ReviewImmunodeficiency-associated lymphomas
Introduction
There are a multitude of factors known to be associated with cancer aetiology, with escape from host immunity only one facet. Transformation of a cell to one with malignant potential in an immunodeficient host may allow clonogenic expansion and eventually clinical cancer.1 The importance of defective immunosurveillance in malignancy is most marked in cells with strong antigenic potential including those that have undergone viral induction. Consistent with this is the observation that the predominant cancer sub-type in immunodeficient subjects is lymphoma (a neoplasm of the immune system), that frequently these lymphomas are driven by viruses such as Epstein-Barr virus (EBV) and that restoration of immunity can result in tumour regression.2 Yet the lack of EBV in a proportion indicates that alternate pathways must also be involved in lymphomagenesis. Indeed the wide clinical spectrum of lymphoproliferative disorders (LPD) encountered in immunodeficiency along with its associations with germ-line and acquired genetic defects, with oncogenic viruses, and with autoimmunity suggests an interplay in which genetic aberrations interact with viral oncogenes, impaired immunosurveillance and chronic antigen stimulation (Fig. 1). Increasing evidence suggests that the immune escape mechanisms utilized by lymphomas in the immunodeficient may have relevance to lymphomas in the overtly “immunocompetent”.3, 4, 5 Thus the study of immunodeficiency-associated lymphoproliferations may serve as a paradigm for the altered immunoregulatory environment present in many lymphoma sub-types.
Section snippets
Primary immune deficiency and lymphoproliferative disorders
The occurrence of lymphoproliferative disorders in patients with a primary immunodeficiency (PID) has been documented in the literature for nearly 40 years.6 These PIDs are a heterogeneous group of genetically determined disorders; hence the lymphoproliferative diseases (LPD) that arise are diverse and variable.
The risk of developing LPD is related to the type of PID. Accurate quantification of this risk is difficult because PID is rare; hence the incidence of lymphoma is low, leading to a
Post-transplant lymphoproliferative disorders
Post-transplant lymphoproliferative disorder (PTLD) represent the group of lymphoid disorders that arise following solid-organ transplantation (SOT) and stem cell transplantation.24, 25, 26, 27 Relative to the immunocompetent, the risk of lymphoma after transplantation is increased by the order of 30 times.28 The incidence of PTLD varies, depending on the intensity of immunosuppression, recipient age, the organ transplanted, the number of previous allografts, and in liver transplant recipients
Methotrexate-associated lymphoproliferative disorders
The development of methotrexate (MTX) by Farber’s team in Boston was a pivotal moment in the modern era of chemotherapy. It remains a critical component of acute lymphoblastic leukaemia therapy, and high-dose MTX is the mainstay for the treatment of lymphomas within the nervous system. Ironically, low-dose MTX, used most commonly in the setting of treatment for RA, psoriasis, dermatomyositis and myasthenia, is implicated in lymphomagenesis. In their most recent classification, the World Health
Tumour necrosis factor antagonists
Experimental evidence and clinical experience with Tumour Necrosis Factor-α inhibitors (anti-TNF) demonstrate the central role for this cytokine in the pathogenesis of Rheumatoid Arthritis (RA), Crohns Disease (CD) and other autoimmune diseases. Three agents are currently licensed: infliximab (a chimeric monoclonal antibody), etanercept (a TNF-α receptor fused to the Fc region of IgG) and adalimumab (a recombinant monoclonal antibody). These agents were initially approved for moderate to severe
Human immunodeficiency virus (HIV) associated lymphomas
Approximately 1–6% of HIV positive patients develop lymphoma each year. However with the widespread use of highly active antiretroviral therapy (HAART) from 1996, the incidence of NHL appears to be declining. This reduction is most marked for Primary Central Nervous System Lymphoma (PCNSL) but is also significant for systemic NHL.108, 109 This should be put in context. In 2006 the World Health Organization estimated 39.5 million people were living with HIV and that during that year there were
Conclusion
Although primary or acquired immunodeficiency is the most well established risk factor for lymphoma, genetic predisposition to these malignancies has been shown by the strong aggregation of lymphoma in otherwise healthy families.160 In some cases, evidence suggests that genetic susceptibility to lymphoma is mediated by “selective immunodeficiency” in overtly immunocompetent subjects. For example, there have been several findings linking genetic polymorphisms with lymphoma susceptibility.
Conflict of interest statement
None declared.
Acknowledgements
M.K.G. gratefully acknowledges the support of the National Health & Medical Research Council, the Royal Australasian College of Physicians, the Queensland State Department of Trade and Innovation, the Cancer Council of Queensland, the Cancer Collaborative Group and the Leukaemia Foundation.
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