Oral Lichen Planus - Fakultas Kedokteran Gigi - Beranda · 2020-07-03 · Oral lichen planus •...

Oral Lichen Planus

Michael J. McCullough, Mohammad S. Alrashdan, and NicolaCirillo

AbstractLichen planus (LP) is a chronic, inflammatory,mucocutaneous, immune-mediated conditionwith variable clinical presentations. Oral lichenplanus (OLP) is the oral variant and affectsabout 1–2% of the general adult populationwith characteristic relapses and remissions.OLP is about twice as common in females asin males. The most commonly involved oralsites are the buccal mucosa, lateral surfaces ofthe tongue, and gingivae, respectively. Sixclinical patterns of OLP are described in liter-ature: reticular, plaque-like, erythematous, ero-sive/ulcerative, papular, and bullous. Helperand cytotoxic T lymphocytes, in addition toantigen-presenting cells, represent the keycells in the inflammatory infiltrate in OLP and

play an essential role in its pathogenesis. Thediagnosis of OLP is usually made by clinicaland histological examinations. Lesions similarto OLP may develop as a reaction to dentalrestorative materials or systemic medicationsor conditions and are called oral lichenoidreactions (OLR). OLP and OLR may collec-tively be referred to as oral lichenoid lesions(OLLs). Management of symptomatic OLLsvaries considerably and ranges from elimina-tion of precipitating factors – local or systemicto long-term pharmacological interventions,mainly with topical immunosuppressants, cor-ticosteroids in particular. In the light of theongoing debate regarding the malignant trans-formation potential of OLLs, a long-term fol-low-up protocol is essential.

KeywordsOral lichen planus • Oral lichenoid lesions •Oral lichenoid reactions • Malignanttransformation

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Genetic Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Infectious Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Psychological Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Trauma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4Systemic Associations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

M.J. McCullough (*)Oral Anatomy, Medicine, and Surgery Section, MelbourneDental School, Faculty of Medicine, Dentistry & HealthSciences, The University of Melbourne, Carlton, VIC,Australiae-mail: [email protected]

M.S. AlrashdanFaculty of Dentistry, Department of Oral Medicine andOral Surgery, Jordan University of Science andTechnology, Irbid, Jordane-mail: [email protected]

N. CirilloMelbourne Dental School and Oral Health CRC, Faculty ofMedicine, Dentistry and Health Sciences, The Universityof Melbourne, Carlton, VIC, Australiae-mail: [email protected]

# Springer International Publishing AG 2017C.S. Farah et al. (eds.), Contemporary Oral Medicine,DOI 10.1007/978-3-319-28100-1_14-1

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Pathogenesis of OLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6The Immunology of the Oral Cavity . . . . . . . . . . . . . . . . . . 6Pathogenic Mechanisms of OLP . . . . . . . . . . . . . . . . . . . . . . 7

Clinicopathologic Features . . . . . . . . . . . . . . . . . . . . . . . . . . 13Clinical Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Signs, Symptoms, Clinical Behavior and OLP

Scoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Histopathology of OLP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Oral Lichenoid Reactions (OLR) . . . . . . . . . . . . . . . . . . . . . 16Cutaneous Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18Other Mucosal Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Malignant Potential of OLP . . . . . . . . . . . . . . . . . . . . . . . . . 19OLL and Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21Tumors Developing in OLP and their

Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Patient Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25Topical Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26Systemic Drug Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Miscellaneous Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30Follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Introduction

The term lichen planus (LP) is derived from theGreek word leichen meaning tree moss and theLatin planus meaning flat. Erasmus Wilson firstdescribed the condition LP in 1869, as a chronicinflammatory disease affecting the skin, scalp,nails, and mucosa, with possible rare malignanttransformation (Farhi and Dupin 2010). LP mayinvolve the hair follicles (lichen planopilaris,resulting in scarring alopecia), nails, esophagus,and, more seldom, the eyes, urinary tract, nasalmucosa, and larynx (Parashar 2011).

The oral variant, oral lichen planus (OLP), is achronic inflammatory disease affecting the oralmucosa with characteristic relapses and remis-sions (Scully et al. 1998; Eisen et al. 2005; Lodiet al. 2005a). While cutaneous lesions of LP aregenerally self-limiting and pruritic, oral lesionsare commonly chronic, non-remissive, and canbe a source of morbidity (Scully et al. 1998).

The diagnosis of OLP is usually made by clin-ical and histological examinations. However, inclassical lesions (bilateral, reticular pattern), it is

possible to make a diagnosis based on their clin-ical appearance alone (Epstein et al. 2003). Addi-tionally, there is a spectrum of oral lichenoidlesions (OLLs) that may confuse the differentialdiagnosis. These include lichenoid contactlesions, lichenoid drug reactions, and lichenoidlesions of graft-versus-host disease. Systemicmedications, such as nonsteroidal anti-inflammatory drugs, antihypertensives, and oralhypoglycemics, can contribute to the develop-ment of oral lichenoid reactions (OLRs) (Ismailet al. 2007). Dental restorative materials, includ-ing amalgam, gold, and nickel, may also berelated to localized OLRs in a number of patients(Epstein et al. 2003).

Treatment is not always necessary, unlessOLLs are symptomatic (Scully et al. 1998). Man-agement of symptomatic OLLs varies consider-ably and ranges from elimination of precipitatingor provoking local and systemic factors, psycho-social interventions, to long-term pharmacologi-cal therapies. Thus, although OLP localizes to theoral cavity, there are broader implications in termsof patient management that warrant careful con-sideration. The ongoing controversy as to whetherOLP is associated with an increased risk of malig-nant transformation adds further complexity tothis disease.

Epidemiology

The estimated prevalence of OLP in general adultpopulation is 0.5–2% (Scully et al. 1998; Eisenet al. 2005). However, because of a lack of stan-dardized approaches to the clinical diagnosis ofOLP and OLL, it is difficult to draw accuratefigures about the prevalence of OLP. In a demo-graphic study from Sweden, 20,333 people aged15 and above were examined for signs of OLP.The prevalence reported was 1.9%, 1.6% in men,and 2.2% in women (Axell and Rundquist 1987).Another demographic study from India showed aprevalence of 2.6% (Murti et al. 1986). A reportfromMalaysia showed a relatively low prevalenceof 0.38% (Zain et al. 1997).

There is a slight female predisposition (female/male sex ratio is 1.5–2:1), and the age of onset is

2 M.J. McCullough et al.

generally between 30 and 60 years (Scully et al.1998; Al-Hashimi et al. 2007; Farhi and Dupin2010). However, there have been case reports ofOLP occurring in children, with a 17% prevalenceof oral involvement in a population of 100 childrendiagnosed with LP at a mean age of 8.7 years inone report (Kanwar and De 2010).

Genital and cutaneous LP are associated withapproximately 20% and 15% of OLP cases,respectively, while it is estimated that OLP occursin 70–77% of patients with cutaneous LP (Scullyet al. 1998; Farhi and Dupin 2010; Kanwar and De2010).

Etiology

OLP is not a classical autoimmune disorder, andthe precise etiology of this condition is unknown.However, given that cell-mediated immunedysregulation targeting the stratified squamousepithelia has been shown to be associated withthe pathogenesis of OLP (Epstein et al. 2003;Eisen et al. 2005; Lodi et al. 2005a), it is possiblethat a LP-specific epidermal antigen is present insome epithelial cells. The nature of the antigen,however, remains uncertain. Several predisposingfactors have been reported to be associated withOLP and OLLs.

Genetic Background

Genetic background seems to play a role in OLPpathogenesis as several familial cases have beenreported (Bermejo-Fenoll and Lopez-Jornet2006); however the association has not been con-sistent. In terms of HLA associations, an increasein HLA-B15, Bw57, B5, B7, BX, DR2 and adecrease in the frequency of HLA-DQ1, DR4,and B18 has been noted for OLP (Roitberg-Tambur et al. 1994). On the other hand, in acomprehensive 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 cytokineshave been postulated to be associated with the

clinical presentation of LP. Interferon-gamma(IFN-γ) UTR 5644 genotype frequencies showeda 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 beensuggested that genetic polymorphism of the firstintron of the promoter gene of IFN-gamma maybe an important risk factor to develop oral lesionsof LP, whereas an increase in the frequency of308A TNF-alpha allele may best contribute tothe development of additional skin involvement.

More recently, the concept that a particulargenetic background may be important in a subsetof patients with OLP has been presented(Carrozzo et al. 2011). In particular, this studysuggested that those patients who had both OLPand chronic hepatitis C infection may well haveparticular HLA-Cw* alleles (Carrozzo et al.2011).

Nevertheless, the overall statement that OLP isa genetically determined disease has not beenconfirmed, and further studies in different geo-graphic areas are required.

Infectious Agents

Many infectious agents, principally viruses, havebeen studied in association with OLP, but theevidence is generally sparse. Other infectiousagents, such as Helicobacter pylori, were alsosuggested to have a link to OLP by some authors(Shimoyama et al. 2000).

The viruses for which an association with OLPhas been suspected can be classified in twogroups: (1) viruses for which an association withOLP has been anecdotally suggested and(2) viruses for which there is abundant documen-tation of an association with OLP, although withmarked geographic disparities (discussed in sec-tion “Systemic Associations”).

Varicella zoster virus (VZV), Epstein-Barrvirus (EBV), cytomegalovirus (CMV), humanherpesvirus 6 (HHV6), human papillomavirus(HPV), and human immunodeficiency virus(HIV) have all been postulated in different studiesto have an association with an increased incidence

Oral Lichen Planus 3

of OLP, yet definitive evidence for the associationis lacking (Lodi et al. 2005a; Farhi and Dupin2010).

For example, the receptor for EBV (CD21) wasshown to be upregulated in OLP, and a signifi-cantly higher optometric density of EBV anti-earlier antigen (EA) IgG positivity has beenreported in a sample of OLP patients (n = 22)compared with controls (n = 22), despite no dif-ference in the frequency of both EBV IgG andIgM for EA and nuclear antigen-1 (EBNA)(Pedersen 1996).

In summary, while association between OLPand infectious agents has been reported, at presentthere is no evidence for a causative role of thesemicroorganisms in OLP.

Psychological Factors

Psychological factors are thought to play a role inthe pathogenesis of OLP. A group of OLP patients(n = 9) exhibited higher levels of anxiety, greaterdepression, and increased vulnerability to psycho-logical disorders, as opposed to a group of20 healthy controls (Soto Araya et al. 2004).

In another study that involved 100 OLPpatients, those with erosive LP were shown toexhibit higher depression scores than patientswith nonerosive LP (Rojo-Moreno et al. 1998).In addition to the chronic discomfort that canresult in stress, patients with OLP were shown tobe concerned about the possibility of malignancy,the contagious nature of the disease, and the lackof available patient educational materials(Burkhart et al. 1997).

Exacerbations of OLP have been linked toperiods of psychological stress and anxiety insome studies (Rojo-Moreno et al. 1998).

In a study that involved 40 OLP patients(20 reticular and 20 erosive OLP) assessed against25 healthy controls using the psychological Min-nesota Multiphasic Personality Inventory(MMPI)-202 test, Ivanovski et al. hypothesizedthat prolonged emotive stress in many OLPpatients may lead to psychosomatization(as shown by significantly higher mean scores ofinternalization ratio index in OLP groups) which

in turn may contribute to the initiation and clinicalexpression of OLP (Ivanovski et al. 2005). How-ever, as a common issue in studies of this type, theauthors were unable to determine whether theobserved psychological alterations constitute adirect 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 correlatedand significantly higher than a control group(mean state anxiety level = 49 vs. 40, cortisollevels = 1.46 vs. 0.93 μg/dl) (Koray et al. 2003).

In conclusion, in spite of the presence of higherlevels of psychological stress and anxiety amongOLP patients, the question remains whether thepsychological factors contribute to the etiology ofOLP 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 etiologicalfactors may exert their effects (Scully et al. 1998).However, no studies were conducted to verify thishypothesis.

The Koebner phenomenon (isomorphicresponse), whereby OLP lesions develop inresponse to mechanical trauma, may partiallyexplain why OLP lesions develop commonly insites prone to trauma, i.e., the buccal mucosa orlateral 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 withhepatitis C, hypertension, diabetes, thyroid dis-ease, and graft versus host disease.

