Skip to main content

Advertisement

SpringerLink
Log in

A single-centre experience of post-renal transplant lymphoproliferative disorder

  • Original Article
  • Published:
Transplant International

Abstract

Post-transplant lymphoproliferative disorder (PTLD) complicates 1 to 10% of all transplantations. Previous clinicopathological studies of PTLD have been limited by small numbers, short follow-up times, outdated data, heterogeneity of pooled solid-organ transplant results, and selective inclusion of early-onset disease. We therefore undertake here a retrospective analysis and identify all cases of PTLD that complicated renal transplantation at the Princess Alexandra Hospital between 30 June 1969 and 31 May 2001. Tumour samples were subsequently retrieved for pathological review and for Epstein–Barr virus-encoded RNA in situ hybridisation (EBER-ISH). Of 2,030 renal transplantation patients, 29 (1.4%) developed PTLD after a median period of 0.5 years (range 0.1 to 23.3 years). PTLD patients were more likely to have received cyclosporine (76% versus 62%, P<0.05), tacrolimus (10% versus 2%, P<0.05) and OKT3 (28% versus 10%, P<0.01). As the burden of immunosuppression increased from dual, to triple, to OKT3 therapy, the risks of early onset, extensive-stage, polymorphic, Epstein–Barr virus (EBV)-associated and fatal PTLD progressively increased. The majority of patients presented with an extra-nodal mass (45%), were afebrile (76%), and had stage-IV disease (60%). EBER-ISH was positive in 58%. Actuarial 5-year disease-free survival was 53.7%. The independent predictors of mortality on multivariate Cox regression were polymorphic histology (HR 7.4, 95% CI 1.5–37) and an international prognostic index (IPI) >1 (HR 2.7, 95% CI 1.1–6.8). Compared with other treatments, chemotherapy was associated with higher survival rates (100% versus 18% at 3 years, P=0.0001). In conclusion, PTLD is more likely, occurs earlier, and is more often fatal, in the setting of intensive immunosuppression. Nevertheless, excellent long-term outcomes are achievable with early recognition and institution of appropriate treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. Anonymous (1993) A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987–994

    PubMed  Google Scholar 

  2. Baiocchi RA, Caligiuri MA (1994) Low-dose interleukin 2 prevents the development of Epstein–Barr virus (EBV)-associated lymphoproliferative disease in scid/scid mice reconstituted i.p. with EBV-seropositive human peripheral blood lymphocytes. Proc Natl Acad Sci U S A 91:5577–5581

    Google Scholar 

  3. Batiuk TD, Barry JM, Bennett WM, Meyer MM, Tolzman D, Norman DJ (1993) Incidence and type of cancer following the use of OKT3: a single center experience with 557 organ transplants. Transplant Proc 25:1391

    CAS  PubMed  Google Scholar 

  4. Blanche S, Le Deist F, Veber F, Lenoir G, Fischer AM, Brochier J, Boucheix C, Delaage M, Griscelli C, Fischer A (1988) Treatment of severe Epstein–Barr virus-induced polyclonal B-lymphocyte proliferation by anti-B-cell monoclonal antibodies. Two cases after HLA-mismatched bone marrow transplantation. Ann Intern Med 108:199–203

    CAS  PubMed  Google Scholar 

  5. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971) Report of the Committee on Hodgkin's Disease Staging Classification. Cancer Res 31:1860–1861

    CAS  PubMed  Google Scholar 

  6. Cleary ML, Nalesnik MA, Shearer WT, Sklar J (1988) Clonal analysis of transplant-associated lymphoproliferations based on the structure of the genomic termini of the Epstein–Barr virus. Blood 72:349–352

    CAS  PubMed  Google Scholar 

  7. Cohen JI (1991) Epstein–Barr virus lymphoproliferative disease associated with acquired immunodeficiency. Medicine (Baltimore) 70:137–160

    Google Scholar 

  8. Fischer A, Blanche S, Le Bidois J, Bordigoni P, Garnier JL, Niaudet P, Morinet F, Le Deist F, Fischer AM, Griscelli C, et al. (1991) Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. N Engl J Med 324:1451–1456

