Abstract
Oral lichen planus is a chronic inflammatory disease of unknown etiology or pathogenesis with varied disease severity that waxes and wanes over a long period of time. Although a common oral mucosal disease, accurate diagnosis is often challenging due to the overlapping clinical and histopathological features of oral lichen planus and other mucosal diseases. Other immune-mediated mucocutaneous diseases can exhibit lichenoid features including mucous membrane pemphigoid, chronic graft-versus-host disease, and discoid lupus erythematosus. Reactive changes to dental materials or to systemic medications can mimic oral lichen planus both clinically and histologically. In these situations the clinical presentation can be useful, as oral lichen planus presents as a multifocal process and is usually symmetrical and bilateral. Dysplasia of the oral cavity can exhibit a lichenoid histology, which may mask the potentially premalignant features. Proliferative verrucous leukoplakia, an unusual clinical disease, can often mimic oral lichen planus clinically, requiring careful correlation of the clinical and pathologic features.
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Main
Diagnosing oral lichen planus can be challenging due to various conditions that have overlapping features—both clinically and histologically. The terminology, classification, and diagnosis of oral lichenoid lesions have been explored, debated, and analyzed for decades.1, 2, 3, 4 Many names have been used in the literature, which contribute to the confusion surrounding terminology, impeding our ability to develop effective approaches to diagnosis and management. The differential diagnosis of oral lichenoid lesions includes other immune-mediated mucocutaneous diseases, and reactive and inflammatory conditions.
The malignant potential of oral lichen planus is fraught with controversy due to lack of reliable histologic diagnostic criteria and in some reports the diagnosis of oral lichen planus was made exclusively on the clinical presentation without histologic confirmation.5, 6, 7, 8, 9, 10, 11 Oral dysplasia can exhibit lichenoid features masking the potentially cancerous component.12, 13 The presence of dysplasia in an oral lichenoid lesion precludes a diagnosis of oral lichen planus and rendering the diagnosis of oral lichen planus with dysplasia can result in patient mismanagement. Proliferative verrucous leukoplakia is an uncommon oral disease that, due to the multifocal presentation, can mimic oral lichen planus clinically and histologically, particularly in its early stages.1, 2, 14, 15 However, there are distinct architectural changes in proliferative verrucous leukoplakia including hyperkeratotic verrucous epithelium that can aid a pathologist.
An accurate diagnosis of oral lichen planus and oral lichen planus mimics cannot be made in a vacuum and it is essential that clinicians provide patient information including site, symptoms, and other relevant information with the biopsy requisition. Correlation of the clinical presentation coupled with the histologic features is essential when examining oral biopsies with lichenoid features.
Oral lichen planus and benign lichenoid lesions
Oral Lichen Planus
Oral lichen planus is a relatively common mucocutaneous disease with an estimated prevalence of 0.22 to 5% worldwide.16 Oral lichen planus is more prevalent in females and most often presents in the fourth to eighth decade.16, 17, 18, 19 Although rare, pediatric involvement occurs and in one study 18% of the childhood lichen planus cases had oral involvement.20, 21 Although up to 60% of patients with cutaneous lichen planus have oral manifestation, only a minority of oral lichen planus patients (15%) develop cutaneous lichen planus.18, 22 Other anatomic sites of involvement include the genitalia and both peno-gingival syndrome and vulvo–vaginal–gingival syndrome have been reported in up to 20% of patients with oral lichen planus.18 Esophageal involvement can occur with oral lichen planus but is unusual. Lichen planus can involve the scalp (resulting in scarring alopecia), nails, and conjunctivae.23
Oral lichen planus is a multifocal disease and presents more or less in a symmetrical distribution, typically affecting the buccal mucosa, tongue, lips, gingiva, and rarely the palate and floor of mouth.1, 16, 24 In the oral cavity, there are six clinical presentations of oral lichen planus: reticular, atrophic (erythematous), erosive, papular, plaque, and bullous (Figure 1a–d). Many of these patterns occur simultaneously or sequentially. The most characteristic clinical presentation is intersecting white lines (striae) with or without erythema that can be pigmented in some ethnic groups.16, 17, 18, 25 Plaque-like oral lichen planus is most commonly found on the dorsal tongue and has been reported to be more common in cigarette smokers.25 Erosive oral lichen planus when associated with severe ulcerations can mask the typical oral lichen planus striae but careful clinical examination will often show the recognizable features of oral lichen planus. Gingival involvement by oral lichen planus usually presents as desquamative gingivitis and is clinically indistinguishable from other diseases including mucous membrane pemphigoid and pemphigus vulgaris.1, 2 The facial gingiva is most commonly affected but in severe cases both palatal and lingual gingival mucosa can be involved.
