Oral Lichen Planus. Michael J. McCullough, Mohammad S. Alrashdan, and Nicola Cirillo. Contents

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

2 2 M.J. McCullough et al. Pathogenesis of OLP... 6 The Immunology of the Oral Cavity... 6 Pathogenic Mechanisms of OLP... 7 Clinicopathologic Features Clinical Appearance Signs, Symptoms, Clinical Behavior and OLP Scoring Systems Histopathology of OLP Oral Lichenoid Reactions (OLR) Cutaneous Lesions Other Mucosal Lesions Malignant Potential of OLP OLL and Cancer Tumors Developing in OLP and their Carcinogenesis Patient Management Topical Agents Systemic Drug Treatment Miscellaneous Agents Follow-up Conclusion Cross-References References Introduction The term lichen planus (LP) is derived from the Greek word leichen meaning tree moss and the Latin planus meaning flat. Erasmus Wilson first described the condition LP in 1869, as a chronic inflammatory disease affecting the skin, scalp, nails, and mucosa, with possible rare malignant transformation (Farhi and Dupin 2010). LP may involve the hair follicles (lichen planopilaris, resulting in scarring alopecia), nails, esophagus, and, more seldom, the eyes, urinary tract, nasal mucosa, and larynx (Parashar 2011). The oral variant, oral lichen planus (OLP), is a chronic inflammatory disease affecting the oral mucosa with characteristic relapses and remissions (Scully et al. 1998; Eisen et al. 2005; Lodi et al. 2005a). While cutaneous lesions of LP are generally self-limiting and pruritic, oral lesions are commonly chronic, non-remissive, and can be a source of morbidity (Scully et al. 1998). The diagnosis of OLP is usually made by clinical and histological examinations. However, in classical lesions (bilateral, reticular pattern), it is possible to make a diagnosis based on their clinical appearance alone (Epstein et al. 2003). Additionally, there is a spectrum of oral lichenoid lesions (OLLs) that may confuse the differential diagnosis. These include lichenoid contact lesions, lichenoid drug reactions, and lichenoid lesions of graft-versus-host disease. Systemic medications, such as nonsteroidal antiinflammatory drugs, antihypertensives, and oral hypoglycemics, can contribute to the development of oral lichenoid reactions (OLRs) (Ismail et al. 2007). Dental restorative materials, including amalgam, gold, and nickel, may also be related to localized OLRs in a number of patients (Epstein et al. 2003). Treatment is not always necessary, unless OLLs are symptomatic (Scully et al. 1998). Management of symptomatic OLLs varies considerably and ranges from elimination of precipitating or provoking local and systemic factors, psychosocial interventions, to long-term pharmacological therapies. Thus, although OLP localizes to the oral cavity, there are broader implications in terms of patient management that warrant careful consideration. The ongoing controversy as to whether OLP is associated with an increased risk of malignant transformation adds further complexity to this disease. Epidemiology The estimated prevalence of OLP in general adult population is 0.5 2% (Scully et al. 1998; Eisen et al. 2005). However, because of a lack of standardized approaches to the clinical diagnosis of OLP and OLL, it is difficult to draw accurate figures about the prevalence of OLP. In a demographic study from Sweden, 20,333 people aged 15 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 a prevalence of 2.6% (Murti et al. 1986). A report from Malaysia showed a relatively low prevalence of 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

3 Oral Lichen Planus 3 generally between 30 and 60 years (Scully et al. 1998; Al-Hashimi et al. 2007; Farhi and Dupin 2010). However, there have been case reports of OLP occurring in children, with a 17% prevalence of oral involvement in a population of 100 children diagnosed with LP at a mean age of 8.7 years in one report (Kanwar and De 2010). Genital and cutaneous LP are associated with approximately 20% and 15% of OLP cases, respectively, while it is estimated that OLP occurs in 70 77% of patients with cutaneous LP (Scully et al. 1998; Farhi and Dupin 2010; Kanwar and De 2010). Etiology OLP is not a classical autoimmune disorder, and the precise etiology of this condition is unknown. However, given that cell-mediated immune dysregulation targeting the stratified squamous epithelia has been shown to be associated with the pathogenesis of OLP (Epstein et al. 2003; Eisen et al. 2005; Lodi et al. 2005a), it is possible that a LP-specific epidermal antigen is present in some epithelial cells. The nature of the antigen, however, remains uncertain. Several predisposing factors have been reported to be associated with OLP and OLLs. Genetic Background Genetic background seems to play a role in OLP pathogenesis as several familial cases have been reported (Bermejo-Fenoll and Lopez-Jornet 2006); however the association has not been consistent. In terms of HLA associations, an increase in HLA-B15, Bw57, B5, B7, BX, DR2 and a decrease in the frequency of HLA-DQ1, DR4, and B18 has been noted for OLP (Roitberg- Tambur et al. 1994). On the other hand, in a comprehensive review of literature, Porter et al. reported no significant association with any particular HLA types in familial LP (Porter et al. 1997). Genetic polymorphisms of several cytokines have been postulated to be associated with the clinical presentation of LP. Interferon-gamma (IFN-γ) UTR 5644 genotype frequencies showed a significant increase in number of T/T homozygotes in a sample of OLP patients (n = 44) compared with controls (n = 140) (40.9% vs. 22.9%; p = ) (Carrozzo et al. 2004). It has been suggested that genetic polymorphism of the first intron of the promoter gene of IFN-gamma may be an important risk factor to develop oral lesions of LP, whereas an increase in the frequency of 308A TNF-alpha allele may best contribute to the development of additional skin involvement. More recently, the concept that a particular genetic background may be important in a subset of patients with OLP has been presented (Carrozzo et al. 2011). In particular, this study suggested that those patients who had both OLP and chronic hepatitis C infection may well have particular HLA-Cw* alleles (Carrozzo et al. 2011). Nevertheless, the overall statement that OLP is a genetically determined disease has not been confirmed, and further studies in different geographic areas are required. Infectious Agents Many infectious agents, principally viruses, have been studied in association with OLP, but the evidence is generally sparse. Other infectious agents, such as Helicobacter pylori, were also suggested to have a link to OLP by some authors (Shimoyama et al. 2000). The viruses for which an association with OLP has been suspected can be classified in two groups: (1) viruses for which an association with OLP has been anecdotally suggested and (2) viruses for which there is abundant documentation of an association with OLP, although with marked geographic disparities (discussed in section Systemic Associations ). Varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV6), human papillomavirus (HPV), and human immunodeficiency virus (HIV) have all been postulated in different studies to have an association with an increased incidence

4 4 M.J. McCullough et al. of OLP, yet definitive evidence for the association is lacking (Lodi et al. 2005a; Farhi and Dupin 2010). For example, the receptor for EBV (CD21) was shown to be upregulated in OLP, and a significantly higher optometric density of EBV antiearlier antigen (EA) IgG positivity has been reported in a sample of OLP patients (n = 22) compared with controls (n = 22), despite no difference in the frequency of both EBV IgG and IgM for EA and nuclear antigen-1 (EBNA) (Pedersen 1996). In summary, while association between OLP and infectious agents has been reported, at present there is no evidence for a causative role of these microorganisms in OLP. Psychological Factors Psychological factors are thought to play a role in the pathogenesis of OLP. A group of OLP patients (n = 9) exhibited higher levels of anxiety, greater depression, and increased vulnerability to psychological disorders, as opposed to a group of 20 healthy controls (Soto Araya et al. 2004). In another study that involved 100 OLP patients, those with erosive LP were shown to exhibit higher depression scores than patients with nonerosive LP (Rojo-Moreno et al. 1998). In addition to the chronic discomfort that can result in stress, patients with OLP were shown to be concerned about the possibility of malignancy, the contagious nature of the disease, and the lack of available patient educational materials (Burkhart et al. 1997). Exacerbations of OLP have been linked to periods of psychological stress and anxiety in some studies (Rojo-Moreno et al. 1998). In a study that involved 40 OLP patients (20 reticular and 20 erosive OLP) assessed against 25 healthy controls using the psychological Minnesota Multiphasic Personality Inventory (MMPI)-202 test, Ivanovski et al. hypothesized that prolonged emotive stress in many OLP patients may lead to psychosomatization (as shown by significantly higher mean scores of internalization ratio index in OLP groups) which in turn may contribute to the initiation and clinical expression of OLP (Ivanovski et al. 2005). However, as a common issue in studies of this type, the authors were unable to determine whether the observed psychological alterations constitute a direct cause or a consequence of OLP. When the levels of anxiety and salivary cortisol were measured in a group of OLP patients (n = 40), the scores were statistically correlated and significantly higher than a control group (mean state anxiety level = 49 vs. 40, cortisol levels = 1.46 vs μg/dl) (Koray et al. 2003). In conclusion, in spite of the presence of higher levels of psychological stress and anxiety among OLP patients, the question remains whether the psychological factors contribute to the etiology of OLP or represent a part of resulting morbidity. Trauma Trauma as such has not been reported as an etiological factor in OLP, although it has been postulated as a mechanism by which other etiological factors may exert their effects (Scully et al. 1998). However, no studies were conducted to verify this hypothesis. The Koebner phenomenon (isomorphic response), whereby OLP lesions develop in response to mechanical trauma, may partially explain why OLP lesions develop commonly in sites prone to trauma, i.e., the buccal mucosa or lateral surfaces of the tongue (Eisen et al. 2005). Systemic Associations OLP may be associated with some systemic diseases; however, few have been thoroughly investigated. The most studied are the associations with hepatitis C, hypertension, diabetes, thyroid disease, and graft versus host disease. Hepatitis C Virus (HCV) Along with porphyria cutanea tarda and cryoglobulinemia, OLP is one of the three dermatologic diseases that have been most frequently reported in patients infected with HCV (Farhi and

