Critical Thoughts on Oral Lichen Planus

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DENTISTRY AND ORAL SCIENCES
CRITICAL THOUGHTS
ON ORAL LICHEN PLANUS
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CRITICAL THOUGHTS
ON ORAL LICHEN PLANUS
DANTE A. MIGLIARI, DDS, PHD

AND
SÍLVIO K. HIROTA, DDS, PHD
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CONTENTS
Acknowledgments vii
Chapter 1 Introduction 1
Chapter 2 Addressing Important Aspects of OLP 5
Chapter 3 Background 15
Chapter 4 General Overview of OLP 17
Chapter 5 Diagnosis of OLP 27
Chapter 6 Additional Research and Further Comments 47
Chapter 7 Future Directions 69
References 71
About the Authors 79
Index 81
ACKNOWLEDGMENTS
We would to like to thank our clinical interns at the Department of

Stomatology, Division of Oral Medicine, School of Dentistry,
University of São Paulo, Brazil: Dr. Ana Paula Fukushima and Dr. Ana
Cristina Posch Machado. We also wish to thank our postgraduate
students: Dr. Inês Fugitaro Otobe, Dr. Gabriela Artico, and Dr. Luciano
Figueiredo. Their dedication and effective participation in providing
unrestricted assistance to the patients that went beyond the need of
diagnosis and treatment is greatly appreciated.
We also extend our special thanks to Dr. Norberto Sugaya, a friend
and long-time colleague at the Department of Stomatology, Division of
Oral Medicine, University of São Paulo, Brazil.
We would also like to express our deepest gratitude to Dr. Evandro
A. Rivitti (Physician, Professor, and Chairman of the Division of
Dermatology, Clinics Hospital, School of Medicine, University of São
Paulo, Brazil) for providing many years of substantial support during
our professional development.
In addition, we would like to take this opportunity to express our
gratitude to Dr. Flair Jose Carrilho (Physician, Professor, and
Chairman, Outpatient Clinic for Liver Diseases, Division of
Gastroenterology, Clinics Hospital, School of Medicine, University of
viii Dante A. Migliari and Sílvio K. Hirota
São Paulo, Brazil) for constant support and interest in the study of the
association between liver disease and oral manifestations of lichen
planus.
We also extend our sincere gratitude to Dr. Valéria Aoki
(Physician, Associate Professor, and Head of the Laboratory of
Cutaneous Immunopathology, Division of Dermatology, Clinics
Hospital, School of Medicine, University of São Paulo, Brazil); to the
biologists Alexandre M. Perigo and Lígia Fukimori; and to Eliete Silva
(Laboratory of Cutaneous Immunopathology, Division of Dermatology,
Clinics Hospital, School of Medicine, University of São Paulo, Brazil).
We greatly appreciate our friendly interactions and their full
involvement in the processing and interpretation of the direct
immunofluorescence data.
Chapter 1
INTRODUCTION
Oral lichen planus (OLP), a chronic inflammatory disease of the

oral mucosa, is among the most common oral changes observed in
clinical settings. Although classic OLP is idiopathic in nature, the
disease is immunologically mediated; however, it is not categorized as a
strictly autoimmune process.
Epidemiological studies have indicated that OLP affects between
0.1% and 4% of the general population, with a recent meta-analysis
reporting a prevalence rate closer to the lower end of the range
(approximately 0.9%). Both middle-aged and older adults are at greater
risk for OLP, with a peak incidence between 50 and 59 years of age.
The disease occurs less frequently in young people and is quite rare in
children. Most studies have also reported that women are on average
twice as likely to develop OLP than men, although some studies have
reported a female/male ratio of 3 or 4:1.
Studies focusing on OLP have adopted different designs based on
their objectives. Some retrospective OLP studies included more than
500 patients, whereas most prospective studies, especially those
designed to assess therapeutic responses, included fewer than 100
patients. Several literature reviews have also provided a critical analysis
2 Dante A. Migliari and Sílvio K. Hirota
of conflicting results emerging from these studies and the more

controversial aspects of OLP. Among these reviews, Scully et al. (1998)
is worthy of special attention, as they cover virtually all OLP-related
topics investigated until that point.
Despite the extensive number of publications related to OLP, its
etiology remains unknown. As such, most investigations in this area
have focused on etiopathogenic mechanisms. OLP is thought to be
initiated by the selective sensitization of keratinocytes in an organism
genetically predisposed to the development of OLP. Such sensitization
is likely triggered by exposure to exogenous or endogenous agents (e.g.,
drugs, allergens, or microorganisms) that produce alterations in the
antigenic structure of keratinocytes. Antigenic-induced keratinocytes
may then activate CD8+ cytotoxic T lymphocytes, which, in turn, may
induce progressive apoptosis in keratinocytes and lead to the
development of OLP lesions. Although the cytotoxic activity of CD8+ T
lymphocytes implies that autoimmune mechanisms are involved in the
development of OLP, such mechanisms remain speculative, and OLP
has yet to be characterized as an autoimmune disease. Authors, for the
most part, favor the classic characterization of OLP as a chronic, non-
infectious inflammatory disease.
Several studies have also focused on the diagnosis of OLP.
Clinically, OLP is relatively easy to recognize; however, various
aspects of OLP lesions remain puzzling and have attracted the interest
of clinicians and researchers worldwide. Typically, OLP is
characterized by the presence of slightly raised white striae usually
crossing each other and forming a lacelike arrangement. These striae
usually occur bilaterally and are arranged symmetrically, preferentially
affecting the buccal mucosa. While the diagnosis of OLP is most often
simple, some reports have described atypical cases in which the clinical
and histopathological criteria of OLP are not met. Conflicting findings
in this area have fueled the controversy surrounding OLP, in part due to
the lack of a clear diagnostic definition.
Introduction 3
Developing definitive diagnostic criteria for OLP requires a focus

on specific characteristics of the disease. In this regard, some studies
have attempted to characterize OLP as a potentially malignant disease.
The carcinogenic properties of OLP lesions have been emphatically
debated both in papers and at scientific meetings. A critical review by
Mattsson, Jontell, and Holmstrup (2002) highlighted that addressing
this controversy requires an analysis of the criteria used to diagnose
OLP, arguing that in the selected studies in which malignant
transformations of OLP lesions were observed, all OLP diagnoses were
based on well-defined clinical and histopathological criteria. However,
the diagnostic criteria for malignant transformation of OLP were
explicitly stated only in the study by Holmstrup et al. (1988). Mattsson,
Jontell, and Holmstrup (2002) further argued that the relevant studies
were conducted by experienced investigators, which, subjectively,
obstructs a judicious assessment on whether the cases of OLP that have
undergone a malignant transformation were, in fact, those of OLP
lesions. Moreover, Van der Meij et al. (1999, 2002) and van der Meij
and van der Waal (2003) noted that both intra- and inter-individual
factors can influence the subjective interpretation of clinical and
histopathological features in cases of suspected OLP, thereby leading to
diagnostic errors. Several researchers have commented that most such
errors occur when lesions of a dysplastic nature that present with
histologic lichenoid characteristics are diagnosed as OLP.
Despite the ongoing controversy regarding the association between
OLP and oral cancer, some evidence suggests that patients with OLP
are at a higher risk of developing oral cancer than the general
population. Three studies (van der Meij, Schepman, and van der Waal,
2003; Carbone et al., 2009; van der Waal, 2014), seemingly based on
well-documented data, have shown that OLP may exhibit an intrinsic
capacity for malignant transformation, with an incidence rate of
malignant transformation in OLP cases ranging from 0.4% to 1.7%.
The abovementioned controversy highlights the importance of
characterizing OLP lesions based on well-defined criteria. However,
while some criteria were established by the World Health Organization

