Israel Penn International Transplant Tumor Research Articles

Comanaging an Organ Transplantation and Melanoma

Objective: To determine malignant melanoma cause-specific and overall survival among patients with melanoma diagnosed after organ transplantation compared with a national sample with malignant melanoma. Design: Retrospective review. Setting: Mayo Clinic sites. Patients: Immunosuppressed organ transplant recipients with malignant melanoma identified from surgical and medical databases at Mayo Clinic (1978-2007), the Organ Procurement and Transplantation Network/United Network for Organ Sharing database (1999-2006), and the Israel Penn International Transplant Tumor Registry (1967-2007). Main Outcome Measures: Prognostic analyses by Breslow thickness and Clark level of overall and melanoma cause-specific survival. Expected survival rates were estimated by applying the age-, sex-, and calendar year–specific survival rates of patients with malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program to the study cohort. Results: Malignant melanoma was diagnosed in 638 patients (724 cases) after transplantation. Breslow thickness was available for 123 patients; Clark level, for 175. Three-year overall survival rates for patients stratified by Breslow thickness (≤0.75, 0.76-1.50, 1.51-3.00, and >3.00 mm) were 88.2%, 80.8%, 51.2%, and 55.3%, respectively, and 3-year cause-specific survival rates (95% confidence intervals) were 97.8% (93.7%-100%), 89.4% (76.5%-100%), 73.2% (53.2%-100%), and 73.9% (56.4%-96.6%), respectively. Three-year cause-specific survival rates (95% confidence intervals) for patients stratified by Clark level (I-IV) were 100%, 97.4% (92.4%-100%), 82.8% (65.3%-100%), and 65.8% (51.8%-83.7%), respectively. For patients with Breslow thickness of 1.51 to 3.00 mm and Clark level III or IV, the cause-specific survival rate in the study sample was significantly different from the expected estimates for patients with the same Breslow thickness or Clark level. Conclusions: Compared with the expected survival rates derived from malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program, immunosuppressed organ transplant recipients with thicker melanomas (ie, with a Clark level of III or IV or a Breslow thickness of 1.51 to 3.00 mm) had a significantly poorer malignant melanoma cause-specific survival rate. The overall survival rate was worse among patients with a prior history of transplantation, regardless of Breslow thickness or Clark level.

Malignant Melanoma in Solid Transplant Recipients

To determine malignant melanoma cause-specific and overall survival among patients with melanoma diagnosed after organ transplantation compared with a national sample with malignant melanoma. Retrospective review. Mayo Clinic sites. Immunosuppressed organ transplant recipients with malignant melanoma identified from surgical and medical databases at Mayo Clinic (1978-2007), the Organ Procurement and Transplantation Network/United Network for Organ Sharing database (1999-2006), and the Israel Penn International Transplant Tumor Registry (1967-2007). Prognostic analyses by Breslow thickness and Clark level of overall and melanoma cause-specific survival. Expected survival rates were estimated by applying the age-, sex-, and calendar year-specific survival rates of patients with malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program to the study cohort. Malignant melanoma was diagnosed in 638 patients (724 cases) after transplantation. Breslow thickness was available for 123 patients; Clark level, for 175. Three-year overall survival rates for patients stratified by Breslow thickness (≤ 0.75, 0.76-1.50, 1.51-3.00, and >3.00 mm) were 88.2%, 80.8%, 51.2%, and 55.3%, respectively, and 3-year cause-specific survival rates (95% confidence intervals) were 97.8% (93.7%-100%), 89.4% (76.5%-100%), 73.2% (53.2%-100%), and 73.9% (56.4%-96.6%), respectively. Three-year cause-specific survival rates (95% confidence intervals) for patients stratified by Clark level (I-IV) were 100%, 97.4% (92.4%-100%), 82.8% (65.3%-100%), and 65.8% (51.8%-83.7%), respectively. For patients with Breslow thickness of 1.51 to 3.00 mm and Clark level III or IV, the cause-specific survival rate in the study sample was significantly different from the expected estimates for patients with the same Breslow thickness or Clark level. Compared with the expected survival rates derived from malignant melanoma cases reported in the Surveillance, Epidemiology, and End Results Program, immunosuppressed organ transplant recipients with thicker melanomas (ie, with a Clark level of III or IV or a Breslow thickness of 1.51 to 3.00 mm) had a significantly poorer malignant melanoma cause-specific survival rate. The overall survival rate was worse among patients with a prior history of transplantation, regardless of Breslow thickness or Clark level.