5 Oral Lichen Planus 5 Dupin 2010). The first report appeared in 1991 (Mokni et al. 1991) and suggested an association between OLP and HCV seropositivity. Since then, the association has been well documented in some Mediterranean populations (Carrozzo et al. 1996; Erkek et al. 2001), in Japan (Nagao et al. 1995), and in a United States metropolitan population (Beaird et al. 2001). Nevertheless, an association between OLP and HCV seropositivity could not be demonstrated in France (Dupin et al. 1997), the United Kingdom (Ingafou et al. 1998), and in countries with high HCV prevalence, such as Egypt (HCV prevalence estimated at 14.7%) (Ibrahim et al. 1999), and Nigeria (HCV prevalence estimated to range from 5% to 20%) (Daramola et al. 2002). A systematic review of HCV prevalence in LP patients and in matched controls without LP yielded 25 relevant studies, including eight with only OLP (Lodi et al. 2004). A significantly higher proportion of HCV seropositivity was documented in patients with OLP, with an odds ratio (OR) of 5.7 (95% confidence interval, ). This association was stronger in Mediterranean countries (OR 6.63, 95% CI, ) but disappeared in Northern Europe such as in Germany and the United Kingdom (OR 2.14, 95% CI, ). Three more recent independent meta-analyses (Shengyuan et al. 2009; Lodi et al. 2010; Petti et al. 2011) have provided robust evidence that LP and HCV are associated. Overall, there is a significant positive association noted in studies across the world, although the association is more homogeneous in studies from East and Southeast Asia and South America than in studies from the Middle East and Europe (Baccaglini et al. 2013). In HCV-positive patients, the estimated prevalence of LP is % (Farhi and Dupin 2010) being higher than expected in the respective geographic areas. In a study from Italy, 44 OLP patients positive for HCV were compared to a group of 144 OLP patients negative for HCV. HCV-related OLP group showed a significantly higher association with HLA class II allele HLA-DR6 (52% vs. 18%), which may partially explain the peculiar geographical heterogeneity of the association between HCV and OLP, probably depending on the presence of certain HLA subtypes (Carrozzo et al. 2001). Hypertension and Diabetes Mellitus Although OLP patients do not seem to have an increased risk of diabetes, diabetics who develop OLP were reported to have an increased frequency of atrophic-erosive lesions, especially affecting the tongue (Bagan et al. 1993). However, this was not confirmed in any further studies. An association between OLP, diabetes mellitus, and hypertension was first described by Grinspan in a small series of seven patients (Grinspan et al. 1966). The triad was later named as Grinspan s syndrome. Although Grinspan s syndrome may be seen clinically, the association between the three conditions may represent a coincidental finding or probably an OLR to medications used to manage hypertension or diabetes rather than a true syndrome (Scully et al. 1998). Thyroid Dysfunction The association between OLP and thyroid dysfunction was recently investigated in a retrospective Finnish study that confirmed a link between OLP and hypothyroidism in particular (Siponen et al. 2010). This study compared data of 222 OLP patients with 222 age- and sex-matched controls and revealed that 10% of OLP patients (n = 15) versus 5% of the controls (n = 11) had hypothyroidism (OR 2.39, , CI 95%). Other studies suggested a relationship between OLP and hyperthyroidism. Overall, more welldesigned, large population-based studies are required to confirm whether an association between OLP and thyroid disorders does exist. Graft Versus Host Disease (GVHD) Nearly 15,000 patients worldwide receive allogenic hematopoietic cell transplants (HSCT) each year, and GVHD will eventually develop in about 40 70% and will represent the leading cause of death in such patients (Imanguli et al. 2008). Acute GVHD occurs within the first 100 days of transplantation and comprises dermatitis, enteritis, and hepatitis with immunosuppression and cachexia. Chronic GVHD develops after day

6 6 M.J. McCullough et al. 100 and comprises an autoimmune-like syndrome comparable to ulcerative colitis, primary biliary cirrhosis, Sjögren s syndrome, rheumatoid arthritis, and lupus-like disease with glomerulonephritis. The skin is a primary target in chronic GVHD and exhibits either a lichenoid eruption or sclerodermatous changes (Lodi et al. 2005a). Oral involvement occurs in 33 75% of patients with acute GVHD and up to 80% of patients with chronic GVHD (Imanguli et al. 2008). Oral mucosal GVHD resembles OLP both clinically and histologically. Squamous cell carcinoma (SCC) may develop in oral and cutaneous chronic GVHD, as reported in few case reports (Lodi et al. 2005b). Most patients who undergo allogeneic HSCT receive stem cells from MHC-identical donors. In these patients, GVHD is initiated by donor T cells that recognize a subset of host peptides called minor histocompatibility antigens (mihas). Although the antigen specificity of LP and mucocutaneous GVHD is probably distinct, it is likely that they share similar immunological effector mechanisms resulting in T-cell infiltration, epithelial basement membrane disruption, basal keratinocyte apoptosis, and clinical disease (Lodi et al. 2005a). The role of TNF-alpha as a major effector molecule in GVHD has been confirmed in a number of experimental systems. Importantly, neutralizing anti-tnf-alpha antibodies have been shown to alleviate cutaneous and intestinal GVHD in both mice and humans (Herve et al. 1992; Brown et al. 1999). Pathogenesis of OLP Much is still not known about the etiopathogenesis of OLP. OLP is characterized by a chronic T-cell inflammatory infiltrate with basal cell degeneration including vacuolar degeneration, hyperkeratosis or parakeratosis, and sawtooth rete ridges (Sugerman et al. 1993, 2002; Zhou et al. 2002). The mechanism that irreversibly switches on this process resulting in the chronic disease state is currently unknown. There are multiple theories on OLP pathogenesis and the mechanisms that underpin the ongoing chronic inflammatory process. In order to better understand the pathobiological events that underlie the development of OLP lesions, it is important to recall some basic concepts of oral immunology. The Immunology of the Oral Cavity The oral cavity immune system consists of innate and adaptive immune system components. The innate immune system consists of all the immune defenses that lack an immunologic memory (Delves and Roitt 2000). In the oral cavity the oral mucosa serves as a mechanical barrier to microbial colonization. Loss of tissue integrity places the oral cavity at risk of opportunistic microbial infection. Saliva makes up another portion of the oral innate immune system. Saliva is rich in water and mucin that acts to provide a moist barrier that helps to limit microbial colonization. It also consists of numerous ions, such as bicarbonate, phosphate, etc., that neutralize ph and keep the saliva supersaturated to prevent tooth demineralization. Salivary antibodies, specifically secretory IgA, exist in saliva and act as a first line of defense by limiting colonization and invasion of microorganisms into the epithelium (Brandtzaeg 2007; Feller et al. 2013). Saliva contains numerous nonimmune innate factors such as salivary peroxidase, myeloperoxidase, lysozyme, cystatins, proline-rich proteins, mucin, peroxidase, lactoferrin, and statherin which also work to prevent microbial colonization through antifungal, antibacterial, antiviral, and antiparasitic properties (Tenovuo 1998). The oral innate immune response also consists of phagocytic cells such as macrophages and neutrophils. Macrophages are phagocytic cells derived from monocytes, while neutrophils are polymorphonuclear granulocytes. Both work to detect infections organisms and destroy infectious organisms through the process of phagocytosis (Aderem 2003). Eosinophils, basophils, and mast cells also constitute part of the oral innate response working to protect against parasites (eosinophils) while also being involved in the host allergic reactions. Mast cells especially are

