Introduction
Renal transplantation remains the treatment of choice for eligible candidates with end-stage renal disease (ESRD), because it offers improved quality and increased quantity of life to these patients. In the early days of renal transplantation, the lack of potent immunosuppressants resulted in very high acute rejection rates leading to early graft loss and overall poor graft and patient survival. Since the advent of potent immunosuppressants in the 1980s and 1990s, both short-term and long-term graft outcomes have improved. The patient survival also improved, but because of the vascular toxicity and immunosuppressive potency of the immunosuppressive drug combinations used, cardiovascular and infectious disease complications became major concerns. Recognition of these causes of mortality led to the institution of a wide range of pre- and posttransplant screening protocols, better diagnosis and treatment of infectious diseases, aggressive risk factor management, reduction in immunosuppressive medication doses, prophylactic treatments, and early interventional therapies, all of which ultimately led to an increase in the lifespan of these patients.
In addition, the increase in the average age of donors and recipients, use of potent immunosuppressants to decrease acute rejection rates, and an overall improved long-term transplant patient survival has resulted in an increase in the incidence of postrenal transplant cancer. Screening for posttransplant cancer is expensive, and protocols vary from center to center. Unfortunately, the risk factors for posttransplant cancer are often difficult to modify, the treatment options are frequently limited, and prognosis for metastatic disease is overall very poor. In this chapter, we will discuss the incidence, risk factors, potential origins, outcomes, preventive and surveillance strategies, and treatment of postrenal transplant cancer.
Incidence of postrenal transplant cancer
The increased relative risk for cancer in renal transplant recipients (RTRs) compared with the general population has been well established based on data from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), Collaborative Transplant Study (CTS), Canadian Transplant Registry, Scientific Registry of Transplant Recipients (SRTR), United Network of Organ Sharing (UNOS), and Israel Penn International Transplant Tumor Registry (IPITTR). The extent of increased risk for different cancer types is consistent in different parts of the world. But the cancer incidence varies among different registries because of the variable reporting of data, different patient demographics, different eras of data measurement, changing and different induction and maintenance immunosuppression protocols across different transplant centers, and methods used for calculating risk. Countries with a single-payer system like Canada, the United Kingdom, and Australia may be able to estimate incidences more accurately compared with countries with multiple payer systems. For example, the estimated sensitivity for identifying cancer using SRTR data was 52.5% and compared with 84.3% for linked central cancer registries. Despite the underreporting of late events, like cancer, or lack of denominators in voluntary registries like IPITTR, it is acknowledged that RTRs incur at least an overall three- to fivefold increased risk of cancer compared with the general population. , ,
The incidence of cancer postrenal transplantation increases with time. Among RTRs, the average age at diagnosis of cancer is about 40 years and the average time from transplantation to cancer diagnosis is 3 to 5 years. The time between transplantation and development of cancer, however, varies depending on cancer subtype. Cancers such as lymphoma and Kaposi sarcoma occur early after transplantation, whereas epithelial cancers tend to occur later. Excluding skin cancer, data from the United States Renal Data System estimate a cumulative incidence of cancer at 7.5% at 3 years after transplantation. Data from IPITTR estimate the incidence of cancer to be 20% at 10 years after transplantation, and data from ANZDATA estimate the incidence of cancer to be 10% at 10 years and 30% at 20 years after renal transplantation.
Standardized incidence ratio (SIR) can be used to estimate the relative risk of cancer in RTRs relative to the cancer incidence in the general population, after allowing for differences in age, gender, and year of diagnosis. Based on data from ANZDATA, RTRs between 1980 and 2005 had a SIR of 3.56 for all cancers. A study of 175,732 US solid organ transplant recipients (58% of which were RTRs, 21% liver, 10% heart, and 4% lung), during the period of 1987 to 2008, revealed a SIR of 2.1 for all cancers. The increase in SIR was not the same for all types of cancers. The SIRs for nonmelanoma skin cancer and Kaposi sarcoma among the solid organ transplant (SOT) recipients were markedly increased at 14 and 62, respectively. Among the RTRs, the SIR for renal cancer was 7 and for non-Hodgkin lymphoma (NHL), it was 6. These high SIRs for NHL and kidney cancer were particularly increased for the youngest recipients, reflecting large increases relative to the general population.
