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.

Detection of Epstein-Barr virus DNA in saliva of HIV-1-infected individuals with oral hairy leukoplakia.

We present three cases of oral hairy leukoplakia (OHL) in whom the diagnosis was established by EBV DNA detection in whole saliva. Three HIV-infected patients came to the Oral Medicine Clinic with similar chief complaints of asymptomatic white lesions on the tongue. All patients were diagnosed with suspected OHL and oral thrush also in the first patient. A multiplex PCR DNA microarray was performed to detect EBV DNA in saliva collected by spitting method. All saliva samples showed positive results for EBV DNA, and the definitive diagnosis of OHL was made. Resolution of lesions was found at 1- to 2-month follow-up after treatment with application of acyclovir 5% cream 5 times daily. Additionally, anti-fungal treatment was given to the first patient and anti-retroviral treatment to the first and second patients. EBV is mostly transmitted by asymptomatic shedding into saliva. Therefore, the detection of salivary EBV DNA is useful in establishing a definitive diagnosis of OHL allowing more effective treatment for both HIV-infected patients receiving ART and treatment-naïve patients at any CD4 + count.

Oral hairy leukoplakia in healthy immunocompetent patients: a small case series.

BACKGROUND: Oral hairy leukoplakia (OHL) is caused by the Epstein-Barr virus (EBV) and usually presents in patients with human immunodeficiency virus (HIV) infection and systemic immunosuppression. It is rarely seen in patients who are immunocompetent. It is clinically characterised as an asymptomatic, soft, white and corrugated lesion that cannot be scraped from the surface it adheres to. METHODS: Immunocompetent patients with OHL attending Bristol Dental Hospital within the last 6 months were identified. EBV infection was demonstrated using EBV in situ hybridization. Clinical features and medical history were determined by reviewing medical records. CASE REPORT: Four cases of OHL in immunocompetent individuals were identified. All lesions were located on the lateral borders of the tongue. DISCUSSION: OHL should be considered as a differential diagnosis for white patches on the lateral borders of the tongue in apparently healthy immunocompetent patients, even when they do not have a typical corrugated appearance. OHL should no longer be regarded as pathognomonic for HIV infection or systemic immunosuppression.

Epstein-Barr virus in the pathogenesis of oral cancers.

Epstein-Barr virus (EBV) is a ubiquitous gamma-herpesvirus that establishes a lifelong persistent infection in the oral cavity and is intermittently shed in the saliva. EBV exhibits a biphasic life cycle, supported by its dual tropism for B lymphocytes and epithelial cells, which allows the virus to be transmitted within oral lymphoid tissues. While infection is often benign, EBV is associated with a number of lymphomas and carcinomas that arise in the oral cavity and at other anatomical sites. Incomplete association of EBV in cancer has questioned if EBV is merely a passenger or a driver of the tumorigenic process. However, the ability of EBV to immortalize B cells and its prevalence in a subset of cancers has implicated EBV as a carcinogenic cofactor in cellular contexts where the viral life cycle is altered. In many cases, EBV likely acts as an agent of tumor progression rather than tumor initiation, conferring malignant phenotypes observed in EBV-positive cancers. Given that the oral cavity serves as the main site of EBV residence and transmission, here we review the prevalence of EBV in oral malignancies and the mechanisms by which EBV acts as an agent of tumor progression.

Oral hairy leukoplakia arising in a patient with hairy cell leukaemia: the first reported case.

Oral hairy leukoplakia (OHL) is an oral mucosal lesion that is associated with Epstein-Barr virus infection. It commonly presents as an asymptomatic, non-removable white patch on the lateral borders of the tongue in individuals who are immunocompromised. Historically, OHL was thought to be pathognomonic of HIV infection; however, it is now an established phenomenon in a range of conditions affecting immune competence. Hairy cell leukaemia (HCL) is a rare chronic B cell lymphoproliferative disease named after the distinctive cytology of the atypical cells. We report the first case of OHL arising in an individual with HCL that resolved following remission of the haematological malignancy.

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.

Twenty-first-century oral hairy leukoplakia--a non-HIV-associated entity.