7 Oral Lichen Planus 7 thought to play an important immunological role in OLP (Zhou et al. 2002). Natural killer (NK) cells target and destroy tumor cells as well as viruses as part of the oral innate immune response by recognizing peptides presented in the context of major histocompatibility complex (MHC) class I molecules. The complement system is a series of 20 serum glycoproteins that form membrane attack complexes; opsonization and chemoattractants work to upregulate phagocytosis and mobilize the host immune system to clear pathogens (Delves and Roitt 2000). The adaptive immune response in the oral cavity consists of antigen-presenting cells (APC), T cells and B cells. The main difference between the adaptive and innate immune system is the adaptive immune system s ability to tailor the response to suit different pathogens as well as remember past microbial and viral challenges. The adaptive immune system also uses MHC molecules, specifically MHC I and II, to distinguish self from nonself to allow for a targeted immune response (Delves and Roitt 2000). The APCs of the adaptive immune system recognize foreign, nonhost proteins, known as antigens. APC of the adaptive immune system includes macrophages, B cells, dendritic cells, and Langerhans cells. Langerhans cells reside in the epidermis with the highest counts found in the nonkeratinized oral mucosal tissues including the ventral tongue, soft palate, lip, and floor of mouth (Daniels 1984). Langerhans cells are thought to potentially play a role in the pathogenesis of OLP (Sugerman et al. 2002; Roopashree et al. 2010; Gueiros et al. 2012). The major task of plasma cells (which are terminally differentiated B lymphocytes), is to produce immunoglobulins, specifically IgA, IgG, IgM, IgE, and IgD. Secretory IgA is the primary antibody of the oral cavity found in present in saliva which acts as the first line of defense (Brandtzaeg 2007; Feller et al. 2013). The other major task of B cells is the production of memory B cells whose function is to circulate through the body and mount a rapid response against previously recognized antigens (Delves and Roitt 2000). T cells are the major effector cell in cellmediated immunity. They consist of helper T cells (CD4+) which recognize MHC class II molecules, cytotoxic T cells (CD8+) which recognize MHC class I molecules present on all cells, regulatory T cells which are essential for preventing autoimmune diseases while also limiting chronic inflammation, NK cells, and memory T cells (Delves and Roitt 2000; Vignali et al. 2008). Helper T cells play an important role in coordinating the adaptive immune response by promoting cellular (cytotoxic T-cell-mediated, via activation of TH1) or humoral (B-cell-mediated, via TH2 activation) types of response. Cytotoxic T cells on recognition of a foreign antigen induce apoptosis in the infected cell. OLP is characterized by T-cell accumulation, specifically cytotoxic T-cell accumulation, within the superficial lamina propria that is directed at the basal cell layer (Sugerman et al. 2002; Roopashree et al. 2010). It is this chronic cytotoxic T-cell inflammatory process which defines the chronicity of OLP. Pathogenic Mechanisms of OLP The work of Sugerman and colleagues in the 1990s and early 2000s in the field of OLP pathogenesis and disease mechanisms established the basis of most research conducted thereafter (Sugerman et al. 1994, 1995, 1996, 2000, 2000, 2002; Khan et al. 2003). In general these mechanisms can be divided into specific and nonspecific ones, which involve T cells and dendritic cells activated by specific (yet unknown) antigens and MMPs, cytokines and other immune cells, respectively. A number of biochemical changes, including altered keratinocyte antigen expression and altered keratinocyte function, have been previously suggested to be early events in OLP pathogenesis (Holmstrup and Dabelsteen 1979). It was originally proposed that following altered keratinocyte antigen expression, a CD8+ T cell on routine surveillance in the epithelium may encounter the keratinocyte antigen by chance ( chance encounter hypothesis). Alternatively, the CD8+ T cell may be attracted to the epithelium

8 8 M.J. McCullough et al. by keratinocyte-derived chemokines ( directed migration hypothesis) (Sugerman et al. 2002). The migration of activated T cells in the OLP infiltrate to oral epithelium can be mediated by intercellular and vascular adhesion molecules (ICAM-1 and VCAM) (Eisen et al. 1990). Upregulation of ELAM-1, ICAM-1, and VCAM-1, especially by endothelial cells in the subepithelial vascular plexus in OLP, was demonstrated in an immunohistochemical study that assessed various endothelial-associated adhesion molecules in frozen sections from 12 OLP cases and nine normal controls (Regezi et al. 1996). Biopsy specimens from patients with OLP consistently showed significantly higher levels of expression of the three molecules. The prolonged overexpression of adhesion molecules on endothelial cells may represent the molecular basis for the so-called reactive isomorphism seen in OLP patients. Previous studies have shown that in OLP there is an upregulation of epithelial basement membrane extracellular matrix (ECM) proteins, including collagen types IV and VII, laminin and certain integrins possibly serving as pathways for T-cell migration (Eversole 1997). Finally, cytokines (IL-1, IL-8, IL-10, IL-12, and TNF-α), secreted by keratinocytes in OLP, are also chemotactic for lymphocytes ultimately leading to tissue destruction in OLP (Sugermann et al. 1996). The cell-mediated immunological response seen in OLP, possibly initiated by endogenous or exogenous factors, is thought to result in the production of TNF-α and IFN-γ and keratinocyte/tcell/antigen-presenting dendritic cell associations (Eisen et al. 2005; Lodi et al. 2005; Payeras et al. 2013). The increased production of TH1 cytokines is a key and early event in LP. This even is, at least in part, genetically controlled, and genetic polymorphism of cytokines seems to govern whether lesions develop in the mouth alone (IFN-γ associated) or in the mouth and skin (TNF-α associated) (Carrozzo et al. 2004, Scully and Carrozzo 2008). TNF-α may stimulate the activation of nuclear factor kappa B (NF-κB) whose increased expression has been seen in OLP (Santoro et al. 2003). Because NF-κB translocation in keratinocytes may induce the production of several inflammatory cytokines, it could be partially responsible for the characteristic, chronic course of OLP similar to other chronic inflammatory diseases such as psoriasis and rheumatoid arthritis (Eisen et al. 2005). The cellular and molecular constituents of these pathogenic events will be discussed in detail in the following paragraphs. Putative OLP Antigens While OLP is not considered to be a typical autoimmune disease, it is believed that one or more epithelial antigens are present in basal keratinocytes. Antigens that are presented by MHC class II receptor are processed through an endosomal cellular pathway, while antigens that are presented by MHC class I are processed through a cytosolic cellular pathway (Sugerman et al. 2002). Hence, the putative antigen presented by MHC class II to CD4+ helper T cells in OLP may differ from that presented by MHC class I to CD8+ cytotoxic T cells. Alternatively, a single antigen may gain access to both the endosomal and cytosolic cellular pathways of antigen presentation (Sugerman et al. 2002; Roopashree et al. 2010). Whether one or more different antigens are involved in disease pathogenesis, it has been suggested that simultaneous antigen presentation to CD8+ and CD4+ T cells in the context of MHC classes I and II, respectively, is required to develop persistent T-cell infiltration and CD8+ cytotoxic T-cell activity in OLP (Sugerman et al. 2002). A unifying hypothesis of the specific mechanisms thought to play a role in the pathogenesis of OLP was introduced by Sugerman et al. (2002). The hypothesis is based on a theoretical interaction between CD8+ T cells and CD4+ T cells through a request cytotoxic activity (RCA) cell surface molecule expressed by CD8+ T cells and a RCA receptor expressed by the CD4+ T cells to allow confirmation and initiation of cytotoxic activity by CD8+ T cells. The hypothesis stresses that this interaction can only take place after each type of the T-cell antigen receptors is engaged with a related foreign antigen (Ag), i.e., Ag1 in the context of MHC class I engaged by CD8+

