Successful Treatment of Intracranial Methotrexate-associated Lymphoproliferative Disorder without Epstein-Barr Virus Infection Using Rituximab, Methotrexate, Procarbazine, and Vincristine: A Case Report

Abstract

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) occurs in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX). MTX-LPD is typically associated with Epstein-Barr virus (EBV) infection and regresses with MTX discontinuation. On the other hand, EBV-negative MTX-LPDs are less common and are more likely to show partial or no regression after MTX discontinuation. There were no standard chemotherapeutic options for refractory MTX-LPD. We present a case of EBV-negative MTX-LPD in the central nervous system (CNS) that was successfully treated with rituximab, methotrexate, procarbazine, and vincristine (R-MPV), followed by reduced-dose whole-brain radiotherapy (rdWBRT), following the same treatment protocol as primary CNS lymphoma. A 59-year-old woman with RA treated with MTX presented with gradually developing staggered gait, memory deficit, and disorientation. Multiple lesions with heterogeneous contrast enhancement were discovered using brain magnetic resonance imaging. The patient was suspected of having MTX-LPD, but discontinuing MTX did not result in regression of the brain lesions. She underwent a biopsy from the left parietal lesion. The tissue was pathologically diagnosed as diffuse large B-cell lymphoma. Furthermore, pathological examination through EBV-encoded ribonucleic acid in situ hybridization demonstrated a lack of EBV infection. She was ultimately diagnosed with EBV-negative CNS MTX-LPD. We applied chemotherapy with R-MPV and rdWBRT. The patient achieved a complete response. In the case of CNS MTX-LPD without EBV infection, chemotherapy with R-MPV followed by rdWBRT may be considered.

Keywords: methotrexate; methotrexate-associated lymphoproliferative disorder (MTX-LPD); primary central nervous system lymphoma (PCNSL); rheumatoid arthritis; rituximab, methotrexate, procarbazine, and vincristine (R-MPV).

Fig. 1

Brain MRI upon admission and after MTX withdrawal and FDG-PET findings after MTX withdrawal. A: Gd-T1WI upon admission showing multiple lesions in the bilateral cerebral hemisphere and basal ganglia. B: FLAIR images upon admission showing hyperintensity surrounding lesions. C: Gd-T1WI after MTX withdrawal showing no regression. D: FDG-PET after MTX withdrawal showing increased FDG uptake in the lesion.

Fig. 2

The pathological findings of the left parietal lesion. A: Hematoxylin and eosin (H&E) staining (original magnification ×40) showing lymphocytic cells, some of which show perivascular cuffing. B: H&E staining (original magnification ×400) showing diffuse and perivascular infiltration of large atypical lymphoid cells. C: Immunostaining for CD20 (original magnification ×400) demonstrating a positive result. D: In situ hybridization (original magnification ×400) showing no evidence of EBER.

Fig. 3

Brain MRI findings after 7 cycles of chemotherapy with R-MPV and rdWBRT. A and B: Gd-T1WI (A) and FLAIR (B) showing no evidence of lesions.