    CAS  PubMed  Google Scholar 

  9. Frizzera G, Hanto DW, Gajl Peczalska KJ, Rosai J, McKenna RW, Sibley RK, Holahan KP, Lindquist LL (1981) Polymorphic diffuse B-cell hyperplasias and lymphomas in renal transplant recipients. Cancer Res 41:4262–4279

    CAS  PubMed  Google Scholar 

  10. Gruber SA, Skjei KL, Sothern RB, Robison L, Tzardis P, Moss A, Gillingham K, Canafax DM, Matas AJ, Dunn DL (1991) Cancer development in renal allograft recipients treated with conventional and cyclosporine immunosuppression. Transplant Proc 23:1104–1105

    CAS  PubMed  Google Scholar 

  11. Hanto DW, Frizzera G, Gajl Peczalska J, Purtilo DT, Klein G, Simmons RL, Najarian JS (1981) The Epstein–Barr virus (EBV) in the pathogenesis of posttransplant lymphoma. Transplant Proc 13:756–760

    CAS  PubMed  Google Scholar 

  12. Hanto DW, Frizzera G, Purtilo DT, Sakamoto K, Sullivan JL, Saemundsen AK, Klein G, Simmons RL, Najarian JS (1981) Clinical spectrum of lymphoproliferative disorders in renal transplant recipients and evidence for the role of the Epstein–Barr virus. Cancer Res 41:4253–4261

    CAS  PubMed  Google Scholar 

  13. Hanto DW, Frizzera G, Gajl Peczalska KJ, Sakamoto K, Purtilo DT, Balfour HH, Jr, Simmons RL, Najarian JS (1982) Epstein–Barr virus-induced B-cell lymphoma after renal transplantation: acyclovir therapy and transition from polyclonal to monoclonal B-cell proliferation. N Engl J Med 306:913–918

    Google Scholar 

  14. Hanto DW, Gajl Peczalska KJ, Frizzera G, Arthur DC, Balfour HH Jr, McClain K, Simmons RL, Najarian JS (1983) Epstein–Barr virus (EBV) induced polyclonal and monoclonal B-cell lymphoproliferative diseases occurring after renal transplantation. Clinical, pathologic, and virologic findings and implications for therapy. Ann Surg 198:356–369

    CAS  PubMed  Google Scholar 

  15. Hanto DW, Frizzera G, Gajl Peczalska KJ, Simmons RL (1985) Epstein–Barr virus, immunodeficiency, and B cell lymphoproliferation. Transplantation 39:461–472

    CAS  PubMed  Google Scholar 

  16. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD (2000) The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 13:193–207

    CAS  PubMed  Google Scholar 

  17. Ho M, Jaffe R, Miller G, Breinig MK, Dummer JS, Makowka L, Atchison RW, Karrer F, Nalesnik MA, Starzl TE (1988) The frequency of Epstein–Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 45:719–727

    CAS  PubMed  Google Scholar 

  18. Hoelzer D, Thiel E, Loffler H, Bodenstein H, Plaumann L, Buchner T, Urbanitz D, Koch P, Heimpel H, Engelhardt R (1984) Intensified therapy in acute lymphoblastic and acute undifferentiated leukemia in adults. Blood 64:38–47

    CAS  PubMed  Google Scholar 

  19. Hummel M, Anagnostopoulos I, Dallenbach F, Korbjuhn P, Dimmler C, Stein H (1992) EBV infection patterns in Hodgkin's disease and normal lymphoid tissue: expression and cellular localization of EBV gene products. Br J Haematol 82:689–694

    CAS  PubMed  Google Scholar 

  20. Khatri VP, Baiocchi RA, Bernstein ZP, Caligiuri MA (1997) Immunotherapy with low-dose interleukin-2: rationale for prevention of immune-deficiency-associated cancer. Cancer J Sci Am 3 [Suppl 1]:S129–136

  21. Khouri IF, Romaguera J, Kantarjian H, Palmer JL, Pugh WC, Korbling M, Hagemeister F, Samuels B, Rodriguez A, Giralt S, Younes A, Przepiorka D, Claxton D, Cabanillas F, Champlin R (1998) Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma. J Clin Oncol 16:3803–3809