(WHO) in 1978, there are still many publications of case series and case
reports that refrain from following the accepted criteria for the specific
diagnosis of OLP. More accurately diagnosing OLP will require the
complete characterization of both the clinical and histopathological
features of the disease.
Chapter 2
ADDRESSING IMPORTANT
ASPECTS OF OLP
Clinically, OLP is a polymorphic disease, with a predominance of

the reticular form, which is defined by the presence of white striae
(Wickham’s striae) and/or white papules. The white striae are slightly
raised, exhibiting a linear, lacelike, radial, or circinate pattern, whereas
the white papules may appear isolated or coalesced, forming a linear or
plaque-papular pattern (Figure 1). These reticular formations are
required for the clinical diagnosis of OLP.
Nonetheless, reticular formations can be observed in other forms of
the disease, including atrophic (or erythematous), erosive, and plaque
forms. It is particularly important to screen for the presence of white
striae and/or papules inside or in the peripheral areas of these other
forms during the diagnostic process of OLP. Patients with atrophic OLP
exhibit an erythematous area with reticular formations in the periphery
or center of the lesion, while patients with the erosive form exhibit
atrophic characteristics accompanied by ulceration. The papular form is
a subtype of reticular OLP in which the disease manifests as white
papules only. The plaque form is characterized by the presence of flat
white lesions with either a smooth or a rough surface. Although rarely

observed, the bullous form is characterized by the presence of erosive
features evolving from a blister. Different forms of OLP may coexist in
the same patient.
Figure 1. A unilateral— but typical—oral lichen planus lesion, exhibiting isolated and
linear white papules together with white striae in a linear and radial pattern.
Figure 2. A typical case of the reticular form of oral lichen planus accompanied by a
desquamative-like lesion (erythematous areas) on the marginal and attached gingiva
mucosa.
OLP lesions are usually bilateral and symmetrical, predominantly

affecting the buccal mucosa and ventral–lateral surface of the tongue.
OLP also commonly affects the labial mucosa and gingiva. The plaque
form occurs most frequently on the dorsal surface of the tongue and the
gingiva mucosa. Notably, a diagnosis of the plaque form of OLP
requires that reticular striation be present in the lesion periphery and/or
Addressing Important Aspects of OLP 7
in the other areas of the oral mucosa; that is, it would be impossible to
make a clinical diagnosis of OLP based exclusively on the presence of
an isolated white plaque. Such a manifestation would be more
indicative of oral leukoplakia, even with some histopathological
features of OLP. OLP in the gingiva can also manifest as desquamative
gingivitis, which is characterized by the presence of erythematous
areas, usually diffuse, affecting either the attached or the marginal
gingiva.
Figure 3. Reticular oral lichen planus in a linear pattern.
Figure 4. Oral lichen planus (OLP) presenting as multiple white plaques on the tongue
and a circinate pattern on the upper lip mucosa. A diagnosis of plaque-form OLP
requires the presence of striae in the plaque periphery or elsewhere on the oral mucosa.
Aesthetic issues may arise when lesions are located in visible areas
(i.e., the lip vermillion border). In a few cases, OLP may occur in a
single location, often characterized as unilateral manifestation. Under

these circumstances, some diagnostic challenges may occur mainly
when the classic striations are absent (Figures 2, 3, 4, 5, and 6).
Figure 5. Classic plaque-form oral lichen planus with interlaced white striae in the
lesion periphery, located on the dorsal surface of the tongue.
Figure 6. A classic clinical case of oral lichen planus (OLP), confirmed via biopsy.
Predominantly papular lesions are observed on the buccal mucosa, while extensive
plaque–papular lesions are observed in the hard palate, including a small
erythematous–atrophic area on the left side. Note: the palatal lesion alone would not be
possible to be clinically characterized as OLP.
OLP symptoms are most frequently observed in patients with the

atrophic or erosive form of OLP, the latter of which has been associated
with intense pain. However, many patients are asymptomatic,

particularly those with reticular/papular forms of OLP, often leading to
incidental detection of OLP during clinical examination of the oral
mucosa.
2.1. CLINICAL AND HISTOPATHOLOGICAL

INTERRELATIONSHIP
A careful examination of the oral mucosa greatly facilitates the

diagnosis of OLP. The disease history also plays a part in the diagnostic
process, because OLP has a chronic clinical course. Although
recommended, a biopsy is not mandatory, and long-term follow-up is
much more important than relying entirely on histopathological
analyses. However, when specimens are available, one should be able
to observe liquefactive degeneration of the epithelial basal layer
together with predominantly lymphocytic infiltrates arranged in a
subepithelial band. Epithelial dysplasia excludes the diagnosis of OLP.
It is important to note that the histopathological characteristics of OLP
may not be in full display, even in patients with clinically typical
lesions. Similarly, lesions lacking the main characteristic features of
OLP, i.e., a reticular formation, may exhibit the characteristic
histopathology of OLP. For these reasons, OLP diagnosis should be
based on both clinical and histopathological features. It should be
noted, however, that histopathological examination in OLP is relevant
because it is used primarily for excluding the presence of epithelial
dysplasia rather than as an ultimate tool for the diagnosis of OLP. The
presence of epithelial dysplasia does not mean that the lesion will
inexorably undergo malignant transformation, which is nearly a
dominant consensus among researchers involved with studies of oral
potentially malignant disorders. Identifying the signs of epithelial
dysplasia is a matter of using strict criteria for diagnosing OLP,
excluding cases that show this epithelial change. Cases that do not
fulfill the requirements for a confident diagnosis of OLP should be
provided with a diagnosis other than OLP, treated (if indicated), and
placed under close clinical monitoring (Figures 7 and 8).
Figure 7. A misleading case in which a tongue lesion biopsy suggested histological

features of oral lichen planus, despite clinical features suggestive of multifocal oral
leukoplakia (note the absence of striae in either lesion). Elliptical tissue loss can be
observed in the central area of the tongue lesion, without ulceration. Management for
leukoplakia is recommended in such cases.
Figure 8. A suspicious dysplastic lesion on the lateral border of the tongue. This lesion
may be mistaken for an atrophic-erosive oral lichen planus, given that histopathologic
findings revealed moderate dysplasia accompanied by lichenoid features. Management
of this type of lesion includes the use of a high-power laser followed by close
periodical monitoring.
OLP can coexist with lichen planus (LP) lesions on other epithelial
(genital, ocular, and esophageal) or cutaneous surfaces. Cutaneous
lesions are less polymorphic, usually exhibiting papules or purple
erythematous plaques with white striations (Wickham’s striae) and
more frequently affecting the flexor surfaces (wrists and ankles), lower
limbs, and lower dorsal region. Extra-oral LP lesions should be
included as part of the examination and differential diagnosis. In
contrast to OLP, malignant change in cutaneous LP is a rare event. The
very few cases reported in the literature are not well described
regarding the preexisting cutaneous lesions of LP and their process to
turn into malignancy (Sigurgeirsson and Lindelöf 1991). According to
these authors, one hypothesis for malignant transformation of cutaneous
LP is that the pruritic symptoms associated with LP on the lower leg,
e.g., prompt patients to scratch the lesion repeatedly, which may induce
the development of malignant neoplasia at the LP site.
2.2. NON-IDIOPATHIC OLP
OLP lesions may also be induced by certain systemic medications,

in which case, patients are diagnosed with an oral lichenoid drug
reaction (OLDR). If the lesion is in direct/close contact with dental
restorations (mainly amalgams), a diagnosis of oral lichenoid contact
reaction (OLCR) should be considered. The clinical and
histopathological features of these hypersensitivity profiles correspond
to those of classic OLP lesions. OLDR diagnosis is subjective, as it can
only be confirmed when re-exposure following discontinuation of the
drug leads to re-emergence of the lesions. Diagnoses of OLCR can be
confirmed if replacement of the metallic restoration with another
nonmetallic material results in lesion improvement or resolution. A skin
test for hypersensitivity to mercury (the main component in amalgam
restorations) may aid in the diagnosis of OLCR. However, previous
studies have reported that the skin-patch test underperforms when

compared with clinical procedures to disclose lesions associated with
OLCR. In contrast to idiopathic OLP, oral lichenoid reactions (either
OLDR or OLCR) have not been associated with the potential for
malignant transformation, although this aspect also remains
controversial because of the lack of clear diagnostic methods.
Importantly, no clear-cut cases of malignant transformation have been
reported in peer-reviewed journals following oral lichenoid reactions.
Several studies have demonstrated that OLP is associated with
ulcerative colitis, vitiligo, bacterial and viral infections, multiple
sclerosis, hypertension, diabetes, autoimmune thyroiditis, and chronic
liver diseases. Although the findings remain inconclusive, some studies
have also reported a relationship between emotional stress and OLP
lesions. In addition to triggering the development of OLP lesions,
emotional disturbances may lead to lesion progression in some cases.
Despite these speculations, no studies have demonstrated that
attenuating emotional stress significantly improves oral health in
patients with OLP.
2.3. THERAPEUTIC MANAGEMENT
Among the various studies that have investigated therapeutic

strategies for OLP, none have reported successful outcomes. While
there is no cure for OLP, symptoms can be managed. In contrast to
cutaneous LP lesions, which are typically less aggressive and self-
limiting, oral manifestations of LP are more persistent, long-lasting, and
may cause intense discomfort, especially in patients with erosive and
atrophic forms of the disease. Therapeutic management aims to control
symptoms and monitor OLP progression. First-line treatment with
topical corticosteroids has demonstrated moderate-to-good efficacy in
most patients. Systemic corticosteroid therapy may be utilized in some
cases, and intralesional corticotherapy can aid in the treatment of

recalcitrant cases. Substitute medications for corticosteroids include
retinoids, dapsone, thalidomide, and immunosuppressants. Notably,
these medications are all associated with adverse reactions, especially
systemic corticosteroids. Therefore, the risks and benefits of each
medication should be carefully evaluated when attempting to manage
OLP. Lifestyle changes (i.e., cessation of smoking/alcohol use) should
be recommended among patients with OLP.
Chapter 3
BACKGROUND
Over the last 20 years, we have published a few studies related to

