Reversible methotrexate-associated lymphoma of the liver in rheumatoid arthritis: a unique case of primary hepatic lymphoma

Abstract

Primary hepatic lymphoma (PHL) is an extremely rare disease, frequently associated with viruses such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immune deficiency virus (HIV). On the other hand, an increased risk of lymphoproliferative disorders (LPD) has been demonstrated in patients treated with immunosuppressive drugs such as methotrexate (MTX) for rheumatoid arthritis (RA). The role of Epstein-Barr virus (EBV) has been discussed in the pathogenesis of the immunodeficiency-associated LPDs. We here describe a RA patient, who developed PHL during RA treatment. The patient was a 64 year-old Japanese male with a 2-year history of RA, who had been treated with MTX at weekly dose of 8–14 mg for 2 years and infliximab (IFX) for 7 months. He presented with a 2 month history of generalized malaise, right hypochondrium pain and fever. Contrast-enhanced computed tomography (CECT) of the abdomen showed multiple irregular and nodular liver masses with a maximum of 13 cm in diameter on the right liver. Biopsy specimens demonstrated CD20-positve diffuse large B-cell lymphoma (DLBCL), but EBV was not identified by EBV-encoded RNA in situ hybridization. Serology for HBV, HCV, human T-cell leukemia virus I (HTLV-I), and HIV was negative. His symptoms disappeared following discontinuation of RA treatment including MTX. A drastic regression of the tumor masses was further obtained without cytotoxic chemotherapy. In addition, although the patient had no past history of liver dysfunction before MTX therapy, persistent elevation of liver enzymes has been observed during MTX treatment. These findings show a causative role of MTX in the development of reversible PHL in the patient.

Treatment of advanced stage methotrexate-associated lymphoproliferative disorders (MTX-LPDs) with methotrexate discontinuation

“…Improvement or regression of MTX-LPD lesions occurs in 30%–59% of patients following discontinuation of MTX 1 2 4. This improvement following discontinuation of these immunosuppressive agents is further proof of the association between these medications and LPDs2 5 Complete remission seems to occur relatively shortly (average of 1 month) after MTX discontinuation 6. Partial remission takes longer to appreciate (average of 2–3 months) after MTX is stopped 6–8.…”

Other immunomodulatory agent-related lymphoproliferative diseases: a single-center series of 72 biopsy-confirmed cases

“…The increased risk for lymphoproliferative disorders in the post-transplant population [1,[41][42][43][44][45] and case reports with a clear relation in time between therapy initiation and the development of lymphoproliferative disorders [46,47] support the existence of a causative role between immunosuppressive/immunomodulatory therapy and lymphoproliferative disorders. This causative role of immunomodulatory/suppressive therapy in immunosuppressive/immunomodulatory agent-related lymphoproliferative disorders has been repeatedly suggested by case reports of lymphoproliferative disorders regression following discontinuation of methotrexate [48][49][50][51][52], anti-TNFα therapy [53][54][55][56] thiopurines [55], tacrolimus [57], and others [56]. A limitation in studying the effect of these drugs on lymphoproliferative disorder incidence is the still open question how long after cessation of therapy the immunosuppressive/immunomodulatory effects of these drugs linger.…”

Hepatic methotrexate-associated lymphoproliferative disorders identified by multiple liver tumors: a case report and review of the literature

“…According to the World Health Organization classification of tumors of hematopoietic and lymphoid tissue, other iatrogenic immunodeficiency-associated LPD are lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases or conditions other than in post-transplant settings [4]. Primary hepatic lymphoma is very rare and accounts for 0.4% of extranodal non-Hodgkin’s lymphoma and 0.016 to 0.06% of all non-Hodgkin’s lymphoma [1, 4]. To date, there have only been ten cases of hepatic MTX-LPD reported in the English literature by PubMed [1–3, 5–11].…”

“…Methotrexate (MTX), an immunosuppressant, is widely used as the standard therapeutic drug for rheumatoid arthritis (RA) [1]. With the increasing frequency of use of MTX, adverse effects of MTX have been reported, one of which is known as MTX-associated lymphoproliferative disorders (MTX-LPD) [2].…”