Post-transplant Lymphoproliferative Disease
 

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Post-transplant lymphoproliferative disorder/disease (PTLD) is a B-cell proliferation disorder following infection with EpsteineBarr virus due to therapeutic immunosuppression after organ ...

Post-transplant lymphoproliferative disorder/disease (PTLD) is a B-cell proliferation disorder following infection with EpsteineBarr virus due to therapeutic immunosuppression after organ transplantation. The more intense the immunosuppression, the higher the incidence of PTLD and the earlier it occurs. The cornerstone of successful treatment of PTLD is reduction or withdrawal of immunosuppression.

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Post-transplant Lymphoproliferative Disease Document Transcript

  • 1. Post-transplant Lymphoproliferative Disease
  • 2. Review Article Post-transplant lymphoproliferative disease S. Rajagopalan Consultant, Department of Nephrology, Apollo Hospital, Chennai, India a r t i c l e i n f o Article history: Received 16 January 2013 Accepted 18 January 2013 Available online 30 January 2013 Keywords: Transplant Immunosuppression EBV B cells PTLD a b s t r a c t Post-transplant lymphoproliferative disorder/disease (PTLD) is a B-cell proliferation dis- order following infection with EpsteineBarr virus due to therapeutic immunosuppression after organ transplantation. The more intense the immunosuppression, the higher the incidence of PTLD and the earlier it occurs. The cornerstone of successful treatment of PTLD is reduction or withdrawal of immunosuppression. Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. Transplant patients may develop infectious mononucleosis- like lesions or polyclonal polymorphic B-cell hyperplasia due to EpsteineBarr virus (EBV) infection. Some of these B cells may undergo mutations which will render them malignant, giving rise to a lymphoma. Most cases of PTLD are observed in the first post-transplant year. Reduction of immunosup- pression inherently carries the risk of allograft dysfunction or loss. The reversibility, partial or complete, with reduction of immunosuppression, differentiates PTLD from the lympho- proliferative disorders observed in patients who are immu- nocompetent. Studies have documented the adverse impact of subclinical CMV (cytomegalovirus) and EBV viremia on graft function.1 1. Epidemiology, morbidity and mortality The incidence of PTLD varies with the type of transplanted allograft. It is much higher in heart or heart-lung transplants, presumably reflecting the need for more intense immunosuppression in these patients. In terms of lympho- proliferative disease occurring in the allograft itself, it de- pends on the graft in question. The lungs very frequently are a site of involvement in patients undergoing heart-lung, or heart alone, transplant. In cardiac transplant, the heart itself seldom is involved. In renal allografts, the graft kidney is affected approximately one third of the time, which is similar to graft involvement rates in liver and bone marrow trans- plant cases. The incidence in renal transplant recipients is around 1 per cent, a risk of lymphoma about 20 times greater than in the general population. The two main aetiological mechanisms are EBV infection and immunosuppression. EBV infection can be detected in about 90 per cent of patients and is almost al- ways a primary infection. Thus, seronegative recipients are those predominantly at risk and this explains why children are commonly affected in contrast to lymphoma in the gen- eral population. Swinnen et al examined the incidence of PTLD in patients undergoing cardiac transplant and using OKT3 (murine E-mail address: drrajagopalan_s@apollohospitals.com. Available online at www.sciencedirect.com journal homepage: www.elsevier.com/locate/apme a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved. http://dx.doi.org/10.1016/j.apme.2013.01.014