OLP. In the first of these studies, we analyzed more than 8,000 oral
mucosal records from the Department of Stomatology at the University
of São Paulo School of Dentistry. Approximately 90 cases of OLP, only
63 of which had consistent documentation, were identified, resulting in
an OLP prevalence of 0.8% among patients with oral mucosal disease
referred to our Department. Our other OLP studies focused on
therapeutic approaches, association with hepatitis C, association with
systemic medications, association with hyposalivation and Candida
spp. colonization, association with psychological factors, association
with amalgam restoration, association with thyroid autoimmune
disorders, and association with malignancy. The main results of these
studies are comprehensively described in the next section.
Chapter 4
GENERAL OVERVIEW OF OLP
4.1. ETIOLOGY AND PATHOGENESIS
The etiology of OLP remains unknown; however, immunohisto-

chemical analyses have indicated that the pathogenesis of the disease
appears to be associated with an immuno-cellular response involving
antigen-presenting cells and an inflammatory infiltrate consisting
predominantly of T lymphocytes. While the antigenic stimulus
responsible for the immune response remains to be elucidated, several
factors have been implicated as potential initiators of the immune
response, including microorganisms, drugs, foods, dental restorative
materials, tumor antigens, and autoantigens.
At the beginning of the pathogenic process, the antigenic stimulus
to the epithelial tissue is transferred to the host immune system via
antigen-presenting cells. These cells are required for the induction of
the immuno-cellular response, given that both Langerhans cells (LCs)
in the epithelium and dendritic cells in the submucosal tissue are potent
stimulators of T lymphocytes. LCs move from the epithelial tissue to
the regional lymph nodes via the submucosa. Within the lymph nodes,
they interact with CD4+ T lymphocytes, thereby inducing the cellular
immune response. This induction process is mediated by interactions

between cell surface molecules—specifically, intercellular adhesion
molecule-1 (ICAM-1, CD54) and major histocompatibility class II
complex (MHC II)—and LCs. Moreover, interactions between antigens
associated with lymphocyte function (e.g., LFA-1, CD11a) and T
lymphocytes also play a role. These events lead to the activation of
CD8+ cytotoxic T lymphocytes, a process mediated by the expression of
the major histocompatibility class I complex (MHC I). Excessive
release of cytokines such as interleukin-2 (IL-2), interferon-gamma
(IFN-γ), and tumor necrosis factor-alpha (TNF-α) thus occurs,
maintaining the activation of CD8+ T lymphocytes. Subsequently, CD8+
T lymphocytes move from the lymph nodes to the epithelial tissue by
means of a transport gradient, characterizing the effector phase of the
cellular immune response. Interactions between CD8+ T lymphocytes
and activated keratinocytes result in extensive tissue destruction, which
is histologically characterized by liquefaction of the basal layer, lysis of
basal epithelial cells, and keratinocyte necrosis (apoptosis). The
continuous release of immunological mediators leads to an increase in
lymphocyte activity, maintaining cytokine production not only by T
lymphocytes but also by immunocompetent keratinocytes and mast
cells. Together, these phenomena favor the progression and chronicity
of the disease.
Altogether, the presence of inflammatory lymphocytic infiltrates, as
demonstrated by histopathological and immunohistochemical analyses,
the chronic clinical course of the disease, and the satisfactory response
to corticosteroids suggest the immunological nature of OLP. However,
whether development of the disease is associated with a variety of
antigenic stimuli or occurs as a consequence of autoantigen expression
remains to be determined.
General Overview of OLP 19
4.2. EPIDEMIOLOGY
OLP manifests mainly in adults (average age, 50 years), occurring

predominantly in women at a male/female ratio varying from 1:2 to 1:4.
Children are rarely affected. There appear to be no ethnic differences
among affected individuals, although some studies have reported a
higher frequency of OLP among Caucasians. The reported prevalence
of OLP ranges from 0.1% to 4% of the general population, depending
on the sample studied.
Previously, no studies have investigated the prevalence of OLP in
the Brazilian population. However, in a random sample of 898 patients
seeking dental treatment at our general clinic, suggestive signs of OLP
were identified in six patients, indicating a prevalence of 0.6%. This
rate is similar to that reported by Li et al. (2020) for general global
(0.89%) and clinical populations (0.98%).
The characteristics of OLP have been investigated in various
countries, including the United States, United Kingdom, Denmark,
Hungry, Italy, Spain, Sweden, Croatia, Australia, New Zealand, China,
and Israel. Although clinical findings were similar among these
populations, some studies reported key differences when the disease
was investigated in relation to systemic factors and lifestyle.
4.3. CLINICAL PRESENTATION OF LICHEN PLANUS
LP is a chronic, non-infectious inflammatory disease affecting the

skin and/or mucosa. The prevalence of exclusively cutaneous lesions
ranges from 0.9% to 1.2%. Simultaneous involvement of the skin and
oral mucosa has been reported in 5–25% of cases. Patients with OLP
may also present with lesions in other extra-oral locations, such as the
genital mucosa or (less frequently) the scalp, nails, esophagus, and
conjunctiva. The identification of LP in more than one location is
critical in determining the most appropriate treatment strategies. While

cutaneous lesions tend to heal spontaneously in less than 3 years, oral
lesions have a more chronic clinical course and may persist for more
than 20 years (or even for life), with spontaneous resolution occurring
in <10% of cases.
4.4. ORAL LESIONS
Morphologically, OLP is essentially characterized by the presence

of slightly raised white striae. Lesions tend to be bilateral and
symmetrical, preferentially affecting the buccal mucosa. The
morphological characteristics of oral lesions also tend to be distinct
from those observed in other locations. The clinical manifestations and
anatomical locations of the lesions may vary throughout the chronic
course of the disease. Clinically, these polymorphous lesions are
categorized basically into four types: reticular, atrophic/erythematous,
erosive, and plaque. Each form may occur either in isolation or in
combination with the other forms. In one of our studies, the percentage
of patients exhibiting bilateral, symmetrical involvement of mainly the
buccal mucosa was 90%, with unilateral involvement occurring in the
remaining 10%. However, even in cases of unilateral involvement, the
presence of slightly elevated white striae or white papules is necessary
for a strict clinical diagnosis of OLP. Lesions lacking some clinical
and/or histopathological features of classic OLP are referred to as oral
lichenoid lesions (OLLs). Despite the argument that the risk of
malignant transformation is greater for OLLs than for true OLP lesions,
there is no evidence to support this claim, and clinical management is
identical for both types of lesions (Figures 9 and 10).
Figure 9. Unilateral lesions. Case A: atrophic-erythematous form. Case B: erosive

form. White areas, including striae, plaque, and papules are observed in both cases.
Although these clinical manifestations more commonly reflect oral lichenoid forms,
histological findings are conclusive of oral lichen planus. In such cases, a biopsy is
recommended to rule out other diagnoses such as dysplastic lesions. A punch biopsy is
indicated for these types of lesions as two specimens, for each lesion, can be obtained
from different areas, increasing diagnostic accuracy with minimal additional harm to
patients.
Figure 10. A bilateral ulcerated lesion of the buccal mucosa exhibiting radial striations
in the periphery. Note that the typical slightly elevated white striae are absent. Two
biopsy specimens are provided: one exhibits microscopic features suggestive of
nonspecific inflammatory infiltrate, while the other is conclusive of oral lichen planus.
A diagnosis of oral lichenoid lesion was made in this case.
Although OLP can manifest anywhere in the oral mucosa, lesions

predominantly affect the buccal mucosa, followed by the tongue,
gingiva, lips, palate, and floor of the mouth. In most patients, OLP
lesions can be observed in multiple intraoral locations. Except in cases
of gingival manifestations, isolated OLP lesions occur less frequently.
Indeed, previous studies have reported that approximately 10% of
patients with OLP present with exclusively gingival lesions. Gingival
manifestations are characterized by desquamative gingivitis (DG),

