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.

Case presentation: 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.

Keywords: B-cell neoplasm; Epstein–Barr virus; Epstein–Barr virus-positive mucocutaeneous ulcer disease; Immunosenescence; Lymphoproliferative disorder; Radiation therapy; Rituximab.

Fig. 1

CT of neck demonstrating bilateral diffuse lymphadenopathy with the largest lymph node measuring 2.4 cm (arrow)

Fig. 2

Biopsy of right incisural ulcer and left palatal perimolar ulcer. Hematoxylin and eosin (H&E) stain demonstrating scattered large atypical lymphocytes with occasional Hodgkin Reed-Sternberg (HRS) morphology in a background of mixed inflammatory infiltrate. These large atypical cells are positive for CD30

Fig. 3

CT of neck demonstrating prominent maxillary gingival and palatal swelling and ulcerations with significant loss of maxillary teeth on the left side

Fig. 4

a Left sided facial swelling causing lip droop and associated drooling. b , c Left palatal EBVMCU with associated maxillary teeth loss. d EBVMCU along right upper inner gum line extending from incisors to molars. e Hypertrophy of right upper gum line

Fig. 5

Hematoxylin and eosin (H&E) stain of left palatal ulcer demonstrating a heterogeneous admixture of large atypical lymphocytes with occasional Hodgkin Reed-Sternberg (HRS) morphology, small lymphocytes, and histiocytes. HRS cells express CD30, PAX5, and EBER1 consistent with EBV-infected B-lymphocytes

Fig. 6

Axial and sagittal views of radiotherapy plan

Fig. 7

Post-radiation treatment response with resolution of the ulcers along right inner gingiva and left palate. Facial swelling has also resolved