  • 3. monoclonal anti-CD3 antibody) as immunosuppression and found an incidence of 6.2% in patients who had received a dose of 75 mg or less. The mean time to development of PTLD was 11 months, compared with an incidence of 35.25% and a mean interval of 1.5 months in patients who received doses of greater than 75 mg. With prednisolone and azathioprine alone, the mean time to developing PTLD is 50 months. Cyclosporin therapy reduced this to 5 months. Use of tacrolimus and use of antilymphocyte globulins have been associated with much earlier and more frequent presentation of PTLD.2 Majority of PTLDs are of non-Hodgkin’s lymphoma subtype and makeup about 93% of lymphoma encountered in this setting. Out of those 86% of post-transplant lymphomas are of B-cell origin and about 14% of lymphomas are of T-cell origin, whereas less than 1% are of null cell origin.3 Cohen (1991) reviewed cases of PTLD in the literature involving renal, cardiac, heart-lung, liver, and bone marrow transplantation. In the case of renal allografts, 60% of patients developed PTLD within 6 months of transplantation, but the mean time was 32 months. He noted that patients treated with cyclosporin had a mean time to development of PTLD of 5 months. Survivors were more likely to have a shorter time interval to development of PTLD than those who died, they were more likely to have polyclonal lesions and B-cell hyper- plasia, and they were more likely to have involvement of graft or lymph nodes.4 Shapiro et al found an overall incidence of PTLD of 1.9% in a population of 1316 patients undergoing kidney transplants at the University of Pittsburgh from 1989 to 1997. The inci- dence in adults was 1.2%, with a much higher incidence in pediatric patients (i.e., 10.1%). The time interval to diagnosis of PTLD ranged from less than 1 month to 49 months in adults. The 1- and 5-year patient and graft survival rates in adults were 93% and 86% and 80% and 60%, respectively. The authors concluded that although PTLD is more common in renal transplant pediatric recipients receiving tacrolimus, they have a more favorable prognosis.5 PTLD forms a heterogenous group of tumors, ranging from B-cell hyperplasia to immunoblastic lymphoma, the latter portending a more grim prognosis. All PTLD, however, irre- spective of histology, is potentially, and frequently, fatal. Mortality rates could be as high as 60e100%. The presentation and clinical course are variable. At one end of the spectrum is aggressive disease with diffuse involvement, resulting in rapid demise of the patient; at the other end of the spectrum are localized lesions that are indolent and slow growing over months, as opposed to days or weeks. The former occur early in the post-transplantation period and are more often poly- clonal lesions. Late-onset PTLD tends to be monoclonal and heralds a worse prognosis. Polyclonal lesions, however, have a more favorable prognosis. They, unlike monoclonal lesions, tend to occur early and are responsive to reduction of immunosuppression. Primary CNS involvement is associated with significantly higher mortality rates, 88% at 6 months in one study. CNS disease requires intrathecal therapy or local- ized radiation therapy because intravenous chemotherapy and monoclonal antibodies do not cross the blood-brain bar- rier adequately. Hauke et al reported their experience with PTLD occurring in patients after solid organ transplantation. In this retrospective review of 32 patients, the 5-year survival rate was 59%, with 45% of patients diagnosed within the first year following transplantation. Six out of 8 patients surgically treated remain alive and disease free. Characteristics asso- ciated with poorer survival were diagnosis within the first year post-transplant, monoclonal tumors, and presentation with an infectious mononucleosis-like syndrome.6 LeBlond et al, in a series of 61 patients who had undergone kidney, lung, liver, or heart transplantation, found that factors predictive for shorter survival (univariate analysis) in PTLD included a performance status (PS) greater than or equal to 2, increased number of sites involved (i.e., >1 versus 1), primary central nervous system (CNS) involvement, T-cell origin, monoclonality, nondetection of EBV in the tumor, and treat- ment based on chemotherapy (in addition to reduction in immunosuppression).7 2. Pathophysiology The disease is an uncontrolled proliferation of B lymphocytes following infection with EpsteineBarr virus. EBV is a herpes virus that is thought to infect as much as 95% of the adult population. Primary infection with EBV usually results in mild, self-limiting illness in childhood and the clinical syndrome of infectious mononucleosis in adults. It was found over 3 de- cades ago by electron microscopy of cells cultured from a Burkitt lymphoma. Since 1968, it has been known to cause infectious mononucleosis and has been associated with non- Hodgkin lymphoma and oral hairy leukoplakia in patients with HIV infection and with nasopharyngeal carcinoma, par- ticularly in Southeast Asia. Once a person is infected with EBV, the virus persists