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Transplantation is the treatment of choice for most patients with end-stage kidney disease because it incurs both survival and quality of life benefits. However, transplantation of any biological material from a donor to a host will unavoidably carry some risk of disease transmission, such as infection and malignancy [1-4]. Although the incidence of cancer transmission is low (approximately two cases per 10 000 organ transplant recipients) , if it occurs, significant morbidity and mortality are likely. Over the recent years, there have been increasing reports of fatal donor cancer transmission worldwide , such as the transmission of glioblastoma multiforme (GBM)  from donors with a history of cerebral tumors and transmission of melanoma from donors with localized disease as long as 32 years prior to lung transplantation . Transplant clinicians are therefore reluctant to accept organs from donors with a cancer history, except for those with low-grade tumors such as small, localized renal cell carcinomas (RCCs) or those with treated localized solid organ and skin cancers [8-12].
Despite concerted efforts by the transplant community to incorporate evidence of donor transmission risk into policy and guidelines for organ screening and acceptance such as the World Health Organisation (WHO) , the Italian National Transplant Centre (CNT)  and the European Union–funded Projects on Vigilance and Surveillance of Substances of Human Origin  and European Framework for the Evaluation of Organ Transplants , the current recommendations for rejecting or accepting a donor organ with a history of malignancy are based predominantly on single case reports in different transplant settings . In addition, published guidelines for the screening of donor organs and tissues in transplantation have been inconsistent, particularly among donors with borderline transmission risk . In this study, we aimed to systematically review the totality of published evidence on the confirmed cases of donor cancer transmission among kidney transplant recipients and to determine the cancer-specific survival of recipients with donor-transmitted cancers.
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Although the overall risk of donor cancer transmission is small, kidney transplant recipients with donor-transmitted melanoma, sarcoma and lung cancers have the worst prognosis with advanced stage metastatic disease at the time of diagnoses. The overall survival for patients with metastatic lung cancer and melanoma is less than 50% 2 years after initial diagnoses. In comparison, the prognoses for recipients with renal cancer are favorable, with a 5-year survival rate of over 70%. Treatment options for patients with donor-transmitted cancers are also limited. Immunosuppression withdrawal appears to be the treatment of choice in most cases, but often at the expense of graft dysfunction and failure with return to dialysis.
Given the continual shortage of donor organs, coupled with the growing number of patients requiring renal replacement therapy, the number of patients waiting and dying on the kidney transplant waiting list is continuously rising. There is increasing pressure among transplant units worldwide to increase the overall donor pool, including the use of extended criteria donors, donors of extreme ages, donors with prolonged intensive care admission and donors who may potentially transmit disease to their recipients [25, 26]. However, the use of these marginal donors is often associated with a greater risk of undiagnosed disease such as cancers and infections .
The observed findings with reference to the outcomes of patients with transmitted melanomas and lung cancers were not unexpected. Melanoma is an immune-driven malignancy. Melanoma cells can remain dormant for a long period of time, but may reactivate as late recurrence, metastatic disease or newly developed de novo melanomas under the influence of immunosuppression . The outcomes of recipients with transmitted lung cancers were also poor and a similar immunological mechanism may be implicated, where transplantation of the organ harboring dormant metastases allowed subsequent tumor growth in the immunosuppressed host [29, 30].
On the contrary, our findings suggested that the outcomes of those with transmitted donor renal cancers are generally reasonable. The majority of these tumors are small, localized and not apparent at the time of the transplanted surgery. There was also substantial variability in the duration from transplantation to cancer development, suggesting that many of these tumors may perhaps be less susceptible to the influence of immunosuppression or may have a longer sojourn time from preclinical phase to clinical manifestation compared to other solid organ cancers.
Similar findings were observed by a recent initiative, the NOTIFY project, commissioned by the WHO and in collaboration with the Italian CNT. Their recommendations were derived from the Council of Europe Guide to Safety and Quality Assurance for the transplantation of organs, tissues and cells , an internally conducted literature review and expert opinions. Their findings suggested that donors with a history of malignant melanomas, lung cancers, sarcomas and grade IV central nervous system (CNS) neoplasms are considered unacceptable for donation. Given the somewhat positive outcomes of certain donor cancer types and the scarcity of available donors to meet the continuous demand for organs, several exceptions have been made for donors with a cancer history and are considered acceptable for transplantation. These include donors with a history of grade I–II neoplasms of the CNS or grade III in the absence of ventriculo-peritoneal or ventriculo-atrial shunts, previous craniotomy, and previous radiotherapy or chemotherapy and donors with low-grade, small and localized RCC . In general, donors with RCC diagnosed at the time of organ recovery could be considered as suitable donors if the tumor is less than 4 cm, Fuhrman grade I or II and the margins of resection are tumor free .
