DISEASE of the MONTH J Am Soc Nephrol 15: 1582–1588, 2004 EBERHARD RITZ, FEATURE EDITOR

DISEASE OF THE MONTH J Am Soc Nephrol 15: 1582–1588, 2004 EBERHARD RITZ, FEATURE EDITOR

Malignancy in Renal Transplantation

CHRISTIAN MORATH,* MARTINA MUELLER,† HARTMUT GOLDSCHMIDT,‡ VEDAT SCHWENGER,* GERHARD OPELZ,§ and MARTIN ZEIER* Departments of *Nephrology, †Gastroenterology, ‡Hematology/Oncology, and §Transplant Immunology, University of Heidelberg, Heidelberg, Germany.

An increased incidence of malignant tumors in transplant (10). Among other factors, duration and intensity of immuno- recipients was recognized as early as in the 1970s, and this suppression emerged as a particularly powerful risk factor (10). effect was ascribed to the administration of immunosuppres- Incidence and type of cancer after renal transplantation vary sive medication (1,2). In the early days of transplantation between centers, countries, and time periods (11). Some of this medicine, however, the clinician faced fulminant acute rejec- variation is accounted for by the impact of competing causes of tion episodes and severe infections; malignancy after trans- death. For instance, according to a report from the Glasgow plantation represented only a minor problem. With longer graft transplant program, during the first 14 yr of the program (1969 survival and older donors (as well as recipients) and with the to 1982), 40% of patient deaths were attributed to infection, introduction of more potent immunosuppressive medication, 23% to cardiovascular disease, and 10% to malignancies. Dur- malignancy represents a major burden in transplantation med- ing the subsequent 14 yr, deaths resulting from infection de- icine. The overall incidence of malignancy after renal trans- creased substantially, and the relative and absolute frequency plantation has been reported as being 3 to 5 times higher of death from cardiovascular disease and malignancy increased compared with the general population (3,4). However, an in- concomitantly (9,11). creased frequency is not found for all types of cancer (Figure In single-center reports from Glasgow and Leiden, death due 1). According to the Cincinnati Transplant Tumor Registry and to malignancy was found in 15% and 14% of kidney graft other reports, the most frequent types of tumors are posttrans- recipients, respectively (9,12). In contrast, only 2.6% of renal plant lymphoproliferative disorder (PTLD) and squamous cell allograft recipients in Japan were reported to have developed a carcinoma (lip, cervix, vulva, skin) (5,6). malignancy between 1970 and 1995 (13).

Epidemiology Pathogenesis Many retrospective analyses do not adequately reflect the Malignancy after transplantation can develop in three different magnitude of the problem (3,5). The cumulative prevalence of ways: malignancy increases with the duration of follow-up. After 10 • yr, the risk of cancer in transplant patients was recently re- De novo occurrence in the recipient • ported as being 13.8-fold higher in transplant recipients than in Recurrent malignancy in the recipient • the background population (7). When patients on hemodialysis Transmission of malignancy from the donor were compared with transplanted patients, the risk of developing cancer was 10 times higher in the latter group (8,9). The De Novo Occurrence of Malignancy in the progressive increase with time of observation is impressively Recipient illustrated by the Australian experience. In this high-risk set- Immunosuppression and Malignant Transformation ting of fair-skinned individuals with intense exposure to sun- In renal transplant recipients, the frequency of two types of light, the cumulative incidence of skin cancer, calculated by malignancies stands out: skin cancer and lymphoproliferative life-table analysis, increases progressively from 7% after 1 yr, disease. The spectrum for the latter ranges from benign PTLD to 45% after 11 yr, and 70% after 20 yr of immunosuppression to non-Hodgkin lymphoma (NHL). Evaluation of the literature on PTLD is complicated by the fact that reports commonly include cases with polyclonal proliferation as well as monoclonal lymphoproliferative disorders. According to the litera- Correspondence to Dr. Christian Morath, Department of Nephrology, Univer- ture, malignancies of the lymphoproliferative system occur sity of Heidelberg, Bergheimerstr. 56 a, 69 115 Heidelberg, Germany. Phone: 49-6221-9112-0; Fax: 49-6221-9112-79; E-mail: christian_morath@med. mostly within the first three yr after renal transplantation. The uni-heidelberg.de high overall risk of malignancy in heavily immunosuppressed 1046-6673/1506-1582 patients is primarily due to the development of NHL. It has Journal of the American Society of Nephrology been claimed that the introduction of new and more potent Copyright © 2004 by the American Society of Nephrology immunosuppressive regimens is associated with an increased DOI: 10.1097/01.ASN.0000126194.77004.9B incidence of cancer after renal transplantation (14), but this J Am Soc Nephrol 15: 1582–1588, 2004 Malignancy and Immunosuppression — A Historical Perspective 1583

