Introduction and background. Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that infects nearly every human being by young adulthood. Most EBV infections occur asymptomatically during childhood, but EBV is associated with a wide variety of human diseases including the infectious mononucleosis syndrome, Hodgkin's lymphoma, African Burkitt's lymphoma and nasopharyngeal carcinoma. EBV is also an opportunistic pathogen in immunocompromised patients, associated with lymphoproliferative diseases and oral hairy leukoplakia.
EBV infection is transmitted from person to person by contact with infectious body fluids. Oral contact with infectious saliva is the most common route of transmission, but EBV infection may also be transmitted by sexual contact or exposure to breast milk. Like all herpesviruses, EBV establishes a life-long, persistent infection of its host.
Acquisition of HIV infection stimulates reactivation of pre-existing, latent EBV infection. Asymptomatic, high level, oral EBV shedding occurs in up to 90% of HIV-infected patients, even before the clinical manifestations of immunodeficiency are apparent. While not all HIV-infected patients develop EBV-associated disease, persistent EBV replication and progressive immune dysfunction can eventually result in oral hairy leukoplakia and/or EBV-associated lymphoma.
Epidemiology. Hairy leukoplakia is one of the most common, virally-induced, oral diseases of individuals with HIV infection. The point prevalence may be as high as 25%.[1,2] In adults, hairy leukoplakia is more common in men[3,4] and in cigarette smokers. Hairy leukoplakia is rarely reported in children, but probably is more common than has been generally recognized. The occurrence of hairy leukoplakia is not well correlated with CD4 T cell count or the onset of AIDS,[1-3] and the lesion can be found in patients with CD4 T cell counts over 500 cells/[mm.sup.3]. Antiretroviral and antiherpesviral therapy reduces the prevalence of hairy leukoplakia. Since the advent of highly active antiretroviral therapy (HAART), the prevalence of hairy leukoplakia has declined, but the lesion is still common. Of note, hairy leukoplakia is not limited to HIV infection. It also occurs in iatrogenically immunosuppressed patients and has been described in otherwise healthy individuals.
Clinical manifestations. Hairy leukoplakia is a white, shaggy-appearing, lesion that typically occurs on the lateral borders of the tongue.[7-10] Lesions may be either continuous or discontinuous along both tongue borders, and they are often not bilaterally symmetric. Lesions are adherent, and only the most superficial layers can be removed by scraping. There is no associated erythema or edema of the surrounding tissue. Hairy leukoplakia may also involve dorsal and ventral tongue surfaces, the buccal mucosa, or the gingiva.[7,9,11,12] On the ventral tongue, buccal mucosa, or gingiva, the lesion may be flat and smooth, lacking the characteristic "hairy" appearance.
The natural history of hairy leukoplakia is variable. Lesions may frequently appear and disappear spontaneously. Hairy leukoplakia is often asymptomatic and many patients are unaware of its presence. Some patients with hairy leukoplakia do experience symptoms including mild pain, dysesthesia, alteration of taste, and the psychological impact of its unsightly cosmetic appearance.[7,8,13,14] Hairy leukoplakia is not a malignant or premalignant lesion.[8,15] One retrospective epidemiologic study associated hairy leukoplakia with the subsequent development an EBV-associated lymphoma in HIV-infected patients, but this has not been studied prospectively.
Differential diagnosis. The gross appearance of the hairy leukoplakia lesion may be variable, resulting in possible misdiagnosis. Other oral lesions with a similar appearance to hairy leukoplakia include the following:
1) Candidiasis or thrush typically occurs as a flat lesion, removable by scraping and revealing an erythematous base. However, hyperplastic candidiasis lesions are adherent and do not wipe off, making this disease especially difficult to distinguish from hairy leukoplakia. Resolution of the lesion with antifungal therapy suggests candidiasis over hairy leukoplakia. However, hairy leukoplakia lesions are commonly also infected with Candida, further confusing the clinical diagnosis.
2) Frictional keratosis typically occurs on the lateral borders of the tongue as a consequence of tongue biting by the molar teeth or some other abrasive irritant. This lesion should quickly resolve after removal of the provoking stimulus.
