Hairy Leukoplakia of the oral cavity and tongue

Hairy leukoplakia is in no way associated with hair growth on the surface of the skin, but is a disease of the mucous membranes in which the pathological areas are covered with filiform white villi, noticeable only after histological examination. Hairy oral leukoplakia, first described in 1984, is a mucosal disease associated with the Epstein-Barr virus infection, and is found exclusively in people with immunosuppression. Visually, it looks like a plaque located symmetrically.

Epidemiology

The disease was first discovered and described in 1984 in America in a patient infected with AIDS. Scientists have traced the relationship between the two pathologies. From a quarter to half of cases, hairy leukoplakia was detected in HIV-infected people.

The overall prevalence rate of oral leukoplakia in 2003 ranged from 1.7 to 2.7% among the general population. [1]

Hairy leukoplakia is more common in homosexual men with HIV infection (38%) than among heterosexual men with HIV infection (17%). [2]  A cross-sectional study in Brazil reported data collected from clinical examinations, interviews, and medical records of adult patients treated at an HIV / AIDS clinic at the University Hospital of the Federal University of Rio Grande. Three hundred people were observed (from April 2006 to January 2007). Of these patients, 51% were men, and the average age was 40 years. The most common was candidiasis (59.1%), followed by hairy leukoplakia (19.5%). 

Causes of the hairy leukoplakia

This pathology is one of the forms of leukoplakia - a dystrophic change in the mucosal epithelium, expressed in keratinization. It occurs in 50% of patients with untreated HIV infection, especially in those whose CD4 count is less than 0.3 × 10 ⁹  / L. [3]This pathology has a clear prognostic value for the subsequent development of AIDS and is classified as a clinical marker of HIV infection in the Center for Disease Control and Prevention of Category B. [4]Hairy leukoplakia of the oral cavity is also found in people with leukemia and transplantation of organs and bone marrow, as well as in patients receiving systemic steroids. 

Risk factors

In addition to HIV infection, AIDS, immunodeficiencies of another etiology, the risk factors include daily smoking of a large number of cigarettes, promiscuous homosexual relationships. Among the patients there were people with ulcerative colitis, other diseases of the gastrointestinal tract, Behcet's syndrome, affecting the mucous membranes of the oral cavity, genitals, eyes. An hereditary predisposition is also important, diabetes contributes to the pathology, mechanical injuries (dentures, fillings, etc. In the mouth).

Pathogenesis

The pathogenesis of hairy leukoplakia of the oral cavity is complex and involves the interaction of stable replication of the Epstein-Barr virus and virulence, systemic immunosuppression and suppression of local host immunity. [5]The virus first affects the basal cells of the epithelium in the throat, there it goes into the replicative phase, is released and is in the saliva of a person for life. It also penetrates into B cells, where a latent state can remain indefinitely until circumstances favorable for its reproduction occur and most often it is an immune dysfunction.

Symptoms of the hairy leukoplakia

Hairy leukoplakia can develop asymptomatically for a long time. The first signs are expressed in the appearance of a white coating on the lateral surfaces of the tongue, in its upper and lower parts, less often on the inside of the cheeks, on the gums, soft palate. Mostly they are symmetrical in nature, able to disappear for a while, and then appear. [6]Sometimes cracks form on the tongue, slight pain appears, a perversion of sensitivity, a change in taste. [7]

Gradually, the lesion fuses merge into whitish stripes, alternating with healthy pinks. Outwardly, it looks like a washboard. Hairy leukoplakia of the mouth and tongue is slowly progressing, individual folds form plaques on the mucosa up to 3 mm in size, their borders are fuzzy and they cannot be removed by scraping.

In addition to the localization described above, pathology occurs much less often in women on the vulva, clitoris, cervix, in men - on the head of the penis, which is facilitated by mechanical, chemical factors (found in men 30 and more years old).

Hairy leukoplakia with HIV is accompanied by weight loss, excessive sweating at night, causeless diarrhea, and febrile seizures.

Stages

Hairy leukoplakia is a long-term chronic dystrophic process of mucous membranes that goes through several stages:

• proliferation, proliferation of cells;
• keratinization of squamous epithelium;
• cell sclerosis (pathological regeneration, replacement with connective tissue).

