LICHEN PLANUS: ORAL MANIFESTATIONS, DIFFERENTIAL DIAGNOSIS AND TREATMENT

Uvod: Neka od tipičnih kožnih oboljenja, kao što su Pemphigus vulgaris, Pemphigoid mucosae oris, Erythema exudativum multiforme, Sclerodremia, Dermatitis herpetiformis-Duhring i Lichen planus, lokalizuju se i u usnoj duplji. Cilj: Cilj rada je da se precizira dijagnoza i terapija Lichen planusa sa manifestacijama u usnoj duplji. Metode:. Analizom literature i na osnovu kliničkog iskustva lekara ispitivane su najčešće oralne manifestacije Lichen planusa. Rezultati: Ovo oboljenje najčešće se javlja kod pacijenata srednjih godina (30 – 60 godina) i češće je kod žena nego kod muškaraca. Oralni Lichen planus retko se viđa kod dece. Bolest se javlja kod 0,5% – 2% populacije. Klinička istorija potvrđuje vezu između oralnog Lichen planus-a i oralnog karcinoma, stoga ovo oboljenje treba smatrati kao prekanceroznu leziju. Zaključak: Dermatoze u ustima najčešće se lokalizuju na obraznoj sluzokoži, i to u visini okluzalne linije i na sluzokoži retromolarnog predela, ali se mogu javiti i na sluzokoži jezika, poda usne duplje i usana.

• Pušenje -Gorsky i sar. 15 razmatrali su mogućnost korelacije između različitih kliničkih manifestacija lihena i pušenja, gde je Introduction Lichen planus, in addition to viral infections and aphthous ulcers, ranks third place among oral mucosal diseases. The first skin descriptions of Lichen planus were published by Wilson in 1869, but mucous changes were also noted by other authors 1 . The possibility of the appearance of oral lesions without skin manifestations was first described by Audry in 1894, and especially highlighted by Dubreuilh in 1906 2 , who indicated that the pathohistological changes of oral lesions corresponds to the pathohistological changes of skin changes. This was followed by a number of authors who, in addition to white papules and plaque lesions in the oral cavity, began to describe numerous variants of the disease, starting with Poor in 1905 3 , who first described vesicular-bullous lesions, then ulcerative and atrophic ones, which were specifically described by Lortat-Jacob et al. in 1929 3 .

Etiology
The exact etiology is unknown, but several predisposing factors can be the cause of oral Lichen planus (OLP) 4 . The most important factors in the onset of this disease are: • Stress -nervousness and emotional instability are very common in people with this disease. Clinical examinations indicate that the disease occurs one to two weeks after severe emotional distress (death of a close family member, tension at work, mental fatigue, etc.) 5,6 , so that the neurogenic origin is most associated with this disease.
• Autoimmunity -Many studies have shown that anti-basal antibodies (anti-BCA), which persist for months or years in patients with oral Lichen planus, may be autoantibodies that occur against altered antibasal antibodies 7,8,9 . Deposits of IgG, IgM and complement C3-class immunoglobulins were found in skin and oral changes 10 .
• Genetic predisposition -this disease is cosmopolitan, but has been shown to occur more frequently in people with HLA-A 3 , B 5 , A 28 , B 7 -B 8 -DRW 9 11,12 . Data on HLA markers for oral Lichen planus are highly dependent on the studied population 12,13 . Women are affected more often than men, with an onset time between ages 30 and 60 14 . In rare cases, children may be affected. primećeno da je osetljivost sluzokože povezana sa pušenjem. Neumann-Jensen i sar. 16 naveli su da je OLP bio ređi kod pušača nego kod nepušača 17 , tako da se pušenje ne može zasigurno obeležiti kao jedan od faktora koji su izazivači OLP.

