also may demonstrate an ANA pattern in

epithelia; however, these autoantibody deposits are

typically found in the spinous cell layer. In CUS,

IIF using a tissue substrate, such as guinea pig or

monkey esophagus, also exhibits the SES-ANA

pattern.120

Patient management with CUS is distinct from OLP

and some OLP mimics. Corticosteroids and dapsone

therapy in CUS are less effective than hydroxy-

chloroquine.21,119,121 Studies have found clinical

remission and decreased autoantibody titers after treat-

ment with hydroxychloroquine. Due to the small

Fig. 5. A, CUS presenting as desquamative gingivitis. The clinical presentation is similar to OLP, MMP, and pemphigus vulgaris.

B, IIF shows nuclear staining of the basal and epithelial cells in the lower third of the epithelium on monkey esophagus substrate

incubated with the patient sera (images courtesy of Dr. Lynn Solomon). CUS, chronic ulcerative stomatitis; OLP, oral lichen

planus; MMP, mucous membrane pemphigoid; IIF, indirect immunofluorescence.

Fig. 4. cGVHD involving the buccal mucosa and lips in a patient who underwent a stem cell transplant for sickle cell disease.

A, The lesions are thickened white papules that focally coalesce to form white plaques. Atrophic erythematous areas are also

present. B, Histopathologic features of cGVHD from oral lesions showing a lichenoid pattern of the epithelium with hydropic

degeneration of the basal cells overlying a moderate lymphocytic infiltrate (H&E stain, original magnification �250). The

epithelium in oral cGVHD often shows intracellular edema, basal cell degeneration (arrows), and inflammatory cell exocytosis.

cGVHD, chronic graft-versus-host disease; H&E, hematoxylin and eosin.




number of cases reported, our understanding of the

etiopathogenesis, natural history, and optimal manage-

ment of CUS is limited.

Oral lichenoid drug reactions. Many systemic

medications can cause oral lichenoid drug reactions

(OLDR) (Table II).21,30-32 Both reticular and erosive

patterns may be seen in OLDR with or without cuta-

neous lesions. The exact incidence of OLDR is

unknown, although it is more commonly reported in

adults and rarely in the pediatric population.124

The time interval between initiation of a medication

and onset of OLDR can vary widely, ranging from

weeks to a year or more. OLDR may present as a

single oral lesion, unlike the bilateral/multifocal

presentation of OLP. The most commonly reported

offending medications include nonsteroidal anti-

inflammatory drugs, anticonvulsants, antihyperten-

sives, antimalarials, and antiretrovirals.21,28-30 The

pathogenesis of OLDR is uncertain, and standardized

diagnostic criteria for OLDR have not been estab-

lished. If a temporal relationship between a medication

use and the onset of lesions can be established,

discontinuation of the suspected offending medication

is recommended. Coordination with the medication

prescriber is strongly encouraged. Resolution of the

lesions after drug discontinuation may require many

months or longer.

The microscopic features of OLDR share similarities

to OLP, with some notable differences. The epithelium

in OLDR may have a higher number of apoptotic ker-

atinocytes (colloid or Civatte bodies) than in OLP.9,125

A more diffuse lymphocytic infiltrate mixed with

plasma cells and eosinophils may be seen in OLDR.

The inflammatory infiltrate often extends deep into the

lamina propria, unlike the superficial band-like infiltrate

typical of OLP. A perivascular chronic inflammatory

cell infiltrate is frequently seen in OLDR. However,

microscopic findings are generally considered nonspe-

cific, and clinical information, including a temporal

association with use of any systemic medications and

demonstration of cause and effect relationship, are still

required to establish the diagnosis of OLDR.

