Oral Hairy Leukoplakia in Immunocompetent Patients Revisited with Literature Review.

Oral hairy leukoplakia (OHL) is an Epstein-Barr virus (EBV) related lesion seen in severely immunocompromised patients especially, those with concomitant human immunodeficiency virus (HIV) infection. It has been rarely reported in immunocompetent patients. OHL most often presents on the lateral border of the tongue as an asymptomatic, white, and corrugated plaque that does not rub off. With Institutional Review Board (IRB) approval, the University of Florida Oral & Maxillofacial Pathology Biopsy Service archives spanning 1994-2020 were queried. All cases of OHL affecting immunocompetent patients were identified. Data related to age, gender, clinical presentation, results of Epstein-Barr virus in situ hybridization (EBER-ISH), and periodic acid-Schiff (PAS)-fungus stains were recorded. Medical history and histology of all cases were reviewed for confirmation of diagnosis. A total of 11 cases were identified, the majority of which were males (63.6%) with a mean age of 62 years. All patients were Caucasian. Lesions entirely were located on the lateral borders of the tongue. OHL should not be considered pathognomonic for HIV infection and should be included in the differential diagnoses of keratotic lesions affecting the lateral border of tongue even in immunocompetent elderly patients. The etiology of OHL in this group of patients is not clearly understood.

Considerations in the diagnosis of oral hairy leukoplakia-an institutional experience.

OBJECTIVE: We report here the 10-year experience with oral hairy leukoplakia (OHL) at the Division of Oral and Maxillofacial Pathology at the University of North Carolina at Chapel Hill, NC, USA. STUDY DESIGN: All the associated hematoxylin and eosin and Epstein-Barr virus encoding region in situ hybridization slides of OHL cases between January 1, 2008, and February 1, 2017, were retrieved and reviewed. Collected demographic characteristics, clinical presentation, medical and social histories were reviewed and reported. RESULTS: Six OHL cases with confirmed in situ hybridization showed predilection for the lateral tongue. The study included 3 females and 3 males (mean age 50.5 years; age range 29-70 years). One patient had known HIV-positive status before biopsy was performed. Three patients had reported a history of heavy smoking. Other medical conditions reported were history of breast cancer, a long history of corticosteroid inhaler use for asthma treatment, high cholesterol, diabetes, and hypertension. CONCLUSIONS: The findings of this study indicate the need to include OHL as a potential entity in the differential diagnosis of leukoplakic tongue lesions, regardless of the patient's HIV status. In addition, the presence of OHL in the patient requires investigation of various explanations for EBV infection, including immunosuppression caused by HIV infection or chronic steroid use.

Oral lesions as an important marker for HIV progression.

BACKGROUND: Oral hairy leukoplakia (OHL) is a benign lesion caused by Epstein-Barr virus (EBV) replication in the oral epithelium affecting the borders of the tongue. It is strongly associated with immunosuppression, especially in HIV+ adults but is uncommon in pediatric population. The aim of the study is to show the importance of the correct diagnosis of OHL and its influence on HIV treatment.We report two cases of HIV+ adolescent patients that presented with leukoplakic lesions on the border of the tongue, suggestive of OHL. OHL diagnosis was confirmed in only one case through EBV in situ hybridization. After confirmation of the diagnosis, the patient with OHL was referred to an infectious disease specialist with the decision to start antiretroviral therapy. CONCLUSION: OHL definitive diagnosis can help clinical management of pediatric HIV+ patients.

Hairy leukoplakia; lessons learned: 30-plus years.

Well into the fourth decade of the HIV/AIDS pandemic, we can look back on the early years, the initial discoveries, and the broad sweep of the progress of our understanding of the nature, causes, and significance of the oral lesions seen in those infected with the virus. Prominent among these is oral hairy leukoplakia (HL), a previously unknown lesion of the mouth associated with Epstein-Barr virus (EBV) and initially seen only in people with AIDS, in the then-recognized risk groups, or those shown to be HIV positive. Subsequently, it became clear that the distribution of HL extends well beyond the HIV spectrum. In this brief review, we consider the clinical and histological features of HL, discuss how it was discovered, explore its cause, diagnosis, relationship with AIDS, pathogenesis, significance in EBV biology, options for management, and how it changes with HIV/AIDS therapy.

Oral hairy leukoplakia in an HIV-negative patient.

