Journal of Hepatology
Volume 44, Issue 1 , Pages 19-23, January 2006

Who is at risk for post-transplant lymphoproliferative disorders (PTLD) after liver transplantation?

The Transplant Center at The Cleveland Clinic Foundation, Department of General Surgery/A110, 9500 Euclid Avenue, Cleveland Clinic Foundation, Cleveland, OH 44195, USA

published online 08 November 2005.

Article Outline

Abbreviations: PTLD, port-transplant lymphoproliferative disorders, LTX, liver transplantation, EBV, Epstein–Barr virus, HCV, hepatitis C virus, CMV, cytomegalovirus

 

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication that may occur after any type of organ transplant requiring the use of exogenous immunosuppression. A review of the incidence of PTLD at a large single center noted the frequency of PTLD was 1.0% for renal transplant recipients, and 3.3, 2.7, and 3.8% for recipients of heart, liver, and heart–lung grafts respectively [1]. The incidence of PTLD has remained relatively stable in liver transplantation (LTX) in recent years, even with the advent of more potent immunosuppressive regimens. This is due, in part, to increased awareness and strategies for prophylaxis, monitoring and/or improved treatment options [2]. While there may still be some discrepancies in how PTLD is defined and characterized [3], in general, it is defined as a polyclonal or monoclonal lymphoid proliferation, generally of B-cells, generally of recipient origin [4], that occurs in the scenario of impaired T-cell function secondary to pharmacological immunosuppression. It includes a spectrum of entities ranging from polyclonal mononucleosis-like syndromes to monoclonal and monomorphic high-grade neoplastic lesions.

Several factors such as nature of immunosuppressive therapy, Epstein–Barr Virus (EBV) serological status, and underlying recipient disease have been reported to contribute to the development of PTLD. The aim of this review is to examine the associated variables for PTLD development in the context of LTX.

Back to Article Outline

1. Incidence 

According to analysis from single center and registry reports, the incidence of PTLD increased with the advent of calcineurin inhibitor use and anti-lymphocyte globulins, but during the last decade has stayed relatively stable. The reported incidence of PTLD in LTX recipients ranges from 1 to 2% in the adult population [1]. In the pediatric population, the incidence has been reported to be greater (5–15%) due to a higher percentage of EBV seronegative patients at the time of transplant, pointing to EBV as one of the major factors involved in the pathophysiology of PTLD [5], [6].

Back to Article Outline

2. Risk factors 

2.1. Immunosuppression 

While immunosuppression has been credited with significant improvements in LTX outcomes, the complications of long-term immunosuppression can be life threatening, including an increased risk of post-transplant malignancies [7]. The introduction of Cyclosporin A (CSA) was accompanied by increased rates of PTLD [8]. In reviewing published series, it is clear that the use of calcineurin inhibitors, OKT3 and antithymocyte globulins (ATG), potently suppress recipient T cell function, which in turn contributes to the expansion of EBV-infected B cells, increasing the risk of PTLD [9], [10]. On the other hand, the use of mycophenolate mofetil (MMF), sirolimus and anti-IL2 receptor monoclonal antibodies (Basiliximab, Daclixumab) has not been clearly associated with an increased risk of PTLD development after LTX [11], [12], [13].

2.2. Epstein–barr virus (EBV) 

EBV infects and immortalizes B-cells by the interaction of the viral surface glycoprotein gp350/200 with the cell surface protein CD21 of B-cells [14]. EBV causes 2 types of B cell infections: (a) lytic infection, where the virus replicates within the cell, viral particles are assembled and released resulting in cell death; and (b) viral incorporation into host DNA resulting in latency, where little infectious virus is produced.

