Oral lichen planus

Abstracts

O líquen plano da mucosa oral (LPO) é afecção relativamente comum, que pode aparecer isolado ou associado ao líquen plano cutâneo, havendo, no entanto, significantes diferenças clínicoevolutivas: o LPO tende a ser crônico, recidivante e de difícil tratamento, levando a importante morbidade, principalmente em sua forma erosiva. Novas formas clínicas agressivas têm sido salientadas na literatura, como a forma gingivo-vulvar. Este artigo revisa a etiopatogenia, as formas clínicas, a diagnose diferencial e laboratorial, a prognose e o tratamento do LPO, além de mencionar, brevemente, a experiência dos autores com esta enfermidade, vivida no Ambulatório de Estomatologia da Divisão de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo

Líquen plano; Líquen plano bucal; Medicina bucal

CONTINUED MEDICAL EDUCATION

Oral lichen planus^*

Marcello Menta Simonsen Nico^I; Juliana Dumet Fernandes^II; Silvia Vanessa Lourenço^III

^IPhD - Professor, Department of Dermatology, University of São Paulo School of Medicine. Outpatient Clinic of Stomatology, Service of Dermatology, Clinics Hospital, University of São Paulo School of Medicine (FMUSP - São Paulo (SP), Brazil

^IIPhD - University of São Paulo. Assistant professor of Dermatology, State University of Feira de Santana (UEFS)- Feira de Santana (BA), Brazil

^IIIFaculty Member (livre-docente) - Associate Professor, Department of Stomatology, University of São Paulo School of Dentistry - São Paulo (SP), Brazil

Mailing address

ABSTRACT

Oral lichen planus (OLP) is a relatively common mucosal disease that can present isolated or associated with cutaneous lichen planus. Contrarily to its cutaneous counterpart, though, OLP tends to be chronic, relapsing, and difficult to treat. Severe morbidity is related to erosive forms, and more aggressive presentations have been described, such as the "gingivo-vulvar syndrome". This article reviews the current knowledge about the pathogenesis, clinical picture, differential and laboratorial diagnosis, prognosis, and treatment of OLP.

Keywords: Lichen planus; Lichen planus, oral; Oral medicine

INTRODUCTION

Lichen planus is a T-cell mediated chronic inflammatory mucocutaneous disease of unknown cause. ¹ It is characterized by a papular skin eruption that occurs in most cases between 30 and 60 years of age; however, occurrence in children has been increasingly observed. ^2-4 It may affect the mucous membranes, particularly the oral and genital mucosa, and very rarely, the mucosa of the anus, nose, larynx, conjunctiva and urethra. Oral mucosal lesions occur in 50 to 70% of the patients with lichen planus and may be exclusive in 20 to 30% of them. ^5-7 Nonetheless, skin lesions of lichen planus were observed in 15% of the patients with diagnosis of oral lichen planus (OLP). ⁸ It is estimated that the prevalence of OLP varies from 0.5 to 4% of the general population, ^9-13 being more common in females.^2,7,14-16 A hundred and three patients with OLP were treated at the Outpatient Clinic of Stomatology, Division of Dermatology, Clinics Hospital, University of São Paulo School of Medicine, between 2003 and 2010; 33 of these patients were men and 70, women (unpublished data). The objective of this study is to review the etiopathogenesis, clinical manifestations, diagnosis and treatment of OLP.

ETIOPATHOGENESIS

Although it is believed that OLP is a T-cell mediated autoimmune disease, its cause remains unknown. ¹⁷ Current evidence suggests that the disease is related to an alteration of cell-mediated immunity, triggered by endogenous or exogenous factors, which^18.19 results in an altered response to autoantigens. Most activated T cells in the inflammatory infiltrate of OLP are CD8 +.^20.21 Activated T cells of the inflammatory infiltrate, associated with increased production of Th1 cytokines (IL-1, IL-8, IL-10, IL-12, TNF-α) increase the expression of intercellular adhesion molecules (ICAM-1) on Langerhans cells and macrophages, leading to presentation of major histocompatibility complex antigens by keratinocytes. This altered immune response results in apoptosis of keratinocytes in the basal layer and may determine disease activity.^22-27 Other mechanisms that may also be involved in the etiopathogenesis of the disease are mast cell degranulation and activation of matrix metalloproteinases.¹³ Moreover, some researchers believe that the chronicity of OLP can be partly explained by a deficiency in the mechanisms of immunosuppression mediated by transforming growth factor beta; ²⁸ however, the causes that lead to the onset of the process have not yet been fully clarified.