Hepatitis C Virus (HCV)Along with porphyria cutanea tarda andcryoglobulinemia, OLP is one of the three derma-tologic diseases that have been most frequentlyreported in patients infected with HCV (Farhi and


Dupin 2010). The first report appeared in 1991(Mokni et al. 1991) and suggested an associationbetween OLP and HCV seropositivity. Since then,the association has been well documented in someMediterranean 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 associationbetween OLP and HCV seropositivity could notbe demonstrated in France (Dupin et al. 1997), theUnited Kingdom (Ingafou et al. 1998), and incountries with high HCV prevalence, such asEgypt (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 LPpatients and in matched controls without LPyielded 25 relevant studies, including eight withonly OLP (Lodi et al. 2004). A significantlyhigher proportion of HCV seropositivity wasdocumented in patients with OLP, with an oddsratio (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 inGermany and the United Kingdom (OR 2.14,95% CI, 0.6–7.7). Three more recent independentmeta-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 instudies across the world, although the associationis more homogeneous in studies from East andSoutheast Asia and South America than in studiesfrom the Middle East and Europe (Baccagliniet 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 OLPpatients positive for HCV were compared to agroup of 144 OLP patients negative for HCV.HCV-related OLP group showed a significantlyhigher association with HLA class II alleleHLA-DR6 (52% vs. 18%), which may partiallyexplain the peculiar geographical heterogeneity ofthe association between HCV and OLP, probably

depending on the presence of certain HLA sub-types (Carrozzo et al. 2001).

Hypertension and Diabetes MellitusAlthough OLP patients do not seem to have anincreased risk of diabetes, diabetics who developOLP were reported to have an increased fre-quency of atrophic-erosive lesions, especiallyaffecting the tongue (Bagan et al. 1993). How-ever, this was not confirmed in any further studies.

An association between OLP, diabetesmellitus, and hypertension was first described byGrinspan in a small series of seven patients(Grinspan et al. 1966). The triad was later namedas Grinspan’s syndrome. Although Grinspan’ssyndrome may be seen clinically, the associationbetween the three conditions may represent acoincidental finding or probably an OLR to med-ications used to manage hypertension or diabetesrather than a true syndrome (Scully et al. 1998).

Thyroid DysfunctionThe association between OLP and thyroid dys-function was recently investigated in a retrospec-tive Finnish study that confirmed a link betweenOLP and hypothyroidism in particular (Siponenet al. 2010). This study compared data of 222 OLPpatients with 222 age- and sex-matched controlsand 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 betweenOLP and hyperthyroidism. Overall, more well-designed, large population-based studies arerequired to confirm whether an associationbetween 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 inabout 40–70% and will represent the leadingcause of death in such patients (Imanguli et al.2008).

Acute GVHD occurs within the first 100 daysof transplantation and comprises dermatitis, enter-itis, and hepatitis with immunosuppression andcachexia. Chronic GVHD develops after day


100 and comprises an autoimmune-like syndromecomparable to ulcerative colitis, primary biliarycirrhosis, Sjögren’s syndrome, rheumatoid arthri-tis, and lupus-like disease with glomerulonephri-tis. The skin is a primary target in chronic GVHDand exhibits either a lichenoid eruption orsclerodermatous changes (Lodi et al. 2005a).

Oral involvement occurs in 33–75% of patientswith acute GVHD and up to 80% of patients withchronic GVHD (Imanguli et al. 2008). Oral muco-sal GVHD resembles OLP both clinically andhistologically.

Squamous cell carcinoma (SCC) may developin oral and cutaneous chronic GVHD, as reportedin few case reports (Lodi et al. 2005b). Mostpatients who undergo allogeneic HSCT receivestem cells from MHC-identical donors. In thesepatients, GVHD is initiated by donor T cells thatrecognize a subset of host peptides called minorhistocompatibility antigens (miHAs). Althoughthe antigen specificity of LP and mucocutaneousGVHD is probably distinct, it is likely that theyshare similar immunological effector mechanismsresulting in T-cell infiltration, epithelial basementmembrane disruption, basal keratinocyte apopto-sis, and clinical disease (Lodi et al. 2005a).

The role of TNF-alpha as a major effectormolecule in GVHD has been confirmed in a num-ber of experimental systems. Importantly, neutral-izing anti-TNF-alpha antibodies have been shownto alleviate cutaneous and intestinal GVHD inboth mice and humans (Herve et al. 1992;Brown et al. 1999).

Pathogenesis of OLP

Much is still not known about theetiopathogenesis of OLP. OLP is characterizedby a chronic T-cell inflammatory infiltrate withbasal 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 thechronic disease state is currently unknown.There are multiple theories on OLP pathogenesisand the mechanisms that underpin the ongoing

chronic inflammatory process. In order to betterunderstand the pathobiological events that under-lie the development of OLP lesions, it is importantto recall some basic concepts of oral immunology.

The Immunology of the Oral Cavity

The oral cavity immune system consists of innateand adaptive immune system components. Theinnate immune system consists of all the immunedefenses that lack an immunologic memory(Delves and Roitt 2000). In the oral cavity theoral mucosa serves as a mechanical barrier tomicrobial colonization. Loss of tissue integrityplaces the oral cavity at risk of opportunisticmicrobial infection.

Saliva makes up another portion of the oralinnate immune system. Saliva is rich in waterand mucin that acts to provide a moist barrierthat helps to limit microbial colonization. It alsoconsists of numerous ions, such as bicarbonate,phosphate, etc., that neutralize pH and keep thesaliva supersaturated to prevent tooth deminerali-zation. Salivary antibodies, specifically secretoryIgA, exist in saliva and act as a first line of defenseby 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 consistsof phagocytic cells such as macrophages and neu-trophils. Macrophages are phagocytic cellsderived from monocytes, while neutrophils arepolymorphonuclear granulocytes. Both work todetect infections organisms and destroy infectiousorganisms through the process of phagocytosis(Aderem 2003). Eosinophils, basophils, andmast cells also constitute part of the oral innateresponse working to protect against parasites(eosinophils) while also being involved in thehost allergic reactions. Mast cells especially are


thought to play an important immunological rolein OLP (Zhou et al. 2002). Natural killer(NK) cells target and destroy tumor cells as wellas viruses as part of the oral innate immuneresponse by recognizing peptides presented inthe context of major histocompatibility complex(MHC) class I molecules. The complement sys-tem is a series of 20 serum glycoproteins that formmembrane attack complexes; opsonization andchemoattractants work to upregulate phagocytosisand mobilize the host immune system to clearpathogens (Delves and Roitt 2000).

The adaptive immune response in the oral cav-ity consists of antigen-presenting cells (APC), Tcells and B cells. The main difference between theadaptive and innate immune system is the adap-tive immune system’s ability to tailor the responseto suit different pathogens as well as rememberpast microbial and viral challenges. The adaptiveimmune system also uses MHC molecules, spe-cifically MHC I and II, to distinguish self fromnonself to allow for a targeted immune response(Delves and Roitt 2000). The APCs of the adap-tive immune system recognize foreign, nonhostproteins, known as antigens. APC of the adaptiveimmune system includes macrophages, B cells,dendritic cells, and Langerhans cells. Langerhanscells reside in the epidermis with the highestcounts found in the nonkeratinized oral mucosaltissues including the ventral tongue, soft palate,lip, and floor of mouth (Daniels 1984).Langerhans cells are thought to potentially playa 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 areterminally differentiated B lymphocytes), is toproduce immunoglobulins, specifically IgA, IgG,IgM, IgE, and IgD. Secretory IgA is the primaryantibody of the oral cavity found in present insaliva which acts as the first line of defense(Brandtzaeg 2007; Feller et al. 2013). The othermajor task of B cells is the production of memoryB cells whose function is to circulate through thebody and mount a rapid response against previ-ously recognized antigens (Delves and Roitt2000).

T cells are the major effector cell in cell-mediated immunity. They consist of helper Tcells (CD4+) which recognize MHC class II mol-ecules, cytotoxic T cells (CD8+) which recognizeMHC class I molecules present on all cells, regu-latory T cells which are essential for preventingautoimmune diseases while also limiting chronicinflammation, 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 promotingcellular (cytotoxic T-cell-mediated, via activationof TH1) or humoral (B-cell-mediated, via TH2activation) types of response. Cytotoxic T cellson recognition of a foreign antigen induce apo-ptosis in the infected cell. OLP is characterized byT-cell accumulation, specifically cytotoxic T-cellaccumulation, 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 inflammatoryprocess which defines the chronicity of OLP.

Pathogenic Mechanisms of OLP

The work of Sugerman and colleagues in the1990s and early 2000s in the field of OLP patho-genesis and disease mechanisms established thebasis 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 nonspecificones, which involve T cells and dendritic cellsactivated by specific (yet unknown) antigens andMMPs, cytokines and other immune cells,respectively.

A number of biochemical changes, includingaltered keratinocyte antigen expression andaltered keratinocyte function, have been previ-ously suggested to be early events in OLP patho-genesis (Holmstrup and Dabelsteen 1979). It wasoriginally proposed that following alteredkeratinocyte antigen expression, a CD8+ T cellon routine surveillance in the epithelium mayencounter the keratinocyte antigen by chance(“chance encounter” hypothesis). Alternatively,the CD8+ Tcell may be attracted to the epithelium


by keratinocyte-derived chemokines (“directedmigration” hypothesis) (Sugerman et al. 2002).

The migration of activated T cells in the OLPinfiltrate to oral epithelium can be mediated byintercellular and vascular adhesion molecules(ICAM-1 and VCAM) (Eisen et al. 1990).Upregulation of ELAM-1, ICAM-1, andVCAM-1, especially by endothelial cells in thesubepithelial vascular plexus in OLP, was demon-strated in an immunohistochemical study thatassessed various endothelial-associated adhesionmolecules in frozen sections from 12 OLP casesand nine normal controls (Regezi et al. 1996).Biopsy specimens from patients with OLP con-sistently showed significantly higher levels ofexpression of the three molecules. The prolongedoverexpression of adhesion molecules on endo-thelial cells may represent the molecular basis forthe so-called reactive isomorphism seen in OLPpatients. Previous studies have shown that in OLPthere is an upregulation of epithelial basementmembrane extracellular matrix (ECM) proteins,including collagen types IV and VII, laminin andcertain integrins – possibly serving as pathwaysfor 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 tissuedestruction in OLP (Sugermann et al. 1996).

The cell-mediated immunological responseseen in OLP, possibly initiated by endogenous orexogenous 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 evenis, at least in part, genetically controlled, andgenetic 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, Scullyand Carrozzo 2008).

TNF-α may stimulate the activation of nuclearfactor kappa B (NF-κB) whose increased expres-sion has been seen in OLP (Santoro et al. 2003).Because NF-κB translocation in keratinocytesmay induce the production of several

inflammatory cytokines, it could be partiallyresponsible for the characteristic, chronic courseof OLP similar to other chronic inflammatorydiseases such as psoriasis and rheumatoid arthritis(Eisen et al. 2005).

The cellular and molecular constituents ofthese pathogenic events will be discussed in detailin the following paragraphs.

Putative OLP AntigensWhile OLP is not considered to be a typical auto-immune disease, it is believed that one or moreepithelial antigens are present in basalkeratinocytes. Antigens that are presented byMHC class II receptor are processed through anendosomal cellular pathway, while antigens thatare presented by MHC class I are processedthrough a cytosolic cellular pathway (Sugermanet al. 2002). Hence, the putative antigen presentedby MHC class II to CD4+ helper T cells in OLPmay differ from that presented by MHC class I toCD8+ cytotoxic T cells. Alternatively, a singleantigen may gain access to both the endosomaland cytosolic cellular pathways of antigen presen-tation (Sugerman et al. 2002; Roopashree et al.2010).

Whether one or more different antigens areinvolved in disease pathogenesis, it has beensuggested that simultaneous antigen presentationto CD8+ and CD4+ Tcells in the context of MHCclasses I and II, respectively, is required todevelop 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 ofOLP was introduced by Sugerman et al. (2002).The hypothesis is based on a theoretical interac-tion between CD8+ T cells and CD4+ T cellsthrough a “request cytotoxic activity” (RCA) cellsurface molecule expressed by CD8+ Tcells and aRCA receptor expressed by the CD4+ T cells toallow confirmation and initiation of cytotoxicactivity by CD8+ T cells. The hypothesis stressesthat this interaction can only take place after eachtype of the T-cell antigen receptors is engagedwith a related foreign antigen (Ag), i.e., Ag1 inthe context of MHC class I engaged by CD8+


T-cell antigen receptors and Ag2 in the context ofMHC class II engaged by CD4+ T-cell antigenreceptors. To date, sound experimental evidenceto support this theory is lacking.