Rendering the correct diagnosis requires good communication with the clinician who hopefully is familiar with both the clinical and histologic features of lichen planus. As the diagnosis of lichen planus requires evaluation of the basement membrane zone (BMZ), biopsies of oral lichen planus must include intact, full thickness epithelium. A biopsy of only the ulcerative component will not show the interface changes necessary for diagnosis.
The American Academy of Oral and Maxillofacial Pathology recently published a position paper on the histologic diagnostic guidelines of oral lichen planus modifying the criteria reported by van der Meij and van der Waal.26, 27 The microscopic features of oral lichen planus are highly variable, as biopsies from hypertrophic, atrophic, or erosive sites can exhibit different histologic features. Interface mucositis is a hallmark of oral lichen planus. Hydropic degeneration of the basal cells with scattered dyskeratotic keratinocytes (Civatte, colloid, hyaline, or cytoid bodies) along the epithelial interface is seen (Figure 2a–d).1, 27 At the basement zone, hugging the basal cells is a band-like, predominately T-lymphocyte infiltrate. A ‘sawtooth’ pattern of the rete can be observed in oral lichen planus but this histologic finding is more common in cutaneous LP.16 The epithelium can also appear acanthotic or atrophic corresponding to the clinical presentation. In general, the inflammation is superficial rather than deep and perivascular inflammation is not typically present. Other histologic findings include a homogeneous eosinophilic deposit at the epithelial–lamina propria interface, melanosis, and melanin incontinence with associated melanophages (Figure 3a and b). The presence of melanin is not specific to oral lichen planus and can be seen in oral biopsies from other oral inflammatory disorders.28 Biopsies of erosive oral lichen planus lack many of the histologic hallmarks of lichen planus and arriving at a definitive diagnosis can be difficult (Figure 4a and b).
Direct immunofluorescence of oral lichen planus is nonspecific and includes shaggy fibrin and/or complement (C3) deposits in a granular or linear pattern along the BMZ.29, 30 IgM-positive colloid bodies can also be identified. This direct immunofluorescence pattern can be seen in other inflammatory conditions, as well as in premalignant and malignant oral lesions.31 Therefore, direct immunofluorescence is not necessary to make the diagnosis of oral lichen planus, although direct immunofluorescence can be useful to distinguish oral lichen planus from other vesiculobullous diseases such as mucous membrane pemphigoid and chronic ulcerative stomatitis (Table 1).29, 30 Indirect immunofluorescence is negative in oral lichen planus.
Benign Lichenoid Lesions
Oral lichenoid lesions are well documented and can have a variety of etiologies. Table 1 lists the various histologic mimics of oral lichen planus and compares the clinical features, histology, and immunopathology with oral lichen planus. Mucous membrane pemphigoid is a heterogeneous group of subepithelial blistering autoimmune diseases that mostly affect the mucosa and can result in scarring. Mucous membrane pemphigoid and oral lichen planus can be clinical mimics, in particular when presenting as desquamative gingivitis, but direct immunofluorescence can be helpful in separating between these two diseases (Figure 5a–d).1, 2 Most patients with mucous membrane pemphigoid will have continuous linear deposits of IgG, IgM, or IgA and complement (C3) along the BMZ on direct immunofluorescence.32 Indirect immunofluorescence is less sensitive in mucous membrane pemphigoid as patients exhibit inconsistently circulating autoantibodies directed against the BMZ, although the use of a salt-split skin substrate can increase IIF sensitivity.33, 34 Immunoblot assays and enzyme-linked immunosorbent assay increases the sensitivity and specificity of detected autoantibodies in mucous membrane pemphigoid sera.35
Systemic drug exposure can cause oral lichenoid drug reactions.1, 3, 4 A variety of medications have been implicated in oral lichenoid drug reaction (Table 2); the most frequently reported are nonsteroidal anti-inflammatory drugs, anti-hypertensives, and anti-malarials. The pathogenesis and exact incidence of oral lichenoid drug reaction is unknown. One study theorizes that prone patients have polymorphisms of the cytochrome P450 enzymes resulting in altered metabolism of some medications but this proposal requires confirmational studies.36 The oral lichenoid drug reaction is more common in adults and is rarely reported in children. An oral lichenoid drug reaction generally presents as a single lesion unlike oral lichen planus. Establishing a relationship to the offending medication can be difficult, as the time interval between initiation of medication and the development of oral lichenoid drug reaction can range from weeks to a year or more. Table 1 highlights the histologic differences between oral lichenoid drug reaction and oral lichen planus including a more diffuse mixed inflammatory infiltrate with perivascular inflammation (Figure 6a). The microscopic findings in oral lichenoid drug reactions are considered nonspecific and clinical information including a temporal relationship with the use of systemic medications and resolution of the lesions following drug discontinuation aid in the diagnosis of an oral lichenoid drug reaction.
