Lichen Planus
Diseases

Author: Paola Franco
Date: 16/09/2007

Description

DEFINITION W

"An inflammatory, pruritic disease of the skin and mucous membranes, which can be either generalized or localized. It is characterized by distinctive purplish, flat-topped papules having a predilection for the trunk and flexor surfaces. The lesions may be discrete or coalesce to form plaques. Histologically, there is a "saw-tooth" pattern of epidermal hyperplasia and vacuolar alteration of the basal layer of the epidermis along with an intense upper dermal inflammatory infiltrate composed predominantly of T-cells. Etiology is unknown."

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Update on oral lichen planus: etiopathogenesis and management.Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, Holmstrup P, Mutlu S, Porter S, Wray D. Eastman Dental Institute for Oral Health Care Sciences, University of London, United Kingdom.

EPIDEMIOLOGY

  • Race: OLP affects all racial groups.
  • Sex: The female-to-male ratio is 1.4:1.
  • Age: OLP predominantly occurs in adults older than 40 years, although younger adults and children can be affected.

E’ una malattia che interessa circa tra l’1 ed il 3% della popolazione generale, quindi una malattia abbastanza comune. La prevalenza delle manifestazioni orali varia tra lo 0, 1 e il 2,2%. Colpisce maggiormente il sesso femminile piuttosto che quello maschile. Solitamente ne sono affetti individui adulti o anziani. Nei bambini è raro.

SYMPTOMS

The appearance of lichen planus depends on whether the skin or the lining (mucous membranes) inside the mouth or vagina are affected:

  • Skin involvement: The usual skin involvement with lichen planus consists of flat-topped lilac or violet spots a few millimeters in diameter on the skin. These spots tend to be located on the inner wrists, forearms, the lower legs just above the ankles, and the lower part of the back.
    A variant of this disease is called hypertrophic lichen planus. This condition appears as thick, reddish-brown lesions that are covered with scales. These spots tend to be on the shins, but they can occur anywhere on the body. This is an especially itchy and persistent (chronic) variant of lichen planus.
  • Mucous membranes: Lichen planus of the mucous membranes is common. Dentists often come across it as a white, lacy rash on the inside of the cheeks of people who are unaware of the condition. About half of the people affected with lichen planus have the rash inside of their mouths (oral mucosa). The oral rash often occurs prior to any skin involvement.

More troublesome, although rare, is erosive lichen planus, which can be quite sore and uncomfortable. This erosive form typically causes the patient to complain of the shallow and often quite painful, recurrent ulcers in the mouth.

Lichen planus can affect the female genitals, including the vagina. This condition can be confused with sexually transmitted diseases (STDs), although lichen planus is neither sexually transmitted nor contagious.
Sometimes, lichen planus produces pits and grooves in the nails as well

DIAGNOSIS

The history, typical oral lesions, and skin involvement are usually sufficient to diagnose OLP, though laboratory studies and biopsy may be required.
Direct immunofluorescence testing can help in distinguishing erosive or the rare bullous OLP from pemphigus vulgaris, benign mucous membrane pemphigoid, dermatitis herpetiformis, and linear immunoglobulin A (IgA) disease. However, OLP has no specific features at direct or indirect immunofluorescence testing.
Some studies show an increased incidence of C albicans infection in patients with OLP.
Periodic acid-Schiff (PAS) staining of biopsy specimens and candidal cultures or smears may be performed. However, these tests may be of limited clinical value because oral C albicans is present in more than 70% of the population.
The presence of C albicans and the oral load of this organism do not aid either the diagnosis or the treatment of OLP.

Other Tests:

Skin patch testing may be helpful in identifying a contact allergy in some patients with OLP.
The current recommendation is to use a standard series; a dental prosthesis series; and a metal salt series that includes gold, mercury, and palladium salts as well as other salts of metals used in dental restorations.
Late readings, or those obtained at 10 and 17 days after the application of the skin patch, may be required.
The most common allergy is related to mercury contained in amalgam restorations. Compared with patients with lesions in other locations, patients with lesions near the amalgam restoration have a higher rate of positive patch test results to mercury. When the amalgam restorations are removed, patients with a positive result have a higher remission rates (47-100% depending on the study) than that of patients without this positive result.
Although the assessment of hepatic function in the treatment of otherwise healthy southern European and Japanese patients with OLP may be warranted, similar screening in British and American patients appears to be of limited benefit. Formal studies are still ongoing. Consider hepatic biochemical testing only when patients have proven OLP and suspected liver disease.

