Indian Journal of Dental Research

REVIEW ARTICLE
Year
: 2011  |  Volume : 22  |  Issue : 6  |  Page : 827--834

Oral lichenoid lesions: Clinico-pathological mimicry and its diagnostic implications


Santhosh Kumar S Hiremath1, Alka D Kale2, Seema Charantimath2,  
1 Department of Oral Pathology, Bharati Vidyapeeth Deemed University Dental College, Wanaleswadi, Sangli, Maharashtra, India
2 Department of Oral Pathology, KLE VK Institute of Dental Sciences, Nehru Nagar, Belgaum, Karnataka, India

Correspondence Address:
Santhosh Kumar S Hiremath
Department of Oral Pathology, Bharati Vidyapeeth Deemed University Dental College, Wanaleswadi, Sangli, Maharashtra
India

Abstract

Oral cavity is commonly affected by number of lichenoid lesions, whose clinical and histopathologic features overlap due to the presence of inflammatory cells in connective tissue. Segregation of these lichenoid lesions is mandatory as each may embody a distinct disease entity in terms of cause, diagnosis and prognosis. The literature discussed in the article is an attempt to segregate individual lichenoid lesions by defining clinical and histopathologic variations among each other, which avoids the diagnostic problem.



How to cite this article:
Hiremath SS, Kale AD, Charantimath S. Oral lichenoid lesions: Clinico-pathological mimicry and its diagnostic implications.Indian J Dent Res 2011;22:827-834


How to cite this URL:
Hiremath SS, Kale AD, Charantimath S. Oral lichenoid lesions: Clinico-pathological mimicry and its diagnostic implications. Indian J Dent Res [serial online] 2011 [cited 2014 Oct 25 ];22:827-834
Available from: http://www.ijdr.in/text.asp?2011/22/6/827/94679


Full Text

Oral mucosa is affected by a number of lichenoid lesions, the etiology of which is attributed to infective, inflammatory, dysplastic and immune-mediated conditions, resulting in distinct disease entities in terms of diagnosis and prognosis. [1],[2],[3] Yet, their clinical and histopathologic features overlap and create a diagnostic dilemma for the clinician as well as pathologists. Overlapping of features is due to the presence of intense inflammatory cells in the juxtaepithelium. [4],[5] To further complicate the issue, the use of generic terminology "lichenoid", which is a histopathologic description for inflammatory cells in the stroma, has created a source of confusion in segregating lichenoid lesions. [2] However, distinguishing these Oral lichenoid lesions (OLL) from one another is mandatory as some of the OLL [such as graft versus host disease (GVHD), amalgam associated lichenoid reaction, Discoid lupus erythematosus (DLE) of lip] have high propensity for malignancy. [6],[7]

Also, from the diagnostic and prognostic point of view, it is essential to separate inflammatory oral lichenoid tissue reaction from a precancerous lesion that elicits lichenoid inflammatory infiltrate. In fact, this discrimination can be done based on the presence or absence of dysplastic changes in the epithelium. However, reactive regenerative atypia (RRA) and early phase of oral proliferative verrucous leukoplakia (OPVL) show features of lichenoid inflammatory infiltrate in the stroma. [8],[9] In case of RRA, care should be taken not to overinterpret as a dysplasia. RRA consists of regenerative epithelium with atypical cytological features associated with inflammatory stroma, usually present at the margins of an ulcer, in traumatic lesion and in oral lichen planus (OLP). [8] On the other hand, OPVL is a precancerous lesion which exhibits lymphocytic infiltrate, basal vacuolar degeneration, containing apoptotic cells and eosinophilic bodies, similar to lichenoid stomatitis. [9] Diagnostic discrimination between lichenoid stomatitis and the above-mentioned two lesions can be done by careful assessment of clinical presentation, achieving final diagnosis by clinico-pathological correlation and close follow-up of the patients.

The concept of malignant transformation of OLP is highly controversial and a subject of debate which has added several layers of complexities into the scientific literature. Based on the previous published data, there was a division among the researchers regarding the concept of malignant transformation of OLP. Few were convinced that OLP is inherently precancerous, whereas others were not persuaded that this is so. However, irrespective of individual belief and understanding, malignant transformation of OLP is distinctly rare and this would logically reduce the "premalignant" designation of OLP. Critical analysis of large number of reported malignant transformation cases disclosed serious flaws in the documentation of the initial diagnosis of OLP. These include final diagnosis rendered solely based on clinical diagnosis and photomicrographs of OLP published in previous studies showing atypical/dysplastic features in the epithelium, and false diagnosis as OLP based on the mere mimicry of lichenoid infiltrate in stroma to an extent of ignoring atypical features within the epithelium. Many authors stated that the concept of malignant transformation of OLP was based on only retrospective studies and they believed such studies require prospective study group with large number of patients and long follow-up. [2],[5],[7],[10] Hence, based on all these findings, it is convincing to believe that OLP is innocent until it is proved premalignant based on good scientific documentation.