9 Oral Lichen Planus 9 T-cell antigen receptors and Ag2 in the context of MHC class II engaged by CD4+ T-cell antigen receptors. To date, sound experimental evidence to support this theory is lacking. Cell-Mediated Immunity CD8+ T Cells An early immunohistochemical study assessing the lymphocytic infiltrate in OLP showed this to be composed almost exclusively of T cells, and the majority of T cells within the epithelium and adjacent to damaged basal keratinocytes were activated CD8+ lymphocytes (Kilpi 1988). CD8 + T cells were also co-localized with apoptotic keratinocytes in OLP lesions (Sugerman et al. 2000). The dominant role of CD8+ T cells and CD4+ T cells in OLP pathogenesis was further confirmed by the expression of the chemokines CCR5 and CXCR3, known to be selectively expressed by TH1, in the infiltrating lymphocytes, in addition to the CD8+ T-cell respective ligand RANTES/CCL5 and IP-10/CXCL10 (Iijima et al. 2003). Analysis of these previous data suggests that CD8+ T cells are involved in disease pathogenesis and that activated CD8+ T cells may trigger keratinocyte apoptosis in OLP. T-cell lines and clones isolated in vitro from LP lesions were more cytotoxic against autologous lesional keratinocytes than T cells from the clinically normal skin of LP patients, and the majority of noncytotoxic clones were CD4+ (helper/inducer clones) (Sugerman et al. 2000). Furthermore, the cytotoxic activity of CD8+ lesional T-cell clones was partially blocked with anti-mhc class I monoclonal antibody (Sugerman et al. 2000). Hence, early in OLP lesion formation, CD8+ lesional T cells may recognize an antigen associated with MHC class I on lesional keratinocytes. Following antigen recognition and activation, CD8+ cytotoxic T cells are thought to trigger keratinocyte apoptosis (Sugerman et al. 2002). Activated CD8+ T cells (and possibly keratinocytes) may release chemokines that attract additional lymphocytes and other immune cells into the developing OLP lesion. This has been suggested by studies that found significantly higher chemokine production within OLP lesions when compared to normal or chronically inflamed gingival tissues (Yamamoto and Osaki 1995). CD4+ T Cells The majority of intraepithelial lymphocytes in OLP have been shown to be CD8+ cytotoxic T cells (Sugerman et al. 2002), while studies have shown that most lymphocytes in the lamina propria are CD4+ helper T cells (Ishii 1987; Kilpi 1988). A mixed helper and suppressor activity among OLP lesional T-cell clones in vitro was identified, suggesting that the balance between immunological help and suppression may determine the clinical behavior of the disease (Sugerman et al. 1994). In this interesting report, Sugerman et al. reported that the majority of T lymphocyte lines extracted from six biopsy specimens of OLP (n = 13) expressed the α/β T-cell receptor of which 11 were CD8+ and two were CD4+ (Sugerman et al. 1994). Hence, an early event in OLP lesion formation may be a presentation of a MHC class II antigen to CD4+ helper T cells, followed by keratinocyte apoptosis triggered by CD8+ cytotoxic T cells. MHC class II antigen presentation in OLP may be mediated by Langerhans cells (LCs) or keratinocytes. Furthermore, increased numbers of LCs have been reported in OLP lesions with upregulated MHC class II expression (Villarroel Dorrego et al. 2002). Keratinocytes in OLP have also been shown to express MHC class II (Ichimura et al. 2006). High levels of antigen expression, CD40 and CD80 expression, and IL-12 secretion by MHC class II + antigen-presenting cells (APC) in OLP are thought to promote a TH1 CD4+ T-cell response with IL-2 and IFN-γ secretion (Sugerman et al. 2002). Analysis of these data together suggests that LCs or keratinocytes in OLP may present antigen associated with MHC class II to CD4+ helper T cells that are stimulated to secrete the TH1 cytokines IL-2 and IFN-γ. Subsequently, CD8+ cytotoxic T cells may be activated by the combination of (i) antigen associated with MHC class I on basal keratinocytes and (ii) TH1 CD4+

10 10 M.J. McCullough et al. T-cell-derived IL-2 and IFN-γ. Activated CD8+ cytotoxic T cells may then trigger basal keratinocyte apoptosis in OLP (Sugerman et al. 2002). However, it is essential to note that this hypothesis has never been proven by robust evidence. A recently discovered subgroup of CD4+ T cells, namely, TH17 CD4+ subgroup, has been shown to produce IL-26 and IL-22, in addition to IL-17, which are known to be, when uncontrolled, inducers of the inflammatory response in different autoimmune conditions, such as multiple sclerosis, psoriasis, and lupus (Payeras et al. 2013). The proportion of lesional Th1 and Th17 cells and serum IL-17 levels in patients with OLP (n = 40) were shown to be significantly greater than controls (n = 15), especially in the atrophicerosive OLP patients compared with those presenting with reticular OLP, suggesting that Th17 cells and their cytokine Th17 might play an important role in OLP pathogenesis (Xie et al. 2012). Dendritic Cells (DCs) DCs have an important role in the immunological response as they activate T cells through antigenic stimulation (Banchereau et al. 2000). Studies have revealed an increase in the number of DCs in OLP, indicating that they may be associated with its pathogenesis (Santoro et al. 2005; Gueiros et al. 2012). According to Santoro et al., the increase of different subsets of DCs, such as Langerhans cells (LCs), stromal DCs, and plasmacytoid dendritic cells (PDCs), may promote the inflammatory response in OLP (Santoro et al. 2005). Among these, LCs have been the most studied DCs. These cells reside in the supra-basal layers of the stratified epithelium of the skin and oral mucosa and have the principle function of capturing and presenting antigens. When LCs capture antigen, they are activated, migrate to the regional lymph nodes, and are introduced to the T lymphocytes, producing a primary immune response (Payeras et al. 2013). Subsequently, when LCs recapture antigen, this antigen will be presented and recognized by T lymphocytes circulating memory and will induce a secondary immune response (Barrett and Raja 1997). In the OLP lesions, a large number of LCs are present in the basal layer of the epithelium (Villarroel Dorrego et al. 2002). It has been postulated that in these lesions the LCs play an important role in presenting antigen to the T lymphocyte through class II MHC molecules, introducing not only an initial sensitivity to the antigen (primary immune response) but also a subsequent secondary immune response and thus the appearance of the clinical signs of the disease (Payeras et al. 2013). Mast Cells Mast cells are preferentially located in the lamina propria, near blood vessels and nerves. They are derived from the CD34+ hematopoietic progenitor that has the ability to activate T lymphocyte, undergo degranulation, and release a series of mediators that modulate the inflammatory response (Payeras et al. 2013). Studies have shown an increased mast cell density in OLP with approximately 60% of them being degranulated, compared with 20% in normal buccal mucosa (Sugerman et al. 2002). Utilizing IHC, mast cell density in OLP was found to be markedly higher in the basement membrane rupture sites as compared to intact sites, suggesting that this cell might play a direct role in the basement membrane destruction, as well as in the T CD8+ lymphocyte migration to the intraepithelial region (Zhou et al. 2002). Thus, mast cells have been proposed to be involved in the pathogenesis of OLP. Mast cell degranulation in OLP releases a range of pro-inflammatory mediators such as TNF-α, chymase, and tryptase. TNF-α has been shown to upregulate endothelial cell adhesion molecule (CD62E, CD54, and CD106) expression in OLP that is required for lymphocyte adhesion to the luminal surfaces of blood vessels and subsequent extravasation (Zhao et al. 1997). Chymase, a mast cell protease, is a known activator of MMP-9 (Fang et al. 1997). It has been proposed that basement membrane disruption in OLP may be mediated by mast cell proteases directly or indirectly via activation of T- cell-secreted MMP-9 (Sugerman et al. 2002).

11 Oral Lichen Planus 11 Both TNF-α and chymase stimulate secretion of RANTES by T lymphocytes which in turn stimulate mast cells to release TNF-α and chymase. This cyclical activity has been suggested to contribute to the chronicity of OLP (Roopashree et al. 2010). Macrophages Macrophages are phagocyte cells derived from blood monocytes, recruited in the tissues in the presence of chemotactic signals. They are present in the healthy oral mucosa and in larger numbers during pathological processes (Merry et al. 2012). Macrophages are classified as M1 (pro-inflammatory) or M2 (anti-inflammatory) according to the functions of their effectors (Mantovani et al. 2004). The M1 macrophages might exacerbate OLP manifestation through the production of pro-inflammatory agents such as TNF-α or IL-1b. These agents, in turn, regulate the presence of adhesion molecules on the endothelial cell surface inducing the production of chemokines (RANTES) by the keratinocytes and resulting in an increase in the lesional inflammatory cells recruitment. Furthermore, it has been shown that the production of TNF-α by the macrophages can initiate the basal keratinocyte apoptosis and indirectly increase the disruption rate of the basement membrane by MMP-9, produced by T cells (Merry et al. 2012). Soluble Factors Matrix Metalloproteinases (MMPs) MMPs are a family of zinc-containing endo-proteinases with at least 20 members with the principal function of proteolytic degradation of connective tissue matrix proteins. MMPs share biochemical properties but retain distinct substrate specificities (Zhou et al. 2001). MMP proteolysis is regulated by the action of endogenous inhibitors, including the tissue inhibitors of metalloproteinases (TIMPs), which are thought to form stable inactive enzyme-inhibitor complexes with MMPs or pro-mmps (Sugerman et al. 2002). An imbalance between MMPs and TIMPs can be associated with the process of tissue destruction seen in some pathologies, including cancer, arthritis, and cardiovascular diseases (Bode 2003). The primary source of MMPs in OLP is probably the immune infiltrate. In one study, culture supernatants from OLP lesional T cells contained a higher concentration of MMP-9 and TIMP-1 than those obtained from peripheral blood T cells in both the same OLP patients group and the healthy controls, suggesting the presence of additional MMP-9 activators in the OLP lesional T-cell supernatants (Zhou et al. 2001). MMP-9 activators released from the OLP T cell are believed to help in activating pro-mmp-9, resulting in basement membrane disruption (Roopashree et al. 2010). Rubaci et al. (2012) showed that the expression of MMP-2 (1.3 vs. 0.7) and MMP-7 (1.7 vs. 0.6) in epithelium and connective tissues from OLP lesions was greater than normal oral mucosa (P < 0.05). This IHC study was undertaken on a cohort of 29 OLP patients and ten healthy controls. Likewise, the study revealed that MMP-2/TIMP-1 and MMP-7/ TIMP-1 ratios were higher in the OLP patient group than in the control group (P < 0.05). These results support the view that increased MMP expression and imbalance between MMPs and TIMPs may play a role in the pathology of OLP. Chemokines Chemokines are a family of small cytokines (proteins that are involved in cell signaling and mediating immune reactions), which were initially identified by their modulator action on the inflammatory response (Payeras et al. 2013). More attention has been given to these proteins recently, especially due to their potential function on endothelial cells and possible involvement in chronic inflammation and tumor progression (Kiefer and Siekmann 2011). Moreover, evidence has shown the role chemokines play in different autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, through lymphocyte recruitment and establishment of ectopic lymphoid structures in the target organs in affected individuals (Godessart and Kunkel 2001). RANTES (regulated on activation, normal T cell expressed and secreted) is a member of the CC chemokine family and is produced by various