DIF findings in perilesional tissue in OLDR show

shaggy deposition of fibrin at the BMZ and IgM posi-

tive colloid or cytoid bodies, similar to OLP.126 Unlike

OLP, IIF testing may detect circulating antibodies

directed to the basal cells with an annular fluorescent

distribution, often termed a “string of pearls” pattern,

aiding in the diagnosis of OLDR (Figure 6).127

Oral lichenoid contact hypersensitivity reaction. A

variety of agents are known to cause oral lichenoid

Table II. Triggers of oral lichenoid drug reactions21,28-30

Type of trigger Specific examples

Antianxiety/psychotropic agents Benzodiazepines

Lithium

Tricyclic antidepressants

Antibiotics Isoniazid

Rifampin

Streptomycin

Tetracyclines

Anticonvulsants Carbamazepine

Phenytoin

Valproate

Antidiabetics Glipizide

Insulin

Tolbutamide

Antifungals Amphotericin B

Ketoconazole

Antihypertensives Atenolol

Captopril

Chorothiazide

Enalapril

Furosemide

Hydroclorothiazide

Metoprolol

Propranolol

Antimalarials Chloroquine

Hydroxychloroquine

Quininacrine

Quinidine

Antiretrovirals Zidovudine

Nonsteroidal anti-inflammatory drugs Naproxen

Ibuprofen

Diclofenac

Indomethacin

Aspirin

Miscellaneous Bismuth

Dapsone

Gold

Penicillamine

Allopurinol

Fig. 6. IIF for OLDR, showing circulating antibodies directed

to the basal cells in an annular fluorescent pattern called a

“string of pearls” (arrows). This pattern is not present in OLP.

IIF, indirect immunofluorescence; OLDR, oral lichenoid drug

reactions; OLP, oral lichen planus.




contact hypersensitivity reaction (OLCHR).21,28-30

These include metals, composites, and glass ionomers

used in dental restorations (Table III).31 Amalgam

restorations in direct contact with mucosa may cause

lichenoid lesions, and are most commonly seen on the

buccal mucosa and/or lateral border of tongue

(Figure 7A). These lesions are similar in appearance

to OLP, but typical unilateral distribution and contact

with a restoration contrasts with the usual bilateral/

multifocal clinical presentation of OLP without regard

to restorations. Upon removal of the restoration, the

lesions generally resolve.128 Flavoring agents such as

cinnamon, menthol, eugenol, and peppermint have

also been associated with OLCHR, with lesions at the

site of contact, also most often on the lateral border

of the tongue or buccal mucosa (Figure 8A).21

Cinnamon or cinnamic aldehyde-containing products

can induce a cinnamon stomatitis with characteristic

histopathology. Resolution of lesions upon discontinu-

ation of the offending agent is rapid.

Similar to OLDR, the microscopic features of

OLCHR are not specific and overlap greatly with OLP.

Amalgam associated OLCHR may exhibit lymphoid

follicles (Figure 7B).31,128 Biopsies from cinnamon-

induced OLCHR demonstrate marked epithelial

acanthosis with elongated rete ridges and a mixed

inflammatory infiltrate containing lymphocytes, plasma

cells, histiocytes, and eosinophils (Figure 8B).129,130

Interface mucositis and characteristic deep

perivascular infiltrates are seen (Figure 8C). The DIF

may be similar to OLP, and the IIF testing is negative.30

Lupus erythematosus. Both systemic and discoid

(chronic cutaneous) lupus erythematosus (SLE/DLE)

can affect the oral mucosa in 25% of cases.21,28-30 The

oral presentation of SLE cannot be distinguished

reliably from oral DLE. Oral lesions are typically

distributed on the hard palate, buccal mucosa, and

gingiva, and the lesions present with a central area of

ulceration or atrophy, with erythema surrounded by

white radiating striae (Figure 9A). Palatal lesions may

be purely erythematous and patchy in distribution.

The clinical presentation can mimic OLP, particularly

atrophic or erosive OLP. However, unlike OLP,

which usually presents with oral lesions alone,

patients with oral lesions of lupus erythematosus

typically exhibit concurrent cutaneous lesions and

clinical indications of photosensitivity. Evidence of

systemic inflammatory disease may also be

encountered, a finding helpful in guiding the

diagnostic process.30,131

The histopathology of oral lupus erythematosus is

highly variable and influenced by the anatomic site and

the age of the lesion. The microscopic features are not

specific and overlap with those found in OLP, OLDR,

and OLCHR. The epithelium may exhibit either atro-

phy or pseudoepitheliomatous hyperplasia, hyperkera-

tosis with keratin plugging, and a thickened basement

membrane showing reactivity with periodic acid Schiff

stain.21,132,133 The lamina propria is often edematous,

and the inflammatory cell infiltrate in the superficial

lamina propria can range from paucicellular to

lymphocyte-rich (Figure 9B). Colloid bodies sometimes

are present. Melanin incontinence may be seen adjacent

to the epithelium. Superficial and deep perivascular

inflammatory infiltrates are often present.

