Hairy Leukoplakia

Synonyms and related keywords: oral hairy leukoplakia, OHL, AIDS, HIV, Epstein-Barr virus, EBV, immunosuppression, immunocompromise, homosexual men, IV drug users


INTRODUCTION

Background: Oral hairy leukoplakia (OHL) is an oral mucosal disease that first was described in 1984. It is associated with Epstein-Barr virus (EBV) and occurs almost exclusively in patients who are immunocompromised, particularly those infected with HIV.

Pathophysiology: Affected mucosa has diminished numbers of Langerhans cells and T-helper cells. Keratinocytes do not contain HIV, but EBV receptors have been detected in surrounding normal mucosa. Whether OHL develops after superinfection with EBV or activation of latent infection due to reduced immune surveillance is not known. Latent membrane protein-2 (LMP-2) may regulate reactivation from latency by interfering with normal B-cell signal transduction processes, which may be important for viral persistence. Multiple strains of EBV have been demonstrated in OHL lesions.

Frequency:

• In the US: Incidence of OHL in homosexual men and IV drug users who are infected with HIV is approximately 4%, but some evidence suggests that incidence is decreasing. The decreasing prevalence may be partially due to use of protease inhibitors. One study found that the 6-year incidence of OHL was 32% among 291 men in San Francisco who were HIV positive.

• Internationally: Incidence is similar to incidence in the United States.

Mortality/Morbidity:

• Median CD4 count when OHL is first detected is 468/mL. In persons without AIDS-defining disease, the probability of developing AIDS without highly active antiretroviral therapy (HAART) is 48% by 16 months and 83% at 31 months.

• Concomitant OHL and hepatitis B viral (HBV) infection increases the risk of early progression to AIDS 4-fold.

• Median survival time after OHL diagnosis is 20 months. In patients with CD4 count greater than or equal to 300/mL, OHL was associated with median survival time of 25 months, compared to 52 months in unaffected patients.

Race: No racial predilection has been established.

Sex: OHL is observed more commonly in homosexual men who are HIV positive. In one study, OHL was observed in 6.1% of women who were HIV positive.

Age: No age predilection has been established.

CLINICAL

History: Patients may complain of nonpainful white plaque along the lateral tongue borders. The appearance may change daily.

Physical:

• OHL appears as a nonpainful white plaque along the lateral tongue borders. Accentuation of vertical folds with white irregularly thickened mucosa is evident.

• Despite the name, a "hairy" appearance is less common.

• In unusual cases, disease may spread to contiguous sites such as the mouth floor, tonsillar pillars, ventral tongue, and pharynx.

• OHL changes in appearance daily.

Causes:

• OHL has been associated with HIV infection and is a sign of AIDS. More recently, it has been described in patients with other forms of severe immunodeficiency including those associated with chemotherapy, organ transplant, and leukemia. Rarely, it may occur in patients who are immunocompetent.

• OHL has been described in association with Behçet syndrome and ulcerative colitis.

• Smoking more than a pack of cigarettes a day is correlated positively with development of OHL in men who are HIV positive.

• The risk of developing OHL doubles with each 300-unit decrease in CD4 count.

• No increase in OHL was observed when controlled for number of oral sex partners.

DIFFERENTIALS

Candidiasis
Condyloma Acuminatum
Syphilis

Other Problems to be Considered:

Frictional keratosis
Squamous cell carcinoma
Geographic tongue
Lichen planus
Tobacco-associated leukoplakia
Human papillomavirus (HPV)–induced neoplasia
Condyloma acuminatum
Syphilitic mucous patch

White oral lesions resembling OHL have been observed in patients negative for both HIV and EBV. Yeast and bacteria may be present but do not contribute to the process. Candida (thrush) is common in immunodeficient persons, is not adherent, is more generalized, and may be painful. Frictional keratosis (from rubbing upon poorly fitting dental work or jagged teeth) may appear similar but is usually unilateral.

WORKUP

Lab Studies:

• Diagnosis is usually made clinically.

• Previously, definitive diagnosis required demonstration of lesional EBV, but EBV prevalence in mucosal scrapings from individuals who are HIV positive is the same regardless of whether they are affected with OHL.

• A relatively easy method of generating nucleic acid probes by polymerase chain reaction (PCR) for detection of EBV-DNA by in situ hybridization has been described.

Procedures:

• Biopsy may be useful for exclusion of other entities such as dysplasia and hyperplasia.

Histologic Findings: The mucosal epithelium is acanthotic and hyperkeratotic, with occasional parakeratosis. Vacuolated keratinocytes are evident in the spinous layer only, a key to histopathologic diagnosis. Cowdry type A nuclear inclusions may be observed in vacuolated cells.

Electron microscopy demonstrated 100-nm intranuclear virions and 240-nm encapsulated virus particles.

TREATMENT

Medical Care:

• OHL is rarely treated specifically.

• Appropriate treatment for HIV and AIDS is most effective.

• Painful superinfection with Candida can be addressed with medical therapy.

Consultations: Consultations with dermatologists or infectious disease specialists may be in order depending upon the underlying disease process resulting in OHL.

Diet: Diet may be as tolerated.

MEDICATION

OHL is rarely treated. Painful superinfection with Candida can be addressed with nystatin and other antifungals. Recurrence is frequent and requires periodic retreatment. Symptomatic patients have been treated with podophyllum resin. Acyclovir, valacyclovir, famciclovir, ganciclovir, or foscarnet are often effective therapies for EBV and, therefore, OHL. Institution of HAART, now standard care in the United States, is also useful. See Early Symptomatic HIV Infection and Acquired Immunodeficiency Syndrome (AIDS).

