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  1. 1. Slide 1 Post-Transplant Malignancies In 1963, Israel (Sol) Penn, MD, joined the transplantation  program at the University of Colorado in Denver under the direction of Thomas E. Starzl, MD. Over the ensuing years, Dr Penn noticed the increased frequency of lymphoma development in transplant recipients and reported this observation in 1968 at the inaugural meeting of the Transplantation Society, in Paris. At that meeting, other investigators reported similar experiences with malignancies noted at greater frequency in transplantation patients than in the general population. In 1969, Dr Penn started the Denver Transplant Tumor Registry to examine this phenomenon.  Subsequently, Dr Penn moved to Cincinnati as chief of surgery at the Cincinnati Veterans Administration Hospital, and the registry was renamed the Cincinnati Transplant Tumor Registry. After Dr Penn’s death, in 1999, the registry was renamed the Israel Penn International Transplant Tumor Registry (IPITTR) in his honor. To date, more than 7000 US cases and 9000 international cases have been reported to this registry. A registry Web site (www.IPITTR.uc.edu) has been created for submission of data on donor, de novo, and preexisting malignancies, as well as for obtaining consultations, based on registry data, regarding the management of donor and recipient malignancies. 
  2. 2. Slide 2 Post-Transplant Malignancies Cancers of the skin and post-transplant lymphoproliferative disorder (PTLD) make up and post-transplant lymphoproliferative disorder (PTLD) make up approximately 50% of the cancers reported to the IPITTR. Post-transplant malignancies have been reported in recipients of all types of solid organs. De novo malignancies have been reported most commonly in renal transplant recipients, the largest and the longest monitored group of transplant recipients in the United States. 1,2 Thus, patients who received kidneys account for the majority (62.1%) of cases reported to the registry. This group is immediately followed in order of cancer incidence by cardiac transplant recipients. Patients with cardiac transplants make up a significantly smaller proportion of US organ recipients than those with hepatic transplants (12.2% vs 19.6%, respectively) 3 yet account for a greater proportion of post-transplant malignancies reported to the IPITTR (24.3% vs 7.9%, respectively). These data demonstrate the possible link between not only duration but also intensity of immunosuppression and the post-transplant incidence of cancer. Lung and pancreas recipients constitute the smallest segments of reported patients (1.4% and 0.5%, respectively). Cancers that occur with an increased relative frequency in transplant recipients compared with the general population include PTLD, cancer of the hepatobiliary system, Kaposi’s sarcoma (KS), renal cell cancer, vulvar and perineal cancers, solid neuroendocrine sarcomas, Merkel cell tumors, and carcinoids. 1,2,4-7
  3. 3. Slide 3  Post-Transplant Malignancies De novo post-transplant malignancies have been associated with the long-term administration of immunosuppressive agents. Notably, immunosuppressed patients, including those with human immunodeficiency virus infection as well as transplant recipients, have had a high reported incidence of virally stimulated malignancies, such as KS (human herpesvirus 8 [HHV-8]) and PTLD (Epstein-Barr virus [EBV]). These malignancies have been reported as early as 1 month, but may be identified as late as 25 years, after transplantation.1  In the cases reported to the IPITTR, the mean time to the development of post-transplant malignancy is 63 months after transplantation (median time, 47 months). Kaposi’s sarcoma occurs at the shortest interval post-transplantation, a mean of 21 months (median, 13 months). Next earliest in occurrence is PTLD, at a mean of 35 months (median, 13 months). Epithelial malignancies, including skin cancers, have been reported after a mean of 66 months (median, 51 months) following the transplant procedure. Cancer of the vulva, uterus, or cervix has the longest latency, occurring after a mean interval from transplantation of 114 months (median, 51 months).
