Oral Lichen Planus
Michael J. McCullough, Mohammad S. Alrashdan, and Nicola
Cirillo
Abstract
Lichen planus (LP) is a chronic, inflammatory,
mucocutaneous, immune-mediated condition
with variable clinical presentations. Oral lichen
planus (OLP) is the oral variant and affects
about 1–2% of the general adult population
with characteristic relapses and remissions.
OLP is about twice as common in females as
in males. The most commonly involved oral
sites are the buccal mucosa, lateral surfaces of
the tongue, and gingivae, respectively. Six
clinical patterns of OLP are described in liter-
ature: reticular, plaque-like, erythematous, ero-
sive/ulcerative, papular, and bullous. Helper
and cytotoxic T lymphocytes, in addition to
antigen-presenting cells, represent the key
cells in the inflammatory infiltrate in OLP and
M.J. McCullough (*)
Oral Anatomy, Medicine, and Surgery Section, Melbourne
Dental School, Faculty of Medicine, Dentistry & Health
Sciences, The University of Melbourne, Carlton, VIC,
Australia
e-mail: m.mccullough@unimelb.edu.au
M.S. Alrashdan
Faculty of Dentistry, Department of Oral Medicine and
Oral Surgery, Jordan University of Science and
Technology, Irbid, Jordan
e-mail: msalrashdan3@just.edu.jo
N. Cirillo
Melbourne Dental School and Oral Health CRC, Faculty of
Medicine, Dentistry and Health Sciences, The University
of Melbourne, Carlton, VIC, Australia
e-mail: nicola.cirillo@unimelb.edu.au
# Springer International Publishing AG 2017
C.S. Farah et al. (eds.), Contemporary Oral Medicine,
DOI 10.1007/978-3-319-28100-1_14-1
play an essential role in its pathogenesis. The
diagnosis of OLP is usually made by clinical
and histological examinations. Lesions similar
to OLP may develop as a reaction to dental
restorative materials or systemic medications
or conditions and are called oral lichenoid
reactions (OLR). OLP and OLR may collec-
tively be referred to as oral lichenoid lesions
(OLLs). Management of symptomatic OLLs
varies considerably and ranges from elimina-
tion of precipitating factors – local or systemic
to long-term pharmacological interventions,
mainly with topical immunosuppressants, cor-
ticosteroids in particular. In the light of the
ongoing debate regarding the malignant trans-
formation potential of OLLs, a long-term fol-
low-up protocol is essential.
Keywords
Oral lichen planus • Oral lichenoid lesions •
Oral lichenoid reactions • Malignant
transformation
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Genetic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Psychological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Systemic Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1
2 M.J. McCullough et al.

possible to make a diagnosis based on their clin-

Pathogenesis of OLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
The Immunology of the Oral Cavity . . . . . . . . . . . . . . . . . . 6 ical appearance alone (Epstein et al. 2003). Addi-
Pathogenic Mechanisms of OLP . . . . . . . . . . . . . . . . . . . . . . 7 tionally, there is a spectrum of oral lichenoid
Clinicopathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . 13 lesions (OLLs) that may confuse the differential
Clinical Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 diagnosis. These include lichenoid contact
Signs, Symptoms, Clinical Behavior and OLP lesions, lichenoid drug reactions, and lichenoid
Scoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 lesions of graft-versus-host disease. Systemic
Histopathology of OLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Oral Lichenoid Reactions (OLR) . . . . . . . . . . . . . . . . . . . . . 16 medications, such as nonsteroidal anti-
Cutaneous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 inflammatory drugs, antihypertensives, and oral
Other Mucosal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 hypoglycemics, can contribute to the develop-
Malignant Potential of OLP . . . . . . . . . . . . . . . . . . . . . . . . . 19 ment of oral lichenoid reactions (OLRs) (Ismail
OLL and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 et al. 2007). Dental restorative materials, includ-
Tumors Developing in OLP and their ing amalgam, gold, and nickel, may also be
Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
related to localized OLRs in a number of patients
Patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 (Epstein et al. 2003).
Topical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 Treatment is not always necessary, unless
Systemic Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
Miscellaneous Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 OLLs are symptomatic (Scully et al. 1998). Man-
Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 agement of symptomatic OLLs varies consider-
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
ably and ranges from elimination of precipitating
or provoking local and systemic factors, psycho-
Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
social interventions, to long-term pharmacologi-
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 cal therapies. Thus, although OLP localizes to the
oral cavity, there are broader implications in terms
of patient management that warrant careful con-
Introduction sideration. The ongoing controversy as to whether
OLP is associated with an increased risk of malig-
The term lichen planus (LP) is derived from the nant transformation adds further complexity to
Greek word leichen meaning tree moss and the this disease.
Latin planus meaning flat. Erasmus Wilson first
described the condition LP in 1869, as a chronic
inflammatory disease affecting the skin, scalp, Epidemiology
nails, and mucosa, with possible rare malignant
transformation (Farhi and Dupin 2010). LP may The estimated prevalence of OLP in general adult
involve the hair follicles (lichen planopilaris, population is 0.5–2% (Scully et al. 1998; Eisen
resulting in scarring alopecia), nails, esophagus, et al. 2005). However, because of a lack of stan-
and, more seldom, the eyes, urinary tract, nasal dardized approaches to the clinical diagnosis of
mucosa, and larynx (Parashar 2011). OLP and OLL, it is difficult to draw accurate
The oral variant, oral lichen planus (OLP), is a figures about the prevalence of OLP. In a demo-
chronic inflammatory disease affecting the oral graphic study from Sweden, 20,333 people aged
mucosa with characteristic relapses and remis- 15 and above were examined for signs of OLP.
sions (Scully et al. 1998; Eisen et al. 2005; Lodi The prevalence reported was 1.9%, 1.6% in men,
et al. 2005a). While cutaneous lesions of LP are and 2.2% in women (Axell and Rundquist 1987).
generally self-limiting and pruritic, oral lesions Another demographic study from India showed a
are commonly chronic, non-remissive, and can prevalence of 2.6% (Murti et al. 1986). A report
be a source of morbidity (Scully et al. 1998). from Malaysia showed a relatively low prevalence
The diagnosis of OLP is usually made by clin- of 0.38% (Zain et al. 1997).
ical and histological examinations. However, in There is a slight female predisposition (female/
classical lesions (bilateral, reticular pattern), it is male sex ratio is 1.5–2:1), and the age of onset is
Oral Lichen Planus
generally between 30 and 60 years (Scully et al.
1998; Al-Hashimi et al. 2007; Farhi and Dupin
2010). However, there have been case reports of
OLP occurring in children, with a 17% prevalence
of oral involvement in a population of 100 children
diagnosed with LP at a mean age of 8.7 years in
one report (Kanwar and De 2010).
Genital and cutaneous LP are associated with
approximately 20% and 15% of OLP cases,
respectively, while it is estimated that OLP occurs
in 70–77% of patients with cutaneous LP (Scully
et al. 1998; Farhi and Dupin 2010; Kanwar and De
2010).
Etiology
OLP is not a classical autoimmune disorder, and
the precise etiology of this condition is unknown.
However, given that cell-mediated immune
dysregulation targeting the stratified squamous
epithelia has been shown to be associated with
the pathogenesis of OLP (Epstein et al. 2003;
Eisen et al. 2005; Lodi et al. 2005a), it is possible
that a LP-specific epidermal antigen is present in
some epithelial cells. The nature of the antigen,
however, remains uncertain. Several predisposing
factors have been reported to be associated with
OLP and OLLs.
Genetic Background
Genetic background seems to play a role in OLP
pathogenesis as several familial cases have been
reported (Bermejo-Fenoll and Lopez-Jornet
2006); however the association has not been con-
sistent. In terms of HLA associations, an increase
in HLA-B15, Bw57, B5, B7, BX, DR2 and a
decrease in the frequency of HLA-DQ1, DR4,
and B18 has been noted for OLP (Roitberg-
Tambur et al. 1994). On the other hand, in a
comprehensive review of literature, Porter et al.
reported no significant association with any par-
ticular HLA types in familial LP (Porter et al.
1997).
Genetic polymorphisms of several cytokines
have been postulated to be associated with the
3
clinical presentation of LP. Interferon-gamma
(IFN-γ) UTR 5644 genotype frequencies showed
a significant increase in number of T/T homozy-
gotes in a sample of OLP patients (n = 44) com-
pared with controls (n = 140) (40.9% vs. 22.9%;
p = 0.0022) (Carrozzo et al. 2004). It has been
suggested that genetic polymorphism of the first
intron of the promoter gene of IFN-gamma may
be an important risk factor to develop oral lesions
of LP, whereas an increase in the frequency of
308A TNF-alpha allele may best contribute to
the development of additional skin involvement.
More recently, the concept that a particular
genetic background may be important in a subset
of patients with OLP has been presented
(Carrozzo et al. 2011). In particular, this study
suggested that those patients who had both OLP
and chronic hepatitis C infection may well have
particular HLA-Cw* alleles (Carrozzo et al.
2011).
Nevertheless, the overall statement that OLP is
a genetically determined disease has not been
confirmed, and further studies in different geo-
graphic areas are required.
Infectious Agents
Many infectious agents, principally viruses, have
been studied in association with OLP, but the
evidence is generally sparse. Other infectious
agents, such as Helicobacter pylori, were also
suggested to have a link to OLP by some authors
(Shimoyama et al. 2000).
The viruses for which an association with OLP
has been suspected can be classified in two
groups: (1) viruses for which an association with
OLP has been anecdotally suggested and
(2) viruses for which there is abundant documen-
tation of an association with OLP, although with
marked geographic disparities (discussed in sec-
tion “Systemic Associations”).
Varicella zoster virus (VZV), Epstein-Barr
virus (EBV), cytomegalovirus (CMV), human
herpesvirus 6 (HHV6), human papillomavirus
(HPV), and human immunodeficiency virus
(HIV) have all been postulated in different studies
to have an association with an increased incidence
4 M.J. McCullough et al.
of OLP, yet definitive evidence for the association
is lacking (Lodi et al. 2005a; Farhi and Dupin
2010).
For example, the receptor for EBV (CD21) was
shown to be upregulated in OLP, and a signifi-
cantly higher optometric density of EBV anti-
earlier antigen (EA) IgG positivity has been
reported in a sample of OLP patients (n = 22)
compared with controls (n = 22), despite no dif-
ference in the frequency of both EBV IgG and
IgM for EA and nuclear antigen-1 (EBNA)
(Pedersen 1996).
In summary, while association between OLP
and infectious agents has been reported, at present
there is no evidence for a causative role of these
microorganisms in OLP.
Psychological Factors
Psychological factors are thought to play a role in
the pathogenesis of OLP. A group of OLP patients
(n = 9) exhibited higher levels of anxiety, greater
depression, and increased vulnerability to psycho-
logical disorders, as opposed to a group of
20 healthy controls (Soto Araya et al. 2004).
In another study that involved 100 OLP
patients, those with erosive LP were shown to
exhibit higher depression scores than patients
with nonerosive LP (Rojo-Moreno et al. 1998).
In addition to the chronic discomfort that can
result in stress, patients with OLP were shown to
be concerned about the possibility of malignancy,
the contagious nature of the disease, and the lack
of available patient educational materials
(Burkhart et al. 1997).
Exacerbations of OLP have been linked to
periods of psychological stress and anxiety in
some studies (Rojo-Moreno et al. 1998).
In a study that involved 40 OLP patients
(20 reticular and 20 erosive OLP) assessed against
25 healthy controls using the psychological Min-
nesota Multiphasic Personality Inventory
(MMPI)-202 test, Ivanovski et al. hypothesized
that prolonged emotive stress in many OLP
patients may lead to psychosomatization
(as shown by significantly higher mean scores of
internalization ratio index in OLP groups) which
in turn may contribute to the initiation and clinical
expression of OLP (Ivanovski et al. 2005). How-
ever, as a common issue in studies of this type, the
authors were unable to determine whether the
observed psychological alterations constitute a
direct cause or a consequence of OLP.
When the levels of anxiety and salivary corti-
sol were measured in a group of OLP patients
(n = 40), the scores were statistically correlated
and significantly higher than a control group
(mean state anxiety level = 49 vs. 40, cortisol
levels = 1.46 vs. 0.93 μg/dl) (Koray et al. 2003).
In conclusion, in spite of the presence of higher
levels of psychological stress and anxiety among
OLP patients, the question remains whether the
psychological factors contribute to the etiology of
OLP or represent a part of resulting morbidity.
Trauma
Trauma as such has not been reported as an etio-
logical factor in OLP, although it has been postu-
lated as a mechanism by which other etiological
factors may exert their effects (Scully et al. 1998).
However, no studies were conducted to verify this
hypothesis.
The Koebner phenomenon (isomorphic
response), whereby OLP lesions develop in
response to mechanical trauma, may partially
explain why OLP lesions develop commonly in
sites prone to trauma, i.e., the buccal mucosa or
lateral surfaces of the tongue (Eisen et al. 2005).
Systemic Associations
OLP may be associated with some systemic dis-
eases; however, few have been thoroughly inves-
tigated. The most studied are the associations with
hepatitis C, hypertension, diabetes, thyroid dis-
ease, and graft versus host disease.
Hepatitis C Virus (HCV)
Along with porphyria cutanea tarda and
cryoglobulinemia, OLP is one of the three derma-
tologic diseases that have been most frequently
reported in patients infected with HCV (Farhi and
Oral Lichen Planus
Dupin 2010). The first report appeared in 1991
(Mokni et al. 1991) and suggested an association
between OLP and HCV seropositivity. Since then,
the association has been well documented in some
Mediterranean populations (Carrozzo et al. 1996;
Erkek et al. 2001), in Japan (Nagao et al. 1995),
and in a United States metropolitan population
(Beaird et al. 2001). Nevertheless, an association
between OLP and HCV seropositivity could not
be demonstrated in France (Dupin et al. 1997), the
United Kingdom (Ingafou et al. 1998), and in
countries with high HCV prevalence, such as
Egypt (HCV prevalence estimated at 14.7%)
(Ibrahim et al. 1999), and Nigeria (HCV preva-
lence estimated to range from 5% to 20%)
(Daramola et al. 2002).
A systematic review of HCV prevalence in LP
patients and in matched controls without LP
yielded 25 relevant studies, including eight with
only OLP (Lodi et al. 2004). A significantly
higher proportion of HCV seropositivity was
documented in patients with OLP, with an odds
ratio (OR) of 5.7 (95% confidence interval,
3.5–9.4). This association was stronger in Medi-
terranean countries (OR 6.63, 95% CI, 4.7–9.4)
but disappeared in Northern Europe such as in
Germany and the United Kingdom (OR 2.14,
95% CI, 0.6–7.7). Three more recent independent
meta-analyses (Shengyuan et al. 2009; Lodi et al.
2010; Petti et al. 2011) have provided robust evi-
dence that LP and HCV are associated. Overall,
there is a significant positive association noted in
studies across the world, although the association
is more homogeneous in studies from East and
Southeast Asia and South America than in studies
from the Middle East and Europe (Baccaglini
et al. 2013).
