The First 100 Cases of Epstein-Barr Virus-Positive Mucocutaneous Ulcers

In 2016, the World Health Organization provisionally classified Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) as a lymphoid neoplasm under the subcategory of mature B-cell neoplasms. Here we describe a 59-year-old Chinese woman with a long history of recurrent sinus and oropharyngeal infections and was diagnosed initially with EBVMCU and later, diffuse large B-cell lymphoma (DLBCL). She had sought medical attention after a particularly long bout of increased facial pressure and nasal obstruction. As a young adult she had undergone a tonsillectomy, adenoidectomy, and received innumerable treatments for bronchiectasis and recurrent sinopulmonary infections. A sinus computerized tomography (CT) scan showed mucosal thickening and swellings of the left frontal posterior sinus. A subsequent ¹⁸fludeoxyglucose (¹⁸FDG) positron emission tomography (PET)-CT scan showed a large hypermetabolic mass (standardized uptake value [SUV] 30.6) centered in the left half of the nasopharynx and sinus processes and extending across the mid-line. She underwent an endoscopic turbinate reduction with removal of a polypoid soft-tissue mass. Immunohistochemical studies indicated large atypical lymphoid cells that stained positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and variably for BCL-6, CD15, CD45, and CD79a. The Ki-67 proliferation index was 100% in the atypical cells. Tissue blocks were reviewed locally and at the National Institute of Health and were felt to be most consistent with EBVMCU. She received 4000 cGy involved-field external-beam radiation therapy over 20 fractions. At completion of treatment, no residual abnormalities were identified and no additional adjuvant therapy was pursued.

Three years later she presented to medical attention with shortness of breath and a non-productive cough. A PET-CT scan showed whiteout of the left lung and intense ¹⁸FDG uptake in a left perihilar nodule (SUV of 18). Bronchoscopy revealed many reactive polypoid bronchial wall masses and a complete collapse of the lower left lobe due to an obstructing mass. The left lower lobe intraluminal mass biopsies however showed EBV-positive DLBCL of non-germinal center phenotype. She received six cycles of conventional R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) and 36 months later she remains cancer free but with persistent bronchial inflammatory nodules and recurrent infections.

Using the key words "EBV mucocutaneous ulcers," "EBV-associated lymphoproliferative disorders," and "lymphoproliferative disorders," we identified 100 cases of EBVMCU in the literature. EBVMCU is manifested as a well-circumscribed ulcer typically unifocal (90%) and of the oropharynx (58%), gastrointestinal (GI) tract (20%), and skin (20%). Immunohistochemical studies of the ulcers reveal monoclonal B-immunoblasts staining positively for CD20, CD30, EBER-1, MUM-1, OCT-2, and PAX-5 and staining variably for BCL-6, CD15, CD45, and CD79a. EBVMCU is most commonly associated with medication-induced (iatrogenic) immunosuppression (65%), advanced age-associated immunosenescence (27%), and primary (3%) and acquired (3%) immunodeficiencies. The median age for all EBVMCU cases is 68.5 (range, 16 -101) years. Of the 65 cases where medication-induced immunosuppression contributed to EBVMCU, 45 (69%) were in patients greater than 60 years-old. EBVMCU is a predominantly indolent disease reminiscent of post-transplant lymphoproliferative disorders in which conservative strategies are primarily employed with potential escalation to B-cell targeted therapy with or without cytotoxic chemotherapy, resection, and/or radiotherapy. Surveillance for EBVMCU should follow B-cell directed therapies and should be considered in the differential diagnosis in cases of suspected lymphoma relapse. Additionally, other LPDs, including lymphomas, should be monitored after resolution of EBVMCU. Due to overlap of the immunohistochemical profiles and risk factors associated with EBVMCU and other ulcerative LPDs of the oral and sinus cavities, nasopharynx, or GI tract, EBVMCU should be considered in the differential diagnosis to prevent under- or over-diagnosis and their associated potential repercussions.