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Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders.

Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders. Dr.Abhijit K Korane. INCIDENCE OF CANCER AFTER RENAL TRANSPLANT. The incidence of cancer in renal transplant recipients ranges from 2.3–31%.

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Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders.

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  1. Malignancies following kidney transplantation:- Post transplant Lymphoproliferative disorders. Dr.Abhijit K Korane.

  2. INCIDENCE OF CANCER AFTER RENAL TRANSPLANT.

  3. The incidence of cancer in renal transplant recipients ranges from 2.3–31%. • The risk of de novo malignancies is increased in transplant recipients, with a relative risk 3–5 times that of the general population. (Andres A. Cancer incidence after immunosuppressive treatment following kidney transplantation. Crit Rev Oncol Hematol 2005; 56: 71–85)

  4. Data from the Collaborative Transplant Study (CTS) show an increase of at least 3-fold in the incidence of cancer compared with the expected incidence in general population. • Australia and New Zealand Dialysis and Transplant (ANZDATA) registry shows a standardized incidence ratio of 3.46 for all cancers reported in Australia and New Zealand between 1980 and 2005 in patients after a first transplant

  5. ANZDATA. Australia and New Zealand Dialysis and Transplant Registry, 2006.

  6. Study that included of over 35,000 first time renal transplant recipients the cancer rates for, • colon, lung, prostate, stomach, esophagus, pancreas, ovary and breast, were roughly twofold higher. • melanoma, leukemia, hepatobiliary tumors, cervical and vulvovaginal tumors were approximately fivefold more common; • testicular and bladder cancers were increased approximately threefold; 15-fold more common. Finally, • KS, NHL and nonmelanoma skin cancers were encountered with over 20-fold increased frequency. (Penn, I. Cancers complicating organ transplantation. N Engl J Med 1990;323:1767.)

  7. Defining Characteristics of PTLD

  8. PTLD refers not to a single disease but to a syndrome that includes a wide range of abnormal hyperplastic (inflammatory or reactive) and neoplastic lymphocyte growths, ranging from a benign self-limited form of lymphoproliferation to an aggressive, widely disseminated disease.

  9. INCIDENCE OF PTLD

  10. The disease occurs in around 1–10% of transplant recipients, is the most common malignancy in transplanted children, and is second only to squamous cell cancer in adults. (Penn I. The problem of cancer in organ Transplant recipients: an overview. Transplant Sci 1994;4:23–32.)

  11. Over 50% of PTLD cases are associated with primary EBV infection and this accounts for the particular risk to paediatric transplant recipients.

  12. Cincinnati Transplant Tumor Registry (CTTR) which has collected data on more than 6,000 patients. • According to the CTTR,PTLD accounts for 16% of cancers intransplant recipients compared with 5% in the general population.

  13. Collaborative Transplant Study (CTS) database reported incidence of NHL in 200 000 solid organ recipients. • The cumulative incidence of NHL in renal transplant recipients between 1985 and 2001 was significantly increased.

  14. The incidence of NHL is generally highest in the first year after transplant, • The relative risk of lymphoma was 11.8 compared with the general population.

  15. Incidence in India • The overall incidence of malignancies in Indian transplant recipients is not known. • Less than 2% of primarily azathioprine-prednisolone treated transplant recipients developed cancers. (Sakhuja V, Jha V, Ghosh AK, Singh SK, Chugh KS. Low incidence of malignancies following renal transplantation in India. Nephrology 1995; 1:301)

  16. Conclusions, from single centre studies, • The overall incidence of malignancies is lower in contrast to the western countries, 2. The skin cancer incidence is much lower, 3. PTLD is the commonest malignancy in the Indian transplant population, 4. Majority of PTLD is encountered after the first year. (Sakhuja V, Jha V, Ghosh AK, Singh SK, Chugh KS. Low incidence o malignancies following renal transplantation in India. Nephrology 1995; 1:301)

  17. In analysis of 294 patients followed up for more than 6 months after transplantation six malignancies were noted in four patients, giving an incidence of 2%. • Among 157 of those who were followed up for more than 2 years, the incidence was 3.8%. Most of these patients were from the pre- CNI era.