DIF of both SLE and DLE tissue samples shows

granular or shaggy deposits of IgG, IgM, and/or C3 in

the BMZ.21,30,132 These findings are helpful in differ-

entiating lupus erythematosus from OLP. Immuno-

globulin deposits are found in virtually all cases of

SLE. DLE shows positivity on DIF in approximately

70% of the cases, and IIF results in DLE are usually

negative.

Proliferative verrucous leukoplakia. Proliferative

verrucous leukoplakia (PVL) is an unusual form of oral

leukoplakia that can mimic OLP clinically and micro-

scopically.28,29,134,135 The diagnosis of PVL is often

made in retrospect, as this precancerous condition can be

difficult to diagnose, particularly in its early stages. The

lesions typically grow slowly over a few years to decades.

The multifocal presentation of PVL, with propensity for

gingiva, palate, tongue, and buccal mucosa, is a feature in

Table III. Triggers of oral lichenoid contact hyper-

sensitivity reactions21,28-31

Type of trigger Specific examples

Metals used in dental

restorations

0.1% mercury chloride

1% ammoniated mercury

Beryllium

Bismuth

Chromium

Cobalt

Copper

Gold

Metallic mercury

Nickel

Palladium

Silver

Tin

Other dental restorative

materials

Acrylate compounds

Composite

Glass ionomer

Porcelain

Flavoring agents Balsam of Peru

Cinnamon (cinnamic aldehyde)

Eugenol

Menthol

Mint (mentha piperita)

Tartar control toothpaste




common with OLP (Figures 10A and B).134-136 Ventral

tongue andfloor ofmouth are uncommon sites affected by

PVL. The lesions can vary in appearance, and include

hyperkeratotic plaques, erythematous atrophic regions,

and ulceration.136 Histopathologically, PVL typically

shows hyperkeratosis associated with interface

mucositis, resembling OLP (Figure 10C). However, the

presence of a verrucous epithelial architectural change

distinguishes PVL from OLP (Figures 10C and D). In

addition, the PVL lesions often show basal cell

expansion, nuclear crowding, and varying degrees of

cellular atypia (Figures 10C and D). Of note, verrucous

hyperplasia/hyperkeratosis has been found to show

fibrinogen deposition at BMZ on DIF in approximately

42% of cases, and to show both fibrinogen and C3

deposition in approximately 3% of cases.28 Therefore,

DIF cannot be used to distinguish OLP from PVL, and

differentiation between these two diseases is based

upon histopathological features. The overlapping

clinical and histopathological features between OLP

and PVL remain one of the greatest challenges in the

diagnosis of OLP, especially in the initial stage of PVL,

when the verrucous architectural change and/or the

degree of cellular atypia are often mild.

Oral epithelial dysplasia. As emphasized previously,

OLP tends to be characterized by symmetric multifocal

clinical expression. Although oral epithelial dysplasia

Fig. 7. A, OLCHR to dental amalgam presenting as areas of erythema with white plaques at periphery (arrow). Note the large

amalgam restorations that directly contact the affected mucosa. B, OLCHR to dental amalgam often has a dense lymphocytic

infiltrate, which can form tertiary follicles (arrow, H&E stain, original magnification �100). OLCHR, oral lichenoid contact

hypersensitivity reaction; H&E, hematoxylin and eosin.

Fig. 8. A, OLCHR to cinnamon flavored chewing gum. Within 10 days of discontinuing the gum, the lesion completely resolved.