  • Procedures:
    Biopsy may be required to exclude malignancy or to differentiate between OLP and other white or chronic ulcerative oral lesions, including reactive keratoses, chronic hyperplastic candidosis, epithelial dysplasia, discoid lupus erythematosus, gastrointestinal disease (including oral Crohn disease), and anemic states.
  • Histologic Findings:
    Histopathologic examination of lesional tissue is the most relevant investigation in cases of OLP.
    Consistent findings include a bandlike subepithelial mononuclear infiltrate consisting of T cells and histiocytes, increased numbers of intraepithelial T cells, and degenerating basal keratinocytes that form colloid (Civatte, hyaline, cytoid) bodies, which appear as homogenous eosinophilic globules. Variable findings include parakeratosis, acanthosis, and sawtooth rete pegs.

Macroscopic, microscopic and immune histological appearance of an oral lichen planus and a subsequently arising squamous cell carcinoma. Macroscopic (A) and microscopic (B) picture of the squamous cells carcinoma. p53 expression (C to E, single positive cells are indicated by arrows), Erk 1/2 phosphorylation (F to H, increased expression is indicated by closed triangles) and Bax expression (I to K, reduced expression is indicated by open triangles) in mucosa before (C, F, I) and after (D, G, J) tacrolimus treatment, as well as in the arising squamous cell carcinoma (E, H, K); magnification: A 5×, C to K 20×. All lesions were obtained by surgical excision, fixed in formalin and embedded in paraffin. Five μm sections of tumor lesions were fixed in acetone and air dried for 30 min. Slides were incubated for 30 min with the indicated specific primary antibodies (anti-p53 [clone D07] and anti-Bax [polyclonal], DAKO, Hamburg, Germany; anti-pErk 1/2 [clone E10], Cell Signalling, BioLabs New England, Frankfurt, Germany) at predetermined dilutions ranging from 1:200 to 1:800.(Ref.)

Degeneration of the basal keratinocytes and disruption of the anchoring elements of the epithelial basement membrane and basal keratinocytes (eg, hemidesmosomes, filaments, fibrils) weakens the epithelial-connective tissue interface. As a result, histologic clefts (ie, Max-Joseph spaces) may form, and blisters on the oral mucosa (bullous lichen planus) may be seen at clinical examination. B cells and plasma cells are uncommon findings.

Immunoglobulin or complement deposits are not a consistent feature of OLP. In some instances, fibrinogen and fibrin are deposited in a linear pattern in the basement membrane zone. Colloid bodies contain fibrin, immunoglobulin M (IgM), C3, C4, and keratin. Laminin and fibronectin staining may be absent in areas of heavy fibrin deposition and colloid body formation. This finding suggests basement membrane damage in these areas.

In OLP, electron microscopy is used principally as a research tool. The ultrastructure of the colloid bodies suggests that they are apoptotic keratinocytes, and recent studies using the end-labeling method revealed DNA fragmentation in these cells. Electron microscopy shows breaks, branches, and duplications of the epithelial basement membrane in OLP.

distinguere meglio i dati osservati, l'ipotesi, e i fattori di rischio che vanno spostati dopo. Se il TNF è coinvolto alcuni polimorfismi del promoter sono fattori di rrischio ma lo sono per tutte le malattie autoimmuni e dovrebbero essere descritti nella scheda del TNF et. ci provi almeno un poco

PATHOGENESIS

Current data suggest that OLP is a T-cell–mediated autoimmune disease in which autocytotoxic CD8+ T cells trigger apoptosis of oral epithelial cells.

The dense sub-epithelial mononuclear infiltrate in OLP is composed of T cells and macrophages, and there are increased numbers of intra-epithelial T cells. Most T cells in the epithelium and adjacent to the damaged basal keratinocytes are activated CD8+ lymphocytes. Therefore, early in the formation of OLP lesions, CD8+ T cells may recognize an antigen associated with the major histocompatibility complex (MHC) class I on keratinocytes. After antigen recognition and activation, CD8+ cytotoxic T cells may trigger keratinocyte apoptosis. Activated CD8+ T cells (and possibly keratinocytes) may release cytokines that attract additional lymphocytes into the developing lesion.