EBV is a key factor in the pathophysiology of PTLD and the presence of EBV DNA within neoplastic tissue supports a role of viral proteins in the propagation of PTLD. Approximately 10 associated EBV genes are expressed in EBV associated PTLD—BCRF 1 and BARF 1 proteins allow infected cells to avoid immune detection, while LMP1 and LMP2 membrane proteins apparently act as oncogenes, permitting infected B cells to avoid apoptosis and proliferate in uncontrolled fashion [15].

The incidence of PTLD in EBV seronegative recipients has been reported to be as high as 24 times greater than that for EBV seropositive recipients, suggesting that seroconversion in the context of immunosuppression represents an increased risk. The transplantation of an EBV-negative recipient is associated with a higher risk of PTLD, due to the susceptibility to a primary EBV infection, either through transplantation of an EBV-positive organ (the majority of adult donors are EBV seropositive), transfusion of blood products with EBV infected B cells, or from the community at large. Thus, almost many seronegative patients will seroconvert after transplantation.

Reactivation of latent infection in the EBV seropositive recipient can also lead to PTLD. It is believed that EBV-specific CD8+T cells suppress transformed B cell proliferation. When these cytotoxic T lymphocytes are suppressed with exogenous immunosuppression, transformed B-cells can proliferate leading to clinical syndromes ranging from polyclonal lymphoid hyperplasia to monoclonal malignancies such as B-cell (and occasionally T-cell) lymphomas. The balance between EBV viral load and recipient immunity is suggested by the finding that a high viral load itself is not predictive of PTLD development (except for perhaps in primary EBV infections) [16], [17]. The combination of a high EBV load plus a EBV-specific T-cell depleted state, is more predictive of the higher risk to develop PTLD [18].

The utility of monitoring EBV viral loads in LTX recipients has not been clearly demonstrated—while some studies have suggested that high EBV DNA copies detected by polymerase chain reaction (PCR) in peripheral blood are associated with a higher risk of subsequent development of PTLD, others have not [19]. This may be due to the technical differences in methods of measurement, or the nature of the population at risk—in the pediatric population viral load monitoring has high sensitivity, but low specificity; on the other hand, in the adult population, EBV viral load monitoring was associated with a high specificity but low sensitivity [20].

The majority of PTLD in solid organ transplant (SOT) patients are of recipient origin, reflecting escape of recipient EBV-positive cells from immune surveillance. In a smaller number of cases (<10%), they are of donor origin, indicating that lymphoid cells transplanted with the allograft can undergo proliferation in a ‘tolerant’ environment created by the donor liver and immunosuppression. Donor PTLD has been reported in liver allograft recipients, and frequently involves the transplanted organ. It has been noted that PTLD of donor origin has a better outcome, and that could be because both the EBV antigens and the donor MHC antigens on the donor derived PTLD cells represent a stronger immune stimulus for the host response [21].

In contrast, non-EBV related PTLD have also been described—they usually develop later after transplantation in comparison with EBV related PTLD, however, little is known about the inciting factors in this variation of PTLD [22], [23], [24]. EBV negative PTLD have historically represented less than 5% of PTLD, although recently incidences up to 23% have been noted [24]. In addition, these EBV negative PTLD tend to be late onset and monomorphic with worse outcome [22]. The search for an infectious etiology has not proven definitive, occasional HHV-8 and Heliobacter have been noted, and preliminary data suggests that SV40 was positive in 15% of PTLD (Michael Nalesnik, personal communication, July 2002).

2.3. Age 

A higher incidence of PTLD has been noted in the pediatric population (age 0–18 years) for whom the incidence ranges from 1 up to 15% after LTX. PTLD represent the most common tumors in children after organ transplantation, being 52% of all tumors vs. 15% in adult recipients [5], [6], [7]. This is related to the fact that EBV-naive transplant recipients are at an increased risk for the development of PTLD. Although age may not be an independent risk factor, some reports mention that a younger age, independent of EBV status, is associated to a higher risk; children younger than 5 years are at greatest risk for PTLD—this risk declines with increasing age. In the adult population there was a higher risk when patients were older than 50 years.