Liver graft procurement in donors with central nervous system cancers

The recent study by Kashyap et al. confirmed with a large, single-center experience that donors with central nervous system (CNS) tumors should be proposed for liver donation, as we recently advocated. In their series of 42 liver donors with CNS tumors and a mean follow-up of 29 months, 20 donors had grade IV astrocytoma or glioblastoma multiforme, and none of the recipients developed recurrence of these aggressive tumors. Kashyap et al. observed 1 case of metastatic recurrence of the donor CNS cancer, which was a juvenile pilocytic astrocytoma of the cervical spinal cord. The real risk of CNS cancer transmission with liver transplantation is not known. It may vary according to the aggressiveness of the CNS cancer (histology), the previous treatments (radiotherapy, open skull surgery, and shunting), and the length of the delay between the diagnosis of the CNS cancer and brain death. It may also vary according to the recipient’s immunosuppression, because calcineurin inhibitors have demonstrated an effect on cancerous cell activation. The transmission risk has been largely overestimated by the Israel Penn International Transplant Tumor Registry (IPITTR). The IPITTR estimated this risk to be as high as 40% with grade III/IV astrocytoma. This overestimation is related to the nature of this voluntary and retrospective registry. The transmission risk should be scientifically determined from the ratio of the number of patients who have experienced transmission to the entire population of patients at risk, and it is likely that the IPITTR lacks important information on the denominator of this ratio. The IPITTR and isolated case reports are responsible for the negative reputation of donors with CNS cancers. Prospective, multicenter registries and some large, single-center experiences, such as Kashyap et al.’s study, have demonstrated that the risk of CNS cancer transmission should be evaluated as 0% to 3%, and these data have to be better defined by further prospective, large-scale registries. In comparison with the actual, unacceptable death rates on the liver waiting lists, which have led to the development of living related liver transplantation and its 0.5% donor mortality risk and transplant tourism, this risk of CNS cancer transmission with liver transplantation may seem acceptable, especially for fully informed patients who have a high risk of death on the waiting lists. Organ transplantation carries a small but real risk of occult cancer transmission anyway.

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Posttransplant Lymphoproliferative Disorder Following Kidney Transplant

Extended criteria donors: The case for liver procurement in donors with a central nervous system malignancy

