Hairy Leukoplakia

Oral hairy leukoplakia (OHL; see the image below) is a disease of the mucosa that is associated with Epstein-Barr virus (EBV) and occurs mostly in people with HIV infection, including those without a diagnosis of AIDS. HIV-negative people can have OHL as well, especially those with organ transplants and other immunocompromised disease. The first case in an HIV-negative patient was reported in 1999 in a 56-year-old patient with acute lymphocytic leukemia; later, many cases were reported in heart, kidney, and bone marrow transplant recipients and in patients with hematologic malignancies. OHL has also been reported in individuals who are not immunocompromised.

Lateral tongue in oral hairy leukoplakia.

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OHL is a benign lesion with low morbidity and thus does not require specific treatment in every case. Treatment may be indicated to address symptoms attributable to the lesion or to accommodate a patient's desire to eliminate the lesion for cosmetic reasons. Available treatment options include antiviral therapy, topical therapy (podophyllin or retinoic acid), and ablative therapy. (See Treatment.)

EBV, a ubiquitous herpesvirus estimated to infect 90% of the world's population, is linked to a growing number of diseases, especially in immunocompromised hosts. Like all herpesviruses, EBV establishes a lifelong persistent infection. The pathogenesis of hairy leukoplakia is clearly complex, potentially requiring a convergence of multiple factors (eg, EBV coinfection, productive EBV replication, EBV genetic evolution, expression of specific "latent" EBV genes, and immune escape). All of these factors are likely facilitated by local and systemic host immunodeficiency.

EBV initially infects basal epithelial cells in the pharynx, where it enters a replicative state leading to the release of infectious virus into the saliva throughout the life of the infected person. In the pharynx, the virus also enters B cells, where it persists indefinitely in a latent state. Cytotoxic T lymphocytes cannot eliminate EBV from the body, but they are essential in maintaining the latent state of the infection. In states of immune dysfunction where the number of EBV-specific cytotoxic T lymphocytes is decreased, the number of circulating EBV-infected B cells increases.

In addition, a marked decrease or an absence of Langerhans cells may be observed in hairy leukoplakia biopsy specimens. Langerhans cells are the antigen-presenting immune cells that are required for an immune system response to the viral infection, and a deficiency of these cells may permit EBV to replicate persistently and escape immune recognition.

OHL is associated with HIV infection and/or immunosuppression. The risk of developing oral hairy leukoplakia doubles with each 300-unit decrease in the CD4⁺ count. In a study by Bravo et al, a high viral load was strongly associated with the occurrence of oral lesions in HIV patients, independently of the CD4⁺ cell count. Subsequently, this was described in patients with other forms of severe immunodeficiency including those associated with chemotherapy, organ transplant, and leukemia.

OHL also is associated with Behçet syndrome and ulcerative colitis.

Smoking more than one pack of cigarettes a day is positively correlated with the development of OHL in HIV-positive men. No increase in OHL was observed when the number of oral sex partners was controlled for.

OHL may not be the traditional lesion reported only in HIV-positive individuals and other immunosuppressed individuals. A growing number of reports of OHL in other populations are being published. In a small case series from Bristol Dental Hospital, four cases were reported in immunocompetent individuals over a 6-month period. All lesions were on the tongue and tested positive for EBV. The authors concluded that the diagnosis of OHL should not be limited to HIV-positive individuals or to those with immunosuppression.

Alramadhan et al investigated an oral and maxillary pathology archive spanning the period 1994-2020 to look for cases of OHL occurring in immunocompetent individuals. Eleven cases were found, all positive for EBV. Of these, 63.6% were males (mean age, 62 y), and all were White. All lesions were located on the lateral borders of the tongue. The etiology of OHL in this group of patients was not clear. The authors concluded that OHL should not be considered pathognomonic for HIV infection and should be included in the differential diagnosis of other keratotic lesions, especially in elderly individuals.

OHL has been found in solid-organ transplant recipients on immunosuppressive therapy and in individuals with hematologic malignancies, autoimmune diseases, and other systemic inflammatory conditions, as well as in immunocompetent individuals. Long-term inhaled topical and systemic steroid therapy has been identified as a risk factor in the development of OHL. Hypogammaglobulinemia secondary to long-term anticonvulsant treatment with lamotrigine has also been associated with OHL.

In a study (N = 35; 25 male, 10 female; average age, 61 y [range, 33-86]) investigating non-HIV-associated OHL, 28 patients had respiratory problems requiring long-term steroid inhaler use, four had autoimmune diseases requiring immunosuppressant therapy, and four had diabetes. Most of the patients (34/35) had lesions located on the tongue, where the lateral border was the most common site. (See the image below.) Candida coinfection was present in 24 cases.

