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Post-Transplant Malignancy

The Role Of Immunosuppression

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Abstract

Immunosuppressed organ allograft recipients have a 3- to 4-fold increased risk of developing tumours, but the risk of developing certain cancers is increased several hundredfold. With the exception of skin and lip cancers,most of the common malignancies seen in the general population are not increased in incidence. Instead, there is a higher frequency of some relatively rare tumours, including post-transplant lymphomas and lymphoproliferative disorders (PTLD), Kaposi’s sarcoma (KS), renal carcinomas, in situ carcinomas of the uterine cervix, hepatobiliary carcinomas, anogenital carcinomas and various sarcomas (excluding KS). Skin and lip cancers present some unusual features: a remarkable frequency of KS, reversal of the ratio of basal to squamous cell carcinomas seen in the general population, the young age of the patients, and the high incidence of multiple tumours (in 43%of the patients). Anogenital cancers occur at a much younger age than in the general population. Salient features of PTLD are the high frequency of Epstein-Barr virus-related lesions, frequent involvement of extranodal sites, a marked predilection for the brain and frequent allograft involvement.

As the immunosuppressed state per se and various potentially oncogenic viruses play a major role in causing these cancers, preventative measures include reducing immunosuppression to the lowest level compatible with good allograft function and prophylactic measures against certain virus infections. Reduction of exposure to sunlight may also decrease the incidence of skin cancer. In addition to conventional treatments (resection, radiation therapy, chemotherapy) patients may receive antiviral drugs, interferon-α and various other manipulations of the immune system. A significant percentage of cases of PTLD and KS respond to reduction or cessation of immunosuppressive therapy.

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References

  1. Penn I, Hammond W, Brettschneider L, et al. Malignant lymphomas in transplantation patients. Transplant Proc 1969; 1: 106–12

    PubMed  CAS  Google Scholar 

  2. Penn I. Why do immunosuppressed patients develop cancer? In: Pimentel E, editor. Critical reviews in oncogenesis. Boca Raton (FL): CRC Press, 1989: 27–52

    Google Scholar 

  3. Penn I. The problem of cancer in organ transplant recipients: an overview. Transplant Sci 1994; 4: 23–32

    PubMed  CAS  Google Scholar 

  4. Penn I. Malignancy after immunosuppressive therapy: how can the risk be reduced? Clin Immunother 1995; 9: 207–18

    Article  Google Scholar 

  5. Penn I. post-transplant malignancies. Transplant Proc 1999; 31(1-2): 1260–2

    Article  PubMed  CAS  Google Scholar 

  6. Penn I. De novo cancers in organ allograft recipients. Curr Opin Organ Transplant 1995; 3: 188–96

    Google Scholar 

  7. Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressive treatment. Am J Med 1985; 78Suppl. 1A: 44–9

    Article  PubMed  CAS  Google Scholar 

  8. Sheil AGR. Skin cancer in renal transplant recipients. Transplant Sci 1994; 4: 42–5

    PubMed  CAS  Google Scholar 

  9. Blohme I, Brynger H. Malignant disease in renal transplant patients. Transplantation 1985; 39: 23–35

    PubMed  CAS  Google Scholar 

  10. Harwood AR, Osoba D, Hofstader SL, et al. Kaposi’s sarcoma in recipients of renal transplants. Am J Med 1979; 67(5): 759–65

    Article  PubMed  CAS  Google Scholar 

  11. Schröter GPJ, Weil III R, Penn I, et al. Hepatocellular carcinoma associated with chronic hepatitis B virus infection after kidney transplantation [letter]. Lancet 1982; 2: 381–2

    Article  PubMed  Google Scholar 

  12. Sillman F, Stanek A, Sedlis A, et al. The relationship between human papillomavirus and lower genital intraepithelial neoplasia in immunosuppressed women. Am J Obstet Gynecol 1984; 150: 300–8

    PubMed  CAS  Google Scholar 

  13. Porreco R, Penn I, Droegemueller W, et al. Gynecologic malignancies in immunosuppressed organ homograft recipients. Obstet Gynecol 1975; 45: 359–64

    PubMed  CAS  Google Scholar 

  14. Euvrard S, Kanitakis J, Pouteil-Noble C, et al. Skin cancers in organ transplant recipients. Ann Transplant 1997; 2: 28–32

    PubMed  CAS  Google Scholar 

  15. Sheil AGR, Disney APS, Mathew TH, et al. De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc 1993; 25: 1383–4

    PubMed  CAS  Google Scholar 

  16. Hartevelt MM, Bouwes-Bavinck JN, Koote AM, et al. Incidence of skin cancer after renal transplantation in the Netherlands. Transplantation 1990; 49(3): 506–9

