Vol. - No.

- Month 2016

Diagnosis of oral lichen planus: a position paper of the

American 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;-:1-23)

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
a
Department of Diagnostic Sciences, Texas A&M University College
of Dentistry, Dallas, TX, USA.
b delineated until the work of William Dubreuilh in 1906.4
Louisville Oral Pathology Laboratory, Louisville, KY, USA.
c
Department of Oral Health and Diagnostic Sciences, College of
Dental Medicine, Augusta University, Augusta, GA, USA.
d
Department of Dental Medicine, Hofstra North Shore-Long Island
Jewish Health System, New Hyde Park, NY, USA.
e
Professor 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.
Ó 2016 Published by Elsevier Inc.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2016.05.004
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 COMPLEXITIES
Historical background
The initial clinical description of lichen planus (LP) is
generally attributed to Ferdinand Ritter von Hebra, 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
Efforts to identify key clinical 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 features
The prevalence of LP is estimated at 0.22% to 5%
worldwide,6 and the incidence of OLP is estimated at

1
ORAL AND MAXILLOFACIAL PATHOLOGY
2 Cheng et al.
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 direct
immunofluorescence findings
Microscopic 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
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Month 2016
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 pathogenesis
The 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
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Volume -, Number - Cheng et al. 3

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
4 Cheng et al. Month 2016

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.

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
Management
Appropriate 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
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Volume -, Number - Cheng et al. 5
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
ORIGINAL ARTICLE
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 transformation
Ever 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

6
ORAL AND MAXILLOFACIAL PATHOLOGY
Cheng et al.
Pathologic condition Clinical features Histopathological features Immunofluorescent findings
OLP Multifocal, usually bilateral affecting buccal mucosa, Reticular form: Hyperkeratosis with basal cell degeneration, DIF: Usually negative, may
tongue, lips, and gingiva; can appear as desquamative necrosis of basal and parabasal keratinocytes, and a band-like see shaggy fibrinogen
gingivitis; white reticular patches with or without predominantly lymphocytic infiltrate adjacent to basal cells. deposition at BMZ and
erosions and ulcerations. Erosive form: Sub-basal separation with basal cell degeneration; colloid bodies.
inflammation may contain plasma cells; reactive, regenerative, IIF: Negative.
or reparative epithelial changes may be seen in these cases and,
depending on the degree of ulceration, pathologic features may
be less distinct.
MMP Often presents as desquamative gingivitis; erosions and Sub-basilar epithelial separation without basal cell liquefaction; DIF: Linear IgG and C3 at
ulcers without a reticular component; rare intact bullae; inflammation mixed and often sparse. BMZ; less often IgA,
frequently affects other oral mucosal sites, such as IgM, and fibrin.
buccal mucosa and palate. 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 Combined features of lichen planus and pemphigoid Features of OLP (basal cell degeneration, thickening and dissolution DIF: Same as MMP.
pemphigoides (vesicles or bullae) on oral mucosa, skin, or both. of basement membrane, band-like lymphocytic infiltrate in IIF: Immunoglobulin
Most often affects buccal mucosa and gingiva, although superficial lamina propria), MMP (sub-basilar epithelial (most often IgG) at BMZ.
palate, vestibule, and labial mucosa can also be involved. separation), or both.
Chronic graft-versus- Similar to OLP; history of bone marrow transplant. Basal cell degeneration with subepithelial lymphocytic infiltrate (may DIF: May be similar to OLP.
host disease be sparse). IIF: Negative.
Chronic ulcerative Similar to OLP. Similar to OLP. DIF: Stratified SES-ANA
stomatitis in lower third of epithelium.
IIF: SES-ANA positive.
Oral lichenoid Similar to OLP; may see a temporal relationship with Similar to OLP but mixed inflammation, may extend into the deep DIF: Similar to OLP.
drug reactions offending drug, but delayed onset of more than 1 year lamina propria, may show perivascular inflammation. IIF: Usually negative.
has been reported.
Oral lichenoid contact Can be unilateral or bilateral; topographic relationship to Similar to OLP but inflammation mixed; may see lymphoid follicles DIF: Similar to OLP.
hypersensitivity dental restorations, flavoring agents (Table III). in reactions to dental materials; perivascular inflammation and IIF: Usually negative.
reactions scattered eosinophils; epithelial acanthosis in cinnamon reaction.
Lupus erythematosus Oral involvement in up to 25% of cases and resembles erosive Similar to OLP; sometimes deep perivascular inflammation. DIF: Linear band or
OLP; hard palate often affected; central area of ulceration continuous granular IgG,
surrounded by radiating keratotic striae. IgM, IgA, or C3 at BMZ.
IIF: Negative.
Proliferative verrucous Multifocal keratotic lesions with a predilection for the gingiva, Varies, but one pattern may exhibit a lichenoid appearance with a DIF: May show fibrinogen
leukoplakia palate, and tongue in elderly females; erosive lesions can band-like inflammatory cell infiltrate, saw-tooth rete ridges, and deposition along BMZ
occur, mimicking erosive OLP. inflammatory cell transmigration through the epithelium; IIF: Unknown.
hyperchromatic, pleomorphic nuclei with varying degrees of
cytologic atypia may be present.