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Smoking habits -Gorsky et al. 15 considered the possibility of a correlation between different clinical manifestations of lichen and smoking, where it was observed that mucosal sensitivity was associated with smoking. Neumann-Jensen et al. 16 stated that OLP was less frequent in smokers than in non-smokers 17 so that smoking could not be linked as one of the contributing factors to OLP with certainty.
• Dental materials -amalgam, gold, composite fillings, as well as metals (cobalt, nickel, palladium) released from certain dental fillings, i.e., from the layers of the filling materials themselves lead to lichenoid reactions and gingival inflammation 18,19 . Earlier research indicates that lichenoid reactions occur as a product of galvanic potential between metals in the mouth 19,20 . However, recent research indicates that inflammation occurs as a result of mediator cells and the materials themselves in patients who have been exposed to this reaction for a long time.

Clinical feature
Oral Lichen planus occurs in 0.1-4% of individuals depending on the population examined and is generally a disease of middle and older-aged people, more frequently in women than in men with a ratio of 2:1. Although there is a certain percentage of patients with oral changes that are older than 60 years, the range of the years is similar to the age of patients who have only skin changes. There is also a small number of patients with oral changes that occur at an early age-the youngest patient was 7 years old 2 . This is a rare case. Oral lesions are usually bilateral and involve the buccal mucosa (occlusal line level and retromolar area) in about 90% of all cases 21 . The most frequently it appears on the tongue (its edges and dorsal surface), the submucosa of the lips, the floor of the mouth, the gingiva, the alveolar ridge and the most rarely in the palate 22 . Lichen planus can occur in the mouth in six different forms. The most common forms are reticular, plaque-shaped, erosive and atrophic 23 . Bullous and papillary types are usually found in combination with other forms. Patients with oral Lichen planus may have periods of remission and exacerbati.

Reticular form of Lichen planus
This is the most common type of Lichen planus in the mouth. The disease occurs in the form of whitish papules the size of a chiodine head. They are seen as whitish lines or bands. Individual papules can only be seen with a magnifying glass. This type is often seen in the facial mucosa, in the form of white filaments slightly raised above the mucosa. These lines are also called Wickham's striae 24 . They are localised in the area of the occlusal line, the retromolar area, the edges of the tongue, the labial and buccal surfaces of the fixed gingiva, to the submucosa of the lips and the hard palate 24 . It occurs most rarely in the soft palate and the floor of the mouth. Subepithelial tissue always has a thick lymphocyte infiltration. This type of Lichen planus rarely goes into a malignant form. It often occurs along with other forms.

Plaque form of Lichen planus
It is seen as a thin layer of plaque of various sizes, a smooth and slightly more tangled surface than the surrounding tissue. The most common localizations are the cheek, palate, tongue, and gingiva, and rarely in the floor of the mouth. In the histological feature of the superficial layers of the epithelium, parakeratosis and hyperkeratosis are present, and in the subepithelial layer a lymphocytic infiltrate 25 . This type of Lichen planus is most commonly seen in smokers 3 . The Lichen planus, in plaque form, often alters to malignant form along with erosive and atrophic forms 25 .

Papilary form of Lichen planus
This form is characterized by small white pinpoint papules size of 0.5 mm that are asymptomatic. It can occur along with other forms of Lichen planus. Papules occur symmetrically on the facial mucosa, but also on the dorsal side of the tongue and the hard palate 26 . They are usually individual, but can also produce white creations. Mucosal inflammation is present. Histologically, parakeratosis and hyperkeratosis are expressed in the upper layers, while diffuse lymphocyte infiltration is present in subepithelial layer 26 . The disease starts without symptoms, and if they do occur, the disturbances are very mild in the form of tightness and roughness of the mucous membranes, dryness, gentle burning and burning in the mouth. The prognosis is good, although there may rarely be a spontaneous withdrawal of changes. In these variants, the epithelial changes are hyperkeratotic 27 .
There is no epithelial atrophy and therefore no ulceration. In some patients, the lesions may be confluent and resemble leukoplakia, where there may be a papular, linear, or annular arrangement of white areas 28 . As these lesions are generally asymptomatic, they are often detected accidentally by the patient or at regular dental checkups by the dentist.