which is not exclusive to the diagnosis of OLP. In such cases, the
disease manifests in its erythematous form on the attached and marginal
gingiva. Sometimes, it is accompanied by white striae or patches in
combination with the erythematous areas or at the edge of the gingival
papilla. Other areas of the oral mucosa should also be examined for
OLP forms. Once the presence of classic white striae in OLP is
excluded, this type of gingival manifestations can also occur in patients
with mucous membrane pemphigoid (MMP), pemphigus vulgaris (PV),
or other autoimmune or inflammatory diseases such as bullous
pemphigoid, IgA linear dermatoses, and psoriasis. Although rare, mild-
to-severe gingival manifestations have also been reported in patients
experiencing allergic reactions to toothpaste or mouthwash. The
diagnosis of DG related to an allergic reaction usually requires a
negative result in direct immunofluorescence (DIF) analysis, which
enables its differentiation from other conditions when the causative
agent cannot be identified. Furthermore, the presence of local irritating
factors (e.g., dental biofilm and calculus) increases the severity of
gingival inflammation and can often alter the clinical and
histopathological features (Figures 11, 12, and 13).
Figure 11. Desquamative gingivitis in a patient with oral lichen planus (mostly of the
erythematous type), in combination with white papules and striae on the left buccal
mucosa.
Figure 12. Case A: A diffuse erythema accompanied by tiny striations (arrow) on the
attached gingival mucosa whose histopathological findings were suggestive of oral
lichen planus (OLP). Case B: A diffuse erythema affecting the attached gingival
mucosa. Microscopic findings were suggestive of nonspecific inflammatory infiltrate.
The differential diagnosis should mainly include OLP, an allergic reaction to
toothpaste, and membrane mucous pemphigoid. In such cases, direct
immunofluorescence analysis is also recommended.
Figure 13. Discreet erythema of a desquamative gingivitis lesion on the upper left
gingival mucosa (blue arrow). Some tiny white papules are observed on the alveolar
bridge of a missing tooth, on the upper right side (blue arrow). The biopsy finding was
suggestive of oral lichen planus.
OLP symptomatology typically depends on the clinical presentation

of the disease. The predominantly white lesions (observed in the
reticular and plaque forms) are usually asymptomatic and often
diagnosed during routine examination, mainly when the disease
manifests on limited areas of the oral mucosa. However, lesions
dominated by erythematous areas (observed in the erosive and atrophic
forms) are accompanied by intense pain and discomfort, usually

interfering with the patient’s quality of life.
4.5. KOEBNER PHENOMENON
The Koebner phenomenon, which is more often associated with

cutaneous LP and other mucocutaneous diseases, may also be observed
in the oral cavity. Mechanical trauma resulting from dental procedures,
chronic friction caused by the irregular surfaces of prostheses or
restorations, mucosal suctioning habits, and other factors may promote
the formation of new lesions in the affected area. Reportedly,
elimination of these factors can lead to a decrease in lesion severity or
complete resolution of the lesions. Although, in our practice, we have
never observed complete resolution of an idiopathic OLP lesion after
trauma, trauma resolution often leads to substantial relief in affected
patients.
4.6. EXTRA-ORAL LESIONS
4.6.1. Cutaneous LP
Cutaneous LP lesions are characterized by papular, erythematous–

violaceous eruptions. Such lesions tend to be bright, polygonal in shape,
and permeated by keratotic striae (Wickham’s striae). The clinical
course of the disease is self-limiting, with an average duration of 8-18
months between the first manifestation and the spontaneous resolution
of the lesions. The main clinical variants of cutaneous LP lesions
include hypertrophic, atrophic, bullous, erythematous, erosive, annular,
actinic, linear, and acute forms.
Lesions are typically bilateral and symmetrical, preferentially

affecting the flexor surfaces of the wrists, lower-third of the legs,
thighs, sacral region, and abdomen. The lesions may occur along a
linear path following excoriation or trauma (Koebner phenomenon).
Itching may be mild to severe at the lesion site, and residual
pigmentation may be observed.
4.6.2. Genital LP
Lesions affecting the genital mucosa usually present as papules that

coalesce into annular plaques. The presence of LP in both the gingiva
and genitourinary tract constitutes the vulvovaginal gingival syndrome
in women and the penile–gingival syndrome in men, which together
occur in approximately 1.4% of patients with OLP. The few patients in
our clinic with oral and vaginal involvement were referred to a
gynecologist for further evaluation and treatment. DG is the most
frequent type of OLP lesions in patients with concomitant genital LP
lesions.
4.6.3. Nail LP
Nail involvement is observed in 10% of LP cases. Occurring most

often in the fingernails, such manifestations are usually observed in
patients with oral and cutaneous LP lesions. Clinically, nail LP lesions
are characterized by longitudinal striations, fragmentation and friability
of the nail border, and progressive atrophy/darkening. The differential
diagnosis should include onychomycosis, alopecia areata, and psoriasis.
4.6.4. Esophageal LP
LP lesions affecting the esophagus most frequently manifest in the

reticular form. Most esophageal LP lesions are asymptomatic, and thus
remain undiagnosed. When patients do experience symptoms, the most
common complaint is dysphagia, with patients usually first visiting
gastroenterologists for their condition.
4.6.5. Conjunctival LP
Conjunctival involvement is rare, having been reported in only a

few cases. However, ocular manifestations of LP can be quite serious,
as they can result in irreversible damage to the ocular surface and loss
of vision due to corneal scarring. Conjunctival LP lesions are
characterized by erythema, which can develop into conjunctivitis and
lead to scarring. Ocular LP may occur in isolation (i.e., without
systemic involvement). In such cases, the differential diagnosis should
include MMP.
4.6.6. Scalp LP
Scalp lesions are observed in approximately 1% of patients with

OLP. Such lesions typically manifest with perifollicular erythema and
plaque alopecia. Although confirmation of the diagnosis requires
histopathological analysis, DIF may aid in excluding other
inflammatory cutaneous diseases with similar manifestations, such as
erythematous discoid lupus.
Chapter 5
DIAGNOSIS OF OLP
The use of strict clinical criteria for diagnosing OLP has been
reported in a limited number of studies, and only for cases in which the
clinical characteristics of the disease were fully met. The diagnosis of
OLP made exclusively on a clinical basis accounts for <40% of the
cases. The authors of these studies have argued that, in most cases, the
clinical presentation lacks some of the classic aspects required for a
confident clinical diagnosis of OLP, thereby requiring a biopsy.
Additionally, they have also reasoned that the biopsy aids to rule out
similar entities and, fundamentally, to detect the presence of epithelial
dysplasia. McCartan, Flint, and McCreary (2000, 2003) objected to the
use of strict clinical criteria, given that other diseases such as
leukoplakia, lupus erythematosus, and even oral squamous cell
carcinoma (OSCC) may be similar in clinical appearance to OLP. Most
clinical researchers have argued that a histopathological diagnosis is
essential and that such analyses should be accompanied by DIF when
possible.
Some authors (van der Meij, Schepman, van der Waal, 2003) have
emphasized the application of more precise combination of the clinical
and histopathological diagnostic criteria of OLP due to some
inconsistency of the criteria established by the WHO (1978).