We report the case of a 31-year-old woman with systemic lupus erythematosus who was found to have oral hairy leukoplakia (OHL). She was on immunosuppressive therapy but was human immunodeficiency virus (HIV)-negative. OHL has been previously reported in HIV-negative patients who were immunosuppressed for other reasons, such as solid organ or hematopoietic stem cell transplantation, hematologic malignancies, or systemic diseases. To the best of our knowledge, this is the first case of OHL in an HIV-negative patient reported in the otolaryngology literature. It adds to the growing list of cases of OHL in HIV-negative patients and serves as a reminder to physicians to include OHL in the differential diagnosis for oral cavity lesions in all immunosuppressed patients. The article also summarizes the current state of knowledge about the pathogenesis of OHL, its relation to the Epstein-Barr virus, and the treatment options.

The advantages of oral cytopathology in the early diagnosis of HIV/AIDS: three case reports.

Oral lesions are common in human immunodeficiency virus (HIV)-infected patients, which may indicate impairment of the patient's general health status, and, in many cases, the oral lesions are the first sign of an HIV infection. Oral hairy leukoplakia (OHL) is a benign lesion of the oral mucosa related to Epstein-Barr virus (EBV) observed in HIV-positive individuals. The aim of this study was to report the contribution of oral cytopathology in the investigation of the HIV/AIDS status of patients as well as in the clinical and subclinical identification of OHL. Three patients were referred to the Oral Medicine Clinic in 2010. The patients were submitted to oral examination, and scrapes of the tongue were obtained. The Papanicolaou staining technique was used, and cytopathological analysis showed nuclear changes corresponding to cytopathic effects of EBV epithelial infection and candidiasis. The final diagnosis was OHL and candidiasis. Based on cytopathological diagnosis, an HIV serologic test was requested which revealed positive HIV serology. None of the patients was aware of their HIV serological status, and thus the cytopathology, by identifying OHL, contributed to the early diagnosis of HIV/AIDS. Cytopathology should be used as a routine procedure and it may be the method of choice for clinical and subclinical OHL diagnosis.

Depletion of Langerhans cells in the tongue from patients with advanced-stage acquired immune deficiency syndrome: relation to opportunistic infections.

AIMS: To quantify and compare the expression of Langerhans cells (LCs) in the tongue mucosa of AIDS patients with different opportunistic infections, and from acquired immune deficiency syndrome (AIDS) and non-AIDS patients with normal tongues, using autopsy material. METHODS AND RESULTS: Human leucocyte antigen D-related (HLA-DR), CD1a and CD83 antibodies were used to identify and quantify LCs by immunohistochemistry in tongue tissue of 40 AIDS patients (10 with lingual candidiasis, 10 with lingual herpes, 10 with oral hairy leukoplakia and 10 with no lesions) and 23 tongues from human immunodeficiency virus (HIV)-negative control patients. Quantification was performed by means of conventional morphometry in four different regions (anterior, middle, posterior and lateral) of the tongue. The results were expressed as positive cells per area of epithelium. The AIDS patients presented a lower density of CD1a(+) cells (P < 0.001), HLA-DR (P < 0.003) and CD83 (P < 0.001) in all regions of the tongue compared to the non-AIDS control group. However, no differences in any of the markers were found when AIDS patients with different opportunistic infections were compared with AIDS patients without tongue infection. CONCLUSIONS: Advanced stage AIDS patients showed a depletion of LCs in the tongue mucosa. HIV infection induces cytopathic changes in LCs, contributing to their depletion regardless of the presence of oral infections.

Iatrogenic oral hairy leukoplakia: report of two cases.

Oral hairy leukoplakia (OHL) presents as a white, plaque-like lesion typically occurring on the lateral border of the tongue. This condition is caused by the Epstein-Barr virus, a human herpesvirus that often establishes lifelong, asymptomatic latent infection. OHL, initially described in immunocompromised men infected with the human immunodeficiency virus (HIV), has also been described in other severely immunocompromised patients. Only rarely has OHL been reported in less profoundly immunocompromised patients primarily in the setting of corticosteroid therapy. Here we report on two additional cases of OHL attributable to immunosuppressive medications.

Oral hairy leukoplakia in HIV-negative patients: report of 10 cases.