In HCV-positive patients, the estimated preva-
lence of LP is 1.6–20% (Farhi and Dupin 2010)
being higher than expected in the respective geo-
graphic areas. In a study from Italy, 44 OLP
patients positive for HCV were compared to a
group of 144 OLP patients negative for HCV.
HCV-related OLP group showed a significantly
higher association with HLA class II allele
HLA-DR6 (52% vs. 18%), which may partially
explain the peculiar geographical heterogeneity of
the association between HCV and OLP, probably
5
depending on the presence of certain HLA sub-
types (Carrozzo et al. 2001).
Hypertension and Diabetes Mellitus
Although OLP patients do not seem to have an
increased risk of diabetes, diabetics who develop
OLP were reported to have an increased fre-
quency of atrophic-erosive lesions, especially
affecting the tongue (Bagan et al. 1993). How-
ever, this was not confirmed in any further studies.
An association between OLP, diabetes
mellitus, and hypertension was first described by
Grinspan in a small series of seven patients
(Grinspan et al. 1966). The triad was later named
as Grinspan’s syndrome. Although Grinspan’s
syndrome may be seen clinically, the association
between the three conditions may represent a
coincidental finding or probably an OLR to med-
ications used to manage hypertension or diabetes
rather than a true syndrome (Scully et al. 1998).
Thyroid Dysfunction
The association between OLP and thyroid dys-
function was recently investigated in a retrospec-
tive Finnish study that confirmed a link between
OLP and hypothyroidism in particular (Siponen
et al. 2010). This study compared data of 222 OLP
patients with 222 age- and sex-matched controls
and revealed that 10% of OLP patients (n = 15)
versus 5% of the controls (n = 11) had hypothy-
roidism (OR 2.39, 1.05–5.61, CI 95%).
Other studies suggested a relationship between
OLP and hyperthyroidism. Overall, more well-
designed, large population-based studies are
required to confirm whether an association
between OLP and thyroid disorders does exist.
Graft Versus Host Disease (GVHD)
Nearly 15,000 patients worldwide receive allo-
genic hematopoietic cell transplants (HSCT)
each year, and GVHD will eventually develop in
about 40–70% and will represent the leading
cause of death in such patients (Imanguli et al.
2008).
Acute GVHD occurs within the first 100 days
of transplantation and comprises dermatitis, enter-
itis, and hepatitis with immunosuppression and
cachexia. Chronic GVHD develops after day
6 M.J. McCullough et al.
100 and comprises an autoimmune-like syndrome
comparable to ulcerative colitis, primary biliary
cirrhosis, Sjögren’s syndrome, rheumatoid arthri-
tis, and lupus-like disease with glomerulonephri-
tis. The skin is a primary target in chronic GVHD
and exhibits either a lichenoid eruption or
sclerodermatous changes (Lodi et al. 2005a).
Oral involvement occurs in 33–75% of patients
with acute GVHD and up to 80% of patients with
chronic GVHD (Imanguli et al. 2008). Oral muco-
sal GVHD resembles OLP both clinically and
histologically.
Squamous cell carcinoma (SCC) may develop
in oral and cutaneous chronic GVHD, as reported
in few case reports (Lodi et al. 2005b). Most
patients who undergo allogeneic HSCT receive
stem cells from MHC-identical donors. In these
patients, GVHD is initiated by donor T cells that
recognize a subset of host peptides called minor
histocompatibility antigens (miHAs). Although
the antigen specificity of LP and mucocutaneous
GVHD is probably distinct, it is likely that they
share similar immunological effector mechanisms
resulting in T-cell infiltration, epithelial basement
membrane disruption, basal keratinocyte apopto-
sis, and clinical disease (Lodi et al. 2005a).
The role of TNF-alpha as a major effector
molecule in GVHD has been confirmed in a num-
ber of experimental systems. Importantly, neutral-
izing anti-TNF-alpha antibodies have been shown
to alleviate cutaneous and intestinal GVHD in
both mice and humans (Herve et al. 1992;
Brown et al. 1999).
Pathogenesis of OLP
Much is still not known about the
etiopathogenesis of OLP. OLP is characterized
by a chronic T-cell inflammatory infiltrate with
basal cell degeneration including vacuolar degen-
eration, hyperkeratosis or parakeratosis, and saw-
tooth rete ridges (Sugerman et al. 1993, 2002;
Zhou et al. 2002). The mechanism that irrevers-
ibly switches on this process resulting in the
chronic disease state is currently unknown.
There are multiple theories on OLP pathogenesis
and the mechanisms that underpin the ongoing
chronic inflammatory process. In order to better
understand the pathobiological events that under-
lie the development of OLP lesions, it is important
to recall some basic concepts of oral immunology.
The Immunology of the Oral Cavity
The oral cavity immune system consists of innate
and adaptive immune system components. The
innate immune system consists of all the immune
defenses that lack an immunologic memory
(Delves and Roitt 2000). In the oral cavity the
oral mucosa serves as a mechanical barrier to
microbial colonization. Loss of tissue integrity
places the oral cavity at risk of opportunistic
microbial infection.
Saliva makes up another portion of the oral
innate immune system. Saliva is rich in water
and mucin that acts to provide a moist barrier
that helps to limit microbial colonization. It also
consists of numerous ions, such as bicarbonate,
phosphate, etc., that neutralize pH and keep the
saliva supersaturated to prevent tooth deminerali-
zation. Salivary antibodies, specifically secretory
IgA, exist in saliva and act as a first line of defense
by limiting colonization and invasion of microor-
ganisms into the epithelium (Brandtzaeg 2007;
Feller et al. 2013). Saliva contains numerous non-
immune innate factors such as salivary peroxi-
dase, myeloperoxidase, lysozyme, cystatins,
proline-rich proteins, mucin, peroxidase,
lactoferrin, and statherin which also work to pre-
vent microbial colonization through antifungal,
antibacterial, antiviral, and antiparasitic properties
(Tenovuo 1998).
The oral innate immune response also consists
of phagocytic cells such as macrophages and neu-
trophils. Macrophages are phagocytic cells
derived from monocytes, while neutrophils are
polymorphonuclear granulocytes. Both work to
detect infections organisms and destroy infectious
organisms through the process of phagocytosis
(Aderem 2003). Eosinophils, basophils, and
mast cells also constitute part of the oral innate
response working to protect against parasites
(eosinophils) while also being involved in the
host allergic reactions. Mast cells especially are
Oral Lichen Planus
thought to play an important immunological role
in OLP (Zhou et al. 2002). Natural killer
(NK) cells target and destroy tumor cells as well
as viruses as part of the oral innate immune
response by recognizing peptides presented in
the context of major histocompatibility complex
(MHC) class I molecules. The complement sys-
tem is a series of 20 serum glycoproteins that form
membrane attack complexes; opsonization and
chemoattractants work to upregulate phagocytosis
and mobilize the host immune system to clear
pathogens (Delves and Roitt 2000).
The adaptive immune response in the oral cav-
ity consists of antigen-presenting cells (APC), T
cells and B cells. The main difference between the
adaptive and innate immune system is the adap-
tive immune system’s ability to tailor the response
to suit different pathogens as well as remember
past microbial and viral challenges. The adaptive
immune system also uses MHC molecules, spe-
cifically MHC I and II, to distinguish self from
nonself to allow for a targeted immune response
(Delves and Roitt 2000). The APCs of the adap-
tive immune system recognize foreign, nonhost
proteins, known as antigens. APC of the adaptive
immune system includes macrophages, B cells,
dendritic cells, and Langerhans cells. Langerhans
cells reside in the epidermis with the highest
counts found in the nonkeratinized oral mucosal
tissues including the ventral tongue, soft palate,
lip, and floor of mouth (Daniels 1984).
Langerhans cells are thought to potentially play
a role in the pathogenesis of OLP (Sugerman et al.
2002; Roopashree et al. 2010; Gueiros et al.
2012).
The major task of plasma cells (which are
terminally differentiated B lymphocytes), is to
produce immunoglobulins, specifically IgA, IgG,
IgM, IgE, and IgD. Secretory IgA is the primary
antibody of the oral cavity found in present in
saliva which acts as the first line of defense
(Brandtzaeg 2007; Feller et al. 2013). The other
major task of B cells is the production of memory
B cells whose function is to circulate through the
body and mount a rapid response against previ-
ously recognized antigens (Delves and Roitt
2000).
7
T cells are the major effector cell in cell-
mediated immunity. They consist of helper T
cells (CD4+) which recognize MHC class II mol-
ecules, cytotoxic T cells (CD8+) which recognize
MHC class I molecules present on all cells, regu-
latory T cells which are essential for preventing
autoimmune diseases while also limiting chronic
inflammation, NK cells, and memory T cells
(Delves and Roitt 2000; Vignali et al. 2008).
Helper T cells play an important role in coordinat-
ing the adaptive immune response by promoting
cellular (cytotoxic T-cell-mediated, via activation
of TH1) or humoral (B-cell-mediated, via TH2
activation) types of response. Cytotoxic T cells
on recognition of a foreign antigen induce apo-
ptosis in the infected cell. OLP is characterized by
T-cell accumulation, specifically cytotoxic T-cell
accumulation, within the superficial lamina pro-
pria that is directed at the basal cell layer
(Sugerman et al. 2002; Roopashree et al. 2010).
It is this chronic cytotoxic T-cell inflammatory
process which defines the chronicity of OLP.
Pathogenic Mechanisms of OLP
The work of Sugerman and colleagues in the
1990s and early 2000s in the field of OLP patho-
genesis and disease mechanisms established the
basis of most research conducted thereafter
(Sugerman et al. 1994, 1995, 1996, 2000, 2000,
2002; Khan et al. 2003). In general these mecha-
nisms can be divided into specific and nonspecific
ones, which involve T cells and dendritic cells
activated by specific (yet unknown) antigens and
MMPs, cytokines and other immune cells,
respectively.
A number of biochemical changes, including
altered keratinocyte antigen expression and
altered keratinocyte function, have been previ-
ously suggested to be early events in OLP patho-
genesis (Holmstrup and Dabelsteen 1979). It was
originally proposed that following altered
keratinocyte antigen expression, a CD8+ T cell
on routine surveillance in the epithelium may
encounter the keratinocyte antigen by chance
(“chance encounter” hypothesis). Alternatively,
the CD8+ T cell may be attracted to the epithelium
8 M.J. McCullough et al.
by keratinocyte-derived chemokines (“directed
migration” hypothesis) (Sugerman et al. 2002).
The migration of activated T cells in the OLP
infiltrate to oral epithelium can be mediated by
intercellular and vascular adhesion molecules
(ICAM-1 and VCAM) (Eisen et al. 1990).
Upregulation of ELAM-1, ICAM-1, and
VCAM-1, especially by endothelial cells in the
subepithelial vascular plexus in OLP, was demon-
strated in an immunohistochemical study that
assessed various endothelial-associated adhesion
molecules in frozen sections from 12 OLP cases
and nine normal controls (Regezi et al. 1996).
Biopsy specimens from patients with OLP con-
sistently showed significantly higher levels of
expression of the three molecules. The prolonged
overexpression of adhesion molecules on endo-
thelial cells may represent the molecular basis for
the so-called reactive isomorphism seen in OLP
patients. Previous studies have shown that in OLP
there is an upregulation of epithelial basement
membrane extracellular matrix (ECM) proteins,
including collagen types IV and VII, laminin and
certain integrins – possibly serving as pathways
for T-cell migration (Eversole 1997). Finally,
cytokines (IL-1, IL-8, IL-10, IL-12, and TNF-α),
secreted by keratinocytes in OLP, are also chemo-
tactic for lymphocytes ultimately leading to tissue
destruction in OLP (Sugermann et al. 1996).
The cell-mediated immunological response
seen in OLP, possibly initiated by endogenous or
exogenous factors, is thought to result in the pro-
duction of TNF-α and IFN-γ and keratinocyte/T-
cell/antigen-presenting dendritic cell associations
(Eisen et al. 2005; Lodi et al. 2005; Payeras et al.
2013). The increased production of TH1 cyto-
kines is a key and early event in LP. This even
is, at least in part, genetically controlled, and
genetic polymorphism of cytokines seems to gov-
ern whether lesions develop in the mouth alone
(IFN-γ associated) or in the mouth and skin
(TNF-α associated) (Carrozzo et al. 2004, Scully
and Carrozzo 2008).
TNF-α may stimulate the activation of nuclear
factor kappa B (NF-κB) whose increased expres-
sion has been seen in OLP (Santoro et al. 2003).
Because NF-κB translocation in keratinocytes
may induce the production of several
inflammatory cytokines, it could be partially
responsible for the characteristic, chronic course
of OLP similar to other chronic inflammatory
diseases such as psoriasis and rheumatoid arthritis
(Eisen et al. 2005).
The cellular and molecular constituents of
these pathogenic events will be discussed in detail
in the following paragraphs.
Putative OLP Antigens
While OLP is not considered to be a typical auto-
immune disease, it is believed that one or more
epithelial antigens are present in basal
keratinocytes. Antigens that are presented by
MHC class II receptor are processed through an
endosomal cellular pathway, while antigens that
are presented by MHC class I are processed
through a cytosolic cellular pathway (Sugerman
et al. 2002). Hence, the putative antigen presented
by MHC class II to CD4+ helper T cells in OLP
may differ from that presented by MHC class I to
CD8+ cytotoxic T cells. Alternatively, a single
antigen may gain access to both the endosomal
and cytosolic cellular pathways of antigen presen-
tation (Sugerman et al. 2002; Roopashree et al.
2010).
Whether one or more different antigens are
involved in disease pathogenesis, it has been
suggested that simultaneous antigen presentation
to CD8+ and CD4+ T cells in the context of MHC
classes I and II, respectively, is required to
develop persistent T-cell infiltration and CD8+
cytotoxic T-cell activity in OLP (Sugerman et al.
2002).
A unifying hypothesis of the specific mecha-
nisms thought to play a role in the pathogenesis of
OLP was introduced by Sugerman et al. (2002).
The hypothesis is based on a theoretical interac-
tion between CD8+ T cells and CD4+ T cells
through a “request cytotoxic activity” (RCA) cell
surface molecule expressed by CD8+ T cells and a
RCA receptor expressed by the CD4+ T cells to
allow confirmation and initiation of cytotoxic
activity by CD8+ T cells. The hypothesis stresses
that this interaction can only take place after each
type of the T-cell antigen receptors is engaged
with a related foreign antigen (Ag), i.e., Ag1 in
the context of MHC class I engaged by CD8+
Oral Lichen Planus
T-cell antigen receptors and Ag2 in the context of
MHC class II engaged by CD4+ T-cell antigen
receptors. To date, sound experimental evidence
to support this theory is lacking.
Cell-Mediated Immunity
CD8+ T Cells
An early immunohistochemical study assessing
the lymphocytic infiltrate in OLP showed this to
be composed almost exclusively of T cells, and
the majority of T cells within the epithelium and
adjacent to damaged basal keratinocytes were
activated CD8+ lymphocytes (Kilpi 1988). CD8
+ T cells were also co-localized with apoptotic
keratinocytes in OLP lesions (Sugerman et al.
