title: Diagnostic and therapeutic challenges of EBV-positive mucocutaneous ulcer: a case report and systematic review of the literature.
abstract: BACKGROUND
  Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a recently recognized B cell lymphoproliferative disorder that is driven by latent EBV infection and causes discrete ulcerations in the oropharynx, gastrointestinal tract, and skin. Local attenuation of immunosurveillance associated with iatrogenic immunosuppressant use, primary immunodeficiency, or age-associated immunosenescence has been implicated as a predisposing factor. This disorder is likely under reported, as it was only first defined in 2010 and shares histological features with other B-cell proliferative neoplasms. The first case series that described EBVMCU suggested that EBVMCU is generally self-limited and is likely to resolve without treatment. Since that publication, additional cases have been reported that describe a more heterogeneous clinical course, often requiring aggressive therapy. We now systematically review all published cases of EBVMCU and detail a case of aggressive and progressive EBVMCU, including diagnostic and management challenges, as well as successful treatment with radiation therapy.
  
  
  METHODS
  A forty-nine year old woman presented with painful and debilitating multifocal oral EBVMCU that initially responded to four weekly doses of rituximab. Her disease relapsed within 3 months and continued to progress and cause significant morbidity. She was successfully treated with local external beam radiation therapy of 30 Gy in 15 fractions, with duration of response of at least 6 months.
  
  
  CONCLUSIONS
  We suggest that although many patients with EBVMCU experience a self-limited course, for others EBVMCU can be a debilitating, persistent disorder that requires aggressive therapy to prevent disease progression. CD20- and CD30-directed antibody therapy, local radiation therapy, local surgical excision, systemic chemotherapy, and a combination of these therapies have all been successfully used to treat EBVMCU with high rates of durable clinical remission. As EBVMCU is not currently included in the 2008 WHO classification of lymphoproliferative disorders and no evidence-based guidelines or expert opinions have been proposed to guide therapy, this case report and systematic review provides a foundation on which to guide therapeutic decisions.
authors.affiliation: Department of Hematology Oncology, Fred Hutchinson Cancer Research Center, University of Washington Allied Hospitals, 1100 Fairview Ave N-D5-100, Seattle, WA 98109-1024 USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Roberts
authors.affiliation: Department of Laboratory Medicine, UW Hematopathology Laboratory, University of Washington, Box 358081, 825 Eastlake Ave E, Seattle, WA 98109 USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, University of Washington, 1959 NE Pacific St, 1st floor, NN106, Seattle, WA 98195 USA.
authors.forename: Jay Justin
authors.initials: JJ
authors.lastname: Liao
keywords: B-cell neoplasm; Epstein–Barr virus; Epstein–Barr virus-positive mucocutaeneous ulcer disease; Immunosenescence; Lymphoproliferative disorder; Radiation therapy; Rituximab