The relationship between OLP and hepatitis C virus is not stable, since the prevalence of this virus in patients varies based on studies, ranging from 0% to over 60%, according to the country where these studies are conducted. ^{1, 29-32} The rates of HCV infection in patients with LP appear to be high in Japan, Italy and Brazil ³³ and low in the U.S., France, Nordic countries, UK and Germany. ³¹ However, results in Brazil are controversial, as a recent study shows. ⁴ Data by these authors show a frequent observation in our clinical practice: it is rare to diagnose HCV positivity in patients with OLP, but it is common to see OLP in individuals known to be carriers of the virus.

The difference in the prevalence of HCV infection in different geographic locations may not have been clearly explained, but it is believed to be due to differences in the socioeconomic status and to the selection bias of the subjects studied (mean age and gender) in their respective countries . ^1,31,35 Given this geographical heterogeneity, the hypothesis that some genetic change may facilitate the development of OLP in a subgroup of patients with hepatitis C has been raised ^31.32 A recent meta-analysis of the literature led us to conclude that " HCV infection is associated with a statistically significant risk for the development of OLP, suggesting that the presence of either HCV or certain types of lichen planus can be used as predictive markers of one another in certain geographical regions."³³ Therefore, it is suggested that research of liver abnormalities or HCV infection in patients with OLP should be conducted only in individuals with suspicious clinical and epidemiological history.

Genetic polymorphisms of several cytokines also appear to be associated with the clinical presentation of the disease. Interferon- polymorphisms have been associated to lichen planus with exclusive oral involvement, and TNF-α polymorphisms have been associated with forms that affect the oral mucosa and skin. It is, however, hasty to say that OLP is a genetically determined disease. These findings must be confirmed by studies conducted in different geographical areas. ¹⁹

A severe form of the disease, the so-called "vulvovaginal-gingival syndrome" of lichen planus appears to be associated with an HLA class II allele (HLA-DBQ1). ³⁶

Another interesting aspect to be discussed is the presence of lesions identical to those of lichen planus in graft versus host disease (GVHD). Clinical and histopathological findings of lichenoid oral lesions in chronic GVHD are indistinguishable from idiopathic OLP lesions. In GVHD, donor T lymphocytes attack tissue antigens of the minor histocompatibility complex of the host cell. Thus, GVHD appears as an interesting model in the study of the pathophysiology of OLP. ³²

Several authors have also shown that oral lichenoid reactions may result from contact with dental restoration materials, especially those containing amalgam, metallic mercury or ammoniated mercury. This can be shown in those cases in which the replacement of these materials leads to the improvement of OLP lesions, a fact mainly observed when there are no skin lesions and all oral lesions are in contact with the restorations. ^1,32,37-40

The importance attributed to psychological factors varies according to the authors; there is controversy over whether psychiatric disorders (anxiety, depression) are involved in the genesis of the disease or are a consequence of chronic painful lesions. In a study of 16 patients with OLP without mental complaints and without subjective need for psychiatric help, psychiatric examination showed that 5 of them had a moderate disorder and one had signs of "neurosis." Association with depression ⁴¹ is reported by some authors and refuted by others. ^41.42

CLINICAL MANIFESTATIONS

OLP may present in the following forms: reticular, atrophic, papular, erosive, bullous and erythematous. These different clinical presentations represent variations of intensity and duration of the disease (Figures 1-6). These different forms may present simultaneously, and the predominant clinical morphology can change over time in the same patient.^43.44 OLP lesions are often bilateral and symmetrical, which differentiates them from contact lichenoid reactions of the oral mucosa. Unilateral lesions of OLP are rare and atypical. ⁴¹ The most affected sites are the buccal and gingival mucosa, back of the tongue, lip mucosa and lip vermilion. ^2,4,43-45 The gingival mucosa is frequently affected, and the disease presents in the form of "chronic desquamative gingivitis." OLP lesions may appear at sites of trauma (koebnerization).

 

The primary lesion of OLP is a small opalescent papule, whitish and keratotic (not removable with a spatula). Lesions may be isolated or assume different patterns; for instance, arboriform, striated or annular. These features are commonly found bilaterally in the buccal mucosa. ^2,6,46-50 Lesions at the back of the tongue tend to be more keratotic, isolated or plaque-like, due to the peculiar characteristics of this epithelium.^2,6,46,47 Lesions of long evolution tend to become atrophic due to epithelial tissue correction. Depapillation of the tongue caused by atrophy may result in gustatory changes, with consequent burning upon contact with certain foods.

In the erosive form, bright red well-demarcated erosions are observed, characteristically surrounded by typical papulae. When the disease progresses rapidly, bullae may be rarely observed. Pain is usually intense and can affect the patient's quality of life. ^48.49

Lesions identical to those described above may also appear in the lip vermillion and tend to diffusely affect this area; however, they almost always respect the boundary between the lip vermillion and skin of the lip, unlike some other cheilitis.