Importantly, histopathological findings depend on the activity of the
disease and the area biopsied, meaning that they are not always
conclusive for the diagnosis of OLP. Thus, histopathological diagnoses
are often classified as conclusive of LP, compatible with LP, or non-LP
(note: the terms LP and OLP are interchangeable when referring to
histopathological findings. Oral pathologists may sometimes use the
OLP terminology, while general pathologists may prefer to use the LP
terminology). In our view, the clinical criteria described in the previous
sections are sufficient for the diagnosis and management of OLP in the
vast majority of cases. Rödström et al. (2004) resorted to clinical
criteria, exclusively, in 38% of 1,028 cases, in one of the most
extensive study of OLP cases ever reported. Histopathological
examinations should be performed in OLP cases where classic
characteristics, such as the absence of slightly raised white striae in a
bilateral arrangement, are not met. In such cases, a clinical diagnosis
compatible with OLP or OLL should be made, possibly including other
differential diagnoses. Location is also a factor to consider when
performing biopsy. Lesions that are located in an area of higher risk of
malignization, such as the ventral and lateral border of the tongue and
the floor of the mouth, and that failed to exhibit confident clinical
characteristics of OLP should be biopsied. Biopsy should be mainly
performed in cases of unilateral involvement, as this can sometimes
indicate the presence of a dysplastic lesion (such as leukoplakia) or
superficial OSCC. In some cases of unilateral involvement, the
presence of an erythematosus lesion interspersed with white patches
and some striations may be mistaken for an OLP lesion, necessitating a
differential diagnosis based on biopsy findings. It should be pointed out
that, although the histopathological examination may not disclose the
exact pathology of the lesion under clinical evaluation, it can be useful
to rule out malignancy, which, by itself, constitutes a significant
finding, as it will reassure the patient about the benign nature of the
Diagnosis of OLP 29
lesion. Fortunately, both a dysplastic lesion and an OSCC mimicking an

OLP lesion are uncommon events.
Figure 14. Bilateral lesions on the gingiva mucosa exhibiting signs suggestive of
atrophic−erythematous oral lichen planus (OLP). Biopsy revealed no features of lichen
planus (LP), only nonspecific inflammatory infiltrates without signs of dysplasia. The
clinical (i.e., working) diagnosis should be oral lichenoid lesion (OLL). In such cases,
management should include periodic follow-up, treatment with moderate-potency
topical corticosteroids (if necessary, and cautiously), periodontal cleaning, instructions
on oral hygiene, and prosthesis.
Figure 15. Multiple forms of oral lichen planus (OLP) in the same patient. Plaque-
papular form lesions can be observed on the buccal mucosae, while atrophic and
plaque form lesions can be observed on the dorsal surface of the tongue. Given that
typical forms observed on the buccal mucosa, these tongue lesions may also confirm
OLP; however, the atrophic nature of the tongue lesion along with the presence of the
white plaque is concerning. In such cases, punch biopsy should be performed in both
lesions of the tongue to exclude signs of dysplasia.
Figure 16. An extensive unilateral homogeneous white plaque lesion on the buccal
mucosa. The histopathological finding was conclusive of oral lichen planus (OLP).
Given that slightly raised white striae are seen inside and in lesion periphery, it is
possible to agree with a conclusive diagnosis of OLP. This is a patient came to our
clinic for a full prosthetic rehabilitation unaware of the existence of the lesion.
Figure 17. A unilateral lesion on the buccal mucosa exhibiting a combination of

erythema, white striae, and plaque. A diagnosis of erythematous oral lichen planus is
very likely; however, the presence of diffuse and extensive erythema is also a relevant
characteristic of dysplastic lesions. A biopsy for this case is necessary.
Diagnosis of OLP 31
Figure 18. A suspicious dysplastic or oral squamous cell carcinoma lesion on the
dorsal surface of the tongue. The histopathological examination reveals only mild
dysplasia and a lichenoid infiltrate. Surgical intervention, preferably with laser, is the
best management for this type of lesion. Follow-up examinations should include a
detailed inspection of the whole oral mucosa.
A biopsy, therefore, may not be necessary when unilateral lesions

exhibit the classic clinical features of OLP, in which case a diagnosis of
OLP and appropriate follow-up may be sufficient. Clearly, doubts
always surface in a clinical environment and performing a biopsy in
suspected cases of unilateral OLP seems like a prudent and sensible
decision (Figures 14, 15, 16, 17, and 18).
5.1. DIFFERENTIAL DIAGNOSIS OF OLP
Several researchers have noted similarities in the clinical

presentations of OLP and other diseases that may complicate the
diagnostic process. Previous reports have, therefore, suggested that the
following be included in the differential diagnosis for OLP: bullous
dermatitis caused by linear IgA, lupus erythematosus, MMP, PV,
psoriasis, drug-induced reactions, recurrent aphthous stomatitis,
leukoplakia, frictional keratosis, hyperplastic candidosis, secondary
syphilis, and OSCC. Based on our experience, the discoid form of lupus
erythematosus and drug-induced reactions can manifest similarly to
classic OLP. However, this is quite uncommon. Differential diagnosis
is mostly required for OLP when the lesions are unilateral, when classic
characteristics of these lesions are lacking, or when the lesions are
localized exclusively on the gingival mucosa (Figures 19 and 20).
Figure 19. A case in which exclusion of discoid lupus was necessary. The lesion on the
buccal mucosa is typical of reticular oral lichen planus (OLP), while that on the lip is
more suggestive of lupus. Direct immunofluorescence findings were negative for
lupus, although histopathological analysis suggested OLP. Specimens for both
examinations were obtained via a biopsy of the buccal mucosa. Follow-up would
include referring the patient to a dermatologic center.
Figure 20. A case of frictional keratoses. Although typical striae are missing, it
resembles reticular oral lichen planus.
Diagnosis of OLP 33
The non-idiopathic OLP forms, the so-called OLDRs and OLCRs

are clinically, histologically, and immunologically similar to classic
OLP lesions. OLDRs occur as eruptions following the use of systemic
drugs or topical medication that exhibit systemic absorption. The drugs
most frequently associated with the development of OLDRs are
antihypertensives, oral hypoglycemic agents, antimalarials, and non-
steroidal anti-inflammatory drugs (NSAIDs). Some studies have
reported a greater tendency toward erosive and unilateral lesions in
patients with suspected OLDRs, although there is no consensus on this
observation.
Figure 21. A suspected case of lichenoid drug reaction (LDR). Carbamazepine was
among the medications taken by the patient. (a, b) Initial consultation. (c,d) Partial
remission was observed 4 weeks after discontinuing carbamazepine. Histopathological
findings suggest oral lichen planus; however, the diagnosis was revised to oral
leukoplakia, given that his last biopsy revealed moderate dysplasia on the left buccal
mucosa.
The diagnostic criteria for OLDR are broad and subjective, with
reliable diagnosis occurring only when a lesion reappears following the
reintroduction of the drug after a withdrawal period. However, no such
instances have been observed in clinical practice. Furthermore, cases of
suspected OLDR are rare. In our previous studies, we observed few
significant differences in the types of systemic medications taken by the

OLP and control groups. Indeed, the use of antihypertensive agents was
more common in the control group than in the OLP group, suggesting
that such agents may help to prevent the development of OLP (Figure
21).
Figure 22. (a) An extensive leuko-erythroplakia lesion on the buccal mucosa whose
differential diagnosis would include nonhomogeneous leukoplakia or erythematous-
atrophic oral lichenoid lesion. The tongue’s ventral surface is also involved, but it does
not appear clearly in the picture. The presence of extensive and multiple amalgam
fillings was also thought to be the lesion-causing agent. A skin-patch test was deemed
necessary for this case, with positive results for mercury, leading to a diagnosis of oral
lichenoid contact reaction. (b) Replacement of the amalgam restorations with resin-
matrix ceramic resulted in almost complete lesion’s resolution.
In contrast, OLCRs are relatively common, resulting from direct

contact between dental restorations (mainly amalgams) and the oral
mucosa. In cases of uncertainty, a cutaneous sensitivity test including
components of the restorative material may aid in the diagnosis of
OLCR. In most cases, replacing the restorative material with
nonmetallic components leads to the resolution of the oral lesion within
6-8 weeks. OLCRs seem to have become a thing of the past in oral
medicine now that amalgam fillings are becoming less common in
dental practice. In one of our previous studies, more substantial post-
replacement improvements were observed in patients with lesions in
Diagnosis of OLP 35
direct contact with the amalgam restoration than in patients with lesions
close to the area of contact. Nonetheless, all patients exhibited
significant improvement, if not complete remission. Similarly, most
other previous studies have reported that the healing process is better
for the lesions that are closer to the amalgam restoration, regardless of
the skin-patch findings. While some authors have proposed that lesions
associated with OLCRs may undergo malignant transformation, this
hypothesis remains controversial. Our analysis revealed no scientific
evidence to suggest that OLCR lesions can become malignant (Figure
22).
Apart from OLCRs, allergic reactions affecting the oral mucosa are
relatively uncommon. However, when they do occur, such reactions are
typically mediated by IgE (type I) or T lymphocytes (type IV). These
manifes-tations may be related to several substances that can act as
allergens, including toothpaste, mouthwash, food, and (more
frequently) restorative materials (e.g., mercury, nickel, and acrylic).
While diagnoses are primarily based on clinical criteria, in some cases,
histopathological examinations and direct immunofluorescence may be
necessary to exclude other pathologies.
5.2. HISTOPATHOLOGICAL FINDINGS
Most authors have recommended that OLP diagnosis be made based