Erosive-ulcerative form of Lichen planus
This is a very common form of the disease. It localizes to the buccal mucosa, gingiva, tongue, palate and floor of the oral cavity. Most rarely, it occurs on the lips vermilion. This form of Lichen is characterized by the destruction of the oral epithelium 29 . When bullae occur, their bursting results in irregularly shaped erosive-ulcerative surfaces of varying sizes. The ulcerative surfaces are covered with a yellowish fibrinous exudate and are surrounded by an inflamed zone. Erosiveulcerative changes mainly occur as a consequence of bullae bursting, but there are cases when they occur without prior formation of bullous efflorescence 30 .
Patients' subjective ailments are pronounced, with the pain accompanying diet, speech and fluid consumption. Discomfort and pain can also be present spontaneously 29 . The mucosa is sensitive to mechanical irritation and dental trauma before other characteristic lesions appear. These lesions have glossy surfaces and tend to separate from the adjacent mucosa with a clear demarcation border 29,30 .
Histologically, degenerative changes of the basal layer of the epithelium with signs of atrophy and the appearance of erosions and ulceration are seen 31 . Around the erosiveulcerative changes in the epithelium, cellular infiltration with the dominance of neutrophilic granulocytes is pronounced, while lymphocytic infiltration is present in the subepithelium.
The erosive-ulcerative form of Lichen planus could be transformed into a malignant one due to the possible lichenoid degeneration 30 . There are three forms of erosive lichen planus: the bullous, atrophic, and ulcerative form.
The bullous form is characterized by the appearance of vesicles and bullae filled with clear serous content with possible erythrocyte hemorrhage. They are formed by the accumulation of fluid in the subepithelial connective tissue 32 . Due to the thin coating of the vesicles, they burst when speaking and eating and lead to painful sensations 32 .
Kod lihenoidne reakcije, erupcije imaju tendenciju ka unilateralnoj pojavi. This form is most commonly seen on buccal mucosa. Hydropic degeneration is expressed in the basal layer of the epithelium. Lymphocyte infiltration is dominant, which increases after bursting of bullae 32,33 . Subjective ailments are very pronounced, pain is aggravated by eating, and also a spontaneous pain is present. These two forms must be regularly monitored for the possibility of malignant alteration. • The atrophic form (erythematous form) is a less common form of Lichen planus. It most commonly occurs on the dorsal side of the tongue and gingiva. The epithelium of the tongue is atrophic, becoming thin with pronouncedly redness and inflammation. Filiform and fungiform papillae disappear and the tongue is smooth and polished (Lingua glabra) 10 . This atrophic form can also occur as a result of the healing of erosive-ulcerative forms and manifest itself with epithelial atrophy. Gingival changes are most commonly expressed in the upper jaw in the fixed gingival area, in the form of limited atrophic pores. The gingival epithelium becomes thin and dry so it is prone to injuries, while in the basal layer there is a hydropic degeneration, and dense lymphocyte infiltration is observed in the subepithelial layer 10,19 . • The ulcerative form is characterized by destruction of the oral epithelium. The ulcerative surfaces are covered with whitishyellowish fibrinous exudates and are surrounded by an inflammation zone on the part of the mucosa corresponding to the zone of inflammation. Ulcerative lesions are the result of damaged bullae, but they can also occur without the formation of bullous efflorescences.
The two particular forms that occur in this disease are Grinspan syndrome and lichenoid reactions.
The resulting lichenoid reactions can be classified as type IV hypersensitivity reactions 37 . In lichenoid reactions, eruptions tend to be unilateral.
The diagnosis is made based on biopsy and hematologically indirect immunofluorescence, where a series of beads is seen as confirmation of a lichenoid eruption 37 . A diffuse lichenoid infiltrate with deep perivascular lymphocytic infiltrate is also noticed.
Unlike the real Lichen planus, the medication-induced lichenoid eruptions disappear after the discontinuation of the medications. Medication-induced lichenoid eruptions extremely rarely attack buccal mucosa when a white stripe pattern occurs 38 . It is thought that medications only mask the latent disease of Lichen planus or the spread of a previous disorder, before inducing a new disease 38 .

