Immunosuppression: A critical and obvious risk factor in this patient population is the use of immunosuppression. This includes not only the maintenance therapies but also induction strategies such as T cell depletion that add to the overall suppressive burden. Indeed, the level and intensity of immunosuppression have been correlated to higher rates of cancer in solid organ transplant recipients that have greater exposures [8]. Immunosuppression may also have untoward effects on innate and adaptive immunity in the context of tumor surveillance [9, 10]. Additionally, the class of agent also has specific impact on cancer development. Depletional induction therapies have been associated with EBV-mediated PTLD [11]. The use of belatacept, the costimulatory inhibitor, is also associated with a higher risk of PTLD, particularly in EBV-naïve recipients who received EBV-seropositive organs. Calcineurin inhibitors, both cyclosporine A and tacrolimus, may promote cancer formation by stimulating transforming growth factor beta (TGFβ) with enhanced small vessel growth [12, 13]. Clinical evidence is not conclusive, however, of a direct relationship between CNI use and higher rates of malignancy [14, 15].

The antimetabolite azathioprine is known to sensitize skin to UV light-mediated damage. However, the mycophenolate mofetil may lower cancer development [16, 17] through its primary inhibition of inosine monophosphate dehydrogenase, an enzyme elevated in a number of malignancies [18, 19]. There are insufficient data, however, to support this notion as a preventive therapy.

Of significant interest this decade has been the growing number of reports using inhibitors of mammalian target of rapamycin (mTORi). This class of agents has antiproliferative and inhibitory properties for a variety of other solid tumors [20] through inhibition of VEGF. In kidney transplant recipients converted to mTORi [21] or on mTORi-based maintenance therapy [22], the incidence of cancers was reduced compared to CNI-based regimens, particularly NMSC, although these are retrospective studies and with limited follow-up. More recent prospective studies converting to mTORi have shown slower rates of skin cancer growth and prevention of further recurrences as demonstrated in a recent clinical trial [23]. The use of mTORi for maintenance immunosuppression in recipients with prior cancer and for those in whom cancer develops has been advocated by some in the field [24]. However, the relative lack of prospective, well-controlled studies using mTORi for prevention of all malignancies makes this strategy difficult to recommend in all situations.

Preexisting cancer: A critical risk to posttransplant disease is cancer prior to transplantation. Recurrence risk is dependent on the type of tumor, stage [25], management, and the interval between treatment of the tumor and a subsequent renal transplant. High rates of recurrence have been observed with multiple myeloma [26], suggesting a critical treatment plan prior to considering transplantation. Consequently, malignancy-free waiting periods are recommended for each cancer type in order to alleviate the morbidity of cancer recurrence after transplantation (Table 25.3) [27, 28].

Donor–derived transmitted tumors: Prior to 2000, cancer transmission from deceased donor organs was thought to be relatively uncommon with a rate of 0.017 % [29], but a relatively high mortality when they occur. These rates, however, were based on registry data that were incomplete [30]. Further reports from the IPTTR suggested that transmission rates for donors with malignancy were substantially higher at 42 %, with the highest rate of transmission from known cancer-bearing donors to be in renal transplant recipients [31]. CNS tumors were the most commonly identified in donors, and the highest transmission rates were for choriocarcinoma and melanoma. These data support the need for better assessment of donor malignancy history and risk of transmission. Recognizing the limitations of this voluntary registry, analysis of donor OPTN/UNOS data from 2000 to 2005 indicated that only 2 % of deceased donor organs came from donors with history of malignancy [32]. In this series, nonmelanoma squamous cell cancers of the skin, CNS tumors, and uterine cancer were the most common cancers noted in donors. Recently, a malignancy subcommittee for the OPTN/UNOS Disease Transmission Advisory Committee analyzed current literature and created levels of risk from 0 (no risk) to 4 (high risk) and also a category for unknown risk [33]. Additionally, all possible cancers were classified by this scheme based on clinical behavior of the tumor, cure probability, and time to metastasize (Table 25.4). These guidelines provide a basis to the donor surgeon in terms of appropriate utilization of donor organs and allow the informed risk assessment to the recipient who may succumb to their end-stage disease prior to transplantation.