Month 2016
(continued on next page)

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OOOO ORIGINAL ARTICLE
Volume -, Number - Cheng et al. 7

discussion in “Challenges in Diagnosis of OLP”).

and occasional C3 deposition

OLP, oral lichen planus; DIF, direct immunofluorescence; BMZ, basement membrane zone; IIF, indirect immunofluorescence; MMP, mucous membrane pemphigoid; Ig, immunoglobulin; SES-ANA,
Immunofluorescent findings
In fact, it is not uncommon to see microscopic
DIF: May show fibrinogen,
lichenoid features in dysplasia and oral squamous
cell carcinoma (OSCC).97,98 Therefore, misdiagnosis
IIF: Unknown. of OLP can occur, especially when limited clinical
along BMZ.

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
(hyperchromatism, pleomorphism, increased nuclear/cytoplasmic

distinguish or exclude epithelial dysplasia from

the OLP diagnosis.19 Application of WHO criteria
infiltrate; however, the inflammatory cell infiltrate is often
Characterized by various degree of atypical cellular changes

ratio); may sometimes exhibit a band-like inflammatory

has appeared to reveal great interobserver and

intraobserver variability.99 Others use the modified
diagnostic criteria proposed by van der Meij and
Histopathological features

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
mixed in cell types.

complex issues concerning the potential or actual

transformation of OLP to oral cancer.

CHALLENGES IN DIAGNOSIS OF OLP

The 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
Typically presents as a single isolated white plaque

on a spectrum, potentially influenced by the stage of

(leukoplakia) or red plaque (erythroplakia).

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

recent therapy of the condition, the clinical types
Clinical features

(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.
squamous epithelium-specific antinuclear antibody.

These challenges are discussed in detail below.

Various disorders may present with clinical and/or

histopathologic features similar to OLP (oral
lichenoid lesions)
The terminology, classification, and diagnosis of oral
Table I. Continued

lichenoid lesions have been debated and discussed for

Pathologic condition

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

literature to signify this group of conditions, contrib-
Oral epithelial

uting to confusion surrounding terminology and

dysplasia

impeding progress in developing effective approaches

to diagnosis and management. The focus of this section
is on differentiating OLP from lichenoid lesions. More
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
8 Cheng et al. Month 2016