    Article  PubMed  CAS  Google Scholar 

  17. Mullen DL, Silberberg SG, Penn I, et al. Squamous cell carcinoma of the skin and lip in renal homograft recipients. Cancer 1976; 37: 729–34

    Article  PubMed  CAS  Google Scholar 

  18. Barr BB, Benton EC, McLaren K, et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet 1989; 2(8656): 224–5

    Article  PubMed  CAS  Google Scholar 

  19. Glover MT, Niranjan N, Kwan JTC, et al. Non-melanoma skin cancer in renal transplant recipients: the extent of the problem and a strategy for management. Br J Plast Surg 1994; 47: 86–9

    Article  PubMed  CAS  Google Scholar 

  20. McGregor JM, Berkhout RJM, Rozycka M, et al. Mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene 1997; 15: 1737–40

    Article  PubMed  CAS  Google Scholar 

  21. Festenstein H, Garrido F. MHC antigens and malignancy. Nature 1986; 322: 502–3

    Article  PubMed  CAS  Google Scholar 

  22. Dausset J, Colombani J, Hors J. Major histocompatibility complex and cancer, with special reference to human familial tumors (Hodgkin’s disease and other malignancies). Cancer Surv 1982; 1: 119–47

    Google Scholar 

  23. Bouwes Bavinck JN. Epidemiological aspects of immunosuppression: role of exposure to sunlight and human papillomavirus on the development of skin cancer. Hum Exp Toxicol 1995; 14: 98

    Article  PubMed  CAS  Google Scholar 

  24. Bouwes Bavinck JN, Claas FJJ, Hardie D, et al. Relation between HLAAntigens and skin cancer in renal transplant recipients in Queensland, Australia. J Invest Dermatol 1997; 1008: 708–11

    Article  Google Scholar 

  25. Lennard L, Thomas M, Harrington C, et al. Skin cancer in renal transplant patients is associated with increased concentrations of 6-thioguanine nucleotide in red blood cells. Br J Dermatol 1985; 113: 723–9

    Article  PubMed  CAS  Google Scholar 

  26. Hemmens VJ, Moore DE. Photochemical sensitization by azathioprine and its metabolites: II. Azathioprine and nitroimidazole metabolites. Photochem Photobiol 1986; 43(3): 257–62

    Article  PubMed  CAS  Google Scholar 

  27. Bouwes Bavinck JN, Hardie D, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. Transplantation 1996; 61: 715–21

    Article  PubMed  CAS  Google Scholar 

  28. Nalesnik MA. Clinicopathologic features of post-transplant lymphoproliferative disorders. Ann Transplant 1997; 2: 33–40

    PubMed  CAS  Google Scholar 

  29. Nalesnik MA, Locker J, Jaffe R, et al. Experience with post-transplant lymphoproliferative disorder in solid organ transplant recipients. Clin Transplant 1992; 6: 249–52

    PubMed  Google Scholar 

  30. Penn I. Immunosuppressive agents, immunodeficiency states andmalignancy. In: Lieberman R, Mukherjee A, editors. Principles of drug development in transplantation and autoimmunity. Austin (TX): RG Landes, 1996: 93–102

    Google Scholar 

  31. Penn I. The role of immunosuppression in lymphoma formation. Springer Semin Immunopathol 1998; 20(3-4): 343–55

    Article  PubMed  CAS  Google Scholar 

  32. Penn I, Porat G. Central nervous system lymphomas in organ allograft recipients. Transplantation 1995; 59: 240–4

    PubMed  CAS  Google Scholar 

  33. Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporine-steroid therapy. Lancet 1984; I: 583–7

    Article  Google Scholar 

  34. Hanto DW. Classification of Epstein-Barr virus-associated post-transplant lymphoproliferative diseases: implications for understanding their pathogenesis and developing rational treatment strategies. Ann Rev Med 1995; 46: 381–94

    Article  PubMed  CAS  Google Scholar 

  35. Ho M, Jaffe R, Miller G, et al. The frequency of Epstein-Barr virus infection and associated lymphoproliferative syndrome after transplantation and its manifestations in children. Transplantation 1988; 45: 719–27

    Article  PubMed  CAS  Google Scholar 

  36. Cao S, Cox K, Esquivel CO, et al. post-transplant lymphoproliferative disorders and gastrointestinal manifestations of Epstein-Barr virus infection in children following liver transplantation. Transplantation 1998; 66: 851–6

