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. The Epstein-Barr virus is a ubiquitous organism, achieving asymptomatic lifelong carrier status in a large proportion 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 derivations. 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 revisions to the World Health Organization classifications.
One of the most noteworthy risk factors for EBV positive mucocutaneous ulcer is immunosuppression. There are reports of this condition n the setting of iatrogenic (56%), advanced age (40%) and primary (4%) immunosuppression. 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. Reports also suggest that immunosenescence is a significant predisposing factor for patients who are also on immunomodulating drugs.
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 approximately 52 reported cases. It was first identified in 2010 and is associated with immunosuppression, both iatrogenic, primary and age-related. There is a slight male predominance in presentation with a median age of 77 years in immunosenescent cases and 63 years in iatrogenic cases.
Although the pathogenesis of EBV positive mucocutaneous ulcer is not fully established, it is thought to correlate with a diminished T cell repertoire in immunosuppressed patients leading to a reduced 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 are able to manage the EBV induced B cell proliferation and keep the virus in the dormant state. In immunosuppressed patients with EBVMCU, the immune system is only able to keep the virus in a dormant state systemically. Thus, exposure to a site restricted immune-modulating factor can lead to a localized EBV driven lymphoproliferation.
Biopsies of EBV positive mucocutaneous ulcer demonstrate surface ulceration with an infiltrate of atypical lymphoid cells. This lymphoid component is variable in appearance and appears as a diffuse large B-cell lymphoma, classic Hodgkin lymphoma, or as atypical immunoblasts. 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 — the lesional B-cell express B-cell markers PAX5, CC79a, OCT2, and BOB1. There is frequently downregulation of CD20 was present in a proportion of cases reported. CD30, CD15, and MUM1, similar to the phenotype of classic Hodgkin lymphoma. EBER in situ hybridization is positive in many cells with a variety of cell sizes, which is in contrast to classic Hodgkin lymphoma where only large cells are EBV-positive.
EBV positive mucocutaneous ulcer typically presents with isolated, sharply well-circumscribed ulcerations on the oropharyngeal mucosa (52%), on the skin (29%) or the in the gastrointestinal tract (19%). Symptoms are typically directly related to the ulcer, to include weight loss secondary to odynophagia, and abdominal emergencies. Patients lack systemic symptoms, lymphadenopathy, organomegaly or bone marrow involvement. The propensity for localization to the oropharynx and gastrointestinal tract is thought to be related to the initial site of viral inoculation and the subsequent persistence of latent EBV in associated lymphoid tissues (i.e., Waldeyer’s ring and gut-associated lymphoid tissue). Typically the clinical course is waxing and waning, with worsening of lesion-associated tissue damage when maintaining or increasing iatrogenic immunosuppression.
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, post-transplant lymphoproliferative disorder, or classic Hodgkin Lymphoma. EBVMCU typically is a localized condition and does not involve the bone marrow, lymph nodes, liver or spleen and is not associated with EBV viremia. Work up of this condition typically involves histologic evaluation with immunohistochemistry. Imaging with or without bone marrow biopsy may be performed to rule out systemic involvement.
Most cases of EBV positive mucocutaneous ulcer have a benign course and respond well to conservative management. In these cases, the patients are reported to have complete remission either spontaneously, or in response to reduction of their immunosuppressive therapies. However, there are reports of more persistent and debilitating cases that required more aggressive treatment. Reports exist of CD20 or CD30 directed antibody therapy, local radiation, surgical excision, chemotherapy or a combination of these treatments with excellent response.
The differential diagnosis for EBV positive mucocutaneous ulcer includes the following:
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 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. EBV positive mucocutaneous ulcer also shares morphologic and phenotypic characteristics with CHL, specifically the presence of CD30/CD15 positive Reed-Sternberg like cells. Although, CHL rarely presents as extranodal disease. Finding EBV positivity in a variety of cells sizes favors EBVMCU or PTLD. When DLBCL or CHL are 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.
EBV positive mucocutaneous ulcer has a favorable prognosis. Most cases regress spontaneously or with reduction of immunosuppressive therapy. Although there have been rare cases reported that exhibit a relapsing and remitting course without progression. Persistent cases have been reported to resolve with radiation, chemotherapy or other localized treatments.
The sequelae of EBV positive mucocutaneous ulcer is 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. Ulcers can appear in any part of the gastrointestinal tract causing abdominal emergencies.
The successful diagnosis and treatment of EBV positive mucocutaneous ulcer 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. Thus, the prompt diagnosis and treatment of EBVMCU requires astute primary care providers as well a multidisciplinary healthcare team, to include the patient's physician, pathologists, radiologists, dentists, infectious disease nurse, gastrointestinal specialists, and other supporting ancillary lab and clinical staff. Early diagnosis and treatment of EBVMCU can vastly decrease sequelae and improve patient outcomes.
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