2.4. Type of allograft 

While liver allograft recipients have a lower risk of developing PTLD when compared to other solid organs, such as heart, lung or small bowel—the incidence of liver/small bowel is as high as for small bowel transplants alone [25]. The explanation for this discrepancy may be related to the use of less potent overall immunosuppression regimens in LTX as compared to other organs.

2.5. Hepatitis C and PTLD 

Hepatitis C Virus (HCV) is a hepatotropic virus with a number of associated extrahepatic manifestations. These include, among others, hematological, neurological, renal and dermatological disorders [34]. HCV also been reported to have a lymphotropic capacity, causing expansion of B cell clones and the production of cryoglobulinemia and frank lymphomas [26], [27], [28]. This leads to the implication of HCV in the pathogenesis of PTLD, not only in post-liver transplant patients, but also in other organ transplants as well. Viral replication has been detected in either active or latent forms in peripheral lymphocytes of patients with HCV infections. This has been associated with secondary types II and III mixed cryoglobulinemia (MC). These two syndromes share clinical manifestations but with long-term follow up, type II MC can degenerate into non-Hodgkins lymphoma [29].

The understanding of the mechanism by which HCV mediates or potentiates the development of PTLD is still in evolution [30]. However, unlike EBV, HCV cannot integrate into the human genome—HCV is an RNA virus with no DNA intermediates of replication. This excludes the possibility of direct genetic integration of viral sequences in the human genome. HCV infection is inherently a chronic one in most cases and this chronic lymphoid stimulation may lead to clonal expansion of B-cells. As shown in Fig. 1, the t(14:18) translocation has been reported in peripheral lymphocytes of HCV-infected patients and leads to the activation of the anti-apoptotic gene Bcl-2 [31], [32]. This phenomenon may help explain how HCV may be implicated, not only in PTLD, but also in other forms of malignancy associated with HCV infection. Lastly, the HCV envelope protein E2 has been shown in laboratory experiments to bind the CD81 molecule, which is expressed on the cell surface of both hepatocytes and B-lymphocytes. This interaction may increase the rate of VDJ rearrangements and subsequently enhances the sensitivity of B-cells to be activated and expand secondary to antigen specific stimulation [32].

  • View full-size image.
  • Fig. 1. 

    Presumed molecular changes that lead to malignant transformation of B-cells secondary to HCV infection. Reproduced from Clin Exp Rheumatol 2003; 21(6 Suppl 32):S78–84.

2.6. Cytomegalovirus 

Cytomegalovirus (CMV) infection has been also reported to be associated with an increased risk of PTLD. Seronegative CMV transplant recipients who received a CMV positive allograft had a 4–6 fold higher risk of PTLD [33]. In a study of 40 adult, EBV seronegative, LTX recipients where 33% developed PTLD—a diagnosis of CMV infection posttransplant increased the incidence of PTLD to 7.3% [22].

2.7. Underlying disease 

There are several reports that have associated the underlying liver disease as a risk factor for PTLD. For example, autoimmune disorders such as autoimmune hepatitis or primary biliary cirrhosis may predispose to PTLD [34]. Another described association was reported for liver transplant recipients with Langerhans cell histiocytosis [35]. Hepatitis C was associated with a 10.5% frequency of PTLD in liver transplant patients, compared with other etiologies where the frequency was 1.7%, while alcoholic cirrhosis was also associated with PTLD [36].

Back to Article Outline

3. Discussion 

PTLD is a disease entity with multifactorial pathogenesis that requires further investigation of the factors and mechanisms of disease. It is clear that the major protagonist in the pathophysiology of PTLD is the relationship of an immunosuppressed state and EBV infection. Nevertheless, the changing profile of PTLD with increasing non-EBV PTLD and the possible role of CMV and HCV warrant further study.