Cell-Mediated Immunity

CD8+ T CellsAn early immunohistochemical study assessingthe lymphocytic infiltrate in OLP showed this tobe composed almost exclusively of T cells, andthe majority of T cells within the epithelium andadjacent to damaged basal keratinocytes wereactivated CD8+ lymphocytes (Kilpi 1988). CD8+ T cells were also co-localized with apoptotickeratinocytes in OLP lesions (Sugerman et al.2000). The dominant role of CD8+ T cells andCD4+ T cells in OLP pathogenesis was furtherconfirmed by the expression of the chemokinesCCR5 and CXCR3, known to be selectivelyexpressed by TH1, in the infiltrating lymphocytes,in addition to the CD8+ T-cell respective ligandRANTES/CCL5 and IP-10/CXCL10 (Iijima et al.2003).

Analysis of these previous data suggests thatCD8+ Tcells are involved in disease pathogenesisand that activated CD8+ T cells may triggerkeratinocyte apoptosis in OLP. T-cell lines andclones isolated in vitro from LP lesions weremore cytotoxic against autologous lesionalkeratinocytes than T cells from the clinically nor-mal skin of LP patients, and the majority of non-cytotoxic clones were CD4+ (helper/inducerclones) (Sugerman et al. 2000).

Furthermore, the cytotoxic activity of CD8+lesional T-cell clones was partially blocked withanti-MHC class I monoclonal antibody(Sugerman et al. 2000). Hence, early in OLPlesion formation, CD8+ lesional T cells may rec-ognize an antigen associated with MHC class I onlesional keratinocytes. Following antigen recog-nition and activation, CD8+ cytotoxic T cells arethought to trigger keratinocyte apoptosis(Sugerman et al. 2002).

Activated CD8+ T cells (and possiblykeratinocytes) may release chemokines thatattract additional lymphocytes and other immunecells into the developing OLP lesion. This has

been suggested by studies that found significantlyhigher chemokine production within OLP lesionswhen compared to normal or chronically inflamedgingival tissues (Yamamoto and Osaki 1995).

CD4+ T CellsThe majority of intraepithelial lymphocytes inOLP have been shown to be CD8+ cytotoxic Tcells (Sugerman et al. 2002), while studies haveshown that most lymphocytes in the lamina pro-pria are CD4+ helper T cells (Ishii 1987; Kilpi1988). A mixed helper and suppressor activityamong OLP lesional T-cell clones in vitro wasidentified, suggesting that the balance betweenimmunological 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 Tlymphocyte lines extracted from six biopsy spec-imens of OLP (n = 13) expressed the α/β T-cellreceptor of which 11 were CD8+ and two wereCD4+ (Sugerman et al. 1994).

Hence, an early event in OLP lesion formationmay be a presentation of aMHC class II antigen toCD4+ helper T cells, followed by keratinocyteapoptosis triggered by CD8+ cytotoxic T cells.MHC class II antigen presentation in OLP maybe mediated by Langerhans cells (LCs) orkeratinocytes. Furthermore, increased numbersof LCs have been reported in OLP lesions withupregulated MHC class II expression (VillarroelDorrego et al. 2002).

Keratinocytes in OLP have also been shown toexpress MHC class II (Ichimura et al. 2006). Highlevels of antigen expression, CD40 and CD80expression, and IL-12 secretion by MHC class II+ antigen-presenting cells (APC) in OLP arethought to promote a TH1 CD4+ T-cell responsewith IL-2 and IFN-γ secretion (Sugerman et al.2002).

Analysis of these data together suggests thatLCs or keratinocytes in OLP may present antigenassociated with MHC class II to CD4+ helperT cells that are stimulated to secrete the TH1cytokines IL-2 and IFN-γ. Subsequently, CD8+cytotoxic T cells may be activated by thecombination of (i) antigen associated with MHCclass I on basal keratinocytes and (ii) TH1 CD4+


T-cell-derived IL-2 and IFN-γ. Activated CD8+cytotoxic T cells may then trigger basalkeratinocyte apoptosis in OLP (Sugerman et al.2002). However, it is essential to note that thishypothesis has never been proven by robustevidence.

A recently discovered subgroup of CD4+ Tcells, namely, TH17 CD4+ subgroup, has beenshown to produce IL-26 and IL-22, in additionto IL-17, which are known to be, whenuncontrolled, inducers of the inflammatoryresponse in different autoimmune conditions,such as multiple sclerosis, psoriasis, and lupus(Payeras et al. 2013).

The proportion of lesional Th1 and Th17 cellsand serum IL-17 levels in patients with OLP(n = 40) were shown to be significantly greaterthan controls (n = 15), especially in the atrophic-erosive OLP patients compared with those pre-senting with reticular OLP, suggesting that Th17cells and their cytokine Th17 might play animportant role in OLP pathogenesis (Xie et al.2012).

Dendritic Cells (DCs)DCs have an important role in the immunologicalresponse as they activate T cells through antigenicstimulation (Banchereau et al. 2000). Studies haverevealed an increase in the number of DCs in OLP,indicating that they may be associated with itspathogenesis (Santoro et al. 2005; Gueiros et al.2012). According to Santoro et al., the increase ofdifferent subsets of DCs, such as Langerhans cells(LCs), stromal DCs, and plasmacytoid dendriticcells (PDCs), may promote the inflammatoryresponse in OLP (Santoro et al. 2005).

Among these, LCs have been the most studiedDCs. These cells reside in the supra-basal layersof the stratified epithelium of the skin and oralmucosa and have the principle function of captur-ing and presenting antigens. When LCs captureantigen, they are activated, migrate to the regionallymph nodes, and are introduced to the T lympho-cytes, producing a primary immune response(Payeras et al. 2013). Subsequently, when LCsrecapture antigen, this antigen will be presentedand recognized by T lymphocytes circulating

memory and will induce a secondary immuneresponse (Barrett and Raja 1997).

In the OLP lesions, a large number of LCs arepresent 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 lymphocytethrough class II MHC molecules, introducing notonly an initial sensitivity to the antigen (primaryimmune response) but also a subsequent second-ary immune response and thus the appearance ofthe clinical signs of the disease (Payeras et al.2013).

Mast CellsMast cells are preferentially located in the laminapropria, near blood vessels and nerves. They arederived from the CD34+ hematopoietic progeni-tor that has the ability to activate T lymphocyte,undergo degranulation, and release a series ofmediators that modulate the inflammatoryresponse (Payeras et al. 2013). Studies haveshown an increased mast cell density in OLPwith approximately 60% of them beingdegranulated, compared with 20% in normal buc-cal mucosa (Sugerman et al. 2002).

Utilizing IHC, mast cell density in OLP wasfound to be markedly higher in the basementmembrane rupture sites as compared to intactsites, suggesting that this cell might play a directrole in the basement membrane destruction, aswell as in the T CD8+ lymphocyte migration tothe intraepithelial region (Zhou et al. 2002). Thus,mast cells have been proposed to be involved inthe pathogenesis of OLP. Mast cell degranulationin OLP releases a range of pro-inflammatorymediators such as TNF-α, chymase, and tryptase.TNF-α has been shown to upregulate endothelialcell adhesion molecule (CD62E, CD54, andCD106) expression in OLP that is required forlymphocyte adhesion to the luminal surfaces ofblood vessels and subsequent extravasation (Zhaoet al. 1997). Chymase, a mast cell protease, is aknown activator of MMP-9 (Fang et al. 1997).

It has been proposed that basement membranedisruption in OLP may be mediated by mast cellproteases directly or indirectly via activation of T-cell-secreted MMP-9 (Sugerman et al. 2002).


Both TNF-α and chymase stimulate secretion ofRANTES 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).

MacrophagesMacrophages are phagocyte cells derived fromblood monocytes, recruited in the tissues in thepresence of chemotactic signals. They are presentin the healthy oral mucosa and in larger numbersduring 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 macrophagesmight exacerbate OLP manifestation through theproduction of pro-inflammatory agents such asTNF-α or IL-1b. These agents, in turn, regulatethe presence of adhesion molecules on the endo-thelial cell surface inducing the production ofchemokines (RANTES) by the keratinocytes andresulting in an increase in the lesional inflamma-tory cells recruitment. Furthermore, it has beenshown that the production of TNF-α by the mac-rophages can initiate the basal keratinocyte apo-ptosis and indirectly increase the disruption rate ofthe basement membrane by MMP-9, produced byT 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 ofconnective tissue matrix proteins. MMPs sharebiochemical properties but retain distinct sub-strate specificities (Zhou et al. 2001). MMP pro-teolysis is regulated by the action of endogenousinhibitors, including the tissue inhibitors of meta-lloproteinases (TIMPs), which are thought to formstable inactive enzyme-inhibitor complexes withMMPs or pro-MMPs (Sugerman et al. 2002). Animbalance between MMPs and TIMPs can beassociated with the process of tissue destruction

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, culturesupernatants from OLP lesional T cells containeda higher concentration of MMP-9 and TIMP-1than those obtained from peripheral blood T cellsin both the same OLP patients group and thehealthy controls, suggesting the presence of addi-tional MMP-9 activators in the OLP lesionalT-cell supernatants (Zhou et al. 2001).

MMP-9 activators released from the OLP T cellare 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 (1.3vs. 0.7) and MMP-7 (1.7 vs. 0.6) in epitheliumand connective tissues from OLP lesions wasgreater than normal oral mucosa (P < 0.05). ThisIHC study was undertaken on a cohort of 29 OLPpatients and ten healthy controls. Likewise, thestudy revealed that MMP-2/TIMP-1 and MMP-7/TIMP-1 ratios were higher in the OLP patientgroup than in the control group (P < 0.05). Theseresults support the view that increased MMPexpression and imbalance between MMPs andTIMPs may play a role in the pathology of OLP.

ChemokinesChemokines are a family of small cytokines (pro-teins that are involved in cell signaling and medi-ating immune reactions), which were initiallyidentified 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 chronicinflammation and tumor progression (Kiefer andSiekmann 2011). Moreover, evidence has shownthe role chemokines play in different autoimmunediseases, such as rheumatoid arthritis and multiplesclerosis, through lymphocyte recruitment andestablishment of ectopic lymphoid structures inthe target organs in affected individuals(Godessart and Kunkel 2001).

RANTES (regulated on activation, normal Tcell expressed and secreted) is a member of theCC chemokine family and is produced by various


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 recruitmentof lymphocytes, monocytes, natural killer cells,eosinophils, basophils, and mast cells in OLP(Roopashree et al. 2010). This chemokine has anumber of cell surface receptors (CCR1, CCR3,CCR4, CCR5, CCR9, and CCR10) that have beenidentified 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 RANTESsecreted by OLP lesional T cells may attractmast cells into the developing OLP lesion andsubsequently stimulate mast cell degranulation.Degranulating mast cells in OLP would releaseTNF-α and chymase which in turn upregulatesOLP lesional T-cell RANTES secretion.According to this hypothesis, such a cyclicalmechanism may underlie OLP chronicity.

Ichimura et al. (2006) analyzed thechemokines and their receptors expressed in theepithelium of OLP by means of DNA microarray.The study found that high levels of MIP-3a/LARC/CCL20, and its receptor CCR6, areexpressed on the lesional epithelium. Further-more, DC-CK1/CCL18, ELC/CCL19, SDF-1/CXCL12, and CXCR4 expressions were alsoincreased. Immunohistological analysis showedthat high numbers of LCs were present in theepithelium of OLP. Lesional epithelium alsoexpressed high levels of the ligands specific forCXCR3 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) andthat LCs residing in the lesional epithelia mayrepresent a mature phenotype. Moreover, infiltra-tion of T cells in OLP could be mediated bysignaling pathways through CXCR3 and CCR5.

Thus, it would appear that there is adysregulation of specific chemokines, and chemo-kine receptors, and that this would appear to berelated to expression of chemokine receptors onLCs. Similar to the observed dysregulation ofMMPs/TIMPs and keratinocyte/basement mem-brane noted above, this may be either involved

in the etiopathogenesis of OLP or a byproduct ofthe disease.

Epithelial Components

The Epithelial Basement MembraneKeratinocytes contribute to the structure of theepithelial basement membrane by secreting colla-gen IV and laminin V into the basement mem-brane zone (Marinkovich et al. 1993). Evidencefrom mouse models suggests that keratinocytesrequire a basement membrane-derived cell sur-vival signal to prevent the onset of apoptosis(Pullan et al. 1996). Similarly, lack of appropriateECM anchorage results in a form of cell deathcalled “anoikis.” Thus, an intact basement mem-brane is required for keratinocytes survival, andreciprocally healthy keratinocytes are necessaryfor normal basement membrane integrity.