Distinguishing these lichenoid lesions from one another with limited clinical and histopathologic features creates a diagnostic problem. Hence, it is necessary for the clinicians and pathologists to familiarize with the clinico-pathologic patterns of oral lichenoid disorders to develop accurate diagnostic and prognostic assessment. The following literature is an attempt to segregate individual lichenoid lesions by defining clinical and histopathologic variation among each other, which avoids diagnostic problems.

 Classification of Oral Lichenoid Lesions



Van der Waal I updated the classification [Table 1] of OLL, [11] which distinguished these lesions into four types. Along with this classification, few other specific lesions [e.g. OLP, lupus erythematosus (LE), erythema multiforme (EM)] and premalignant lesions [Oral lichenoid dysplasia (OLD)] are also considered in the present literature as they are characterized by lichenoid tissue reaction.{Table 1}

Oral lichen planus

Oral lichen planus (OLP) is a chronic inflammatory disorder affecting stratified squamous epithelium. The disease is relatively common and affects approximately 2% of the total population [12] and 9% of all the white lesions of the oral cavity. [13] OLP can be present anywhere in the oral cavity and is almost invariably a bilateral disease on the buccal mucosa. Buccal mucosa is most commonly involved, followed by structures such as tongue, labial gingiva, hard palate and floor of the mouth. [14] OLP of gingiva is also called as "desquamative gingivitis" and it is not diagnostic either clinically or histopathologically. Clinical features resemble vesiculo-erosive lesions and histopathologic features are altered by superimposed gingivitis. [12]

Present trends classify OLP into three major clinical presentations: Reticular (white lines, papules, plaque), erythematous (atrophic) and erosive (ulcerated and bullae). [15],[16] For clinical diagnosis of OLP, erythematous and erosive forms should be associated with reticular pattern (Wickham's Striae) and lesion should be bilaterally symmetrical [Figure 1] and [Figure 2]. [17] These features help clinically differentiate OLP from other vesiculo-erosive diseases such as pemphigus and pemphigoid which are characterized by isolated areas of erythema and erosions. [2],[16] Lesions on the dorsum of the tongue are difficult to distinguish from leukoplakia. Studies have documented more than one similarly appearing pathological condition involving multiple sites of oral mucus membrane. In such instances, it is advisable to take multiple biopsies. [5] {Figure 1}{Figure 2}

Histopathologic assessment of OLP is rather subjective and insufficiently reproducible. Factors such as diverse information provided by the clinician, training and experience of the pathologist play an important role in the final histopathologic features of OLP. [18] However, classical and essential histopathologic features of OLP are band of inflammatory cells, chiefly lymphocytes, in the juxtaepithelium [Figure 3], liquefaction degeneration in the basal cell layer [Figure 4], normal epithelial maturation and cytomorphology. Disturbance in the epithelial maturation and presence of atypical features even in the presence of band of inflammatory cells in the stroma (i.e. atypical lichenoid change) is a disqualifying feature of OLP. [2],[17] World Health Organization proposed a set of modified diagnostic criteria to differentiate OLP and OLL clinically and histopathologically [Table 2]. [17] These criteria may help in the diagnosis of true OLP. The histopathologic features have been summarized in [Table 3].{Figure 3}{Figure 4}{Table 2}{Table 3}

Other histopathologic features which are neither essential nor pathognomonic of OLP are surface parakeratosis, civatte bodies and fibrinous precipitate at the epithelial stromal junction. These features overlap with histopathologic features of DLE and other lichenoid lesions. Additional features are candle dripping, ragged separation of epithelium from lamina propria. [2],[10]

Classical clinical and histopathologic features are altered by superinfection with Candida albicans. [19],[20] Candidal infection of OLP lesions has been demonstrated in biopsies of between 0 and 17% cases, with no apparent predilection for any clinical type of OLP. [21] Histopathologic features induced by candidal infection are epithelial hyperplasia (acanthosis), with thick layer of keratinization, superficial microabscess intraepithelial inflammatory cells, chiefly neutrophils, throughout the layer of epithelium, intracellular edema adjacent to the microabscess and large amount of hyphae of C. albicans in the upper layer of the epithelium under Periodic Acid Schiff (PAS) staining. [22]

OLP is a syndrome diagnosis that is based on several clinical and histopathologic criteria. Thus, the diagnostic approach is best described as method of pattern recognition both clinically and histopathologically. [18] Hence, final diagnosis should be achieved by the correlation of clinical and histopathologic features.

