Are You Confident of the Diagnosis?
What you should be alert for in the history
Oral hairy leukoplakia (OHL) is usually asymptomatic, and the unexpected esthetic appearance often alerts an individual to its presence. Rarely, patients complain of mild burning or pain, especially with eating or drinking. Look for known immune suppression or risk factors such as human immunodeficiency virus (HIV) infection or organ transplantation. Lesions may resolve and recur spontaneously, especially in situations of immune restoration.
Characteristic findings on physical examination
Exam reveals white or gray adherent (cannot be scraped off easily) plaques, commonly on the bilateral sides of the tongue (Figure 1). The surface is thickened with vertical furrows, creating a corrugated or verrucous (hairy) appearance. Occasionally, plaques occur on the dorsal or ventral tongue, buccal, or other oral mucosal sites, where the plaques may appear smoother.
Expected results of diagnostic studies
Diagnosis is usually clinical. Shave biopsy for histopathology can be supportive and may eliminate more concerning premalignant leukoplakias. Changes include epithelial hyperplasia with parakeratosis and acanthosis, ballooned and vacuolated keratinocytes in the upper epidermal layers with margination of nuclear chromatin and Cowdry type inclusion bodies, and minimal inflammatory infiltrate (Figure 2, Figure 3). Candidal hyphae and bacterial colonies may be present.
Cytologic scrapings sent for routine Papanicolaou stain (PAP) may be a useful alternative to biopsy. Definitive diagnosis requires detection of the presence of Epstein-Barr virus (EBV) by immunohistochemistry (Figure 4), polymerase chain reaction (PCR), or in situ hybridization.
Pseudomembranous candidiasis (thrush) is also common in immunocompromised patients, but is creamy white; easily scraped off; usually involves multiple locations on the palate, buccal mucosa, and tongue; and has fungal elements on potassium hydroxide (KOH) preparation. Hyperplastic candidiasis is harder to differentiate, with its white firmly adherent plaques, but it usually affects areas prone to trauma, such as the anterior buccal mucosa, is often seen in smokers, and is KOH-positive. Both respond to therapeutic trials of antifungals, and candidasis often accompanies OHL (see “Unusual Clinical Scenarois” below).
Lichen planus has reticular lace-like white plaques on the buccal mucosa, gingivae, or lateral tongue; may erode or ulcerate causing pain; and can have accompanying cutaneous lesions. Graft-versus-host disease may mimic oral lichen planus and should be considered in appropriate patients.
Proliferative verrucous leukoplakia (oral florid papillomatosis) is rare, favors elderly patients, presents with slow-growing white plaques that enlarge and become verrucous and multifocal with time, may develop on the buccal or gingival tissue first, and warrants biopsy, given its aggressive progression to carcinoma.
Frictional keratosis from tongue biting or other trauma can cause irregular rough white plaques, frequently on the buccal mucosa or lateral tongue, is usually recognizable on history, and resolves with a change in habits.
Smokers and tobacco chewers can develop flat gray or white plaques that become more verrucous with time, involve many locations in the mouth, and need to be biopsied to exclude dysplasia or malignancy, if suspected.
Pseudo-oral hairy leukoplakia is rarely reported, and clinically and histologically resembles OHL, yet has no evidence of EBV and occurs in individuals without immune suppression.
Who is at Risk for Developing this Disease?
First described during the outset of the AIDS epidemic in 1984, OHL is seen almost exclusively in immunocompromised people, primarily HIV-infected individuals, but occasionally is seen in hematologic and solid organ transplant recipients, those with hematologic malignancies, and in a few cases, in patients treated with topical, inhaled, or systemic corticosteroids or other immunosuppressant medications.
Rare reports in healthy individuals also exist. There is no sex or race predilection. Adults are more commonly affected than children. Incidence of OHL generally increases in an individual in parallel with the degree of immunosuppression. In HIV-infected patients, a few cases of OHL have been seen as a component of the immune reconstitution syndrome.
What is the Cause of the Disease?
OHL is an oral manifestation of EBV, or human herpesvirus 4, infection, and more than 90% of the worldwide adult population has latent EBV. Candidal overgrowth may or may not contribute to pain or burning symptoms.