In the December issue of Liver Transplantation, Durand et al.1 extensively reviewed the issue of extended criteria donors in liver transplantation. They mentioned the problem of donors with a history of malignancy and recommended in Table 2 that donors with grade III/IV central nervous system (CNS) malignant tumors be rejected as the risk of malignancy transmission is estimated at 40%. This estimation is in fact very controversial. The risk of CNS cancer transmission should be evaluated with the ratio of the number of patients who have experienced transmission to the entire population of patients who have received an organ from donors with CNS cancer.2 For decades, donors with CNS cancer have been accepted as potential donors as CNS cancer very rarely spreads outside the CNS.3 With increasing experience in transplantation, a few cases of CNS cancer transmission have been reported,4 and caution has been advised. It was progressively learned that the risk of transmission is higher if the donor had a history of craniotomy, radiotherapy, or ventriculoperitoneal shunt.5 The Cincinnati Transplant Tumor Registry, established by Israel Penn, has collected cases of cancer transmission in organ transplant recipients for decades. This registry, now called the Israel Penn International Transplant Tumor Registry (IPITTR), is based on voluntary reports of cancer cases in organ recipients. In this database, the calculated risk of donor cancer transmission with grade III/IV CNS cancer is 40%,6 and this estimation was reproduced in Durand et al.'s review of marginal liver donors.1 However, this estimation is biased. First, the IPITTR has collected cases since the 1970s and may not reflect the actual practice of organ transplantation. Moreover, the denominator of the ratio is certainly underestimated in the IPITTR, as it receives cases of cancer in recipients on a voluntary basis and is not designed to scientifically register and analyze malignancies in donors, which have to be prospectively recorded to achieve a good estimation of the total ratio. The underestimation of the denominator of this ratio is the cause of the high calculated risk of CNS cancer transmission in the IPITTR. More scientifically, the United Network for Organ Sharing (UNOS) collected data from donors with a history of malignancy.7, 8 Between 2000 and 2005, they registered 1069 donors with a history of malignancy, including 642 donors with CNS malignancy. There were 175 glioblastomas, 152 astrocytomas, 31 pituitary tumors, 8 ependymomas, 31 oligodendrogliomas, and 165 other malignancies. These 642 donors allowed the procurement and transplantation of 179 liver grafts. From this large consecutive series, only 1 donor with glioblastoma multiforme transmitted cancer to 3 separate recipients of his kidney, liver, and lung.8 The overall transmission of CNS cancer with liver transplantation was 0.55% (1/179), and it was 1.8% (1/55) for the highest risk group (glioblastoma multiforme). The only donor who transmitted cancer to his recipients had particular risk factors, including the presence of enlarged thoracic lymph nodes whose later pathology revealed cancerous involvement.9 In a perfect world without organ donor shortage, all extended criteria donors would be avoided as they carry an increased risk of graft failure and recipient death. However, in real life, we, the members of the transplant community, face the problems of long waiting lists and waiting list mortality. We try to limit this mortality by the extension of donation criteria to marginal donors, such as donation after cardiac death donors (up to 10% primary nonfunction) and living donors (0.2%-0.5% mortality for healthy donors). The issue of organ donation for patients with grade III/IV CNS malignant tumors should be evaluated according to the balance between the risk of cancer transmission and the chances of being transplanted with a non–extended criteria donor. The risk of transmission of donor grade III/IV CNS malignancy has not been determined yet; it is certainly lower than the unacceptable value of 40% reported by the IPITTR and much closer to the value of 1% to 2% estimated by the UNOS database, a more acceptable figure. Recommending the avoidance of liver procurement from donors with a grade III/IV CNS malignancy on the basis of the IPITTR may lead to a much higher number of deaths on the waiting list versus potential transmissions of cancer to the recipients, and it also may put at legal risk those transplant physicians who would accept such extended criteria donors. The real transmission risk should be evaluated with further prospective studies using, for example, the UNOS or Eurotransplant database. Meanwhile, we think that liver grafts from donors with a grade III/IV CNS malignancy should be used with caution by center-based allocation in fully informed patients who have a high risk of death on the waiting lists or as a replacement for living donor liver transplantation. Olivier Detry*, * Department of Abdominal Surgery and Transplantation, Centre Hospitalier Universitaire de Lièe, University of Lièe, Lièe, Belgium.

De Novo Cancers Arising in Organ Transplant Recipients are Associated With Adverse Outcomes Compared With the General Population

Transplant recipients are at increased risk of malignancy; however, the influence of transplantation on cancer outcomes has not been rigorously defined. The purpose of this study was to examine the influence of transplantation on the outcomes of individual cancers. De novo nonsmall cell lung cancer, colon cancer, breast cancer, prostate cancer, bladder cancer, renal cell cancer (RCC), and malignant melanoma data in 635 adult (>18 years of age) transplant recipients (from the Israel Penn International Transplant Tumor Registry) were compared with data from 1,282,984 adults in the general population (from the Surveillance, Epidemiology, and End Results database). Compared with the general population, transplant patients were more likely to have early stage (AJCC stage 0-II) RCC, but more advanced (AJCC stage >II) colon cancer, breast cancer, bladder cancer, and malignant melanoma. Compared with the general population, disease-specific survival was worse in the transplant population for colon cancer (all stages), nonsmall cell lung cancer (stage II), breast cancer (stage III), prostate cancer (stage II, III, and IV), bladder cancer (stage III), and RCC (stage IV). Multivariate analyses demonstrated transplantation to be a negative risk factor for survival for each cancer studied, and transplantation and cancer stage at diagnosis to be the most profound negative survival predictors. These analyses indicate that, for several common cancers, transplant patients experience worse outcomes than the general population. The data also suggest that cancers in transplant recipients are more aggressive biologically at the time of diagnosis.