Ten cases of oral hairy leukoplakia (OHL) in HIV- negative patients are presented. Eight of the 10 patients were on steroid treatment for chronic obstructive pulmonary disease, 1 patient was on prednisone as part of a therapeutic regimen for gastrointestinal stromal tumor, and 1 patient did not have any history of immunosuppression. There were 5 men and 5 women, ages 32-79, with mean age being 61.8 years. Nine out of 10 lesions were located unilaterally on the tongue, whereas 1 lesion was located at the junction of the hard and soft palate. All lesions were described as painless, corrugated, nonremovable white plaques (leukoplakias). Histologic features were consistent with Epstein-Barr virus-associated hyperkeratosis suggestive of OHL, and confirmatory in situ hybridization was performed in all cases. Candida hyphae and spores were present in 8 cases. Pathologists should be aware of OHL presenting not only in HIV-positive and HIV-negative organ transplant recipients but also in patients receiving steroid treatment, and more important, certain histologic features should raise suspicion for such diagnosis without prior knowledge of immunosuppression.

[Leukoplakia and erythroplakia--two orale precursor lesions]. / Leukoplakie und Erythroplakie--Zwei orale Präkursorläsionen.

The oral leukoplakia/erythroplakia is one of the most common epithelial precursor lesions of the oral squamous cell carcinoma. A clinical distinction is drawn between homogeneous and non-homogeneous as well as proliferative verrucous leukoplakia and erythroplakia. Due to the fact that the oral squamous cell carcinoma has a poor prognosis it is very important to decrease morbidity and mortality by systematic primary, secondary and tertiary prevention of the oral leukoplakia/erythroplakia. On the basis of histological classification systems the risk of malignant transformation can be evaluated, a defined therapy can be induced and the prognosis can be derived.

Targeted therapy of oral hairy leukoplakia with gentian violet.

Oral hairy leukoplakia (OHL) is a common oral manifestation of HIV infection. Clinically, these lesions appear as white plaques on the edges of the tongue. Pathophysiologically, these lesions occur because of infection of oral epithelium with Epstein-Barr virus (EBV). No universally effective therapy exists for OHL. We have previously shown that EBV infection and EBV viral products induce the generation of reactive oxygen. We have also demonstrated that the Food and Drug Administration-approved over-the-counter medication gentian violet is a potent inhibitor of reactive oxygen species. We thus chose to treat a patient with biopsy-proven OHL with topical gentian violet. Gentian violet solution was applied topically to the tongue of a patient with OHL. Complete clinical resolution was noted after three treatments. Treatment with topical gentian violet resulted in resolution of the lesions. Further studies with larger numbers of patients are required. The application of gentian violet can be used as a method to OHL treatment. Gentian violet is an inexpensive and safe therapy and, given that it inhibits reactive oxygen, this old therapy is now a targeted novel therapy.

Prevalence of oral hairy leukoplakia and epithelial infection by Epstein-Barr virus in pregnant women and diabetes mellitus patients--cytopathologic and molecular study.

Oral hairy leukoplakia (OHL) is generally reported in patients with severe immunosuppression, except for a few cases in individuals with moderate degree of immunodeficiency. It is a white lesion that appears mainly in the lateral border of the tongue, caused by Epstein-Barr virus (EBV). The nuclear changes caused by EBV (Cowdry A inclusion, ground glass and nuclear beading), observed in cytopathology, are specific and enough for the definitive diagnosis of OHL, independent of the identification of the virus. Here we investigated the prevalence of OHL and the presence of EBV-DNA in the lateral borders of the tongue from 90 pregnant women, 90 diabetes mellitus (DM) patients, 30 healthy individuals (negative group) and 30 HIV+ with OHL (positive group). Smears were analyzed by cytopathology and polymerase chain reaction (PCR). A case of subclinical OHL and candidiasis was identificated in a DM patient by cytopathologic analysis. PCR results demonstrated EBV-DNA in 65% of the pregnant women, in 35% of DM patients, and in 20% of the healthy individuals. We concluded that DM patients can develop OHL with a low prevalence. Furthermore, the prevalence of the EBV in lateral border of the tongue is larger in pregnant women than in healthy individuals.

Prevalence of oral hairy leukoplakia and epithelial infection by Epstein-Barr virus in pregnant women and diabetes mellitus patients: cytopathologic and molecular study

Oral hairy leukoplakia (OHL) is generally reported in patients with severe immunosuppression, except for a few cases in individuals with moderate degree of immunodeficiency. It is a white lesion that appears mainly in the lateral border of the tongue, caused by Epstein-Barr virus (EBV). The nuclear changes caused by EBV (Cowdry A inclusion, ground glass and nuclear beading), observed in cytopathology, are specific and enough for the definitive diagnosis of OHL, independent of the identification of the virus. Here we investigated the prevalence of OHL and the presence of EBV-DNA in the lateral borders of the tongue from 90 pregnant women, 90 diabetes mellitus (DM) patients, 30 healthy individuals (negative group) and 30 HIV+ with OHL (positive group). Smears were analyzed by cytopathology and polymerase chain reaction (PCR). A case of subclinical OHL and candidiasis was identificated in a DM patient by cytopathologic analysis. PCR results demonstrated EBV-DNA in 65 percent of the pregnant women, in 35 percent of DM patients, and in 20 percent of the healthy individuals. We concluded that DM patients can develop OHL with a low prevalence. Furthermore, the prevalence of the EBV in lateral border of the tongue is larger in pregnant women than in healthy individuals.

