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PURPOSE: To determine the clinicopathologic features of lymphoproliferative disorders (LPD) that occur in the setting of methotrexate (MTX) therapy for rheumatic diseases (RD) and to define the relationship between the presence of Epstein-Barr virus (EBV) in tumor cells and the response of LPD to MTX withdrawal. PATIENTS AND METHODS: In addition to nine new cases, we analyzed 28 cases previously reported in the literature of LPD in patients receiving MTX for RD. In addition to MTX, immunosuppressive therapy included corticosteroids in 19 patients, azathioprine in three, and cyclosporine in one. Extranodal disease was identified in 16 patients, but none had CNS involvement. Pathologic findings included five cases of Hodgkin's disease and seven low-grade lymphomas. The remaining patients had intermediate or aggressive lymphomas. In situ hybridization studies (ISHS) for EBV-RNA transcripts were positive in 12 of 27 patients (44%). RESULTS: Among 37 patients, 16 were initially observed after MTX withdrawal without additional antitumor therapy. Six achieved a spontaneous complete remission (CR), three had a partial response (PR), one had a minimal response, and six had no response to MTX withdrawal. Of 10 responding patients, EBV was detected by ISHS (n = 6) or polymerase chain reaction (PCR) (n = 2); one patient had a CR despite the absence of EBV by PCR and one had a CR but did not have viral assays performed. Only one of six patients with negative EBV by ISHS or PCR responded to MTX withdrawal. CONCLUSION: MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.
Salloum et al. (Sat,) studied this question.