2000). The dominant role of CD8+ T cells and
CD4+ T cells in OLP pathogenesis was further
confirmed by the expression of the chemokines
CCR5 and CXCR3, known to be selectively
expressed by TH1, in the infiltrating lymphocytes,
in addition to the CD8+ T-cell respective ligand
RANTES/CCL5 and IP-10/CXCL10 (Iijima et al.
2003).
Analysis of these previous data suggests that
CD8+ T cells are involved in disease pathogenesis
and that activated CD8+ T cells may trigger
keratinocyte apoptosis in OLP. T-cell lines and
clones isolated in vitro from LP lesions were
more cytotoxic against autologous lesional
keratinocytes than T cells from the clinically nor-
mal skin of LP patients, and the majority of non-
cytotoxic clones were CD4+ (helper/inducer
clones) (Sugerman et al. 2000).
Furthermore, the cytotoxic activity of CD8+
lesional T-cell clones was partially blocked with
anti-MHC class I monoclonal antibody
(Sugerman et al. 2000). Hence, early in OLP
lesion formation, CD8+ lesional T cells may rec-
ognize an antigen associated with MHC class I on
lesional keratinocytes. Following antigen recog-
nition and activation, CD8+ cytotoxic T cells are
thought to trigger keratinocyte apoptosis
(Sugerman et al. 2002).
Activated CD8+ T cells (and possibly
keratinocytes) may release chemokines that
attract additional lymphocytes and other immune
cells into the developing OLP lesion. This has
9
been suggested by studies that found significantly
higher chemokine production within OLP lesions
when compared to normal or chronically inflamed
gingival tissues (Yamamoto and Osaki 1995).
CD4+ T Cells
The majority of intraepithelial lymphocytes in
OLP have been shown to be CD8+ cytotoxic T
cells (Sugerman et al. 2002), while studies have
shown that most lymphocytes in the lamina pro-
pria are CD4+ helper T cells (Ishii 1987; Kilpi
1988). A mixed helper and suppressor activity
among OLP lesional T-cell clones in vitro was
identified, suggesting that the balance between
immunological help and suppression may deter-
mine the clinical behavior of the disease
(Sugerman et al. 1994). In this interesting report,
Sugerman et al. reported that the majority of T
lymphocyte lines extracted from six biopsy spec-
imens of OLP (n = 13) expressed the α/β T-cell
receptor of which 11 were CD8+ and two were
CD4+ (Sugerman et al. 1994).
Hence, an early event in OLP lesion formation
may be a presentation of a MHC class II antigen to
CD4+ helper T cells, followed by keratinocyte
apoptosis triggered by CD8+ cytotoxic T cells.
MHC class II antigen presentation in OLP may
be mediated by Langerhans cells (LCs) or
keratinocytes. Furthermore, increased numbers
of LCs have been reported in OLP lesions with
upregulated MHC class II expression (Villarroel
Dorrego et al. 2002).
Keratinocytes in OLP have also been shown to
express MHC class II (Ichimura et al. 2006). High
levels of antigen expression, CD40 and CD80
expression, and IL-12 secretion by MHC class II
+ antigen-presenting cells (APC) in OLP are
thought to promote a TH1 CD4+ T-cell response
with IL-2 and IFN-γ secretion (Sugerman et al.
2002).
Analysis of these data together suggests that
LCs or keratinocytes in OLP may present antigen
associated with MHC class II to CD4+ helper
T cells that are stimulated to secrete the TH1
cytokines IL-2 and IFN-γ. Subsequently, CD8+
cytotoxic T cells may be activated by the
combination of (i) antigen associated with MHC
class I on basal keratinocytes and (ii) TH1 CD4+
10
T-cell-derived IL-2 and IFN-γ. Activated CD8+
cytotoxic T cells may then trigger basal
keratinocyte apoptosis in OLP (Sugerman et al.
2002). However, it is essential to note that this
hypothesis has never been proven by robust
evidence.
A recently discovered subgroup of CD4+ T
cells, namely, TH17 CD4+ subgroup, has been
shown to produce IL-26 and IL-22, in addition
to IL-17, which are known to be, when
uncontrolled, inducers of the inflammatory
response in different autoimmune conditions,
such as multiple sclerosis, psoriasis, and lupus
(Payeras et al. 2013).
The proportion of lesional Th1 and Th17 cells
and serum IL-17 levels in patients with OLP
(n = 40) were shown to be significantly greater
than controls (n = 15), especially in the atrophic-
erosive OLP patients compared with those pre-
senting with reticular OLP, suggesting that Th17
cells and their cytokine Th17 might play an
important role in OLP pathogenesis (Xie et al.
2012).
Dendritic Cells (DCs)
DCs have an important role in the immunological
response as they activate T cells through antigenic
stimulation (Banchereau et al. 2000). Studies have
revealed an increase in the number of DCs in OLP,
indicating that they may be associated with its
pathogenesis (Santoro et al. 2005; Gueiros et al.
2012). According to Santoro et al., the increase of
different subsets of DCs, such as Langerhans cells
(LCs), stromal DCs, and plasmacytoid dendritic
cells (PDCs), may promote the inflammatory
response in OLP (Santoro et al. 2005).
Among these, LCs have been the most studied
DCs. These cells reside in the supra-basal layers
of the stratified epithelium of the skin and oral
mucosa and have the principle function of captur-
ing and presenting antigens. When LCs capture
antigen, they are activated, migrate to the regional
lymph nodes, and are introduced to the T lympho-
cytes, producing a primary immune response
(Payeras et al. 2013). Subsequently, when LCs
recapture antigen, this antigen will be presented
and recognized by T lymphocytes circulating
M.J. McCullough et al.
memory and will induce a secondary immune
response (Barrett and Raja 1997).
In the OLP lesions, a large number of LCs are
present in the basal layer of the epithelium
(Villarroel Dorrego et al. 2002). It has been pos-
tulated that in these lesions the LCs play an impor-
tant role in presenting antigen to the T lymphocyte
through class II MHC molecules, introducing not
only an initial sensitivity to the antigen (primary
immune response) but also a subsequent second-
ary immune response and thus the appearance of
the clinical signs of the disease (Payeras et al.
2013).
Mast Cells
Mast cells are preferentially located in the lamina
propria, near blood vessels and nerves. They are
derived from the CD34+ hematopoietic progeni-
tor that has the ability to activate T lymphocyte,
undergo degranulation, and release a series of
mediators that modulate the inflammatory
response (Payeras et al. 2013). Studies have
shown an increased mast cell density in OLP
with approximately 60% of them being
degranulated, compared with 20% in normal buc-
cal mucosa (Sugerman et al. 2002).
Utilizing IHC, mast cell density in OLP was
found to be markedly higher in the basement
membrane rupture sites as compared to intact
sites, suggesting that this cell might play a direct
role in the basement membrane destruction, as
well as in the T CD8+ lymphocyte migration to
the intraepithelial region (Zhou et al. 2002). Thus,
mast cells have been proposed to be involved in
the pathogenesis of OLP. Mast cell degranulation
in OLP releases a range of pro-inflammatory
mediators such as TNF-α, chymase, and tryptase.
TNF-α has been shown to upregulate endothelial
cell adhesion molecule (CD62E, CD54, and
CD106) expression in OLP that is required for
lymphocyte adhesion to the luminal surfaces of
blood vessels and subsequent extravasation (Zhao
et al. 1997). Chymase, a mast cell protease, is a
known activator of MMP-9 (Fang et al. 1997).
It has been proposed that basement membrane
disruption in OLP may be mediated by mast cell
proteases directly or indirectly via activation of T-
cell-secreted MMP-9 (Sugerman et al. 2002).
Oral Lichen Planus
Both TNF-α and chymase stimulate secretion of
RANTES by T lymphocytes which in turn stimu-
late mast cells to release TNF-α and chymase.
This cyclical activity has been suggested to con-
tribute to the chronicity of OLP (Roopashree et al.
2010).
Macrophages
Macrophages are phagocyte cells derived from
blood monocytes, recruited in the tissues in the
presence of chemotactic signals. They are present
in the healthy oral mucosa and in larger numbers
during pathological processes (Merry et al. 2012).
Macrophages are classified as M1
(pro-inflammatory) or M2 (anti-inflammatory)
according to the functions of their effectors
(Mantovani et al. 2004). The M1 macrophages
might exacerbate OLP manifestation through the
production of pro-inflammatory agents such as
TNF-α or IL-1b. These agents, in turn, regulate
the presence of adhesion molecules on the endo-
thelial cell surface inducing the production of
chemokines (RANTES) by the keratinocytes and
resulting in an increase in the lesional inflamma-
tory cells recruitment. Furthermore, it has been
shown that the production of TNF-α by the mac-
rophages can initiate the basal keratinocyte apo-
ptosis and indirectly increase the disruption rate of
the basement membrane by MMP-9, produced by
T cells (Merry et al. 2012).
Soluble Factors
Matrix Metalloproteinases (MMPs)
MMPs are a family of zinc-containing endo-pro-
teinases with at least 20 members with the princi-
pal function of proteolytic degradation of
connective tissue matrix proteins. MMPs share
biochemical properties but retain distinct sub-
strate specificities (Zhou et al. 2001). MMP pro-
teolysis is regulated by the action of endogenous
inhibitors, including the tissue inhibitors of meta-
lloproteinases (TIMPs), which are thought to form
stable inactive enzyme-inhibitor complexes with
MMPs or pro-MMPs (Sugerman et al. 2002). An
imbalance between MMPs and TIMPs can be
associated with the process of tissue destruction
11
seen in some pathologies, including cancer, arthri-
tis, and cardiovascular diseases (Bode 2003).
The primary source of MMPs in OLP is prob-
ably the immune infiltrate. In one study, culture
supernatants from OLP lesional T cells contained
a higher concentration of MMP-9 and TIMP-1
than those obtained from peripheral blood T cells
in both the same OLP patients group and the
healthy controls, suggesting the presence of addi-
tional MMP-9 activators in the OLP lesional
T-cell supernatants (Zhou et al. 2001).
MMP-9 activators released from the OLP T cell
are believed to help in activating pro-MMP-9,
resulting in basement membrane disruption
(Roopashree et al. 2010). Rubaci et al. (2012)
showed that the expression of MMP-2 (1.3
vs. 0.7) and MMP-7 (1.7 vs. 0.6) in epithelium
and connective tissues from OLP lesions was
greater than normal oral mucosa (P < 0.05). This
IHC study was undertaken on a cohort of 29 OLP
patients and ten healthy controls. Likewise, the
study revealed that MMP-2/TIMP-1 and MMP-7/
TIMP-1 ratios were higher in the OLP patient
group than in the control group (P < 0.05). These
results support the view that increased MMP
expression and imbalance between MMPs and
TIMPs may play a role in the pathology of OLP.
Chemokines
Chemokines are a family of small cytokines (pro-
teins that are involved in cell signaling and medi-
ating immune reactions), which were initially
identified by their modulator action on the inflam-
matory response (Payeras et al. 2013). More atten-
tion has been given to these proteins recently,
especially due to their potential function on endo-
thelial cells and possible involvement in chronic
inflammation and tumor progression (Kiefer and
Siekmann 2011). Moreover, evidence has shown
the role chemokines play in different autoimmune
diseases, such as rheumatoid arthritis and multiple
sclerosis, through lymphocyte recruitment and
establishment of ectopic lymphoid structures in
the target organs in affected individuals
(Godessart and Kunkel 2001).
RANTES (regulated on activation, normal T
cell expressed and secreted) is a member of the
CC chemokine family and is produced by various
12
cells, including activated T lymphocytes, bron-
chial epithelial cells, rheumatoid synovial fibro-
blasts, oral keratinocytes, and mast cells.
RANTES plays a critical role in the recruitment
of lymphocytes, monocytes, natural killer cells,
eosinophils, basophils, and mast cells in OLP
(Roopashree et al. 2010). This chemokine has a
number of cell surface receptors (CCR1, CCR3,
CCR4, CCR5, CCR9, and CCR10) that have been
identified in OLP (Sugerman et al. 2002).
The role that RANTES may play in OLP path-
ogenesis was hypothesized by Sugerman and col-
leagues (2002) who suggested that RANTES
secreted by OLP lesional T cells may attract
mast cells into the developing OLP lesion and
subsequently stimulate mast cell degranulation.
Degranulating mast cells in OLP would release
TNF-α and chymase which in turn upregulates
OLP lesional T-cell RANTES secretion.
According to this hypothesis, such a cyclical
mechanism may underlie OLP chronicity.
Ichimura et al. (2006) analyzed the
chemokines and their receptors expressed in the
epithelium of OLP by means of DNA microarray.
The study found that high levels of MIP-3a/
LARC/CCL20, and its receptor CCR6, are
expressed on the lesional epithelium. Further-
more, DC-CK1/CCL18, ELC/CCL19, SDF-1/
CXCL12, and CXCR4 expressions were also
increased. Immunohistological analysis showed
that high numbers of LCs were present in the
epithelium of OLP. Lesional epithelium also
expressed high levels of the ligands specific for
CXCR3 and CCR5 (e.g., RANTES/CCL5).
Based on these results, it was suggested that infil-
tration of LCs may be regulated by CCR6
(as these receptors are expressed by LCs) and
that LCs residing in the lesional epithelia may
represent a mature phenotype. Moreover, infiltra-
tion of T cells in OLP could be mediated by
signaling pathways through CXCR3 and CCR5.
Thus, it would appear that there is a
dysregulation of specific chemokines, and chemo-
kine receptors, and that this would appear to be
related to expression of chemokine receptors on
LCs. Similar to the observed dysregulation of
MMPs/TIMPs and keratinocyte/basement mem-
brane noted above, this may be either involved
M.J. McCullough et al.
in the etiopathogenesis of OLP or a byproduct of
the disease.
Epithelial Components
The Epithelial Basement Membrane
Keratinocytes contribute to the structure of the
epithelial basement membrane by secreting colla-
gen IV and laminin V into the basement mem-
brane zone (Marinkovich et al. 1993). Evidence
from mouse models suggests that keratinocytes
require a basement membrane-derived cell sur-
vival signal to prevent the onset of apoptosis
(Pullan et al. 1996). Similarly, lack of appropriate
ECM anchorage results in a form of cell death
called “anoikis.” Thus, an intact basement mem-
brane is required for keratinocytes survival, and
reciprocally healthy keratinocytes are necessary
for normal basement membrane integrity.
Keratinocytes undergoing cell death are no
longer able to perform this reciprocal function,
and as such keratinocyte apoptosis triggered by
intraepithelial CD8+ cytotoxic T cells may result
in epithelial basement membrane disruption in
OLP, thus fueling anoikis and allowing for non-
specific T lymphocytes present in the sub-
epithelial zone to migrate into the epithelium
(Chainani-Wu et al. 2001). Both keratinocyte apo-
ptosis and basement membrane disruption may be
involved in the pathogenesis of OLP, and such a
cyclical mechanism has been postulated to under-
lie disease chronicity (Sugerman et al. 2002;
Lodi et al. 2005a).