Oral lichenoid contact reactions have been described and are associated with a variety of topical agents including dental materials and flavoring agents (Table 2).1, 3, 4, 37 Lichenoid lesions can occur from mucosa in direct contact to amalgam restorations and are seen most commonly on the lateral tongue or buccal mucosa.37, 38 The histology often shows tertiary lymphoid follicle formation composed of B cells containing follicular dendritic cells surrounded by T cells and macrophages similar to tonsils (Figure 6b).1, 2, 38 Unlike oral lichen planus, oral lichenoid contact reaction to amalgam are usually single and will resolve with removal of the amalgam. Oral lichenoid contact reaction to cinnamon-containing products such as gums and candies can cause a hypersensitivity reaction termed cinnamon stomatitis.1, 2, 3 The histology overlaps with oral lichen planus, although in cinnamon stomatitis marked epithelial acanthosis with elongated rete ridges and a mixed inflammatory cell infiltrate with perivascular inflammation is present (Figure 7a and b).39, 40 Similar to oral lichenoid contact reaction to amalgam, discontinuing the cinnamon product will quickly result in resolution of the mucosal lesions.
Both discoid lupus erythematosus and systemic lupus erythematosus can have oral manifestations that are similar in appearance to oral lichen planus.1, 3, 4 The oral mucosa can be affected in up to 25% of patients with lupus erythematosus. Intraoral lupus erythematosus lesions are not distributed in a symmetrical pattern such as oral lichen planus and are found throughout the oral cavity including hard palate, buccal mucosa, lip, and gingiva.4, 41 The lesions typically have a central atrophic or ulcerated area surrounded by radiating white striae. The margins of the lesion are less defined than oral lichen planus. Most patients with oral manifestations of lupus erythematosus will also have concurrent cutaneous lesions and other characteristics of lupus erythematosus such as photosensitivity.41
The histologic features of oral lupus erythematosus is not specific and overlaps with other oral lichenoid lesions including oral lichen planus, oral lichenoid contact reaction, and oral lichenoid drug reaction.42, 43 The epithelium can range from atrophic to hyperplastic with keratin plugging and a thickened basement membrane. The inflammation in the lamina propria can be mixed or lymphocyte rich and range from paucicellular to band like, similar to oral lichen planus. Perivascular inflammatory infiltrates are usually present but this finding overlaps with oral lichenoid contact reaction and oral lichenoid drug reaction. Civatte bodies and interface mucositis can be observed and melanin incontinence adjacent to the epithelium may be seen. Direct immunofluorescence of perilesional tissue of oral systemic lupus erythematosus and discoid lupus erythematosus shows granular or shaggy deposits of IgG, IgM, and/or C3 in the BMZ.3, 4, 42 These findings are present in practically all cases of systemic lupus erythematosus, while direct immunofluorescence is positive in ~70% of tissue samples from discoid lupus erythematosus. Indirect immunofluorescence is generally negative in discoid lupus erythematosus while antinuclear antibodies (ANA) are a serological hallmark in systemic lupus erythematosus.
Chronic graft versus host disease is a serious complication following allogeneic hematopoietic stem cell transplantation (bone marrow transplantation). Up to 80% of graft recipients may develop chronic graft versus host disease, usually within the first 6–24 months following transplantation.1, 44 The most commonly affected areas are the skin, liver, oral cavity, and eyes, and in some cases oral chronic graft versus host disease may be the only affected anatomic site.45 Oral chronic graft versus host disease can have a variety of presentations, some of which overlap clinically with oral lichen planus. The reticular form is most common, with or without erosions mimicking oral lichen planus. Patients diagnosed with chronic graft versus host disease have an increased risk for the development of oral cancer and should be screened yearly.46, 47
Appropriate clinical history is necessary in formulating a diagnosis as oral lichen planus and chronic graft versus host disease have overlapping histology.48, 49 Numerous colloid bodies can be present along with basal cell degeneration. The inflammatory infiltrate in chronic graft versus host disease may be mixed containing plasma cells and eosinophils and also may not be as intense as in oral lichen planus. Direct immunofluorescence findings are similar to oral lichen planus and indirect immunofluorescence is negative.
