Continuing Education Activity

Epstein-Barr virus (EBV)–positive B-cell lymphoproliferative disorders are a spectrum of diseases that range from self-limiting, localized conditions to aggressive lymphomas. The EBV is ubiquitous, achieving asymptomatic lifelong carrier status in many of the world's population. The pathophysiology of this latent infection is due to the interaction of EBV with the memory B-cells of a healthy, immunocompetent individual. This activity reviews the pathophysiology of EBV-positive mucocutaneous ulcers and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the presentation of a patient with EBV-positive mucocutaneous ulcer.

• Evaluate a patient with EBV-positive mucocutaneous ulcer.

• Assess the treatment options for EBV-positive mucocutaneous ulcer.

• Determine modalities to improve care coordination among interprofessional team members to improve outcomes for patients affected by EBV-positive mucocutaneous ulcers.

Introduction

Epstein-Barr virus (EBV)–positive B-cell lymphoproliferative disorders (LPDs) are a spectrum of diseases that range from self-limiting, localized conditions to aggressive lymphomas. Epstein-Barr virus is ubiquitous, achieving asymptomatic lifelong carrier status in many of the world's population. The pathophysiology of this latent infection is due to the interaction of EBV with the memory B-cells of a healthy, immunocompetent individual. Disruptions in the balance of this interaction are believed to result in the lymphoproliferation of various cell derivatives. EBV-positive mucocutaneous ulcer (EBVMCU) is an indolent condition on this spectrum of LPDs, which localizes to the skin and mucosal surfaces. It is a rare lymphoproliferation that gained recognition as a new entity in the 2016 World Health Organization classifications revisions.[1][2]

Etiology

Epstein-Barr virus (EBV), also known as human herpesvirus 4, is transmitted via saliva and has a propensity to infect B-cells. The virus can persist in humans asymptomatically throughout their lifetime; however, it can also result in delayed complications such as lymphoproliferative disorders. One of the most noteworthy risk factors for developing EBV-positive mucocutaneous ulcers is immunosuppression. This condition has been reported in the setting of iatrogenic immunosuppression (56%), advanced age-associated immunosenescence (40%), and primary immunosuppression (4%).[3] Many commonly used immunosuppressive drugs have correlations with the development of EBVMCU, including methotrexate, cyclosporin A, azathioprine, tacrolimus, TNF inhibitors, mycophenolate, and topical steroid treatment.[1] Reports also suggest that immunosenescence is a significant predisposing factor for patients on immunomodulating drugs.[3]

Epidemiology

The incidence of EBV-positive mucocutaneous ulcer is likely highly underestimated, given its self-limiting course, in addition to its rarity amongst the spectrum of EBV-positive lymphoproliferative disorders with only a limited number of reported cases in the literature. It was first identified in 2010 and is associated with both iatrogenic, primary, and age-related immunosuppression.[4] A slight female predominance has been reported, with a median patient age of 66.4 years.[5] 

Pathophysiology

Although the pathogenesis of EBV-positive mucocutaneous ulcers is not fully established, it is thought to correlate with reduced levels of T-cells in immunosuppressed patients, reducing the ability to target all EBV-associated antigens. This suppression results in a proliferation of only restricted clones of EBV-specific T-cells when encountering the virus. In the immunocompetent individual, the cytotoxic T-cells can manage the EBV-induced B-cell proliferation and keep the virus dormant. In immunosuppressed patients with EBVMCU, the immune system can only keep the virus in a dormant state systemically. Thus, exposure to additional immune-modulating factors at a particular site can lead to localized EBV-driven lymphoproliferation.[6][7]

Histopathology

Biopsies of EBV-positive mucocutaneous ulcers demonstrate surface ulceration with infiltrates of atypical lymphoid cells. This lymphoid component is variable in appearance and can have a similar histological appearance to that of diffuse large B-cell lymphoma (DLBCL) and classic Hodgkin lymphoma (cHL). There may be a mixed inflammatory infiltrate with lymphocytes, plasma cells, histiocytes, and eosinophils. Often, there is a rim of reactive T-cells around the EBV-positive B-cell areas. Immunoblasts have been shown to express markers consistent with B-cell immunophenotypes.[3][8]