OBJECTIVE: This study presents the clinicopathologic features of a series (N = 35) of patients with non-human immunodeficiency virus (HIV)-associated oral hairy leukoplakia (OHL). METHODS: Patients with non-HIV-associated OHL were identified from three centers. Epstein-Barr virus infection was demonstrated by using EBV early ribonucleic acid in situ hybridization. The presence of Candida co-infection was evaluated by diastase periodic acid-Schiff staining. The clinical features were determined by review of the medical records. RESULTS: Twenty-eight patients had intercurrent respiratory problems requiring long-term steroid inhaler use, four suffered from autoimmune diseases requiring immunosuppressant therapy, and four had diabetes. The majority of lesions were located on the tongue, and 24 showed evidence of Candida co-infection. CONCLUSIONS: In the twenty-first century, the presence of OHL should not be regarded as pathognomic for HIV infection or significant systemic immunosuppression. Local and systemic immunosuppression, in the form of steroid inhaler use, is a risk factor for the development of OHL.

Epstein-Barr virus: dermatologic associations and implications: part I. Mucocutaneous manifestations of Epstein-Barr virus and nonmalignant disorders.

Epstein-Barr virus (EBV) is a ubiquitous virus that has been implicated in a wide range of human diseases, many of which have mucocutaneous manifestations. As a member of the herpesviridae family, EBV causes lifelong infection by establishing latency in B lymphocytes. An intact immune response is critical in preventing progression of EBV disease, and the clinical manifestations of infection are dependent on the intricate relationship between virus and host immune system. This review provides a comprehensive overview of the epidemiology, pathophysiology, and diagnostic testing in EBV infection. In part I of this continuing medical education article, the mucocutaneous manifestations of EBV infection are reviewed with an emphasis on pathophysiology and management.

Oral hairy leukoplakia in healthy, immunocompetent individuals.

Oral hairy leukoplakia (OHL), while typically associated with HIV infection and immunosuppression, is rarely seen in HIV negative immunocompetent individuals. We report on two cases of OHL in immunocompetent patients.

Oral hairy leukoplakia diagnosis by Epstein-Barr virus in situ hybridization in liquid-based cytology.

OBJECTIVE: To establish a definitive diagnosis of oral hairy leukoplakia (OHL) by in situ hybridization for Epstein-Barr virus (EBV) detection with liquid-based cytology (LBC), using the ThinPrep® Pap Test, and to compare its efficacy with the traditional method of performing biopsy. METHODS: Thirty-three individuals divided into three groups were included in this study. Group 1 consisted of 15 human immunodeficiency virus (HIV)-positive patients with a clinical and histopathological diagnosis of OHL on the lateral border of the tongue. Group 2 consisted of 10 HIV-positive individuals with neither OHL nor other oral lesions. Group 3 consisted of 10 immunocompetent HIV-negative individuals with neither OHL nor other oral lesions. For each patient from the three groups, exfoliative LBC was performed on the lateral border of the tongue using ThinPrep. For the patients from group 1, a 6-mm-diameter punch biopsy was obtained from the same anatomic site as the brush collection to confirm the diagnosis of OHL by histopathology with in situ hybridization. Slides were prepared for morphological cellular analysis using Papanicolaou (Pap) staining, and for EBV detection using in situ hybridization. RESULTS: Thirteen of the 15 patients from group 1 were confirmed on punch biopsy as OHL, providing the gold standard for the study. The sensitivity of LBC followed by a Pap-stained smear was 62% and the specificity was 90%. The sensitivity of LBC followed by in situ hybridization was 100% and the specificity was 100%. CONCLUSIONS: Exfoliative LBC associated with EBV in situ hybridization is a simple, effective and non-invasive diagnostic tool for OHL.

Epstein-Barr virus and skin manifestations in childhood.