 Lichenoid Reactions



Lichenoid reactions are induced by either a systemic medication or a topical antigen. These conditions are clinically and histopathologically similar to OLP. All these conditions have to be diagnosed based on the proper clinical history followed by histopathologic assessment.

Lichenoid reactions associated with drugs (lichenoid drug reactions)

Clinical and histopathologic appearance resembles a delayed hypersensitivity reaction. It has been hypothesized that drugs or their metabolites with the capacity to act as heptans trigger a lichenoid reaction. Drugs which elicit lichenoid drug reactions (LDR) are listed in [Table 4]. [23] LDR cause hyperkeratotic striae, plaques, erosions and ulcers of mucosa resembling OLP. [20] A history of exposure to drugs is mandatory for the clinical diagnosis.{Table 4}

There is a little deviation in the histopathologic features from the characteristic histopathologic features of OLP. The infiltrate is often not band like, but extends into the deeper stroma, with plasma cells and eosinophils which predominate the inflammatory component [Figure 5]. [1] Infiltration of suprabasal cells rather than basal and parabasal cells has been noted which can produce extensive degeneration in the lower prickle cell layer, prompting spongiotic vesicle formation, apoptosis and colloid body formation with no marked disruption of the basal cell layer which can remain relatively intact [Table 3]. Deep perivascular infiltrate is also characteristic. [2],[20],[24] History of exposure to drug is essential for the diagnosis of LDR. However, withdrawal of the drug will slowly resolve the condition.{Figure 5}

Lichenoid reactions associated with amalgam and other dental restorations

Lichenoid stomatitis associated with dental restorations, particularly amalgam, is very common. Amalgam and mercury components are known heptans to elicit lichenoid reactions. [1],[20] Common anatomical sites involved are posterior buccal mucosa and lateral border of the tongue which are in direct contact with the restoration. The lesions are always unilateral. [25] The key clinical information required to confirm the diagnosis of amalgam restoration is the close topographic relationship between the restoration and the lesion. The lesion should be very sharply demarcated and fit the outline of the restoration neatly. Less well-localized lesions which respond less reliably to replacement of amalgam are less easily ascribed to restorations. [20]

Histopathologic features which are different from OLP include predominant formation of lymphoid follicles [Figure 6] chiefly consisting of plasma cells and neutrophils. In spite of dense inflammatory cells in the stroma, liquefaction degeneration of basal cells is little [Table 3]. [20] Any restorations associated with lichenoid reactions should be replaced by gold or synthetic resin. This is probably the simplest course of action in inconclusive cases because resolution confirms the diagnosis more reliably.{Figure 6}

Lichenoid reactions associated with cinnamon and its products (Stomatitis venenata)

Topical exposure to cinnamon containing products elicits lichenoid stomatitis. It is prudent to rule out the exposure of cinnamon if patient complains of severe pain, burning and urticarial swelling in the oral mucosa, accompanied by clinical lichenoid morphology. [26] Along with local discomfort, the lesions demonstrate erythema, fissures, ulcerations, lichenoid appearing red and white lesions, vesicles and peeling of overlying mucosa. With complete avoidance of cinnamon, the lesion progressively regresses and tends to resolve completely within weeks or months. [2]

Histopathologic features include lichenoid infiltrate predominated by plasmacytic component and perivascular cuffing by the plasmacytes. Regarding the status of epithelium, different authors quoted different histopathologic features. According to a few authors, epithelium is hyperorthokeratotic or hyperparakeratotic, and hyperplasia of epithelium is occasionally in a psoriasiform pattern. Others have stated that in severe cases, Munro-type neutrophilic abscess develops superficially in the epithelium [Table 3]. [2],[20]