  18. More recent analysis, a total of 26malignancies out of 1400 transplant patients, giving an incidence of 1.4%. PTLD formed the largest chunk, accounting for 19 cases (63.3%).

  19. Pathophysiology

  20. Most PTLDs are of B-cell origin • Early onset PTLDs are mainly regarded as EBV–driven lymphoproliferations that are frequently polyclonal or oligoclonal, • Late onset PTLDs are true monoclonal lymphoid malignancies that are not necessarily associated with EBV infection

  21. Over 95% of the adult population worldwide is infected with EBV, with infection usually occurring in childhood. • Initial infection of B lymphocytes in pharyngeal lymphoid tissues follows transmission of virus through salivary exchange.

  22. Primary infection of healthy individuals is not accompanied by disease, although infectious mononucleosis occurs in around 50% of individuals in whom infection is delayed until adolescence.

  23. Primary disease in the transplant recipient is transmitted from an EBV seropositive person to an EBV seronegative recipient. • Reactivation infection occurs in the immunocompromised host who is seropositive at the time of transplantation because of EBV exposure in childhood or adolescence

  24. Epstein-Barr Virus EBV is an enveloped herpesvirus with a 172 kb double stranded DNA genome.

  25. Core:- single linear molecule of dsDNA . • Capsid:- Surrounding the core is an icosahedralcapsid with a 100 nm diameter constructed of 162 capsomeres. • Tegument:- Between the capsid and envelope. It consists of viral enzymes. • Envelope:- The envelope is the outer layer of the virion.

  26. PRIMARY EBV INFECTION

  27. Immunosuppressed patients are at risk for B-cell lymphoproliferative diseases, • These diseases are a heterogeneous collection of disorders that usually carry the virus and express the growth program.

  28. Primary EBV infection in vivo generally occurs at an early age and is usually asymptomatic. • Infection if acquired during adolescence result in infectious mononucleosis. • During the early stages of infectious mononucleosis extremely large numbers of EBV-infected B cells circulate in the blood, but they are all resting memory cells.

  29. Resolution of the infection, • Infection by EBV is controlled by both cellular and humoral immune mechanisms. • Antibody limits the spread of infectious virus, and cytotoxic T cells destroy infected cells that express viral proteins.

  30. The major targets for control of EBV by the immune system are memory cells that have initiated viral replication. By killing these cells and preventing the spread of infectious virus by antibody, the immune response reduces the level of infection

  31. A defining feature of herpesviruses is their ability to maintain a latent infection with the virus genome retained in host cells without production of infectious virions.

  32. RISK FACTORS

  33. Risk factors associated with post-transplant malignancy

  34. Primary EBV infection:- Analysis of 381 consecutive non-renal transplant recipients at a US clinic, the risk of PTLD was 24 times higher in EBV-seronegative recipients than in those seropositive for EBV at the time of transplantation. (Walker RC, Marshall WF, Strickler JG et al. Pretransplantation assessment of the risk of lymphoproliferative disorder. Clin Infect Dis 1995; 20: 1346–1353)

  35. Several single-center analyses have found that EBVseronegative patients experienced a 10- 76-fold greater incidence of PTLD when compared with their seropositive counterparts (Preiksaitis JK, Cockfield SM. Epstein-Barr virus and lymphoproliferative disorders after transplantation. In: Bowden RA, Ljungman P, Paya CV, eds. Transplant infections. Philadelphia: Lippincott-Raven,1998:245–63. 12. Ellis D, Jaffe R, Green M, et al. Epstein-Barr virus–related Disorders in children undergoing renal transplantation with tacrolimus-based immunosuppression. Transplantation 1999; 68:997–1003.)

  36. -Use of the monoclonal antibody OKT3, -Cytomegalovirus (CMV)-seropositive donor, -Younger age at transplantation, -Infection with hepatitis C,

  37. Lower incidence of PTLD in Asia compared with Western countries and a lower incidence in recipients from particular ethnic groups including Arabic, Jewish, Black and Mediterranean individuals

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