Keratinocytes undergoing cell death are nolonger able to perform this reciprocal function,and as such keratinocyte apoptosis triggered byintraepithelial CD8+ cytotoxic T cells may resultin epithelial basement membrane disruption inOLP, 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 beinvolved in the pathogenesis of OLP, and such acyclical mechanism has been postulated to under-lie disease chronicity (Sugerman et al. 2002;Lodi et al. 2005a).

Keratinocyte ApoptosisKeratinocyte apoptosis is a common and key fea-ture in the histopathological findings of OLPlesions and is considered a major diagnostic cri-terion (Ismail et al. 2007; Eisen et al. 2005; Scullyet al. 1998). Therefore, keratinocyte apoptosis hasbeen postulated to be intentionally involved in theetiopathogenesis of OLP (Sugerman et al. 2002).

A number of mechanisms have been suggestedby which CD8+ cytotoxic T cells can triggerkeratinocyte apoptosis in OLP. These include(i) T-cell-secreted TNF-α binding to TNF receptor1 (TNFR1) on the keratinocyte surface, (ii) T-cellsurface CD95L (Fas ligand) binding CD95 (Fas)


on the keratinocyte surface, or (iii) T-cell-secretedgranzyme B entering the keratinocyte viaperforin-induced membrane pores (Sugermanet al. 2002). All of these mechanisms may activatethe keratinocyte caspase cascade, resulting inkeratinocyte apoptosis. Elevated levels of TNF-αin the serum of OLP patients were identified(Sugermann et al. 1996).

In summary, while it is well established thatapoptosis of basal keratinocytes is a key feature ofOLP, the exact pathogenic mechanisms have notyet 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

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 sitesand the lips can also be involved (Al-Hashimiet al. 2007; Ismail et al. 2007; Scully and Carrozzo2008). Other common sites of involvementinclude the tongue (Fig. 1c), gingival (Fig. 1d),labial mucosa, and vermilion of the lower lip(Eisen et al. 2005; Al-Hashimi et al. 2007; Scullyand Carrozzo 2008; Parashar 2011). Patients withisolated lip lesions and tongue lesions have beendescribed although many patients who presentwith isolated lesions eventually develop more

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)


widespread disease (Eisen et al. 2005). Lesions ofOLP affecting the palate, floor of the mouth, andupper lip are not common.

The oral manifestations of OLP have beendescribed in many large studies. Clinically, thereare six clinical subtypes of OLP that can be seenindividually 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 ofthese are the reticular, erosive, and plaque-likesubtypes, and these variants can coexist withinthe same patient (Fig. 1).

The reticular lesions, the most recognized formof OLP, encompass white lesions, which appear asa network of connecting and overlapping linesreferred to as Wickham striae, papules, or plaques(Eisen et al. 2005). Although some patients maydisplay an impressive array of diffuse and wide-spread reticulated lesions, they rarely complain ofsymptoms and often are unaware of their pres-ence. In the absence of the classic reticular patternon 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 erosiveform of OLP (Fig. 1b) may present with erythemacaused by inflammation or epithelial thinning, orboth, and ulceration/pseudomembrane formationwith periphery of the lesion surrounded by retic-ular keratotic striae (Ismail et al. 2007). Atrophicand erosive OLP lesions result in varying degreesof discomfort. The number of ulcerations is vari-able as are their size and location; rarely, bullaethat rupture easily may be observed in the erosiveform of OLP (Eisen et al. 2005). If the erosivesubtype of OLP only affects the gingival tissue,the descriptive clinical term desquamative gingi-vitis is often used (Fig. 1d). OLP is confined to thegingiva in about 10% of patients (Mignogna et al.2005; Scully and Carrozzo 2008). Erosive lesionsresembling those observed in othervesiculobullous diseases including pemphigoid,pemphigus, linear IgA disease, and foreign bodygingivitis can also produce desquamative gingivi-tis not easily identified as OLP unless there arecoexistent reticular lesions on the gingiva or else-where in the oral cavity. Two recent cohort studies

found OLP to be the most common cause ofdesquamative gingivitis (71% and 75%), whilepemphigoid 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 thegingiva is uncommon.

In general, bullous and papular forms are rarein the oral mucosa (Parashar 2011). The erosivelesions hardly ever remit spontaneously and maylead to confusion with other vesiculobullous dis-eases, which share similar clinical features (Eisenet al. 2005).

The plaque form of OLPmimics leukoplakia inthat it appears as a white, homogeneous, slightlyelevated, multifocal, smooth lesion. The plaqueform of OLP commonly affects the dorsum of thetongue and buccal mucosa (Ismail et al. 2007).

OLL and OLR have similar features, clinicallyand 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 differentfrom those for OLP (Al-Hashimi et al. 2007).

To better define the criteria for diagnosis ofOLP, the World Health Organization (WHO)devised a set of clinicopathologic criteria in1978 (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 in2003 (Table 2), which resulted in a substantialincrease in consensus and clinicopathologic cor-relation (Epstein et al. 2003; van der Meij and vander Waal 2003). In addition, knowledge abouthistory of systemic diseases, history of drug use,and cutaneous lesions can be helpful in arriving ata definite diagnosis.

Signs, Symptoms, Clinical Behaviorand OLP Scoring Systems

The clinical signs and symptoms of OLP vary. Inmany patients, the onset of OLP is insidious, andpatients are unaware of their oral condition. Somepatients report roughness of the lining of themouth, sensitivity of the oral mucosa to hot orspicy foods, painful oral mucosa, red or white


patches on the oral mucosa, or oral ulcerations(Ismail et al. 2007).

Symptoms and signs can range from patientsbeing unaware of the disease, with lesions that arecompletely asymptomatic as in reticular OLP, tothose experiencingmucosal sensitivity and burningand debilitating pain. Approximately two-thirds ofthe patients affected with OLP experience somedegree of oral discomfort (Parashar 2011).

OLP has periods of relapses and remissions.During a period of exacerbation there will be anincrease in symptoms and clinical signs, whileduring periods of quiescence, symptoms and

signs of OLP are diminished (Ismail et al. 2007).Factors such as stress may aggravate the clinicalpresentation of the disease. Precipitating factorssimilar to the Koebner phenomenon, which ischaracteristic of cutaneous LP whereby lesionsdevelop in response to trauma, can also affectthe oral cavity where sharp cusps and ill-fittingdental prosthesis may be the triggers.

Accumulation of plaque and calculus can alsoexacerbate OLP, probably because of the Koebnerphenomenon (Mignogna et al. 2005). GingivalOLP can eventually lead to gingival recession,advanced periodontal disease, and so forth, and

Table 2 Modified WHO diagnostic criteria of OLP and OLL (van der Meij and van der Waal 2003)

Clinical criteriaPresence of bilateral, more or less symmetrical lesionsPresence 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 mucosaIn all other lesions that resemble OLP but not complete with the aforementioned criteria, the term “clinically compatiblewith” should be usedHistopathological criteriaPresence of well-defined band-like zone of cellular infiltration that is confined to the superficial part of the connective

tissue, consisting mainly of lymphocytesSigns of “liquefaction degeneration” in the basal cell layerAbsence of epithelial dysplasia

When the histopathological features are less obvious, the term “histopathologically compatible with” should be usedFinal diagnosis of OLP or OLLTo achieve a final diagnosis, clinical as well as histopathological criteria should be includedOLP: a diagnosis of OLP requires fulfillment of both clinical and histopathological criteriaOLL: 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

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

Clinical criteriaPresence of white papule, reticular, annular, plaque-type lesions, gray-white lines radiating from the papulesPresence of lacelike network of slightly raised gray-white lines (reticular pattern)Presence of atrophic lesions, with or without erosion, and possibly also bullae

Histopathological criteriaPresence of thickened ortho- or parakeratinized layer in sites that are normally keratinized, and if site is normally

nonkeratinized, this layer may be thinPresence of Civatte bodies in basal layer, epithelium, and superficial part of connective tissuePresence of a well-defined band-like zone of cellular infiltration that is confined to the superficial part of the

connective tissue, consisting mainly of lymphocytesSigns of liquefaction degeneration in the basal cell layer


therapeutic periodontal procedures may aggravatethese conditions (Eisen et al. 2005; Scully andCarrozzo 2008).

Oral post-inflammatory pigmentation (OPP)has been described in patients with OLP andOLR 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 beenproposed to objectively and even subjectivelymeasure OLP disease severity. Several studieshave proposed using scoring systems with theearlier systems based upon a three- or five-pointscale from no disease to severe disease (Eisen et al.1990; Thongprasom et al. 1992). Other scoringsystems base severity on the level of site involve-ment (<> 50% site) (Malhotra et al. 2008).

Some of the more detailed scoring systemshave worked to split OLP into three clinical sub-types, reticular, atrophic/erythematous, and ero-sive/ulcerative (Escudier et al. 2007). For someof these studies the oral cavity is divided intodifferent subsites so each site is given an activ-ity/severity score which can be totaled to give anentire oral cavity score (Chainani-Wu et al. 2001;Piboonniyom et al. 2005; Escudier et al. 2007). Insome of these scoring systems, presence of ery-thema, erosions, or ulceration is graded higherthan the presence of reticular lesions alone(Piboonniyom et al. 2005; Escudier et al. 2007).

One of the main advantages of using a detailedscoring system is the ability to objectively mea-sure disease activity baseline and changes in dis-ease activity for the entire oral cavity and specificsites. Recently attempts have been made to vali-date some of the more detailed scoring systems(Chainani-Wu et al. 2012). Time has also beentaken with these scoring systems to add subjectivemeasures of the patient’s pain and symptomsmak-ing this a complete disease scoring system(Chainani-Wu et al. 2012).

Currently there are many available diseasescoring systems which systems in place to mea-sure changes in subjective and objective diseaseactivity in OLP. At this stage no one system hasbeen universally accepted for use.

Histopathology of OLP

The histologic features of OLP were firstdescribed by Dubreuill in 1906 and later revisedby Shklar in 1972 (Parashar 2011). The WHOdeveloped a set of histopathologic criteria forOLP in 1978, which was most recently modifiedin 2003 (Tables 1 and 2). Definite diagnostic his-tologic findings include liquefactive degenerationof the basal cells, colloid bodies (Civatte, hyaline,cytoid), homogeneous infiltrate of lymphocytesand histiocytes in a dense, band-like patternalong the epithelium-connective tissue interfacein the superficial dermis, cytologically normalmaturation 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 ofulceration, typically seen in erosive LP.

Several histologic criteria are considered asexclusionary in diagnosing OLP, including theabsence of basal cell liquefaction degeneration,polyclonal inflammatory infiltrate, abnormalcytology suggestive of dysplasia, abnormal kera-tinization, flat rete ridges, and absence of colloidbodies (Eisenberg 2000; Ismail et al. 2007).

Oral Lichenoid Reactions (OLR)

There are various lesions that may resemble OLPboth clinically and histopathologically. Theselesions are collectively termed OLR and encom-pass lichenoid drug reactions (LDR) and OLR todental materials, most notably allergic contactsensitivity to amalgam (Koch and Bahmer 1995;Ostman et al. 1996; Thornhill et al. 2003; Issaet al. 2004; Eisen et al. 2005; Ismail et al. 2007).As with OLP, OLRs present clinically with arange of different features ranging from asymp-tomatic striae and plaque-like lesions to painfulerythematous 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 liquefactivedegeneration of the basal cell layer.


Cases of OLRs related to restorative materialswill 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, amalgamalloying metal zinc, copper, silver, gold, or palla-dium (Koch and Bahmer 1995; Suter andWarnakulasuriya 2016). There has been some evi-dence to suggest that some patients withamalgam-associated OLRs represent a truedelayed hypersensitivity reaction as a result ofmetal haptens released from dental restorativematerials (Laine et al. 1999). LDRs will typicallyarise with a direct temporal association when tak-ing certain medications including nonsteroidalanti-inflammatory medications (NSAIDs), someantihypertensive 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 ofLDR; however withdrawal and reexposure to thedrug resulting in resolution and recurrence can beconsidered diagnostic. Patch testing may be avaluable diagnostic tool for OLR as a result of acontact sensitivity to dental materials (Suter andWarnakulasuriya 2016). In cases of a suspectedOLR as a result of amalgam dental restorations,there is evidence to suggest that replacement ofamalgam can result in resolution or improvementof OLR; in some cases this is irrespective of apositive patch testing result (Laine et al. 1992;Ostman et al. 1996; Thornhill et al. 2003; Issaet al. 2004). Thus in cases of suspected OLRs, itis essential that proper testing including histopa-thology and patch testing be undertaken to ensure

Fig. 2 Histopathology ofOLP. (a) Low powerphotomicrograph showingparakeratosis, band-likesubepithelial chronicinflammatory infiltrate, andsawtooth rete ridges (H&E,original magnificationX100). (b) High-powerphotomicrograph showingseveral colloid bodies(arrows) and liquefactivedegeneration of basalkeratinocytes (arrowheads)(H&E, originalmagnification X200)


a correct diagnosis is made as OLP and OLRbenefit from different management protocols.