Melanoma in organ transplant recipients: The old enemy finds a new battleground

Population registry data and published studies have demonstrated that melanomas in the transplant population occur 1.6-2.5 times more commonly compared with the general population. Studies examining possible risk factors have suggested that in this patient population, there is an increased number of melanocytic naevi. Whether this phenomenon is aetiologically related to subsequent melanoma development is currently unclear. Only one study examined the prognosis of melanomas in this population. The Israel Penn International Transplant Tumor Registry has collated patient data voluntarily submitted by transplant physicians throughout the USA since 1968. Analysis of melanomas in this study found that approximately half were Breslow thickness >1.51 mm. Overall, there was a high rate of nodal and distant metastases, with poorer 1-, 3- and 5-year survival rates compared with the general population. There is a paucity of good-quality evidence regarding melanoma in organ transplant recipients. Further research involving international collaborative trials, particularly on risk factors and the prognosis of melanomas in this population, could present a more substantial evidence base from which treatment guidelines based on data could be developed.

Individualization of Immunosuppressive Therapy. III. Sirolimus Associated With a Reduced Incidence of Malignancy

Objective We examined the occurrence of neoplasms among 1008 renal transplant recipients treated with a sirolimus-cyclosporine (CsA) ± prednisone (Pred) regimen. Methods A comprehensive database of demographic, laboratory, clinical, and histopathologic features of these patients all followed in our transplant center was analyzed using Student t test and Mann-Whitney U test for continuous and chi-square test for categorical variables. Comparisons were performed with information in the Israel Penn International Transplant Tumor Registry (IPITTR). Results During the mean patient follow-up of 62.3 ± 26.1 months (range 27.1 to 131), 36 tumors occurred in 35 patients (3.6%) at 32.5 ± 29.8 months. The most common neoplasms were skin tumors (2.4%), a value that was significantly lower than the 6% rate observed with CsA-azathioprine-Pred treatment. Also, the 0.4% incidence of posttransplant lymphoproliferative disorders and 0.2% incidence of renal cell carcinomas were less than half of those previously reported with a combination of tacrolimus and mycophenolate mofetil. The distribution of tumor types was similar to that reported to the IPITTR. The mean trough drug concentrations in affected recipients at the time of diagnosis were within the putative target ranges. Conclusion Renal transplant recipients treated with the sirolimus-CsA ± Pred combination showed a low incidence of tumors of similar types as those encountered with other regimens.

Liver Transplantation for Primary or Metastatic Sarcoma to the Liver

Sarcoma is generally a rare disease in the US, with poor survival in patients with both primary angiosarcoma and metastatic disease from sarcoma and GIST. In order to determine if liver transplantation for sarcoma is a realistic option, we examined records of all patients in the US component of the Israel Penn International Transplant Tumor Registry were reviewed. Those patients with liver failure from primary or metastatic liver sarcoma were evaluated. Patient outcome analysis was then performed. Patient and tumor demographics were reviewed as well as patient survival after transplantation. 19 patients are identified having received liver transplantation after treatment for sarcoma of the liver, 6 patients with primary hepatic sarcoma and 13 patients with metastatic sarcoma of the liver. Recurrence was almost universal in 18 of 19 patients (95%) after a median interval of 6 months. Survival for the group as a whole was 47% for 1-year, 15% for 3-years and 5% for 5-years. Given the early recurrence of tumor and meager 1-year survival outcome, liver transplantation is a poor therapeutic choice for patients with either primary or metastatic liver sarcoma, including high-grade leiomyosarcoma (GIST) regardless of primary site or primary therapy.

Analysis of Factors that Influence Survival with Post-Transplant Lymphoproliferative Disorder in Renal Transplant Recipients: The Israel Penn International Transplant Tumor Registry Experience

Significant mortality is associated with post-transplant lymphoproliferative disorder (PTLD) in kidney transplant recipients (KTX). Univariate/multivariate risk factor survival analysis of US PTLD KTX reported to Israel Penn International Transplant Tumor Registry from November 1968 to January 2000 was performed. PTLD presented 18 (median) (range 1-310) months in 402 KTX. Death rates were greater for those diagnosed within 6 months (64%) versus beyond 6 months (54%, p = 0.04). No differences in death risk for gender, race, immunosuppression, EBV, B or T cell positivity were identified. Death risk increased for multiple versus single sites (73% vs. 53%, hazards ratio (HR) 1.4). A 1-year increase in age increased HR for death by 2%. Surgery was associated with increased survival (55% vs. 0% without surgery) (p < 0.0001). Patients with allograft involvement, treated with transplant nephrectomy alone (n = 20), had 80% survival versus 53% without allograft removal (n = 15) (p < 0.001). Overall survival was 69% for allograft involvement alone versus 36% for other organ involvement plus allograft (n = 19 alive) (p < 0.0001). Death risk was greater for multiple site PTLD and increasing age, and risks were additive. Univariate analysis identified increased death risk for those not receiving surgery, particularly allograft involvement alone.