  4. 4. Slide 4  Post-Transplant Malignancies This abdominal computed tomographic scan shows hepatic PTLD (arrow) that developed in a female patient 1 year post-transplantation. Her immunosuppressive regimen comprised cyclosporine, mycophenolate mofetil, and corticosteroids, with OKT3 induction. Treatment consisted of immunosuppression reduction to corticosteroids only and radiation therapy. The patient also required endoscopic retrograde cholangiopancreatography for placement of a common bile duct stent and a portal vein stent for hilar compression. Post-transplant lymphoproliferative disorder occurs with far greater frequency in the immunosuppressed transplant recipient than do lymphomas in the general population. 1,8,9 Morphologically, PTLD appears as large-cell lesions; 85% are of B-cell, and 15% of T-cell origin. 1 The pathologic spectrum of the B-cell lesions ranges from lymphoid hyperplasia to true lymphoma. From 90% to 95% of the B-cell tumors are thought to arise from EBV co-stimulation. 8   More than 70% of transplant recipients with PTLD have extranodal disease, and involvement of the allograft by the PTLD is frequently encountered.1 This may lead to diagnostic confusion with acute rejection at the site. Post-transplant lymphoproliferative disorder also has a higher incidence of central nervous system (CNS) involvement (21%) than lymphomas in the general population, which are associated with CNS-confined disease in approximately 1% of patients. 1   Like PTLD itself, the therapeutic options for the disease span a continuum, ranging from antiviral therapy to reduction or withdrawal of immunosuppressive agents, anti-CD20 monoclonal antibody, or cytotoxic chemotherapy. Invasive procedures, including radiation therapy and surgical excision, are additional therapeutic modalities, with unclear efficacy.1 8. Penn I. Post-transplant malignancy: the role of immunosuppression. Drug Saf. 2000;23:101-113. 9. Buell JF, Hanaway MJ, Trofe J, et al. Post-transplant lymphoproliferative disorder in liver transplant recipients: a report from the Israel Penn International Transplant Tumor Registry. Liver Transpl. 2001;7:C-71.
  5. 5. Slide 5  Post-Transplant Malignancies There is a relationship that has been shown between the  intensity of immunosuppression and the time to development of PTLD. 10 In patients reported to the IPITTR who had PTLD and had been treated with azathioprine and steroids, the mean time to development of the disease was 50 months. After the introduction of cyclosporine, this interval declined to 13 months, and if induction with OKT3 was included, the mean time post-transplantation to the development of PTLD was 7 months. Moreover, these 3 immunosuppressive regimens have an impact on how early PTLD develops. It occurred within the first 4 months after transplantation in only 12% of the azathioprine-and-prednisone–treated patients, in 31% of patients after addition of cyclosporine, and in 59% of patients when OKT3 was given. Development of PTLD has been reported with all the different immunosuppressive agents used, and it appears to be related not to any single agent but to the degree of immunosuppression induced.  10. Trofe J, Buell JF, First MR, Hanaway MJ, Beebe TM, Woodle ES. The role of immunosuppression in lymphoma. Paper  presented at: 3rd Symposium on Immunodeficiency and Malignancy; February 16-17, 2001; Berlin, Germany.
  6. 6. Slide 6  Post-Transplant Malignancies Skin cancer is the most common malignancy reported after transplantation.1 There are many differences between skin cancers in transplant recipients and those in the general population. The most common skin cancer in the general population is basal cell cancer, with a ratio of basal cell to squamous cell cancers of 5 to 1. In transplant recipients, however, squamous cell carcinoma is the most commonly encountered skin cancer, with a ratio to basal cell carcinoma of 1.8 to 1.1 The frequency of malignant melanoma is almost twice as high in transplant recipients as in the general population. 11 The mean age of development of skin cancer in transplant recipients is 30 years, compared with 65 years in the general population. 1   The skin cancers encountered in transplant recipients are much more aggressive than those in the general population and are frequently multicentric in origin. 1,12 Lymph node metastasis has been reported in approximately 6% of transplant patients and mortality resulting from the dissemination of skin cancer, in approximately 5%.1 Lymph node metastasis and death from skin cancers are rare in the general population, except in cases of malignant melanoma.13 The development of squamous cell carcinoma of the skin after organ transplantation has been clearly related to exposure to UV light, with the highest incidence being reported in transplant recipients in Australia. 1   11. Penn I. Malignant melanoma in organ allograft recipients. Transplantation. 1996;61:274-278. 12. Buell JF, Trofe J, Hanaway MJ, et al. Malignancies of the skin after liver transplantation: a report from the Israel Penn International Transplant Tumor Registry. Liver Transpl. 2001;7:C-40. 13. Shelton RM. Skin cancer: a review and atlas for the medical provider. Mt Sinai J Med. 2001;68:243-252.
