Resolution of methotrexate‐induced Epstein‐Barr virus‐associated mucocutaneous ulcer

Abstract

A 65-year-old man presented with a swollen right cheek. His significant medical history included immunoglobulin M monoclonal gammopathy of undetermined significance (IgM MGUS) of 7 g/l with immune paresis and he was on oral methotrexate for his long standing rheumatoid arthritis. On examination, he was found to have a 7 × 5 cm ulcerated lesion on his hard palate (top left). A biopsy of the buccal mucosal ulcer showed a dense lymphoid infiltrate in which there was a population of atypical large lymphoid cells, some with multi–lobated nuclei and Reed-Sternberg-like morphology (top right). These cells were positive for CD20, CD15, BCL6, MUM1/IRF4, Epstein-Barr virus (EBV) latent membrane protein 1 (bottom left) and OCT2. There was an extensive background population of reactive T cells. He went on to have staging computed tomography (CT) and magnetic resonance imaging (MRI) scans as part of a workup for lymphoma. MRI of his neck showed a 3 cm flat enhancing lesion with normal appearances of the rest of the upper aero-digestive tract and no cervical lymphadenopathy. A CT scan of the thorax, abdomen and pelvis showed no evidence of lymphadenopathy and lactate dehydrogenase was normal. His bone marrow demonstrated no morphological evidence of infiltration but there was a small monoclonal B-cell population demonstrable by flow cytometry, consistent with the history of IgM MGUS. Given the anatomical location of the lesion, the history of immunosuppression, the presence of EBV in the primary lesion and the absence of documented disease elsewhere, a diagnosis of EBV-associated mucocutaneous ulcer was made. The methotrexate was stopped and the lesion regressed over the next 5 months (bottom right). The patient remains well without recurrence 19 months from the original diagnosis. Mucocutaneous ulcer is part of the spectrum of EBV-associated lymphoproliferative disease, typically seen in elderly patients in the context of immunosuppression with agents such as methotrexate, ciclosporin and azathioprine, although it can also occur in the context of age-related immune senescence or cytotoxic chemotherapy. It is characterized by large EBV-positive B cells with ‘Hodgkin-like’ morphology, which show strong expression of CD30 and IRF4. Downregulation of the B-cell phenotype with loss of CD20 and expression of CD15 is sometimes seen. Monoclonal immunoglobulin gene rearrangement is demonstrable in approximately one in three patients. Typically, presentation is with a well circumscribed ulcerated lesion in the oropharynx or gastrointestinal tract. This is an important entity to recognize, as many lesions will regress on cessation of the immunosuppressive agents.