Epstein-Barr virus (EBV) is a human B-lymphotropic herpes virus and one of the most common viruses in humans. Specific skin signs related to EBV infection are the exanthem of mononucleosis, which is observed more frequently after ingestion of amoxicillin, and oral hairy leukoplakia, a disease occurring mostly in immunocompromised subjects with HIV infection. Other more uncommon cutaneous disorders that have been associated with EBV infection include virus-related exanthems or diseases such as Gianotti-Crosti syndrome, erythema multiforme, and acute genital ulcers. Other skin manifestations, not correlated to virus infection, such as hydroa vacciniforme and drug-induced hypersensitivity syndrome have also been linked to EBV. The putative involvement of EBV in skin diseases is growing similarly to other areas of medicine, where the role of EBV infection is being investigated in potentially debilitating inflammatory diseases. The prognosis of EBV infection in healthy, immunocompetent individuals is excellent. However, lifelong infection, which is kept in check by the host immune system, determines an unpredictable risk of pathologic unpredictable scenarios. In this review, we describe the spectrum of non-tumoral dermatological manifestations that can follow EBV primary infection or reactivation of EBV in childhood.

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.

Human papillomavirus and Epstein Barr virus in oral hairy leukoplakia among HIV positive Venezuelan patients.

Oral hairy leukoplakia (OHL) is commonly found in individuals infected with HIV and represents the most frequent oral manifestation. The purpose of this study was to detect the presence of Human Papillomavirus (HPV) and Epstein Barr Virus (EBV) in OHL of HIV+ Venezuelan patients. We evaluated 21 HIV+ adult patients with clinically present OHL lesions: 11 under antiretroviral therapy, 10 without therapy, and 10 oral mucosal samples as controls. Nested-PCR was used to detect EBV and HPV infection. The INNO-LiPA HPV Genotyping v2 was applied to determine the HPV genotype. The EBV genome was found in 16/21 (76%) of the HIV+ patients with OHL. No difference was observed in EBV+ and EBV- patients related to antiretroviral therapy viral load and CD4+ Tcell coant. HPV-DNA was observed in 7/21 HIV positive cases (33%). The HPV genotypes detected were: 6, 11, 31, 33, 52, and 56/74. The most frequently HPV found was genotype 6 in 7/7, while two cases were HPV-11 and two HPV-52. Of the positive cases, 5/7 (71%) presented co-infection with more than one HPV genotype and 4/7 (57%) had HPV coinfection with high and low risk types. No case was EBV or HPV positive in the control group. In this study, a higher EBV prevalence was observed in OHL-HIV+ patients, confirming the etiologic role in this entity. A considerable number of cases were positive for HPV infection, and many patients presented coinfection with more than one HPV genotype as well as the presence of high oncogenic risk HPV in OHL.

Human papillomavirus and Epstein Barr virus in oral hairy leukoplakia among HIV positive Venezuelan patients

Oral hairy leukoplakia (OHL) is commonly found in individuals infected with HIV, and represents the most frequent oral manifestation. The purpose of this study was to detect the presence of Human Papillomavirus (HPV) and Epstein Barr Virus (EBV) in OHL of HIV+ Venezuelan patients. We evaluated 21 HIV+ adult patients with clinically present OHL lesions: 11 under antiretroviral therapy, 10 without therapy, and 10 oral mucosal samples as controls. Nested-PCR was used to detect EBV and HPV infection. The INNO-LiPA HPV Genotyping v2 was applied to determine the HPV genotype. The EBV genome was found in 16/21 (76%) of the HIV+ patients with OHL. No difference was observed in EBV+ and EBV- patients related to antiretroviral therapy viral load and CD4+ T cell count. HPV-DNA was observed in 7/21 HIV positive cases (33%). The HPV genotypes detected were: 6, 11, 31, 33, 52, and 56/74. The most frequently HPV found was genotype 6 in 7/7, while two cases were HPV-11 and two HPV-52. Of the positive cases, 5/7 (71%) presented co-infection with more than one HPV genotype and 4/7 (57%) had HPV coinfection with high and low risk types. No case was EBV or HPV positive in the control group. In this study, a higher EBV prevalence was observed in OHL-HIV+ patients, confirming the etiologic role in this entity. A considerable number of cases were positive for HPV infection, and many patients presented coinfection with more than one HPV genotype as well as the presence of high oncogenic risk HPV in OHL.