OLP lesions contain increased levels of the cytokine tumor necrosis factor (TNF)–alpha (Younes, 1996; Sklavounou, 2000). Basal keratinocytes and T cells in the subepithelial infiltrate express TNF in situ (Khan, 2003; Thongprasom, 2006). Keratinocytes and lymphocytes in cutaneous lichen planus express elevated levels of the p55 TNF receptor, TNF-RI (Simon, 1997). T cells in OLP contain mRNA for TNF and secrete TNF in vitro (Simark-Mattsson, 1999). Serum and salivary TNF levels are elevated in OLP patients (Karagouni, 1994; Sugerman, 1996; Sklavounou, 2004; Rhodus, 2005). TNF polymorphisms have been identified in patients with OLP, and they may contribute to the development of additional cutaneous lesions (Carrozzo, 2004). OLP has been treated successfully with thalidomide (Dereure, 1996; Camisa, 2000), while thalidomide is known to suppress TNF production (Sampaio, 1991; Moreira, 1993). Together, these data implicate TNF in the pathogenesis of OLP.

The lichen planus antigen is unknown, although it may be a self-peptide (or altered self-peptide), in which case lichen planus would be a true autoimmune disease. The role of autoimmunity in the pathogenesis is supported by many autoimmune features of OLP, including its chronicity, onset in adults, predilection for females, association with other autoimmune diseases, occasional tissue-type associations, depressed immune suppressor activity in patients with OLP, and the presence of autocytotoxic T-cell clones in lichen planus lesions. The expression or unmasking of the lichen planus antigen may be induced by drugs (lichenoid drug reaction), contact allergens in dental restorative materials or toothpastes (contact hypersensitivity reaction), mechanical trauma (Koebner phenomenon), viral infection, or other unidentified agents

The clinical presentation of lichen planus may also resemble other conditions, including:

Lichenoid drug reaction
Discoid Lupus Erythematosus
Chronic Ulcerative Stomatitis
Pemphigus Vulgaris
Benign Mucous Membrane Pemphigoid
Oral leukoplakia
Frictional keratosis

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Figure 1. Hypothesis for antigen presentation and T-cell activation in OLP. Initially, the CD8+ T-cell antigen receptor engages a specific foreign antigen (Ag 1) in the context of MHC class I on the basal keratinocyte target cell in OLP [1]. The CD8+ T-cell may then seek CD4+ T-cell confirmation by expressing the hypothetical "request cytotoxic activity" (RCA) cell surface molecule [2]. The CD4+ T-cell expresses the hypothetical "RCA receptor" (RCA R) [4], but only following CD4+ T-cell antigen receptor engagement of a related foreign antigen (Ag 2) in the context of MHC class II on the antigen-presenting cell (basal keratinocyte or Langerhans cell in OLP) [3]. Ligation between RCA and RCA R in combination with co-stimulatory signals from the MHC class II+ antigen-presenting cell (e.g., CD40, CD80, and IL-12 binding CD154, CD28, and IL-12 R, respectively, on the CD4+ T-cell) initiates Th1 differentiation of the CD4+ T-cell that then secretes IL-2 and IFN- [5]. Receptors for IL-2 and IFN- are expressed by the CD8+ T-cell, but only following (i) specific engagement of the CD8+ T-cell antigen receptor in the context of MHC class I and/or (ii) ligation between RCA and RCA R. The CD4+ Th1 cytokines (IL-2 and IFN-) are detected by the CD8+ T-cell and interpreted as confirmation to proceed with target cell (basal keratinocyte) lysis. Keratinocyte activation by (i) the CD4+ or CD8+ T-cell following receptor-antigen-MHC trimerization or (ii) exogenous agents such as viral infection, bacterial products, mechanical trauma, systemic drugs, or contact sensitivity up-regulates keratinocyte cytokine and chemokine secretion [6] that promotes lymphocyte extravasation and directs lymphocyte migration into the site of the developing OLP lesion.