12 12 M.J. McCullough et al. cells, including activated T lymphocytes, bronchial epithelial cells, rheumatoid synovial fibroblasts, oral keratinocytes, and mast cells. RANTES plays a critical role in the recruitment of lymphocytes, monocytes, natural killer cells, eosinophils, basophils, and mast cells in OLP (Roopashree et al. 2010). This chemokine has a number of cell surface receptors (CCR1, CCR3, CCR4, CCR5, CCR9, and CCR10) that have been identified in OLP (Sugerman et al. 2002). The role that RANTES may play in OLP pathogenesis was hypothesized by Sugerman and colleagues (2002) who suggested that RANTES secreted by OLP lesional T cells may attract mast cells into the developing OLP lesion and subsequently stimulate mast cell degranulation. Degranulating mast cells in OLP would release TNF-α and chymase which in turn upregulates OLP lesional T-cell RANTES secretion. According to this hypothesis, such a cyclical mechanism may underlie OLP chronicity. Ichimura et al. (2006) analyzed the chemokines and their receptors expressed in the epithelium of OLP by means of DNA microarray. The study found that high levels of MIP-3a/ LARC/CCL20, and its receptor CCR6, are expressed on the lesional epithelium. Furthermore, DC-CK1/CCL18, ELC/CCL19, SDF-1/ CXCL12, and CXCR4 expressions were also increased. Immunohistological analysis showed that high numbers of LCs were present in the epithelium of OLP. Lesional epithelium also expressed high levels of the ligands specific for CXCR3 and CCR5 (e.g., RANTES/CCL5). Based on these results, it was suggested that infiltration of LCs may be regulated by CCR6 (as these receptors are expressed by LCs) and that LCs residing in the lesional epithelia may represent a mature phenotype. Moreover, infiltration of T cells in OLP could be mediated by signaling pathways through CXCR3 and CCR5. Thus, it would appear that there is a dysregulation of specific chemokines, and chemokine receptors, and that this would appear to be related to expression of chemokine receptors on LCs. Similar to the observed dysregulation of MMPs/TIMPs and keratinocyte/basement membrane noted above, this may be either involved in the etiopathogenesis of OLP or a byproduct of the disease. Epithelial Components The Epithelial Basement Membrane Keratinocytes contribute to the structure of the epithelial basement membrane by secreting collagen IV and laminin V into the basement membrane zone (Marinkovich et al. 1993). Evidence from mouse models suggests that keratinocytes require a basement membrane-derived cell survival signal to prevent the onset of apoptosis (Pullan et al. 1996). Similarly, lack of appropriate ECM anchorage results in a form of cell death called anoikis. Thus, an intact basement membrane is required for keratinocytes survival, and reciprocally healthy keratinocytes are necessary for normal basement membrane integrity. Keratinocytes undergoing cell death are no longer able to perform this reciprocal function, and as such keratinocyte apoptosis triggered by intraepithelial CD8+ cytotoxic T cells may result in epithelial basement membrane disruption in OLP, thus fueling anoikis and allowing for nonspecific T lymphocytes present in the subepithelial zone to migrate into the epithelium (Chainani-Wu et al. 2001). Both keratinocyte apoptosis and basement membrane disruption may be involved in the pathogenesis of OLP, and such a cyclical mechanism has been postulated to underlie disease chronicity (Sugerman et al. 2002; Lodi et al. 2005a). Keratinocyte Apoptosis Keratinocyte apoptosis is a common and key feature in the histopathological findings of OLP lesions and is considered a major diagnostic criterion (Ismail et al. 2007; Eisen et al. 2005; Scully et al. 1998). Therefore, keratinocyte apoptosis has been postulated to be intentionally involved in the etiopathogenesis of OLP (Sugerman et al. 2002). A number of mechanisms have been suggested by which CD8+ cytotoxic T cells can trigger keratinocyte apoptosis in OLP. These include (i) T-cell-secreted TNF-α binding to TNF receptor 1 (TNFR1) on the keratinocyte surface, (ii) T-cell surface CD95L (Fas ligand) binding CD95 (Fas)

13 Oral Lichen Planus 13 Fig. 1 Clinical presentation of patients with OLP: (a) reticular, (b) erosive/ulcerative, (c) atrophic and plaque-like, and (d) desquamative gingivitis (atrophic and erosive forms) on the keratinocyte surface, or (iii) T-cell-secreted granzyme B entering the keratinocyte via perforin-induced membrane pores (Sugerman et al. 2002). All of these mechanisms may activate the keratinocyte caspase cascade, resulting in keratinocyte apoptosis. Elevated levels of TNF-α in the serum of OLP patients were identified (Sugermann et al. 1996). In summary, while it is well established that apoptosis of basal keratinocytes is a key feature of OLP, the exact pathogenic mechanisms have not yet been elucidated. Clinicopathologic Features OLP is the most common mucocutaneous condition 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 gingival tissues (Axell and Rundquist 1987). Clinical Appearance OLP classically presents in a bilateral, symmetrical pattern with the buccal mucosa (bilaterally) being the most typical site of involvement (Fig. 1); however, any other oral mucosal sites and the lips can also be involved (Al-Hashimi et al. 2007; Ismail et al. 2007; Scully and Carrozzo 2008). Other common sites of involvement include the tongue (Fig. 1c), gingival (Fig. 1d), labial mucosa, and vermilion of the lower lip (Eisen et al. 2005; Al-Hashimi et al. 2007; Scully and Carrozzo 2008; Parashar 2011). Patients with isolated lip lesions and tongue lesions have been described although many patients who present with isolated lesions eventually develop more

14 14 M.J. McCullough et al. widespread disease (Eisen et al. 2005). Lesions of OLP affecting the palate, floor of the mouth, and upper lip are not common. The oral manifestations of OLP have been described in many large studies. Clinically, there are six clinical subtypes of OLP that can be seen individually or in combination: reticular, plaquelike, atrophic, erosive, papular, and bullous (Ismail et al. 2007; Scully and Carrozzo 2008; Farhi and Dupin 2010). The most common of these are the reticular, erosive, and plaque-like subtypes, and these variants can coexist within the same patient (Fig. 1). The reticular lesions, the most recognized form of OLP, encompass white lesions, which appear as a network of connecting and overlapping lines referred to as Wickham striae, papules, or plaques (Eisen et al. 2005). Although some patients may display an impressive array of diffuse and widespread reticulated lesions, they rarely complain of symptoms and often are unaware of their presence. In the absence of the classic reticular pattern on oral mucosal surfaces, it is challenging to clinically diagnose non-reticular types (Fig. 1b, d) (Scully and Carrozzo 2008). Histologic confirmation of the diagnosis is thus required. The erosive form of OLP (Fig. 1b) may present with erythema caused by inflammation or epithelial thinning, or both, and ulceration/pseudomembrane formation with periphery of the lesion surrounded by reticular keratotic striae (Ismail et al. 2007). Atrophic and erosive OLP lesions result in varying degrees of discomfort. The number of ulcerations is variable as are their size and location; rarely, bullae that rupture easily may be observed in the erosive form of OLP (Eisen et al. 2005). If the erosive subtype of OLP only affects the gingival tissue, the descriptive clinical term desquamative gingivitis is often used (Fig. 1d). OLP is confined to the gingiva in about 10% of patients (Mignogna et al. 2005; Scully and Carrozzo 2008). Erosive lesions resembling those observed in other vesiculobullous diseases including pemphigoid, pemphigus, linear IgA disease, and foreign body gingivitis can also produce desquamative gingivitis not easily identified as OLP unless there are coexistent reticular lesions on the gingiva or elsewhere in the oral cavity. Two recent cohort studies found OLP to be the most common cause of desquamative gingivitis (71% and 75%), while pemphigoid and pemphigus were next in frequency (Leao et al. 2008; Lo Russo et al. 2009). OLP isolated to a single oral site other than the gingiva is uncommon. In general, bullous and papular forms are rare in the oral mucosa (Parashar 2011). The erosive lesions hardly ever remit spontaneously and may lead to confusion with other vesiculobullous diseases, which share similar clinical features (Eisen et al. 2005). The plaque form of OLP mimics leukoplakia in that it appears as a white, homogeneous, slightly elevated, multifocal, smooth lesion. The plaque form of OLP commonly affects the dorsum of the tongue and buccal mucosa (Ismail et al. 2007). OLL and OLR have similar features, clinically and histologically, to OLP, but have a less characteristic morphology or have a distinct cause, unlike OLP. OLL therefore needs to be distinguished because treatment modalities are different from those for OLP (Al-Hashimi et al. 2007). To better define the criteria for diagnosis of OLP, the World Health Organization (WHO) devised a set of clinicopathologic criteria in 1978 (Table 1) (Kramer et al. 1978). However, these criteria lacked consensus regarding a clinical and histologic diagnosis of OLP, and so modifications were proposed to the WHO criteria in 2003 (Table 2), which resulted in a substantial increase in consensus and clinicopathologic correlation (Epstein et al. 2003; van der Meij and van der Waal 2003). In addition, knowledge about history of systemic diseases, history of drug use, and cutaneous lesions can be helpful in arriving at a definite diagnosis. Signs, Symptoms, Clinical Behavior and OLP Scoring Systems The clinical signs and symptoms of OLP vary. In many patients, the onset of OLP is insidious, and patients are unaware of their oral condition. Some patients report roughness of the lining of the mouth, sensitivity of the oral mucosa to hot or spicy foods, painful oral mucosa, red or white