Chronic ulcerative stomatitis is a rare mucocutaneous disease that can mimic both erosive oral lichen planus and mucous membrane pemphigoid. First described in 1990, the exact incidence is unknown with around 50 reported cases to date.50, 51, 52 Similar to oral lichen planus, chronic ulcerative stomatitis affects mainly women in the fifth to sixth decade. Chronic ulcerative stomatitis mostly involves the gingiva, tongue, and buccal mucosa but can affect all oral anatomic sites. Gingival involvement presents as desquamative gingivitis indistinguishable from oral lichen planus and mucous membrane pemphigoid.50, 52
Histologically, no unique features are present to allow for differentiation of chronic ulcerative stomatitis from oral lichen planus. A band-like predominately lymphocytic infiltrate, hydropic basal cell degeneration, cytoid bodies, and atrophic stratified squamous epithelium is seen.52, 53 Fortunately, direct immunofluorescence can separate chronic ulcerative stomatitis from oral lichen planus. Direct immunofluorescence of perilesional tissue in chronic ulcerative stomatitis demonstrates IgG antibodies in the nuclei of basal and parabasal epithelial cell in a speckled and/or granular pattern known as the stratified epithelium specific-ANA pattern.50, 51, 53 Some autoimmune diseases including lupus erythematosus, scleroderma, CREST syndrome (calcinosis, Raynaud’s phenomenon, esophageal involvement, sclerodactyly, and telangiectasia) have an ANA pattern in epithelia; however, unlike chronic ulcerative stomatitis, the autoantibody deposits are present in the spinous layer. Nevertheless, tangential cutting may create difficulties in interpretation. A shaggy fibrin band at the BMZ can also be seen on direct immunofluorescence similar to oral lichen planus. ANA-SES is identified by indirect immunofluorescence using either guinea pig or monkey esophagus as a tissue substrate in chronic ulcerative stomatitis.50
Oral lichen planus and potentially malignant lesions
Oral Epithelial Dysplasia with Lichenoid Features
The malignant potential of oral lichen planus has been debated since the first report in 1924 and to date the controversy is unresolved.6 A recently published meta-analysis and systemic review of malignant transformation rates of oral lichen planus evaluating 16 studies with a total of 7806 patients had an overall average rate of 1.09%.7 Of the 88 patients who developed oral squamous cell carcinoma, the most common oral anatomic site was the tongue (51%) followed by the buccal mucosa (32%). The female to male ratio of 3:1 was similar in both the oral lichen planus group and the subset of patients who developed squamous cell carcinoma. This finding is opposite from conventional oral squamous cell carcinoma where the female to male ratio is 1:3. The average age of the oral lichen planus patients when they developed squamous cell carcinoma was almost 10 years older than the non-cancer oral lichen planus group (60 years of age versus 51 years of age).7
To date, it is unclear whether oral lichen planus is an independent risk factor for malignant transformation. Separating confounding risk factors for oral squamous cell carcinoma including tobacco use when evaluating studies is unrealistic as many studies have not recorded secondary risk factors. Numerous studies have investigated various mechanisms involved in carcinogenesis including p53, PCNA, loss of heterozygosity at the tumor suppressor gene loci, and cytogenetic abnormalities.54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 None of the data show convincing or consistent findings of the premalignant potential of oral lichen planus. The inflammatory cell infiltrate associated with oral lichen planus has been proposed to be a mechanism for malignant transformation.67 This proposal is not without merit as other chronic inflammatory diseases have been linked to cancer such as colon cancer in long-standing inflammatory bowel disease precipitated by intestinal microflora.68 Conversely, other data suggest that inflammatory and immune systems may inhibit tumorigenesis.