Keratinocyte Apoptosis
Keratinocyte apoptosis is a common and key fea-
ture in the histopathological findings of OLP
lesions and is considered a major diagnostic cri-
terion (Ismail et al. 2007; Eisen et al. 2005; Scully
et al. 1998). Therefore, keratinocyte apoptosis has
been postulated to be intentionally involved in the
etiopathogenesis of OLP (Sugerman et al. 2002).
A number of mechanisms have been suggested
by which CD8+ cytotoxic T cells can trigger
keratinocyte apoptosis in OLP. These include
(i) T-cell-secreted TNF-α binding to TNF receptor
1 (TNFR1) on the keratinocyte surface, (ii) T-cell
surface CD95L (Fas ligand) binding CD95 (Fas)
Oral Lichen Planus
Fig. 1 Clinical presentation of patients with OLP: (a) reticular, (b) erosive/ulcerative, (c) atrophic and plaque-like, and
(d) desquamative gingivitis (atrophic and erosive forms)
on the keratinocyte surface, or (iii) T-cell-secreted
granzyme B entering the keratinocyte via
perforin-induced membrane pores (Sugerman
et al. 2002). All of these mechanisms may activate
the keratinocyte caspase cascade, resulting in
keratinocyte apoptosis. Elevated levels of TNF-α
in the serum of OLP patients were identified
(Sugermann et al. 1996).
In summary, while it is well established that
apoptosis of basal keratinocytes is a key feature of
OLP, the exact pathogenic mechanisms have not
yet been elucidated.
Clinicopathologic Features
OLP is the most common mucocutaneous condi-
tion in the mouth and affects approximately 1–2%
of the population (Axell and Rundquist 1987).
Areas which are typically affected include the
13
buccal mucosa, tongue, alveolar ridge, and gingi-
val tissues (Axell and Rundquist 1987).
Clinical Appearance
OLP classically presents in a bilateral, symmetri-
cal pattern with the buccal mucosa (bilaterally)
being the most typical site of involvement
(Fig. 1); however, any other oral mucosal sites
and the lips can also be involved (Al-Hashimi
et al. 2007; Ismail et al. 2007; Scully and Carrozzo
2008). Other common sites of involvement
include the tongue (Fig. 1c), gingival (Fig. 1d),
labial mucosa, and vermilion of the lower lip
(Eisen et al. 2005; Al-Hashimi et al. 2007; Scully
and Carrozzo 2008; Parashar 2011). Patients with
isolated lip lesions and tongue lesions have been
described although many patients who present
with isolated lesions eventually develop more
14
widespread disease (Eisen et al. 2005). Lesions of
OLP affecting the palate, floor of the mouth, and
upper lip are not common.
The oral manifestations of OLP have been
described in many large studies. Clinically, there
are six clinical subtypes of OLP that can be seen
individually or in combination: reticular, plaque-
like, atrophic, erosive, papular, and bullous
(Ismail et al. 2007; Scully and Carrozzo 2008;
Farhi and Dupin 2010). The most common of
these are the reticular, erosive, and plaque-like
subtypes, and these variants can coexist within
the same patient (Fig. 1).
The reticular lesions, the most recognized form
of OLP, encompass white lesions, which appear as
a network of connecting and overlapping lines
referred to as Wickham striae, papules, or plaques
(Eisen et al. 2005). Although some patients may
display an impressive array of diffuse and wide-
spread reticulated lesions, they rarely complain of
symptoms and often are unaware of their pres-
ence. In the absence of the classic reticular pattern
on oral mucosal surfaces, it is challenging to clin-
ically diagnose non-reticular types (Fig. 1b, d)
(Scully and Carrozzo 2008). Histologic confirma-
tion of the diagnosis is thus required. The erosive
form of OLP (Fig. 1b) may present with erythema
caused by inflammation or epithelial thinning, or
both, and ulceration/pseudomembrane formation
with periphery of the lesion surrounded by retic-
ular keratotic striae (Ismail et al. 2007). Atrophic
and erosive OLP lesions result in varying degrees
of discomfort. The number of ulcerations is vari-
able as are their size and location; rarely, bullae
that rupture easily may be observed in the erosive
form of OLP (Eisen et al. 2005). If the erosive
subtype of OLP only affects the gingival tissue,
the descriptive clinical term desquamative gingi-
vitis is often used (Fig. 1d). OLP is confined to the
gingiva in about 10% of patients (Mignogna et al.
2005; Scully and Carrozzo 2008). Erosive lesions
resembling those observed in other
vesiculobullous diseases including pemphigoid,
pemphigus, linear IgA disease, and foreign body
gingivitis can also produce desquamative gingivi-
tis not easily identified as OLP unless there are
coexistent reticular lesions on the gingiva or else-
where in the oral cavity. Two recent cohort studies
M.J. McCullough et al.
found OLP to be the most common cause of
desquamative gingivitis (71% and 75%), while
pemphigoid and pemphigus were next in fre-
quency (Leao et al. 2008; Lo Russo et al. 2009).
OLP isolated to a single oral site other than the
gingiva is uncommon.
In general, bullous and papular forms are rare
in the oral mucosa (Parashar 2011). The erosive
lesions hardly ever remit spontaneously and may
lead to confusion with other vesiculobullous dis-
eases, which share similar clinical features (Eisen
et al. 2005).
The plaque form of OLP mimics leukoplakia in
that it appears as a white, homogeneous, slightly
elevated, multifocal, smooth lesion. The plaque
form of OLP commonly affects the dorsum of the
tongue and buccal mucosa (Ismail et al. 2007).
OLL and OLR have similar features, clinically
and histologically, to OLP, but have a less charac-
teristic morphology or have a distinct cause,
unlike OLP. OLL therefore needs to be distin-
guished because treatment modalities are different
from those for OLP (Al-Hashimi et al. 2007).
To better define the criteria for diagnosis of
OLP, the World Health Organization (WHO)
devised a set of clinicopathologic criteria in
1978 (Table 1) (Kramer et al. 1978). However,
these criteria lacked consensus regarding a clini-
cal and histologic diagnosis of OLP, and so mod-
ifications were proposed to the WHO criteria in
2003 (Table 2), which resulted in a substantial
increase in consensus and clinicopathologic cor-
relation (Epstein et al. 2003; van der Meij and van
der Waal 2003). In addition, knowledge about
history of systemic diseases, history of drug use,
and cutaneous lesions can be helpful in arriving at
a definite diagnosis.
Signs, Symptoms, Clinical Behavior
and OLP Scoring Systems
The clinical signs and symptoms of OLP vary. In
many patients, the onset of OLP is insidious, and
patients are unaware of their oral condition. Some
patients report roughness of the lining of the
mouth, sensitivity of the oral mucosa to hot or
spicy foods, painful oral mucosa, red or white
Oral Lichen Planus 15

Table 1 Original WHO diagnostic criteria of OLP (Kramer et al. 1978)

Clinical criteria
Presence of white papule, reticular, annular, plaque-type lesions, gray-white lines radiating from the papules
Presence of lacelike network of slightly raised gray-white lines (reticular pattern)
Presence of atrophic lesions, with or without erosion, and possibly also bullae
Histopathological criteria
Presence of thickened ortho- or parakeratinized layer in sites that are normally keratinized, and if site is normally
nonkeratinized, this layer may be thin
Presence of Civatte bodies in basal layer, epithelium, and superficial part of connective tissue
Presence of a well-defined band-like zone of cellular infiltration that is confined to the superficial part of the
connective tissue, consisting mainly of lymphocytes
Signs of liquefaction degeneration in the basal cell layer

Table 2 Modified WHO diagnostic criteria of OLP and OLL (van der Meij and van der Waal 2003)
Clinical criteria
Presence of bilateral, more or less symmetrical lesions
Presence of a lacelike network of slightly raised gray-white lines (reticular pattern)
Erosive, atrophic, bullous, and plaque-like lesions are only accepted as a subtype in the presence of reticular lesions
elsewhere in the oral mucosa
In all other lesions that resemble OLP but not complete with the aforementioned criteria, the term “clinically compatible
with” should be used
Histopathological criteria
Presence of well-defined band-like zone of cellular infiltration that is confined to the superficial part of the connective
tissue, consisting mainly of lymphocytes
Signs of “liquefaction degeneration” in the basal cell layer
Absence of epithelial dysplasia
When the histopathological features are less obvious, the term “histopathologically compatible with” should be used
Final diagnosis of OLP or OLL
To achieve a final diagnosis, clinical as well as histopathological criteria should be included
OLP: a diagnosis of OLP requires fulfillment of both clinical and histopathological criteria
OLL: the term OLL will be used under the following conditions
(1) Clinically typical of OLP but histopathologically only “compatible with” OLP
(2) Histopathologically typical of OLP but clinically only “compatible with” OLP
(3) Clinically “compatible with” OLP and histopathologically “compatible with” OLP

patches on the oral mucosa, or oral ulcerations
(Ismail et al. 2007).
Symptoms and signs can range from patients
being unaware of the disease, with lesions that are
completely asymptomatic as in reticular OLP, to
those experiencing mucosal sensitivity and burning
and debilitating pain. Approximately two-thirds of
the patients affected with OLP experience some
degree of oral discomfort (Parashar 2011).
OLP has periods of relapses and remissions.
During a period of exacerbation there will be an
increase in symptoms and clinical signs, while
during periods of quiescence, symptoms and
signs of OLP are diminished (Ismail et al. 2007).
Factors such as stress may aggravate the clinical
presentation of the disease. Precipitating factors
similar to the Koebner phenomenon, which is
characteristic of cutaneous LP whereby lesions
develop in response to trauma, can also affect
the oral cavity where sharp cusps and ill-fitting
dental prosthesis may be the triggers.
Accumulation of plaque and calculus can also
exacerbate OLP, probably because of the Koebner
phenomenon (Mignogna et al. 2005). Gingival
OLP can eventually lead to gingival recession,
advanced periodontal disease, and so forth, and
16
therapeutic periodontal procedures may aggravate
these conditions (Eisen et al. 2005; Scully and
Carrozzo 2008).
Oral post-inflammatory pigmentation (OPP)
has been described in patients with OLP and
OLR as diffuse brown or black pigmentation fol-
lowing the lichenoid lesions distribution
(Mergoni et al. 2011).
Currently there is no universally accepted scor-
ing system for OLP; however many have been
proposed to objectively and even subjectively
measure OLP disease severity. Several studies
have proposed using scoring systems with the
earlier systems based upon a three- or five-point
scale from no disease to severe disease (Eisen et al.
1990; Thongprasom et al. 1992). Other scoring
systems base severity on the level of site involve-
ment (<> 50% site) (Malhotra et al. 2008).
Some of the more detailed scoring systems
have worked to split OLP into three clinical sub-
types, reticular, atrophic/erythematous, and ero-
sive/ulcerative (Escudier et al. 2007). For some
of these studies the oral cavity is divided into
different subsites so each site is given an activ-
ity/severity score which can be totaled to give an
entire oral cavity score (Chainani-Wu et al. 2001;
Piboonniyom et al. 2005; Escudier et al. 2007). In
some of these scoring systems, presence of ery-
thema, erosions, or ulceration is graded higher
than the presence of reticular lesions alone
(Piboonniyom et al. 2005; Escudier et al. 2007).
One of the main advantages of using a detailed
scoring system is the ability to objectively mea-
sure disease activity baseline and changes in dis-
ease activity for the entire oral cavity and specific
sites. Recently attempts have been made to vali-
date some of the more detailed scoring systems
(Chainani-Wu et al. 2012). Time has also been
taken with these scoring systems to add subjective
measures of the patient’s pain and symptoms mak-
ing this a complete disease scoring system
(Chainani-Wu et al. 2012).
Currently there are many available disease
scoring systems which systems in place to mea-
sure changes in subjective and objective disease
activity in OLP. At this stage no one system has
been universally accepted for use.
M.J. McCullough et al.
Histopathology of OLP
The histologic features of OLP were first
described by Dubreuill in 1906 and later revised
by Shklar in 1972 (Parashar 2011). The WHO
developed a set of histopathologic criteria for
OLP in 1978, which was most recently modified
in 2003 (Tables 1 and 2). Definite diagnostic his-
tologic findings include liquefactive degeneration
of the basal cells, colloid bodies (Civatte, hyaline,
cytoid), homogeneous infiltrate of lymphocytes
and histiocytes in a dense, band-like pattern
along the epithelium-connective tissue interface
in the superficial dermis, cytologically normal
maturation of the epithelium, sawtooth rete ridges,
and hyperkeratosis (orthokeratosis or para-
keratosis) (Fig. 2) (Eisenberg 2000; Eisen et al.
2005; Ismail et al. 2007; Parashar 2011). In addi-
tion, the surface epithelium may show signs of
ulceration, typically seen in erosive LP.
Several histologic criteria are considered as
exclusionary in diagnosing OLP, including the
absence of basal cell liquefaction degeneration,
polyclonal inflammatory infiltrate, abnormal
cytology suggestive of dysplasia, abnormal kera-
tinization, flat rete ridges, and absence of colloid
bodies (Eisenberg 2000; Ismail et al. 2007).
Oral Lichenoid Reactions (OLR)
There are various lesions that may resemble OLP
both clinically and histopathologically. These
lesions are collectively termed OLR and encom-
pass lichenoid drug reactions (LDR) and OLR to
dental materials, most notably allergic contact
sensitivity to amalgam (Koch and Bahmer 1995;
Ostman et al. 1996; Thornhill et al. 2003; Issa
et al. 2004; Eisen et al. 2005; Ismail et al. 2007).
As with OLP, OLRs present clinically with a
range of different features ranging from asymp-
tomatic striae and plaque-like lesions to painful
erythematous and ulcerative lesions. Histopatho-
logically OLRs align with OLP showing a band-
like lymphohistiocytic infiltrate (mainly T cell)
within the lamina propria as well as liquefactive
degeneration of the basal cell layer.
Oral Lichen Planus 17

Fig. 2 Histopathology of
OLP. (a) Low power
photomicrograph showing
parakeratosis, band-like
subepithelial chronic
inflammatory infiltrate, and
sawtooth rete ridges (H&E,
original magnification
X100). (b) High-power
photomicrograph showing
several colloid bodies
(arrows) and liquefactive
degeneration of basal
keratinocytes (arrowheads)
(H&E, original
magnification X200)

Cases of OLRs related to restorative materials
will typically present in a direct topographic rela-
tionship with the restorative material. The aller-
gens thought to be responsible for amalgam-
contact sensitivity include mercury, amalgam
alloying metal zinc, copper, silver, gold, or palla-
dium (Koch and Bahmer 1995; Suter and
Warnakulasuriya 2016). There has been some evi-
dence to suggest that some patients with
amalgam-associated OLRs represent a true
delayed hypersensitivity reaction as a result of
metal haptens released from dental restorative
materials (Laine et al. 1999). LDRs will typically
arise with a direct temporal association when tak-
ing certain medications including nonsteroidal
anti-inflammatory medications (NSAIDs), some
antihypertensive medications, oral hypoglyce-
mics, penicillamine, and antimalarial medications
(Epstein et al. 2003; Bagan et al. 2004;
Al-Hashimi et al. 2007; Ismail et al. 2007).