Forms

There are several types of leukoplakia:

• flat - looks like a slightly rough film that cannot be removed with a spatula, with serrated outlines;
• verrucous - is a towering plaque with a diameter of 2-3 mm whitish color;
• erosive - appears in the foci of the first two leukoplakia in the form of erosion, sometimes cracks;
• leukoplakia of smokers or Tappeiner - is formed in areas of hard and soft palate, they become completely keratinized with a gray-white color with interspersed reddish dots - the mouths of the ducts of the salivary glands;
• candidiasis - chronic candidal infection joins;
• hairy leukoplakia - infection with the Epstein-Barra virus disease.

Complications and consequences

Unpleasant consequences and complications of hairy leukoplakia include a change in taste, inflammation of the oral mucosa due to infection with Candida fungi (candida stomatitis), and mouth discomfort: tingling, burning.

Diagnostics of the hairy leukoplakia

Diagnosis of the disease is based on the clinical picture and laboratory studies. A histology is carried out, which detects the "shaggy" of the affected areas in the upper epithelial layer. Superficial infection (candidiasis), keratinization of the mucous membrane, thickening and increase in the prickly and granular layers of the epithelium, and inflammation may be present in the smear.

Epstein-Barr virus is detected in a mucosal biopsy. An HIV test is also used, the number of T-helper T cells is determined (with leukoplakia it is below normal). EBV can be detected by several methods, such as polymerase chain reaction (PCR), immunohistochemistry, electron microscopy and in situ hybridization (ISH), the latter being considered the gold standard for diagnosis. [8]

Additional methods include instrumental examination by a photodiagnoscope (ultraviolet irradiation and observation of tissue luminescence), electron microscopic (directing electron flows, study the structure of tissues at the subcellular and micromolecular levels), and the use of optical coherence tomography.

Differential diagnosis

Differential diagnosis includes oral candidiasis, lichen planus, oral intraepithelial neoplasia caused by human papillomavirus, and squamous cell carcinoma of the oral cavity. In most cases, oral hairy leukoplakia can be diagnosed clinically and does not require a confirmatory biopsy.

Treatment of the hairy leukoplakia

Hairy leukoplakia most often does not require special treatment and often goes away with HAART if it is associated with HIV infection. [9]Drug therapy is primarily aimed at suppressing the Epstein-Barr virus. Special nutritional requirements are also presented: spicy, hot, salty, sour food is excluded from the diet.

It will take special care for the mucous membranes of the mouth, namely rinsing with antiseptics. Local drugs are used to improve tissue trophism, and general strengthening agents, biostimulants will be needed, and if necessary, analgesics.

Therapy for hairy leukoplakia is designed to restore patient comfort, restore the normal appearance of the tongue, and prevent other diseases of the oral cavity. [10]Suggested treatments include surgery, systemic antiviral therapy, and topical treatment. 

Medication

Gentian violet is a triphenylmethane dye that was synthesized by Charles Louth in 1861 under the name Violet de Paris. Churchman in 1912 demonstrated the bacteriostatic effect of crystalline violet against gram-positive microorganisms in vitro and in animal models, as well as the antimycotic effect of this agent against several species of Candida. [11]Since then, several studies have evaluated the antibacterial and antifungal effects.

The antiviral properties of gentian violet have been investigated based on the fact that viral EBV products induce reactive oxygen production, and gentian violet is a potent inhibitor of reactive oxygen species. [12]Given that crystalline violet is well tolerated, human approved, and inexpensive, Bhandarkar et al  [13] conducted a study using enzian violet (2%) as a topical treatment for hairy leukoplakia in one HIV-infected man. Gentian violet was applied topically to the lesion three times in one month. Complete regression of the disease was observed after one month of observation, and relapse was not observed one year after treatment.

Podophyllinum is a dry, alcoholic extract of the rhizomes and roots of Podophyllum peltatum. It is a fat-soluble substance that penetrates cell membranes and inhibits cell replication; this substance is commonly used as a local chemotherapeutic agent. [14]It is inexpensive, easy to use and effective over a long period of time. 

The results of using a 25% alcohol solution of podophyllin as a local therapy for volostat leukoplakia are significant, especially in the first week after application. In a series of cases, nine patients received a 25% podophyllin salt in tincture of benzoin compound. The results showed a complete regression of all lesions: five patients within one week and four after the second application in a week. These four patients had more extensive lesions. In another study, six men with hairy leukoplakia were treated with 25% podophyllinum once a day, healing of all lesions was confirmed after three to five days. [15]Gowdy et al evaluated ten HIV-infected patients with hairy leukoplakia in the tongue and treated one side with a single topical application of a 25% solution of podophyllic resin. The other side was used as a control. Patients were evaluated on the second, seventh and thirty days of the study. They described a slight change in taste, burning, and pain with a short duration. There was a regression of lesions, especially on the second day after application.