Diagnosis of oral Lichen planus
The diagnosis of OLP consists of clinical examination, sampling for pathohistological diagnosis, histochemical or immunohistochemical analysis of the tissue.
Pathohistological examination -the histological preparation of a biopsied specimen shows three main characteristics: -hyperkeratosis and parakeratosis of the upper layers, -hydropic degeneration of the basal layer of the epithelium, -dense infiltration of lymphocytes in the upper corium beneath the epithelium, -"shaped teeth" may occur with skin lesions 24 .
Imunofluorescentna ispitivanja rade se iz lihenskih papula gde se uočavaju agregati IgG-a, IgM-a i komponente komplementa C 3. Ćelijski infiltrat u lamini proprii sastoji se od T-limfocita, i to većeg procenta T 4 limfocita u odnosu na T 8 limfocite 38 . Čistu predominaciju T 4 limfocita u odnosu na T 8 limfocite u lamini proprii kod Lichen planus-a, u odnosu na njihov odnos u normalnoj mukozi (npr. kod Leucoplakie), treba podvući, zato što ovo može biti važan diferencijalno-dijagnostički podatak. Aktivirani T-limfociti sekretuju interferon, koji zauzvrat indukuje sintezu HLA-DR od strane keratocita 40  Immunofluorescence examination is performed with lichen papules where the aggregates of IgG, IgM, and the C 3 complement component are observed. The cellular infiltrate in lamina propria consists of T-lymphocytes, with a higher percentage of T 4 lymphocytes compared to the T 8 38 . An evident predominance of T 4 lymphocytes with compared to T 8 lymphocytes in lamina propria in Lichen planus relative to their ratio in normal mucosa (e.g. Leucoplakia) should be examined because this may be an important differential diagnostic information. Activated T-lymphocytes secrete interferon, which in turn induces HLA-DR synthesis by keratocytes 40 . Interleukin production by T 4 lymphocytes activates T 8 lymphocytes, which direct their cytotoxicity to keratocytes. Cytotoxicity can be increased by the presence of HLA-DR class II antigens on the keratinocyte membrane 41 . When it comes to Lichen planus, a numerous keratocytes positive for HLA class II antigens were present at the basement membrane level 41 . A considerable amount of Langerhans cells can also be found in the epithelium 41 . This increase of Langerhans cells and basal keratocytes, positive for HLA class II antigens, may have diagnostic significance when comparing lichen planus lesions with other oral lesions 40,41 .