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.
detailed information concerning each of the conditions specimens usually showing the epithelium detached
discussed below is available in several previously from the lamina propria (Figure 3B). Biopsies of
published articles.28,29 The following conditions can epithelium which are cleanly detached from the
mimic OLP both clinically and microscopically. underlying lamina propria or do not contain any
connective tissue should cause a pathologist to
Mucous membrane pemphigoid. Mucous membrane suspect MMP. In contrast to OLP, the basal epithelial
pemphigoid (MMP) is a chronic autoimmune blistering cells affected by MMP do not exhibit hydropic
mucocutaneous disease characterized by subepithelial degeneration or colloid bodies.28,29 The patchy and
vesicles and bullae. MMP occurs in all age groups, and variable subepithelial inflammatory infiltrate found in
is most common between the 6th and 8th decades. Any MMP consists of a mixed population of lymphocytes,
mucosal site may be affected in MMP; however, the plasma cells, and scattered eosinophils. The micro-
oral and ocular mucosae are most commonly involved. scopic appearance of erosive OLP and MMP can
Oral MMP can clinically mimic erosive OLP when overlap greatly, and a definitive diagnosis of MMP
presenting as desquamative gingivitis (Figure 3A). requires DIF.
Gingiva is involved in more than 60% of cases of The majority of patients with MMP (80%-100%) will
oral MMP. The buccal mucosa, palate, alveolar ridge, have continuous linear deposits of immunoglobulin (Ig)
tongue, and lower lip may also be involved. A G, IgM, or IgA, and complement (C3) along the BMZ
positive Nikolsky sign is commonly seen in MMP, on DIF,100 distinguishing MMP from OLP (Figure 3C).
but may also be encountered in the bullous form of Most MMP patients do not show detectable circulating
OLP. Due to frequent minor trauma to the oral antibodies with IIF; however, use of a salt-split skin
mucosa, intact vesicles or blisters are not often seen substrate can increase IIF sensitivity, and the circulating
in oral MMP. Postinflammatory atrophy can mimic antibody binding site(s) can be localized either at the
the atrophic form of OLP.100 roof or the floor of the split, depending on the specific
The histopathology of MMP classically shows distribution of autoantigens of MMP in the BMZ.101-103
subepithelial clefting similar to erosive OLP, with Serologic tests, using immunoblot and enzyme-linked
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Volume -, Number - Cheng et al. 9
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 to MMP,
which most 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.
ORIGINAL 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
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
10 Cheng et al. Month 2016

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.

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.

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
OOOO ORIGINAL ARTICLE
Volume -, Number - Cheng et al. 11

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 Fig. 6. IIF for OLDR, showing circulating antibodies directed
Chorothiazide to the basal cells in an annular fluorescent pattern called a
Enalapril “string of pearls” (arrows). This pattern is not present in OLP.
Furosemide IIF, indirect immunofluorescence; OLDR, oral lichenoid drug
Hydroclorothiazide reactions; OLP, oral lichen planus.
Metoprolol
Propranolol
Antimalarials Chloroquine pathogenesis of OLDR is uncertain, and standardized
Hydroxychloroquine diagnostic criteria for OLDR have not been estab-
Quininacrine lished. If a temporal relationship between a medication
Quinidine use and the onset of lesions can be established,
Antiretrovirals Zidovudine
discontinuation of the suspected offending medication
Nonsteroidal anti-inflammatory drugs Naproxen
Ibuprofen is recommended. Coordination with the medication
Diclofenac prescriber is strongly encouraged. Resolution of the
Indomethacin lesions after drug discontinuation may require many
Aspirin months or longer.
Miscellaneous Bismuth
The microscopic features of OLDR share similarities
Dapsone
Gold to OLP, with some notable differences. The epithelium
Penicillamine in OLDR may have a higher number of apoptotic ker-
Allopurinol 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.
number of cases reported, our understanding of the The inflammatory infiltrate often extends deep into the
etiopathogenesis, natural history, and optimal manage- lamina propria, unlike the superficial band-like infiltrate
ment of CUS is limited. typical of OLP. A perivascular chronic inflammatory
cell infiltrate is frequently seen in OLDR. However,
Oral lichenoid drug reactions. Many systemic microscopic findings are generally considered nonspe-
medications can cause oral lichenoid drug reactions cific, and clinical information, including a temporal
(OLDR) (Table II).21,30-32 Both reticular and erosive association with use of any systemic medications and
patterns may be seen in OLDR with or without cuta- demonstration of cause and effect relationship, are still
neous lesions. The exact incidence of OLDR is required to establish the diagnosis of OLDR.
unknown, although it is more commonly reported in DIF findings in perilesional tissue in OLDR show
adults and rarely in the pediatric population.124 shaggy deposition of fibrin at the BMZ and IgM posi-
The time interval between initiation of a medication tive colloid or cytoid bodies, similar to OLP.126 Unlike
and onset of OLDR can vary widely, ranging from OLP, IIF testing may detect circulating antibodies
weeks to a year or more. OLDR may present as a directed to the basal cells with an annular fluorescent
single oral lesion, unlike the bilateral/multifocal distribution, often termed a “string of pearls” pattern,
presentation of OLP. The most commonly reported aiding in the diagnosis of OLDR (Figure 6).127
offending medications include nonsteroidal anti-
inflammatory drugs, anticonvulsants, antihyperten- Oral lichenoid contact hypersensitivity reaction. A
sives, antimalarials, and antiretrovirals.21,28-30 The variety of agents are known to cause oral lichenoid
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
12 Cheng et al. Month 2016