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Figure 2. Unifying hypothesis for the pathogenesis of OLP. (A) A lichen planus antigen is expressed in association with MHC class I molecules on basal keratinocytes at the OLP lesion site [1]. Antigen-specific CD8+ cytotoxic T-lymphocytes (CTLs) are activated in the OLP epithelium (possibly with help from Th1 CD4+ T-cells, as shown in Fig. 1) and trigger keratinocyte apoptosis via secreted TNF- binding the TNF- receptor (TNF-R1) [2], although roles for granzyme B and Fas cannot be excluded at this stage. TNF- may be activated and released from the CTL surface by lesional MMPs. (B) Activated T-cells undergo intra-lesional clonal expansion and release RANTES and other cytokines [3] that up-regulate mast cell CCR1 expression and stimulate intra-lesional mast cell migration and degranulation [4]. Degranulating mast cells release TNF-, which up-regulates endothelial cell adhesion molecule expression for lymphocyte adhesion and extravasation [5]. Mast cell TNF- also up-regulates RANTES [6] and MMP-9 [7] secretion by OLP lesional T-cells. Activated lesional T-cells (and possibly keratinocytes) secrete chemokines that attract extravasated lymphocytes toward the OLP epithelium [8]. Degranulating mast cells release chymase that damages the epithelial basement membrane directly [9] or indirectly via activation of MMP-9 secreted by OLP lesional T-cells [10]. Epithelial basement membrane disruption facilitates the passage of lymphocytes into the OLP epithelium [11] and denies keratinocytes a cell survival signal, resulting in further keratinocyte apoptosis [12]. (A) Represents the boxed area in (B).

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TREATMENT

The treatment of patients with lichen planus must be individualized. Patients vary greatly in severity of symptoms, extent of lesion involvement and response to treatment. Many treatment options are discussed in the literature, each with its own risk profile. Unfortunately, larger randomized trials to support the effectiveness of most of these treatments are lacking, and many treatments are recommended based on anecdotal evidence. Another factor to consider when treating patients with cutaneous lichen planus is that spontaneous remissions occur in the majority of patients after one year.

Potent topical corticosteroids are used to treat the early or localized lesions of patients with cutaneous lichen planus. These ointments or creams are applied to the affected areas twice daily, with an initial trial treatment period of two to three weeks to monitor efficacy. Occlusion may be used to enhance the effect of the topical medication. For resistant or hyperkeratotic plaques, intralesional injections of triamcinolone acetonide (Kenalog) may be used.

Oral corticosteroids are the most common treatment for patients with generalized cutaneous lichen planus although recommendations concerning dosage and duration of therapy vary. The recommended prednisone dosage is 30 to 60 mg once daily for four to six weeks, with the dosage then tapered over the following four- to six-week period. Other studies suggest treating patients at lower doses of prednisone or with other forms of corticosteroids, including short courses of oral prednisolone or intravenous methylprednisolone. While systemic corticosteroids alleviate symptoms in most patients, it is unclear whether this therapy affects the total duration of the disease.

If corticosteroid resistance occurs, other treatment options are available. One controlled trial demonstrated efficacy of treatment with a dosage of 30 mg daily of acitretin (Soriatane) once daily for eight weeks. When prescribing any retinoid, however, physicians must be familiar with the risk profile because of the severe teratogenicity associated with this class of drugs. Phototherapy using psoralens (PUVA) has also been reported to be effective in corticosteroid resistance. Although the duration of treatment is determined by patient response, good results have been reported after eight weeks of treatment. Multiple other therapies, such as griseofulvin (Grisactin), cyclosporine (Sandimmune), dapsone and hydroxychloroquine (Plaquenil), have been anecdotally reported as effective for the treatment of patients whose lichen planus is corticosteroid-resistant.

A topical corticosteroid is considered first-line therapy for patients with oral lichen planus. One controlled trial demonstrated the effectiveness of fluocinonide (Lidex) ointment applied to dried oral mucosa six times daily for nine weeks. The steroid, in an adhesive base, was prepared by the pharmacy, although Orabase has also been recommended as an occlusive vehicle. Other topical medications and systemic therapies have been used to treat patients with oral lichen planus that is corticosteroid-resistant. These therapies include topical cyclosporine, systemic corticosteroids, topical and systemic retinoids and oral PUVA.

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therapy of OLP by Eisen D. Dermatology Associates of Cincinnati, Inc., OH 45230.

