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      Clinicopathological analysis of methotrexate‐associated lymphoproliferative disorders: Comparison of diffuse large B‐cell lymphoma and classical Hodgkin lymphoma types

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          Abstract

          Patients with rheumatoid arthritis often develop methotrexate‐associated lymphoproliferative disorders ( MTXLPD) during MTX treatment. MTXLPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non‐spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTXLPD (diffuse large B‐cell lymphoma [ DLBCL]‐type [ n = 34] and classical Hodgkin lymphoma [ CHL]‐type [ n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL‐type MTXLPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL‐type MTXLPD patients (76%) required additional chemotherapy. This difference was statistically significant ( P = 0.001). However, overall survival was not significantly different between DLBCL‐type and CHL‐type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTXLPD may be a factor for spontaneous or non‐spontaneous regression after discontinuation of MTX.

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          Methotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression.

          Patients with rheumatoid arthritis (RA) may develop lymphoproliferative disorders (RA-LPD). Immunosuppressive states due to methotrexate (MTX) and Epstein-Barr virus (EBV) reactivation have been regarded as causes. Sometimes spontaneous regression occurs after withdrawal of MTX. The objective of this study was to identify factors predictive of relapse and survival in patients with RA-LPD, and spontaneous regression in patients with RA-LPD treated with MTX (MTX-LPD).
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            Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication.

            Individuals with rheumatoid arthritis (RA) with or without methotrexate (MTX) medication occasionally develop lymphoproliferative disorders (MTX-LPD and non-MTX-LPD, respectively). The hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration might contribute to development of LPD. Our objective was to characterize MTX-LPD in comparison to non-MTX-LPD and sporadic LPD in patients with RA. We compared MTX-LPD to non-MTX-LPD and sporadic LPD by evaluating 48 cases of MTX-LPD, 28 non-MTX-LPD, and 150 sporadic LPD. Later onset age of LPD and female predominance were evident in patients with RA-LPD compared to sporadic LPD. The interval between the diagnosis of RA and LPD in MTX-LPD (median 132 mo) was significantly shorter than that in non-MTX-LPD (240 mo). The frequency of diffuse large B cell lymphoma (DLBCL) and positive rate of Epstein-Barr virus (EBV) in RA-LPD was significantly higher than in sporadic LPD (57.9% vs 42.7%, 27.6% vs 9.9%, respectively). After withdrawal of MTX, 11 of the MTX-LPD cases showed a spontaneous regression of tumors. The 5-year survival rate in RA-LPD (59.2%) was significantly worse than that in sporadic LPD (74.6%). The majority of cases of RA-LPD show similar clinicopathological characteristics irrespective of MTX medication, except for spontaneous regression of LPD after withdrawal of MTX in MTX-LPD, and a shorter interval between the diagnosis of RA and LPD in MTX-LPD than in non-MTX-LPD. RA-LPD cases showed younger age of onset, female predominance, unfavorable prognosis, and higher frequencies of DLBCL and EBV positivity compared to sporadic LPD.
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              Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France.

              A national prospective study was designed to collect all cases of lymphoma appearing in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) throughout France over a period of 3 years. A total of 25 cases of lymphoma were recorded, 18 cases of non-Hodgkin lymphoma (NHL), 3 of which were associated with the presence of Epstein-Barr virus (EBV) in lymphoma cells, and 7 cases of Hodgkin disease (HD), 5 of them associated with EBV. Among the 8 patients who were treated by MTX withdrawal alone, 3 underwent remission, but 2 of them had a relapse, the third patient with clonal EBV-associated large granular lymphocytes T-cell NHL remaining alive in complete remission. The estimated annual incidence rate of NHL in RA patients treated with MTX was 33.3.10(-5) (0-80.5) among men and 16.7.10(-5) (0-33.3) among women. There was no significant excess with the French population as a comparison: the standardized mortality ratio (SMR) adjusted for age and sex was 1.07 (0.6-1.7). The estimated annual incidence rate of HD among men and women was, respectively, 27.8.10(-5) (0-70.1) and 2.8.10(-5) (0- 9.6). The incidence of HD was significantly increased compared with the French incidence, with an SMR adjusted for age and sex of 7.4 (3.0-15.3; P <.001). Thus, this 3-year prospective study indicated that, whereas the risk of NHL was not significantly increased in RA patients treated with MTX, the incidence of HD appeared to be higher in these patients compared to the French population.

                Author and article information

                Contributors
                satou-y@okayama-u.ac.jp
                Journal
                Cancer Sci
                Cancer Sci
                10.1111/(ISSN)1349-7006
                CAS
                Cancer Science
                John Wiley and Sons Inc. (Hoboken )
                1347-9032
                1349-7006
                23 May 2017
                June 2017
                : 108
                : 6 ( doiID: 10.1111/cas.2017.108.issue-6 )
                : 1271-1280
                Affiliations
                [ 1 ] Department of PathologyOkayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences OkayamaJapan
                [ 2 ] Department of Cellular Transplantation Biology (Hematology/Oncology and Respiratory Medicine) Division of Cancer MedicineKanazawa University Graduate School of Medical Sciences KanazawaJapan
                [ 3 ] Department of Human MorphologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences OkayamaJapan
                [ 4 ] Department of Otolaryngology Head and Neck SurgeryOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences OkayamaJapan
                [ 5 ] Department of OtolaryngologyHimeji Red Cross Hospital HimejiJapan
                [ 6 ] Division of PathophysiologyOkayama University Graduate School of Health Sciences OkayamaJapan
                Author notes
                [*] [* ] Correspondence

                Yasuharu Sato, Division of Pathophysiology, Okayama University Graduate School of Health Sciences, 2‐5‐1 Shikata‐cho, Kita‐ku, Okayama 700‐8558, Japan.

                Tel: +81‐86‐235‐7150; Fax: +81‐86‐235‐7156;

                E‐mail: satou-y@ 123456okayama-u.ac.jp

                Author information
                http://orcid.org/0000-0001-6890-1276
                http://orcid.org/0000-0001-5234-6861
                Article
                CAS13249
                10.1111/cas.13249
                5480080
                28380678
                729d2376-b6d9-4639-b7c6-c392b1453bb9
                © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 04 September 2016
                : 10 March 2017
                : 29 March 2017
                Page count
                Figures: 4, Tables: 4, Pages: 10, Words: 6857
                Funding
                Funded by: Grant‐in‐Aid for Scientific Research (C)
                Award ID: JP16K08666
                Categories
                Original Article
                Original Articles
                Pathology
                Custom metadata
                2.0
                cas13249
                June 2017
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.1 mode:remove_FC converted:22.06.2017

                Oncology & Radiotherapy
                epstein‐barr virus,histological findings,methotrexate‐associated lymphoproliferative disorders,rheumatoid arthritis,spontaneous remission

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