for life as a result of latency in B-cell lymphocytes and chronic replication in the cells of the oropharynx. The EBV genome is a linear DNA molecule that encodes for approximately 100 viral proteins that are expressed during replication. The CD21 molecule on the surface of the B-cell is the target receptor of the EBV glycoprotein envelope. Infection of B-cell lympho- cytes with EBV results in either viral replication and B-cell lysis (i.e., lytic replication) or a transformation of the cell with only partial EBV genome expression (i.e., latency). Cell trans- formation is associated with B-cell activation and continuous proliferation. In patients who are immunocompetent, prolif- eration of these transformed B cells usually is controlled by cytotoxic T cells. This is not the case, however, with patients who are immunosuppressed. The viral genome expresses only 9 proteins during latency, when it adopts an episomal configuration. This creates increased difficulty for T-cell recognition, facilitating persis- tent EBV infection, which is thought to occur in resting memory B cells. The 9 proteins expressed are EBV latent membrane proteins ([LMP], i.e., LMP-1, LMP-2A, LMP-2B) and EBV nuclear antigens ([NA], i.e., EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, EBNA-LP). LMP-1 is considered to be an oncogene. Its expression results in increased levels of CD23, which is a B-cell activation antigen. LMP-1 also is known to induce expression of bcl-2, which inhibits apoptosis of an infected cell. LMP-2 prevents reactivation of EBV in latently infected cells. EBNA-1 is responsible for maintaining the a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 358
  • 4. episomal configuration of the latent virus. EBNA-2 up-regu- lates the expression of LMP-1 and LMP-2, which are necessary for transformation of the B-cell. EBV infection results in both a humoral and cellular im- mune response by the host. Cellular immunity is thought to be the more important of the two in terms of regulation and control of proliferation of the infected B lymphocytes by means of CD4 and CD8 cytotoxic T cells and natural killer cells. Antibodies to viral capsid and nuclear proteins are pro- duced, the presence of which facilitates the diagnosis of EBV infection. In individuals who are immunocompetent, these mechanisms work well to prevent outgrowth of EBV-infected lymphocytes. In patients who are immunodeficient, a number of factors compromise these mechanisms. Production of an interleukin-10, an endogenous anti-T cell cytokine, has also been implicated. The immunosuppression required to preserve graft function post-transplantation results in impairment of T-cell immunity and allows for uncontrolled proliferation of EBV-infected B cells, resulting in monoclonal or polyclonal plasmacytic hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immuno- blastic lymphoma. Immune surveillance is impaired. As dis- cussed above, this outgrowth usually is regulated by cytotoxic T cells and natural killer cells. In the initial stages, the proliferation is polyclonal. With mutation and selective growth, the lesion becomes oligoclonal and, later, monoclonal. Cyclosporin was demonstrated many years ago to actually promote the proliferation of B lympho- cytes in vitro. Additionally, lymphocytes from patients treated with cyclosporin following transplantation do not exhibit an appropriate T-cell response to EBV-infected B cells in vitro. The activity of natural killer cells is reduced for several months post-transplantation, impairing cellular immune responsedthe most important regulator of proliferation. Depletion of T cells by use of anti-T-cell antibodies (ATG, ALG and OKT3) in the prevention or treatment of transplant rejection further increases the risk of developing post- transplant lymphoproliferative disorder. Other risk factors that have been identified as predictive for the development of PTLD include use of OKT3, anti- lymphocyte globulin, recipient pretransplant EBV seronega- tivity and donor EBV seropositivity. The incidence of PTLD has been found to be significantly higher in patients who are EBV seronegative pretransplant, compared with those who are seropositive (23.1% versus 0.7%) in Cockfield’s 1993 analysis.8 However, experience at the University of Pittsburgh, in the case of intestinal transplantation, the incidence of PTLD is as high in patients who are EBV seropositive pretransplantation as in patients who are seronegative. 