The presentation form of "desquamative gingivitis" is peculiar, and can occur isolated or associated with lesions in other areas. Painful erosions, which interfere with tooth brushing, are observed in the gingival mucosa. ^{45 ,47-49}

Residual mucosal pigmentation is common in dark-skinned individuals, often associated with the presence of active lesions (lichen planus pigmentosum).

Lesions resulting of the reaction caused by contact of the mucous membranes with dental restorations containing metal are indistinguishable from those of idiopathic lichen planus, except for the fact that they are asymmetrically distributed in the mucosa, because they are near dental restorations. ^{1.33, 37-39} Of the 103 patients, 4 presented these characteristics (unpublished data).

There appears to be no correlation between the extent and severity of oral and skin lesions of lichen planus. ⁸ Concomitant extraoral involvement such as scalp, nails, conjunctiva, esophagus, larynx, urethra, vagina, vulva and perianal region can result in severe morbidity. The association between severe forms of oral and vulvar lichen planus has been recently highlighted ("vulvovaginal-gingival syndrome"). ^36,50,51

Several publications, especially articles in dental journals, address a supposedly "premalignant" potential of OLP lesions. Indeed, several studies have been conducted on the subject, with essentially inconclusive results with regard to possible "risks of malignancy" ^{1.52 -55}. In our opinion, the development of squamous-cell carcinoma in lesions of lichen planus only occurs in very old atrophic-cicatricial lesions, but this is rare. Dermatologists are very familiar with thi situation when it affects the skin, but this phenomenon may involve the mucous membranes (Marjolin's ulcer). Other conditions that may present atrophiccicatricial lesions in the oral mucosa may also be rarely associated with carcinomas, such as lupus erythematosus and syphilitic glossitis. ⁵⁶ Among our 103 patients, three presented with lesions of squamous-cell carcinoma associated with OLP, all of whom with highly cicatricial disease of long evolution (unpublished data).

Unlike cutaneous lichen planus, which in most cases progresses by short-term outbreaks that almost always respond well to treatment or even regress after a few months, OLP is characterized by its chronicity, persistence and resistance to therapy.

DIAGNOSIS

The diagnosis is achieved through clinical and histopathological examination. Histopathological manifestations include acanthotic (keratotic lesions), atrophic (old lesions), prominent or absent (erosive lesions) epithelium. There is liquefaction of the basal layer associated with superficial lymphocytic inflammatory infiltrate at the junction of the epithelium with lamina propria. Numerous eosinophilic spheric bodies are seen in the conjunctival epithelium, known as cytoid bodies, apoptotic bodies or Civatte bodies, in adittion to varying degrees of pigment leakage (Figure 7). ^1,2,50 Interface inflammation reaching excretory portions of minor salivary glands has been recently characterized by our group ("salivary lichen planus", an analogy with lichen planopilaris). ⁵⁷

Biopsies should be preferably done in keratotic areas to avoid erosions, because they are devoid of epithelium, making microscopic examination difficult. ^58.59

Histopathological analysis of specimens of OLP was not always uniform in the analyzed studies. Van der Meij and Van der Waal found that in 42% of cases, in which there was full agreement on the clinical diagnosis of the disease, there was no consensus on histopathological diagnosis ⁶⁰. On the other hand, in 50% of the cases in which there was a consensus, there was no clinical agreement. In our opinion, diagnosis is safe if proper clinical and pathological criteria are followed, dismissing the possibility of other diseases such as traumatic keratosis, lupus erythematosus, erythema polymorphe and incipient tumors. ^59.50

Direct immunofluorescence from perilesional biopsy may be useful to differentiate OLP from other mucosal diseases with an inflammatory component of the interface, especially lupus erythematosus, erythema polymorphe and drug eruptions. The most common finding in OLP is the presence of IgM deposits and, less frequently, of IgA and C3 in subepithelial cytoid bodies. ⁵

DIFFERENTIAL DIAGNOSIS

It depends on the morphology of the lesions. Reticular papular lesions should be differentiated from discoid lupus erythematosus, candidiasis, morsicatio buccarum (mucosal exfoliation due to the habit of nibbling) and other traumatic injuries, mucous patches of secondary syphilis, pilous leukoplakia and incipient squamous-cell carcinoma. Erosive lichen planus should be adequately differentiated from aphthae, mucous membrane pemphigoid, pemphigus vulgaris, drug reactions, erythema polymorphe and acute lesions of lupus erythematosus. The differential diagnosis of the pigmented form is done with multiple causes of mucosal pigmentation.