Lichenoid reactions associated with graft versus host diseases

GVHDs occur mainly in the recipients of allergic bone marrow transplantation to treat life-threatening diseases of blood and bone marrow such as leukemia, aplastic anemia or disseminated metastatic diseases. [10] Diagnosis of GVHDs is essentially clinico-pathological as 85% of GVHDs elicit clinical and histopathologic features of OLP. [1] GVHDs are classified into acute and chronic forms. [2] Histopathologic features include epithelial maturation disturbances, with dyskeratosis, basal squamatization, subepithelial vaculation at the stromal interface and sparse lymphocytic infiltration in the upper lamina propria. Perivascular cuffing of inflammatory cells is evident [Table 3]. [2] One study has reported partial cleavage between the epithelium and connective tissue in 32% of cases. [27] Long-standing diseases often show marked fibrosis of the corium with little active epithelial damage. The histopathologic picture resembles "burn out" lichen planus. [20]

Lupus erythematosus

Oral lesions can occur in both in systemic and cutaneous forms of LE and oral lesions precede skin lesions. [1],[28] Similar clinical and histopathologic features have been demonstrated between OLP and LE, yet discrepancies between the two lesions have been identified. Clinical feature includes the fact that LE has a predilection for the vermillion area, palate and buccal mucosa. In contrast to OLP, lesions of LE are unilateral. [29] DLE appears as erythematous plaques with fine-drawn keratotic, LP-like white striae radiating from their outer border. [30]

Histopathologic features favoring Oral LE over OLP include edema of the superficial lamina propria; marked perivascular lymphocytic infiltration; relatively deeper stromal extension of the inflammatory infiltrate [Table 3]; deposition of mosaic like, cobbled appearing, PAS-positive material in the basement membrane zone (in contrast to OLP's more demarcated, slender PAS-positive deposit); and PAS-positive widening of walls of vascular channels. Epithelium shows surface atrophy, and hyperkeratosis with keratin plugging. [1],[29]

Systemic lupus erythematosus (SLE) can be distinguished based on systemic clinical features [31] and serological investigations. [32] SLE is a group of immunologically based diseases manifesting in multi-organ system. The presence of four or more of the following features is considered diagnostic of SLE. Malar rash, discoid rash, photosensitivity, oral and nasopharyngeal ulcers, non-erosive arthritis, serositis, renal disorders, neurological disorders, hematological disorders and immunologic disorders. [31]

Serological test for autoantibodies yields positive results in patients with SLE. The anti-nuclear antibody (ANA) test is regarded as liable and relatively specific test for SLE. Another serological test for SLE is the LE Cell test. It is less sensitive and specific than the ANA test. [32]

Erythema multiforme

EM is a reactive vesiculoulcerative disease that may affect the skin and mucus membrane. Oral lesions precede the skin lesions. Depending on the severity, EM can be classified into EM minor, EM major, Steven Johnson Syndrome and toxic epidermolysis necrosis (TEN). Steven Johnson Syndrome and TEN tend to be drug related. EM has more predilections for anterior part of the oral cavity. The lips may be blood crusted and show bullae or ulceration. Some lesions are recurrent and are triggered by Herpes virus infection. [33],[34] Recurrent attacks are mistaken for viral infection and herpetiform apthae.

Diagnosis in typical recurrent cases is usually based on the clinical findings and biopsy is performed to exclude viral or apthous ulceration. This is essential as diagnosis of viral infection would contraindicate systemic steroid therapy. Histological features are only diagnostic if the lesions are biopsied at an early stage. [20] Histopathologic feature includes edematous epithelium and the lymphocytic infiltrate in the upper lamina propria that may extend into the epithelium. Epithelial destruction is marked and there is often both subepithelial and intraepithelial bullae containing mononuclear cells. Inflammatory infiltrate consists of neutrophils, eosinophils and occasional lymphocytes [Table 3]. [34]

Oral lichenoid dysplasia

The possible malignant transformation of OLP is the subject of an ongoing, controversial discussion in the literature. A case of carcinoma arising in lichen planus of the oral mucus membrane was first described in 1910 by Hallopeau. Since then, several retrospective and case report studies have been published in this regard. [35]

But contradicting these studies, many published reports documented that there was an error in the initial diagnosis of OLP and many alleged malignant transformation of OLP consistently demonstrates the tendency of pathologists to be mesmerized by lichenoid infiltrates to the point of overlooking subtle dysplasia. [18] Krutchkoff and Eisenberg assigned the term lichenoid dysplasia (LD) to any lesion which shows dysplasia with lichenoid features. LD has a true propensity for malignancy. It is neither a variant nor a transitional form of OLP. The two conditions share essentially no pathogenetic relationships, but their similarity is the presence of lichenoid inflammatory infiltrate. In OLP, lichenoid infiltrate represents cell-mediated immune response provoked by different antigens, whereas in OLD, lichenoid infiltrate represents immune surveillance mechanism against atypical epithelial cells. [5],[36]