on the combination of clinical and histopathological features. While a
biopsy is not required, it may help exclude other pathologies,
particularly in cases of unilateral manifestation. Importantly,
histopathological analysis does not necessarily lead to a definitive
diagnosis of OLP, and no previous studies have reported a close
relationship between the histopathological and clinical features of OLP.
Nonetheless, reticular lesions tend to be associated with moderate
hyperorthokeratosis or hyperparakeratosis, lysis of basal layer cells, and
subepithelial lymphocytic inflammation. While hyperkeratosis is absent

in atrophic forms of OLP, erosive forms of the disease are associated
with epithelial prominence, leading to the exposure of the connective
tissue. Histologically, the main findings include focal hyperkeratosis,
regular acanthosis, hydropic degeneration of the basal layer, band-like
subepithelial lymphocytic inflammatory infiltrate, and necrotic
keratinocytes (colloid or Civatte bodies). Local irritative factors and
secondary infections (e.g., candidiasis) may alter or mask the typical
characteristics of the disease. Whenever possible, these factors should
be eliminated prior to biopsy.
It is essential to call attention to the histopathological findings of
both OLP and OLL lesions given that they are also a source of
misguided diagnoses. Thus, the histopathological features accepted as
conclusive or suggestive of OLP are not exclusively found in lesions
that support a clinical diagnosis of OLP or OLL. Therefore, in the
absence of clinical features associated with either OLP or OLL lesions,
a diagnosis cannot be reached even with a histological finding
indicating features of OLP or OLL.
5.3. ROLE OF DIRECT IMMUNOFLUORESCENCE
Several researchers have highlighted the ability of DIF to support

some diagnoses of OLP, particularly when the differential diagnosis
includes other mucocutaneous diseases such as discoid lupus
erythematosus, PV, mucosal membrane pemphigoid, bullous dermatitis
caused by linear IgA, and erythema multiforme. Although
immunofluorescence cannot affirm the existence of pathognomonic
findings associated with OLP, it may help to support the diagnosis of
OLP while excluding the aforementioned diseases with clinical features
similar to those of OLP. In this respect, mucosal membrane pemphigoid
and discoid lupus erythematosus are the most relevant diseases to
Diagnosis of OLP 37
consider. In cases of suspected OLP, the presence of fluorescence for

anti-fibrinogen antibodies—along with the absence of fluorescence for
anti-IgA, anti-IgG, anti-IgM, and anti-C3 antibodies—throughout the
basement membrane zone (BMZ) can be used to support the diagnosis.
Fibrinogen deposition in the BMZ is observed in linear, granular, and
homogenous patterns. Other DIF findings in OLP that are in association
with anti-fibrinogen in the BMZ are the presence of anti-IgM, anti-IgA,
and anti-C3 antibodies in colloid bodies in the connective or papillary
submucosa. Fluorescence in colloid bodies is not exclusive of OLP
lesions but appears to be found more strongly in this disease and more
frequently with anti-IgM antibodies. When found in isolation, these
cytotoxic bodies do not present a diagnostic value, but in conjunction
with anti-fibrinogen in the BMZ, the specificity for the diagnosis of
OLP increases significantly. To date, it remains unclear whether the
appearance of immunofluorescence reactions in OLP lesions is due to
autoimmune mechanisms or simply to the extravasation of serum
proteins. However, data obtained from clinical, histopathological, and
immunopathological findings may contribute, to some extent, to a
highly accurate diagnosis of OLP.
5.4. SYSTEMIC DISEASES AND OLP
Numerous research groups have aimed to determine whether certain

systemic diseases can predispose to OLP. However, no significant
differences in the frequency of OLP between patients with diabetes
mellitus and systemic arterial hypertension and the general population
have been reported. Any relationship between diabetes or hypertension
and OLP would likely result from the potential role of anti-diabetic
agents or NSAIDs (but not antihypertensives) in the development of
OLP lesions rather than being mediated by the mechanisms of
metabolic changes produced by these diseases.
5.5. PSYCHOLOGICAL DISTURBANCES
While no studies have demonstrated a conclusive cause–effect

relationship between psychiatric disorders and OLP, some authors have
reported that patients with OLP exhibit higher levels of anxiety and
depression than controls and, above all, that anxiety and depression
may lead to the development of OLP. It is more likely that the presence
of the disease itself leads to anxiety and/or depression, apart from
intensifying existing symptoms. OLP tends to manifest in age groups at
increased risk for OSCC, which may increase anxiety in patients aware
of this association. Furthermore, no studies have produced definitive
data to suggest that treating psychological disturbances in patients with
OLP leads to sustained lesion improvement. While patients may
experience better quality of life and symptom attenuation due to
psychological treatment, such improvements would probably not be
accompanied by significant changes in the clinical aspects of OLP.
Interestingly, patients with OLP may also experience xerostomia, which
may or may not be related to hyposalivation. Xerostomia can also
produce separate symptoms (e.g., mouth burning, itching sensations,
dryness, etc.) unrelated to OLP, which may improve following
psychotherapy.
The mechanisms through which psychological disturbances may
lead to the development of OLP remain to be elucidated. In one study,
patients with OLP exhibited higher mean scores on several
psychological assessments, and patients with the erosive form of OLP
exhibited higher serum cortisol levels than controls. The authors of this
study argued that co-occurrence of these features (i.e., high serum
cortisol level and psychological disturbance) may negatively affect
immune homeostasis, predisposing the patient to OLP.
Based on our findings, we argue that anxiety and depression exert
little to no influence on the development of OLP lesions. Moreover,
given that the most-widely accepted hypothesis regarding the
Diagnosis of OLP 39
etiopathogenesis of OLP involves the activation of CD8 + cytotoxic T

cells, it is very unlikely that psychological disturbances may act as a
trigger in producing OLP lesions by activating CD8+ T lymphocytes in
response to the antigens on lesional keratinocytes.
5.6. HEPATITIS C
Perhaps the most controversial finding regarding the association

between OLP and systemic disease arises from studies on chronic liver
disease, particularly hepatitis C, as mixed results have been reported.
The discrepancies may be due to geographical variations in the
prevalence of hepatitis C infection, as the associations with OLP were
observed in areas with a higher prevalence of hepatitis C infection.
However, while our previous clinical study reported a positive
association between hepatitis C and OLP, this association has not been
confirmed in other clinical research centers in Brazil. The association
may be merely coincidental, occurring at random rather than due to
shared etiopathogenic mechanisms. Further studies with a range of
methodologies would be required to verify this association. However,
interest in the relationship between hepatitis C and OLP has waned in
recent years. Ultimately, there is little scientific evidence to warrant a
large-scale clinical investigation on hepatitis C and OLP.
5.7. OLP AND AUTOIMMUNE DISEASE

(HYPOTHYROIDISM)
Previous studies have failed to observe significant increases in the

prevalence of OLP in patients with autoimmune diseases. Nonetheless,
the potential association between hypothyroidism and OLP has received
substantial attention, given that some studies have reported a
significantly higher prevalence of hypothyroidism in patients with OLP

than in controls. Indeed, we observed a similar tendency in most of our
previous studies. Further studies are required to determine the potential
pathological basis for this association. On the other hand, investigations
of the prevalence rate of OLP in hypothyroidism have not found any
significant differences as compared to the OLP prevalence rate in the
general population.
5.8. TREATMENT
Given that there is no cure for OLP, treatment strategies are

primarily directed toward the control of symptoms, particularly in
patients with erosive and atrophic forms of the disease. Asymptomatic
patients may also require periodic treatment. Appropriate treatments are
selected based on the severity of symptoms, the clinical presentation,
the general condition of the patient, and examination findings related to
the effect of OLP on patients’ daily life. Frequently, more than one
treatment modality is necessary due to the chronic nature of the disease
and the innumerable variables related to the development of OLP.
Topical and systemic corticosteroids are the most commonly used drugs
due to their anti-inflammatory and immunosuppressive properties.
However, the use of high-potency corticosteroids can lead to severe
adverse reactions, making it necessary to determine the risks and
benefits of treatment in each patient. Other medications used for OLP
control include cyclosporine, retinoids, thalidomide, and dapsone. The
systemic use of these drugs also requires caution due to the potential for
various, severe side effects.
Patients with OLP lesions are intrinsically predisposed to
developing oral candidosis, a risk that may increase during treatment
with topical medications such as corticosteroids. The concomitant
presence of systemic diseases (e.g., diabetes mellitus) can also increase
Diagnosis of OLP 41
the risk of oral candidosis in patients with OLP. In addition to