    CAS  PubMed  Google Scholar 

  22. Leblond V, Sutton L, Dorent R, Davi F, Bitker MO, Gabarre J, Charlotte F, Ghoussoub JJ, Fourcade C, Fischer A, et al. (1995) Lymphoproliferative disorders after organ transplantation: a report of 24 cases observed in a single center. J Clin Oncol 13:961–968

    CAS  PubMed  Google Scholar 

  23. Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, Gandjbakhch I, Binet JL, Raphael M (1998) Posttransplant lymphoproliferative disorders not associated with Epstein–Barr virus: a distinct entity? J Clin Oncol 16:2052–2059

    Google Scholar 

  24. List AF, Greco FA, Vogler LB (1987) Lymphoproliferative diseases in immunocompromised hosts: the role of Epstein–Barr virus. J Clin Oncol 5:1673–1689

    CAS  PubMed  Google Scholar 

  25. Mathur A, Kamat DM, Filipovich AH, Steinbuch M, Shapiro RS (1994) Immunoregulatory abnormalities in patients with Epstein–Barr virus-associated B cell lymphoproliferative disorders. Transplantation 57:1042–1045

    CAS  PubMed  Google Scholar 

  26. McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, Lane M, Gamble JF, Jones SE, Grozea PN, Gutterman J, Coltman C, Moon TE (1976) hydroxyldaunomycin (Adriamycin) combination chemotherapy in malignant lymphoma. Cancer 38:1484–1493

    CAS  PubMed  Google Scholar 

  27. Mihalov ML, Gattuso P, Abraham K, Holmes EW, Reddy V (1996) Incidence of post-transplant malignancy among 674 solid-organ-transplant recipients at a single center. Clin Transplant 10:248–255

    CAS  PubMed  Google Scholar 

  28. Morrison VA, Dunn DL, Manivel JC, Gajl Peczalska KJ, Peterson BA (1994) Clinical characteristics of post-transplant lymphoproliferative disorders. Am J Med 97:14–24

    CAS  Google Scholar 

  29. Nalesnik MA, Rao AS, Furukawa H, Pham S, Zeevi A, Fung JJ, Klein G, Gritsch HA, Elder E, Whiteside TL, Starzl TE (1997) Autologous lymphokine-activated killer cell therapy of Epstein–Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients. Transplantation 63:1200–1205

    CAS  PubMed  Google Scholar 

  30. Nalesnik MA, Jaffe R, Starzl TE, Demetris AJ, Porter K, Burnham JA, Makowka L, Ho M, Locker J (1988) The pathology of posttransplant lymphoproliferative disorders occurring in the setting of Cyclosporin A prednisone immunosuppression. Am J Pathol 133:173–192

    CAS  PubMed  Google Scholar 

  31. O'Brien S, Bernert RA, Logan JL, Lien YH (1997) Remission of posttransplant lymphoproliferative disorder after interferon alfa therapy. J Am Soc Nephrol 8:1483–1489

    CAS  PubMed  Google Scholar 

  32. Opelz G (1996) Are post-transplant lymphomas inevitable? Nephrol Dial Transplant 11:1952–1955

    Google Scholar 

  33. Opelz G, Henderson R (1993) Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 342:1514–1516

    CAS  PubMed  Google Scholar 

  34. Paiva A, Freitas L, Pratas J, Gomes H, Mota A, Marques A, Furtado AL (1998) Post-transplant lymphoproliferative disease. Nephrol Dial Transplant 13:2968–2971

    CAS  PubMed  Google Scholar 

  35. Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH, Castro Malaspina H, Childs BH, Gillio AP, Small TN, et al. (1994) Infusions of donor leukocytes to treat Epstein–Barr virus-associated lymphoproliferative disorders after allogeneic bone marrow transplantation. N Engl J Med 330:1185–1191

    Google Scholar 

  36. Pedagogos E, Dowling J, Rockman S, Nicholls K, Fraser I, Walker R (1996) Lymphoproliferative disorder post renal transplantation: recent experience at a single centre. Nephrology 2:133–141

