Elsevier

Clinics in Chest Medicine

Volume 26, Issue 4, December 2005, Pages 631-645
Clinics in Chest Medicine

Post-Transplant Lymphoproliferative Disorder

https://doi.org/10.1016/j.ccm.2005.06.014Get rights and content

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Pathophysiology

EBV first was implicated as a cause for malignancy in 1964, when viral particles were discovered in a patient who had Burkitt's lymphoma [9]. Since then, EBV has been implicated as a causative factor in nasopharyngeal carcinoma, Hodgkin's lymphoma, and PTLD. A member of the herpesvirus family, EBV infects and immortalizes B cells. EBV infection usually is asymptomatic in childhood. If the primary infection occurs during adolescence or adulthood, however, infectious mononucleosis occurs.

Classification

PTLD represents a spectrum of lymphoid hyperproliferative states that includes benign conditions, such as infectious mononucleosis-like illnesses and lymphoid hyperplasia, and malignancies, such as B-cell (and, rarely, T-cell) lymphomas, which may take a fulminant course [5]. These disorders generally are associated with EBV infection (either primary infection or reactivation), but there are post-transplant lymphoid neoplasms that are not associated with EBV. Some studies suggest that

Diagnosis and staging

As is the case with all suspected lymphomas, it is critically important to obtain sufficient tissue for diagnosis, usually by excisional biopsy of the involved tissue or lymph node. Current recommendations for identifying a PTLD lesion are described in Table 2.

Noninvasive diagnosis of PTLD is not yet possible, although two blood tests may have some use. Polymerase chain reaction (PCR) testing of the peripheral blood for the presence of EBV-derived DNA is one promising method, but published

Post-transplant lymphoproliferative disorder in solid organ transplant recipients

The risk of developing PTLD after solid organ transplantation is variable and is most dependent on the level of immunosuppression, particularly with specific antilymphocyte therapy. All solid organ transplant recipients are at increased risk for many malignancies, especially those of lymphoid origin [30]. Table 3 lists the observed risk factors for the development of PTLD in solid organ transplant patients. Although many younger patients have not yet been exposed to EBV, it is not clear if the

Post-transplant lymphoproliferative disorder in hematopoietic stem cell transplant recipients

HSCT is performed primarily to cure malignancies and less commonly to treat severe autoimmune, immune deficiency, or metabolic diseases. (For a detailed discussion of HSCT, see the article by Cutler and Antin elsewhere in this issue.) Briefly, HSCT involves the administration of myeloablative doses of chemotherapy or radiation, followed by infusion of stem cells which return to the marrow and reconstitute hematopoiesis in 10 to 21 days, depending on the conditioning regimen and source of cells.

Surveillance

There recently has been interest in surveillance, prophylaxis, and early treatment of PTLD. Experience with monitoring for PTLD is limited, and there are no prospective randomized clinical trials of early interventions. Several compelling reports, however, suggest that surveillance for the presence of primary or reactivated EBV infection may prove useful, and there are small series suggesting that preemptive therapy may prevent PTLD effectively.

Several groups have examined solid organ

Antiviral therapy

Initial attempts to prevent PTLD in the solid organ transplant population focused primarily on using thymidine kinase inhibitors, such as ganciclovir or acyclovir, to eradicate or control EBV in a prophylactic setting for high-risk patients [25], [64], [65], [66], [67]. These drugs inhibit the replication of the EBV-related herpes viruses, herpes simplex, and cytomegalovirus. In vivo, however, these drugs are ineffective against EBV, because EBV-associated lymphomas do not express thymidine

Summary

PTLD is an increasingly recognized complication of solid organ transplantation and HSCT. Prompt diagnosis is key and requires high levels of clinical vigilance. Surveillance for PTLD by monthly PCR for circulating EBV DNA may be appropriate, particularly in such high-risk settings as EBV-seromismatched (donor-positive, recipient-negative) solid organ transplants and T-cell–depleted, HLA-mismatched stem cell transplants. When possible, surgical excision of the node, mass, or affected organ

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References (105)

  • N. Babel et al.

    Monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased frequency of Epstein-Barr Virus (EBV) latently infected B lymphocytes in long-term renal transplant patients

    Transplant Proc

    (2004)
  • A. Lemoine et al.

    Detection of gammopathy by serum protein electrophoresis for predicting and managing therapy of lymphoproliferative disorder in 911 recipients of liver transplants

    Blood

    (2001)
  • S. Feng et al.

    Tumors and transplantation: the 2003 Third Annual ASTS State-of-the-Art Winter Symposium

    Am J Transplant

    (2003)
  • G. Opelz et al.

    Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients

    Lancet

    (1993)
  • P. Ramalingam et al.

    Posttransplant lymphoproliferative disorders in lung transplant patients: the Cleveland Clinic experience

    Mod Pathol

    (2002)
  • B.D. Reams et al.

    Posttransplant lymphoproliferative disorder: incidence, presentation, and response to treatment in lung transplant recipients

    Chest

    (2003)
  • S.Z. Gao et al.

    Post-transplantation lymphoproliferative disease in heart and heart-lung transplant recipients: 30-year experience at Stanford University

    J Heart Lung Transplant

    (2003)
  • S. Paranjothi et al.

    Lymphoproliferative disease after lung transplantation: comparison of presentation and outcome of early and late cases

    J Heart Lung Transplant

    (2001)
  • M. Benkerrou et al.