15 Oral Lichen Planus 15 Table 1 Original WHO diagnostic criteria of OLP (Kramer et al. 1978) Clinical criteria Presence of white papule, reticular, annular, plaque-type lesions, gray-white lines radiating from the papules Presence of lacelike network of slightly raised gray-white lines (reticular pattern) Presence of atrophic lesions, with or without erosion, and possibly also bullae Histopathological criteria Presence of thickened ortho- or parakeratinized layer in sites that are normally keratinized, and if site is normally nonkeratinized, this layer may be thin Presence of Civatte bodies in basal layer, epithelium, and superficial part of connective tissue Presence of a well-defined band-like zone of cellular infiltration that is confined to the superficial part of the connective tissue, consisting mainly of lymphocytes Signs of liquefaction degeneration in the basal cell layer Table 2 Modified WHO diagnostic criteria of OLP and OLL (van der Meij and van der Waal 2003) Clinical criteria Presence of bilateral, more or less symmetrical lesions Presence of a lacelike network of slightly raised gray-white lines (reticular pattern) Erosive, atrophic, bullous, and plaque-like lesions are only accepted as a subtype in the presence of reticular lesions elsewhere in the oral mucosa In all other lesions that resemble OLP but not complete with the aforementioned criteria, the term clinically compatible with should be used Histopathological criteria Presence of well-defined band-like zone of cellular infiltration that is confined to the superficial part of the connective tissue, consisting mainly of lymphocytes Signs of liquefaction degeneration in the basal cell layer Absence of epithelial dysplasia When the histopathological features are less obvious, the term histopathologically compatible with should be used Final diagnosis of OLP or OLL To achieve a final diagnosis, clinical as well as histopathological criteria should be included OLP: a diagnosis of OLP requires fulfillment of both clinical and histopathological criteria OLL: the term OLL will be used under the following conditions (1) Clinically typical of OLP but histopathologically only compatible with OLP (2) Histopathologically typical of OLP but clinically only compatible with OLP (3) Clinically compatible with OLP and histopathologically compatible with OLP patches on the oral mucosa, or oral ulcerations (Ismail et al. 2007). Symptoms and signs can range from patients being unaware of the disease, with lesions that are completely asymptomatic as in reticular OLP, to those experiencing mucosal sensitivity and burning and debilitating pain. Approximately two-thirds of the patients affected with OLP experience some degree of oral discomfort (Parashar 2011). OLP has periods of relapses and remissions. During a period of exacerbation there will be an increase in symptoms and clinical signs, while during periods of quiescence, symptoms and signs of OLP are diminished (Ismail et al. 2007). Factors such as stress may aggravate the clinical presentation of the disease. Precipitating factors similar to the Koebner phenomenon, which is characteristic of cutaneous LP whereby lesions develop in response to trauma, can also affect the oral cavity where sharp cusps and ill-fitting dental prosthesis may be the triggers. Accumulation of plaque and calculus can also exacerbate OLP, probably because of the Koebner phenomenon (Mignogna et al. 2005). Gingival OLP can eventually lead to gingival recession, advanced periodontal disease, and so forth, and

16 16 M.J. McCullough et al. therapeutic periodontal procedures may aggravate these conditions (Eisen et al. 2005; Scully and Carrozzo 2008). Oral post-inflammatory pigmentation (OPP) has been described in patients with OLP and OLR as diffuse brown or black pigmentation following the lichenoid lesions distribution (Mergoni et al. 2011). Currently there is no universally accepted scoring system for OLP; however many have been proposed to objectively and even subjectively measure OLP disease severity. Several studies have proposed using scoring systems with the earlier systems based upon a three- or five-point scale from no disease to severe disease (Eisen et al. 1990; Thongprasom et al. 1992). Other scoring systems base severity on the level of site involvement (<> 50% site) (Malhotra et al. 2008). Some of the more detailed scoring systems have worked to split OLP into three clinical subtypes, reticular, atrophic/erythematous, and erosive/ulcerative (Escudier et al. 2007). For some of these studies the oral cavity is divided into different subsites so each site is given an activity/severity score which can be totaled to give an entire oral cavity score (Chainani-Wu et al. 2001; Piboonniyom et al. 2005; Escudier et al. 2007). In some of these scoring systems, presence of erythema, erosions, or ulceration is graded higher than the presence of reticular lesions alone (Piboonniyom et al. 2005; Escudier et al. 2007). One of the main advantages of using a detailed scoring system is the ability to objectively measure disease activity baseline and changes in disease activity for the entire oral cavity and specific sites. Recently attempts have been made to validate some of the more detailed scoring systems (Chainani-Wu et al. 2012). Time has also been taken with these scoring systems to add subjective measures of the patient s pain and symptoms making this a complete disease scoring system (Chainani-Wu et al. 2012). Currently there are many available disease scoring systems which systems in place to measure changes in subjective and objective disease activity in OLP. At this stage no one system has been universally accepted for use. Histopathology of OLP The histologic features of OLP were first described by Dubreuill in 1906 and later revised by Shklar in 1972 (Parashar 2011). The WHO developed a set of histopathologic criteria for OLP in 1978, which was most recently modified in 2003 (Tables 1 and 2). Definite diagnostic histologic findings include liquefactive degeneration of the basal cells, colloid bodies (Civatte, hyaline, cytoid), homogeneous infiltrate of lymphocytes and histiocytes in a dense, band-like pattern along the epithelium-connective tissue interface in the superficial dermis, cytologically normal maturation of the epithelium, sawtooth rete ridges, and hyperkeratosis (orthokeratosis or parakeratosis) (Fig. 2) (Eisenberg 2000; Eisen et al. 2005; Ismail et al. 2007; Parashar 2011). In addition, the surface epithelium may show signs of ulceration, typically seen in erosive LP. Several histologic criteria are considered as exclusionary in diagnosing OLP, including the absence of basal cell liquefaction degeneration, polyclonal inflammatory infiltrate, abnormal cytology suggestive of dysplasia, abnormal keratinization, flat rete ridges, and absence of colloid bodies (Eisenberg 2000; Ismail et al. 2007). Oral Lichenoid Reactions (OLR) There are various lesions that may resemble OLP both clinically and histopathologically. These lesions are collectively termed OLR and encompass lichenoid drug reactions (LDR) and OLR to dental materials, most notably allergic contact sensitivity to amalgam (Koch and Bahmer 1995; Ostman et al. 1996; Thornhill et al. 2003; Issa et al. 2004; Eisen et al. 2005; Ismail et al. 2007). As with OLP, OLRs present clinically with a range of different features ranging from asymptomatic striae and plaque-like lesions to painful erythematous and ulcerative lesions. Histopathologically OLRs align with OLP showing a bandlike lymphohistiocytic infiltrate (mainly T cell) within the lamina propria as well as liquefactive degeneration of the basal cell layer.