    Google Scholar 

  37. Penn I (1988) Tumors of the immunocompromised patient. Annu Rev Med 39:63–73

    Article  CAS  PubMed  Google Scholar 

  38. Penn I (1990) Cancers complicating organ. N Engl J Med 323:1767–1769

    CAS  PubMed  Google Scholar 

  39. Penn I, Brunson ME (1988) Cancers after cyclosporine therapy. Transplant Proc 20:885–892

    CAS  Google Scholar 

  40. Seiden MV, Sklar J (1993) Molecular genetic analysis of post-transplant lymphoproliferative disorders. Hematol Oncol Clin North Am 7:447–465

    CAS  PubMed  Google Scholar 

  41. Shapiro RS, Chauvenet A, McGuire W, Pearson A, Craft AW, McGlave P, Filipovich A (1988) Treatment of B-cell lymphoproliferative disorders with interferon alfa and intravenous gamma globulin. N Engl J Med 318:1334

    CAS  PubMed  Google Scholar 

  42. Shapiro RS, McClain K, Frizzera G, Gajl Peczalska KJ, Kersey JH, Blazar BR, Arthur DC, Patton DF, Greenberg JS, Burke B (1988) Epstein–Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71:1234–1243

    CAS  PubMed  Google Scholar 

  43. Smith JL, Wilkinson AH, Hunsicker LG, Tobacman J, Kapelanski DP, Johnson M, Wright FH, Behrendt DM, Corry RJ (1989) Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone. Transplant Proc 21:3199–3200

    CAS  PubMed  Google Scholar 

  44. Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW Jr, Hardesty RL (1984) Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporine-steroid therapy. Lancet 1:583–587

    CAS  PubMed  Google Scholar 

  45. Sullivan JL, Byron KS, Brewster FE, Sakamoto K, Shaw JE, Pagano JS (1982) Treatment of life-threatening Epstein–Barr virus infection with acyclovir. Am J Med 73:262–266

    CAS  PubMed  Google Scholar 

  46. Swinnen LJ (2000) Diagnosis and treatment of transplant-related lymphoma. Ann Oncol 11 [Suppl 1]:45–48

    Google Scholar 

  47. Swinnen LJ, Costanzo Nordin MR, Fisher SG, O'Sullivan EJ, Johnson MR, Heroux AL, Dizikes GJ, Pifarre R, Fisher RI (1990) Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients (comments). N Engl J Med 323:1723–1728

    CAS  PubMed  Google Scholar 

  48. Wilkinson AH, Smith JL, Hunsicker LG, Tobacman J, Kapelanski DP, Johnson M, Wright FH, Behrendt DM, Corry RJ (1989) Increased frequency of posttransplant lymphomas in patients treated with cyclosporine, azathioprine, and prednisone. Transplantation 47:293–296

    CAS  PubMed  Google Scholar 

  49. World Health Organization (1979) WHO handbook for reporting results of cancer treatment. WHO, Geneva

Download references

Author information

Authors and Affiliations

  1. Department of Renal Medicine, Level 2, Ambulatory Renal and Transplant Services Building, University of Queensland, Princess Alexandra Hospital, Ipswich Road, QLD 4102, Woolloongabba, Brisbane, Queensland, Australia

    Karen A. Herzig, Allison M. Brown, Carmel M. Hawley, James B. Petrie, Scott B. Campbell, David L. Nicol & David W. Johnson

  2. Departments of Haematology and Oncology, University of Queensland at Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia

    Helen G. Juffs, Devinder Gill, Ralph Cobcroft, Paula Marlton & Damien Thomson

  3. Department of Pathology, Mater Misericordiae Hospital, Brisbane, Queensland, Australia

    Debra Norris

Authors
  1. Karen A. Herzig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Helen G. Juffs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debra Norris
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Allison M. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Devinder Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carmel M. Hawley
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ralph Cobcroft
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. James B. Petrie
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paula Marlton
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Damien Thomson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Scott B. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. David L. Nicol
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. David W. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David W. Johnson.

About this article

Cite this article

Herzig, K.A., Juffs, H.G., Norris, D. et al. A single-centre experience of post-renal transplant lymphoproliferative disorder. Transpl Int 16, 529–536 (2003). https://doi.org/10.1007/s00147-003-0596-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00147-003-0596-0

Keywords

Search

Navigation