Data available from Medicare billing claims during the period 1995 to 2001 in the United States showed that first-time recipients of deceased or living donor kidney transplantations had a twofold increase for common cancers like colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast, a threefold increase for testicular and bladder cancer, a fivefold increase for melanoma, leukemia, hepatobiliary tumors, cervical, and vaginal cancers, a 15-fold increase for kidney cancer, and a 20-fold increase for Kaposi sarcoma, NHL, and nonmelanoma skin cancer compared with the general population ( Fig. 35.1 ).
Specific cancer types
Skin cancer
It is the most common cancer in RTRs and its incidence increases with time after transplantation. Its incidence is 50% at 10 years and 61% at 20 years in Great Britain and 82% at 20 years in Australia. The overall risk for basal cell cancer is increased 10-fold, and squamous cell cancer by up to a 100-fold compared with the general population.
Posttransplant lymphoproliferative disorder (lymphoma)
Epstein Barr virus (EBV) seronegative recipients are at increased risk for posttransplant lymphoproliferative disorder (PTLD). It is thus more common in children compared with adults. Among adults, PTLD rates vary from 0.5% to 1.7% for EBV seropositive and seronegative patients, respectively. NHL risk is the highest in the first year after transplant, decreases between 2 to 4 years, and then increases again at 4 to 5 years. Both nodal and extranodal presentation can occur. Among RTRs, there is a slight predilection for lymphoma to occur in the transplanted kidney. As transplant patients live longer, cases of late (> 10 years posttransplant) lymphoma are also being reported. Data from CTS have shown that central nervous system (CNS) lymphomas are most common in RTRs and use of T-cell depleting therapy increases the risk. CNS lymphomas have also been seen at slightly increased frequency in patients on belatacept. Because of discontinuation of use of OKT-3 and a trend to lesser induction doses of rabbit antithymocyte globulin (rATG), there has been a decrease in the incidence of PTLD in adults. Among children, a decline in PTLD rates has also been observed in recipients transplanted between 2002 to 2012 compared with those transplanted between 2000 to 2009.
Renal cancer
Renal cancers in RTRs occur mostly in the native kidneys. There is a greater frequency of papillary cell cancer compared with the general population and the incidence is higher in patients with a history of analgesic abuse or acquired cystic disease in the kidneys. The RTRs have a 15-fold increase in risk for renal cancer.
Kaposi sarcoma
Kaposi sarcoma commonly involves the skin but can also involve visceral organs. The incidence of Kaposi sarcoma in RTRs varies with the regimen and intensity of immunosuppression and the risk is less in azathioprine-treated patients compared with cyclosporine-treated patients. Compared with the general population, the rate of Kaposi sarcoma among SOTs and patients with acquired immunodeficiency syndrome (AIDS) is about 500 and 20,000 times, respectively. Because of its low incidence in the general population, the SIR for Kaposi sarcoma in RTRs is increased to 61.
Risk factors for postrenal transplant cancer
Immunosuppressive medications and viral infections appear to be the most important factors in causing the increased risk of cancer after renal transplant. Immunosuppressive medications have a negative effect on immune surveillance but affect deoxyribonucleic acid (DNA) repair mechanisms as well, leading to irreversible DNA alteration and subsequent carcinogenesis. Transplant patients are at increased risk for new viral infections and for reactivating latent viral infections. Potent immunosuppression used for postrenal transplantation can lead to unchecked viral replication and subsequent viral oncogenesis. Conversely, reducing or stopping immunosuppression can lead to regression of certain virus-associated cancers.