No specific criteria exist for the diagnosis of
LDR; however withdrawal and reexposure to the
drug resulting in resolution and recurrence can be
considered diagnostic. Patch testing may be a
valuable diagnostic tool for OLR as a result of a
contact sensitivity to dental materials (Suter and
Warnakulasuriya 2016). In cases of a suspected
OLR as a result of amalgam dental restorations,
there is evidence to suggest that replacement of
amalgam can result in resolution or improvement
of OLR; in some cases this is irrespective of a
positive patch testing result (Laine et al. 1992;
Ostman et al. 1996; Thornhill et al. 2003; Issa
et al. 2004). Thus in cases of suspected OLRs, it
is essential that proper testing including histopa-
thology and patch testing be undertaken to ensure
18
a correct diagnosis is made as OLP and OLR
benefit from different management protocols.
Dental Materials
OLR as an allergic reaction to dental materials has
been widely reported, with many studies
documenting contact hypersensitivity to dental
materials such as amalgam (Lind et al. 1986;
Thornhill et al. 2003), composite (Lind 1988),
dental acrylics (van Loon et al. 1992), cobalt
(Torresani et al. 1994), and nickel (Ismail et al.
2007) presenting as OLR. Some studies also
showed resolution of OLR following replacement
of causative restorations. Laine et al. reported a
complete remission of OLR lesions associated
with amalgam in a small cohort of seven patients,
a marked remission in six patients, and no change
in two patients (total n = 15) after amalgam
replacement and a mean follow-up of 3.2 years
(Laine et al. 1992). In another trial, Thornhill et al.
reported that amalgam replacement resulted in
improvement in 93% of patients (28 out of 30)
who had amalgam-contact hypersensitivity
lesions (Thornhill et al. 2003). Gingival OLR
lesions, in particular, were reported to be non-
responsive to amalgam replacement for unknown
reasons (Henriksson et al. 1995).
Diagnosis of OLR will commonly depend on
the topography and distribution of the lesions as in
most cases, OLR are indistinguishable from idio-
pathic OLP, clinically or histologically (Thornhill
et al. 2003). Cutaneous patch testing may also
play a role in differentiating these lesions (Scully
and Carrozzo 2008; Ismail et al. 2007). Thornhill
et al. found that 70% of amalgam-contact hyper-
sensitivity lesions (presented as lichenoid reac-
tions) were patch test positive for amalgam or
mercury compared with only 3.9% of OLP cases
(Thornhill et al. 2003).
To date, OLP and OLR lack internationally
accepted distinguishing features, and the diagno-
sis of OLR can be challenging as the pathogno-
monic features of OLR are yet to be identified
(Ismail et al. 2007).
Recent findings have suggested that OLR
appears to be the result of cell-mediated contact
hypersensitivity to dental materials, in susceptible
M.J. McCullough et al.
individuals who have been sensitized through
long exposure (Ismail et al. 2007).
Systemic Medications
Medications, such as antihypertensives ( in par-
ticular beta-blockers and ACE inhibitors), dap-
sone, oral hypoglycemics, NSAIDs,
penicillamine, phenothiazines, antimalarials, sul-
fonylureas, and gold salts, have been associated
with OLRs (Scully et al. 1998; Al-Hashimi et al.
2007; Ismail et al. 2007).
More recently, OLR induced by antiretroviral
medications for treatment of human immunodefi-
ciency virus (HIV) has been reported (Scully and
Diz Dios 2001). Clinical identification of LDR
has been based largely on subjective criteria
although there may sometimes be a tendency for
the oral lesions to be unilateral and erosive (Eisen
et al. 2005). Histology may be beneficial as
lichenoid lesions may have a more diffuse lym-
phocytic infiltrate and contain eosinophils and
plasma cells, and there may be more colloid bod-
ies than in classical OLP (Eisen et al. 2005; Scully
and Carrozzo 2008).
The most reliable method to diagnose LDRs is
to note if the reaction resolves after the offending
drug is withdrawn and if it returns when the
patient is challenged again. As this is both imprac-
tical and potentially unsafe, empiric withdrawal of
a potentially offending drug and substitution with
another agent may not be warranted. After the
offending drug is withdrawn, it may be months
before the LDR resolves. Interestingly, it was
reported that LDR may develop months or even
years after a patient takes a drug (Eisen et al. 2005).
Cutaneous Lesions
LP may affect the hair follicles, nails, esophagus,
and, less frequently, the eyes, urinary tract, geni-
tals, nasal mucosa, and larynx. Scalp involvement
causes pruritic, follicular and perifollicular, scaly,
violaceous papules, referred to as lichen
planopilaris, and can also lead to permanent
patchy hair loss known as scarring alopecia.
When LP affects nails, it causes pitting, subungual
Oral Lichen Planus
hyperkeratosis, and permanent nail loss (Farhi and
Dupin 2010).
Skin lesions characteristically present as flat-
topped, polygonal, violaceous papules regularly
covered by a network of fine lines affecting the
wrists, ankles, and genitalia (Bornstein et al.
2006). Cutaneous LP may also appear in several
atypical forms that are not easily recognizable. As
previously mentioned, approximately 15% of
patients with OLP develop cutaneous lesions,
while OLP occurs in 70–77% of patients with
cutaneous LP (Eisen 1999; Farhi and Dupin 2010).
Typically, cutaneous lesions develop within
several months after the appearance of the oral
lesions, and the severity of the oral lesions does
not seem to correlate with the extent of cutaneous
involvement, i.e., while OLP is chronic and rep-
resents a common cause of morbidity, cutaneous
lesions are commonly pruritic but self-limiting
(Eisen et al. 2005).
Other Mucosal Lesions
Undoubtedly, the most frequent extraoral site of
involvement in female patients with OLP is the
genital mucosa with lesions developing in 20% of
women with OLP compared with only 2–4% of
men with OLP (Ismail et al. 2007; Scully and
Carrozzo 2008; Farhi and Dupin 2010). The asso-
ciation of LP of the vulva, vagina, and gingiva is
recognized as the vulvovaginal-gingival syn-
drome (Pelisse 1989), and the male counterpart
is known as penogingival syndrome (Bain and
Geronemus 1989).
When LP affects the genital mucosa, the ero-
sive form of the disease is the predominant type
although asymptomatic reticular lesions can be
identified in about a quarter of all patients (Eisen
et al. 2005). Various symptoms including burning,
pain, vaginal discharge, and dyspareunia are fre-
quent and are noted in patients with erythematous
and erosive disease.
Reports of malignant transformation of genital
LP in women (Dwyer et al. 1995) underscore the
need for an early diagnosis and the institution of
prompt treatment for these patients. Although the
concomitant involvement of oral and genital LP is
19
much less common in males than females, recog-
nition and treatment of the disease are important
as malignant transformation of penile LP has also
been reported (Bain and Geronemus 1989).
The clinical features of esophageal LP have
been well documented, and the disease appears
to develop most commonly in patients with OLP
(Evans et al. 2000), while conjunctival, laryngeal,
or other mucosal involvement is rarely reported
(Eisen et al. 2005).
Malignant Potential of OLP
Since the first report of malignant transformation
of OLP (Hallopeau 1910), numerous studies have
attempted to address this issue. Malignant trans-
formation rates ranging from 0% to 12.5% were
reported (Gonzalez-Moles et al. 2008). Although
these findings appear to support the potentially
malignant character of OLP, it remains a contro-
versial topic.
Several authors agreed to a frequency of malig-
nant transformation between 0.4% and 5%, over
periods of observation from 0.5 to over 20 years
with an annual rate between 0.2% and 0.5%. (van
der Meij et al. 2003; Al-Hashimi et al. 2007;
Scully and Carrozzo 2008). However, reviews
limited to selected studies on malignant potential
of OLP with a follow-up of more than 2 years
showed that when strict criteria were applied, the
malignant transformation rate is 0–2% (Ismail
et al. 2007).
It has been thought that the increased risk of
oral cancer appears to be independent of the clin-
ical type of OLP and therapy administered
(Gandolfo et al. 2004).
The first critical review regarding OLP malig-
nant transformation appeared in the Journal of
Oral Pathology about four decades ago
(Krutchkoff et al. 1978), included data published
up to 1977, and the authors recommended strict
criteria (Table 3) to be adopted to definitively
accept the malignant transformation in OLP.
After applying these new criteria, they concluded
that only 15 of the 223 cases reported in the
literature should be unquestionably accepted as
malignant transformation in OLP. The remaining
20
Table 3 Criteria for malignant transformation of OLP
(Krutchkoff et al. 1978)
A. Original diagnosis must have been properly verified,
with histological evidence demonstrating at least the last
two of these four features
Hyperkeratosis or parakeratosis
Sawtoothed rete ridges
Superficial infiltrate of lymphocytes
Basal cell liquefaction
B. History and follow-up
Clinical and histological features of the alleged
transformation must have been adequately described
(information on age and sex of patient and on the precise
location and clinical description of the lesion)
The reported transformation should have had proper
follow-up (minimum of 2 years) with all changes in
clinical features properly recorded
C. Tobacco exposure
Tobacco habits should have been properly documented
to help distinguish between true malignant
transformation and conventional carcinomas occurring in
the mouths of patients who happened to have OLP
cases were excluded for at least one of the follow-
ing reasons: (1) insufficient data to support the
OLP diagnosis, (2) appearance of oral cancer in
an area anatomically distant from the OLP, and
(3) inadequate historical data on previous expo-
sure to carcinogens. The authors commented: “If
OLP prevalence is accepted to be 1–2% of general
population over 15 years, and if malignant trans-
formation rate is 1% in a mean period of 5 years,
then, from 10 to 20 patients per 100 000 inhabi-
tants should develop oral cancer in a mean period
of 5 years. This would indicate that in many parts
of the world all oral carcinomas should develop on
an OLP, which is rather improbable” (Krutchkoff
et al. 1978). They further drew the conclusion that
there was insufficient evidence to accept an inher-
ent biological potential of OLP to progress to
cancer, but they acknowledged that OLP patients
have a slightly higher tendency to develop carci-
nomas compared to individuals without OLP
(Krutchkoff et al. 1978).
Almost 20 years later, van der Meij et al.
(1999a, b) reviewed studies on the malignant
transformation of OLP published from 1977 to
1999, applying the Krutchkoff criteria. During
this period, 98 new malignant transformations
M.J. McCullough et al.
were reported, of which 33 (34%) met the pro-
posed criteria. According to the authors, the high
incidence of malignant transformation described
in many studies may be due to the misdiagnosis of
some lesions as OLP or to the analysis of a highly
selected study population (e.g., predominance of
patients referred to specialists). This investigation
concluded that nearly all of the case reports lacked
precise documentation and that still no consensus
had been established about the criteria for the
histopathologic diagnosis of OLP (van der Meij
et al. 1999a).
van der Meij et al. further emphasized the need
for standard criteria for a firm diagnosis of OLP to
be universally adopted (van der Meij et al. 1999a, b).
The designation OLL was later proposed for
cases that are clinically characteristic and histo-
logically compatible, clinically compatible and
histologically characteristic, or clinically and his-
tologically compatible with OLP (Table 2) (van
der Meij and van der Waal 2003). It is currently
proposed by some key authors that OLL rather
than OLP is at high risk of developing cancer
(Bornstein et al. 2006; van der Meij et al. 2007;
Gonzalez-Moles et al. 2008).
On the other hand, a review by Mattsson et al.
largely based on follow-up studies reported a
higher incidence of oral cancer in OLP patients
and concluded that OLP should be considered a
potentially malignant condition with a transfor-
mation rate of 0.5–2% (Mattsson et al. 2002).
Many other studies using strict diagnostic criteria
have shown a significant risk of malignant trans-
formation of OLP to squamous cell carcinoma
(SCC) (Holmstrup et al. 1988; Gandolfo et al.
2004; Rodstrom et al. 2004).
Finally, the World Health Organization, in its
latest volume on the Pathology and Genetics of
Head and Neck Tumours (Gale et al. 2005), has
recommended the development of diagnostic
criteria to differentiate between OLP and OLL
but declared that both lesions should be consid-
ered at risk of malignant transformation until such
criteria become available.
In 1985, Krutchkoff and Eisenberg (1985)
coined the term lichenoid dysplasia (LD) to
describe lesions that resemble OLP histologically
and also show features of dysplasia. They
Oral Lichen Planus
suggested that OLP has no inherent predisposition
to become malignant and that reported cases of
malignant transformation in OLP lesions were due
to lack of discrimination between OLP and LD or
failure to identify a concomitant exposure to known
carcinogens (Krutchkoff and Eisenberg 1985).
The assumption for the proposal of malignant
potential in LD rather than OLP was that any
departure from normal epithelial maturation and
growth altogether excludes a diagnosis of OLP
(Eisenberg 2000), although consensus on such
criteria has never been reached, and some authors
consider dysplasia a very common feature of OLP
(Lodi et al. 2005b).
The entity LD might correspond to two groups
of conditions: those with clinical features similar to
OLP but dysplastic at the histological level and
those with lichenoid microscopic features (band-
like lymphocytic infiltration in particular) and clin-
ical features which do not resemble classic OLP
(unilateral distribution, absence of reticular lesions)
(Lodi et al. 2005b). The former could represent an
early phase in the malignant transformation of OLP,
while the latter could represent an OLL with under-
lying various clinical conditions that may have
lichenoid histopathology including lichenoid reac-
tions, lupus erythematosus, leukoplakia, erythroleu-
koplakia, and proliferative verrucous leukoplakia
(PVL). PVL, particularly in the early stages, can
have features, both clinical and histologic, that can
be confused with OLP, frequently shows dysplastic
changes, and is characterized by a high malignant
transformation rate (Lodi et al. 2005b).
OLL and Cancer
A very interesting, and potentially informative,
group of patients regarding OLL and oral malig-
nancies are those who underwent allogeneic bone
marrow transplantation and developed oral
GVHD. Oral GVHD is clinically and histologi-
cally indistinguishable from OLP. Case reports
(Abdelsayed et al. 2002) and large studies (Deeg
et al. 1996; Curtis et al. 1997) describe numerous
episodes of oral cancers (mainly SCC) in patients
with oral GVHD. A large study that investigated
the incidence of solid tumors in 20,000 bone
21
marrow transplantation patients found that oral
cancer had the highest risk among cancers, being
11.1 times more frequent than expected (Curtis
et al. 1997). The significant risk factors for OSCC
were chronic GVHD, limited-field irradiation, and
male sex. In one of these studies, head and neck
cancer was the only solid cancer observed in a
group of 78 patients undergoing bone marrow
transplantation for Fanconi anemia, with the fre-
quency of such tumors was 167 times higher than
expected (Deeg et al. 1996).