United Network for Organ Sharing Publication on Scientific Registry of Transplant Recipients Central Nervous System Donor Cancer Transmission Data

Dr. Penn would be pleased to note that the stated United Network for Organ Sharing (UNOS) interpretation of Scientific Registry of Transplant Recipients (SRTR) data on the risk of donor central nervous system (CNS) tumor transmission is identical to his initial opinion published in 1991 (1–4). The manner in which the overall risk of tumor transmission is reported deserves comment. Data regarding the risk of CNS tumor transmission is only relevant when expressed as the following proportion: the number of transplant recipients who experience donor CNS tumor transmission out of the entire population of transplant recipients who receive organs from donors with CNS tumors. Expression of this risk using other denominators (such as all solid-organ donors) can be misleading because the overwhelming majority of the population is not at risk for donor-related CNS tumor transmission. UNOS presentation of data in this manner only means one thing: that donors with a history of CNS tumors are relatively infrequent, and the risk of transmission of a CNS tumor in most patients with CNS tumors is also infrequent. UNOS publications have generally held that the risk of tumor transmission in transplant recipients is small. It is small however, because of two reasons. First, donors with CNS tumors are very infrequent. Second, among donors with CNS tumors, those that are high risk for transmission actually represent a minority of this group of donors. The transplant community must be sophisticated enough, however, to understand that a high-risk population does exist and that great care should be used to identify these donors and avoid use of their organs. When this level of sophistication does not exist, the risk of tumor transmission will be real. Definition of risk factors for tumor transmission requires a critical mass of recipients experiencing these events. For relatively rare events, event-based registries have substantial advantages over mandatory reporting registries, where capture rates are always at issue. The Israel Penn International Transplant Tumor Registry (IPITTR) has the only data set capable of defining risk factors for tumor transmission because it has a substantial number of recipients with donor CNS tumor transmission. In contrast, the paucity of observed donor CNS tumor transmission events in the Australian New Zealand and SRTR registries precludes such analyses. Furthermore, IPITTR collects substantially more detailed information, including pathology reports, and therefore data collected on individual events is substantially more robust. Mandatory reporting registries simply cannot require such detailed reporting from all centers. This issue, more than any other, highlights the importance of both types of registries in answering questions regarding infrequent events such as donor-related CNS tumor transmission. The importance of defining risk factors for donor CNS tumor transmission arises when a transplant team is under time pressure to make a decision about using organs from a donor with a history of CNS tumor. The IPITTR is consulted relatively frequently on these issues, and the purpose of our ongoing work on this issue is to better define those donors with a history of CNS tumors who represent the highest risk of tumor transmission so we can better advise the transplant community in a consultative setting. The IPITTR is continuing to collect highly detailed data on patients in the United States and the international transplant community on patients receiving organs from donors with a history of CNS tumors to better define those donors at highest risk of tumor transmission. Ongoing updates of these data with scientific publication will improve the consultative services on these donors to the international transplant community. Joseph F. Buell Thomas M. Beebe Thomas G. Gross Jennifer Trofe Michael J. Hanaway Rita R. Alloway M. Roy First E. Steve Woodle FACS, The Israel Penn International Transplant Tumor Registry The University of Cincinnati Cincinnati, OH

Skin Cancer Following Transplantation: The Israel Penn International Transplant Tumor Registry Experience