    Therapy for transplant-related lymphoproliferative diseases

    Hematol Oncol Clin North Am

    (1993)
  • D.W. Hanto

    Retransplantation after post-transplant lymphoproliferative diseases (PTLD): when is it safe?

    Am J Transplant

    (2004)
  • A. Karras et al.

    Successful renal retransplantation after post-transplant lymphoproliferative disease

    Am J Transplant

    (2004)
  • M.M. Zutter et al.

    Epstein-Barr virus lymphoproliferation after bone marrow transplantation

    Blood

    (1988)
  • R.A. Nash et al.

    Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases

    Biol Blood Marrow Transplant

    (2003)
  • A. Lange et al.

    B-cell lymphoproliferative syndrome and peripheral blood CD20 + cells expansion after hematopoietic stem cell transplantation: association with fludarabine and anti-thymocyte globulin containing conditioning regimen

    Transplant Proc

    (2003)
  • G. Hale et al.

    Risks of developing Epstein-Barr virus-related lymphoproliferative disorders after T-cell-depleted marrow transplants. CAMPATH Users

    Blood

    (1998)
  • M. Benkerrou et al.

    Anti-B-cell monoclonal antibody treatment of severe posttransplant B- lymphoproliferative disorder: prognostic factors and long-term outcome

    Blood

    (1998)
  • R.E. Curtis et al.

    Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study

    Blood

    (1999)
  • S.A. Riddler et al.

    Increased levels of circulating Epstein-Barr virus (EBV)-infected lymphocytes and decreased EBV nuclear antigen antibody responses are associated with the development of posttransplant lymphoproliferative disease in solid-organ transplant recipients

    Blood

    (1994)
  • A. Savoie et al.

    Direct correlation between the load of Epstein-Barr virus-infected lymphocytes in the peripheral blood of pediatric transplant patients and risk of lymphoproliferative disease

    Blood

    (1994)
  • C.M. Rooney et al.

    Use of gene-modified virus-specific T lymphocytes to control Epstein- Barr-virus-related lymphoproliferation

    Lancet

    (1995)
  • K.G. Lucas et al.

    Semiquantitative Epstein-Barr virus (EBV) polymerase chain reaction for the determination of patients at risk for EBV-induced lymphoproliferative disease after stem cell transplantation

    Blood

    (1998)
  • T.E. Starzl et al.

    Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy

    Lancet

    (1984)
  • E. Haddad et al.

    Treatment of B-lymphoproliferative disorder with a monoclonal anti- interleukin-6 antibody in 12 patients: a multicenter phase 1–2 clinical trial

    Blood

    (2001)
  • L.J. Swinnen et al.

    Aggressive treatment for postcardiac transplant lymphoproliferation

    Blood

    (1995)
  • D. Gill et al.

    Durable and high rates of remission following chemotherapy in posttransplantation lymphoproliferative disorders after renal transplantation

    Transplant Proc

    (2003)
  • A. Faye et al.

    Anti-CD20 monoclonal antibody for post-transplant lymphoproliferative disorders

    Lancet

    (1998)
  • I. Kuehnle et al.

    CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation

    Blood

    (2000)
  • H. Kook et al.

    Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery

    Blood

    (1996)
  • T.N. Small et al.

    Comparison of immune reconstitution after unrelated and related T-cell- depleted bone marrow transplantation: effect of patient age and donor leukocyte infusions

    Blood

    (1999)
  • N.A. Marshall et al.

    Rapid reconstitution of Epstein-Barr virus-specific T lymphocytes following allogeneic stem cell transplantation

    Blood

    (2000)
  • K.G. Lucas et al.

    The development of cellular immunity to Epstein-Barr virus after allogeneic bone marrow transplantation

    Blood

    (1996)
  • C.M. Rooney et al.

    Infusion of cytotoxic T cells for the prevention and treatment of Epstein-Barr virus-induced lymphoma in allogeneic transplant recipients

    Blood

    (1998)
  • A. Gustafsson et al.

    Epstein-Barr virus (EBV) load in bone marrow transplant recipients at risk to develop posttransplant lymphoproliferative disease: prophylactic infusion of EBV-specific cytotoxic T cells

    Blood

    (2000)
  • M.A. Nalesnik et al.

    Autologous lymphokine-activated killer cell therapy of lymphoproliferative disorders arising in organ transplant recipients

    Transplant Proc

    (1997)
  • T.E. Starzl

    Five years' experience in renal transplantation with immunosuppressive drugs: survival, function, complications and the role of lymphocyte depletion by thoracic duct fistula

    Ann Surg

    (1968)
  • I. Penn et al.

    Malignant lymphomas in transplantation patients

    Transplant Proc

    (1969)
  • J.M. Armitage et al.

    Posttransplant lymphoproliferative disease in thoracic organ transplant patients: ten years of cyclosporine-based immunosuppression

    J Heart Lung Transplant

    (1991)
  • M.A. Nalesnik

    Posttransplantation lymphoproliferative disorders (PTLD): current perspectives

    Semin Thorac Cardiovasc Surg

    (1996)
  • D.E. Tsai et al.

    Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long- term follow-up of 42 adult patients

    Transplantation

    (2001)
  • G. Opelz et al.

    Lymphomas after solid organ transplantation: a collaborative transplant study report

    Am J Transplant

    (2003)
  • Cited by (0)

    This work was supported by grant no. CA76931 from the National Institutes of Health (to A.W. Loren) and by a Career Development Award from the American Society of Clinical Oncology (to D.E. Tsai).

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