Oral hairy leukoplakia (OHL) on left lateral tongue in patient who used topical steroid inhaler.

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The authors concluded that the presence of OHL should not be regarded as pathognomonic of HIV infection or significant systemic immunosuppression and that local and systemic immunosuppression caused by steroid inhaler use is a risk factor for the development of OHL.

Ahmed et al reported a case in which OHL developed in an HIV-negative man during baricitinib therapy for alopecia, though they noted the possibility that that the two events might have been occurring independently.

US and international statistics

In the United States, OHL is one of the most common virally induced, oral diseases of HIV-infected individuals, with a point prevalence as high as 25-53%. The 6-year incidence of OHL in this patient population has been reported to be around 32%. A significant trend to a lower prevalence of OHL has been observed since the introduction of highly active antiretroviral therapy (HAART).

Fewer cases of OHL have been reported in non-HIV-infected patients. This is probably due to underdiagnosis and underreporting of this disease in patients with hematologic malignancies and recipients of solid-organ transplants. Some studies have found the prevalence of OHL in renal transplant recipients to be greater than 11%.

Internationally, the incidence of OHL is similar to that in the United States and thereby reflects the prevalence of HIV. In populations where the prevalence of HIV is low, oral mucosal lesions alone are poor prognostic predictors of HIV infection.

In a study from Mexico that examined a selected cohort (N = 1000) of patients with HIV infection, the clinical spectrum of HIV-related oral lesions changed significantly over a period of 12 years, with most oral lesions decreasing in prevalence. The authors suggested that these findings probably reflected improved medical care of HIV-infected persons, earlier detection of HIV infection in the clinical setting, greater use of drugs to prevent secondary AIDS-related opportunistic infections, and wider availability of potent antiretroviral therapy since the introduction of HAART.

A cross-sectional study (N = 300; 51% male, 49% female; mean age, 40 y) from Brazil reported on data collected from clinical examinations, interviews, and medical records for adult patients treated an HIV/AIDS clinic at the University Hospital of the Federal University in Rio Grande. Oral lesions were present in 39% of patients at presentation. In these 39%, the most common oral lesion was candidiasis (59.1%), followed by hairy leukoplakia (19.5%).

A cross-sectional study from Ethiopia that assessed 384 consecutive HIV patients (32.8% male, 67.2% female; mean age, 35.4 y [range, 14-84]) before initiation of antiviral treatment reported a 64.3% overall prevalence of oral lesions, of which the most common were pseudomembraneous candidiasis (20.1%), linear gingival erythema (11.7%), and erythematous candidiasis (9.1%).

A study from Saudi Arabia (N = 596) in which renal transplant recipients (n = 300) were compared with age and sex-matched healthy control subjects (n = 296) found that the prevalence of oral lesions in transplant recipients was 56.8%, compared with 29.7% in control subjects. Gingival overgrowth (21.8%) was the most commonly observed lesion in transplant recipients, followed by candidiasis (17.1%). Leukoplakia was observed in 11.3% of control subjects.

A study from Spain reported only one case of hairy leukoplakia in 500 renal transplant recipients studied.

When associated with HIV infection, hairy leukoplakia is more common in Europe and the United States than in Africa and Asia.

Age-, sex-, and race-related demographics

OHL has not been shown to have any age predilection.

The condition is most frequently observed in homosexual men who are HIV-positive, especially those who smoke.

OHL has not been considered to have any racial predilection. However, one single-center study (N = 4679) found Black patients with HIV infection to be at higher risk for OHL than either race-matched control subjects or White patients with HIV infection.

Most patients with OHL have significant immunosuppression at the time of diagnosis. The median CD4 count at the time of first detection of OHL has been reported to range from 235 to 468/µL. One retrospective analysis showed that OHL occurred mostly in patients with CD4 counts in the range of of 200-500/µL.

In patients with HIV, the median CD4 count when OHL is first detected is 468/µL. OHL occurs relatively soon after HIV seroconversion, typically before the development of AIDS. If patients do not have AIDS-defining disease at the time when OHL is diagnosed, the probability of developing AIDS if they do not receive HAART is 48% by 16 months and 83% at 31 months. In addition, studies have shown that AIDS patients who have OHL have a shorter lifespan than those who do not present with this lesion. Furthermore, if these patients are concomitantly coinfected with hepatitis B virus, the risk of early progression to AIDS increases by a factor of 4.

Additional studies in HIV-seropositive patients have shown that median survival after the diagnosis of oral hairy leukoplakia is approximately 20 months. In patients CD4 counts of 300/μL or greater, OHL is associated with a median survival of 25 months, compared with 52 months in patients with normal counts.