The purpose of this study was to analyze a large series of skin cancers in solid organ transplant recipients to determine their biologic behavior. Methods A retrospective review of all US transplant recipients with skin cancer reported to the Israel Penn International Transplant Tumor Registry was performed. Results Transplant recipients from the United States with skin malignancies were identified (n = 2018) and assigned to 1 of 3 groups: squamous cell cancer (SCC), basal cell cancer (BCC), or combined malignancies (BCC/SCC). Squamous cell to basal cell cancer ratio was found to be 1.9 to 1. The ratio of extrarenal to renal allograft recipients was identical for all 3 groups (3:1). The median interval from transplant to skin cancer diagnosis was greater than 4 years in each group and longest in those with isolated SCC lesions. In the SCC group, there was a 9% incidence of nodal or secondary site involvement affecting the cervix, perineum, or lung. The highest recurrence rate was demonstrated in the combined malignancy group. Cancer-specific deaths were significantly higher in the SCC (8%) and BCC/SCC (6.8%) groups compared to the BCC (3.6%) group. Conclusions This large experience indicates that SCC is more common than BCC in transplant recipients. SCC alone or in combination with BCC appears aggressive and is associated with significant mortality.

Prostate Cancer Prior to Solid Organ Transplantation: The Israel Penn International Transplant Tumor Registry Experience

Introduction Prostate adenocarcinoma (PCA) is the second leading cause of cancer-related deaths in men, and with routine prostrate specific antigen (PSA) screening, is being diagnosed with increasing frequency. To date, reported experiences with transplantation in men with a history of PCA are limited to only a few patients. This study presents the first series of transplant recipients with a history of PCA. Methods Analysis of transplant recipients with a history of pretransplant PCA was performed on the Israel Penn International Transplant Tumor Registry database. PCA were staged using American Joint Committee on Cancer criteria. Statistics analysis was performed by chi-square and Student t tests. Results Ninety patients with preexisting PCA were identified: 77 renal, 10 heart, and three liver transplant recipients. Mean age at PCA diagnosis was 61.3 ± 6.3 years. Median interval between diagnosis and transplantation was 19.3 months, and median follow-up after transplantation was 20.5 months. Median time to PCA recurrence was 10.6 months after transplantation and median survival time with recurrent PCA was 49.2 months after transplant. Patient mortality was 28.8%, and PCA-related death rate was 7.8%. PCA recurrence rate was 17.7%. Tumor recurrence rates in stage I and II disease (14 and 16%) were lower than in stage III disease (36%). Conclusions In conclusion, death rate to disease other than PCA is three times that due to PCA. PCA recurrence rates are relatively low in patients who initially presented with stage I and II disease, and are half that of patients with stage III disease.

Central Nervous System Tumors in Donors: Misdiagnosis Carries a High Morbidity and Mortality

Introduction The cost of misdiagnosis of central nervous system (CNS) tumors in donors has not been previously described. The purpose of this study was to examine the Israel Penn International Transplant Tumor Registry experience with these donors. Methods All cases where an error in diagnosis was made due to intracranial hemorrhage from undiagnosed CNS tumors and where CNS metastases were misdiagnosed as primary brain tumor were examined. Results Forty-two organ recipients with misdiagnosed primary brain deaths from 29 donors were examined. After transplantation these donors were identified with: melanoma (23%), renal cell carcinoma (19%), choriocarcinoma (12%), sarcoma (10%), Kaposi's sarcoma (7%), and variable tumors (22%). The majority of patients were renal allograft recipients (84%) followed by liver ( n = 4) and lung recipients ( n = 1). The most commonly diagnostic error was with intracranial hemorrhage (ICH) (62%). A donor-related transmission rate of 74% (31/42) was identified among those patients with a misdiagnosed brain death. The majority of donor-transmitted cancers were identified in the recipient allograft (71%). Sixty-four percent of recipients suffered diffuse metastatic disease. Overall survival was poor, with a 5-year survival rate of 32% (10/31). Explantation was performed in 17 patients with confirmed donor-transmitted cancer, and in these patients a survival benefit was noted (10/17, 59%, vs 0/14, 0%; P < .01). Conclusions Error in the diagnosis of donor brain death due to CNS tumors has significant and often fatal consequences. Allograft explantation for kidney recipients or retransplantation for extrarenal recipients may provide a survival benefit. Potential donors with unclear etiologies for brain death, particularly ICH, should be considered for a limited brain autopsy after donation.