Differential diagnosis of Lichen planus
Differential diagnosis includes all white lesions that have an oral manifestation: • Leukoplakia -in leukoplakia, the changes are asymmetrical and represent a united white surface, while the surrounding mucosa is not inflamed 28 . In Lichen planus, the changes are symmetrical, reticulate, with inflamed surrounding mucosa 28 . In ambiguous cases, the diagnosis is established by the biopsy.
• Sponge cheek nevus -appears on the mucous membranes of the cheeks immediately after birth. The mucous membrane is whitish, with spongy like tissue and high density 42 . It is sometimes possible to remove the whitish plaque mechanically, so that parts of normal mucosa can also be seen 42 , which is impossible to do in Lichen planus. Diagnosis is done through histological examination -finding of hyperplasia is characteristic, and lamina propria is normal with a slight infiltration of inflammatory cells in the subepithelium.
Erythematodes -A disease that is first excluded by the presence of characteristic changes on the face. In Erythematodes, lesions on the mucous membranes are in the form of slightly raised white surfaces, surrounded by characteristic radial telangiectatic extensions of blood vessels, which build characteristic halo 43 . In the histological picture of Erytematodes there is hyperkeratosis, hydropic degeneration of the basal layer of the epithelium, degeneration of collagen fibers in connective tissue with perivascular infiltration of lymphocytes 43 . The histological picture of Lichen planus differs significantly. Mechanical damage to the oral epithelium -occurs in neurotic persons due to the chewing of the facial mucosa. Clinically and locally, it resembles Lichen planus. The diagnosis is made on the basis of history and clinical differences. The field that is mechanically damaged is in the form of irregular whitish coagulation with discrete erosion 43 . Localization is always in the area of the occlusal line. These mechanical defects do not show polymorphism in the form of white mesh formations, lines or plaque as is the case with Lichen planus 25 . Candidosisa -Chronic forms, localized to the buccal mucous membranes, can occur in the form of white lines. Extreme dryness and loss of flexibility of the epithelium are possible, so the resulting changes show a similarity to Lichen planus 44 . Spongiosis and infiltration of the epithelium by neutrophilic granulocytes are seen in the pathohistological findings in candidosis, as well as epithelial hyperplasia 44 . Pemphigus vulgaris -Differentialdiagnostic, only the erosive-ulcerative and connective-bullous forms of Lichen planus are considered 30 . Diagnostic difference is observed by microscopic findings of segregated Tzanck cells, which are absent in Lichen planus, as well as by finding of acantholytic cells in intraepithelial bullae 45 . Pemphigoid mucosae oris -This dermatosis is used in the differential diagnosis of bullous forms of Lichen planus as it is characterized by the presence of keratotic white lesions, as well as by the fact that it is more present in older women 46 . Lingua geographica -differential-diagnostic, this phenomenon is acute, benign, and the changes occur and disappear spontaneously. They are not of a fixed character, but migrate to the other areas of the tongue 47 , unlike Lichen planus, which is a chronic and therapyresistant disease, while changes occurring in a tongue are of a fixed character 47 .
Erythema exudativum multiformedifferential diagnosis is mainly a clinical one. If necessary, it is virological (exclusion of primary HSV infection). A biopsy is not indicated. Immunohistochemical studies may indicate the presence of immune responses in the basement membrane area (fibrinogen, IgM, C3) 48

Oral Lichen planus therapy
The treatment consists of an interdisciplinary procedure for eliminating predisposing factors for OLP. In oral lichen planus therapy, corticosteroids are administered topically and systemically, with the use of topical administration of antiseptics [50][51][52] . Oral administration of corticosteroids is conducted in the form of a liquid 50 . Penicillin is administered very effectively in high doses 6 . This therapy is based on the effect of penicillin on the adherence of streptococci to the oral epithelial cells, which are considered to be possible drivers of antigenic activity of keratinocytes 52 .
Surgical excision, cryotherapy, CO 2 laser, and ND: YAG laser is used in OLP therapy 53 . In general, surgery is performed only for high-risk cases of malignant alteration, i.e., to remove the high-risk dysplastic area. 53 Photochemotherapy is a new method of removing lichen risk areas using ultraviolet A (UVA) waves, 320 to 400 nm in length 54 . Relaxation, meditation, and hypnosis are increasingly being used as the new methods today, which also appear to have a significant impact on the underlying therapy of the disease 55 .

Treatment of reticular and papular forms of oral Lichen planus
Therapy of such oral manifestations is symptomatic.
Sedatives, antimalarials, ignipuncture, vitamins with local treatment of the oral cavity and a special hygienic-diet regime are used 56 .
Sedatives are indicated in neurotic patients 57 . Hexahydroadiphene chloride (Benifen) is given 2-3 times a day after each meal 57 . Diazepam (Apaurin) from 2-5 mg 3 times a day is also indicated 57 . Antimalarials (Resorchin et al.) with unsalted diets in certain cases produce good results. It is administered 3 times a day (25 mg tablets). The treatment lasts for seven days 56 . If there are no gastrointestinal disorders, treatment with Resorchin is continued as follows: patients take 2 times a day one tablet for the next 7 days. In the last round of 7 days, patients take 1 tablet per day. For the next month, patients only receive maintenance doses of ½ tablet per day 50 .
Ignipuncture is performed under local anesthesia and can produce good results 50 .
Vitamins A, B, and D are used topically to coat affected areas or parenterally 22 .
Locally, the dentist removes dental plaque, calculus and corrects inappropriate fillings and prosthetic work. The hygiene and diet regimen includes a ban on the use of booze, hot and spicy foods, as well as smoking.