Dental MaterialsOLR as an allergic reaction to dental materials hasbeen widely reported, with many studiesdocumenting contact hypersensitivity to dentalmaterials 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 alsoshowed resolution of OLR following replacementof causative restorations. Laine et al. reported acomplete remission of OLR lesions associatedwith amalgam in a small cohort of seven patients,a marked remission in six patients, and no changein two patients (total n = 15) after amalgamreplacement and a mean follow-up of 3.2 years(Laine et al. 1992). In another trial, Thornhill et al.reported that amalgam replacement resulted inimprovement in 93% of patients (28 out of 30)who had amalgam-contact hypersensitivitylesions (Thornhill et al. 2003). Gingival OLRlesions, in particular, were reported to be non-responsive to amalgam replacement for unknownreasons (Henriksson et al. 1995).

Diagnosis of OLR will commonly depend onthe topography and distribution of the lesions as inmost cases, OLR are indistinguishable from idio-pathic OLP, clinically or histologically (Thornhillet al. 2003). Cutaneous patch testing may alsoplay a role in differentiating these lesions (Scullyand Carrozzo 2008; Ismail et al. 2007). Thornhillet al. found that 70% of amalgam-contact hyper-sensitivity lesions (presented as lichenoid reac-tions) were patch test positive for amalgam ormercury compared with only 3.9% of OLP cases(Thornhill et al. 2003).

To date, OLP and OLR lack internationallyaccepted 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 OLRappears to be the result of cell-mediated contacthypersensitivity to dental materials, in susceptible

individuals who have been sensitized throughlong exposure (Ismail et al. 2007).

Systemic MedicationsMedications, 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 associatedwith OLRs (Scully et al. 1998; Al-Hashimi et al.2007; Ismail et al. 2007).

More recently, OLR induced by antiretroviralmedications for treatment of human immunodefi-ciency virus (HIV) has been reported (Scully andDiz Dios 2001). Clinical identification of LDRhas been based largely on subjective criteriaalthough there may sometimes be a tendency forthe oral lesions to be unilateral and erosive (Eisenet al. 2005). Histology may be beneficial aslichenoid lesions may have a more diffuse lym-phocytic infiltrate and contain eosinophils andplasma cells, and there may be more colloid bod-ies than in classical OLP (Eisen et al. 2005; Scullyand Carrozzo 2008).

The most reliable method to diagnose LDRs isto note if the reaction resolves after the offendingdrug is withdrawn and if it returns when thepatient is challenged again. As this is both imprac-tical and potentially unsafe, empiric withdrawal ofa potentially offending drug and substitution withanother agent may not be warranted. After theoffending drug is withdrawn, it may be monthsbefore the LDR resolves. Interestingly, it wasreported that LDR may develop months or evenyears 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 involvementcauses pruritic, follicular and perifollicular, scaly,violaceous papules, referred to as lichenplanopilaris, and can also lead to permanentpatchy hair loss known as scarring alopecia.When LP affects nails, it causes pitting, subungual


hyperkeratosis, and permanent nail loss (Farhi andDupin 2010).

Skin lesions characteristically present as flat-topped, polygonal, violaceous papules regularlycovered by a network of fine lines affecting thewrists, ankles, and genitalia (Bornstein et al.2006). Cutaneous LP may also appear in severalatypical forms that are not easily recognizable. Aspreviously mentioned, approximately 15% ofpatients with OLP develop cutaneous lesions,while OLP occurs in 70–77% of patients withcutaneous LP (Eisen 1999; Farhi and Dupin 2010).

Typically, cutaneous lesions develop withinseveral months after the appearance of the orallesions, and the severity of the oral lesions doesnot seem to correlate with the extent of cutaneousinvolvement, i.e., while OLP is chronic and rep-resents a common cause of morbidity, cutaneouslesions are commonly pruritic but self-limiting(Eisen et al. 2005).

Other Mucosal Lesions

Undoubtedly, the most frequent extraoral site ofinvolvement in female patients with OLP is thegenital mucosa with lesions developing in 20% ofwomen with OLP compared with only 2–4% ofmen with OLP (Ismail et al. 2007; Scully andCarrozzo 2008; Farhi and Dupin 2010). The asso-ciation of LP of the vulva, vagina, and gingiva isrecognized as the vulvovaginal-gingival syn-drome (Pelisse 1989), and the male counterpartis known as penogingival syndrome (Bain andGeronemus 1989).

When LP affects the genital mucosa, the ero-sive form of the disease is the predominant typealthough asymptomatic reticular lesions can beidentified in about a quarter of all patients (Eisenet al. 2005). Various symptoms including burning,pain, vaginal discharge, and dyspareunia are fre-quent and are noted in patients with erythematousand erosive disease.

Reports of malignant transformation of genitalLP in women (Dwyer et al. 1995) underscore theneed for an early diagnosis and the institution ofprompt treatment for these patients. Although theconcomitant involvement of oral and genital LP is

much less common in males than females, recog-nition and treatment of the disease are importantas malignant transformation of penile LP has alsobeen reported (Bain and Geronemus 1989).

The clinical features of esophageal LP havebeen well documented, and the disease appearsto 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 transformationof OLP (Hallopeau 1910), numerous studies haveattempted to address this issue. Malignant trans-formation rates ranging from 0% to 12.5% werereported (Gonzalez-Moles et al. 2008). Althoughthese findings appear to support the potentiallymalignant character of OLP, it remains a contro-versial topic.

Several authors agreed to a frequency of malig-nant transformation between 0.4% and 5%, overperiods of observation from 0.5 to over 20 yearswith an annual rate between 0.2% and 0.5%. (vander Meij et al. 2003; Al-Hashimi et al. 2007;Scully and Carrozzo 2008). However, reviewslimited to selected studies on malignant potentialof OLP with a follow-up of more than 2 yearsshowed that when strict criteria were applied, themalignant transformation rate is 0–2% (Ismailet al. 2007).

It has been thought that the increased risk oforal 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 ofOral Pathology about four decades ago(Krutchkoff et al. 1978), included data publishedup to 1977, and the authors recommended strictcriteria (Table 3) to be adopted to definitivelyaccept the malignant transformation in OLP.After applying these new criteria, they concludedthat only 15 of the 223 cases reported in theliterature should be unquestionably accepted asmalignant transformation in OLP. The remaining


cases were excluded for at least one of the follow-ing reasons: (1) insufficient data to support theOLP diagnosis, (2) appearance of oral cancer inan area anatomically distant from the OLP, and(3) inadequate historical data on previous expo-sure to carcinogens. The authors commented: “IfOLP prevalence is accepted to be 1–2% of generalpopulation 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 periodof 5 years. This would indicate that in many partsof the world all oral carcinomas should develop onan OLP, which is rather improbable” (Krutchkoffet al. 1978). They further drew the conclusion thatthere was insufficient evidence to accept an inher-ent biological potential of OLP to progress tocancer, but they acknowledged that OLP patientshave 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 malignanttransformation of OLP published from 1977 to1999, applying the Krutchkoff criteria. Duringthis period, 98 new malignant transformations

were reported, of which 33 (34%) met the pro-posed criteria. According to the authors, the highincidence of malignant transformation describedin many studies may be due to the misdiagnosis ofsome lesions as OLP or to the analysis of a highlyselected study population (e.g., predominance ofpatients referred to specialists). This investigationconcluded that nearly all of the case reports lackedprecise documentation and that still no consensushad been established about the criteria for thehistopathologic diagnosis of OLP (van der Meijet al. 1999a).

van der Meij et al. further emphasized the needfor standard criteria for a firm diagnosis of OLP tobe universally adopted (van derMeij et al. 1999a, b).

The designation OLL was later proposed forcases that are clinically characteristic and histo-logically compatible, clinically compatible andhistologically characteristic, or clinically and his-tologically compatible with OLP (Table 2) (vander Meij and van der Waal 2003). It is currentlyproposed by some key authors that OLL ratherthan 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 ahigher incidence of oral cancer in OLP patientsand concluded that OLP should be considered apotentially malignant condition with a transfor-mation rate of 0.5–2% (Mattsson et al. 2002).Many other studies using strict diagnostic criteriahave 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 itslatest volume on the Pathology and Genetics ofHead and Neck Tumours (Gale et al. 2005), hasrecommended the development of diagnosticcriteria to differentiate between OLP and OLLbut declared that both lesions should be consid-ered at risk of malignant transformation until suchcriteria become available.

In 1985, Krutchkoff and Eisenberg (1985)coined the term lichenoid dysplasia (LD) todescribe lesions that resemble OLP histologicallyand also show features of dysplasia. They

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 lasttwo of these four featuresHyperkeratosis or parakeratosisSawtoothed rete ridgesSuperficial infiltrate of lymphocytesBasal cell liquefaction

B. History and follow-upClinical and histological features of the alleged

transformation must have been adequately described(information on age and sex of patient and on the preciselocation and clinical description of the lesion)The reported transformation should have had proper

follow-up (minimum of 2 years) with all changes inclinical features properly recordedC. Tobacco exposureTobacco habits should have been properly documented

to help distinguish between true malignanttransformation and conventional carcinomas occurring inthe mouths of patients who happened to have OLP


suggested that OLP has no inherent predispositionto become malignant and that reported cases ofmalignant transformation in OLP lesions were dueto lack of discrimination between OLP and LD orfailure to identify a concomitant exposure to knowncarcinogens (Krutchkoff and Eisenberg 1985).

The assumption for the proposal of malignantpotential in LD rather than OLP was that anydeparture from normal epithelial maturation andgrowth altogether excludes a diagnosis of OLP(Eisenberg 2000), although consensus on suchcriteria has never been reached, and some authorsconsider dysplasia a very common feature of OLP(Lodi et al. 2005b).

The entity LD might correspond to two groupsof conditions: those with clinical features similar toOLP but dysplastic at the histological level andthose 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 anearly phase in the malignant transformation of OLP,while the latter could represent an OLL with under-lying various clinical conditions that may havelichenoid histopathology including lichenoid reac-tions, lupus erythematosus, leukoplakia, erythroleu-koplakia, and proliferative verrucous leukoplakia(PVL). PVL, particularly in the early stages, canhave features, both clinical and histologic, that canbe confused with OLP, frequently shows dysplasticchanges, and is characterized by a high malignanttransformation 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 bonemarrow transplantation and developed oralGVHD. Oral GVHD is clinically and histologi-cally indistinguishable from OLP. Case reports(Abdelsayed et al. 2002) and large studies (Deeget al. 1996; Curtis et al. 1997) describe numerousepisodes of oral cancers (mainly SCC) in patientswith oral GVHD. A large study that investigatedthe incidence of solid tumors in 20,000 bone

marrow transplantation patients found that oralcancer had the highest risk among cancers, being11.1 times more frequent than expected (Curtiset al. 1997). The significant risk factors for OSCCwere chronic GVHD, limited-field irradiation, andmale sex. In one of these studies, head and neckcancer was the only solid cancer observed in agroup of 78 patients undergoing bone marrowtransplantation for Fanconi anemia, with the fre-quency of such tumors was 167 times higher thanexpected (Deeg et al. 1996).

Clearly, bone marrow transplantation patientshave numerous risk factors that may enhancetheir likelihood of developing malignancies (pri-mary immunodeficiencies, immunosuppressivetreatments, viral infections, and probably geneticpredisposition to cancer) that do not allow a com-parison with OLP patients; however, the similarityof the oral conditions and the apparent commontendency to transform are worthy of careful con-sideration (Lodi et al. 2005b). Other lichenoidlesions that can undergo malignant transformationinclude discoid lupus erythematosus, in particularof the lip (Voigtlander and Boonen 1990) andamalgam-associated OLR (Ostman et al. 1996).

Interestingly, in a prospective study on prema-lignant potential of OLP, all cases of malignanttransformation involved lesions that the authorsincluded in the group of OLL because they did notfulfill both clinical and histologic criteria for OLP(van der Meij et al. 2003). In 2007, van der Meijet al. (2007) also studied the number of expectedoral carcinomas in 67 patients with OLP and125 patients with OLL. All malignant transforma-tions (4 of 192, 2.1%) appeared in OLL patients,i.e., an annual OLL malignant transformation rateof 0.71%. Hence, there was no increase in oralcancer risk for patients with OLP but a 142-foldincrease for patients with OLL (P = 0.04).