3) Tobacco-induced leukoplakia occurs in smokers and individuals who chew tobacco. These lesions are typically not shaggy like hairy leukoplakia, and they may occur anywhere in the oral cavity. They are often premalignant and should be evaluated by biopsy and histologic examination.
4) Lichen planus or lichenoid eruptions occur as autoimmune or allergic reactions to an unknown stimulus. In HIV-infected patients, lichen planus often occurs on the buccal mucosa, typically with a reticulated pattern. Oral lichen planus may also be associated with cutaneous lesions.
Histopathology and diagnosis. The diagnosis of hairy leukoplakia can be made by histologic or cytologic examination of excisional biopsy tissue or exfoliated epithelial cells, respectively.[17,18] The histopathology of hairy leukoplakia is characterized by 5 major histologic features.[8,19]
1) There is a hyperkeratosis of the upper epithelial layer that represents an altered pattern of keratin expression in the squamous epithelial cells. This hyperkeratosis is largely responsible for the characteristic shaggy or "hairy" gross appearance of the lesion. Superficial infections of the hyperkeratinized epithelium with bacteria or Candida may also be seen.
2) There is a parakeratosis of the superficial epithelial layer. This abnormal persistence of cell nuclei in the superficial epithelial layers may represent incomplete squamous differentiation.
3) There is an acanthosis of the stratum spinosum in the epithelial mid-layer. This abnormal expansion of cells occurs with foci or layers of ballooning "koilocyte"-like cells. The cell nuclei have a homogenous "ground-glass" appearance and may contain Cowdry type A intranuclear inclusions.
4) There is minimal or absent inflammation in the epithelial and subepithelial tissues.
5) The basal epithelial layer is histologically normal.
Although these characteristic histologic features of hairy leukoplakia are highly suggestive of the diagnosis, none are unique to the lesion. Thus, a definitive diagnosis of hairy leukoplakia requires both an appropriate histologic cytologic appearance and the demonstration of EBV DNA, RNA, or protein within the epithelial cells of the lesion. Several immunohistochemistry and in situ hybridization kits are commercially available for use by the pathology laboratory in the diagnosis of EBV infection. A definitive diagnosis of hairy leukoplakia may be required for research studies but is rarely indicated in general clinical practice. A more important indication for direct tissue examination involves the need to exclude alternative, potentially malignant, diagnoses in selected individual cases.
Pathogenesis. Hairy leukoplakia is associated with productive EBV replication.[20,21] Inhibition of EBV replication with antiviral therapy results in resolution of the hairy leukoplakia lesion within 1-2 weeks. However, productive EBV replication may also occur in normal tongue epithelial cells, without generating the characteristic histopathology of hairy leukoplakia. Thus, productive EBV replication appears to be necessary but not sufficient for the pathogenesis of hairy leukoplakia. The cofactors that contribute to the pathogenesis of the lesion have not yet been identified.
Hairy leukoplakia and the biology of EBV infection in this disease have some unique features that likely contribute to the pathogenesis of this lesion.
1) Hairy leukoplakia frequently contains multiple, co-infecting, EBV strains.[21,24-26] In hairy leukoplakia, the productively replicating EBV undergoes genetic recombination and sequence mutation, generating a complex population of multiple EBV strains, substrains, and recombinant variants.[21,24-27] The pathogenicity of EBV may be enhanced by this genetic heterogeneity.
2) Many EBV genes that typically are associated with latent EBV infection are surprisingly expressed during productive EBV replication in hairy leukoplakia.[28-31] Some of these genes are known to have profound effects upon cellular proliferation, differentiation, and apoptosis, and these EBV gene products may induce the cellular changes that ultimately give rise to the histopathologic features of hairy leukoplakia. Interestingly, many of the "latent" genes expressed in hairy leukoplakia also sustain high rates of genetic mutation in hairy leukoplakia,[21,25-27] potentially altering their pathogenicity or their immunogenicity.
3) There is a marked decrease or an absence of Langerhan's cells in hairy leukoplakia biopsy tissues. Langerhan's cells are the antigen-presenting immune cells that are required for an immune system response to the viral infection. This deficiency of Langerhan's cells may permit EBV to persistently replicate and escape immune recognition.