The dose commonly used in local therapy of volostat leukoplakia ranged from 10 to 20 mg of podophyllin.

As antiviral therapy, drugs such as acyclovir, valaciclovir, famciclovir are used. After discontinuation of systemic antiviral drugs, such as descyclovir, valaciclovir, acyclovir and ganciclovir, recurrences of hairy leukoplakia were often observed. [16]

Acyclovir is a chemotherapeutic antiviral agent that is very effective against herpes simplex viruses types I and II, EBV virus, Varicella zoster virus and cytomegalovirus. The only study using acyclovir cream for topical treatment was conducted by Ficarra et al. [17]The authors observed hairy leukoplakia in 23 of 120 HIV-positive patients (19%) and found complete resolution of the disease in two patients and partial regression in one patient after topical application of acyclovir cream. 

Acyclovir - tablets, the recommended daily dose of 800 mg (200 mg in one tablet), divided into 5 doses. Children under 2 years old are not prescribed, pregnant and lactating women with caution, given the benefit-risk ratio. Side effects are manifested in nausea, diarrhea, fatigue, itching, rash, headache, dizziness. Anemia, jaundice, and hepatitis may develop. The drug is contraindicated for allergies to components, patients with renal and hepatic insufficiency, the elderly should reduce the dose.

If the disease proceeds against the background of HIV infection, reverse transcriptase inhibitors are used: zidovudine, didanosine.

Candidiasis infection is fought with antimycotics: fluconazole, ketoconazole.

Fluconazole - capsules, on the first day of treatment, take 200-400 mg, in the next 100-200 mg for 1-3 weeks before the onset of remission. For children in this form, the drug can be used when they can swallow a capsule, usually after 5 years. The initial daily dose for them is 6 mg / kg, supporting - 3 mg / kg.

Possible side effects are drowsiness, insomnia, anemia, diarrhea, nausea, headache, dry mouth, increased bilirubin levels, transaminases. There are contraindications regarding co-treatment with certain medications (terfenadine, cisapride, astemizole, etc.).

In the treatment of hairy leukoplakia, local keratolytics, retinoic acid preparations are also used.

Vitamins

Vitamin therapy is appropriate in the treatment of leukoplakia. Assign inside oil solutions of tocopherol acetate, retinol. Before swallowing, they are detained for a while in the mouth.

Retinoids are dekeratinizing agents responsible for modulating Langerhans cells in hairy leukoplakia. Topical administration of 0.1% vitamin A twice daily was performed in twelve cases of the disease and regression of lesions was observed after 10 days. [18]Daily use of a solution of tretinoin (Retin-A) for 15-20 days was performed in 22 patients, and 37 patients did not receive treatment. Healing of lesions was observed in 69% of treated patients, and spontaneous regression in 10.8% of untreated patients. [19]Retin-A is an expensive medicine and causes a burning sensation after prolonged use. [20]

Vitamins C, group B are used, including riboflavin, as well as others that strengthen the immune system.

Physiotherapeutic treatment

The protocol for the treatment of hairy leukoplakia has a place for physiotherapeutic methods. These are diathermocoagulation and cryodestruction - procedures used to eliminate areas of hyperkeratosis.

Alternative treatment

Of the alternative methods, you can apply mouthwash with decoctions of medicinal herbs that have an antiseptic effect: chamomile flowers, linden blossom, sage.

Surgery

Excision is a surgical method used for hairy leukoplakia. The most modern is laser ablation, using a laser beam to remove a substance from the surface of the mucosa, it simply evaporates. Another way - cryotherapy is not widespread.

After surgical excision of hairy leukoplakia for three months, no relapse was observed. However, in most patients, new foci of the disease appeared after 3 months of observation. [21]

Given this and comparing the operation with systemic therapy, patients should be recommended local treatment, since it does not cause systemic side effects, less invasive and effective for a long period of time. [22]

Prevention

Proactive measures to prevent disease do not exist.

Forecast

In half of the cases of the disease after treatment, stabilization occurs. The same part is prone to complications (the appearance of new foci). Epstein-Barr virus does not disappear, therapy only suppresses its productive replication.

Although hairy leukoplakia alone does not lead to death, its manifestation against the background of immunodeficiency is a very alarming signal, indicating an unfavorable prognosis for life expectancy (usually 1.5-2 years).