There may be considerable overlap between theclinical and microscopic features of OLR and OLP.Although no association has been establishedbetween OLR and malignant transformation(Mattsson et al. 2002), Larsson and Warfvingeproposed that there may be a similar rate of malig-nant transformation in OLR to that observed inOLP, especially in lesions at the lateral border ofthe tongue, a frequent site for OLR due to the close


contact with silver amalgam restorations. Theyreported that the cancer had developed on anOLR in 4 of 724 patients with tongue cancer(Larsson and Warfvinge 2005).

Tumors Developing in OLP and theirCarcinogenesis

Clinically, carcinomas that develop in previouslydiagnosed OLP lesions have been reported to beexophytic keratotic lesions (Lo Muzio et al. 1998;Fatahzadeh et al. 2004) (Fig. 3a), but some mayalso show endophytic growth patterns (Lo Muzioet al. 1998). Markopoulos et al. (1997) suggestedthat rapid expansion of OLP lesion should raisesuspicion of malignant transformation, butMignogna et al. (2001) found neither the exten-sion nor severity of symptoms a useful indicator

of transformation – rather they considered the lossof lesion homogeneity at a specific site to be mostrelevant. This clinical sign is especially usefulwhen 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 onOLP is their tendency of multiplicity. Mignognaet 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 byDuffey et al. (1996) (20% of patients with secondprimary tumors) and Lo Muzio et al. (1998)(35.7% of patients with second primary tumors).

The relatively high frequency of multipleintraoral localizations of second primary tumorsin previously diagnosed OLP may be attributed to

Fig. 3 Oral squamous cell carcinoma in OLP. Clinicalpresentation of patients with OLP and who subsequentlydeveloped OSCC: (a) An exophytic squamous cell carci-noma that developed on the right lateral tongue in a patientwho previously had histopathologically diagnosed OLP inthe same area. (b) An example of metachronous

carcinomas in an OLP patient whose right buccal mucosahad previously shown histopathological evidence of OLP.Subsequently developed a more florid erythematousmucosa in the same area (pictured) that was biopsied anddiagnosed as OSCC. (c) Eight years later, the same patientdeveloped a second OSCC, controlaterally


the field cancerization phenomenon and indicatesthat OLP may have an intrinsic predisposition totumor development (Mignogna et al. 2007).

The metastatic capacity of carcinomas devel-oping in OLP has been addressed by an earlierreport byMignogna et al. (2002) who showed that24% of these patients had detectable lymph nodemetastases at the time of diagnosis. In their morerecent work, the same authors (Mignogna et al.2007) reported that 94% of 97 neoplastic eventsobserved were TisN0M0 or T1N0M0(intraepithelial neoplasia or microinvasive carci-noma <1 mm) and 6% were stage III (threetumors) or IV (three tumors).

Histopathologically, most tumors detected inOLP are well-differentiated SCCs [70% in thestudy by Lo Muzio et al. (1998); 100% in thestudy by Markopoulos et al. (1997)]. Finally,there are conflicting results on the prognosis ofpatients with neoplasia in OLP, some indicating apoor prognosis (Hietanen et al. 1999; Mignognaet al. 2001; Mignogna et al. 2002), but Mignognaet al. (2007) reported 100% 3-year and 97%5-year survival, although there may have been abias in this study as the neoplastic eventscorresponded to severe dysplasias ⁄carcinomas insitu 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 cancerdevelopment in patients with OLP. It has thereforebeen proposed by some authors that carcinoma-tous transformation is part of the natural history ofthe disease or is attributable to unknown riskfactors (van der Meij et al. 2003).

Several risk factors for malignant transforma-tions in OLP have been proposed. These includeerosive forms, tongue lesions, women more thanmen, and sixth to seventh decades of life, but noneof them gained significant agreement amongresearchers (Gonzalez-Moles et al. 2008).Another relevant issue in the context of malignanttransformation of OLP is whether to includepatients with chronic oral exposure to carcino-gens, as it will probably be impossible to differ-entiate between the transformation caused by

tobacco and that secondary to OLP. For this rea-son, some authors recommend the exclusion ofsmokers with OLP from studies (van der Meijet al. 1999a, b, Lozada-Nur 2000). However,according to Lodi et al. (2005b), although somecases described may be mainly related to tobaccoconsumption, the exclusion of one putative riskfactor based on the presence of another appearsinappropriate and could prevent the identificationof new risk factors. Thus, for example, thisapproach would have impeded identification ofthe super-multiplicative risk of combined tobaccoand 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 asingle study, in which this interaction wasaddressed, it was suggested that alcohol andtobacco, or their interaction, cannot explain theexcess 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 Meijet al. 2003; Gandolfo et al. 2004) found no rela-tionship between tobacco and alcohol consump-tion on one side and malignant transformation onthe other side in OLP patients.

Results published by Rajentheran et al. (1999)indicated that tobacco and alcohol consumptionmay even be lower in these patients than inpatients developing oral cancer in the absence ofOLP. 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 andnone to be alcoholic. Munoz et al. (2007) reportedthat only two out of ten OLP patients who devel-oped OSCC were smokers, none was an alcoholicabuser.

With respect to the clinical form of OLP,numerous authors (Silverman et al. 1985; Barnardet al. 1993; Markopoulos et al. 1997; Hietanenet 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 someseries (Hietanen et al. 1999; Mignogna et al.


2001, 2007), plaque-like OLP lesions were alsorelevant, both when they appeared alone andwhen associated with atrophic-erosive lesions.

Analyses of malignant transformation risk fac-tors have also considered the different intraoralsites of OLP. The tongue appears to be the pre-ferred site for the emergence of cancer (Holmstrupet al. 1988; Barnard et al. 1993; Markopouloset al. 1997; Munoz et al. 2007).

Other studies, however, have reported sitesother than the tongue to have a higher risk ofmalignant transformation in OLP. Mignognaet 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 patientswho were followed up for periods from 4 monthsto 12 years and an overall malignant transforma-tion rate of 3.7%.

Regarding gender and age, there appears to bea general consensus that the risk is higher inwomen than in men (Gonzalez-Moles et al.2008). Some authors reported that an oral cancermost frequently develops on an OLP between thesixth and seventh decade of life (Barnard et al.1993; Hietanen et al. 1999).

The mean interval between OLP diagnosis andcancer diagnosis ranges widely from 20.8 monthsto 10.1 years, although the maximum risk isreportedly between 3 and 6 years after OLP diag-nosis (Gonzalez-Moles et al. 2008). The risk ofmalignant progression may also increase with theuse of immunosuppressive agents. Although nospecific data are available in OLP patients, it iswell 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 epithelialcells to promote cancer progression (Azher et al.2016). The discovery that corticosteroids candirectly target the oral mucosa via GR expressedby oral keratinocytes (Cirillo et al. 2012) mayhave 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 oftransformation (Hietanen et al. 1999; Rajentheran

et al. 1999; Gandolfo et al. 2004; Mignogna et al.2007) and might even reduce it. Thus, it has beenproposed that a microenvironment rich inpro-inflammatory cytokines may be especiallyfavorable for neoplastic promotion, suggestingthat more aggressive immunosuppressant treat-ments against the inflammatory response in OLPmight restore normal immune surveillance andinterrupt neoplastic progression (Eisen 2002). Ina study of OLP patients treated mostly with topi-cal and/or systemic steroids, therapeutic modali-ties did not affect the risk of malignanttransformation (Gandolfo et al. 2004).

Malignant transformation of OLP has beensuggested to be related to, or dependent upon, aseries of molecular stimuli originating in theinflammatory infiltrate (Mignogna et al. 2004).Chronic inflammation has been associated withvarious types of cancer (Clevers 2004), and ithas been widely reported that the inflammatoryinfiltrate can be a strong risk factor for cancerdevelopment in ulcerative colitis, atrophic gastri-tis, and Barret’s esophagitis, among other diseases(Balkwill and Mantovani 2001). In fact, it wasproposed by some authors that OLP could beincluded in this group of diseases (Mignognaet al. 2004). Some molecules and radicals gener-ated by inflammatory cells can act as mutagenicagents for epithelial cells or influence importantcell cycle regulation mechanisms (Gonzalez-Moles et al. 2008).

Most studies on cell proliferation in OLP havereported a marked increase in the proliferation rateof basal epithelial cells (Valente et al. 2001;Gonzalez-Moles et al. 2006), and some authorshave proposed that this might be an importantevent in the development of cancer in OLP(Taniguchi et al. 2002).

Mignogna et al. (2004) presented the possiblerole of each type of inflammatory cells in themalignant transformation of OLP. According totheir hypothesis, macrophages, mast cells, lym-phocytes, and fibroblasts can contribute to theprocess of carcinogenesis in OLP by secretingcytokines, chemokines, MMPs, and RANTESmolecules which have the ability to cause DNAdamage, bypass p53 tumor suppression function,


induce immortalization, and influence growth,survival, angiogenesis, and invasion.

In addition to the proposal that OLP-relatedinflammatory microenvironment is able to initiatetumorigenesis in normal epithelium, this microen-vironment has also been suggested to represent apredisposing and enhancing factor toward themolecular 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 expressionof macrophages, which may in turn affect theimmune surveillance and theoretically the mech-anisms of malignant transformation (Alrashdanet al. 2016).

The role of Candida spp. in the symptomatol-ogy and malignant potential of OLP is unclear.Candida spp. is frequently identified in patientswith intraoral lesions of OLP and other oral poten-tially premalignant or malignant lesions includingoral leukoplakia and OSCC (Zeng et al. 2009;Masaki et al. 2011). Candida spp. has beenshown to present higher frequency and coloniza-tion in those with OSCC compared to controls( p = 0.001 and 0.033, respectively) (Alnuaimiet al. 2015). With reference to OLP, studies haveshown the presence of oral yeast to be anywherebetween 40% and 80% for patients with OLP andaround 20% and 40% for controls (Jainkittivonget al. 2007; Lodi et al. 2007; Masaki et al. 2011).

In relation to the association of Candida spp.and OLP, the evidence is conflicting. Specificallythe evidence is conflicting in terms of whetherthere is a significant relationship between Can-dida spp. and erosive OLP, specifically whetherthis relationship plays a role which enhancesinflammation to aggravate the pathogenic condi-tion (Zeng et al. 2009).

Similarly, there is conflicting evidence withregard to Candida invasion in OLP. At this stageit is not certain if the presence of Candida in OLPand other premalignant and malignant conditionsis simply a coincidental finding and whetherchanges in the local environment as a result ofOLP, such as roughness of the mucosal surfaceand hyperkeratosis, create an ideal environment

which simply favors colonization and overgrowthof Candida spp. (McCullough et al. 2002).

Patient Management

The characteristic clinical aspects of OLP (sym-metry, bilateral distribution) are thought by someresearchers to be sufficient to make a correct diag-nosis especially if there are classic skin lesionspresent (Eisen et al. 2005).

However, an oral biopsy with histopathologicstudy is usually recommended to confirm the clin-ical diagnosis andmainly to exclude dysplasia andmalignancy (Eisen et al. 2005; Al-Hashimi et al.2007; Ismail et al. 2007; Scully and Carrozzo2008).

The histopathologic assessment of OLP hasbeen described as a subjective and insufficientlyreproducible process (van der Meij et al. 1999a),and in about 50% of OLP cases, there is a lack ofclinicopathologic correlation in the diagnosticassessment of OLP (van der Meij and van derWaal 2003). Gingival LP may be more difficultto diagnose, and direct immunofluorescence ofperilesional mucosa may facilitate the diagnosisand exclude other causes such as vesiculobullousdiseases (Eisen et al. 2005). The value of directimmunofluorescence for confirmation of the dis-ease is well accepted, especially with non-diagnostic histopathologic features and for thedesquamative gingivitis form of OLP (Eisenet al. 2005; Scully and Carrozzo 2008).

Direct immunofluorescence studies of OLPhave shown a linear pattern and intense positivefluorescence with antifibrogen outlining the base-ment membrane zone and cytoid-like bodies withpositive immunoglobulin M labeling (Eisen et al.2005; Ismail et al. 2007; Scully and Carrozzo2008). Indirect immunofluorescence studies arenot routinely used in the clinical diagnosis of OLP.