History and Physical

EBVMCU typically presents with isolated, sharply well-circumscribed ulcerations on the oropharyngeal mucosa (52%), on the skin (29%), or in the gastrointestinal tract (19%). Symptoms are typically directly related to the ulcer and include weight loss secondary to odynophagia and can even result in abdominal emergencies. Patients typically lack systemic symptoms, lymphadenopathy, organomegaly, or bone marrow involvement.[3] The propensity for localization to the oropharynx and gastrointestinal tract is related to the initial site of viral inoculation and the persistence of latent EBV in associated lymphoid tissues (ie, Waldeyer’s ring and gut-associated lymphoid tissue). Patients may have a waxing and waning clinical course, worsening lesion-associated tissue damage when maintaining or increasing iatrogenic immunosuppression.[1]

Evaluation

Diagnostic challenges of EBV-positive mucocutaneous ulcer included distinguishing it from other lymphoproliferative disorders, which may be EBV-related, such as diffuse large B-cell lymphoma, posttransplant lymphoproliferative disorder (PTLD), or classic Hodgkin lymphoma. EBVMCU is a localized condition that does not involve the bone marrow, lymph nodes, liver, or spleen and is not associated with EBV viremia. Workup of this condition typically involves histologic evaluation with immunohistochemistry. Imaging with or without bone marrow biopsy may be performed to rule out systemic involvement.[4]

Treatment / Management

Most cases of EBVMCU have a benign course and respond well to conservative management. In these cases, the patients are reported to have complete remission spontaneously or in response to reducing their immunosuppressive therapies. However, there are reports of more persistent and debilitating cases that require more aggressive treatment. Some case reports have indicated excellent response to CD20- or CD30-directed antibody therapy, local radiation, surgical excision, chemotherapy, or a combination of these treatments.[3][9]

Differential Diagnosis

The differential diagnosis for EBVMCU includes the following:

• EBV-positive DLBCL
• Classic Hodgkin lymphoma (cHL)
• Plasmablastic lymphoma
• PTLD
• Anaplastic large cell lymphoma

The clinical features of EBVMCU, specifically the localized nature and absence of a mass lesion, are integral in distinguishing it from DLBCL. These entities share an almost indistinguishable cytologic composition and phenotype. The presence of a sharp circumscription and a band of small T cells at the base of the ulcer can differentiate EBVMCU from the more infiltrative patterns of DLBCL. EBVMCU also shares morphologic and phenotypic characteristics with cHL, specifically the presence of CD30- or CD15-positive Reed-Sternberg–like cells, though cHL rarely presents as an extranodal disease.[6][10][11] Finding EBV positivity in a variety of cell sizes favors EBVMCU or PTLD. When DLBCL or cHL is EBV related, typically, only the large cells are EBER positive. Anaplastic large-cell lymphoma may resemble EBVMCU histologically. However, this entity is a CD30-positive T-cell lymphoma and will not be positive for EBER. 

Prognosis

EBVMCU has a favorable prognosis. Most cases regress spontaneously or with a reduction of immunosuppressive therapy. Some case reports have described a relapsing and remitting course without progression. Persistent cases have been reported to resolve with radiation, chemotherapy, or other localized treatments.[6] 

Complications

The sequelae of EBVMCU are mostly dependent on the location and severity of the ulcers, as they can be extensively destructive to the affected tissue. Persistent, painful ulcerations localized to the oropharynx have been reported to lead to odynophagia and subsequent weight loss. There have been reports of aspiration pneumonia and subsequent sepsis secondary to odynophagia as well. Furthermore, ulcers can appear in any part of the gastrointestinal tract, causing abdominal emergencies.[3][4]

Deterrence and Patient Education

Although many cases of EBVMCU are generally self-limiting and can resolve without treatment, it is important to seek medical care if you develop one. It can be secondary to multiple diagnoses, so additional work-up should be pursued. Furthermore, with an increasing number of cases of EBVMCUs being reported, there have been reports of more aggressive or persistent cases that require additional treatment. 

Pearls and Other Issues

Key facts to keep in mind about EBVMCU are as follows:

• EBVMCU is a B-cell LPD with many appearances, some of which may resemble DLBCL or cHL.
• Atypical lymphoid infiltrates of the skin and mucosal surfaces should undergo evaluation for EBV.
• If the lymphoid infiltrate is EBV-positive, EBVMCU should be considered.
• Diagnosis relies on the clinical history and the exclusion of systemic involvement.

Enhancing Healthcare Team Outcomes

The successful diagnosis and treatment of EBVMCU rely highly on an interprofessional and patient-centered approach. Given the rarity of EBVMCU and its typical self-remitting course, it is likely that this condition is commonly overlooked or misdiagnosed. As early diagnosis and treatment of EBVMCU can vastly decrease sequelae and improve patient outcomes, health care workers need to work together to obtain a prompt diagnosis.