dimers, leading to inactivation of the tumor suppressor gene p53. Malignant proliferation is thought to be a result of the failure to repair such mutations. The relationship between tumorigenesis and immunosuppression is not fully understood. The following points are of interest with respect to the pathogenesis of posttransplant malignancies. Natural killer cells play an important role in the host’s defense against malignancy (27). Depletion of natural killer cells (NK-1.1) in mice increased the implantation and growth of B16 melanoma cells or CT 38 colon carcinoma cells (28). After injecting colonic carcinoma cells into the superior Figure 1. Ratio observed/expected malignancies in graft recipients (76). mesenteric vein of syngenic mice, injection of natural killer cells together with interferon-␥ reduced the tumor cell burden in the liver (29). The administration of anti-T cell antibodies, statement is not supported by solid epidemiologic evidence. e.g., anti-Thy 1.2 or anti-asialo GM-1, was associated with There are conflicting reports on whether the introduction of increased tumor colonization (30). However, this was not true cyclosporine was followed by a higher frequency of malignant for all immunomodulatory antibodies. For instance, anti-CD4 tumors (15,16). It has also been reported that malignancies are monoclonal antibody (keliximab) did not interfere with the more frequent in patients on triple drug regimens that include immune response against malignant cells in mice (30). The cyclosporine, azathioprine, and corticosteroids (17). There is recently introduced immunosuppressive agent rapamycine little dispute that the development of lymphomas is particularly (Sirolimus) is believed to combine immunosuppressive action increased in patients receiving polyclonal or monoclonal anti- with antitumor effects (31). bodies for induction or rescue therapy. This is true for recipi- These clinical and experimental observations are compatible ents of both renal and cardiac allografts (18). In an analysis of with the notion that the increased frequency of malignancies in the United Network of Organ Sharing (UNOS), the risk of allograft recipients results mainly from immunosuppression. malignancy was particularly high in patients who received a But this simple concept does not explain that the excess tumor combination of monoclonal antibodies, tacrolimus, and myco- incidence in kidney recipients is restricted to certain malignan- phenolate mofetil. In patients receiving this immunosuppres- cies, such as skin tumors and lymphoma. It would therefore sive regimen the overall risk of any type of cancer compared appear that immunosuppression alone is not sufficient for with the matched background population was increased by a tumor development: additional risk factors, such as the pa- factor of 5.11, and the risk of PTLD (with the above reserva- tient’s genetic background, viral co-infection, or sun exposure tions) was higher by a factor of 27.2 (19). apparently play also a role (Table 1). The hypothesis that the action of immunosuppressive drugs is responsible for the increased incidence of tumors in trans- Conventional Risk Factors plant recipients is supported by the observation that patients Commonly known risk factors such as advanced age, ciga- also develop tumors if they receive immunosuppressive ther- rette smoking (32), and analgesic abuse (33) are risk factors for apy for conditions other than transplantation, e.g., rheumatoid posttransplant malignancies as well. For instance, in patients arthritis, systemic lupus erythematodes (SLE), or dermatomy- with a history of phenacetin abuse, the risk of developing ositis. An increased frequency of lymphoproliferative disease uroepithelial carcinoma is strikingly increased (34). This ob- in these patients has been attributed to the administration of servation even led to the postulate that nephroureterectomy immunosuppressive agents, such as methotrexate, cyclospor- should be performed before transplantation. ine, or azathioprine (20–22). A relationship between the intensity of immunosuppression Genetic Factors and an increased incidence of tumors has been shown most Genetic factors are known to predispose to the development convincingly for skin cancer. The established risk factors for of malignancies, and this appears to apply also to transplanted basal cell and squamous cell cancer, such as exposure to patients. According to one study, patients who had an invasive sunlight, are also operative in transplanted individuals (23). Yet