Our study has several strengths. To our knowledge, this is the first systematic review of all published data regarding donor cancer transmission in kidney transplantation. Using a rigorous and systematic approach to critical appraisal and data analyses, we were able to generate meaningful prognostic information regarding the outcomes of recipients who have developed donor-transmitted cancers after kidney transplantation and therefore provide valuable evidence for transplant healthcare providers and recipients when considering the benefits and risks involved with using organs from donors with a history of cancer.
There are some limitations to this systematic review. First, we may have underestimated the total number of donor-transmitted malignancies as comprehensive and detailed individual level patient data among those with donor-transmitted cancers were not available from all published registry data. The lack of consistent reporting from these included studies may have precluded accurate assessment of all potential confounders, risk evaluation, diagnostic and treatment effectiveness of each reported case of transmitted malignancy. There was substantial variability in the overall follow-up times between the times of transplantation, times of cancer diagnoses and cancer death across individual studies. As such, direct comparison of cancer-specific mortality rates between cancer types was not feasible. There is likely to be selective underreporting of published donor-transmitted cancer deaths whereas those reporting recipient survival may be more prevalent in the gray literature. In addition, we were unable to provide prognostic information about the morphological and histological stages of all included renal cancers in the review. Although we had included some early case reports, we did not observe major differences in the number, the prognoses and the types of cancers observed between the different eras of transplantation. Also, the reporting of metastatic renal cancers did not seem to correlate with the year of publication, where one case was published in the 1970s and the two cases were from the 1990s [23, 33, 34].
There is ongoing controversy regarding whether lymphoma should be defined as donor-derived cancers (i.e. de novo tumors developing in transplanted donor cells), or donor-transmitted cancers (i.e. cancers that existed in the donor at the time of transplantation) . While posttransplant lymphoproliferative disorders could potentially arise from the recipient or donor lymphocytes, the majority of lymphomas originate from reactivation of previously acquired Epstein–Barr virus (EBV) infection, and of the recipient lymphoid cells after solid organ transplantation . The 15 reported cases of post–kidney transplant lymphomas included in our review were proven to be of donor origin. In addition, three out of these 15 cases occurred in EBV-naïve recipients [37-39]. In general, tumors arising after extended posttransplant intervals are often regarded as donor derived, suggesting that tumor development proceeded in the posttransplant period. However, there is currently no time limit to differentiate these cases from those where small tumors may have been present and transmitted at transplantation . In this study, we had included tumors that may arise any time after transplantation as long as they satisfied our inclusion criteria.
Future research and clinical implications
Our review has focused on donor cancer transmission in kidney transplantation only, which is the most common type of solid organ transplant. It would be informative to conduct future prognostic reviews that describe the outcomes of potential transmitted donor malignancy in other solid organ transplant types, such as liver, lung and cardiac transplants. Future research should also consider comprehensive assessment of individual patient data from all available national and international donors and transplant registries. A donor selection policy screening for possible cancer transmission should be in place for living and deceased donor transplantation, and transplant clinicians should also consult the Notify Library , an open access database, to obtain comprehensive information regarding donor cancer transmission events. For living donation, comprehensive cancer screening among live donors is now in place, particularly for common cancer types such as breast, colorectal, prostate and cervical cancers . However, routine cancer screening among deceased donors is not always feasible, as it is neither a practical nor an efficient use of resource to perform autopsies on all potential donors. Transplant clinicians should be aware of the potential donor's medical history and, if in doubt, should exclude organs from donors with any history of high-risk cancers.
Finally, a system of mandatory reporting for suspected and confirmed cases of donor cancer transmission events is obligatory for monitoring and governance and should be instigated in transplanting centers worldwide. One example of policy implementation in recent years is the Directive 2010/53/EU of the European Parliament and the Council of 7 July 2010 , which set out a judicial framework on quality and safety standards for organ transplantation, stating that Member States shall ensure that there is a reporting system to allow relevant information to be reported and transmitted if a serious adverse event should occur following organ transplantation.