PATIENT RISK FACTORS

Lichen planus is more likely to occur in the presence of:

  • Liver disease
  • Systemic lupus erythmatosis
  • Certain prescription medications
  • Graft vs. host disease
  • Anxiety
  • Stress

The condition is more common in females and in those 30 to 60 years old, while being rare in children and the eldelry.

  • Acquired

TISSUE SPECIFIC RISK FACTORS

  • anatomical:
    • REAZIONI LICHENOIDI E AMALGAMA - Talvolta, lesioni simili a quelle da lichen (chiamate reazioni lichenoidi) si sviluppano all’interno del cavo orale non bilateralmente ma in stretta relazione ad elementi dentari sui quali c’è un otturazione, con più frequenza un’otturazione in amalgama di vecchia data. Anche altri materiali possono dare queste reazioni ma molto più raramente (es: oro, cobalto o resine). Su questi pazienti è opportuno eseguire dei test allergologici per i diversi materiali dentali (patch test allergologici) per valutare una reale allergia alle componenti appena citate (allergia al mercurio metallico o ai sali di mercurio). Tuttavia solo tra il 50 e il 65% dei pazienti analizzati hanno una reale allergia. Le otturazioni in causa possono quindi essere rimosse e sostituite ma il paziente deve essere ben conscio che talvolta la rimozione del materiale scatenante può non essere completamente di aiuto.
      Mercury-specific lymphocytes: an indication of mercury allergy in man.

vascular (due to the local circulation)

physiopathological (due to tissue function and activity)

COMPLICATIONS

OLP and its treatment may predispose people to oral C albicans superinfection.
Patients with OLP may have a slightly increased risk of oral cancer, which they may be able to reduce (see Deterrence/Prevention).
Oral SCC in patients with OLP is a feared complication and a controversial issue.
In retrospective studies, fewer than 5% of patients with OLP who were not using tobacco products developed oral SCC.
Atrophic, erosive, and plaque lesions may be at greater risk of malignant change, although SCC may arise in the unaffected oral mucosa as well.
The most important risk factors of oral SCC remain the concomitant use of alcohol and tobacco products. Any additive effect of OLP is difficult to detect in patients who use both.
Proposed reasons for the increased risk of oral SCC in patients with OLP include the following:
Compared with healthy mucosa, the oral mucosa affected by OLP may be more sensitive to C albicans and to the exogenous mutagens found in tobacco, alcohol, and betel quid.
In patients with OLP, the chronic inflammatory response and the simultaneous healing response of epithelial wounds may increase the likelihood of cancer-forming gene mutations.

VEDI IL CODICE DI QUESTA PAGINA

IL LICHEN PUOFAVORIRE L’INSORGENZA DI UN TUMORE DEL CAVO ORALE?

Il lichen viene definito come una condizione precancerosa, ossia una malattia il cui portatore presenta un rischio maggiore, rispetto ad un paziente che non soffre di lichen, di sviluppare un tumore della bocca. Tra i pazienti che hanno un lichen la percentuale di sviluppare un tumore della bocca è tra l’1 e il 3%, percentuale leggermente più alta rispetto ad una popolazione che non è affetta da lichen. E’ bene inoltre ricordarsi che il lichen è una malattia abbastanza frequente, e quindi le due patologie potrebbero semplicemente sovrapporsi. Inoltre, se il paziente affetto da lichen viene tenuto sotto controllo, almeno annuale, anche dal suo dentista, un qualsiasi cambiamento della malattia potrebbe essere subito segnalato ad un centro specialistico di riferimento.

EPATITE C E LICHEN PLANUS: QUALE RELAZIONE?

In determinate aree geografiche (Italia, Europa Meridionale, Giappone...) molti pazienti affetti da lichen sono affetti anche dal virus dell’epatite C (fino al 30%) e molti di essi scoprono di avere problemi al fegato solo dopo essergli stata diagnosticata la malattia in bocca. Per tale motivo, su tutti i pazienti con diagnosi di lichen, un semplice prelievo di sangue, per valutare la funzionalità del fegato e per ricercare il virus dell’epatite C, dovrebbe essere fatto di routine.

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lichen_planus_istologia2.jpggp2007-09-23T00:00:00
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