From a clinician's standpoint, most PTLD will develop in the first year after LTX. Children have an incidence of PTLD that is at least threefold higher than adults. However, patient survival appears to be better in children. In addition, patients with polymorphic PTLD and those with limited disease also appear to fare better. Interestingly, neither the presence or absence of EBV nor the timing of PTLD presentation appeared to influence overall patient survival. Patients transplanted for alcohol-related liver disease appear to have a similar incidence of PTLD but are at higher risk of mortality. While factors such as CMV and HCV infection appear to influence the risk of PTLD, it is unclear how they do so. Nevertheless, it is important that the transplant physician is aware of them in order to lower their threshold for considering PLTD in an appropriate clinical context. The complexity of the post-LTX clinical picture and the relatively insidious onset of PTLD make a high degree of suspicion crucial for early diagnosis.

While beyond the scope of this review, treatment of PTLD has changed little in principle from the early experiences [37]. The first therapeutic approach is to hold or reduce the immunosuppression—this often controls the disease until the recipient immune system recovers the anti-EBV T cell response. Of interest, is that this approach has also proven to be effective in non-EBV PTLD cases. As a second line of therapy, the anti-CD20 monoclonal antibody (Rituximab) has been utilized with good results, though in cases that the lesions do not express CD20, this agent would not be useful [38]. Anti-B-cell antibodies linked to radionuclides such as iodine-131 or yttrium-90 promise good results but further studies are needed.

The use of antiviral agents such as acyclovir and gancyclovir are effective against replicating virus, but the predominant form of EBV in PTLD is latent. However some virions in the lytic cycle can be present and eliminated with antiviral therapy. The use of EBV-specific immunoglobulin has been suggested to a beneficial effect for prophylaxis in those recipients who are high risk for EBV infection [2]. When there is disseminated PTLD or life threatening PTLD, the therapeutic option is often chemotherapy. Cellular immunotherapy represents another therapeutic approach and consists in collecting and transfusing donor T-cells that were stimulated with EBV-positive B cells, however, there are several logistical issues with this approach [39].

It is important to emphasize the role of HCV with PTLD, since it is the leading cause of end stage liver disease in a large portion of the world. It has been demonstrated that clonal expansion of B-cells triggered by chronic HCV infection may lead to the development of PTLD. Treatment targeted to the HCV can modulate PTLD in this setting [40].

In conclusion, PTLD following LTX it is most often associated with EBV infection in the context of iatrogenic immunosuppression. The identification of particular risk factors for PTLD in a given patient will help to establish an earlier diagnosis and facilitate implementation of the treatment.