Table III. Triggers of oral lichenoid contact hyper- perivascular infiltrates are seen (Figure 8C). The DIF
sensitivity reactions21,28-31 may be similar to OLP, and the IIF testing is negative.30
Type of trigger Specific examples Lupus erythematosus. Both systemic and discoid
Metals used in dental 0.1% mercury chloride (chronic cutaneous) lupus erythematosus (SLE/DLE)
restorations 1% ammoniated mercury
can affect the oral mucosa in 25% of cases.21,28-30 The
Beryllium
Bismuth oral presentation of SLE cannot be distinguished
Chromium reliably from oral DLE. Oral lesions are typically
Cobalt distributed on the hard palate, buccal mucosa, and
Copper gingiva, and the lesions present with a central area of
Gold
ulceration or atrophy, with erythema surrounded by
Metallic mercury
Nickel white radiating striae (Figure 9A). Palatal lesions may
Palladium be purely erythematous and patchy in distribution.
Silver The clinical presentation can mimic OLP, particularly
Tin atrophic or erosive OLP. However, unlike OLP,
Other dental restorative Acrylate compounds
which usually presents with oral lesions alone,
materials Composite
Glass ionomer patients with oral lesions of lupus erythematosus
Porcelain typically exhibit concurrent cutaneous lesions and
Flavoring agents Balsam of Peru clinical indications of photosensitivity. Evidence of
Cinnamon (cinnamic aldehyde) systemic inflammatory disease may also be
Eugenol
encountered, a finding helpful in guiding the
Menthol
Mint (mentha piperita) diagnostic process.30,131
Tartar control toothpaste 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,
contact hypersensitivity reaction (OLCHR).21,28-30 and OLCHR. The epithelium may exhibit either atro-
These include metals, composites, and glass ionomers phy or pseudoepitheliomatous hyperplasia, hyperkera-
used in dental restorations (Table III).31 Amalgam tosis with keratin plugging, and a thickened basement
restorations in direct contact with mucosa may cause membrane showing reactivity with periodic acid Schiff
lichenoid lesions, and are most commonly seen on the stain.21,132,133 The lamina propria is often edematous,
buccal mucosa and/or lateral border of tongue and the inflammatory cell infiltrate in the superficial
(Figure 7A). These lesions are similar in appearance lamina propria can range from paucicellular to
to OLP, but typical unilateral distribution and contact lymphocyte-rich (Figure 9B). Colloid bodies sometimes
with a restoration contrasts with the usual bilateral/ are present. Melanin incontinence may be seen adjacent
multifocal clinical presentation of OLP without regard to the epithelium. Superficial and deep perivascular
to restorations. Upon removal of the restoration, the inflammatory infiltrates are often present.
lesions generally resolve.128 Flavoring agents such as DIF of both SLE and DLE tissue samples shows
cinnamon, menthol, eugenol, and peppermint have granular or shaggy deposits of IgG, IgM, and/or C3 in
also been associated with OLCHR, with lesions at the the BMZ.21,30,132 These findings are helpful in differ-
site of contact, also most often on the lateral border entiating lupus erythematosus from OLP. Immuno-
of the tongue or buccal mucosa (Figure 8A).21 globulin deposits are found in virtually all cases of
Cinnamon or cinnamic aldehyde-containing products SLE. DLE shows positivity on DIF in approximately
can induce a cinnamon stomatitis with characteristic 70% of the cases, and IIF results in DLE are usually
histopathology. Resolution of lesions upon discontinu- negative.
ation of the offending agent is rapid.
Similar to OLDR, the microscopic features of Proliferative verrucous leukoplakia. Proliferative
OLCHR are not specific and overlap greatly with OLP. verrucous leukoplakia (PVL) is an unusual form of oral
Amalgam associated OLCHR may exhibit lymphoid leukoplakia that can mimic OLP clinically and micro-
follicles (Figure 7B).31,128 Biopsies from cinnamon- scopically.28,29,134,135 The diagnosis of PVL is often
induced OLCHR demonstrate marked epithelial made in retrospect, as this precancerous condition can be
acanthosis with elongated rete ridges and a mixed difficult to diagnose, particularly in its early stages. The
inflammatory infiltrate containing lymphocytes, plasma lesions typically grow slowly over a few years to decades.
cells, histiocytes, and eosinophils (Figure 8B).129,130 The multifocal presentation of PVL, with propensity for
Interface mucositis and characteristic deep gingiva, palate, tongue, and buccal mucosa, is a feature in
OOOO ORIGINAL ARTICLE
Volume -, Number - Cheng et al. 13

