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Case 2: Discussion

Epidemiology

Oral hairy leukoplakia (OHL) is considered one of the most common oral disorders in persons infected with HIV, occurring in approximately 15 to 20% of patients[1]. Following the widespread use of highly active antiretroviral therapy in the mid 1990s, the prevalence of oral hairy leukoplakia has significantly declined[2,3]. Persons with OHL generally have moderate to advanced immune suppression, with a median CD4 count of approximately 235 cells/mm3[1]. Oral hairy leukoplakia has clear prognostic value for subsequent development of AIDS[4] and it is classified as a CDC category B clinical marker of HIV disease (in the 1993 CDC classification)[5]. In general, the presence of OHL strongly suggests a diagnosis of HIV, but rare reports have described OHL in immunosuppressed persons with disorders other than HIV, including solid organ and hematopoietic cell transplantation, systemic lupus erythematosus, Behcet's disease, and immune suppression secondary to high-dose oral corticosteroids. There is no evidence that OHL occurs in association with hepatitis C virus infection. In addition, there are no data to suggest OHL develops into premalignant or malignant lesions, such as oral squamous cell carcinoma.

Cause of Oral Hairy Leukoplakia

Several studies utilizing immunofluorescence staining have clearly documented a very strong association of Epstein-Barr virus (EBV) and OHL[6]. Presence of EBV without significant immune suppression, however, does not appear sufficient to cause OHL. Moreover, immunocompromised HIV-infected persons with OHL have a unique state of EBV infection characterized by concurrent expression of replicative and transforming proteins that lead to the development of the histologic features associated with this lesion[7]. Although other viruses, such as human herpes virus-8 and human papillomavirus can sometimes be found in the oral mucosa among persons with OHL, no evidence exists that these viruses play any role in causing or maintaining OHL lesions. In addition, although Candida albicans is often associated with OHL lesions, there is no evidence that it plays a causative role.

Clinical and Histologic Findings

Patients with OHL typically have raised, white, non-removable hyperkeratotic lesions on a oral mucosal surface (Figure 1). The lesions most often cluster on the lateral aspect of the tongue (Figure 2 and Figure 3), but have been observed on other parts of the tongue, the buccal mucosa (Figure 4 and Figure 5), and rarely, the soft palate[8]. The lesions can be unilateral or bilateral. Oral hairy leukoplakia rarely causes clinical symptoms. In most circumstances, the diagnosis of OHL is made on clinical findings and a biopsy of the lesion is typically not performed. If a biopsy is performed, histologic features of OHL consist of nuclear changes (Cowdry type A inclusions, ground glass, nuclear beading), profound acanthosis, lack of an inflammatory infiltrate, enlarged cells, regions of ballooning cells, and epithelial hyperplasia[9,10]. definitive diagnosis requires identifying replicating EBV.

Differential Diagnosis

With respect to differential diagnosis, OHL is most often confused with oral candidiasis, but OHL lesions are strongly adherent and cannot be removed by scraping with a tongue blade, whereas the plaques associated with oropharyngeal candidiasis are usually easily removable. In addition, candidiasis is typically seen on the buccal mucosa, the palate, and the gums rather than on the lateral aspect of the tongue. If the clinical diagnosis remains in question, a Gram's stain or potassium hydroxide (KOH) stain can confirm the diagnosis of candidiasis, though concomitant OHL should also be considered. Geographic tongue, or benign migratory glossitis, can mimic OHL because the border of the lesions can appear white (Figure 6); these lesions are characterized by red atrophic irregular areas surrounded by white to yellowish-white, sharp, slightly raised borders, giving the tongue an overall map-like appearance (Figure 7). Most patients do not have symptoms with this disorder, but 10 to 15% will have associated glossodynia. Geographic tongue can be distinguished from OHL by its characteristic primary location on the dorsal surface of the tongue, the rapid change in the lesions over a period of days or weeks, and its map-like appearance. Other rare oral disorders, such as lichen planus, leukoplakia, and squamous cell carcinoma, can occasional appear similar to OHL. "Hairy tongue" (hyperplastic papillae) generally does not resemble OHL, but can be confused with OHL because of the similarity of the names of the two disorders. Hairy tongue is caused by hyperplasia of the filiform papillae concomitant with a decrease in the normal rate of desquamation, resulting in a thick, matted, hairy dorsal surface of the tongue.