Recipient age, gender, ethnicity, and posttransplant lifespan
Increasing age, male gender, and Caucasian ethnicity have been identified as risk factors for postrenal transplant cancer. , This is important given the fact that the average age of RTRs has increased in recent years. The risk for cancer also increases with time posttransplantation because of an accumulation of risk factors like net cumulative immunosuppression, exposure to viruses, sun exposure, and increased age.
Genetic predisposition
Genetic factors are known to predispose to cancer. For example, people with von Hippel–Lindau disease, Wiskott–Aldrich, Lynch, and Drash syndromes are at increased risk of renal cancer. It is possible that as more genetic risk factors for cancer are identified in the future, that immunosuppression after renal transplant may be suitably modified to take this into account.
Chronic renal disease and dialysis duration
Patients with chronic kidney disease (CKD) and ESRD on dialysis are at increased risk of developing posttransplant cancer. Irrespective of the patient’s age, there is a linear relationship between duration of dialysis before transplantation and the risk for developing cancer posttransplantation. The risk is particularly high for Kaposi sarcoma, lip cancer, lymphoma, and genitourinary cancers.
Presence of cystic kidney disease
In RTRs, renal cancer primarily occurs in native kidneys and not in the transplanted kidney. , Patients with acquired renal cystic disease are at increased risk of developing renal cancer because of malignant transformation of the cysts.
Absence of diabetes
This is associated with increased risk of cancer likely caused by relatively less other competing causes of death, such as cardiovascular disease and infections.
History of prior malignancy
Patients with a history of cancer in remission are a high-risk patient population for renal transplantation, because they have a 30% higher risk of death posttransplantation compared with patients with no history of cancer. A metaanalysis of 32 studies in SOT recipients with history of cancer in remission showed that these patients have increased risk for all-cause mortality, cancer-specific mortality, and are at increased risk for developing de novo malignancies. Patients with history of cancer therefore require personalized screening strategies before placement on waiting list for renal transplantation.
Viral infections
Viruses like EBV, human herpes virus 8 (HHV 8), human papillomaviruses (HPV), and Merkel cell polyomavirus have a propensity to cause cancer in RTRs.
EBV has been conclusively implicated in the development of Hodgkin disease, NHL, and other manifestations of PTLD. Approximately 90% of adults show serologic evidence of past exposure to EBV. Transplantation from an EBV-positive donor to EBV-negative recipient is associated with a 20-fold increase in risk for PTLD and that is why children are at particularly higher risk. The degree of immunosuppression and use of T-cell depleting therapy also increases the risk. Approximately 80% of PTLD is caused by abnormal B-cell proliferation induced by EBV and the virus can be isolated from the involved tissue. The remaining 20% of PTLD is caused by T-cell proliferation. The manifestation has a bimodal distribution, with the first peak occurring within the first 2 years of transplantation and a second peak after 5 years of transplantation. PTLD can also arise in donor tissue and RTRs particularly may develop lymphoma in the transplanted kidney.
HHV 8 infection is associated with the development of Kaposi sarcoma and has also been implicated in the development of multiple myeloma. In RTRs, Kaposi sarcoma can involve skin and visceral organs. Risk factors include donor to recipient transmission, degree of immunosuppression, geographic area of origin, and male gender.
HPV has multiple genotypes that have been associated with different cancers. Transmission of this infection is through close personal contact, including sexual contact. In RTRs, it is associated with skin cancer, head and neck cancers, and anogenital cancers, including vulvar, vaginal, cervical, penile, and anal cancers.
Merkel cell polyomavirus infection can cause Merkel cell carcinoma. It is an aggressive tumor involving skin and neuroendocrine tissue and has a propensity for lymphatic spread.
Cigarette smoking
RTRs who smoke are at increased risk of developing lung cancer compared with RTRs who do not smoke. The relative risk of lung cancer increases with prior and current history of smoking. The mortality risk from lung cancer in RTRs is higher in those who continued cigarette smoking compared with those who stopped cigarette smoking after transplantation. Cigarette smoking is also associated with an increased risk of death and graft loss.