Posttransplant Lymphoproliferative Disorder: Significance of Central Nervous System Involvement

Background Few data exist regarding central nervous system (CNS) involvement in patients with posttransplant lymphoproliferative disorder (PTLD). The purpose of this study was to review the Israel Penn International Transplant Tumor Registry (IPITTR) experience with CNS involvement by PTLD. Methods Nine hundred ten PTLD cases from the United States were reported to the IPITTR and reviewed for CNS involvement. Results One hundred thirty-six transplant recipients with PTLD (15%) had CNS involvement. The highest incidence of CNS involvement occurred in pancreas (3 of 11; 27%) and kidney transplant recipients (76 of 429; 18%). Fifteen cases occurred in children and 121 cases in adults. For both children and adults, isolated CNS disease was associated with better survival when compared with multiple-site involvement (children: 29% vs 0%; adults: 12% vs 6%; P < .05). Three-year survival in PTLD patients with CNS involvement was 9.4% and without CNS involvement was 49.4% ( P < .01). Radiation therapy alone appeared to provide the best survival rates (25%). Conclusions CNS involvement in transplant recipients with PTLD carries an ominous prognosis; however, isolated CNS involvement has a better prognosis than CNS plus extracranial involvement. Radiation therapy alone provides the best results, but this may be a reflection of isolated CNS disease.

De Novo Colorectal Cancer: Five-Year Survival is Markedly Lower in Transplant Recipients Compared With the General Population

Introduction The biological behavior of most solid tumors in transplant recipients has not been adequately compared to the general population. The purpose of the present study was to compare outcomes in de novo colorectal cancer (CRC) following solid organ transplantation to those observed in the general population (SEER) database. Methods All transplant recipients with de novo CRC in the Israel Penn International Transplant Tumor Registry were identified and analyzed and the data were compared to CRC patients in the SEER National Cancer Institute (NCI) database. Results One hundred and fifty transplant recipients with de novo CRC were identified, among which were 93 (62%) kidney, 29 (19.3%) heart, 27 (18%) liver, and 1 (0.7%) lung recipients. Median age of transplant recipients was 54 years, compared to a median age of 72 years for patients in the SEER NCI database. However, compared to patients from the SEER NCI database, recipients with Duke's A through C stage disease were noted to experience a significant decrease in 5-year survival. The results in Duke's C patients were particularly dismal. Conclusions The early age at presentation of CRC in transplant recipients suggests that the development of de novo CRC may be effected by immunosuppression. Decreased 5-year survival rates in transplant recipients compared to the general population suggest that CRC in transplant patients is biologically more aggressive. These data cannot distinguish whether the lower survival rates are because the CRC are inherently biologically more aggressive or whether immunosuppression allows for more aggressive clinical behavior of CRC.

Donor Kidneys With Small Renal Cell Cancers: Can They Be Transplanted?

Introduction The purpose of this study was to determine whether incidentally discovered, small renal cell cancers (RCC) in donor kidneys can be excised and safely transplanted. Methods The Israel Penn International Transplant Tumor Registry database was searched and all small RCC that were identified and resected prior to transplantation of deceased and living donor kidneys were reviewed. Patient demographics, tumor characteristics, recurrence, and survival were examined. Results Fourteen kidneys were identified in which small RCC were noted at the time of procurement and where the tumors were excised ex vivo and then transplanted. Eleven kidneys were obtained from living related donors and three were from deceased donors. Median tumor size was 2 cm (range 0.5 to 4 cm). All 14 tumors were of histological Furhman grade II/VI ( n = 8) or Furhman grade I/VI ( n = 6). All kidneys had pathologically confirmed negative margins. The mean age of the recipients was 40.8 ± 9.2 years, with the majority being men (11 men; 3 women). Median follow-up for this group was 69 months (range 14 to 200 months). There have been no recurrences of tumor in these recipients and the 1-, 3-, and 5-year patient and graft survivals are 100%, 100%, and 93%. Conclusions These data represent the only data available (to our knowledge) on this issue. This experience indicates that donor kidneys with small, incidental RCC and low histological grade (Furhman grade I and II/IV) can be managed with excision and transplantation, with a low risk of tumor recurrence in the recipient.