3. Presentation and clinical features PTLD usually presents as one of four clinical syndromes. An onset similar to acute infectious mononucleosis with con- stitutional upset and tonsilar and cervical lymph node enlargement is the most common mode of presentation dur- ing the first year. Second a fulminating picture with wide- spread infiltration and ominous prognosis can present within weeks of the transplant. Later, a more indolent presentation may be seen with isolated or multiple tumors often involving the gastrointestinal tract, the lungs, or the allograft. Finally, one may see an EBV-negative type of PTLD which is of late onset and clinically resembles non-Hodgkin’s lymphoma. In those patients with localized organ involvement, the brain is frequently involved, much more often than in lymphoma in the general population. Whether PTLD presents as localized or disseminated dis- ease, the tumors are aggressive and rapidly progressive and often are fatal. Clinical presentation is very variable and in- cludes fever (57%), lymphadenopathy (38%), gastrointestinal symptoms (27%), infectious mononucleosis-like syndrome that can be fulminant (19%), pulmonary symptoms (15%), CNS symptoms (13%), and weight loss (9%). Patients may report fever, weight loss, anorexia, lethargy, sore throat, swollen glands, diarrhea, abdominal pain, shortness of breath, neu- rological symptoms, or symptoms that initially would not suggest a diagnosis of PTLD. The most common sites for involvement are lymph nodes (59%), liver (31%), lung (29%), kidney (25%), bone marrow (25%), small intestine (22%), spleen (21%), CNS (19%), large bowel (14%), tonsils (10%), and salivary glands (4%). 4. Evaluation A diagnosis of PTLD is made by having a high index of suspi- cion in the appropriate clinical setting; histopathological evi- dence of lymphoproliferation on tissue biopsy; and the presence of EBV DNA, RNA, or protein in tissue. The EBV status of the recipient usually is established pre- transplantation. Donor EBV status is not always sought rou- tinely because the incidence of infection with EBV in the general population is so high. In primary EBV infection, EBV viral capsid antigen (VCA) immunoglobulin M (IgM) titers are elevated. Reactivation of EBV infection is characterized by more than a 4-fold rise in EBV VCA immunoglobulin G (IgG) titers, com- pared with previously recorded EBV VCA IgG titers. No change in titer suggests past infection. These tests can be performed as part of a PTLD workup. Elevated titers of antibodies to VCA have been identified in recipients of solid organ grafts who developed PTLD. The absence of change in EBV antibody titers does not exclude a diagnosis of PTLD. However, increases in EBV viral load in the peripheral blood have been detected in patients prior to the onset of lymphoproliferative disease, and a decrease in these levels has occurred following effective treatment of PTLD. EBV viral load can be monitored by means of polymer- ase chain reaction (PCR). High viral loads have been found in a high proportion of patients with PTLD, but a high EBV viral titer is not diagnostic. This test is not standardized, and not all patients with PTLD have a high viral load.9 In addition to a high degree of vigilance in the appropriate clinical setting, histological confirmation of lymphoprolifera- tion is mandatory. Histopathologically, the lesion may dem- onstrate plasmacytic hyperplasia, B-cell hyperplasia, B-cell lymphoma, or immunoblastic lymphoma. The pathological diagnosis of PTLD is based on the WHO classification and in- cludes 4 main categories: (1) early lesions, (2) polymorphic a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 59
  • 5. PTLD, (3) monomorphic PTLD, and (4) classic Hodgkin lym- phoma (Fig. 1).10 In practice, a clear separation between the different sub- types is not always possible; early lesions, polymorphic PTLD, and monomorphic PTLD probably represent a spectrum of diseases.11 Immunohistologic staining can be used to confirm the presence of EBV. In situ hybridization with the EBV-encoded RNA (EpsteineBarr early region [EBER]-1) probe (labels EBV- encoded RNA in infected cells) is a reliable means of detect- ing EBV in tissue. It also requires demonstration of the pres- ence of EBV DNA or protein in the biopsied tissue. Nondetection of EBV is associated with tumors that present late, usually are monoclonal, and are more resistant to treat- ment. They are more likely to be disseminated and are less likely to achieve complete remission (Fig. 2). Establishing the clonality of the lesion is important. Tu- mors