    Article  PubMed  CAS  Google Scholar 

  37. Hanto DW, Birkenbach M, Frizzera G, et al. Confirmation of the heterogeneity of post-transplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses. Transplantation 1989; 47: 458–64

    Article  PubMed  CAS  Google Scholar 

  38. Penn I. Sarcomas in organ allograft recipients. Transplantation 1995; 6O: 1485–91

    Article  Google Scholar 

  39. Penn I. Kaposi’s sarcoma in transplant recipients. Transplantation 1997; 64: 669–73

    Article  PubMed  CAS  Google Scholar 

  40. al-Sulaiman MH, Mousa DH, Rassoul Z, et al. Transplant-related Kaposi sarcoma in children. Nephrol Dial Transplant 1994; 9: 443–5

    PubMed  CAS  Google Scholar 

  41. Montagnino G, Bencini PL, Tarantino A, et al. Clinical features and course of Kaposi’s sarcoma in kidney transplant patients: report of 13 cases. Am J Nephrol 1994; 14: 12l–6

    Article  Google Scholar 

  42. al-Sulaiman MH, Al-Khader AA. Kaposi’s sarcoma in renal transplant recipients. Transplant Sci 1994; 4: 46–60

    PubMed  CAS  Google Scholar 

  43. Qunibi W, Akhtar M, Sheth K, et al. Kaposi’s sarcoma: the most common tumor after renal transplantation in Saudi Arabia. Am J Med 1988; 84: 225–32

    Article  PubMed  CAS  Google Scholar 

  44. Gunawardena KA, al-Hasani MK, Haleem A, et al. Pulmonary Kaposi’s sarcoma in two recipients of renal transplants. Thorax 1988; 43: 653–6

    Article  PubMed  CAS  Google Scholar 

  45. Moore PS, Chang Y. Detection of herpes virus-like DNA sequences in Kaposi’s sarcoma in patients with and without HIV infection. N Engl J Med 1995; 332: 1181–5

    Article  PubMed  CAS  Google Scholar 

  46. Kedda MA, Margolius L, Kew MC, et al. Kaposi’s sarcoma-associated herpesvirus in Kaposi’s sarcoma occurring in immunosuppressed renal transplant recipients. Clin Transplant 1996; 10: 429–31

    PubMed  CAS  Google Scholar 

  47. Ensoli B, Barillari G, Gallo RC. Cytokines and growth factors in the pathogenesis of AIDS-associated Kaposi’s sarcoma. Immunol Rev 1992; 127: 147–55

    Article  PubMed  CAS  Google Scholar 

  48. Penn I. Primary kidney tumors before and after renal transplantation. Transplantation 1995; 59: 480–5

    PubMed  CAS  Google Scholar 

  49. Penn I. Cancers of the anogenital region in renal transplant recipients: analysis of 65 cases. Cancer 1986; 58: 611–6

    Article  PubMed  CAS  Google Scholar 

  50. Birkeland SA, Storm HH, Lamm LU, et al. Cancer risk after renal transplantation in the Nordic countries 1964-1986. Int J Cancer 1995; 60: 183–9

    Article  PubMed  CAS  Google Scholar 

  51. Wiesner RH. A long term comparison of tacrolimus (FK506) versus cyclosporine in liver transplantation: a report of the United States FK506 Study Group. Transplantation 1998; 66: 493–9

    Article  PubMed  CAS  Google Scholar 

  52. Jonas S, Rayes N, Neumann U, et al. De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer 1997; 80: 1141–50

    Article  PubMed  CAS  Google Scholar 

  53. Penn I. Cancers in cyclosporine-treated versus azathioprinetreated patients. Transplant Proc 1996; 28: 876–8

    PubMed  CAS  Google Scholar 

  54. Penn I. post-transplant malignancies: clinical preventative measures. In: Schmahl D, Penn I, editors. Cancers in organ transplant recipients. Berlin: Springer-Verlag, 1991: 157–60

    Chapter  Google Scholar 

  55. Pham H, Lemoine A, Salvucci M, et al. Occurrence of gammopathies and lymphoproliferative disorders in liver transplant recipients randomized to tacrolimus (FK506)- or cyclosporine-based immunosuppression. Liver Transplant Surg 1998; 4: 146–51

    Article  CAS  Google Scholar 

  56. Badley AD, Portela DF, Patel R, et al. Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced post-transplant lymphoproliferative disorder. Liver Transplant Surg 1996; 2: 375–82

    Article  CAS  Google Scholar 

  57. Rowe DT, Qu L, Reyes J, et al. Use of quantitative competitive PCR to measure Epstein-Barr virus genome load in the peripheral blood of pediatric transplant patients with lymphoproliferative disorders. J Clin Microbiol 1997; 35: 1612–5