17 Oral Lichen Planus 17 Fig. 2 Histopathology of OLP. (a) Low power photomicrograph showing parakeratosis, band-like subepithelial chronic inflammatory infiltrate, and sawtooth rete ridges (H&E, original magnification X100). (b) High-power photomicrograph showing several colloid bodies (arrows) and liquefactive degeneration of basal keratinocytes (arrowheads) (H&E, original magnification X200) Cases of OLRs related to restorative materials will typically present in a direct topographic relationship with the restorative material. The allergens thought to be responsible for amalgamcontact sensitivity include mercury, amalgam alloying metal zinc, copper, silver, gold, or palladium (Koch and Bahmer 1995; Suter and Warnakulasuriya 2016). There has been some evidence to suggest that some patients with amalgam-associated OLRs represent a true delayed hypersensitivity reaction as a result of metal haptens released from dental restorative materials (Laine et al. 1999). LDRs will typically arise with a direct temporal association when taking certain medications including nonsteroidal anti-inflammatory medications (NSAIDs), some antihypertensive medications, oral hypoglycemics, penicillamine, and antimalarial medications (Epstein et al. 2003; Bagan et al. 2004; Al-Hashimi et al. 2007; Ismail et al. 2007). No specific criteria exist for the diagnosis of LDR; however withdrawal and reexposure to the drug resulting in resolution and recurrence can be considered diagnostic. Patch testing may be a valuable diagnostic tool for OLR as a result of a contact sensitivity to dental materials (Suter and Warnakulasuriya 2016). In cases of a suspected OLR as a result of amalgam dental restorations, there is evidence to suggest that replacement of amalgam can result in resolution or improvement of OLR; in some cases this is irrespective of a positive patch testing result (Laine et al. 1992; Ostman et al. 1996; Thornhill et al. 2003; Issa et al. 2004). Thus in cases of suspected OLRs, it is essential that proper testing including histopathology and patch testing be undertaken to ensure

18 18 M.J. McCullough et al. a correct diagnosis is made as OLP and OLR benefit from different management protocols. Dental Materials OLR as an allergic reaction to dental materials has been widely reported, with many studies documenting contact hypersensitivity to dental materials such as amalgam (Lind et al. 1986; Thornhill et al. 2003), composite (Lind 1988), dental acrylics (van Loon et al. 1992), cobalt (Torresani et al. 1994), and nickel (Ismail et al. 2007) presenting as OLR. Some studies also showed resolution of OLR following replacement of causative restorations. Laine et al. reported a complete remission of OLR lesions associated with amalgam in a small cohort of seven patients, a marked remission in six patients, and no change in two patients (total n = 15) after amalgam replacement and a mean follow-up of 3.2 years (Laine et al. 1992). In another trial, Thornhill et al. reported that amalgam replacement resulted in improvement in 93% of patients (28 out of 30) who had amalgam-contact hypersensitivity lesions (Thornhill et al. 2003). Gingival OLR lesions, in particular, were reported to be nonresponsive to amalgam replacement for unknown reasons (Henriksson et al. 1995). Diagnosis of OLR will commonly depend on the topography and distribution of the lesions as in most cases, OLR are indistinguishable from idiopathic OLP, clinically or histologically (Thornhill et al. 2003). Cutaneous patch testing may also play a role in differentiating these lesions (Scully and Carrozzo 2008; Ismail et al. 2007). Thornhill et al. found that 70% of amalgam-contact hypersensitivity lesions (presented as lichenoid reactions) were patch test positive for amalgam or mercury compared with only 3.9% of OLP cases (Thornhill et al. 2003). To date, OLP and OLR lack internationally accepted distinguishing features, and the diagnosis of OLR can be challenging as the pathognomonic features of OLR are yet to be identified (Ismail et al. 2007). Recent findings have suggested that OLR appears to be the result of cell-mediated contact hypersensitivity to dental materials, in susceptible individuals who have been sensitized through long exposure (Ismail et al. 2007). Systemic Medications Medications, such as antihypertensives ( in particular beta-blockers and ACE inhibitors), dapsone, oral hypoglycemics, NSAIDs, penicillamine, phenothiazines, antimalarials, sulfonylureas, and gold salts, have been associated with OLRs (Scully et al. 1998; Al-Hashimi et al. 2007; Ismail et al. 2007). More recently, OLR induced by antiretroviral medications for treatment of human immunodeficiency virus (HIV) has been reported (Scully and Diz Dios 2001). Clinical identification of LDR has been based largely on subjective criteria although there may sometimes be a tendency for the oral lesions to be unilateral and erosive (Eisen et al. 2005). Histology may be beneficial as lichenoid lesions may have a more diffuse lymphocytic infiltrate and contain eosinophils and plasma cells, and there may be more colloid bodies than in classical OLP (Eisen et al. 2005; Scully and Carrozzo 2008). The most reliable method to diagnose LDRs is to note if the reaction resolves after the offending drug is withdrawn and if it returns when the patient is challenged again. As this is both impractical and potentially unsafe, empiric withdrawal of a potentially offending drug and substitution with another agent may not be warranted. After the offending drug is withdrawn, it may be months before the LDR resolves. Interestingly, it was reported that LDR may develop months or even years after a patient takes a drug (Eisen et al. 2005). Cutaneous Lesions LP may affect the hair follicles, nails, esophagus, and, less frequently, the eyes, urinary tract, genitals, nasal mucosa, and larynx. Scalp involvement causes pruritic, follicular and perifollicular, scaly, violaceous papules, referred to as lichen planopilaris, and can also lead to permanent patchy hair loss known as scarring alopecia. When LP affects nails, it causes pitting, subungual

19 Oral Lichen Planus 19 hyperkeratosis, and permanent nail loss (Farhi and Dupin 2010). Skin lesions characteristically present as flattopped, polygonal, violaceous papules regularly covered by a network of fine lines affecting the wrists, ankles, and genitalia (Bornstein et al. 2006). Cutaneous LP may also appear in several atypical forms that are not easily recognizable. As previously mentioned, approximately 15% of patients with OLP develop cutaneous lesions, while OLP occurs in 70 77% of patients with cutaneous LP (Eisen 1999; Farhi and Dupin 2010). Typically, cutaneous lesions develop within several months after the appearance of the oral lesions, and the severity of the oral lesions does not seem to correlate with the extent of cutaneous involvement, i.e., while OLP is chronic and represents a common cause of morbidity, cutaneous lesions are commonly pruritic but self-limiting (Eisen et al. 2005). Other Mucosal Lesions Undoubtedly, the most frequent extraoral site of involvement in female patients with OLP is the genital mucosa with lesions developing in 20% of women with OLP compared with only 2 4% of men with OLP (Ismail et al. 2007; Scully and Carrozzo 2008; Farhi and Dupin 2010). The association of LP of the vulva, vagina, and gingiva is recognized as the vulvovaginal-gingival syndrome (Pelisse 1989), and the male counterpart is known as penogingival syndrome (Bain and Geronemus 1989). When LP affects the genital mucosa, the erosive form of the disease is the predominant type although asymptomatic reticular lesions can be identified in about a quarter of all patients (Eisen et al. 2005). Various symptoms including burning, pain, vaginal discharge, and dyspareunia are frequent and are noted in patients with erythematous and erosive disease. Reports of malignant transformation of genital LP in women (Dwyer et al. 1995) underscore the need for an early diagnosis and the institution of prompt treatment for these patients. Although the concomitant involvement of oral and genital LP is much less common in males than females, recognition and treatment of the disease are important as malignant transformation of penile LP has also been reported (Bain and Geronemus 1989). The clinical features of esophageal LP have been well documented, and the disease appears to develop most commonly in patients with OLP (Evans et al. 2000), while conjunctival, laryngeal, or other mucosal involvement is rarely reported (Eisen et al. 2005). Malignant Potential of OLP Since the first report of malignant transformation of OLP (Hallopeau 1910), numerous studies have attempted to address this issue. Malignant transformation rates ranging from 0% to 12.5% were reported (Gonzalez-Moles et al. 2008). Although these findings appear to support the potentially malignant character of OLP, it remains a controversial topic. Several authors agreed to a frequency of malignant transformation between 0.4% and 5%, over periods of observation from 0.5 to over 20 years with an annual rate between 0.2% and 0.5%. (van der Meij et al. 2003; Al-Hashimi et al. 2007; Scully and Carrozzo 2008). However, reviews limited to selected studies on malignant potential of OLP with a follow-up of more than 2 years showed that when strict criteria were applied, the malignant transformation rate is 0 2% (Ismail et al. 2007). It has been thought that the increased risk of oral cancer appears to be independent of the clinical type of OLP and therapy administered (Gandolfo et al. 2004). The first critical review regarding OLP malignant transformation appeared in the Journal of Oral Pathology about four decades ago (Krutchkoff et al. 1978), included data published up to 1977, and the authors recommended strict criteria (Table 3) to be adopted to definitively accept the malignant transformation in OLP. After applying these new criteria, they concluded that only 15 of the 223 cases reported in the literature should be unquestionably accepted as malignant transformation in OLP. The remaining