Treatment of vesicular-bullous and erosive-ulcerative forms of oral Lichen planus
Therapy for these forms of oral Lichen planus is targeted and involves relief from discomfort, healing of erosive lesions and increasing the thinness of the epithelial barrier in areas of atrophy. Corticosteroids and tuberculostatics are administered and surgical procedure is performed with these forms of oral Lichen planus, and ultraviolet radiation is rarely used 50,53,54 .
Corticosteroid sprays are administered parenterally and intralesionally. Semi-synthetic corticosteroid triamcinolone spray -known as Kenalog Spray is administered several times a day. Retinoic acid (0.9%) may also be administered in the form of a spray in order to reduce keratinization 58 .
Prednisone, Dexamethason, and other semi-synthetic corticosteroids are administered parenterally 53 . The parenteral dosage is as follows: for the first two weeks of therapy in order to reduce acute symptoms, high doses of corticopreparations (1mg/kg) are administered, and then the dose is gradually reduced (by 10 mg) every three days until the appropriate maintenance dose is achieved within which changes will stagnate or disappear completely 61 .
Intralesional administration of corticosteroids is used to avoid or alleviate their side effects, so Kenalog-40 or Kenalog-10 is applied to the erosive-ulcerative surfaces. The maximum injection is up to 3 mg and the total dose should not exceed 80 mg 61 .
Surgical treatment is induced if the histopathological findings indicate a significant degree of dysplasia and consist of the removal of affected areas, but relapses are common 53 .
A therapy also includes antiseptic mouthwash (with plaque control and secondary infection reduction supplement) 62 and analgesic mouthwash (for discomfort reduction) 62 .
The use of various topical preparations -betamethasone soluble tablets (used dissolved in water for mouthwashing), sprays (beclomethasone), strong steroid pomades (e.g, fluocinonide) mixed with an adhesive base -can lead to the oral candidiasis and complicate the treatment of the disease 63 . Topical antifungal therapy is often indicated in patients with symptomatic oral Lichen planus 64 . Oral candida superinfection may exacerbate the oral symptoms of Lichen planus, so oral candidiasis should be treated promptly. Nystatin or Amphotericin are appropriate medicines but may be inadequate in patients with soric atrophic mucosa 65 . Therefore, miconazole gel and systemic fluconasol are more indicated 66 .

Conclusion
Most of the manifestations in the oral cavity of this disease have a complete benign nature, so they can go into remission after several years. However, in a small percentage of cases (0.4-3.3%), oral lesions undergo malignant changes. For this reason, the long-term course of this disease should be monitored and a rebiopsy should be performed if there is any suspicious change, such as nodular, verrucous, or "velvet-red" in the mucosa. The patient should be advised to report any specific lesion changes or symptoms. It is also ideal to make a photographic record of the patient's changes at each subsequent checkup.
There is also suggestion that if there are erosive and atrophic forms of oral Lichen planus, there is a greater chance of malignant transformation and that these cases should be monitored continuously over the coming period.
Oral Lichen planus is a common oral disease encountered by dentists when examining a patient. It is imperative that the present lesions are accurately identified and an appropriate therapy should be administered. Proper anamnesis, understanding of pathogenesis and clinical presentation is very important for the adequate treatment of all oral manifestations of this, nowadays, very common skin disease.