Prevalence of oral hairy leukoplakia in 120 pediatric patients infected with HIV-1.

Oral hairy leukoplakia (OHL) is an EBV (Epstein-Barr virus) opportunistic infection found in HIV-infected patients. It is an asymptomatic lesion that has an important prognostic value in AIDS. Differently from what takes place with HIV adult patients, OHL has been described in the literature as having a very small prevalence in pediatric patients. Therefore, the aim of this study was to investigate the prevalence of OHL in HIV pediatric patients using cytopathology. The sample consisted of 120 patients who were submitted to oral examination and had material scraped from both sides of their tongues. The diagnostic criterion was based on the identification of nuclear alterations. Clinical OHL was identified in two (1.67%) patients. The cytopathology revealed twenty (16.7%) cases of subclinical OHL. Our results show that in pediatric patients the prevalence of OHL may be larger than that described in the literature.

Prevalence of oral hairy leukoplakia in 120 pediatric patients infected with HIV-1

A leucoplasia pilosa oral (OHL) é uma infecção oportunista causada pelo Vírus Epstein-Barr (EBV) encontrada em pacientes infectados pelo HIV. É uma lesão assintomática que tem um importante valor prognóstico na AIDS. Diferentemente de pacientes adultos, a OHL tem sido descrita na literatura como tendo uma prevalência muito pequena em pacientes pediátricos. Logo, o objetivo deste estudo foi investigar a prevalência da OHL em pacientes pediátricos positivos para o HIV através do uso da citopatologia. A amostra consistiu-se de 120 pacientes, que foram submetidos a exame oral e coleta de material de ambos os lados da língua. O critério diagnóstico foi baseado na identificação de alterações nucleares. A OHL clínica foi identificada em dois (1,67%) pacientes. A citopatologia revelou vinte casos (16,7%) de OHL subclínica. Nossos resultados mostram que a prevalência de OHL em pacientes pediátricos infectados pelo HIV deve ser maior que a relatada na literatura.

Interferon regulatory factor 7 is negatively regulated by the Epstein-Barr virus immediate-early gene, BZLF-1.

Virus infection stimulates potent antiviral responses; specifically, Epstein-Barr virus (EBV) infection induces and activates interferon regulatory factor 7 (IRF-7), which is essential for production of alpha/beta interferons (IFN-alpha/beta) and upregulates expression of Tap-2. Here we present evidence that during cytolytic viral replication the immediate-early EBV protein BZLF-1 counteracts effects of IRF-7 that are central to host antiviral responses. We initiated these studies by examining IRF-7 protein expression in vivo in lesions of hairy leukoplakia (HLP) in which there is abundant EBV replication but the expected inflammatory infiltrate is absent. This absence might predict that factors involved in the antiviral response are absent or inactive. First, we detected significant levels of IRF-7 in the nucleus, as well as in the cytoplasm, of cells in HLP lesions. IRF-7 activity in cell lines during cytolytic viral replication was examined by assay of the IRF-7-responsive promoters, IFN-alpha4, IFN-beta, and Tap-2, as well as of an IFN-stimulated response element (ISRE)-containing reporter construct. These reporter constructs showed consistent reduction of activity during lytic replication. Both endogenous and transiently expressed IRF-7 and EBV BZLF-1 proteins physically associate in cell culture, although BZLF-1 had no effect on the nuclear localization of IRF-7. However, IRF-7-dependent activity of the IFN-alpha4, IFN-beta, and Tap-2 promoters, as well as an ISRE promoter construct, was inhibited by BZLF-1. This inhibition occurred in the absence of other EBV proteins and was independent of IFN signaling. Expression of BZLF-1 also inhibited activation of IRF-7 by double-stranded RNA, as well as the activity of a constitutively active mutant form of IRF-7. Negative regulation of IRF-7 by BZLF-1 required the activation domain but not the DNA-binding domain of BZLF-1. Thus, EBV may subvert cellular antiviral responses and immune detection by blocking the activation of IFN-alpha4, IFN-beta, and Tap-2 by IRF-7 through the medium of BZLF-1 as a negative regulator.