Clinically, lesions of OLD appear similar to that of OLP but these tend to be unilateral and the prevalence is more on the cancer-prone sites such as lateral and ventral surface [Figure 7] of the tongue, floor of the mouth, mandibular lingual alveolar ridge, tonsillar pillar, and soft palate uvula complex. [6] OLL such as amalgam induced and GVHDs have a high susceptibility for malignancy. OPVL, particularly in the early stage, exhibits similar clinical and histopathologic features which can be confused with OLP, frequently shows dysplastic changes and is characterized by a high malignant transformation. [7],[9] It is hypothesized that superinfection with Candida may create a carcinogenic environment by the release of N-nitrosobenzylmethylamine. Continuous use of immunomodulators for the treatment of OLP itself reduces the immunity there by increasing the rate of malignant transformation. [35] It is always possible that more than one disease process can co-exist together. Hence, it is prudent to take multiple biopsies. If multiple biopsies are not possible, biopsy on cancer-prone site is more precise. Ulcerative and erosive forms of OLP have more propensity for transformation, hence biopsy is mandatory. [5] Role of carcinogens (tobacco, alcohol, etc.) in the transformation of OLP into carcinoma is a topic of debate as some authors suggested positive role of carcinogens, while others have reported OLD without any habits. [6]

Histopathologic features that allow separation of OLD from OLP include [Table 3] the presence of dysplasia in the epithelium and the absence of liquefaction degeneration. Cytologic features of epithelial dysplasia may include any two or more of the following, attended by a lymphocytic or heterogeneous lichenoid infiltrate: Cellular pleomorphism, altered nuclear cytoplasmic ratio, nuclear hyperchromasia, altered stratification, abnormal keratinization pattern, loss of intercellular bridges, aberrant and increased mitotic figures [Figure 8]. [36] {Figure 7}{Figure 8}

 Discussion



From the present literature and previous published data, it has been documented that various lichenoid lesions mimic OLP clinically and histopathologically. [1],[2] In spite of similar clinico-pathological features and the use of confusing generic terminology "lichenoid" for all the lesions which show lichenoid infiltrate in the stroma, [1] it is essential for all the clinicians and histopathologists to familiarize with the individual variation among the clinico-pathological features of OLL. [1],[2],[3] Separation of these OLL is essential as some of these have high propensity for malignancy (GVHD, amalgam associated lichenoid reaction, DLE of lip). [6],[7]

To further complicate the issue, histopathologic assessment of OLP is rather subjective and insufficiently reproducible, [18] and in a few instances histopathologic features may not be diagnostic, as OLP evolves through a cycle of exacerbation and quiescence. Biopsy in any condition helps to differentiate whether the lesion is of inflammatory origin or the lesion consists of underlying atypical features in the epithelium. In the case of OLL, histopathologic features are not confirmatory. [37] Thus, in the case of either OLP or OLL, final diagnosis has to be confirmed by clinico-pathological correlation.

Selection of appropriate biopsy site is essential for the accurate diagnosis. Studies have shown selecting reticular lesion for biopsy is more appropriate as these lesions are histopathologically diagnosed as OLP much more consistently than erythematous and erosive lesions. [38] Immunofluorescent studies are adjuvant and not confirmatory for the diagnosis of OLP. [17]

Frequency of malignant transformation of OLP is rare and many studies focusing on such a transformation disclosed serious flaws in the initial diagnosis of OLP. From various published articles, it is evident that it is not OLP, but OLL and OLD which have high propensity for malignancy. [2],[5],[7],[10]

 Conclusion



OLL are the common mucocutaneous diseases with indistinguishable clinico-pathological features and may create diagnostic dilemma. In spite of similar clinico-pathological features, etiology, diagnosis and prognosis differ which mandates separation of OLL. Hence, it is essential for the clinician and histopathologist to familiarize with the individual variations among clinico-pathological features of OLL. To confirm the final diagnosis of any OLL, it is indicated to have a proper clinical history, selection of appropriate biopsy site which is followed by histopathologic assessment of the same. Final diagnosis has to be achieved after the correlation of clinical and histopathologic diagnosis.

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