  7. 7. Slide 7  Post-Transplant Malignancies    The most common women’s malignancies reported to the IPITTR include breast cancer followed by cervical/uterine, vulvar, and ovarian cancer. Like the majority of malignancies reported to the registry, cancers in women occurred most often in renal allograft recipients. Most breast malignancies in registry patients are intraductal (65%), as in the general population, with the remainder lobular and a small percentage inflammatory. One fourth of these malignancies presented with nodal involvement. Conservative resection and radiation were used in a significant proportion (35%) of patients, while simple or modified radical mastectomy remained the principal procedure in most reported patients.  Human papillomavirus and condylomata have been associated as an etiologic factor in the development of vulvar cancer (35% of cases in the IPITTR). A significant proportion of female recipients of transplants had second vulvar malignancies, which consisted of in-field recurrences as well as second primary cancers. Nevertheless, overall vulvar cancer mortality was exceedingly low (4%). Ovarian cancer is a common malignancy in the general population 14 ; however, in immunosuppressed transplant recipients, it appears to be seldom encountered.  14. Runnebaum IB, Stickeler E. Epidemiological and molecular aspects of ovarian cancer risk. J Cancer Res Clin Oncol. 2001;127:73-79.
  8. 8. Slide 8  Post-Transplant Malignancies     Kaposi’s sarcoma accounts for 0.02% to 0.07% of all cases of cancer in the general population and is responsible for between 5% and 6% of the post-transplant malignancies reported to the IPITTR.1,15 Two forms of KS exist: the nonvisceral type, which is localized to the skin, mouth, and oropharynx, and the visceral type, with involvement of the gastrointestinal tract, lymph nodes, and lungs.  Comparison of IPITTR data on US and international recipients of organ allografts in whom post-transplant KS developed reveals differences between the 2 groups. 15 While the gender ratio and visceral KS survival rate are the same or similar in both groups, the US patients are older, more commonly receive antibody induction therapy, less frequently have visceral-type disease, and appear to have better survival with cutaneous KS. Complete remission of both the nonvisceral and visceral types of KS has been reported when immunosuppression reduction or discontinuation has been the only therapy. Patients with the visceral form of the disease more frequently need adjunctive chemotherapy, radiation therapy, and/or surgery. 1 15. Buell J, Hanaway M, Trofe J, Beebe T, First MR, Woodle ES. Kaposi’s sarcoma in transplant recipients: differential features between US and European patients. Paper presented at: 2001 A Transplant Odyssey; August 23, 2001; Istanbul, Turkey.
  9. 9. Slide 9  Post-Transplant Malignancies   Early experiences in transplantation included the use of organs from donors with active malignancies. This practice resulted in the transmission of malignancy to transplant recipients. The largest group of donor malignancies in the United States is CNS cancers. 16,17   Several risk factors have been associated with donor malignancy transmission, including high-grade malignancy, especially astrocytoma, glioblastoma, and medulloblastoma. A history of shunt surgery, extensive surgical resection, chemotherapy, or radiation is also associated with an increased incidence of transmission. Melanoma and choriocarcinoma are associated with the highest incidence of transmission and clearly should be considered donor exclusion criteria. 16   Renal cell cancer is also encountered with a high frequency in the evaluation of donors. In the instance of isolated intraparenchymal renal cell cancer without vascular invasion, multiple cases have been reported to the registry in which the contralateral kidney was transplanted without transmission. In a small group of patients, malignancies were excised with adequate margins, and the kidneys were implanted without a single incidence of transmission. However, in those cases with extracapsular invasion, vascular invasion, or metastatic disease, a high incidence of donor transmission has been observed. Donors with an unclear etiology for intracranial bleeding should be autopsied after donation to avoid the transplantation of high-risk organs. 16 16. Buell JF, Trofe J, Hanaway MJ, et al. Transmission of donor cancer into cardiothoracic transplant recipients. Surgery. 2001;130:660-668. 17. Buell JF, Trofe J, Hanaway MJ, et al. Can patients with CNS tumors safely be used in expanding the donor pool?  Am J Transplantation. 2001;1:220.