It has been proposed that allergy to dentalmaterials is common in patients with OLR. Cuta-neous patch testing is a recognized and acceptedmethod to identify allergens responsible for type Iand IV allergic reactions with Dental SeriesEpicutaneous Test Battery (Trolab) of patch testallergens being commonly used. The test


substances are applied to normal skin of the backand read after 72 h. The patient is considered apatch test positive to an allergen if they developerythematous vesicular or ulcerative reaction atthe 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 numbersof patients being positive in different studies. Inone study, Laine et al. (1992) studied 118 patientswith OLR topographically associated with dentalfillings, 68% of such patients were patch testpositive to metals of fillings materials, particularlymercury and silver nitrate. In another trial, Wonget al. reported a positive patch test in 39% of a totalof 84 patients who presented with OLR related toamalgam fillings (Wong and Freeman 2003).

In a systematic review that analyzed data from14 cohort and five case-controlled studies with atotal of 1,158 patients (27% males and 73%females, age range 23–79 years) with OLR asso-ciated with amalgam, 16–91% of patients werepatch 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 ofclinical involvement, the predominant clinicaltype of lesions, the patient’s symptoms, and age.Reticular lesions that are asymptomatic generallyrequire no therapy but only observation forchange. In general, all treatment should be aimedat managing atrophic and ulcerative lesions, alle-viating symptoms, and potentially decreasing therisk 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 sharpfilling margins, rough surfaces, or badly fittingdentures should receive attention. A drug historyshould be obtained to identify reversible causes oflichenoid eruptions as discontinuation of theoffending agent can be curative (Eisen et al. 2005).

Hypersensitivity reactions should be suspectedwhen OLLs are confined to oral mucosal sites inclose proximity to dental restorations. An optimaloral hygiene program should be instituted inpatients with gingival disease (Eisen et al. 2005).

Many therapeutic modalities have beensuggested in the treatment of OLP, with the mostcurrently accepted and reliable modality being theuse of topical steroids with consideration to begiven for use of systemic steroids in cases ofsevere widespread disease and/or refractorycases of OLP (Vincent et al. 1990; Al-Hashimiet al. 2007).

Topical Agents

GlucocorticoidsThe most commonly employed and useful agentsfor the treatment of OLP are topical corticoste-roids. A response to treatment with midpotencycorticosteroids such as triamcinolone, potent fluo-rinated corticosteroids such as fluocinoloneacetonide and fluocinonide, and superpotent halo-genated corticosteroids such as clobetasol hasbeen 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 clinicaltrials in the context of corticosteroid use for OLP(four were placebo controlled, one assessed sys-temic corticosteroids). Most studies were notfocused on investigating the value of corticoste-roids in the treatment of OLP per se but comparedthe effectiveness of different formulations, differ-ent classes of corticosteroid, different strengths oftopical steroids, and different frequency of appli-cation. The specific medications included in thereview were fluocinonide, fluocinolone acetonide,triamcinolone acetonide, clobetasol propionate,fluticasone propionate, and betamethasone valer-ate/sodium phosphate for topical therapy, withdosages ranging from 0.025%, 0.1%, to 0.5%and the frequency of application varying fromtwo, 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 theoverall conclusion suggests that corticosteroidsare effective in the management of OLP and areunlikely to cause serious side effects (Al-Hashimiet al. 2007). There were no studies determining ifadhesive vehicles are better than mouth rinses.However, empirical evidence seems to suggest


that mouth rinses are of value in patients withwidespread symptomatic OLP where the lesionsare not easily accessible to the placement ofointments or gels. The evidence also suggeststhat higher potency corticosteroids, such asclobetasol, are probably more effective(Al-Hashimi et al. 2007). There was insufficientevidence regarding different dosages, formula-tions, or modes of delivery of topical steroids(e.g., paste, spray, mouthwash) to make anevidence-based recommendation (Al-Hashimiet al. 2007).

The greatest obstacle in using topical cortico-steroids in the mouth is the lack of adherence tothe mucosa for a sufficient length of time. For thisreason, some investigators prefer using topicalcorticosteroids in adhesive pastes although thereis no data that topical steroids in adhesive basesare more effective than as base preparations(Lo Muzio et al. 2001). Elixir forms of corticoste-roids, such as dexamethasone, triamcinolone, andclobetasol, have been used as an oral rinse forpatients with diffuse oral involvement or forelderly patients who may find it technically diffi-cult to apply medication to various active loca-tions of the oral cavity. Careful considerationshould be given to the vehicle as unlike skincompounds, which have been well studied, clini-cal trials that have compared the strength of corti-costeroids in various bases in the oral cavity aregenerally lacking (Eisen et al. 2005).

Few serious side effects arise with topical cor-ticosteroids as they are generally well tolerated.Side effects reported include secondarycandidosis, nausea, oral use not tolerated, refrac-tory response, mucosal atrophy, oral dryness, sorethroat, bad taste, delayed healing, and systemicabsorption (Savage and McCullough 2005;Thongprasom and Dhanuthai 2008).

Given the high rate of commensal oral yeastcarriage in the community, it is expected that somepatients will develop a secondary erythematouscandidosis or pseudomembranous candidosis(thrush) (Thongprasom and Dhanuthai 2008). Asmany as one-third of OLP patients treated withtopical corticosteroids have been reported todevelop secondary candidosis (Vincent et al.1990) which necessitates treatment or instituting

antifungal therapy before the patient begins usingtopical steroids. Many of these patients can beidentified prior to commencing corticosteroidsand preventive treatment initiated coincident orimmediately 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 cigarettesmoking (Savage and McCullough 2005).

Development of candidosis often leads toimmediate interruption to treatment, prolongedand amplified morbidity, additional treatment forthe infection, delayed management of the originalcondition, and clouding of the baseline pathosispresent. Wherever possible, anticipation and pre-vention are preferable to a reactive response.

A refractory response, described by some astachyphylaxis, 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 behelpful for the gingiva; agent of insufficientpotency; incorrect diagnosis; and failure toremove any local cause, for example, a corrodedamalgam restoration causing a OLR (Savage andMcCullough 2005).

Systemic absorption has been reported, and itis thought that absorption of small amountsthrough the oral mucosa can take place, but clin-ical experience and laboratory studies have shownthis not to be of clinical significance in almost allcases (Savage and McCullough 2005).

Interestingly, although systemic absorptionand adrenal suppression were reported withlong-term use of superpotent corticosteroids forchronic skin diseases (Levin and Maibach 2002),this does not seem to be the case with oral corti-costeroids used for OLP (Thongprasom andDhanuthai 2008). Exceptions arise, and this is anissue that should receive consideration with par-ticular patient groups along with the occasionalidiosyncratic response. Patients with medical con-ditions that are of particular concern include dia-betes, hypertension, and tuberculosis. Steroidmouth rinses in patients with extensive areas of


disease and excessive and unmonitored usage arealso a concern.

Therefore, careful and frequent follow-upexaminations are necessary especially withchronic use of topical corticosteroids. Temporaryburning or stinging at the site of application hasalso been reported with triamcinolone acetonide0.1% ointment (Laeijendecker et al. 2006).

In general, it has been recommended that ther-apy should be initiated with a potent preparationto achieve a rapid response, particularly in erosiveOLP lesions, and then lowering the strength withhealing, and eventually once the disease becomesinactive and there is either an absence of lesions orthe presence of only white reticular lesions, therapymay 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 anunwanted systemic dose (Eisen et al. 2005).

Calcineurin InhibitorsCalcineurin inhibitors are microbially derivedimmunosuppressive agents that have been primar-ily used in transplant medicine and in the treat-ment of immune-mediated diseases with theprinciple agents being tacrolimus, pimecrolimus,and cyclosporine (Al Johani et al. 2009).

Calcineurin inhibitors bind to different cyto-plasmic proteins of T lymphocytes (cyclosporineto cyclophilin, tacrolimus, and pimecrolimus toFK506-binding protein) to form complexes thatin turn inhibit calcineurin leading to suppressionof transcription and production of many cyto-kines. Calcineurin inhibitors have been suggestedto be of clinical benefit in the management ofsome immunologically mediated oral mucosaldisorders including OLP (Al Johani et al. 2009).

There are now numerous reports of the efficacyof calcineurin inhibitors in the management ofOLP, and effectiveness has been assessed viaopen-label prospective studies, randomized trials,retrospective studies, case series, and described inseveral case reports (Lodi et al. 2005; Al-Hashimiet al. 2007; Al Johani et al. 2009). Initial studies

focused on patients with symptomatic OLP thathad not responded to topical corticosteroids orwho were at risk of adverse side effects fromcorticosteroids. In their review, Al-Hashimi et al.(2007) assessed four studies regarding cyclospor-ine use for OLP (three used 500 mg mouthwashand one used adhesive gel form). In all of thestudies, the side effects were minimal and mainlyconsisted of a transient burning sensation, badtaste, and high cost. In OLP patients, systemicabsorption is probably low, and most studies didnot detect cyclosporin in peripheral blood. Theresults of all of the studies showed a markedimprovement in the oral symptoms. However,cyclosporine mouth rinse was not significantlybetter than 1% triamcinolone paste in a controlled,randomized prospective trial that involved13 OLP patients randomly assigned to treatmentwith cyclosporine rinse or triamcinolone paste for6 weeks (Sieg et al. 1995).

In general, cyclosporin can be an alternative toconventional treatments for initial control of OLP.However, it should not be considered as a firstdrug of choice because of the high cost of long-term treatment and the availability of effectivealternatives. Severe side effects of systemic cyclo-sporin, such as hypertension and nephrotoxicity,preclude its long-term use for OLP (Lodiet al. 2005).

Tacrolimus is a macrolide immunosuppressantderived from Streptomyces tsukubaensis. It is arelatively selective inhibitor of calcineurin andwas initially developed as a systemic agent tolessen allograft rejection. Tacrolimus has the abil-ity to inhibit T-cell activation at 10–100 timeslower concentration than cyclosporin. Notably,topical tacrolimus seems to penetrate skin betterthan topical cyclosporin (Lodi et al. 2005; AlJohani et al. 2009). Formulated for topical appli-cation in the management of atopic dermatitis(AD), it was approved in 2000 by the UnitedStates Food and Drug Administration (FDA) tobe used in moderate to severe AD for patientsolder than 2 years. Topical tacrolimus has provento be of benefit in the treatment of other disordersincluding cutaneous psoriasis, contact allergy,corticosteroid-induced rosacea, pyodermagangrenosum, alopecia areata, mucocutaneous


LP, and GVHD (Al Johani et al. 2009). Topicaltacrolimus is available in different concentrations(0.03%, 0.1%).

Systemic tacrolimus is substantially lessexpensive and 10–100 times more potent thancyclosporine, even though relative potency oftopical preparations has never been evaluated.Tacrolimus used topically can control symptomsand significantly improve refractory erosive OLP(Hodgson et al. 2003). Local irritation is the mostcommon adverse effect reported (Lodi et al. 2005;Al Johani et al. 2009). Other side effects includetransient taste disturbance and sore throat.Tacrolimus ointment 0.1% was shown to be welltolerated and appeared to be effective in erosiveOLP that did not respond to topical steroids in asmall cohort of six erosive OLP (Morrison et al.2002). Although topical tacrolimus is effectiveand well tolerated, some OLP patients havenoted flare-ups soon after stopping the treatment.The treatment of chronic erosive oral LP with lowconcentrations of tacrolimus was found to yield arapid and important palliative effect in an open-label prospective study that included eight erosiveOLP with 6 months of treatment; however, allpatients relapsed after 12-month follow-up (Oliv-ier et al. 2002). Currently, there remains littleevidence demonstrating that tacrolimus is notablysuperior to topical corticosteroids for the treat-ment of OLP (Al Johani et al. 2009).

Pimecrolimus is derived from the macrolideascomycin and shares the same cellular bindingprotein (FK506-binding protein-12) as tacrolimusand blocks the transcription of cytokines byinhibiting the calcineurin pathway. Topicalpimecrolimus is a cream developed specificallyfor the treatment of AD and approved for thetreatment of patients with mild to moderate ADdisease in patients older than 2 years. There iscurrently limited data on the potential use of topicalpimecrolimus for the treatment of oral mucosaldisease, 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) foundno difference between pimecrolimus 1% creamand tacrolimus 0.1% ointment in managing recal-citrant atrophic-erosive OLP in an 8-week

randomized, double-blind controlled trial,followed by a 6-month follow-up period in30 unresponsive OLP patients. Both agents wereeffective in inducing clinical improvement; how-ever, pimecrolimus showed better stability in ther-apeutic effectiveness with statistically significanthigher number of patients (10 vs. 4) not requiringany further treatment at the end of the follow-upperiod.