intensifying OLP symptoms, Candida albicans infection can produce a
potentially carcinogenic enzyme (N-nitrobenzimethylamine), requiring
antifungal therapy. While some authors have suggested that Candida
spp. is associated with malignant transformation in OLP lesions, there
is no scientific evidence to support this assertion. Further long-term
prospective studies may aid in clarifying this issue. In a previous study,
we compared the prevalence of oral Candida spp. colonization between
patients with OLP lesions, patients with other types of oral lesions, and
the general population and observed no significant differences.
5.9. DESQUAMATIVE GINGIVITIS
During the 1960s, DG was considered a disease related to

hormonal disturbance, as it primarily affected women in their seventh
decade of life. However, this is no longer true. DG is observed in
patients with chronic inflammatory (e.g., OLP) and autoimmune
diseases, mainly PV and MMP. Sloughing of the epithelia can be
observed in most patients with PV and in some with MMP. In patients
with OLP, DG manifests without true desquamation, presenting with
erythema patches, affecting diffuse or restricted areas of the attached
(predominantly) and marginal gingiva. Some cases of DG are
asymptomatic, but patients often report oral discomfort mostly related
to bleeding during meals and oral hygiene. Treatment for DG remains
challenging, and neither corticosteroid mouthwashes nor ointments
have been associated with long-term improvements. While topical
immunosuppressive medications may produce some benefit, the risks of
such treatment typically outweigh the benefits of the necessary long-
term use, thus increasing the risk of cancer. Short-term use of a topical
immunosuppressive agent can provide important lesion improvement
with almost no risk for adverse effects. However, recurrence will
usually occur after the withdrawal of the medication. Similarly, caution

must be exercised when considering the use of high-potency
corticosteroid ointments. To date, no studies have investigated the
treatment outcomes of long-term DG in patients with OLP or other
diseases with an autoimmune etiology. In many cases, DG may remain
without effective control, alternating between periods of quiescence and
relapse. In our study of DG in patients with autoimmune diseases
(mainly PV and MMP), we observed no significant differences in the
efficacy of high-potency topical corticosteroids and placebo. However,
in rare cases, spontaneous remission of gingival lesions was observed in
patients with DG during follow-up.
5.10. MALIGNANCY IN OLP
As previously emphasized, the association between OLP and oral

carcinoma remains controversial. Nonetheless, patients with OLP are
currently considered to be at increased risk for developing OSCC,
compared to patients without OLP. One large retrospective study
(Rödström et al. 2004) involving 1,028 patients with OLP reported
malignant transformation in 0.48% of cases. The lesions in which
malignancies were subsequently observed had been given a histopatho-
logical diagnosis of LP and were of the atrophic erythematous or
erosive forms. On average, malignancies occurred 6.4 years after the
initial diagnosis of OLP. Additionally, the authors concluded that the
rate of OSCC was higher among patients with OLP than among the
general population. Data from the abovementioned and other studies
(Eisen, 2002) suggest a requirement for long-term, if not indefinite,
observation of patients with OLP. In accordance with previously
published data, Eisen (2002, 2003) also observed OSCC in 0.8% of
patients with OLP. Reticular lesions did not lead to carcinoma
development, the rate of which was the highest for erythematous and
Diagnosis of OLP 43
erosive lesions. No patients who had developed oral cancer exhibited

any other potential risk factors. Eisen (2002) further noted that none of
the carcinomas had developed within lesions that had previously
undergone biopsy. Although a correlation between OLP and OSCC
seems likely, the author seemed unsure of the potential for malignant
transformation in OLP lesions.
Recent studies have provided some additional data regarding
malignant transformation in patients with OLP. Among 206 patients
with OLP, Shearston et al. (2019) observed malignant transformation in
only one patient (0.49%). This study reported a very unusual finding:
out of 281 patients clinically diagnosed as having OLP, 44 (15.6%)
showed some degree of epithelial dysplasia and were subsequently
characterized as having oral lichenoid dysplasia (OLD). The authors
clearly stated that all 44 patients with OLD presented clinically typical
OLP lesions, but their histological findings exhibited some degree of
epithelial dysplasia. This raises the question of whether these OLD
cases consistently presented clinical features that, somehow, could not
differentiate them from classic OLP lesions. In this respect, there is no
detailed description regarding the clinical presentation and distribution
of the OLD cases. The authors, nonetheless, highlighted the importance
of histopathological analysis for differentiating OLP lesions from those
exhibiting lichenoid dysplasia.
Another study by Gümrü (2012) reported only one case of
histologically verified malignant transformation (0.27%) among 370
patients with OLP. In addition, the study revealed no correlation
between malignant transformation and alcohol or tobacco use, neither
of which were identified as risk factors for OLP. However, this study
did not present any clinical details of the case that underwent malignant
transformation.
Interestingly, as the rate of malignant transformation that has been
reported in these two studies significantly exceeds the rate of OSCC in
the general population, this adds a further difficulty for the early
diagnosis of OSCC. Given that most cases of OSCC arise from
clinically normal oral mucosa, individuals from the general population

without OLP or any other potentially malignant oral lesion are not
followed up as regularly as patients with OLP.
Figure 23. A case of oral squamous cell carcinoma (OCSC) on the floor of the mouth
(ulceration with elevated borders and signs of infiltration), which developed in a
lesion-free area in a patient with histopathologically confirmed erosive oral lichen
planus (OLP). The OLP lesion was bilaterally located on the buccal mucosa (not
clearly visible here). This represents the only case of combined OLP and OSCC
observed in our clinic thus far. There is no evidence to confirm that OSCC developed
due to the previous existence of an OLP lesion in the oral mucosa; it could just be a
coincidence since both lesions occurred on different sites.
The issue of malignant transformation is of great concern to

clinicians who treat patients with OLP on a regular basis. Over the last
20 years, we have diagnosed and treated approximately 450 patients
with OLP or OLL lesions in our oral medicine clinic, some of whom
continue to attend follow-up visits. These patients originally presented
with at least one of the most accepted criteria for OLP, namely the
presence of white papules and/or raised striae, mostly with bilateral
involvement. These criteria were also applied to cases with unilateral
presentation. Histopathological signs of liquefaction in the basal cell
layer and/or the presence of band-like lymphocytes in the connective
tissue and an absence of epithelial dysplasia were required for cases in
which biopsy was deemed necessary. There were even cases that did
not fall into the category of either OLP or OLL, as they presented only
with weak signs of white striation, coupled with histopathological
Diagnosis of OLP 45
findings of nonspecific inflammatory infiltrate. These cases were also

included and placed under clinical monitoring with the diagnosis of
possible OLLs. To date, none of our patients with OLP developed
OSCC in preexisting OLP or OLL lesions. Indeed, only one case, a
female patient with histologically-confirmed erosive OLP occurring
bilaterally on the buccal mucosa and lateral border of the tongue,
developed OSCC from a clinically normal oral mucosa region on the
floor of the mouth after 8 months of follow-up, resulting in a prevalence
of OSCC of 0.2%. Although this rate is much higher than that in the
Brazilian population for the incidence of OSCC (15 per 100,000
inhabitants, Wünsch-Filho, 2002), this case was considered to have
occurred at random (Figure 23).
Notably, out of the 230 patients diagnosed with OSCC following
histopathological examination at our oral medicine clinic within the
past 15 years, none had preexisting OLP lesions. Taken together, the
absence of malignant transformation in the OLP cases and of OLP
lesions in the patients with OSCC confidently indicate that malignant
transformation of OLP lesions is exceedingly rare (or nonexistent) in
the general Brazilian population. Therefore, OLP lesions follow a
pattern similar to that of cutaneous LP lesions, as they show no
increased risk for malignant transformation.
Furthermore, some studies have reported that patients with OLP are
50–70 times more likely to experience malignant transformation than
the general population, making it difficult to address this issue in
clinical practice. Given the lack of convincing data, we have not
reported these statistics to patients with OLP in our practice.
Yet, the inaccurate characterization of OLP based exclusively on
histopathological grounds may have harmful consequences. This may
occur when some types of lesions with no clinical signs of OLP, except
for the fact that they bear related histopathological features, are
diagnosed as OLP. Some of these lesions, wrongly characterized as
OLP, may progress to OSCC. Such cases have been reported in
reputable scientific journals and defined as a typical characterization of
the malignant transformation of OLP. As this situation has been