Clinically, oral leukoplakia may present with lichenoid features and a clinician may biopsy the area to confirm the clinical impression of oral lichen planus (Figure 8a and b). Oftentimes, biopsies of oral epithelial dysplasia can mimic oral lichen planus on low-power microscopy exhibiting a prominent band-like chronic inflammatory infiltrate subjacent to the basal cells (Figure 9a and b).1 The pathologist is then confronted with a clinical impression of oral lichen planus and a low-power histology of oral lichen planus, and may be lulled into making the diagnosis of oral lichen planus without further investigation. However, it is important to remember that oral lichen planus tends to present as symmetrical multifocal lesions as opposed to the typically isolated lesion of oral epithelial dysplasia.1, 2 A recent study examined the incidence of lichenoid features in oral epithelial dysplasia and oral squamous cell carcinoma including ‘saw-tooth’ rete ridges, interface mucositis, colloid bodies, and basal cell degeneration.12 Lichenoid features were present in 29% of the 352 oral epithelial dysplasia or squamous cell carcinoma and the most frequently encountered features were a band-like inflammatory cell infiltrate (74%) and basal cell degeneration (30%).12 On closer microscopic examination, the classic features of oral epithelial dysplasia including irregular epithelial stratification, loss of basal cell polarity, drop-shaped rete ridges, increased number of mitotic figures, premature keratinization, and hyperchromasia can be detected (Figure 10). This author acknowledges that the presence of intense inflammation can result in cytologic reactive atypia in oral lichen planus and distinguishing oral lichen planus and mild dysplasia can be subjective. However, objective criteria such as a lymphocyte predominate infiltrate versus mixed inflammatory infiltrate can be at times helpful.1, 2, 13 Direct immunofluorescence cannot be used to distinguish oral epithelial dysplasia from oral lichen planus. Direct immunofluorescence findings of fibrinogen and/or C3 deposition at the BMZ has been described in 43% of oral epithelial dysplasia or oral squamous cell carcinoma similar to oral lichen planus.31 Grading oral epithelial dysplasia should be based on the degree of dysplasia (mild, moderate, and severe) rather than using the term lichenoid dysplasia. This term as a diagnosis should be discouraged, as it may create confusion resulting in suboptimal treatment.
An unusual and rare type of oral leukoplakia is proliferative verrucous leukoplakia, a distinct and aggressive form of oral precancer.1, 2, 14, 15 Proliferative verrucous leukoplakia is associated with high recurrence and malignant transformation rates. Proliferative verrucous leukoplakia is mostly seen in older women (>60 years of age; F:M ratio of 4:1).14, 15 The etiology of proliferative verrucous leukoplakia is unknown and is not associated with the usual risk factors for oral cancer including tobacco and alcohol use, and no association with HPV or other viruses have been detected. Proliferative verrucous leukoplakia, similar to oral lichen planus, is a multifocal disease affecting the gingiva, alveolar mucosa, buccal mucosa, palate, and dorsal tongue.14, 15, 69 The ventral tongue and floor of mouth are unusual sites of proliferative verrucous leukoplakia. The clinical presentation of multiple white keratotic plaques can be clinically mistaken for oral lichen planus and oftentimes proliferative verrucous leukoplakia is a diagnosis made in retrospect, particularly in its early stages. The clinical features of proliferative verrucous leukoplakia range from a focal flat white keratosis that with time becomes more diffuse (Figure 11a). Lesions may progress to a warty or verrucoid surface and have erythema, and ultimately can progress to either verrucous squamous cell carcinoma or squamous cell carcinoma.69 Histologically, proliferative verrucous leukoplakia biopsies, particularly in the early stages lack dysplasia but may have interface mucositis mimicking oral lichen planus (Figure 11b). However, there are some distinct histologic features of proliferative verrucous leukoplakia that aid in differentiating from oral lichen planus. Proliferative verrucous leukoplakia often exhibits verruciform epithelial hyperkeratosis, more often orthokeratosis rather than parakeratosis (Figure 12a and b). Progressive lesions may have dysplasia which precludes the diagnosis of oral lichen planus. Direct immunofluorescence cannot be used to differentiate proliferative verrucous leukoplakia from oral lichen planus. Atypical verrucous hyperplasia/hyperkeratosis shows fibrinogen deposition at the BMZ in ~42% of cases and 3% of cases have both fibrinogen and C3 deposition.31
Conclusion
Owing to the tremendous overlap in the clinical and pathologic presentation of inflammatory, reactive, immune-mediated, and potentially premalignant lesions that affect the oral mucosa, oral lichenoid lesions can be a diagnostic challenge. Clinical information is essential as an accurate diagnosis cannot be made in a vacuum. Immunofluorescence may be a helpful adjunct in diagnosing some of the lichenoid lesions such as lupus and chronic ulcerative stomatitis. The presence of dysplasia should preclude the diagnosis of oral lichen planus or other benign lichenoid lesions to ensure appropriate patient management.
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Müller, S. Oral lichenoid lesions: distinguishing the benign from the deadly. Mod Pathol 30 (Suppl 1), S54–S67 (2017). https://doi.org/10.1038/modpathol.2016.121
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DOI: https://doi.org/10.1038/modpathol.2016.121
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