Immune suppression likely facilitates productive viral replication in the mucosal epithelial cells, leading to epidermal hypertrophy and clinical leukokeratosis. It is unclear if reactivation of latent EBV in the musocal epithelium occurs, or if newly acquired EBV from the saliva or from B lymphocytes and/or other leukocytes entering the mucosa contributes to early pathogenesis.
Systemic Implications and Complications
OHL is a benign localized condition without systemic complications or malignant potential. Its presence in someone without known immune compromise, however, should prompt testing for HIV infection.
Prevalence of OHL in HIV patients is around 25%, and many studies have shown it predicts a moderate to severe degree of immunosuppression and progression to AIDS. In the era of highly active antiretroviral therapy (HAART), incidence has decreased, but the appearance of OHL in someone on stable therapy should prompt consideration of new drug resistance and/or impending treatment failure. Transplant recipients developing OHL may need the degree of their immunosuppressive regimen addressed.
No treatment is usually indicated unless symptomatic or esthetically concerning.
Antifungals are recommended if Candida species present (clotrimazole 10mg oral troches five times daily, nystatin 500,000 units oral suspension swish, and swallow four to five times daily, or fluconazole 100mg by mouth daily).
Anti-retrovirals are recommended as a first-line non-specific treatment in HIV-infected individuals, as lesions often resolve as immune function is restored.
(applied in-office, once weekly until resolution)
–podophyllin 25% resin
–podophyllin 25% resin and acyclovir 5% cream
–gentian violet 2%
–acyclovir 5% cream
–retinoic acid 0.05% solution
–acyclovir 800mg by mouth five times daily for 3-4 weeks
–valacyclovir 1000mg by mouth three times daily for 3-4 weeks
Optimal Therapeutic Approach for this Disease
Treatment of OHL is usually unnecessary and interventions should focus on restoration of immune function, if pertinent or possible. For symptomatic or esthetically concerning cases, local treatments are safe, effective, and avoid the potential complications of systemic therapies. Recurrence of OHL within weeks to months of successful treatment is almost inevitable in the setting of persistent immunocompromise, and patients need to be informed of this at the start of any intervention. Treatment of concurrent candidiasis with topical or oral antifungals is recommended (see “Unusual Clinical Scenarios” below).
There are no randomized double-blind placebo-controlled trials of treatment for OHL, and most treatment studies have been performed in HIV-infected patients. The most data exist for use of topical podophyllin 25% resin applied weekly. Clearance rates above 80% or 90% are achieved, often within 6 weeks, although extensive cases may take several months to clear. Recurrence often happens within several months.
Application is in-office. The mucosa is first dried, then a small amount of podophyllin is applied to the areas of OHL with a cotton-tipped applicator, and finally, the patient washes his/her mouth after the resin has dried for a few minutes. No food or drink is allowed for the next hour. Most patients complain of transient taste alteration, burning, or an unpleasant taste.
Podophyllin is contraindicated during pregnancy. No literature exists on substitution of podofilox 0.5% gel or solution for podophyllin. Recent studies suggest that the addition of acyclovir 5% cream for a minute after podophyllin application may improve clearance in poorly responsive cases and prolong the time to recurrence to at least a year.
There are a few reports of successful treatment with retinoic acid 0.05% or 0.1% solution, 2% gentian violet, and topical acyclovir 5% cream alone. Retinoic acid may only work in mild thin plaques, causes progressive burning with repeat applications, and tends to yield quick recurrences. Gentian violet 2% and acyclovir 5% cream appear safe and effective, but only a few patients are reported.
Oral courses of acyclovir or valacyclovir at high doses are highly effective (clearance rates above 80% to 90%). The limited data, however, suggest that time to clearance is similar to topical podophyllin and recurrence is still common and perhaps occurs sooner. Development of viral resistance to these drugs and their potential systemic adverse effects should limit their utility in OHL. Ganciclovir and foscarnet are also reported as effective, but their necessity in most patients is questionable.
Shave excision under local anesthesia offers the advantage of immediate clearance, although pain and swelling may last for a few days after the procedure. The article detailing this approach reported no recurrences at the treated sites at 3 months, but most patients had developed new lesions of OHL in the same time period. The cost and potential surgical complications of this approach need to be considered against the topical therapies available.
Cryotherapy has been shown effective in one report. No reports on use of ablative lasers such as the CO2 laser exist for treatment of OHL specifically, but these modalities are very effective for other forms of leukoplakia and may be expected to yield similar results in OHL.
