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Methotrexate-associated Lymphoproliferative Disorders in Patients With Rheumatoid Arthritis

Clinicopathologic Features and Prognostic Factors

Kurita, Daisuke, MD, PhD*,†; Miyoshi, Hiroaki, MD, PhD*; Ichikawa, Ayako, MD, PhD*; Kato, Koji, MD, PhD; Imaizumi, Yoshitaka, MD, PhD§; Seki, Ritsuko, PhD; Sato, Kensaku, MPH*; Sasaki, Yuya, MD, PhD*; Kawamoto, Keisuke, MD, PhD*; Shimono, Joji, MD, PhD*; Yamada, Kyohei, MD*; Muto, Reiji, MD*; Kizaki, Masahiro, MD, PhD; Nagafuji, Koji, MD, PhD; Tamaru, Jun-ichi, MD, PhD#; Tokuhira, Michihide, MD, PhD; Ohshima, Koichi, MD, PhD*

The American Journal of Surgical Pathology: July 2019 - Volume 43 - Issue 7 - p 869–884
doi: 10.1097/PAS.0000000000001271
Original Articles

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.

Departments of *Pathology

Medicine, Division of Hematology and Oncology, Kurume University School of Medicine, Kurume

Laboratory of Virus Control, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka

§Department of Hematology, Nagasaki University Hospital, Nagasaki

Division of Hematology, Saitama Medical Center

#Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan

M.T. and K.O. contributed equally to this study.

Conflicts of Interest and Source of Funding: This work was supported by JSPS KAKENHI (Grant Number 17K15658 [D.K.]). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Hiroaki Miyoshi, MD, PhD, Department of Pathology, Kurume University School of Medicine, 67 Asahi-machi, Kurume-shi, Fukuoka 830-0011, Japan (e-mail:

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