Clearly, bone marrow transplantation patients
have numerous risk factors that may enhance
their likelihood of developing malignancies (pri-
mary immunodeficiencies, immunosuppressive
treatments, viral infections, and probably genetic
predisposition to cancer) that do not allow a com-
parison with OLP patients; however, the similarity
of the oral conditions and the apparent common
tendency to transform are worthy of careful con-
sideration (Lodi et al. 2005b). Other lichenoid
lesions that can undergo malignant transformation
include discoid lupus erythematosus, in particular
of the lip (Voigtlander and Boonen 1990) and
amalgam-associated OLR (Ostman et al. 1996).
Interestingly, in a prospective study on prema-
lignant potential of OLP, all cases of malignant
transformation involved lesions that the authors
included in the group of OLL because they did not
fulfill both clinical and histologic criteria for OLP
(van der Meij et al. 2003). In 2007, van der Meij
et al. (2007) also studied the number of expected
oral carcinomas in 67 patients with OLP and
125 patients with OLL. All malignant transforma-
tions (4 of 192, 2.1%) appeared in OLL patients,
i.e., an annual OLL malignant transformation rate
of 0.71%. Hence, there was no increase in oral
cancer risk for patients with OLP but a 142-fold
increase for patients with OLL (P = 0.04).
There may be considerable overlap between the
clinical and microscopic features of OLR and OLP.
Although no association has been established
between OLR and malignant transformation
(Mattsson et al. 2002), Larsson and Warfvinge
proposed that there may be a similar rate of malig-
nant transformation in OLR to that observed in
OLP, especially in lesions at the lateral border of
the tongue, a frequent site for OLR due to the close
22
Fig. 3 Oral squamous cell carcinoma in OLP. Clinical
presentation of patients with OLP and who subsequently
developed OSCC: (a) An exophytic squamous cell carci-
noma that developed on the right lateral tongue in a patient
who previously had histopathologically diagnosed OLP in
the same area. (b) An example of metachronous
contact with silver amalgam restorations. They
reported that the cancer had developed on an
OLR in 4 of 724 patients with tongue cancer
(Larsson and Warfvinge 2005).
Tumors Developing in OLP and their
Carcinogenesis
Clinically, carcinomas that develop in previously
diagnosed OLP lesions have been reported to be
exophytic keratotic lesions (Lo Muzio et al. 1998;
Fatahzadeh et al. 2004) (Fig. 3a), but some may
also show endophytic growth patterns (Lo Muzio
et al. 1998). Markopoulos et al. (1997) suggested
that rapid expansion of OLP lesion should raise
suspicion of malignant transformation, but
Mignogna et al. (2001) found neither the exten-
sion nor severity of symptoms a useful indicator
M.J. McCullough et al.
carcinomas in an OLP patient whose right buccal mucosa
had previously shown histopathological evidence of OLP.
Subsequently developed a more florid erythematous
mucosa in the same area (pictured) that was biopsied and
diagnosed as OSCC. (c) Eight years later, the same patient
developed a second OSCC, controlaterally
of transformation – rather they considered the loss
of lesion homogeneity at a specific site to be most
relevant. This clinical sign is especially useful
when only a small area is involved, as OLP usu-
ally affects various areas or a large area.
An important reported feature of the presenta-
tion and clinical course of carcinomas that arise on
OLP is their tendency of multiplicity. Mignogna
et al. (2002) found that 29% of patients develop-
ing carcinomas in OLP had two or more indepen-
dent neoplastic lesions (19% with a second tumor,
10% with >2 metachronous tumors) (Fig. 3b, c).
This finding confirmed previous reports by
Duffey et al. (1996) (20% of patients with second
primary tumors) and Lo Muzio et al. (1998)
(35.7% of patients with second primary tumors).
The relatively high frequency of multiple
intraoral localizations of second primary tumors
in previously diagnosed OLP may be attributed to
Oral Lichen Planus
the field cancerization phenomenon and indicates
that OLP may have an intrinsic predisposition to
tumor development (Mignogna et al. 2007).
The metastatic capacity of carcinomas devel-
oping in OLP has been addressed by an earlier
report by Mignogna et al. (2002) who showed that
24% of these patients had detectable lymph node
metastases at the time of diagnosis. In their more
recent work, the same authors (Mignogna et al.
2007) reported that 94% of 97 neoplastic events
observed were TisN0M0 or T1N0M0
(intraepithelial neoplasia or microinvasive carci-
noma <1 mm) and 6% were stage III (three
tumors) or IV (three tumors).
Histopathologically, most tumors detected in
OLP are well-differentiated SCCs [70% in the
study by Lo Muzio et al. (1998); 100% in the
study by Markopoulos et al. (1997)]. Finally,
there are conflicting results on the prognosis of
patients with neoplasia in OLP, some indicating a
poor prognosis (Hietanen et al. 1999; Mignogna
et al. 2001; Mignogna et al. 2002), but Mignogna
et al. (2007) reported 100% 3-year and 97%
5-year survival, although there may have been a
bias in this study as the neoplastic events
corresponded to severe dysplasias ⁄carcinomas in
situ in most patients, due to a meticulous follow-
up program.
Numerous studies (Silverman et al. 1985;
Markopoulos et al. 1997; Hietanen et al. 1999;
van der Meij et al. 2003; Mignogna et al. 2006)
have been unable to identify risk factors for cancer
development in patients with OLP. It has therefore
been proposed by some authors that carcinoma-
tous transformation is part of the natural history of
the disease or is attributable to unknown risk
factors (van der Meij et al. 2003).
Several risk factors for malignant transforma-
tions in OLP have been proposed. These include
erosive forms, tongue lesions, women more than
men, and sixth to seventh decades of life, but none
of them gained significant agreement among
researchers (Gonzalez-Moles et al. 2008).
Another relevant issue in the context of malignant
transformation of OLP is whether to include
patients with chronic oral exposure to carcino-
gens, as it will probably be impossible to differ-
entiate between the transformation caused by
23
tobacco and that secondary to OLP. For this rea-
son, some authors recommend the exclusion of
smokers with OLP from studies (van der Meij
et al. 1999a, b, Lozada-Nur 2000). However,
according to Lodi et al. (2005b), although some
cases described may be mainly related to tobacco
consumption, the exclusion of one putative risk
factor based on the presence of another appears
inappropriate and could prevent the identification
of new risk factors. Thus, for example, this
approach would have impeded identification of
the super-multiplicative risk of combined tobacco
and alcohol consumption for oral and oropharyn-
geal cancer development.
Therefore, the putative role in OLP transfor-
mation of well-known risk factors for oral cancer
(tobacco and alcohol) has not been properly eval-
uated in most studies (Lodi et al. 2005b). In a
single study, in which this interaction was
addressed, it was suggested that alcohol and
tobacco, or their interaction, cannot explain the
excess risk for oral cancer found in OLP
(Gandolfo et al. 2004).
However, many authors (Murti et al. 1986;
Barnard et al. 1993; Eisen 2002; van der Meij
et al. 2003; Gandolfo et al. 2004) found no rela-
tionship between tobacco and alcohol consump-
tion on one side and malignant transformation on
the other side in OLP patients.
Results published by Rajentheran et al. (1999)
indicated that tobacco and alcohol consumption
may even be lower in these patients than in
patients developing oral cancer in the absence of
OLP. In a cohort of 24 OLP patients with subse-
quent OSCC, Mignogna et al. (Mignogna et al.
2001) found only three patients to be smokers and
none to be alcoholic. Munoz et al. (2007) reported
that only two out of ten OLP patients who devel-
oped OSCC were smokers, none was an alcoholic
abuser.
With respect to the clinical form of OLP,
numerous authors (Silverman et al. 1985; Barnard
et al. 1993; Markopoulos et al. 1997; Hietanen
et al. 1999; Rajentheran et al. 1999; Eisen 2002;
van der Meij et al. 2003) found that atrophic-
erosive forms predisposed to cancer development,
but this remains a controversial issue. In some
series (Hietanen et al. 1999; Mignogna et al.
24
2001, 2007), plaque-like OLP lesions were also
relevant, both when they appeared alone and
when associated with atrophic-erosive lesions.
Analyses of malignant transformation risk fac-
tors have also considered the different intraoral
sites of OLP. The tongue appears to be the pre-
ferred site for the emergence of cancer (Holmstrup
et al. 1988; Barnard et al. 1993; Markopoulos
et al. 1997; Munoz et al. 2007).
Other studies, however, have reported sites
other than the tongue to have a higher risk of
malignant transformation in OLP. Mignogna
et al. (2001) found a significantly higher fre-
quency of carcinomas at the midline of the palate,
gingivae, and lips in a cohort of 502 OLP patients
who were followed up for periods from 4 months
to 12 years and an overall malignant transforma-
tion rate of 3.7%.
Regarding gender and age, there appears to be
a general consensus that the risk is higher in
women than in men (Gonzalez-Moles et al.
2008). Some authors reported that an oral cancer
most frequently develops on an OLP between the
sixth and seventh decade of life (Barnard et al.
1993; Hietanen et al. 1999).
The mean interval between OLP diagnosis and
cancer diagnosis ranges widely from 20.8 months
to 10.1 years, although the maximum risk is
reportedly between 3 and 6 years after OLP diag-
nosis (Gonzalez-Moles et al. 2008). The risk of
malignant progression may also increase with the
use of immunosuppressive agents. Although no
specific data are available in OLP patients, it is
well known that immunosuppressive treatment,
which generally includes corticosteroids, cyclo-
sporine, and tacrolimus, is a risk factor for cancer,
including OSCC (Kruse and Gratz 2009). A grow-
ing body of evidence now suggests that glucocor-
ticoids can act as antiapoptotic agents in epithelial
cells to promote cancer progression (Azher et al.
2016). The discovery that corticosteroids can
directly target the oral mucosa via GR expressed
by oral keratinocytes (Cirillo et al. 2012) may
have salient clinical implications in the under-
standing of the malignant potential of OLP.
However, other authors consider that immuno-
suppressant therapy does not increase the risk of
transformation (Hietanen et al. 1999; Rajentheran
M.J. McCullough et al.
et al. 1999; Gandolfo et al. 2004; Mignogna et al.
2007) and might even reduce it. Thus, it has been
proposed that a microenvironment rich in
pro-inflammatory cytokines may be especially
favorable for neoplastic promotion, suggesting
that more aggressive immunosuppressant treat-
ments against the inflammatory response in OLP
might restore normal immune surveillance and
interrupt neoplastic progression (Eisen 2002). In
a study of OLP patients treated mostly with topi-
cal and/or systemic steroids, therapeutic modali-
ties did not affect the risk of malignant
transformation (Gandolfo et al. 2004).
Malignant transformation of OLP has been
suggested to be related to, or dependent upon, a
series of molecular stimuli originating in the
inflammatory infiltrate (Mignogna et al. 2004).
Chronic inflammation has been associated with
various types of cancer (Clevers 2004), and it
has been widely reported that the inflammatory
infiltrate can be a strong risk factor for cancer
development in ulcerative colitis, atrophic gastri-
tis, and Barret’s esophagitis, among other diseases
(Balkwill and Mantovani 2001). In fact, it was
proposed by some authors that OLP could be
included in this group of diseases (Mignogna
et al. 2004). Some molecules and radicals gener-
ated by inflammatory cells can act as mutagenic
agents for epithelial cells or influence important
cell cycle regulation mechanisms (Gonzalez-
Moles et al. 2008).
Most studies on cell proliferation in OLP have
reported a marked increase in the proliferation rate
of basal epithelial cells (Valente et al. 2001;
Gonzalez-Moles et al. 2006), and some authors
have proposed that this might be an important
event in the development of cancer in OLP
(Taniguchi et al. 2002).
Mignogna et al. (2004) presented the possible
role of each type of inflammatory cells in the
malignant transformation of OLP. According to
their hypothesis, macrophages, mast cells, lym-
phocytes, and fibroblasts can contribute to the
process of carcinogenesis in OLP by secreting
cytokines, chemokines, MMPs, and RANTES
molecules which have the ability to cause DNA
damage, bypass p53 tumor suppression function,
Oral Lichen Planus
induce immortalization, and influence growth,
survival, angiogenesis, and invasion.
In addition to the proposal that OLP-related
inflammatory microenvironment is able to initiate
tumorigenesis in normal epithelium, this microen-
vironment has also been suggested to represent a
predisposing and enhancing factor toward the
molecular changes caused by conventional envi-
ronmental carcinogens, such as tobacco and alco-
hol (Mignogna et al. 2004). Interestingly,
smoking was recently shown to alter the inflam-
matory infiltrate in OLL, reducing the expression
of macrophages, which may in turn affect the
immune surveillance and theoretically the mech-
anisms of malignant transformation (Alrashdan
et al. 2016).
The role of Candida spp. in the symptomatol-
ogy and malignant potential of OLP is unclear.
Candida spp. is frequently identified in patients
with intraoral lesions of OLP and other oral poten-
tially premalignant or malignant lesions including
oral leukoplakia and OSCC (Zeng et al. 2009;
Masaki et al. 2011). Candida spp. has been
shown to present higher frequency and coloniza-
tion in those with OSCC compared to controls
( p = 0.001 and 0.033, respectively) (Alnuaimi
et al. 2015). With reference to OLP, studies have
shown the presence of oral yeast to be anywhere
between 40% and 80% for patients with OLP and
around 20% and 40% for controls (Jainkittivong
et al. 2007; Lodi et al. 2007; Masaki et al. 2011).
In relation to the association of Candida spp.
and OLP, the evidence is conflicting. Specifically
the evidence is conflicting in terms of whether
there is a significant relationship between Can-
dida spp. and erosive OLP, specifically whether
this relationship plays a role which enhances
inflammation to aggravate the pathogenic condi-
tion (Zeng et al. 2009).
Similarly, there is conflicting evidence with
regard to Candida invasion in OLP. At this stage
it is not certain if the presence of Candida in OLP
and other premalignant and malignant conditions
is simply a coincidental finding and whether
changes in the local environment as a result of
OLP, such as roughness of the mucosal surface
and hyperkeratosis, create an ideal environment
25
which simply favors colonization and overgrowth
of Candida spp. (McCullough et al. 2002).
Patient Management
The characteristic clinical aspects of OLP (sym-
metry, bilateral distribution) are thought by some
researchers to be sufficient to make a correct diag-
nosis especially if there are classic skin lesions
present (Eisen et al. 2005).
However, an oral biopsy with histopathologic
study is usually recommended to confirm the clin-
ical diagnosis and mainly to exclude dysplasia and
malignancy (Eisen et al. 2005; Al-Hashimi et al.
2007; Ismail et al. 2007; Scully and Carrozzo
2008).