Education should focus on the relationship between OHL and impaired immunity. Realistic expectations about the recurrence rate and need for continued treatment if immune function remains depressed are needed at the outset. In those patients without immune defects, recurrences and remissions are hard to predict, given the paucity of data in this population. The benign nature of OHL should be emphasized.
Unusual Clinical Scenarios to Consider in Patient Management
Concurrent candidal overgrowth should be recognized and treated, as it may complicate diagnosis and contribute to or explain symptomatology. A KOH preparation in the clinic can confirm the presence of Candida. Two weeks of topical antifungal troches or solutions (or oral azoles for more extensive cases) may resolve those cases of leukoplakia where the diagnosis of OHL is questionable or treat the burning or discomfort in cases of symptomatic OHL.
What is the Evidence?
Bhandarkar, SS, MacKelfresh, J, Fried, L, Arbiser. “Targeted therapy of oral hairy leukoplakia with gentian violet”. J Am Acad Dermatol . vol. 58. 2008. pp. 711-2. (Documents safe use of gentian violet 2% in a case of OHL with complete clearance and no recurrence a year later)
Greenspan, D, Greenspan, JS, Conant, M, Petersen, V, Silverman, S, de Souza. “Oral “hairy” leukoplakia in male homosexuals: evidence of association with both papillomavirus and a herpes-group virus”. Lancet . vol. 2. 1984. pp. 831-4. (The original report of OHL)
Greenspan, JS, de Souza, YG, Regezi, JA, Daniels, TE, Greenspan, D, MacPhail, LA. “Comparison of cytopathic changes in oral hairy leukoplakia with in situ hybridization for EBV DNA”. Oral Dis . vol. 4. 1998. pp. 95-9. (Describes the common histopathologic changes in OHL specimens and addresses the utility of in situ hybridization for definitive diagnosis)
Herbst, JS, Morgan, J, Raab-Traub, N, Resnick. “Comparison of the efficacy of surgery and acyclovir therapy in oral hairy leukoplakia”. J Am Acad Dermatol . vol. 21. 1989. pp. 753-6. (Complete clearance of OHL with no recurrence at 3 months in twelve HIV-infected men; however, ten out of twelve had new foci of OHL develop within that time frame)
Husak, R, Garbe, C, Orfanos. “Oral hairy leukoplakia in 71 HIV-seropositive patients: clinical symptoms, relation to immunologic status, and prognostic significance”. J Am Acad Dermatol . vol. 35. 1996. pp. 928-34. (Report on a large cohort of HIV-infected patients with OHL and the significance it holds for prognosis in this population)
Lozada-Nur, F, Costa. “Retrospective findings of the clinical benefits of podophyllum resin 25% sol on hairy leukoplakia. Clinical results in nine patients”. Oral Surg Oral Med Oral Pathol . vol. 73. 1992. pp. 555-8. (Describes treatment and response of OHL to topical podophyllin resin)
Moura, MDG, Haddad, JPA, Senna, MIB, e Ferreira, EF, Mesquita. “A new topical treatment protocol for oral hairy leukoplakia”. Oral Surg Oral Med Oral Pathol Oral Radiol Endod . vol. 110. 2010. pp. 611-17. (Confirms the response of OHL to topical popophyllin resin and suggests that the addition of topical acyclovir cream may lead to higher response rates in some cases and a longer time to recurrence)
Piperi, E, Omlie, J, Koutlas, IG, Pambuccian. “Oral hairy leukoplakia in HIV-negative patients: report of 10 cases”. Int J Surg Pathol . vol. 18. 2010. pp. 177-83. (Description of OHL in HIV-uninfected, non-transplant patients, the majority receiving treatment with corticosteroids)
Resnick, L, Herbst, JS, Ablashi, DV, Atherton, S, Frank, B, Rosen, L. “Regression of oral hairy leukoplakia after orally administered acyclovir therapy”. JAMA . vol. 259. 1988. pp. 384-88. (Describes treatment and response of OHL to oral acyclovir)
Walling. “Oral hairy leukoplakia: an Epstein-Barr virus-associated disease of patients with HIV”. Res Initiat Treat Action . vol. 6. 2000. pp. 10-5. (Focused overview of OHL for the clinician)
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