It is sometimes difficult to clinically diagnose "desquamative gingivitis" when lesions in other sites are absent. Mucous membrane pemphigoid, pemphigus vulgaris and OLP may present as desquamative gingivitis of very similar clinical aspect; therefore, it is essential to conduct histopathological examination and direct immunofluorescence for proper diagnosis.

TREATMENT

The treatment of OLP aims to relieve the symptoms and minimize the functional impact of the disease. No treatment is effective for all cases of OLP because its cause is unknown. ⁵ Professional experience is, therefore, important. One should take into account the extent of lesions and severity of symptoms. Hence, treatment is individualized for each patient. Exclusive reticular papular lesions are asymptomatic and do not require treatment. Sequelae are observed in exclusively atrophic lesions and these lesions do not respond to any treatment. Erosive lesions are those that require drug therapy because of severe pain.

Oral hygiene practices are important, especially periodontal care given by a professional dentist, when gingival lesions are present, since tartar and dental plaques can stimulate local inflammation and exacerbate disease activity. ^1.61-63 Replacement of metal restorations is indicated when reactions to these substances are suspected. Improvement occurs more commonly in those cases in which all the lesions are located in areas close to the restorations. ^37-39

The drugs most often prescribed are potent topical corticosteroids - mouthwash, ointment or orabase paste, used two to three times a day. It is important to note that creams are never recommended for use in the oral mucosa, and orabase paste is only used for intraoral lesions (wet); lesions located in the lip vermillion should be treated with ointments. Oral and intralesional corticosteroids are almost never used by us in cases of exclusive intraoral manifestation, as the therapeutic target (inflammatory infiltrate) is easily topically treated, if we consider that only bare lesions (erosive) will be treated.

The potency of topical corticosteroids and their frequency of use should be reduced as clinical manifestations and symptoms improve. The intraoral use of topical steroids is safe and well tolerated. The most common adverse effect is oral candidiasis, which can be prevented with the prophylactic use of topical nystatin and by advising the patient not to sleep with dental prostheses.

Erosive gingival lesions are particularly resistant. As previously mentioned, in addition to drug treatment, there should be specialized periodontal monitoring, which has been shown to be very useful. The use of molded dentures to improve contact of the drug with the mucosa is sometimes prescribed. We have not found any need for their use; in addition, exaggerated contact of a potent corticosteroid with the gingival mucosa can lead to retraction. ⁶³

The topical calcineurin inhibitors - tacrolimus and pimecrolimus - were introduced in the treatment of OLP at the beginning of the last decade. They are topical immunosuppressive drugs that have been used as steroid sparers in OLP and have shown interesting therapeutic results.^64-69 Tacrolimus ointment is used at a concentration of 0.1% and pimecrolimus ointment is used at a concentration of 1%. The ointment must be applied twice daily, but use may be increased to four times daily until remission or symptomatic relief. ^1.32 Adverse reactions include burning and stinging at the application site. Systemic levels of pimecrolimus and tacrolimus were detected after application to the oral mucosa. ^68.69 In theory, it is suggested that these drugs may increase the frequency of carcinomas in OLP, because in addition to acting on the immune system, they would also act directly on cells. For instance, according to Becker et al,^{54 70} tacrolimus appears to interfere with a few important intracellular signaling pathways, especially those related to p53 protein, whose mutation is present in several types of cancers. Therefore, the potential systemic absorption and malignancy of such agents reinforce the need for further long-term evaluation of these drugs.

Some authors have reported efficacy of topical retinoids in the treatment of OLP, especially when used in combination with topical corticosteroids for reticular or hyperkeratotic lesions. ^71-73. Imiquimod has been recently used in a small series of cases.⁷⁴ We have not used these drugs.

Several anti-inflammatory drugs commonly used in dermatology, such as levamisole, sulfone, griseofulvin and chloroquine were used by several authors, with anecdotal results and without scientific basis.^3.75-78

Immunosuppressive therapies such as PUVA, methotrexate, azathioprine and mycophenolate mofetil can be attempted in very severe and resistant cases.^79-82

CO ₂ laser treatment has been attempted by some health professionals, but in our opinion, the method lacks scientific basis for this indication (laser is not used in the treatment of cutaneous lichen planus).^83.84

Patients should be periodically followed-up due to the need to gradually reduce the medication and, especially, monitor atrophic-cicatricial lesions.

Individuals with concomitant psychopathology, especially those with symptoms of depression or anxiety, may deserve specialized care. ^1.85

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Publication Dates

• Publication in this collection
  27 Sept 2011
• Date of issue
  Aug 2011

History

• Received
  20 Sept 2010
• Accepted
  25 Oct 2010