The microscopic features of OLCHR to cinnamon show marked epithelial acanthosis with elongation of the rete ridges. B, Per-

ivascular inflammatory cell infiltrate (arrow) is seen (H&E stain, original magnification �250). OLCHR, oral lichenoid contact

hypersensitivity reaction; H&E, hematoxylin and eosin.




usually presents as a solitary lesion with variable

proportions of white change (leukoplakia), red change

(erythroplakia), and ulceration (Figure 11A),137

multifocal expression is well recognized, as seen, for

example, in patients with advanced tobacco-related

mucosal injury and in PVL. Oral epithelial dysplasia is

at times associated with a band-like chronic inflammatory

cell infiltrate in the superficial lamina propriawhich,when

viewed with low-power microscopy, may offer substan-

tial histopathologic mimicry of OLP. Such disease has

been termed “lichenoid dysplasia” (Figures 11B and

C).28,29,98 The incidence of lichenoid features in oral

epithelial dysplasia and OSCC has been investigated in a

recent study by Fitzpatrick et al.,97 in which lichenoid

features (e.g., band-like inflammatory cell infiltrate,

saw-tooth rete ridges, infiltration of the basal layer of the

epithelium by lymphocytes [interface stomatitis], pres-

ence of colloid bodies, and basal cell degeneration) were

foundat least focally in 29%of the 352dysplasia orOSCC

cases. In the cases that showed lichenoid features, band-

like inflammatory cell infiltration and basal cell degener-

ation were the most frequent features encountered,

accounting for 74% and 30%, respectively, of

this group.97 The authors of this article acknowledged

interobserver variability in the interpretation of

histopathologic features as a limitation of the

investigation.

Microscopic differentiation of epithelial dysplasia

from OLP is based on recognition of cytologic atypia in

squamous epithelial cells and identification of distur-

bance in the maturation pattern. However, discrimina-

tion of mild epithelial dysplasia with chronic interface

mucositis from OLP with reactive cellular atypia can be

challenging, requiring subjective assessment of

ostensibly objective morphologic features. Evaluation

of such factors as the maturation pattern and keratino-

cyte cytologic distortion are complicated by the impact

of chronic interface mucositis on basal cell layer defi-

nition, on resolution of lower spinous cell layer matu-

rational sequence, and on keratinocyte degenerative

changes, with potential for close mimicry of cytologic

atypia. As microscopic alterations supporting a diag-

nosis of mild epithelial dysplasia are largely restricted

to the lower spinous and basal cell regions, the impli-

cations of an inflammatory process influencing the

microscopic appearance of this zone are apparent. In

this situation, the inflammatory cell infiltratesdtypi-

cally mixed in epithelial dysplasia with lesser pro-

portions of lymphocytes in favor of plasma cells and

additional cell typesdtend to contrast the lymphocyte

predominance of infiltrates found in OLP.28,29,98

Though a helpful distinction, such data cannot be

taken as surrogates for assessment of the epithelial

maturational status. Where clinical presentation is as an

isolated lesion, a dysplastic disease process should be

strongly suspected. The discriminatory value of

clinical expression as multifocal disease is somewhat

more problematic, particularly in patients with a

history of use of tobacco, and in patients where the

clinical appearance of mucosal lesions falls short of a

definitively lichenoid pattern. It is emphasized that

DIF cannot assist in the differentiation between these

two entities, as fibrinogen and/or C3 deposition at the

BMZ on DIF is characteristic of OLP, and has been

described in 43% of dysplasia or OSCC.26 We

suggest that pathology reports detailing cases

judged likely to represent OLP with significant

reactive cellular atypia should include a comment

Fig. 9. A, Intraoral presentation of SLE of the buccal mucosa presenting as a central area of erosion surrounded by white radiating

striae similar to erosive OLP. B, Biopsy of an oral lesion of lupus erythematosus showing acanthotic epithelium with a patchy

inflammatory cell infiltrate in the lamina propria (H&E stain, original magnification �250). Unlike OLP, the inflammation in lupus

erythematosus extends into the deeper connective tissue and perivascular inflammation is seen. SLE, systemic lupus erythematosus;

OLP, oral lichen planus; H&E, hematoxylin and eosin.




acknowledging a level of pathologist uncertainty

regarding the significance of observed maturational

alterations. In such situations, a diagnosis of OLP

should be considered provisional, with continuing

patient follow-up warranted.