Drug Category: Antifungals -- These agents reduce Candida superinfection.

Drug Name	Nystatin (Nilstat, Mycostatin, Nystex) -- Fungicidal and fungistatic antibiotic obtained from Streptomyces noursei; effective against various yeasts and yeastlike fungi. Changes permeability of fungal cell membrane after binding to cell membrane sterols, causing cellular contents to leak. Treatment should continue until 48 h after disappearance of symptoms. Drug is not absorbed significantly from GI tract.
Adult Dose	200,000 U lozenges; 1-2 lozenges, 4-5 times daily
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Do not use to treat systemic mycoses

Drug Category: Antiviral agents -- Nucleoside analogs initially are phosphorylated by viral thymidine kinase to eventually form a nucleoside triphosphate.

Drug Name	Podophyllum resin (Pod-Ben-25, Podofin, Podocon-25) -- Arrests mitosis in metaphase; active agent is podophyllotoxin; type of podophyllum resin used determines strength. American podophyllum contains one fourth the amount of Indian source. Used in symptomatic OHL.
Adult Dose	Apply 25% liquid for 20 min
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; diabetes; impaired peripheral circulation; avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair
Interactions	None reported
Pregnancy	X - Contraindicated in pregnancy
Precautions	Powerful caustic and severe irritant; do not use if surrounding tissue swollen or irritated; 25% solution should not be applied near mucous membranes; do not use large amounts; avoid contact with cornea; avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair

Drug Name	Acyclovir (Zovirax) -- Has affinity for viral thymidine kinase and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. Patients experience less pain and faster resolution of lesions when used within 48 h from onset of outbreak. May prevent recurrent outbreaks. Early initiation of therapy is imperative.
Adult Dose	400 mg PO bid/qid
Pediatric Dose	20-40 mg/kg bid
Contraindications	Documented hypersensitivity
Interactions	Probenecid or zidovudine prolongs half-life and increases CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or when using nephrotoxic drugs

Drug Name	Valacyclovir (Valtrex) -- Prodrug rapidly converted to active drug acyclovir. More expensive but has more convenient dosing regimen than acyclovir.
Adult Dose	1 g/d PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid, zidovudine, or cimetidine prolongs half-life and increases CNS toxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure and coadministration of nephrotoxic drugs; associated with onset of hemolytic uremic syndrome

Drug Name	Famciclovir (Famvir) -- Pro-drug that when biotransformed into active metabolite, penciclovir, may inhibit viral DNA synthesis/replication.
Adult Dose	500 mg/d PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid or cimetidine may increase toxicity; increases bioavailability of digoxin
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal failure or coadministration of nephrotoxic drugs

Drug Name	Ganciclovir (Cytovene, Vitrasert) -- Indication is for CMV retinitis and prevention of CMV infection in individuals who are HIV positive.
Adult Dose	1000 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Cytotoxic drugs such as dapsone, vinblastine, doxorubicin, pentamidine, flucytosine, vincristine, amphotericin B, trimethoprim/sulfamethoxazole combinations, or other nucleoside analogs may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); imipenem-cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); cyclosporine or amphotericin B may increase serum creatinine; probenecid reduces renal clearance; administration of didanosine either 2 h prior to or simultaneously may increase bioavailability; zidovudine may decrease bioavailability, while ganciclovir increases bioavailability of zidovudine
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; since oral ganciclovir associated with higher rate of CMV retinitis progression than IV formulation, use only when benefits outweigh risks (advanced HIV disease); half-life and plasma/serum concentrations may be increased as result of reduced renal clearance; dosages >6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (11); phlebitis or pain may occur at site of IV infusion despite further dilution in IV fluids; administration should be accompanied by adequate hydration; photosensitization (photoallergy or phototoxicity) may occur

Drug Name	Foscarnet (Foscavir) -- Indicated only for acyclovir-resistant mucocutaneous herpes simplex virus, which occurs almost exclusively in individuals who are HIV positive.
Adult Dose	40 mg/kg IV tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) may increase nephrotoxicity (do not administer unless potential benefits outweigh risks); IV pentamidine may cause hypocalcemia
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause decline in renal function; for correct dosing, obtain 24-h serum creatinine at baseline and continue to monitor (discontinue if serum creatinine less than 0.4 mL/min/kg); hydration may reduce nephrotoxicity Carefully monitor electrolytes (eg, calcium, magnesium); assess for electrolyte and mineral level abnormalities if mild perioral numbness, paresthesia symptoms, or seizures; granulocytopenia and anemia may occur (regularly monitor CBC) Infuse foscarnet solutions into veins with adequate blood flow to avoid local irritation; to avoid toxicity do not administer by rapid or bolus IV injection

FOLLOW-UP

Complications:

• Use of alcohol and tobacco in patients with OHL contributes to formation of squamous cell carcinomas in these patients.

• Immunosuppression is a risk factor for oral cancer.

Prognosis:

• Median CD4 count when OHL is first detected is 468/mL. In persons without AIDS-defining disease, the probability of developing AIDS without HAART is 48% by 16 months and 83% at 31 months.

• Concomitant OHL and hepatitis B viral (HBV) infection increases the risk of early progression to AIDS 4-fold.

• Median survival time after OHL diagnosis is 20 months. In patients with CD4 count greater than or equal to 300/mL, OHL was associated with median survival time of 25 months, compared to 52 months in unaffected patients.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Any patient presenting with OHL who does not carry a diagnosis of HIV infection or AIDS should have a thorough workup to evaluate for HIV infection or immunosuppression.