duration and intensity of immunosuppression emerged as an additional risk factor (24,25). A predisposition to squamous Table 1. Malignancies after renal transplantation—risk cell carcinoma may also be related to the increased prevalence factors of human papilloma virus (HPV) in transplant patients. Pre- Immunosuppression sumably because of immunosuppression, it is found in almost Conventional risk factors, i.e., age, smoking 90% of allograft recipients (26). Viral proteins E6 and E7 of Chronic viral infection HPV inhibit the tumor suppressor gene p53 and are thought to Genetic risk factors be involved in the induction of carcinoma in this high-risk History of treatment with cytotoxic agents, i.e., population. In addition, exposure of the skin to ultraviolet cyclophosphamide radiation causes DNA mutations by formation of thymidine 1584 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1582–1588, 2004 carcinoma before transplantation had a much higher risk (RR munosuppressive conditioning regimen. The animal data are in 2.38) of developing a second invasive carcinoma de novo after good agreement with a large multicenter study of transplanted transplantation (32). Some rare primary renal diseases (partic- patients in which a higher rate of NHL was found in patients ularly von Hippel-Lindau disease) are associated with an in- after the administration of antilymphocyte antibodies (18). trinsically higher risk of developing renal cell carcinoma with Cathomas et al. (42) reported an association of Kaposi sarcoma an aggressive clinical course. When such patients receive a with HHV 8 infection in a series of 18 renal transplant recip- renal allograft, the frequency of renal cell carcinoma increases ients. It is of note that almost all of these patients had received further (35). The risk of carcinoma is also markedly increased monoclonal or polyclonal antibodies as induction or rescue in patients with Wiskott-Aldrich syndrome or Drash syndrome. therapy for steroid-resistant rejection (43). In transplant recipients with these rare syndromes, an excessive Various types of papilloma virus are associated with skin, frequency of lymphoma and Wilms’ tumor was noted (36,37). cervix, penis, or anogenital carcinomas (44). The hypothesis that genetic predisposition plays a role in the Polyoma virus, which has recently attracted considerable genesis of posttransplant malignancies is also supported by the clinical attention, is a double-stranded DNA virus that induces observation that patients with malignancies after transplanta- acute interstitial nephritis in renal transplant recipients (45). It tion often have more than one type of tumor. Patients with as causes not only acute renal dysfunction, but is also tumorigenic many as three different types of tumor have been reported (38). by transforming cells mainly by the action of the middle T In patients with two malignancies, the most common second- antigen (46,47). ary malignancy is a skin tumor. In a retrospective study by At this point, some comments on the mechanism of virus- London et al. (39), skin tumors were found in 10 of 70 renal induced tumor formation may be appropriate. For any virus to allograft recipients who had other types of malignancies. induce uncontrolled cell proliferation in vivo, at least 3 pro- cesses must take place (48,49): Chronic Viral Infections 1. The virus must uncouple the mechanisms controlling Certain viral infections predispose transplant recipients to progress of the cell cycle and cell division. specific types of malignancies (Table 2). Epstein-Barr virus 2. The virus must prevent the host cell from undergoing (EBV) is frequently associated with lymphoma, and human apoptosis. herpes virus 8 (HHV 8) is frequently associated with Kaposi 3. The proliferating cell, bearing viral-derived antigens on its sarcoma (40). NHL results from abnormal lymphoid cell pro- surface, must escape the attention of the host immune liferation after aggressive or prolonged immunosuppression. system. Some 98% of cases with PTLD are associated with latent EBV infection. EBV is a herpes virus that infects most adults and Of particular interest is the escape from apoptosis, which is establishes an asymptomatic B cell infection via T cell–medi- a requirement for sustained growth after transformation of the ated suppression of viral growth (41). T-cell surveillance is host cell by oncogenic viruses. A class of proteins, FLIPs impaired by cyclosporine, and it is even more disturbed by (FADD l Like Interleukin 1B converting enzyme-like protease antibodies directed against T cells, e.g. OKT3 or ATG. In vitro Inhibited Proteins), interfere with the initiation of apoptosis at studies showed that coincubation of EBV-infected B cells with the level of death receptors (50). Some FLIPs are encoded by OKT3 or ATG resulted in