Challenges in reaching a consensus on themicroscopic diagnosis of OLPDefinitive diagnosis of OLP is important because of

implications for therapeutic management.9 However,

many challenges exist in establishing microscopic

diagnostic criteria for OLP. The problems and

difficulties in making the OLP diagnosis based on

histopathologic features alone is evidenced by studies

showing inter- and intraobserver variability.99,138 This

section discusses those challenges, and traces the his-

tory of 2 previously proposed OLP diagnostic criteria

schemes, with comments on the criteria.

The first set of histopathologic criteria for diagnosis

of OLP was published in 1978 by the WHO Collabo-

rating Centre for Oral Precancerous Lesions.19

This seminal article is frequently referred to in the

literature on OLP, although the substance of the

article was focused on defining leukoplakia and

related lesions. The 1978 WHO histopathologic

criteria for OLP (summarized in Table IV) include the

presence of either a hyperorthokeratin or a

hyperparakeratin layer, with a comment that the

degree and type of keratinization and a granular layer

is influenced by the site of disease involvement.

Epithelial thickness may vary, and saw-tooth rete

pegs, indicated to be more common in cutaneous lichen

planus, are seen less frequently in OLP. Civatte

(colloid) bodies may be present in the basal cell layer,

either in the epithelium or in the superficial lamina

propria. “Liquefaction degeneration” of the basal cell

Fig. 10. Clinical and histopathologic features of PVL in a 58-year-old non-smoking male. White, thickened plaques with irregular,

rough surface change are noted on the gingiva of the mandible (A) and maxilla (B). The patient had other sites of involvement as well.

C, Biopsy of (A) showed hyperorthokeratosis, a prominent granular cell layer, and a verrucoid epithelial architecture associated with

interface mucositis. Absence of basal cell degeneration is noted (H&E stain, original magnification�250).D, Biopsy of (B) revealed

different histopathologic features, including a verrucous epithelial architecture with thickened, acanthotic rete ridges (H&E stain,

original magnification�250). Note the lack of inflammation comparedwith imageC. Based on the clinical and histologic findings, the

patient was given a working diagnosis of PVL. PVL, proliferative verrucous leukoplakia; H&E, hematoxylin and eosin.




layer and a narrow band of eosinophilic material in the

BMZ are cited. A well-defined dense infiltrate

comprised predominantly of lymphocytes is confined to

the superficial lamina propria.19

In 2003, Van der Meij and van der Waal1 proposed

modifications to the WHO criteria for OLP. These

modifications were based upon prior studies that

found both inter- and intraobserver variability in the

histopathologic and clinical assessment of OLP.99 The

modified histopathologic criteria include some WHO

criteria, namely, a well-defined band-like zone of

cellular infiltration confined to the superficial lamina

propria consisting mainly of lymphocytes and “lique-

faction degeneration” of the basal cells in the epithe-

lium (Table IV). Confirmation of absence of epithelial

dysplasia in establishing a diagnosis of OLP is

explicitly cited. The authors suggested that

pathologists use the term “histopathologically

compatible with” when the microscopic features are

less obvious. The criteria proposed in 2003 by van

der Meij and van der Waal are referred to as the

modified WHO diagnostic criteria.

Rad et al.138 compared the correlation between

clinical and histopathologic diagnoses of OLP for

both the WHO criteria19 and the 2003 modified WHO

criteria.1 They found increased agreement between

clinicians and pathologists in the diagnosis of OLP

when the modified criteria of OLP were used

compared with the WHO criteria.1 They also found

that clinical assessment by oral medicine clinicians

appeared to show less inter- and intraobserver

variability compared with histopathologic assessment

by pathologists when using the WHO criteria in

making OLP diagnosis, a finding attributed to

subjectivity in histopathologic interpretation.

The difficulty in reaching consensus on the micro-

scopic diagnosis of OLP is partly due to the variations

in the histopathologic features of OLP. The presence of

hyperkeratosis in OLP, as mentioned in the 1978 WHO

histopathologic criteria, is dependent on the site and

type of OLP. Reticular, plaque, and papular types

typically exhibit hyperkeratosis, but atrophic and

erosive types may not. The mononuclear, mainly lym-

phocytic, band-like infiltrate in the superficial lamina

propria is one of the most characteristic microscopic

findings for OLP. However, macrophages and dendritic

cell subsets are also present.49 Significant variation in

the intensity of the inflammatory infiltrate also has

been observed, and may be related to disease activity,

as OLP is known to show a waxing and waning

pattern clinically, and is influenced by therapeutic

intervention before the time of biopsy.