Back to Article Outline

References 

  1. Nalesnik MA, Starzl TE. Epstein–Barr virus, infectious mononucleosis, and posttransplant lymphoproliferative disorders. Transpl Sci. 1994;4:61–79
  2. Rowe DT, Webber S, Schauer EM, Reyes J, Green M. Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transpl Infect Dis. 2001;3:79–87
  3. Paya CV, Fung JJ, Nalesnik MA, Kieff E, Green M, Gores G, et al. Epstein–Barr Virus-induced posttransplant lymphoproliferative disorders. Transplantation. 1999;68:1517–1525
  4. Larson RS, Scott MA, McCurley TL, Vnencak-Jones CL. Microsatellite analysis of posttransplant lymphoproliferative disorders: determination of donor/recipient origin and identification of putative lymphomagenic mechanism. Cancer Res. 1996;56:4378–4481
  5. Smets F, Sokal EM. Epstein–Baar virus-related lymphoproliferation in children after liver transplantation: role of immunity, diagnosis, and management. Pediatr Transplant. 2002;280–287
  6. Newell KA, Alonso EM, Whitington PF, Bruce DS, Millis JM, Piper JB, et al. Post-transplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus and immunosuppression. Transplantation. 1996;62:370–375
  7. Jain A, Nalesnik M, Reyes J, Pokharna R, Mazariegos G, Green M, et al. Posttransplant lymphoproliferative disorders in liver transplantation: a 20-year experience. Ann Surg. 2002;236:429–437
  8. Calne RY, Rolles K, White DJ, Thiru S, Evans DB, McMaster P, et al. Cyclosporin A initially as the only immunosuppressant in 34 recipients of cadaveric organs: 32 kidneys, 2 pancreases, and 2 livers. Lancet. 1979;2:1033–1036
  9. Domingo-Domenech E, de Sanjose S, Gonzalez-Barca E, Romagosa V, Domingo-Claros A, Gil-Vernet S, et al. : Post-transplant lymphomas: a 20-year epidemiologic, clinical and pathologic study in a single center. Haematologica. 2001;86:715–721
  10. Sokal EM, Antunes H, Beguin C, Bodeus M, Wallemacq P, de Ville de Goyet J, et al. Early signs and risk factors for the increased incidence of Epstein–Barr virus-related posttransplant lymphoproliferative diseases in pediatric liver transplant recipients treated with tacrolimus. Transplantation. 1997;64:1438–1442
  11. Chardot C, Nicoluzzi JE, Janssen M, Sokal E, Lerut J, Otte JB, et al. Use of mycophenolate mofetil as rescue therapy after pediatric liver transplantation. Transplantation. 2001;71:224–229
  12. Jimenez-Rivera C, Avitzur Y, Fecteau AH, Jones N, Grant D, Ng VL, et al. Sirolimus for pediatric liver transplant recipients with posttransplant lymphoproliferative disease and hepatoblastoma. Pediatr Transplant. 2004;8:243–248
  13. Langrehr JM, Glanemann M, Guckelberger O, Klupp J, Neumann U, Machens C, et al. A randomized, placebo-controlled trial with anti-interleukin-2 receptor antibody for immunosuppression induction therapy after liver transplantation. Clin Transplant. 1998;12:303–312
  14. Kieff E. Epstein–Barr virus and its replication. In:  Fields BN,  Knipe DM,  Howley PM, editor. Fields virology. Philadelphia, PA: Lippincott-Raven; 1996;p. 2343
  15. Cohen JI. Epstein–Barr virus infection. N Engl J Med. 2000;343:481–492
  16. Rooney CM, Loftin SK, Holladay MS, Brenner MK, Krance RA, Heslop HE, et al. Early identification of Epstein–Barr virus-associated post-transplant lymphoproliferative disease. Br J Haematol. 1995;89:98
  17. Green M, Webber SA. EBV viral load monitoring: unanswered questions. Am J Transplant. 2002;2:894–895
  18. Smets F, Latinne D, Bazin H, Reding R, Otte JB, Buts JP, et al. Ratio between Epstein–Barr viral load and anti-Epstein–Barr virus specific T-cell response as a predictive marker of posttransplant lymphoproliferative disease. Transplantation. 2002;73:1603–1610
  19. Scheenstra R, Verschuuren EA, de Haan A, Slooff MJ, The TH, Bijleveld CM, et al. The value of prospective monitoring of Epstein–Barr virus DNA in blood samples of pediatric liver transplant recipients. Transpl Infect Dis. 2004;6:15–22
  20. Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, et al. Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation. 2001;72:1012–1019