can be monoclonal, oligoclonal, polyclonal, or mixed. Some lymphomas may appear polyclonal by surface immu- noglobulin staining but are monoclonal by immunoglobulin rearrangement. Reports of patients with multiple disease sites, one lesion of which was monoclonal while a distant lesion was polyclonal, have occurred. Monoclonal PTLD has a worse prognosis, so multiple biopsy sites may be useful in defining prognosis in an individual with more than one lesion. Do not assume that if one site is polyclonal, all disease sites are polyclonal. PTLD does not demonstrate the 8:14 or 8:22 translocations associated with Burkitt lymphoma. PTLD can- not be differentiated into benign or malignant tumors. The mortality rate is high, independent of histology. With regard to T-cell lymphoproliferative disorders, these lesions predominantly are monoclonal. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction. It carries an unfavorable prognosis. Radiological evaluation includes computerized tomogra- phy scan of chest, abdomen, pelvis, and head, looking for evidence of hepatosplenomegaly, lymphadenopathy, or abnormal mass. T-cell lymphoproliferative disorders not associated with EBV infection tend to occur at extranodal sites. Reports exist of PTLD presenting in the oral cavity. Gastrointestinal PTLD usually involves the small and large intestine and most common presentation is fever, abdominal pain or perforation.12 It has been observed that gastric PTLD is more common in renal allograft recipients compared to other solid organ Fig. 2 e EBV early RNA (EBER) in PTLD tissue. Fig. 1 e Biopsy of gingival tissue, with haematoxylin and eosin stain demonstrates polymorphous infiltrate of atypical lymphoid cells, which is consistent with post- transplant lymphoproliferative disease (PTLD). a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 360
  • 6. transplantation but the exact cause of this difference is not well understood.13 5. Treatment Starzl et al were the first to suggest reduction, or withdrawal, of immunosuppression as a treatment option for PTLD.14 This serves to allow the patient’s natural immunity to recover and gain control over proliferating EBV-infected cells. Most pa- tients with benign PTLD respond well to this management approach. People with malignant disease often respond inadequately to these measures, and more aggressive treat- ment is necessary. A reduction in immunosuppressive ther- apy is not effective for CNS PTLD. T-cell PTLD usually is not associated with EBV infection and does not respond to immunosuppression dose reduction. Additional measures that have been used include surgical excision of the lesion (which can be curative in cases of localized disease), antiviral therapy, localized radiation ther- apy and chemotherapy, alfa interferon, intravenous gamma globulin, cytotoxic T lymphocytes, and monoclonal anti- bodies, each with varying degrees of success. Acyclovir and ganciclovir both inhibit lytic EBV DNA rep- lication in vitro. Ganciclovir is more potent than acyclovir. However, the majority of EBV-infected cells in lymphoproli- ferative lesions are transformed B cells. Acyclovir inhibits only the replication of linear EBV DNA and is ineffective against episomal EBV DNA, which is the conformation of the EBV genome in latent B lymphocytes. Interferon alfa has been found effective in the treatment of B-cell PTLD in some patients. It functions as both a proin- flammatory and antiviral agent. Interferon alfa inhibits the outgrowth of EBV-transformed B cells, and decreases the oropharyngeal shedding of EBV. It inhibits T helper cells, which release cytokines (i.e., interleukin IL-4, IL-6, IL-10) that promote B-cell proliferation.15 Intravenous immunoglobulin has been used as adjunctive therapy in the management of PTLD. Deficiency or absence of antibody against one of the EBNAs in patients post-trans- plantation has been associated with the subsequent devel- opment of PTLD. Decreasing EBV viral load has been reported to be associated with increased levels of antibody against EBNAs. These 2 factors provide the rationale for the use of intravenous immunoglobulin in the management of PTLD. It has been used mainly in combination with interferon alfa.16,17 A high mortality rate has been associated with the use of chemotherapy in the management of transplant-associated lymphoproliferative disease. In Cohen’s (1991) review of the value of chemotherapy and radiotherapy for the treatment of PTLD in transplant recipients, neither chemotherapy nor radiotherapy