In addition, the subsets of inflammatory cells in the

infiltrate may be influenced by the clinical type (for

example, reticular vs erosive), the anatomic site (buccal

mucosa vs gingiva), or by another concomitant

Fig. 11. Clinical and histologic features of a case of epithelial dysplasia that mimics OLP. A, Scattered white plaques associated

with redness and small ulcers were seen in the left ventral tongue of a 37-year-old male (image courtesy of Dr. Bryan Trump).

B, The biopsy of this case showed a “lichenoid” appearance with a band-like inflammatory cell infiltrate (H&E stain, original

magnification � 250). C, On higher magnification, hyperchromatic nuclei and significant cellular atypia are evident, but basal cell

degeneration is not present (H&E stain, original magnification �400). OLP, oral lichen planus; H&E, hematoxylin and eosin.




inflammatory process. In the erosive form of OLP,

superimposition of neutrophil-rich inflammation related

to the ulcer could alter the microscopic features.

Similarly, the inflammatory cell infiltrate in gingival

OLP lesions is often mixed with plasma cells because

of gingivitis or periodontitis associated with dental

plaque or calculus. A biopsy tissue demonstrating all

typical features of OLP delineated in either the WHO or

the modified WHO criteria would not represent a major

challenge in histopathologic analysis. However, tissue

samples that fulfill some but not all OLP diagnostic

features require pathologists to consider mitigating

factors, as previously delineated. Such assessment

unavoidably involves subjectivity.

The fact that many of the OLP histopathologic

diagnostic features are not specific for OLP can also

influence accuracy of the diagnosis. The presence of an

eosinophilic band at the BMZ, mentioned in the 1978

WHO criteria,19 does not appear to be a consistent

microscopic finding. When identified in an

appropriate histopathologic context, this band is

generally considered supportive of a diagnosis of

OLP. Liquefaction degeneration is one of the

characteristic features of OLP, and was included in

both the 197819 and the 2003 modified WHO

diagnostic criteria.1 However, this feature is also not

specific for OLP, as degeneration of the basal cells

could be seen in biopsy materials from cGVHD,

lupus erythematosus, OLDR, or OLCHR.139-142 The

presence of Civatte (also known as colloid, hyaline, or

cytoid) bodies, which represent anucleated remnants of

epithelial cells, is a feature of OLP and supports the

diagnosis, but also can be found in lupus erythemato-

sus, OLDR, cGVHD, and other interface

Table IV. Comparison of the WHO criteria,19 the modified WHO criteria,1 and the proposed criteria for OLP

WHO criteria Modified WHO criteria Proposed criteria

Clinical criteria Usually multiple, and often symmetric

in distribution

Bilateral, more or less symmetric

lesions

Multifocal symmetric distribution

- White papular, reticular (lace-like

network of slightly raised gray-

white lines), annular, or plaque-

type lesions

- White lines radiating from the

papules

- Atrophic lesions with or without

erosion

- Bullae are rare

- Erosive, atrophic, bullous, and

plaque-type lesions are only

accepted as a subtype in the pres-

ence of reticular lesions elsewhere

in the oral mucosa

- Lace-like network of slightly

raised gray-white lines (reticular

pattern)

White and red lesions exhibiting one or

more of the following forms:

- Reticular/papular

- Atrophic (erythematous)

- Erosive (ulcerative)

- Plaque

- Bullous

Lesions are not localized exclusively to

the sites of smokeless tobacco

placement

Lesions are not localized exclusively

adjacent to and in contact with dental

restorations

Lesion onset does not correlate with the

start of a medication

Lesion onset does not correlate with the

use of cinnamon-containing products

Histopathologic

criteria

Orthokeratosis or parakeratosis

Epithelial thickness varies, saw-tooth

rete ridges sometimes seen

Civatte bodies in the basal layer of the

epithelium or superficial lamina

propria

A narrow band of eosinophilic material

in the basement membrane

Well-defined band-like zone of cellular

infiltration that is confined to the

superficial lamina propria, consisting

mainly of lymphocytes

Well-defined, band-like zone of cellular

infiltration consisting mainly of

lymphocytes and confined to the

superficial lamina propria

Band-like or patchy, predominately

lymphocytic infiltrate in the lamina

propria confined to the epithelium-

lamina propria interface

Liquefaction degeneration in the basal

cell layer

Liquefaction degeneration in the basal

cell layer

Basal cell liquefactive (hydropic)