The histopathologic assessment of OLP has
been described as a subjective and insufficiently
reproducible process (van der Meij et al. 1999a),
and in about 50% of OLP cases, there is a lack of
clinicopathologic correlation in the diagnostic
assessment of OLP (van der Meij and van der
Waal 2003). Gingival LP may be more difficult
to diagnose, and direct immunofluorescence of
perilesional mucosa may facilitate the diagnosis
and exclude other causes such as vesiculobullous
diseases (Eisen et al. 2005). The value of direct
immunofluorescence for confirmation of the dis-
ease is well accepted, especially with non-
diagnostic histopathologic features and for the
desquamative gingivitis form of OLP (Eisen
et al. 2005; Scully and Carrozzo 2008).
Direct immunofluorescence studies of OLP
have shown a linear pattern and intense positive
fluorescence with antifibrogen outlining the base-
ment membrane zone and cytoid-like bodies with
positive immunoglobulin M labeling (Eisen et al.
2005; Ismail et al. 2007; Scully and Carrozzo
2008). Indirect immunofluorescence studies are
not routinely used in the clinical diagnosis of OLP.
It has been proposed that allergy to dental
materials is common in patients with OLR. Cuta-
neous patch testing is a recognized and accepted
method to identify allergens responsible for type I
and IV allergic reactions with Dental Series
Epicutaneous Test Battery (Trolab) of patch test
allergens being commonly used. The test
26
substances are applied to normal skin of the back
and read after 72 h. The patient is considered a
patch test positive to an allergen if they develop
erythematous vesicular or ulcerative reaction at
the site of contact (Ismail et al. 2007).
Skin patch testing to investigate contact sensi-
tivity responses to mercury and amalgam pro-
duced conflicting results with variable numbers
of patients being positive in different studies. In
one study, Laine et al. (1992) studied 118 patients
with OLR topographically associated with dental
fillings, 68% of such patients were patch test
positive to metals of fillings materials, particularly
mercury and silver nitrate. In another trial, Wong
et al. reported a positive patch test in 39% of a total
of 84 patients who presented with OLR related to
amalgam fillings (Wong and Freeman 2003).
In a systematic review that analyzed data from
14 cohort and five case-controlled studies with a
total of 1,158 patients (27% males and 73%
females, age range 23–79 years) with OLR asso-
ciated with amalgam, 16–91% of patients were
patch test positive for at least one mercury com-
pound (Issa et al. 2004).
Treatment of OLP should be directed at achiev-
ing specific goals after considering the degree of
clinical involvement, the predominant clinical
type of lesions, the patient’s symptoms, and age.
Reticular lesions that are asymptomatic generally
require no therapy but only observation for
change. In general, all treatment should be aimed
at managing atrophic and ulcerative lesions, alle-
viating symptoms, and potentially decreasing the
risk of malignant transformation (Eisen et al.
2005; Lodi et al. 2005; Al-Hashimi et al. 2007;
Scully and Carrozzo 2008).
Mechanical trauma or irritants such as sharp
filling margins, rough surfaces, or badly fitting
dentures should receive attention. A drug history
should be obtained to identify reversible causes of
lichenoid eruptions as discontinuation of the
offending agent can be curative (Eisen et al. 2005).
Hypersensitivity reactions should be suspected
when OLLs are confined to oral mucosal sites in
close proximity to dental restorations. An optimal
oral hygiene program should be instituted in
patients with gingival disease (Eisen et al. 2005).
M.J. McCullough et al.
Many therapeutic modalities have been
suggested in the treatment of OLP, with the most
currently accepted and reliable modality being the
use of topical steroids with consideration to be
given for use of systemic steroids in cases of
severe widespread disease and/or refractory
cases of OLP (Vincent et al. 1990; Al-Hashimi
et al. 2007).
Topical Agents
Glucocorticoids
The most commonly employed and useful agents
for the treatment of OLP are topical corticoste-
roids. A response to treatment with midpotency
corticosteroids such as triamcinolone, potent fluo-
rinated corticosteroids such as fluocinolone
acetonide and fluocinonide, and superpotent halo-
genated corticosteroids such as clobetasol has
been reported in 30–100% of treated patients
(Carbone et al. 1999; Thongprasom et al. 2003;
Eisen et al. 2005).
Al-Hashimi et al. (2007) reviewed 12 clinical
trials in the context of corticosteroid use for OLP
(four were placebo controlled, one assessed sys-
temic corticosteroids). Most studies were not
focused on investigating the value of corticoste-
roids in the treatment of OLP per se but compared
the effectiveness of different formulations, differ-
ent classes of corticosteroid, different strengths of
topical steroids, and different frequency of appli-
cation. The specific medications included in the
review were fluocinonide, fluocinolone acetonide,
triamcinolone acetonide, clobetasol propionate,
fluticasone propionate, and betamethasone valer-
ate/sodium phosphate for topical therapy, with
dosages ranging from 0.025%, 0.1%, to 0.5%
and the frequency of application varying from
two, three, to four times a day. The average dura-
tion of the studies was between 4 and 8 weeks,
except for one, which was for 6 months, and the
overall conclusion suggests that corticosteroids
are effective in the management of OLP and are
unlikely to cause serious side effects (Al-Hashimi
et al. 2007). There were no studies determining if
adhesive vehicles are better than mouth rinses.
However, empirical evidence seems to suggest
Oral Lichen Planus
that mouth rinses are of value in patients with
widespread symptomatic OLP where the lesions
are not easily accessible to the placement of
ointments or gels. The evidence also suggests
that higher potency corticosteroids, such as
clobetasol, are probably more effective
(Al-Hashimi et al. 2007). There was insufficient
evidence regarding different dosages, formula-
tions, or modes of delivery of topical steroids
(e.g., paste, spray, mouthwash) to make an
evidence-based recommendation (Al-Hashimi
et al. 2007).
The greatest obstacle in using topical cortico-
steroids in the mouth is the lack of adherence to
the mucosa for a sufficient length of time. For this
reason, some investigators prefer using topical
corticosteroids in adhesive pastes although there
is no data that topical steroids in adhesive bases
are more effective than as base preparations
(Lo Muzio et al. 2001). Elixir forms of corticoste-
roids, such as dexamethasone, triamcinolone, and
clobetasol, have been used as an oral rinse for
patients with diffuse oral involvement or for
elderly patients who may find it technically diffi-
cult to apply medication to various active loca-
tions of the oral cavity. Careful consideration
should be given to the vehicle as unlike skin
compounds, which have been well studied, clini-
cal trials that have compared the strength of corti-
costeroids in various bases in the oral cavity are
generally lacking (Eisen et al. 2005).
Few serious side effects arise with topical cor-
ticosteroids as they are generally well tolerated.
Side effects reported include secondary
candidosis, nausea, oral use not tolerated, refrac-
tory response, mucosal atrophy, oral dryness, sore
throat, bad taste, delayed healing, and systemic
absorption (Savage and McCullough 2005;
Thongprasom and Dhanuthai 2008).
Given the high rate of commensal oral yeast
carriage in the community, it is expected that some
patients will develop a secondary erythematous
candidosis or pseudomembranous candidosis
(thrush) (Thongprasom and Dhanuthai 2008). As
many as one-third of OLP patients treated with
topical corticosteroids have been reported to
develop secondary candidosis (Vincent et al.
1990) which necessitates treatment or instituting
27
antifungal therapy before the patient begins using
topical steroids. Many of these patients can be
identified prior to commencing corticosteroids
and preventive treatment initiated coincident or
immediately prior to the initial applications. Com-
mon conditions that have been proposed to predis-
pose to candidal overgrowth include xerostomia;
systemic and/or topical use of antibiotics, cortico-
steroid asthma inhalants, prostheses, and cigarette
smoking (Savage and McCullough 2005).
Development of candidosis often leads to
immediate interruption to treatment, prolonged
and amplified morbidity, additional treatment for
the infection, delayed management of the original
condition, and clouding of the baseline pathosis
present. Wherever possible, anticipation and pre-
vention are preferable to a reactive response.
A refractory response, described by some as
tachyphylaxis, is characterized by decreasing effi-
cacy of corticosteroids during continued treatment
(Hengge et al. 2006) and may result from a num-
ber of areas including poor patient compliance;
inappropriate instruction and patient use; inappro-
priate application, for example, a carrier may be
helpful for the gingiva; agent of insufficient
potency; incorrect diagnosis; and failure to
remove any local cause, for example, a corroded
amalgam restoration causing a OLR (Savage and
McCullough 2005).
Systemic absorption has been reported, and it
is thought that absorption of small amounts
through the oral mucosa can take place, but clin-
ical experience and laboratory studies have shown
this not to be of clinical significance in almost all
cases (Savage and McCullough 2005).
Interestingly, although systemic absorption
and adrenal suppression were reported with
long-term use of superpotent corticosteroids for
chronic skin diseases (Levin and Maibach 2002),
this does not seem to be the case with oral corti-
costeroids used for OLP (Thongprasom and
Dhanuthai 2008). Exceptions arise, and this is an
issue that should receive consideration with par-
ticular patient groups along with the occasional
idiosyncratic response. Patients with medical con-
ditions that are of particular concern include dia-
betes, hypertension, and tuberculosis. Steroid
mouth rinses in patients with extensive areas of
28
disease and excessive and unmonitored usage are
also a concern.
Therefore, careful and frequent follow-up
examinations are necessary especially with
chronic use of topical corticosteroids. Temporary
burning or stinging at the site of application has
also been reported with triamcinolone acetonide
0.1% ointment (Laeijendecker et al. 2006).
In general, it has been recommended that ther-
apy should be initiated with a potent preparation
to achieve a rapid response, particularly in erosive
OLP lesions, and then lowering the strength with
healing, and eventually once the disease becomes
inactive and there is either an absence of lesions or
the presence of only white reticular lesions, therapy
may be temporarily discontinued (Eisen et al. 2005).
For intractable erosive OLP lesions,
intralesional injections of hydrocortisone, dexa-
methasone, triamcinolone acetonide, and methyl-
prednisolone have been used (Eisen et al. 2005).
Frequent injections of steroids, however, are pain-
ful, not invariably effective, and may result in an
unwanted systemic dose (Eisen et al. 2005).
Calcineurin Inhibitors
Calcineurin inhibitors are microbially derived
immunosuppressive agents that have been primar-
ily used in transplant medicine and in the treat-
ment of immune-mediated diseases with the
principle agents being tacrolimus, pimecrolimus,
and cyclosporine (Al Johani et al. 2009).
Calcineurin inhibitors bind to different cyto-
plasmic proteins of T lymphocytes (cyclosporine
to cyclophilin, tacrolimus, and pimecrolimus to
FK506-binding protein) to form complexes that
in turn inhibit calcineurin leading to suppression
of transcription and production of many cyto-
kines. Calcineurin inhibitors have been suggested
to be of clinical benefit in the management of
some immunologically mediated oral mucosal
disorders including OLP (Al Johani et al. 2009).
There are now numerous reports of the efficacy
of calcineurin inhibitors in the management of
OLP, and effectiveness has been assessed via
open-label prospective studies, randomized trials,
retrospective studies, case series, and described in
several case reports (Lodi et al. 2005; Al-Hashimi
et al. 2007; Al Johani et al. 2009). Initial studies
M.J. McCullough et al.
focused on patients with symptomatic OLP that
had not responded to topical corticosteroids or
who were at risk of adverse side effects from
corticosteroids. In their review, Al-Hashimi et al.
(2007) assessed four studies regarding cyclospor-
ine use for OLP (three used 500 mg mouthwash
and one used adhesive gel form). In all of the
studies, the side effects were minimal and mainly
consisted of a transient burning sensation, bad
taste, and high cost. In OLP patients, systemic
absorption is probably low, and most studies did
not detect cyclosporin in peripheral blood. The
results of all of the studies showed a marked
improvement in the oral symptoms. However,
cyclosporine mouth rinse was not significantly
better than 1% triamcinolone paste in a controlled,
randomized prospective trial that involved
13 OLP patients randomly assigned to treatment
with cyclosporine rinse or triamcinolone paste for
6 weeks (Sieg et al. 1995).
In general, cyclosporin can be an alternative to
conventional treatments for initial control of OLP.
However, it should not be considered as a first
drug of choice because of the high cost of long-
term treatment and the availability of effective
alternatives. Severe side effects of systemic cyclo-
sporin, such as hypertension and nephrotoxicity,
preclude its long-term use for OLP (Lodi
et al. 2005).
Tacrolimus is a macrolide immunosuppressant
derived from Streptomyces tsukubaensis. It is a
relatively selective inhibitor of calcineurin and
was initially developed as a systemic agent to
lessen allograft rejection. Tacrolimus has the abil-
ity to inhibit T-cell activation at 10–100 times
lower concentration than cyclosporin. Notably,
topical tacrolimus seems to penetrate skin better
than topical cyclosporin (Lodi et al. 2005; Al
Johani et al. 2009). Formulated for topical appli-
cation in the management of atopic dermatitis
(AD), it was approved in 2000 by the United
States Food and Drug Administration (FDA) to
be used in moderate to severe AD for patients
older than 2 years. Topical tacrolimus has proven
to be of benefit in the treatment of other disorders
including cutaneous psoriasis, contact allergy,
corticosteroid-induced rosacea, pyoderma
gangrenosum, alopecia areata, mucocutaneous
Oral Lichen Planus
LP, and GVHD (Al Johani et al. 2009). Topical
tacrolimus is available in different concentrations
(0.03%, 0.1%).
Systemic tacrolimus is substantially less
expensive and 10–100 times more potent than
cyclosporine, even though relative potency of
topical preparations has never been evaluated.
Tacrolimus used topically can control symptoms
and significantly improve refractory erosive OLP
(Hodgson et al. 2003). Local irritation is the most
common adverse effect reported (Lodi et al. 2005;
Al Johani et al. 2009). Other side effects include
transient taste disturbance and sore throat.
Tacrolimus ointment 0.1% was shown to be well
tolerated and appeared to be effective in erosive
OLP that did not respond to topical steroids in a
small cohort of six erosive OLP (Morrison et al.
2002). Although topical tacrolimus is effective
and well tolerated, some OLP patients have
noted flare-ups soon after stopping the treatment.
The treatment of chronic erosive oral LP with low
concentrations of tacrolimus was found to yield a
rapid and important palliative effect in an open-
label prospective study that included eight erosive
OLP with 6 months of treatment; however, all
patients relapsed after 12-month follow-up (Oliv-
ier et al. 2002). Currently, there remains little
evidence demonstrating that tacrolimus is notably
superior to topical corticosteroids for the treat-
ment of OLP (Al Johani et al. 2009).
Pimecrolimus is derived from the macrolide
ascomycin and shares the same cellular binding
protein (FK506-binding protein-12) as tacrolimus
and blocks the transcription of cytokines by
inhibiting the calcineurin pathway. Topical
pimecrolimus is a cream developed specifically
for the treatment of AD and approved for the
treatment of patients with mild to moderate AD
disease in patients older than 2 years. There is
currently limited data on the potential use of topical
pimecrolimus for the treatment of oral mucosal
disease, with few reports suggesting it to be effec-
tive in the management of symptoms and erosions/
ulcerations of OLP (Dissemond et al. 2004).