demonstrated any survival advantage compared with overall survival rates of 31%. In fact, survival rates were worse, at 23% and 20%, respectively. Swinnen et al, however, report a retrospective study of 19 cardiac transplant recipients with PTLD who initially were treated with reduced immunosuppression and acyclovir. The patients had all received OKT3 (i.e., monoclonal anti-T-cell antibody) as part of their immunosuppressive regimen. A sta- tistically significant reciprocal relationship exists between the dose of OKT3 used and time interval between transplantation and the onset of PTLD. Six of the patients had polyclonal dis- ease, and 13 had monoclonal. A large proportion of these pa- tients presented early post-transplantation with diffuse and aggressive disease. Those who survived and did not respond to initial management were treated with the combination che- motherapeutic regimen ProMACE-CytaBOM (prednisone, Adriamycin, Cytoxan, etoposide, arabinoside cytosine, bleo- mycin, Oncovin, and methotrexate). Of the 8 patients who received chemotherapy, all had monoclonal disease. This regimen was felt to be adequately immunosuppressive to obviate the need to continue with other immunosuppressive agentsduringchemotherapy,andnoepisodesofgraftrejection occurred. Seventy five per cent of patients achieved a complete remission, and no cases of relapse occurred at 38 months.2 The CHOP combination (cyclophosphamide, Adriamycin, Oncovin, and prednisone) has been used with high remission rates in cardiac transplant patients. However, the dose of doxorubicin in ProMACE-CytaBOM is half that used in CHOP, making ProMACE-CytaBOM less cardiotoxic and a more attractive therapeutic regimen. Benkerrou et al reported the long-term outcome of severe, aggressive PTLD following bone marrow and solid organ trans- plantation treated with B-cell antibodies, anti-CD21, anti-CD24. Eligibility criteria included lymphoproliferations not responsive to reduction in immunosuppression or rapidly progressive dis- ease. Complete remission was achieved in 61% of patients, with a relapse rate of 8%. The overall long-term survival rate was of the order of 46% at 61 months, although survival rates were lower among bone marrow transplant recipients (35%) com- pared with solid organ transplant patients (55%). They also identified as poor prognostic markers multivisceral disease, CNS involvement, and late-onset PTLD, which are findings that are consistent with results published by other authors.18 Rituximab, an anti-CD20 monoclonal antibody, has been used to treat non-Hodgkin lymphoma. Milpied et al in France reported promising results, with response rates of 65%, in patients with PTLD treated with rituximab following solid organ transplantation.19 According to Gross et al, rituximab can be combined with low-dose chemotherapy to create a safe and effective treatment for pediatric patients who have EpsteineBarr virus and PTLD following solid-organ transplantation.20 Papadopoulous et al postulated that the use of donor leu- kocyte infusions might treat PTLD effectively in the allograft recipient. They based this hypothesis on the premise that the donor has cytotoxic T lymphocytes, which are presensitized to the EBV responsible for the lymphoproliferation in the recipientdthe EBV being donor in origin. They studied 5 pa- tients who developed malignant B-cell lymphoma after receiving T-cell depleted allogeneic bone marrow trans- plantation. EBV DNA was detected in each tissue sample. All patients achieved complete clinical and pathological remis- sion in response to unirradiated infusions of donor leuko- cytes.21 The EBV-specific cytotoxic T lymphocytes from the donor, in the case of bone marrow transplantation, have the capability of recognizing and destroying EBV-infected B cells in the recipient. Solid organ transplant patients, however, develop PTLD that can be recipient or donor in origin, which in each case would have to be determined before initiation of a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 5 7 e6 3 61