degeneration

Lymphocytic exocytosis

Absence of epithelial dysplasia Absence of epithelial dysplasia

Absence of verrucous epithelial

architectural change




dermatitis.141,143,144 The presence of saw-tooth rete

pegs is considered supportive but not diagnostic of

OLP.

On the other hand, current knowledge and research

findings in OLP pathogenesis may help us to correlate

the histopathologic features of OLP. Migration of

lymphocytes into the overlying epithelium, or lym-

phocytic exocytosis, is often recognized in OLP and

less so in some of the other oral lichenoid conditions,

such as MMP. An explanation for this distinction

may be that the immune response in MMP targets the

adhesion molecules in the BMZ, while the CD8þ

cytotoxic T cells in OLP attack the basal epithelial

cells.62,63 In addition, eosinophils have not been

implicated in the pathogenesis of OLP, but could be

found in MMP, and are often seen in contact hyper-

sensitivity. Therefore, the presence of eosinophils

suggests OLCHR, rather than OLP. Of note, the

absence of eosinophils and migration of lymphocytes

into the epithelium were not addressed in the 1978

WHO and 2003 modified WHO criteria.

PROPOSED DIAGNOSTIC CRITERIAIn an attempt to exclude oral lichenoid lesions that

are obviously premalignant, and to make the patient

group diagnosed as OLP a more homogeneous pop-

ulation of idiopathic OLP for future research, we

propose a set of diagnostic criteria that include both

clinical and histopathologic criteria (Table IV). We

propose that a diagnosis of OLP requires fulfillment

of all the clinical and the histopathologic criteria. A

decision for diagnosis of OLP is best made by the

clinician with access to patient clinical information,

applying and incorporating an assessment of

histopathologic findings provided by the

pathologist. Where doubt may persist, active

discussion between the clinician and pathologist is

strongly encouraged. Conditions exhibiting chronic

interface mucositis but otherwise failing to satisfy

this set of diagnostic criteria should be designated

by the clinician as oral lichenoid lesions, or the

clinician should provide a descriptive diagnosis,

such as “lichenoid mucositis” or “chronic mucositis

with lichenoid features.”

Regarding the clinical criteria, we propose that OLP

should present as multiple white or mixed white and red

lesions exhibiting one or more of the 6 clinical forms

(Table IV). However, the bullous form is the rarest

among all the clinical forms, and a pure bullous form

of OLP has never been reported. Therefore, when it

does occur, we believe that this form would be seen

in combination with one or more of the other clinical

forms. If the clinical presentation is a pure bullous

form, other vesiculobullous diseases (such as MMP

and pemphigus vulgaris), but not OLP, should

be considered.

Regarding the histopathologic criteria, we agree with

van der Meij and van der Waal1 that confirming the

absence of epithelial dysplasia is necessary before

rendering a diagnosis of OLP. In addition, given the

capacity for PVL to present clinical and histopathologic

features similar to OLP, we also propose that absence

of a verrucous epithelial architecture is necessary for a

diagnosis of OLP. Significant verrucous architecture is

identified by a papillary or verrucous configuration of

the spinous cell layer accompanied by variable levels

of mucosal surface corrugation. Of note, the absence of

a verrucous epithelial architecture was not described in

either the 1978 or the 2003 modified WHO criteria.

In some cases, OLCHR may show microscopic

features that fulfill all the histopathologic criteria

proposed here, and the cause-effect relationship with

an inducing agent may not be clearly noted clinically.

However, the presence of eosinophils or a finding of

perivascular lymphoplasmacytic infiltrate in deep

lamina propria generally excludes the diagnosis of

OLP.

We recognize that adherence to this proposed

guideline may exclude some OLP cases. However, we

believe that implementation of the proposed diagnostic

system will yield a patient population with enhanced

disease homogeneitydcomposed of individuals more

likely to have OLP than one of the several lichenoid

mimics. This in turn will enhance the validity of future

clinical and basic research studies that investigate OLP.