El proposito del presente estudio fue detectar la presencia de virus papiloma humano (VPH) y Epstein Barr (VEB) en Leucoplasia Vellosa Oral (LVO) de pacientes VIH positivos. Se evaluaron 21 pacientes adultos VIH positivos con lesiones clinicas presentes de LVO y 10 casos controles de mucosa sana. Para el diagnostico molecular de VPH y EBV se utilizo Nested PCR. La determinacion de los genotipos se realizo mediante el kit HPV INNO-LiPA genotyping v2. La presencia de genoma de VEB se demostro en un alto porcentaje (76%) en 16/21 de los pacientes VIH positivos con LVO. No se observo relacion entre los pacientes VEB+ y VEBcon el uso de terapia antirretroviral, la carga viral y el contaje de celulas T CD4+. Se demostro la presencia de ADN-VPH en 7/21 (8%) de los casos VIH positivos. Los genotipos de VPH detectados fueron 6, 11, 31, 33, 52, 56/74. El genotipo 6 fue el mas frecuentemente observado en 7/7, dos casos fueron VPH 11 y dos VPH 52. De los casos positivos 5/7 (71%) presentaron coinfeccion con mas de un genotipo de VPH y en 4/7 (57%) se evidencio coinfeccion con tipos de alto y bajo riesgo oncogenico. En el presente estudio se observo una alta prevalencia de VEB en pacientes VIH positivos con LVO, confirmando el papel etiologico en esta entidad. Un considerable numero de casos fueron positivos para VPH. Se observo la presencia de coinfeccion con mas de un tipo viral, asi como la presencia de VPH de alto riesgo.

Epstein Barr Virus detection and latent membrane protein 1 in oral hairyleukoplakia in HIV + Venezuelan patients

Purpose: To determine the prevalence of Epstein Barr Virus (EBV) in oral hairy leukoplakia lesions (OHL) inHIV+ Venezuelan patients. Material and Method: In this case study, we evaluated 21 HIV+ adult patients withclinically present OHL lesions, 11 who were undergoing antiretroviral therapy, 10 who were not undergoingtherapy and 10 HIV-negative adult patients with hyperkeratotic oral mucosal lesions. All of the subjects were assessedat the Infectious Disease Center, Faculty of Dentistry, Central University of Venezuela, and were clinicallyexamined to detect oral mucosal lesions with the confirmed histopathologic diagnosis. Nested-PCR was used todetermine the EBV infection and the latent membrane protein-1 (LMP-1) expression by immunohistochemistry.Results: Of the subjects, 16/21 (76%) of the HIV+/AIDS patients tested positive for EBV, whereas 5/10 (50%) ofthe HIV-negative subjects tested positive for EBV. Conclusions: In the present study, a higher EBV prevalence wasobserved in HIV-positive patients when compared to HIV-negative patients without oral hairy leukoplakia, confirmingthe etiologic role in this entity. The LMP-1 in OHL patients who were both HIV+ and EBV+ was highlyexpressed (60%) at the epithelial basal cells. No association between the alcohol and tobacco consumption wasobserved among the EBV-positive cases (AU)

Epstein Barr Virus detection and latent membrane protein 1 in oral hairy leukoplakia in HIV+ Venezuelan patients.

PURPOSE: To determine the prevalence of Epstein Barr virus (EBV) in oral hairy leukoplakia lesions (OHL) in HIV+ Venezuelan patients. MATERIAL AND METHOD: In this case study, we evaluated 21 HIV+ adult patients with clinically present OHL lesions, 11 who were undergoing antiretroviral therapy, 10 who were not undergoing therapy and 10 HIV-negative adult patients with hyperkeratotic oral mucosal lesions. All of the subjects were assessed at the Infectious Disease Center, Faculty of Dentistry, Central University of Venezuela, and were clinically examined to detect oral mucosal lesions with the confirmed histopathologic diagnosis. Nested-PCR was used to determine the EBV infection and the latent membrane protein-1 (LMP-1) expression by immunohistochemistry. RESULTS: Of the subjects, 16/21 (76%) of the HIV+/AIDS patients tested positive for EBV, whereas 5/10 (50%) of the HIV-negative subjects tested positive for EBV. CONCLUSIONS: In the present study, a higher EBV prevalence was observed in HIV-positive patients when compared to HIV-negative patients without oral hairy leukoplakia, confirming the etiologic role in this entity. The LMP-1 in OHL patients who were both HIV+ and EBV+ was highly expressed (60%) at the epithelial basal cells. No association between the alcohol and tobacco consumption was observed among the EBV-positive cases.

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.