    PubMed  CAS  Google Scholar 

  58. Green M, Reyes J, Rowe D. New strategies in the prevention and management of Epstein-Barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation. Curr Opin Transplant 1998; 3: 143–7

    Article  CAS  Google Scholar 

  59. McDiarmid SV, Jordon S, Kim GS, et al. Prevention and Preemptive therapy of post-transplant lymphoproliferative disease in pediatric liver recipients. Transplantation 1998; 66(12): 1604–11

    Article  PubMed  CAS  Google Scholar 

  60. Kuo PC, Dafoe DC, Alfrey EJ, et al. post-transplant lymphoproliferative disorder and Epstein-Barr virus prophylaxis. Transplantation 1995; 59: 135–8

    Article  PubMed  CAS  Google Scholar 

  61. Aris RM, Maia DM, Neuringer IP, et al. post-transplantation lymphoproliferative disorder in the Epstein-Barr virus-naive lung transplant recipient. Am J Respir Crit Care Med 1996; 154: 1712–7

    PubMed  CAS  Google Scholar 

  62. Bouwes Bavinck JN, Tieben LM, van der Woude FJ, et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13: 1933–8

    CAS  Google Scholar 

  63. Fabia R, Levy MF, Testa G, et al. Colon carcinoma in patients undergoing liver transplantation. Am J Surg 1998; 176: 265–9

    Article  PubMed  CAS  Google Scholar 

  64. Hickey DP, Nalesnik MA, Vivas CA, et al. Renal retransplantation in patients who lost their allografts during management of previous post-transplant lymphoproliferative disease. Clin Transplant 1990 4: 187–90

    Google Scholar 

  65. Min AD. Does interferon precipitate rejection of liver allografts [editorial]? Hepatology 1995; 22: 1333–5

    Article  PubMed  CAS  Google Scholar 

  66. Swinnen LJ. Diagnosis and treatment of organ transplant-related lymphoma. Curr Opin Transplant 1998; 3: 90–5

    Article  Google Scholar 

  67. Benkerrou M, Durandy A, Fischer A, et al. Therapy for transplant-related lymphoproliferative disease. Hematol Oncol Clin North Am 1993; 7: 467–75

    PubMed  CAS  Google Scholar 

  68. Heslop HE, Rooney CM. Adoptive cellular immunotherapy for EBV lymphoproliferative disease. Immunol Rev 1997; 157: 217–22

    Article  PubMed  CAS  Google Scholar 

  69. Emanuel DJ, Lucas KG, Mallory Jr GB, et al. Treatment of post-transplant lymphoproliferative disease in the central nervous system of a lung transplant recipient using allogeneic leukocytes. Transplantation 1997; 63: 1691–4

    Article  PubMed  CAS  Google Scholar 

  70. Nalesnik MA, Rao AS, Furukawa H, et al. Autologous lymphokine-activated killer cell therapy of Epstein-Barr virus-positive and -negative lymphoproliferative disorders arising in organ transplant recipients. Transplantation 1997; 63: 1200–5

    Article  PubMed  CAS  Google Scholar 

  71. Senderowicz AM, Vitetta E, Headlee D, et al. Complete sustained response of a refractory, post-transplantation, large B-cell lymphoma to an anti-CD22 immunotoxin. Ann Intern Med 1997; 126: 882–5

    PubMed  CAS  Google Scholar 

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Acknowledgements

The author wished to thank numerous colleagues, working in the transplant centres throughout the world, who have generously contributed data concerning their patients to the Cincinnati Transplant Tumor Registry.

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  1. Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio, USA

    Israel Penn‡

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  1. Israel Penn‡
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Dr Israel Penn, an outstanding tutor who received numernous honors, died on 18 November 1999 from a B cell lymphoma. Ironically, this was a tumour about which he had written frequently. He started a tumour transplant registry in 1968, and through his own efforts gathered information on more than 15 200 cancers in transplant patients throughout the world, establishing the incidence and consequence of malignant tumours in patients receiving immunosuppression for organ transplantation.

Correspondence: Dr J. Wesley Alexander, College of Medicine, Department of Surgery, Transplant Division, University of Cincinnati, 231 Bethesda Avenue, Cincinnati, Ohio, USA. E-mail: alexanjw@healthall.com Offprints: Ms Kay Blaine, Surgical Services, VA Medical Center, 3200 Vine Street, Cincinnati, Ohio 45220, USA.

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Penn‡, I. Post-Transplant Malignancy. Drug-Safety 23, 101–113 (2000). https://doi.org/10.2165/00002018-200023020-00002

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