  21. Armes JE, Angus P, Southey MC, Battaglia SE, Ross BC, Jones RM, et al. Lymphoproliferative disease of donor origin arising in patients after orthotopic liver transplantation. Cancer. 1994;74:2436–2441
  22. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, et al. Posttransplant lymphoproliferative disorders not associated with Epstein–Barr virus: a distinct entity?. J Clin Oncol. 1998;16:2052–2059
  23. Ghobrial IM, Habermann TM, Macon WR, Ristow KM, Larson TS, Walker RC, et al. Differences between early and late posttransplant lymphoproliferative disorders in solid organ transplant patients: are they two different diseases?. Transplantation. 2005;79:244–247
  24. Nelson BP, Nalesnik MA, Bahler DW, Locker J, Fung JJ, Swerdlow SH. Epstein Barr virus negative post-transplant lymphoproliferative disorders: a distinct entity?. Am J Surg Pathol. 2001;25:324–330
  25. Finn L, Reyes J, Bueno J, Yunis E. Epstein–Barr virus infections in children after transplantation of the small intestine. Am J Surg Pathol. 1998;22:299–309
  26. Michaelis S, Kazakov DV, Schmid M, Dummer R, Burg G, Kempf W. Hepatitis C and G viruses in B-cell lymphomas of the skin. J Cutan Pathol. 2003;30:369–372
  27. Starkebaum G, Sasso EH. Hepatitis C and B cells: induction of autoimmunity and lymphoproliferation may reflect chronic stimulation through cell-surface receptors. J Rheumatol. 2004;31:416–418
  28. Bianco E, Marcucci F, Mele A, Musto P, Cotichini R, Sanpaolo MG, et al. Prevalence of hepatitis C virus infection in lymphoproliferative diseases other than B-cell non-Hodgkin's lymphoma, and in myeloproliferative diseases: an Italian Multi-Center case-control study. Haematologica. 2004;89:70–76
  29. Agnello V. Hepatitis C virus infection and type II cryoglobulinemia: an immunological perspective. Hepatology. 1997;26:1375–1379
  30. Hezode C, Duvoux C, Germanidis G, Roudot-Thoraval F, Vincens AL, Gaulard P, et al. Role of hepatitis C virus in lymphoproliferative disorders after liver transplantation. Hepatology. 1999;30:775–778
  31. Giannelli F, Moscarella S, Giannini C, Caini P, Monti M, Gragnani L, et al. Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation. Blood. 2003;102:1196–1201
  32. Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, et al. Binding of hepatitis C virus to CD81. Science. 1998;282:938–941
  33. Walker RC, Marshall WF, Strickler JG, et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis. 1995;20:1346–1353
  34. Shpilberg O, Wilson J, Whiteside TL, Herberman RB. Pre-transplant immunological profile and risk factor analysis of post-transplant lymphoproliferative disease development: the results of a nested matched case-control study: the University of Pittsburgh PTLD Study Group. Leuk Lymphoma. 1999;36:109
  35. Newell KA, Alonso EM, Kelly SM, Rubin CM, Thistlethwaite JR, Whitington PF. Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children. J Pediatr. 1999;131:98
  36. Duvoux C, Pageaux GP, Vanlemmens C, Roudot-Thoraval F, Vincens-Rolland AL, Hezode C, et al. Risk factors for lymphoproliferative disorders after liver transplantation in adults: an analysis of 480 patients. Transplantation. 2002;74:1103–1109
  37. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984;1:583–587
  38. Ghobrial IM, Habermann TM, Ristow KM, Ansell SM, Macon W, Geyer SM, et al. Prognostic factors in patients with post-transplant lymphoproliferative disorders (PTLD) in the rituximab era. Leuk Lymphoma. 2005;46:191–196
  39. Popescu I, Macedo C, Zeevi A, Nellis J, Patterson KR, Logar A, et al. Ex vivo priming of naive T cells into EBV-specific Th1/Tc1 effector cells by mature autologous DC loaded with apoptotic/necrotic LCL. Am J Transplant. 2003;3:1369–1377
  40. Tursi A, Brandimarte G, Torello M. Disappearance of gastric mucosa-associated lymphoid tissue in hepatitis C virus-positive patients after anti-hepatitis C virus therapy. J Clin Gastroenterol. 2004;38:360–363

PII: S0168-8278(05)00674-4

doi:10.1016/j.jhep.2005.10.008

Journal of Hepatology
Volume 44, Issue 1 , Pages 19-23, January 2006

Article Tools

* Image Usage & Resolution