  • 7. treatment. In the case of PTLD that is recipient in origin, to obtain cytotoxic T lymphocytes the recipient’s T cells would need to be stimulated against EBV ex vivodtechnology that is not yet available. 6. Prevention Prophylactic measures may include screening of donors and recipients for baseline EBV data, risk stratification, and using grafts from donors who are EBV seronegative where possible for seronegative recipients. EBV may be transmitted in blood transfusions, so the use of leukocyte filters may reduce the risk of EBV transmission from blood products. The use of routine acyclovir as prophylaxis is felt to be largely ineffective, as reported by Trigg et al and others.22 Darenkov et al reported a dramatic reduction in the inci- dence of PTLD in high-risk patients treated with anti- lymphocyte globulin when prophylactic therapy was administered in the form of ganciclovir (if donor/recipient were cytomegalovirus [CMV] positive) or acyclovir (if CMV negative) during anti-lymphocyte antibody therapy.23 Davis et al looked at the benefit of antiviral prophylaxis (intravenous ganciclovir followed by high-dose oral acyclovir) in kidney-pancreas and liver allograft recipients, again in the context of the use of antilymphocyte globulin. They found that the incidence of PTLD was lower with prophylactic anti- viral treatment.24 Birkeland et al reported that primary or reactivated EBV infection correlated with acute graft rejection and the inci- dence of PTLD. They additionally found that the use of acy- clovir (3200 mg/d for 3 months post-transplantation) was protective against primary or reactivated EBV infection and that the addition of mycophenolate mofetil resulted in further reduction of infection or reactivation. These patients also had been treated with antilymphocyte globulin. Serial monitoring of EBV viral load may be beneficial in the recognition of early PTLD and could be used to prevent pro- gression with the introduction of preemptive therapy.25 7. Surgery/radiotherapy In addition to boosting the immune system by reducing immunosuppression, surgical resection or the use of localized radiation therapy has been of value in some patients with PTLD.26 For a lesion that is focal, this approach may be cura- tive. Surgical management or focal radiation therapy is useful, especially for the treatment of localized complications of the disease. In Cohen’s (1991) review, survival rates of the order of 74% were noted for patients treated by surgical excision of the lesion, compared with an overall survival rate of 31%. Field radiation therapy now is felt to be the most effective treat- ment for PTLD involving the CNS. Conflicts of interest The author has none to declare. r e f e r e n c e s 1. Li L, Chaudhuri A, Weintraub LA, et al. Subclinical cytomegalovirus and EpsteineBarr virus viremia are associated with adverse outcomes in pediatric renal transplantation. Pediatr Transplant. 2007;11:187e195 [PubMed]. 2. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al. Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med. Dec 20 1990;323(25):1723e1728 [Medline]. 3. Penn I. The changing pattern of posttransplant malignancies. Transplant Proc. 1991;23:1101e1103 [PubMed]. 4. Cohen JI. EpsteineBarr virus infection. N Engl J Med. Aug 17 2000;343(7):481e492 [Medline]. 5. Shapiro R, Nalesnik M, McCauley J. Posttransplant lymphoproliferative disorders in adult and pediatric renal transplant patients receiving tacrolimus-based immunosuppression. Transplantation. Dec 27 1999;68(12):1851e1854 [Medline]. 6. Hauke R, Smir B, Greiner T. Clinical and pathological features of posttransplant lymphoproliferative disorders: influence on survival and response to treatment. Ann Oncol. Jun 2001;12(6):831e834 [Medline]. 7. Leblond V, Dhedin N, Mamzer Bruneel MF, et al. Identification of prognostic factors in 61 patients with posttransplantation lymphoproliferative disorders. J Clin Oncol. Feb 1 2001;19(3):772e778 [Medline]. 8. Cockfield SM, Preiksaitis JK, Jewell LD, Parfrey NA. Post- transplant lymphoproliferative disorder in renal allograft recipients. Clinical experience and risk factor analysis in a single center. Transplantation. Jul 1993;56(1):88e96 [Medline]. 9. Rooney CM, Loftin SK, Holladay MS. Early identification of EpsteineBarr virus-associated posttransplantation lymphoproliferative disease. Br J Haematol. Jan 1995;89(1):98e103 [Medline]. 10. Swerdlow SH, Webber SA, Chadburn A, Ferry JA. Posttransplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissue. Lyon: IARC; 2008:343e350. 11. Parker A, Bowles K, Bradley JA, et al. Diagnosis of post- transplant lymphoproliferative disorder in solid organ transplant recipients e BCSH and BTS guidelines. Br J Haematol; Apr 16 2010 [Medline]. 12. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80:1233e1243 [PubMed]. 13. Ponticelli C, Passerini P. Gastrointestinal complications in renal transplant recipients. Transpl Int. 2005;18:643e650 [PubMed]. 14. 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