These investigations are urgently needed to elucidate

disease pathogenesis and malignant transformation

potential, and to develop possible ancillary diagnostic

protocols that could guide future efforts to enhance the

diagnostic process.

It is also worth noting that even this set of strict

criteria cannot exclude a few rare OLP mimics, such as

LPP, CUS, or paraneoplastic pemphigus without DIF

and IIF. We also cannot exclude the possibility of

emerging PVL, as the characteristic verrucous archi-

tectural changes in epithelium may not yet be apparent,

while the clinical and histopathologic features may

fulfill our proposed criteria. Therefore, the diagnostic

process of OLP should not be viewed as ending with an

initial biopsy. Continued patient clinical follow-up

evaluation to monitor therapeutic responses and any

alterations in appearance of the lesions are necessary as

part of the diagnostic process. Additional biopsy for

DIF and/or histopathologic evaluation may be deemed

necessary to reach a final diagnosis.

RECOMMENDATIONS TO CLINICIANSAs clinicopathologic correlation is required in the

diagnosis of OLP, all patients considered for a




diagnosis of OLP are required to have an oral mucosal

biopsy and histopathologic evaluation. A decision

concerning the number of tissue samples to be obtained

is guided by several considerations. Patients displaying

mucosal alterations and lesion distribution fully

consistent with OLP may only require a single tissue

sample for histopathologic evaluation. As patterns of

oral clinical presentation show increasing divergence

from the typical clinical features of OLP, justification

for multiple site sampling addressing areas with

contrasting mucosal clinical features (re: ulceration,

verrucous change) is correspondingly increased. This

decision process is also influenced by pertinent aspects

of the patient history, such as prior diagnosis of cuta-

neous LP and use of tobacco products. For cases of

OLP showing presumably reactive cellular atypia

microscopically (see “Oral epithelial dysplasia”), close

clinical follow-up is necessary, as the true nature of the

cellular atypia may reveal with time.

As specific clinical features are essential in the

proposed diagnostic criteria, we recommend the use of

a checklist (Table V) to assist the clinician in the

identification and collection of data pertinent to

the diagnosis of OLP. The completed checklist should

be included with biopsy specimens submitted to oral

pathologists for evaluation. This checklist is not

intended to replace biopsy requisition forms employed

by pathology laboratories, nor should it substitute for

patient clinical assessment instruments used by

clinicians. Rather it is intended that use of this

checklist will work to assure that information

pertinent to the diagnostic process is readily available

to the pathologist. In this way, clinicopathologic

correlation is supported, increasing the likelihood of

achieving an accurate diagnosis.

CONCLUSIONThe diagnosis of OLP is based on both clinical and

histopathologic features. Therefore, certain clinical in-

formation is essential, and clinicians need to work

closely with their pathologists to address questions and

ambiguities that may arise. In an attempt to form a more

homogeneous patient group of OLP patients for future

research and to assure diagnostic accuracy in support of

favorable patient care outcomes, a set of diagnostic

criteria is proposed. Additional immunofluorescence

studies may occasionally be needed, and long-term

observation of disease behavior and progression is

necessary, not only for treatment but also to refine or

validate the initial diagnosis of OLP.

The authors thank the members of the Research Committee of

the American Academy of Oral and Maxillofacial Pathology,

Drs. Lynn Solomon, Kelly Magliocca, Nasser Said-Al-Naief,

and Bruno Jham; and the three anonymous reviewers, whose

valuable suggestions and comments all enhanced the final

quality of this paper.

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Clinical history YES NO

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______________________

cGVHD, chronic graft-versus-host disease.




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Reprint requests:

Yi-Shing Lisa Cheng, DDS, MS, PhD

Associate Professor

Diagnostic Sciences

Texas A&M University

College of Dentistry

3302 Gaston Ave

Dallas

TX, USA

[email protected]
































































mailto:[email protected]

Diagnosis of oral lichen planus: a position paper of the ......2017/02/01 · Diagnosis of oral lichen planus: a position paper of the American Academy of Oral and Maxillofacial Pathology

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