In a recent study, Arduino et al. (2014) found
no difference between pimecrolimus 1% cream
and tacrolimus 0.1% ointment in managing recal-
citrant atrophic-erosive OLP in an 8-week
29
randomized, double-blind controlled trial,
followed by a 6-month follow-up period in
30 unresponsive OLP patients. Both agents were
effective in inducing clinical improvement; how-
ever, pimecrolimus showed better stability in ther-
apeutic effectiveness with statistically significant
higher number of patients (10 vs. 4) not requiring
any further treatment at the end of the follow-up
period.
The theoretical increased risk of developing
malignancy with use of either tacrolimus or
pimecrolimus has been raised with the FDA; in
the USA “Black Box” warning attached to these
agents is based on theoretical increased risk of
malignancy (SCC and lymphoma) in patients
using these agents for cutaneous psoriasis. In a
recent case report of a patient with OLP, the top-
ical use of tacrolimus 0.1% was suggested to be
the cause of the development of an SCC of the
tongue (Becker et al. 2006). Therefore, some
authors believe that the use of these agents should
be restricted and patients should be made aware of
these concerns (Al-Hashimi et al. 2007). On the
other hand, other researchers find that although
systemic tacrolimus may increase the risk of
malignancy, there is no strong evidence that top-
ical application of tacrolimus is associated with
such an increased risk (Al Johani et al. 2009). In
support of this view, a recent case-control study
that involved 294 patients did not find any
increased risk of lymphoma in patients with AD
treated with topical calcineurin inhibitors
(Arellano et al. 2007).
Overall, there remains little information of the
carcinogenic potential of tacrolimus or
pimecrolimus, and the new recommendations from
the European Medicines Agency state that the ben-
efits of these calcineurin inhibitors outweigh the
risks. The European Medicines Agency, however,
recommends intermittent use of topical tacrolimus
with the lowest strength possible and only for short
periods of time (Al Johani et al. 2009).
Retinoids
Systemic and topical forms of retinoids have been
used in the treatment of OLP (Lodi et al. 2005;
Al-Hashimi et al. 2007). Topical tretinoin or isotret-
inoin has been used to treat OLP, particularly
30
atrophic-erosive forms, with considerable improve-
ment (Scardina et al. 2006), but retinoids often cause
adverse effects and are less effective than topical
corticosteroids (Scully and Carrozzo 2008).
Topical Antifungal Therapy in OLP
The role Candida plays in the symptomatology of
OLP is currently unknown. Based on the current
evidence, a question therefore arises as to whether
antifungals are required to treat symptomatic OLP
along with corticosteroids, not only prevent sec-
ondary candidosis and the symptoms associated
with this but also as a prophylactic treatment to
reduce Candida spp. overgrowth and the associ-
ated factors which may encourage a carcinogenic
event. A randomized double-blinded clinical trial
undertaken by Lodi et al. (2007) with 35 patients
reviewed the efficacy of topically applied
clobetasol propionate with and without topical
miconazole in patients with symptomatic OLP.
Results showed significant improvement in both
the test ( p = 0.0020) and control ( p < 0.001)
groups, and it was concluded while miconazole
prevented secondary candidosis, which occurred
in 30% of control subjects; however adjunctive
topical antifungal treatment did not affect the effi-
cacy of treatment or improve outcomes such as
pain or lesion extension (Lodi et al. 2007). Due to
the current lack of controlled studies and literature
in this particular area, recent systemic review by
Lodi et al. (2012) and Cochrane review by
Thongprasom et al. (2011) concluded that there
is currently insufficient evidence to determine
whether adjunctive antifungal therapy is effective
in the treatment of oral lichen planus
(Thongprasom et al. 2011; Lodi et al. 2012).
Systemic Drug Treatment
Several studies have reported that systemic corti-
costeroids are the most effective treatment for
OLP; however, a comparative study that involved
a total of 49 OLP patients did not find differences
in response between systemic prednisone (1 mg/
kg/day) with topical clobetasol in an adhesive
base (n = 26) and topical clobetasol alone
M.J. McCullough et al.
(n = 23) after a mean follow-up period of
36 months (Carbone et al. 2003). Complete remis-
sion was achieved in 68% of the prednisone group
and 705 of the topical clobetasol group
(P = 0.94).
Systemic corticosteroids are, therefore, usually
reserved for cases where topical approaches have
failed, where there is recalcitrant, erosive, or ery-
thematous OLP, or for widespread OLP when the
skin, genitals, esophagus, or scalp is also involved
(Al-Hashimi et al. 2007; Scully and Carrozzo
2008). Prednisolone 40–80 mg daily is usually
sufficient to achieve a response: its toxicity
requires that it should be used only when neces-
sary, at the lowest dose, and for the shortest time
possible with recommendation of (5–7 days) and
then withdrawn abruptly, or the dose should be
reduced by 5–10 mg/day gradually over
2–4 weeks (Scully and Carrozzo 2008). Adverse
effects are possible even with short courses but
may be minimized if patients can tolerate the same
total dose on alternate days.
Systemic calcineurin inhibitors are associated
with significant adverse effects including hyper-
tension, nephrotoxicity, and infections secondary
to immunosuppressive status of the patients which
correlated with the dosage, blood levels, and dura-
tion of therapy (Al Johani et al. 2009). Moreover,
systemic tacrolimus can increase the risk of malig-
nancy (e.g., oropharyngeal and skin cancers) by
suppressing immune surveillance and inhibiting
DNA repair and apoptosis (Yarosh et al. 2005).
Therefore, systemic calcineurin inhibitors are not
recommended for OLP treatment.
Miscellaneous Agents
Azathioprine
Azathioprine has been reportedly successful as a
“steroid-sparing agent” for cutaneous LP, and
there is limited published evidence suggesting it
may have a similar role in recalcitrant OLP
(Silverman et al. 1991). In general, the results
are no better than systemic steroids alone or sys-
temic steroids in conjunction with topical steroids
(Lodi et al. 2005b).
Oral Lichen Planus
Dapsone
Dapsone has been used in the treatment of erosive
OLP with some benefit (Beck and Brandrup
1986). It should be considered in resistant cases,
particularly when severe erosive lesions are pre-
sent. Significant adverse effects such as hemolysis
have been reported, and thus the use of dapsone in
the treatment OLP is generally not recommended
(Matthews et al. 1989).
Mycophenolate Mofetil
Mycophenolate has shown promise as an alterna-
tive to azathioprine as an immunomodulatory
agent with a better safety profile in the manage-
ment of graft rejection in organ transplant recipi-
ents, and GVHD, and therefore may be a
candidate for use in recalcitrant OLP (Eisen
2003). In a recent retrospective review of clinical
responses of ten patients with severe ulcerative LP
(vulvovaginal with gingival involvement, n = 8;
penogingival, n = 1; oral, n = 1) treated with
mycophenolate, Wee et al. (2012) showed remis-
sion in six patients, well-controlled disease in one,
and partially controlled in the other three. The
mean duration for mycophenolate treatment was
3.7 years, and the mean follow-up was 4.2 years.
Mycophenolate was well tolerated in all patients
except in two who reported mild headaches and
tiredness (Wee et al. 2012).
Aloe vera
Aloe vera (AV) is a cactus-like plant that belongs
to the Liliaceae family. The reported pharmaco-
logical actions of AV include anti-inflammatory,
antibacterial, antiviral, and antifungal properties
and hypoglycemic effects (Yagi et al. 2002). Top-
ical Aloe vera is an emerging new modality in the
treatment of OLP that has been recently investi-
gated. In a randomized double-blind study, AV
mouthwash significantly improved the oral qual-
ity of life for 32 OLP patients over a period of
3 months as compared to a placebo group
(Salazar-Sanchez et al. 2010). In another study,
comparable effects of AV mouthwash were
reported when compared to 0.1% triamcinolone
acetonide paste in a group of OLP patients (n = 23
each) in terms of VAS of pain, burning sensation,
clinical presentation, and healing of the OLP
31
lesions after 2 months from the beginning of treat-
ment (Mansourian et al. 2011).
According to a recent Cochrane review
(Thongprasom et al. 2011), there is weak evidence
from two placebo-controlled RCTs, using differ-
ent formulations, that AV may be associated with
a reduction in pain in OLP (Choonhakarn et al.
2008; Salazar-Sanchez et al. 2010). It should be
emphasized that the above trials used different AV
formulations and the amount of active drug sub-
stance in AV varies depending also on the age of
the plant, the growing and harvesting conditions,
the parts of the plant, and the extraction methods
used. The great level of variability could have
affected the results of the published studies and
represents a challenge for future research
(Thongprasom et al. 2013).
Biologics
The management of various immune-mediated
disorders has changed dramatically by the advent
of biologic therapies. Biologics are designed by
recombinant biotechnology to target particular
steps in the pathogenesis of immunoinflammatory
diseases. Structurally, biologics include receptor
fusion proteins, monoclonal antibodies, and
recombinant cytokines. Functionally, biologics
can be divided into T-cell or cytokine modulators
(Zhang et al. 2011). Various immunobiologics
have been recently applied in the treatment of
psoriasis and rheumatic diseases as biologic
immunomodulators may represent a more effec-
tive and targeted approach than conventional
treatment modalities (Shirota et al. 2008).
Various diseases including Behcet’s disease,
recurrent aphthous stomatitis, benign mucous
membrane pemphigoid, and LP are considered
potential candidates for the use of biologics
(O’Neill 2008).
After the pathogenesis of OLP has been thor-
oughly investigated, several biologic agents,
especially those targeting T cells such as TNF-α
inhibitors, are suggested as a future alternative to
steroid therapy. However, possible reactions and
side effects will always be a major concern (Zhang
et al. 2011).
TNF-α inhibitors currently available are
etanercept, infliximab, and adalimumab, all of
32
which are FDA approved for psoriasis. The clin-
ical feasibility has been demonstrated not only by
a successful treatment of LP with etanercept
(Yarom 2007) but also by the efficacy of
adalimumab for the treatment of cutaneous and
OLP (Chao 2009). Moreover, there are several
ongoing clinical trials to evaluate the safety and
effectiveness of etanercept in treating oral and
cutaneous LP. According to a recent review by
O’Neill and Scully (2013), the best data, although
limited, are for the use of the T-cell modulator
alefacept in OLP. Limitations on future studies
with such agents include the need for continuous
or intermittent use of anti-TNF-α therapy for long-
term control of OLP and the fact that TNF-α
blockers have the potential for initiating lichenoid
eruptions (Asarch et al. 2009).This possibly
accounts for the rarity of reports of use of TNF
antagonists in LP to date and may be a barrier to
further use. Additional concerns center around the
potential for reactivation of viral infections with
concern about those patients with LP who have
concomitant HCV infection (Lodi et al. 2010).
The potential risk of malignancy in LP and those
reports of the development of oral cancer in
patients receiving TNF-α blockers may be an
additional reason to use these agents with caution
(O’Neill and Scully 2013).
Other Agents and Treatment Modalities
Other agents have been suggested for OLP treat-
ment but with weaker evidence. These include
levamisole, amitriptyline, amlexanox, hyaluronic
acid, thalidomide, ignatia, curcuminoids, lyco-
pene, phototherapy, lasers, surgery, and cryosur-
gery (Lodi et al. 2005; Al-Hashimi et al. 2007;
Thongprasom et al. 2013).
In conclusion, it appears that although a wide
range of treatment options is available for patients
with OLP, the level of clinical efficacy is incon-
sistent, and individualized protocols are required
in cases with recalcitrant OLP.
Recently, Lodi et al. (2012) reviewed 28 ran-
domized controlled trials (RCTs) in the context of
interventions for OLP. Although topical corticoste-
roids are considered to be the first-line treatment,
no RCTs were identified that compared topical
M.J. McCullough et al.
corticosteroids with placebo in patients with symp-
tomatic OLP. From the 28 trials included in this
systematic review, the wide range of interventions
compared means there is insufficient evidence to
support the superior effectiveness of any specific
treatment (Lodi et al. 2012).
Follow-up
Patient follow-up ranging from every 2 months to
annually is accepted as part of long-term care for
patients with OLP largely to screen for changes
that may indicate malignant transformation
(Mignogna et al. 2006). At a minimum, annual
monitoring is recommended (Al-Hashimi et al.
2007; Parashar 2011) and favorably two to four
reviews (Scully et al. 1998; Mattsson et al. 2002;
van der Meij et al. 2007). More frequent exami-
nations are recommended for patients with OLL
with dysplasia.
If changes are noted in a lesion at follow-up
visits, then an additional biopsy or biopsies should
be performed and the follow-up intervals short-
ened (Ismail et al. 2007).
For those OLP patients who develop OSSC,
Mignogna et al. (2002) proposed the strict follow-
up of patients with oral and neck examinations
every 2 months during the 5- to 9-month period
after the diagnosis of oral carcinoma, when the
risk of metastasis or second primary tumor is
maximum. The same authors subsequently
reported that a program of three follow-up exam-
inations a year enables detection of malignant
transformation in early or microinvasive
intraepithelial states, which generally have a
very good prognosis (Mignogna et al. 2006).
Conclusion
LP is a common chronic inflammatory disease of
the skin and oral mucosa with an estimated prev-
alence of 0.5–2%. Although the cause of OLP is
unknown, it is thought to result from the complex
interplay of host, lifestyle, and environmental fac-
tors resulting in cell-mediated immune
Oral Lichen Planus
dysregulation. The oral appearance of OLP has
been described as six clinical subtypes seen indi-
vidually or in combination (reticular, plaque-like,
atrophic, erosive, papular, and bullous), with the
most common being reticular occurring bilaterally
in the posterior buccal mucosa.
Symptoms and signs can range from patients
being unaware of the disease, with lesions that are
completely asymptomatic as in reticular OLP, to
those experiencing mucosal sensitivity and burn-
ing and debilitating pain. Treatment generally
consists of the topical use of anti-inflammatory
agents for symptomatic relief. Malignant transfor-
mation of OLP remains a controversy and vari-
ably reported between 0% and 5%. Obviously
there is much that remains unknown regarding
oral mucosal lichen planus, such as the exact
cause, pathogenic mechanism involved, and pro-
cess by which malignant transformation occurs.
Further directed research is required so that we
may be able to best advise and treat our patients.
Cross-References
▶ Clinical Evaluation of Oral Diseases
▶ Clinical Immunology in Diagnoses of Maxillo-
facial Disease
▶ Cutaneous Pathology of the Head and Neck
Region
▶ Gingival Pathology
▶ Interface Between Oral and Systemic Disease
▶ Laboratory Medicine and Diagnostic Pathology
▶ Normal Variation in the Anatomy, Biology and
Histology of the Maxillofacial Region
▶ Oral and Maxillofacial Fungal Infections
▶ Oral Manifestations of Systemic Diseases and
their Treatments
▶ Oral Mucosal Malignancies
▶ Oral Ulcerative Lesions
▶ Oral Vesicular and Bullous Lesions
▶ Orofacial Pain in Patients with Cancer and
Mucosal Diseases
▶ Pharmaco-Therapeutic Approaches in Oral
Medicine
▶ White and Red Lesions of the Oral Mucosa
33
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