Chemotherapy for Posttransplant Lymphoproliferative Disorder: The Israel Penn International Transplant Tumor Registry Experience

Introduction Very little published data exist regarding the results of chemotherapy treatment of posttransplant lymphoproliferative disorder (PTLD). The purpose of the study was to review the Israel Penn International Transplant Tumor Registry experience with PTLD treated with chemotherapy. Methods Patients with PTLD who received chemotherapy were identified and data collected regarding demographics, tumor characteristics, recurrence rates, and survival. Results One hundred ninety three solid organ transplant recipients with PTLD who received chemotherapy were identified. Most patients were male (142:51) and Caucasian (148; 16 AA, 29 unspecified). Most PTLD were B-cell predominant (81%), monoclonal (71), and CD 20+ (60% of patients tested). Organ transplanted included: kidney, 92 (48%); heart, 54 (28%); liver, 30 (16%); pancreas, 8 (4%); and lung, 9 (5%). Median time to presentation posttransplant was 24.5 months (range 0.8 to 226.5 months). Ninety patients received CHOP, 12 ProMACE, 65 other multidrug regimens, and 23 patients received single-agent chemotherapy. Five-year survival for these four regimens were: 24%, 25%, 32%, and 5%. PTLD-specific death rates were 34%, 34%, 40%, and 48%. Conclusions Single-agent chemotherapy appears to be inferior to other chemotherapy regimens for PTLD as it is associated with lower survival.

Experience with 274 Cardiac Transplant Recipients with Posttransplant Lymphoproliferative Disorder: A Report from the Israel Penn International Transplant Tumor Registry

Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication that occurs in a small but significant minority of solid organ transplant recipients. Published experiences with PTLD in cardiac transplant recipients are limited to relatively small single-center reports. This report presents experience with 274 cases of PTLD in cardiac transplant recipients reported to the Israel Penn International Transplant Tumor Registry (IPITTR). PTLD carried an ominous prognosis: Kaplan Meier survival after PTLD diagnosis was 45%, 33%, 30%, and 13%, respectively, at 1, 3, 5, and 10 years. Common causes of death included: PTLD, cardiovascular collapse, and infection; all occurred at a median of less than 6 months. Risk of death from cardiovascular collapse secondary to immunosuppression withdrawal was substantial (28%), indicating that a fine balance exists between death from PTLD and from sudden cardiac death due to acute rejection. PTLD therapy in the majority of patients consisted of combination therapy (49%). Survival in patients receiving immunosuppression minimization (ISM) alone was 32%, with ISM plus other therapy was 27%, and with other therapies not containing ISM was 11% (P < 0.01). PTLD in cardiac transplant recipients is associated with low long-term survival rates. Analysis of PTLD therapies and outcomes suggest that immunosuppression minimization, when applied, improves survival. However, risk of sudden death may mitigate the positive effect of ISM. This observation has important implications for ISM in PTLD therapy in cardiac transplant recipients. Carefully designed prospective studies are needed to evaluate the positive and negative effects of ISM in cardiac transplant recipients with PTLD.

Gliomas following organ transplantation: analysis of the contents of a tumor registry

The author and others have described a series of patients in whom gliomas have developed following solid organ transplantation. Additionally, patients infected with human immunodeficiency virus reportedly have an increased incidence of gliomas. The author sought to examine the association between the immunosuppressive state in organ transplant recipients and the development of gliomas. Reported cases of tumor in the transplant population of the Israel Penn International Transplant Tumor Registry (IPITTR) were examined. These cases were compared with predicted cases in the 2001 American Cancer Society (ACS) estimates. Of the 7256 malignant tumors listed in the IPITTR database, 19 (0.3%) were primary brain tumors, including 14 gliomas. Tumors known to occur at an increased frequency in transplant recipients accounted for a 1.6- to 2.9-fold increased percentage of cases in the IPITTR compared with 2001 ACS estimates. Tumors not thought to occur with an increased frequency in this population, such as gastrointestinal malignancy and lung cancer, had ratios of 0.19 to 0.35. The corresponding ratio for primary brain tumors was 0.19. None of the six cases previously described by the author and his colleagues was reported to the IPITTR. Primary brain tumors, including gliomas, do not appear to be overrepresented in the IPITTR, indicating that they may not arise with increased frequency in transplant recipients. Nevertheless, one cannot exclude the possibility that neurooncologists may have underreported such cases to this voluntary tumor registry.