The pathogenesis of hairy leukoplakia is clearly complex, potentially requiring a convergence of factors including EBV co-infection, productive EBV replication, EBV genetic evolution, expression of specific EBV "latent" genes, and immune escape. All of these factors are likely facilitated by local and systemic host immunodeficiency. The study of hairy leukoplakia will elucidate mechanisms of EBV molecular pathogenesis and immunopathogenesis that may be applicable to other EBV-associated diseases.
Management. As a benign lesion with low morbidity, hairy leukoplakia does not require specific treatment in every case. Indications for treatment include symptoms attributable to the lesion, or a patient's desire to eliminate the lesion for cosmetic reasons. The variable natural history of the lesion and its tendency toward spontaneous resolution should be considered in any management decision. Several treatment options are available.
1) Systemic antiviral therapy usually achieves resolution of the lesion within 1-2 weeks of therapy.[13,22,23,33] Oral therapy with acyclovir requires high doses (800 mg five times per day) to achieve therapeutic levels. Valacyclovir (1000 mg three times a day) and famciclovir (500 mg three times a day) are newer antiviral drugs with higher oral bioavailability than acyclovir and can be dosed less often. Antiviral drugs inhibit productive EBV replication but do not eliminate the latent state of infection. Hairy leukoplakia often recurs several weeks after the cessation of antiviral therapy.
2) Topical therapy with podophyllin resin 25% solution usually achieves resolution after 1-2 treatment applications.[34-37] The treatments may temporarily cause local pain, discomfort and alteration of taste. Podophyllin has cellular cytotoxic effects, but the mechanism of action in resolving hairy leukoplakia is not known. Again, hairy leukoplakia often recurs several weeks after successful podophyllin therapy.
3) Topical therapy with retinoic acid (tretinoin) has been reported to resolve hairy leukoplakia.[14,38] Retinoic acids are known to inhibit EBV replication in vitro and induce epithelial cell differentiation. As with the antiviral agents and podophyllin, hairy leukoplakia often recurs several weeks after successful retinoic acid therapy.
4) Two forms of ablative therapy can also be considered for small hairy leukoplakia lesions. Cryotherapy has been reported as successful but is not widely used. Surgical excision may be useful in cases where histologic examination of the lesion might be diagnostically important.
Summary. Oral hairy leukoplakia is a common, benign, opportunistic EBV infection of the oral cavity of patients with HIV. It is important to differentiate hairy leukoplakia from other, more serious, oral lesions that may have a similar clinical appearance. In some cases, this is best accomplished by biopsy and histologic examination of the tissue. Several treatment options are available for symptomatic hairy leukoplakia lesions, but none prevent the recurrence of the lesion after therapy. Research studies into the pathogenesis and treatment of oral hairy leukoplakia and other HIV-associated and EBV-associated oral lesions are currently being conducted at the Bering Dental Clinic in Houston.
Acanthosis: a benign overgrowth of skin.
Apoptosis: "programmed" cell death.
Buccal: referring to the cheeks.
Dysesthesia: an unpleasant and unusual sensation.
Edema: tissue swelling that is the result of water accumulation.
Epithelial cells: cells that are on the surface of the body or that line body cavities.
Erythema: a redness of skin or tissue, caused by inflammation.
Gingiva: dental tissue commonly called gums.
Histopathology: the study of microscopic processes and changes in diseased or otherwise abnormal tissues.
Hyperkeratosis: an overgrowth of skin usually caused by an increase in the size of cells.
Hyperplastic: characterized by an abnormal increase in the number of cells making up a tissue.
Iatrogenically: induced by medical treatment or procedures (inadvertently).
Immunogenicity: the ability to cause an immune response in an organism.
Keratosis: a skin lesion that may be rough or scaly in appearance.
Lichenoid eruptions: a skin condition where there is damage to the lower epidermis along with a focused chronic inflammation between the epidermal and dermal layers of skin.
Lymphoma: a tumor of the lymphoid tissue (usually malignant).
Morbidity: the incidence of a disease or all diseases in a population.
Mucosa: the mucous membranes that line body passages and cavities (e.g., inside the mouth).
Reticulated: having thread-like fibers or lines in a pattern.
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