Methtrexate-associated lymphoproliferative disorders. A clinicopathological study of 13 Japanese cases

Pathol Res Pract. 2006;202(9):679-85. doi: 10.1016/j.prp.2006.05.007. Epub 2006 Jul 21.


We conducted clinicopathological and immunohistochemical analyses to investigate the prevalence of Epstein-Barr virus (EBV) among 13 cases with methotrexate (MTX)-associated lymphoproliferative disorder (LPD). The subjects of this study were four men and nine women ranging in age from 53 to 78 years (mean: 63 years). All 13 patients had received low dose MTX therapy for 1-13 years before the onset of LPD (mean: 5.8 years). LPDs were found at extranodal sites in six cases, and the disease stage was advanced in seven cases. The present study confirmed certain aspects of a previous observation made in the USA, including the following findings (i) the cases commonly showed diffuse large B-cell lymphomas (n=4) and Hodgkin lymphomas (HL) (n=3), (ii) EBV-encoded small RNA (EBER) + cells were identified in seven cases (60%), which is a much higher percentage than would be expected in lymphomas occurring in a general population, and (iii) three cases of polymorphous small lymphocytic or lymphoplasmacytic infiltrate achieved spontaneous remission of LPDs after MTX withdrawal. Of seven cases of EBER + in our series, three cases were PSLLPI, and two were HL. EBER + tumor cells were detected in only two (30%) of the seven cases with non-Hodgkin lymphomas. The present study suggests that EBV- associated non-Hodgkin lymphomas comprise only a portion of all non-Hodgkin lymphomas among MTX-associated LPDs.

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / adverse effects*
  • Arthritis, Rheumatoid / drug therapy
  • Epstein-Barr Virus Infections / epidemiology*
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Lymphoproliferative Disorders / chemically induced*
  • Lymphoproliferative Disorders / virology*
  • Male
  • Methotrexate / adverse effects*
  • Middle Aged
  • Prevalence
  • RNA, Viral / isolation & purification


  • Antimetabolites, Antineoplastic
  • RNA, Viral
  • Methotrexate