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Lymphoma and Plasma Cell Neoplasms


Other iatrogenic immunodeficiency-associated lymphoproliferative disorders

Reviewer: Dragos Luca, M.D. (see Reviewers page)
Revised: 23 January 2012, last major update January 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.


● Lymphoid proliferations or lymphomas that arise in patients treated with immunosuppressive drugs for autoimmune diseases or conditions other than in the allograft/autograft transplant setting (WHO, 2008)


● Spectrum from polymorphic proliferations resembling polymorphic post-transplantation lymphoproliferative disorders (P-PTLD) to cases that fulfil the criteria for diffuse large B cell lymphoma, other B-cell lymphomas, peripheral T/NK-cell lymphomas or classical Hodgkin lymphoma


● Frequency not well known, difficult to differentiate if due to iatrogenic immunosuppression, underlying disorder or chance
● Rate probably is based on presence of underlying disease (rheumatoid arthritis, inflammatory bowel disease, psoriasis and psoriatic arthritis) and particular drug taken
● First drug reported in this context is methotrexate, predominantly in the setting of rheumatoid arthritis
● Striking association between hepatosplenic T cell lymphoma and young patients with Crohn's disease treated with infliximab plus azathioprine or 6-mercaptopurine



● EBV infection, although rate varies from 40% in rheumatoid arthritis cases treated with methotrexate, 80% in Hodgkin lymphoma, 25% in diffuse large B cell lymphoma, 0% in hepatosplenic T cell lymphoma
● Other important factors are chronic inflammation, chronic antigen stimulation, genetic background
● Patients with rheumatoid arthritis have 2-20x risk of lymphoma even in the absence of methotrexate
● Hepatosplenic T cell lymphoma not common in older patients receiving infliximab for inflammatory bowel disease or rheumatoid arthritis


● Patients treated with methotrexate: 40-50% extranodal (GI, skin, liver, spleen, lung, kidney, thyroid, bone marrow, soft tissue)
● Hepatosplenic T cell lymphoma patients with Crohn's disease patients treated with infliximab: usually spleen, liver, bone marrow

Clinical features

● Similar to immunocompetent patients with the same type of lymphoma

Treatment and prognosis

● Regression after drug withdrawal occurs in a significant proportion of patients with methotrexate-associated lymphoproliferate disorders (majority in EBV+ cases)
● Regression rates: diffuse large B cell lymphoma up to 40%, classical Hodgkin lymphoma up to 30%; most require chemotherapy with an overall survival for diffuse large B cell lymphoma of 50%; following initial regression after drug discontinuation, some patients have recurrences and require chemotherapy
● Regression is rare for disease due to TNFα blockers
● Hepatosplenic lymphoma due to infliximab is usually fatal, similar to regular HSTL


Micro description

● Different distribution of histologic types when compared to other immunodeficiency settings
● Probable increase in Hodgkin lymphoma and Hodgkin lymphoma-like lymphoid proliferations
● For patients treated with methotrexate: diffuse large B cell lymphoma (35-60%), classical Hodgkin lymphoma (12-25%, usually mixed cellularity), follicular lymphoma (5-10%), also Burkitt lymphoma, MALT lymphoma and peripheral T cell lymphoma; P-PTLD or P-PTLD-like infiltrates in ~15%

Micro Images

Diffuse large B cell lymphoma in metrotrexate treated rheumatoid arthritis (fig.1)

Nodular sclerosing classic Hodgkin lymphoma in metrotrexate treated dermatomyositis (fig.2)


● Similar to corresponding lymphomas in non-immunocompromised patients

Genetics & molecular

● Similar to corresponding lymphomas in non-immunocompromised patients

Additional references

N Engl J Med 1993;328:1317, Arthritis Rheum 2007;56:1433, Inflamm Bowel Dis 2007;13:1024
Arthritis Rheum 2002;46:3151, Arthritis Rheum 2003;48:1543, Int J Cancer 2000;88:497, Blood 2002;99:3909

End of Lymphoma and Plasma Cell Neoplasms > Other > Other iatrogenic immunodeficiency-associated lymphoproliferative disorders

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