Sun exposure and geographical location
Sun exposure is a well-established risk factor for the development of skin cancer in RTRs. Sun exposure before transplantation, intensity of immunosuppression, older age, use of calcineurin inhibitors (CNIs) versus mammalian target of rapamycin inhibitor (mTORi) increase the risk. Skin cancer occurs more frequently in sun-exposed areas. Skin pigmentation modifies the risk and African American recipients are at much less risk for skin cancer in sun-exposed areas compared with white Americans.
Type of donor
Recipients of living donor kidneys are at reduced risk of cancer, particularly PTLD and genitourinary (GU) cancers, when compared with recipients of expanded criteria donors (ECD). This is independent of their age, gender, and duration on dialysis. Intense inflammatory response posttransplantation among the ECD kidney recipients has been speculated to contribute to the increased cancer risk in this patient population.
Donor transmitted cancer
Many different types have cancers have been reported to be transmitted through donors. In RTRs, the incidence of donor transmitted cancer has been reported to be less than 1 in 3000 (< 0.03%). These events are rare, so that there may be an underestimation of their true incidence. Within the US, the Disease Transmission Advisory Committee (DTAC), in Europe, the Council of Europe and globally, a World Health Organization-sponsored website ( www.notifylibrary.org ) now actively collect data on donor transmitted cancer and infections.
Immunosuppressive drug therapy
Net cumulative immunosuppression, antibody induction, type of maintenance immunosuppressive medications, number of immunosuppressive medications, rejection treatment, and use of immunosuppressive medications before transplant all contribute to the risk of postrenal transplant cancer.
Immunosuppression may lead to decreased immune surveillance of nascent cancer and may also predispose to viral infections that are oncogenic. The overall risk for postrenal transplant cancer is driven by the duration and intensity of immunosuppression (net immunosuppression). Indirect evidence for this comes from studies showing an increased incidence of cancer in patients treated with intense immunosuppression for treatment of acute rejection and in patients treated with immunosuppression for primary glomerular disease before transplantation. Patients with human immunodeficiency virus/AIDS also have similarly increased rates of oncogenic virus-driven cancers, further supporting that immune deficiency plays a significant role in increased risk. Patients on mTORi have been reported to have reduced risk of cancer; however, this reduced incidence has not been shown to improve the overall survival of RTRs. Although it is possible that small differences exist among the maintenance immunosuppressive drugs, these are likely to be clinically less important given the far greater effect of other known risk factors.
Induction therapy
Induction therapy is used in most patients at the time of renal transplant to avoid early rejection. The induction agents include monoclonal antibodies, such as basiliximab (antiinterleukin [IL]-2 receptor antibody) and alemtuzumab (anti-CD52), or polyclonal lymphocyte-depleting antibodies like horse or rATG/thymoglobulin. OKT3/muromonab is more potent than rATG and was associated with increased risk for lymphoma, but it is no longer commercially available. Non-rATG preparations have also been shown to be associated with increased risk for PTLD. rATG is more potent than equine ATG in depleting peripheral blood lymphocytes and is presently the most commonly used polyclonal antibody in the US and worldwide. The risk of infections and cancer increases with increasing dose of T-cell depleting agents and thus over the years, the standard total induction dose of rATG has decreased from 14 to 6 mg/kg. The antibodies against T-cells deplete both CD4+ and CD8+ T-cells, which are crucial in adaptive antiviral immunity, and their depletion increases the risk for diseases caused by uncontrolled virus replication. Polyclonal antibodies also target natural killer (NK) cells, B-cells, and plasma cells, which another mechanism to enable development of EBV-driven PTLD. IL-2 receptor antagonist (IL-2Ra) induction does not appear to be associated with an increase in risk for cancer. , ,
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