The theoretical increased risk of developingmalignancy with use of either tacrolimus orpimecrolimus has been raised with the FDA; inthe USA “Black Box” warning attached to theseagents is based on theoretical increased risk ofmalignancy (SCC and lymphoma) in patientsusing these agents for cutaneous psoriasis. In arecent case report of a patient with OLP, the top-ical use of tacrolimus 0.1% was suggested to bethe cause of the development of an SCC of thetongue (Becker et al. 2006). Therefore, someauthors believe that the use of these agents shouldbe restricted and patients should be made aware ofthese concerns (Al-Hashimi et al. 2007). On theother hand, other researchers find that althoughsystemic tacrolimus may increase the risk ofmalignancy, there is no strong evidence that top-ical application of tacrolimus is associated withsuch an increased risk (Al Johani et al. 2009). Insupport of this view, a recent case-control studythat involved 294 patients did not find anyincreased risk of lymphoma in patients with ADtreated with topical calcineurin inhibitors(Arellano et al. 2007).

Overall, there remains little information of thecarcinogenic potential of tacrolimus orpimecrolimus, and the new recommendations fromthe European Medicines Agency state that the ben-efits of these calcineurin inhibitors outweigh therisks. The European Medicines Agency, however,recommends intermittent use of topical tacrolimuswith the lowest strength possible and only for shortperiods of time (Al Johani et al. 2009).

RetinoidsSystemic and topical forms of retinoids have beenused 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


atrophic-erosive forms, with considerable improve-ment (Scardina et al. 2006), but retinoids often causeadverse effects and are less effective than topicalcorticosteroids (Scully and Carrozzo 2008).

Topical Antifungal Therapy in OLPThe role Candida plays in the symptomatology ofOLP is currently unknown. Based on the currentevidence, a question therefore arises as to whetherantifungals are required to treat symptomatic OLPalong with corticosteroids, not only prevent sec-ondary candidosis and the symptoms associatedwith this but also as a prophylactic treatment toreduce Candida spp. overgrowth and the associ-ated factors which may encourage a carcinogenicevent. A randomized double-blinded clinical trialundertaken by Lodi et al. (2007) with 35 patientsreviewed the efficacy of topically appliedclobetasol propionate with and without topicalmiconazole in patients with symptomatic OLP.Results showed significant improvement in boththe test ( p = 0.0020) and control ( p < 0.001)groups, and it was concluded while miconazoleprevented secondary candidosis, which occurredin 30% of control subjects; however adjunctivetopical antifungal treatment did not affect the effi-cacy of treatment or improve outcomes such aspain or lesion extension (Lodi et al. 2007). Due tothe current lack of controlled studies and literaturein this particular area, recent systemic review byLodi et al. (2012) and Cochrane review byThongprasom et al. (2011) concluded that thereis currently insufficient evidence to determinewhether adjunctive antifungal therapy is effectivein 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 forOLP; however, a comparative study that involveda total of 49 OLP patients did not find differencesin response between systemic prednisone (1 mg/kg/day) with topical clobetasol in an adhesivebase (n = 26) and topical clobetasol alone

(n = 23) after a mean follow-up period of36 months (Carbone et al. 2003). Complete remis-sion was achieved in 68% of the prednisone groupand 705 of the topical clobetasol group(P = 0.94).

Systemic corticosteroids are, therefore, usuallyreserved for cases where topical approaches havefailed, where there is recalcitrant, erosive, or ery-thematous OLP, or for widespread OLP when theskin, genitals, esophagus, or scalp is also involved(Al-Hashimi et al. 2007; Scully and Carrozzo2008). Prednisolone 40–80 mg daily is usuallysufficient to achieve a response: its toxicityrequires that it should be used only when neces-sary, at the lowest dose, and for the shortest timepossible with recommendation of (5–7 days) andthen withdrawn abruptly, or the dose should bereduced by 5–10 mg/day gradually over2–4 weeks (Scully and Carrozzo 2008). Adverseeffects are possible even with short courses butmay beminimized if patients can tolerate the sametotal dose on alternate days.

Systemic calcineurin inhibitors are associatedwith significant adverse effects including hyper-tension, nephrotoxicity, and infections secondaryto immunosuppressive status of the patients whichcorrelated 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) bysuppressing immune surveillance and inhibitingDNA repair and apoptosis (Yarosh et al. 2005).Therefore, systemic calcineurin inhibitors are notrecommended for OLP treatment.

Miscellaneous Agents

AzathioprineAzathioprine has been reportedly successful as a“steroid-sparing agent” for cutaneous LP, andthere is limited published evidence suggesting itmay have a similar role in recalcitrant OLP(Silverman et al. 1991). In general, the resultsare no better than systemic steroids alone or sys-temic steroids in conjunction with topical steroids(Lodi et al. 2005b).


DapsoneDapsone has been used in the treatment of erosiveOLP with some benefit (Beck and Brandrup1986). It should be considered in resistant cases,particularly when severe erosive lesions are pre-sent. Significant adverse effects such as hemolysishave been reported, and thus the use of dapsone inthe treatment OLP is generally not recommended(Matthews et al. 1989).

Mycophenolate MofetilMycophenolate has shown promise as an alterna-tive to azathioprine as an immunomodulatoryagent with a better safety profile in the manage-ment of graft rejection in organ transplant recipi-ents, and GVHD, and therefore may be acandidate for use in recalcitrant OLP (Eisen2003). In a recent retrospective review of clinicalresponses of ten patients with severe ulcerative LP(vulvovaginal with gingival involvement, n = 8;penogingival, n = 1; oral, n = 1) treated withmycophenolate, Wee et al. (2012) showed remis-sion in six patients, well-controlled disease in one,and partially controlled in the other three. Themean duration for mycophenolate treatment was3.7 years, and the mean follow-up was 4.2 years.Mycophenolate was well tolerated in all patientsexcept in two who reported mild headaches andtiredness (Wee et al. 2012).

Aloe veraAloe vera (AV) is a cactus-like plant that belongsto the Liliaceae family. The reported pharmaco-logical actions of AV include anti-inflammatory,antibacterial, antiviral, and antifungal propertiesand hypoglycemic effects (Yagi et al. 2002). Top-ical Aloe vera is an emerging new modality in thetreatment of OLP that has been recently investi-gated. In a randomized double-blind study, AVmouthwash significantly improved the oral qual-ity of life for 32 OLP patients over a period of3 months as compared to a placebo group(Salazar-Sanchez et al. 2010). In another study,comparable effects of AV mouthwash werereported when compared to 0.1% triamcinoloneacetonide paste in a group of OLP patients (n= 23each) in terms of VAS of pain, burning sensation,clinical presentation, and healing of the OLP

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 evidencefrom two placebo-controlled RCTs, using differ-ent formulations, that AV may be associated witha reduction in pain in OLP (Choonhakarn et al.2008; Salazar-Sanchez et al. 2010). It should beemphasized that the above trials used different AVformulations and the amount of active drug sub-stance in AV varies depending also on the age ofthe plant, the growing and harvesting conditions,the parts of the plant, and the extraction methodsused. The great level of variability could haveaffected the results of the published studies andrepresents a challenge for future research(Thongprasom et al. 2013).

BiologicsThe management of various immune-mediateddisorders has changed dramatically by the adventof biologic therapies. Biologics are designed byrecombinant biotechnology to target particularsteps in the pathogenesis of immunoinflammatorydiseases. Structurally, biologics include receptorfusion proteins, monoclonal antibodies, andrecombinant cytokines. Functionally, biologicscan be divided into T-cell or cytokine modulators(Zhang et al. 2011). Various immunobiologicshave been recently applied in the treatment ofpsoriasis and rheumatic diseases as biologicimmunomodulators may represent a more effec-tive and targeted approach than conventionaltreatment modalities (Shirota et al. 2008).

Various diseases including Behcet’s disease,recurrent aphthous stomatitis, benign mucousmembrane pemphigoid, and LP are consideredpotential 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-αinhibitors, are suggested as a future alternative tosteroid therapy. However, possible reactions andside effects will always be a major concern (Zhanget al. 2011).

TNF-α inhibitors currently available areetanercept, infliximab, and adalimumab, all of


which are FDA approved for psoriasis. The clin-ical feasibility has been demonstrated not only bya successful treatment of LP with etanercept(Yarom 2007) but also by the efficacy ofadalimumab for the treatment of cutaneous andOLP (Chao 2009). Moreover, there are severalongoing clinical trials to evaluate the safety andeffectiveness of etanercept in treating oral andcutaneous LP. According to a recent review byO’Neill and Scully (2013), the best data, althoughlimited, are for the use of the T-cell modulatoralefacept in OLP. Limitations on future studieswith such agents include the need for continuousor intermittent use of anti-TNF-α therapy for long-term control of OLP and the fact that TNF-αblockers have the potential for initiating lichenoideruptions (Asarch et al. 2009).This possiblyaccounts for the rarity of reports of use of TNFantagonists in LP to date and may be a barrier tofurther use. Additional concerns center around thepotential for reactivation of viral infections withconcern about those patients with LP who haveconcomitant HCV infection (Lodi et al. 2010).The potential risk of malignancy in LP and thosereports of the development of oral cancer inpatients receiving TNF-α blockers may be anadditional reason to use these agents with caution(O’Neill and Scully 2013).

Other Agents and Treatment ModalitiesOther agents have been suggested for OLP treat-ment but with weaker evidence. These includelevamisole, amitriptyline, amlexanox, hyaluronicacid, 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 widerange of treatment options is available for patientswith OLP, the level of clinical efficacy is incon-sistent, and individualized protocols are requiredin cases with recalcitrant OLP.

Recently, Lodi et al. (2012) reviewed 28 ran-domized controlled trials (RCTs) in the context ofinterventions for OLP. Although topical corticoste-roids are considered to be the first-line treatment,no RCTs were identified that compared topical

corticosteroids with placebo in patients with symp-tomatic OLP. From the 28 trials included in thissystematic review, the wide range of interventionscompared means there is insufficient evidence tosupport the superior effectiveness of any specifictreatment (Lodi et al. 2012).

Follow-up

Patient follow-up ranging from every 2 months toannually is accepted as part of long-term care forpatients with OLP largely to screen for changesthat may indicate malignant transformation(Mignogna et al. 2006). At a minimum, annualmonitoring is recommended (Al-Hashimi et al.2007; Parashar 2011) and favorably two to fourreviews (Scully et al. 1998; Mattsson et al. 2002;van der Meij et al. 2007). More frequent exami-nations are recommended for patients with OLLwith dysplasia.

If changes are noted in a lesion at follow-upvisits, then an additional biopsy or biopsies shouldbe 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 examinationsevery 2 months during the 5- to 9-month periodafter the diagnosis of oral carcinoma, when therisk of metastasis or second primary tumor ismaximum. The same authors subsequentlyreported that a program of three follow-up exam-inations a year enables detection of malignanttransformation in early or microinvasiveintraepithelial states, which generally have avery good prognosis (Mignogna et al. 2006).

Conclusion

LP is a common chronic inflammatory disease ofthe skin and oral mucosa with an estimated prev-alence of 0.5–2%. Although the cause of OLP isunknown, it is thought to result from the complexinterplay of host, lifestyle, and environmental fac-tors resulting in cell-mediated immune


dysregulation. The oral appearance of OLP hasbeen described as six clinical subtypes seen indi-vidually or in combination (reticular, plaque-like,atrophic, erosive, papular, and bullous), with themost common being reticular occurring bilaterallyin the posterior buccal mucosa.

Symptoms and signs can range from patientsbeing unaware of the disease, with lesions that arecompletely asymptomatic as in reticular OLP, tothose experiencing mucosal sensitivity and burn-ing and debilitating pain. Treatment generallyconsists of the topical use of anti-inflammatoryagents for symptomatic relief. Malignant transfor-mation of OLP remains a controversy and vari-ably reported between 0% and 5%. Obviouslythere is much that remains unknown regardingoral mucosal lichen planus, such as the exactcause, pathogenic mechanism involved, and pro-cess by which malignant transformation occurs.Further directed research is required so that wemay 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 NeckRegion

▶Gingival Pathology▶ Interface Between Oral and Systemic Disease▶LaboratoryMedicine and Diagnostic Pathology▶Normal Variation in the Anatomy, Biology andHistology of the Maxillofacial Region

▶Oral and Maxillofacial Fungal Infections▶Oral Manifestations of Systemic Diseases andtheir Treatments

▶Oral Mucosal Malignancies▶Oral Ulcerative Lesions▶Oral Vesicular and Bullous Lesions▶Orofacial Pain in Patients with Cancer andMucosal Diseases

▶ Pharmaco-Therapeutic Approaches in OralMedicine

▶White and Red Lesions of the Oral Mucosa

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