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.

common with OLP (Figures 10A and B).134-136 Ventral
tongue and floor of mouth 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
ORAL AND MAXILLOFACIAL PATHOLOGY
14 Cheng et al.
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.
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 propria which, 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
found at least focally in 29% of the 352 dysplasia or OSCC
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
OOOO
Month 2016
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
OOOO ORIGINAL ARTICLE
Volume -, Number - Cheng et al. 15

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 compared with image C. 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.

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 the
microscopic diagnosis of OLP
Definitive 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
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
16 Cheng et al. Month 2016

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.

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
OOOO ORIGINAL ARTICLE
Volume -, Number - Cheng et al. 17

Table IV. Comparison of the WHO criteria,19 the modified WHO criteria,1 and the proposed criteria for OLP
WHO criteria
Clinical criteria Usually multiple, and often symmetric
in 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
Histopathologic Orthokeratosis or parakeratosis
criteria 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
Liquefaction degeneration in the basal
cell layer
Modified WHO criteria
Bilateral, more or less symmetric
lesions
- 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)
Well-defined, band-like zone of cellular
infiltration consisting mainly of
lymphocytes and confined to the
superficial lamina propria
Liquefaction degeneration in the basal
cell layer
Absence of epithelial dysplasia
Proposed criteria
Multifocal symmetric distribution
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
Band-like or patchy, predominately
lymphocytic infiltrate in the lamina
propria confined to the epithelium-
lamina propria interface
Basal cell liquefactive (hydropic)
degeneration
Lymphocytic exocytosis
Absence of epithelial dysplasia
Absence of verrucous epithelial
architectural change

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
ORAL AND MAXILLOFACIAL PATHOLOGY
18 Cheng et al.
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 CRITERIA
In 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
OOOO
Month 2016
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 CLINICIANS
As clinicopathologic correlation is required in the
diagnosis of OLP, all patients considered for a
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Volume -, Number - Cheng et al. 19
Table V. Proposed checklist for clinical information
regarding oral lichenoid lesions
Clinical history
History of organ transplant or cGVHD?
History of lupus erythematosus (systemic or discoid)?
History of hepatitis C and/or other liver diseases?
Has the patient used any cinnamon-containing foods or
products, such as chewing gum, mints, or tartar-
control toothpaste, at a time that correlates with the
onset of oral lesion(s)?
History of use of tobacco (any form)?
Does the onset of the oral lesions correlate with
initiation of a medication?
Clinical presentation YES
Does the patient have multiple
oral lesions? If yes, list the
sites of involvement.
Does the patient have only a
single isolated oral lesion?
If so, describe the site.
Is/are the lesion(s) limited to
area(s) with direct contact
with dental restorations?
Does clinically normal oral
mucosa peel on rubbing
(positive Nikolsky sign)?
What is the appearance of the __ White striations and/or papules
lesion(s)? (Check all that __ Diffuse redness
apply for each lesion, and __ Ulceration surrounded by white
enter additional features.) plaques
__ Ulceration surrounded by white
striations
__ White plaques with redness
__ White plaques without redness
Other features:
______________________
cGVHD, chronic graft-versus-host disease.
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
ORIGINAL ARTICLE
a checklist (Table V) to assist the clinician in the
identification and collection of data pertinent to
YES NO
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
NO correlation is supported, increasing the likelihood of
achieving an accurate diagnosis.
CONCLUSION
The 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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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
Ycheng@bcd.tamhsc.edu