Methotrexate-associated Lymphoproliferative Disorders in Patients With Rheumatoid Arthritis: Clinicopathologic Features and Prognostic Factors

Daisuke Kurita, Hiroaki Miyoshi, Ayako Ichikawa, Koji Kato, Yoshitaka Imaizumi, Ritsuko Seki, Kensaku Sato, Yuya Sasaki, Keisuke Kawamoto, Joji Shimono, Kyohei Yamada, Reiji Muto, Masahiro Kizaki, Koji Nagafuji, Jun Ichi Tamaru, Michihide Tokuhira, Koichi Ohshima

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)


Methotrexate (MTX) carries a risk of lymphoproliferative disorders (LPDs), but MTX-associated LPDs (MTX-LPDs) can resolve spontaneously after MTX withdrawal. However, the precise clinicopathologic features of MTX-LPD remain unclear. We aimed to investigate the clinicopathologic characteristics, outcomes, and prognostic factors for histologic types of MTX-LPD. Paraffin-embedded tissue samples of 219 patients with MTX-LPD were analyzed. In total, 30,33,106, and 26 had reactive lymphoid hyperplasia (RH), polymorphic-LPD (Poly-LPD), diffuse large B-cell lymphomas (DLBCLs), and classic Hodgkin lymphoma (CHL), respectively. The clinicopathologic features of RH, Poly-LPD, DLBCLs, and CHL were as follows: extranodal involvement: 13.8% (4/29), 36.4% (12/33), 69.5% (73/105), and 15.4% (4/26); Epstein-Barr virus encoded RNA positivity: 55.2% (16/29), 71.9% (23/32), 45.3% (48/106), and 76.9% (20/26); necrosis: 0% (0/29), 51.5% (17/33), 34.3% (36/105), and 12.0% (3/25); and Hodgkin Reed-Sternberg-like cells: 17.2% (5/29), 50% (14/28), and 19.8% (21/106). The median duration from MTX withdrawal to the time of disease regression was 10.4, 3.0, 4.2, and 2.7 months for RH, Poly-LPD, DLBCLs, and CHL. After MTX withdrawal, progression-free survival was the greatest for RH, followed by for Poly-LPD, DLBCL, and CHL (all P<0.05). Overall survival did not differ significantly between the groups. On univariate analysis, the predictive factors for progression-free survival included plasma cell infiltrate for CHL, eosinophil infiltrate, age above 70 years, and extensive necrosis for Poly-LPD, while they were Epstein-Barr virus encoded RNA positivity and International Prognostic Index risk for DLBCL on multivariate analysis. In conclusion, histologic categorization and histology-specific factors could be useful for predicting MTX-LPD progression after MTX withdrawal.

Original languageEnglish
Pages (from-to)869-884
Number of pages16
JournalAmerican Journal of Surgical Pathology
Issue number7
Publication statusPublished - Jul 1 2019

All Science Journal Classification (ASJC) codes

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine


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