Therapy

Fortunately, OHL usually does not generally require specific therapy. In addition, most patients will experience gradual resolution of OHL after taking potent antiretroviral therapy. Nevertheless, some patients may desire specific treatment for their OHL, either because of symptoms or cosmetic reasons. Several reports have described resolution of OHL in response to therapy with high-dose acyclovir (Zovirax), but lesions typically recurred after discontinuing acyclovir[11]. One HIV-infected patient with prominent OHL had complete resolution of the lesions after therapy with famciclovir (Famvir) 250 mg tid for 14 days[12]. In the largest series involving antiviral therapy for OHL, 16 of 19 patients with OHL responded to valacyclovir (Valtrex) 1,000 mg tid when given for 28 days[13]. Several reports have described HIV-infected patients who had improvement in OHL lesions with the use of topical agents, including a single application of 25% podophyllin resin[14], one or two applications of 25% podophyllin resin given on a weekly basis[15], and several applications of a 2% gentian violet solution given over a 1 month period[16]. In a study involving 46 HIV-infected patients with OHL, investigators compared weekly applications of topical 25% podophyllin resin alone versus topical 25% podophyllin resin combined with topical 5% acyclovir cream and both groups has excellent responses, although patients in the combined group had slightly better responses[17]. A subsequent study with 42 HIV-infected patients and OHL examined treatment responses using weekly applications of three topical regimens: 25% podophyllin resin, 25% podophyllin resin combined with topical 5% acyclovir cream, and 25% podophyllin resin combined with topical 1% penciclovir cream[18]. Overall, most patients had significant improvement in the lesions by 7 to 8 weeks, with the 25% podophyllin resin combined with topical 5% acyclovir cream producing the most effective responses[18].

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    Figure 1. Oral Hairy Leukoplakia

    Characteristic hyperkeratotic, white, non-removable oral hairy leukoplakia lesion.


    Figure 1
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    Figure 2. Oral Hairy Leukoplakia Lesion on Lateral Tongue

    In this patient, oral hairy leukoplakia was most evident on the lateral aspect on the tongue. The lesions would not have been evident without examining the lateral tongue.


    Figure2
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    Figure 3. Extensive Oral Hairy Leukoplakia Lesion on Lateral Tongue

    This patient had extensive oral hairy leukoplakia plaques that covered most of the the lateral aspect on the tongue.


    Figure 3
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    Figure 4. Diffuse Oral Hairy Leukoplakia Lesion on Buccal Mucosa

    This patient had diffuse oral hairy leukoplakia on the buccal mucosa. Note these lesions are not the typical hyperkeratotic lesions, but appear more as a thin white film overlaying the buccal mucosa.


    Figure 4
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    Figure 5. Localized Oral Hairy Leukoplakia Lesion on Buccal Mucosa

    This patient had localized faint patches of oral hairy leukoplakia on the buccal mucosa.


    Figure 5
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    Figure 6. Geographic Tongue (Benign Migratory Glossitis) Resembling OHL

    Geographic Tongue (Benign Migratory Glossitis) Resembling OHL.


    Figure 6
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    Figure 7. Geographic Tongue (Benign Migratory Glossitis) on Dorsal Surface of Tongue

    Typical lesion of benign migratory glossitis characterized by irregular atrophic, erythematous areas partially surrounded by white, slightly raised borders on the dorsal surface of the tongue. These lesions cause the tongue to have a geographic or map-like appearance.


    Figure 7