ongoing for decades, the controversy regarding the malignant
transformation of OLP has only grown, due to the absence of strict
criteria for the diagnosis of OLP, or negligence in following them.
Our findings stand in contrast to those suggesting that OLP is a
potentially malignant disease. To date, the accumulated evidence
remains inadequate to classify OLP as potentially malignant, and to
reach a consensus. Furthermore, most of our patients with OSCC—
except those with long-term exposure to risk factors associated with
malignancy (e.g., excessive alcohol consumption, which is reported by
approximately 40% of men with OSCC, or the presence of oral
leukoplakia or dysplastic lesion at the site of malignancy, which
accounts for 17% of the cases)—exhibited no other risk factors for
malignancy. A significant percentage of our patients with OSCC may
have had a genetic predisposition for malignancy. Moreover,
malnutrition is known to increase the risk of malignancy in developing
countries. Indeed, a 2005 report by the WHO noted that >70% of
cancer-related deaths occurred in middle- and low-income countries.
Malnutrition was observed in most of our patients with a history of
excessive alcohol consumption prior to OSCC. Food deficiency,
however, was more likely related to chronic alcoholism and may act
synergistically in the development of malignancy.
Chapter 6
ADDITIONAL RESEARCH
AND FURTHER COMMENTS
To achieve a better understanding of OLP, we designed an

additional study to analyze some clinical and histopathological features
of the disease, with an emphasis on characteristics that may be relevant
for diagnosis. As such, we incorporated DIF analysis in the diagnostic
process for OLP. In addition to emphasizing appropriate treatment
approaches, we sought to analyze, as much as possible, long-term
changes in the clinical features of the disease.
6.1. PATIENTS AND METHODS
This latest case series included 59 patients (44 women and 15 men)
with lesions characteristic or suggestive of OLP. All patients underwent
a specialized evaluation to determine the clinical status of their oral
mucosa and were examined following a defined clinical protocol. We
collected data related to age, sex, ethnicity, oral symptoms, disease
duration, lesion characteristics, locations of involvement, the presence
of cutaneous and other mucosal lesions, systemic diseases, drug use,
habits, and dental conditions.
6.2. CONCOMITANT INFECTION WITH CANDIDA SPP.
Cytological examinations were performed to identify cases of

concomitant candidosis in patients with oral lesions as well as exclude
the presence of Candida spp. infection prior to biopsy. Specimens were
obtained by gently scraping the surface of the lesion with a #15 scalpel
blade and subsequently placed on glass slides and fixed in 95% ethyl
alcohol. In the laboratory, specimens were stained with periodic acid-
Schiff (PAS). Another method used for identifying Candida infection
was direct examination using 10% KOH (hydroxide potassium).
Patients with positive findings, i.e., detection of pseudohyphae in the
smears, were treated with antifungals for 2 weeks. Such examinations
were critical in eliminating Candida spp. as a causative or aggravating
symptomatology and helping to avoid histopathological misdiagnosis in
cases of Candida-induced epithelial dysplasia.
6.3. CLINICAL AND HISTOPATHOLOGICAL

DIAGNOSIS OF OLP
Diagnosis of OLP was defined based on (a) the presence of striae

and/or white papules in linear, interlaced, circinate, or radial
arrangements; (b) bilateral involvement of the oral mucosa, mainly the
buccal mucosa and lateral border of the tongue; (c) histopathological
signs of liquefaction in the basal cell layer (i.e., degenerative changes to
the basal cells) accompanied by a well-defined band-like zone of
primarily lymphocytic inflammatory infiltrate confined to the
superficial part of the connective tissue; and (d) absence of epithelial
dysplasia. Histopathological findings were classified as conclusive of
OLP; compatible with OLP; or non-OLP (non-OLP is characterized
when the histopathological findings consist almost exclusively of
nonspecific inflammatory infiltrate).
Additional Research and Further Comments 49
6.4. DATA ANALYSIS
Table 1. Clinical profile of patients with oral lichen planus (OLP)

(N = 59)
Characteristic Men Women Total

N = 15 N = 44 N = 59
Age variation 28 to 70 years 11 to 81 years old 11 to 81 years old
(mean) (55 years) (50.6 years old) (51.7 years old)
Duration time of the lesion 2 mo − 15 yr 2 m −13 yr 2 mo − 15 yr
(mean) (4.6 yr) (3.1 yr) (3.4 yr)
unknown 5 patients 6 patients 11 patients
Habits
Only Smoking 7 8 15
Only Alcohol - - -
Smoking and Alcohol 4 - 4
Quit habit 3 2 5
Medical history
No Disease 4 9 13
Hypertension 4 16 20
Diabetes 3 8 11
Hypothyroidism 0 7 7
Allergy 1 6 7
Viral hepatitis 1 3 4
Other 5 13 18
Emotional disturbances
Depression 2 8 10
Anxiety 2 9 11
None 11 2 38
OLP = oral lichen planus
mo = months
yr = years
Summary
Out of a total of 59 patients, 11 patients (18.6%) were unaware of the existence of their oral lesions,
and diagnosis was made during routine dental check-ups. Medical history revealed that most of
the patients (46; 78%) had some type of systemic disease. The most prevalent diseases were
systemic arterial hypertension (20; 33.9%), non-insulin dependent diabetes (11; 18.6%), and
hypothyroidism (7; 11.9%). The daily use of systemic medication was reported by 31 patients (6
men and 25 women; 52.5%). There was no statistically significant difference between male and
female patients regarding the regular use of medications (2 with Yates correction, P = 0.408).
However, altogether, women used a higher number of different medications (16 types). The daily
use of two or more medications was reported by 4 men and 17 women. Antihypertensive,
antidiabetic, antidepressant drugs, and nonsteroidal anti-inflammatory drugs were the drugs most
often used by both sexes, with thyroid medications most often used by women.

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Additional books and e-books in this series can be found

DANTE A. MIGLIARI, DDS, PHD

NOTICE TO THE READER

Library of Congress Cataloging-in-Publication Data

Published by Nova Science Publishers, Inc. † New York

We would to like to thank our clinical interns at the Department of

Oral lichen planus (OLP), a chronic inflammatory disease of the

of conflicting results emerging from these studies and the more

Developing definitive diagnostic criteria for OLP requires a focus

while some criteria were established by the World Health Organization

Clinically, OLP is a polymorphic disease, with a predominance of

white lesions with either a smooth or a rough surface. Although rarely

OLP lesions are usually bilateral and symmetrical, predominantly

Figure 3. Reticular oral lichen planus in a linear pattern.

single location, often characterized as unilateral manifestation. Under

OLP symptoms are most frequently observed in patients with the

with intense pain. However, many patients are asymptomatic,

2.1. CLINICAL AND HISTOPATHOLOGICAL

A careful examination of the oral mucosa greatly facilitates the

Figure 7. A misleading case in which a tongue lesion biopsy suggested histological

2.2. NON-IDIOPATHIC OLP

OLP lesions may also be induced by certain systemic medications,

studies have reported that the skin-patch test underperforms when

2.3. THERAPEUTIC MANAGEMENT

Among the various studies that have investigated therapeutic

cases, and intralesional corticotherapy can aid in the treatment of

Over the last 20 years, we have published a few studies related to

GENERAL OVERVIEW OF OLP

4.1. ETIOLOGY AND PATHOGENESIS

The etiology of OLP remains unknown; however, immunohisto-

immune response. This induction process is mediated by interactions

OLP manifests mainly in adults (average age, 50 years), occurring

4.3. CLINICAL PRESENTATION OF LICHEN PLANUS

LP is a chronic, non-infectious inflammatory disease affecting the

critical in determining the most appropriate treatment strategies. While

4.4. ORAL LESIONS

Morphologically, OLP is essentially characterized by the presence

Figure 9. Unilateral lesions. Case A: atrophic-erythematous form. Case B: erosive

Although OLP can manifest anywhere in the oral mucosa, lesions

manifestations are characterized by desquamative gingivitis (DG),

OLP symptomatology typically depends on the clinical presentation

forms) are accompanied by intense pain and discomfort, usually

4.5. KOEBNER PHENOMENON

The Koebner phenomenon, which is more often associated with

4.6. EXTRA-ORAL LESIONS

Cutaneous LP lesions are characterized by papular, erythematous–

Lesions are typically bilateral and symmetrical, preferentially

Lesions affecting the genital mucosa usually present as papules that

Nail involvement is observed in 10% of LP cases. Occurring most

LP lesions affecting the esophagus most frequently manifest in the

Conjunctival involvement is rare, having been reported in only a

Scalp lesions are observed in approximately 1% of patients with

inconsistency of the criteria established by the WHO (1978).

lesion. Fortunately, both a dysplastic lesion and an OSCC mimicking an

Figure 17. A unilateral lesion on the buccal mucosa exhibiting a combination of

A biopsy, therefore, may not be necessary when unilateral lesions

5.1. DIFFERENTIAL DIAGNOSIS OF OLP

Several researchers have noted similarities in the clinical