20 20 M.J. McCullough et al. Table 3 Criteria for malignant transformation of OLP (Krutchkoff et al. 1978) A. Original diagnosis must have been properly verified, with histological evidence demonstrating at least the last two of these four features Hyperkeratosis or parakeratosis Sawtoothed rete ridges Superficial infiltrate of lymphocytes Basal cell liquefaction B. History and follow-up Clinical and histological features of the alleged transformation must have been adequately described (information on age and sex of patient and on the precise location and clinical description of the lesion) The reported transformation should have had proper follow-up (minimum of 2 years) with all changes in clinical features properly recorded C. Tobacco exposure Tobacco habits should have been properly documented to help distinguish between true malignant transformation and conventional carcinomas occurring in the mouths of patients who happened to have OLP cases were excluded for at least one of the following reasons: (1) insufficient data to support the OLP diagnosis, (2) appearance of oral cancer in an area anatomically distant from the OLP, and (3) inadequate historical data on previous exposure to carcinogens. The authors commented: If OLP prevalence is accepted to be 1 2% of general population over 15 years, and if malignant transformation rate is 1% in a mean period of 5 years, then, from 10 to 20 patients per inhabitants should develop oral cancer in a mean period of 5 years. This would indicate that in many parts of the world all oral carcinomas should develop on an OLP, which is rather improbable (Krutchkoff et al. 1978). They further drew the conclusion that there was insufficient evidence to accept an inherent biological potential of OLP to progress to cancer, but they acknowledged that OLP patients have a slightly higher tendency to develop carcinomas compared to individuals without OLP (Krutchkoff et al. 1978). Almost 20 years later, van der Meij et al. (1999a, b) reviewed studies on the malignant transformation of OLP published from 1977 to 1999, applying the Krutchkoff criteria. During this period, 98 new malignant transformations were reported, of which 33 (34%) met the proposed criteria. According to the authors, the high incidence of malignant transformation described in many studies may be due to the misdiagnosis of some lesions as OLP or to the analysis of a highly selected study population (e.g., predominance of patients referred to specialists). This investigation concluded that nearly all of the case reports lacked precise documentation and that still no consensus had been established about the criteria for the histopathologic diagnosis of OLP (van der Meij et al. 1999a). van der Meij et al. further emphasized the need for standard criteria for a firm diagnosis of OLP to be universally adopted (van der Meij et al. 1999a, b). The designation OLL was later proposed for cases that are clinically characteristic and histologically compatible, clinically compatible and histologically characteristic, or clinically and histologically compatible with OLP (Table 2) (van der Meij and van der Waal 2003). It is currently proposed by some key authors that OLL rather than OLP is at high risk of developing cancer (Bornstein et al. 2006; van der Meij et al. 2007; Gonzalez-Moles et al. 2008). On the other hand, a review by Mattsson et al. largely based on follow-up studies reported a higher incidence of oral cancer in OLP patients and concluded that OLP should be considered a potentially malignant condition with a transformation rate of 0.5 2% (Mattsson et al. 2002). Many other studies using strict diagnostic criteria have shown a significant risk of malignant transformation of OLP to squamous cell carcinoma (SCC) (Holmstrup et al. 1988; Gandolfo et al. 2004; Rodstrom et al. 2004). Finally, the World Health Organization, in its latest volume on the Pathology and Genetics of Head and Neck Tumours (Gale et al. 2005), has recommended the development of diagnostic criteria to differentiate between OLP and OLL but declared that both lesions should be considered at risk of malignant transformation until such criteria become available. In 1985, Krutchkoff and Eisenberg (1985) coined the term lichenoid dysplasia (LD) to describe lesions that resemble OLP histologically and also show features of dysplasia. They

21 Oral Lichen Planus 21 suggested that OLP has no inherent predisposition to become malignant and that reported cases of malignant transformation in OLP lesions were due to lack of discrimination between OLP and LD or failure to identify a concomitant exposure to known carcinogens (Krutchkoff and Eisenberg 1985). The assumption for the proposal of malignant potential in LD rather than OLP was that any departure from normal epithelial maturation and growth altogether excludes a diagnosis of OLP (Eisenberg 2000), although consensus on such criteria has never been reached, and some authors consider dysplasia a very common feature of OLP (Lodi et al. 2005b). The entity LD might correspond to two groups of conditions: those with clinical features similar to OLP but dysplastic at the histological level and those with lichenoid microscopic features (bandlike lymphocytic infiltration in particular) and clinical features which do not resemble classic OLP (unilateral distribution, absence of reticular lesions) (Lodi et al. 2005b). The former could represent an early phase in the malignant transformation of OLP, while the latter could represent an OLL with underlying various clinical conditions that may have lichenoid histopathology including lichenoid reactions, lupus erythematosus, leukoplakia, erythroleukoplakia, and proliferative verrucous leukoplakia (PVL). PVL, particularly in the early stages, can have features, both clinical and histologic, that can be confused with OLP, frequently shows dysplastic changes, and is characterized by a high malignant transformation rate (Lodi et al. 2005b). OLL and Cancer A very interesting, and potentially informative, group of patients regarding OLL and oral malignancies are those who underwent allogeneic bone marrow transplantation and developed oral GVHD. Oral GVHD is clinically and histologically indistinguishable from OLP. Case reports (Abdelsayed et al. 2002) and large studies (Deeg et al. 1996; Curtis et al. 1997) describe numerous episodes of oral cancers (mainly SCC) in patients with oral GVHD. A large study that investigated the incidence of solid tumors in 20,000 bone marrow transplantation patients found that oral cancer had the highest risk among cancers, being 11.1 times more frequent than expected (Curtis et al. 1997). The significant risk factors for OSCC were chronic GVHD, limited-field irradiation, and male sex. In one of these studies, head and neck cancer was the only solid cancer observed in a group of 78 patients undergoing bone marrow transplantation for Fanconi anemia, with the frequency of such tumors was 167 times higher than expected (Deeg et al. 1996). Clearly, bone marrow transplantation patients have numerous risk factors that may enhance their likelihood of developing malignancies (primary immunodeficiencies, immunosuppressive treatments, viral infections, and probably genetic predisposition to cancer) that do not allow a comparison with OLP patients; however, the similarity of the oral conditions and the apparent common tendency to transform are worthy of careful consideration (Lodi et al. 2005b). Other lichenoid lesions that can undergo malignant transformation include discoid lupus erythematosus, in particular of the lip (Voigtlander and Boonen 1990) and amalgam-associated OLR (Ostman et al. 1996). Interestingly, in a prospective study on premalignant potential of OLP, all cases of malignant transformation involved lesions that the authors included in the group of OLL because they did not fulfill both clinical and histologic criteria for OLP (van der Meij et al. 2003). In 2007, van der Meij et al. (2007) also studied the number of expected oral carcinomas in 67 patients with OLP and 125 patients with OLL. All malignant transformations (4 of 192, 2.1%) appeared in OLL patients, i.e., an annual OLL malignant transformation rate of 0.71%. Hence, there was no increase in oral cancer risk for patients with OLP but a 142-fold increase for patients with OLL (P = 0.04). There may be considerable overlap between the clinical and microscopic features of OLR and OLP. Although no association has been established between OLR and malignant transformation (Mattsson et al. 2002), Larsson and Warfvinge proposed that there may be a similar rate of malignant transformation in OLR to that observed in OLP, especially in lesions at the lateral border of the tongue, a frequent site for OLR due to the close

22 22 M.J. McCullough et al. Fig. 3 Oral squamous cell carcinoma in OLP. Clinical presentation of patients with OLP and who subsequently developed OSCC: (a) An exophytic squamous cell carcinoma that developed on the right lateral tongue in a patient who previously had histopathologically diagnosed OLP in the same area. (b) An example of metachronous contact with silver amalgam restorations. They reported that the cancer had developed on an OLR in 4 of 724 patients with tongue cancer (Larsson and Warfvinge 2005). Tumors Developing in OLP and their Carcinogenesis Clinically, carcinomas that develop in previously diagnosed OLP lesions have been reported to be exophytic keratotic lesions (Lo Muzio et al. 1998; Fatahzadeh et al. 2004) (Fig. 3a), but some may also show endophytic growth patterns (Lo Muzio et al. 1998). Markopoulos et al. (1997) suggested that rapid expansion of OLP lesion should raise suspicion of malignant transformation, but Mignogna et al. (2001) found neither the extension nor severity of symptoms a useful indicator carcinomas in an OLP patient whose right buccal mucosa had previously shown histopathological evidence of OLP. Subsequently developed a more florid erythematous mucosa in the same area (pictured) that was biopsied and diagnosed as OSCC. (c) Eight years later, the same patient developed a second OSCC, controlaterally of transformation rather they considered the loss of lesion homogeneity at a specific site to be most relevant. This clinical sign is especially useful when only a small area is involved, as OLP usually affects various areas or a large area. An important reported feature of the presentation and clinical course of carcinomas that arise on OLP is their tendency of multiplicity. Mignogna et al. (2002) found that 29% of patients developing carcinomas in OLP had two or more independent neoplastic lesions (19% with a second tumor, 10% with >2 metachronous tumors) (Fig. 3b, c). This finding confirmed previous reports by Duffey et al. (1996) (20% of patients with second primary tumors) and Lo Muzio et al. (1998) (35.7% of patients with second primary tumors). The relatively high frequency of multiple intraoral localizations of second primary tumors in previously diagnosed OLP may be attributed to