increased B cell proliferation and class ␥ herpes viruses, e.g., herpes virus Saimiri (HVS) or immortalization (42). Such a mechanism is also likely to play HHV 8. So-called viral FLIPs (vFLIPs) inhibit apoptosis a role in vivo. Schmidtko et al. (42) described EBV-associated through several apoptosis-reducing receptors (CD95, TNF-R1, PTLD after renal transplantation in primates, and this was TRAMP/DR3, and TRAIL-R1) that presumably share common particularly prominent in animals receiving an aggressive im- signaling pathways (51). All viruses encoding vFLIPs can transform cells in vitro and are associated with tumors in susceptible hosts. HVS causes lymphoma and leukemia in Table 2. Viruses related to malignancies after susceptible primates and induces stable growth transformation transplantationa of human T cells in vitro. HHV 8 is associated with Kaposi sarcoma and multicentric Castleman disease. EBV Lymphoma Another important pathway for virus-induced malignancy is HHV 8 Kaposi sarcoma interference with the p53 tumor suppressor gene (52). P53 Lymphoma induces cell cycle arrest or apoptosis in response to DNA Human papillomaviruses Cervix cancer damage. Small DNA viruses use distinct mechanisms to (HPV) Penis carcinoma counter p53. They either bind directly to p53 and inhibit Vulvar carcinoma p53-mediated transcriptional activation, or they promote the HPV 58 Bowen disease degradation of p53 via the ubiquitin pathway. HPV 8, 19 Nonmelanoma skin cancer HPV 16, 20 Skin and tonsillar carcinoma Geographical Differences HCV, HBV Hepatocellular carcinoma A survey of the literature shows that the relative frequency a EBV, Ebstein-Barr virus; HHV 8, human herpesvirus type 8; of malignancy after renal transplantation varies widely be- HCV, hepatitis-C virus; HBV, hepatitis-B virus. tween different geographical regions. In Japan, tumors of di- J Am Soc Nephrol 15: 1582–1588, 2004 Malignancy and Immunosuppression — A Historical Perspective 1585 gestive organs (50%)—liver, stomach, colon, rectum—are the study of 1297 renal allograft recipients with a history of ma- most frequently observed posttransplant tumors, in good agree- lignancy (59). For tumors diagnosed and treated before trans- ment with the generally high prevalence of GI cancers in this plantation, the frequency of recurrence after transplantation country. In contrast, the frequency of skin cancer and lym- was 21%. For tumors diagnosed and treated after transplanta- phoma is low in Japan (13). In the United Kingdom, the most tion the respective figure was 33%. Among tumors diagnosed frequent posttransplant malignancies are lymphoma, renal cell and treated before transplantation, the frequency of recurrence carcinoma, carcinoma of the digestive system, and bronchial after transplantation was highest for breast cancer, symptom- carcinoma (39). In Saudi Arabia, the most frequent malignan- atic renal cell cancer, sarcoma, bladder cancer, and multiple cies are Kaposi sarcoma, lymphoma (particularly in children), myeloma (59). skin malignancy (with melanoma being more frequent in children than in adults), and anogenital cancers (53). In Australia, the risk of developing posttransplant skin cancer, particularly Management of the Allograft Recipient with spinocellular carcinoma, is extremely high. The most favored De Novo Malignancy after Transplantation explanation for this unique Australian experience is that a When a patient develops a malignancy de novo after renal fair-skinned Caucasoid population is exposed to excessive transplantation, the question arises whether it is useful to ultraviolet light (54). In South East Asia, where hepatitis B and reduce or stop immunosuppression. The underlying idea is that C infections are endemic, the frequency of liver cancer after this move might allow rejection of the malignancy by the renal transplantation is high (55). recipient’s recovering immune system. If immunosuppression is stopped, particularly early after transplantation, graft moni- Transmission of Malignancy from the Donor toring at short intervals is necessary; otherwise fulminant re- Transmission of a tumor via (micro)metastases of an undi- jection may be discovered too late, with the potential conse- agnosed malignancy in the donor is rare, but this possibility quence of graft rupture. Removal of the graft is often advisable. must also be considered in the differential diagnosis of malig- Successful reduction or cessation of immunosuppression nancy after transplantation. According to data from the Organ was reported in transplanted patients who developed NHL and Procurement and Transplantation Network/UNOS, a total of 21 Kaposi sarcoma (60). Despite this the rate of death remained donor-related malignancies was reported in 108,062 transplant high in patients with posttransplant lymphoma. Therapeutic recipients (56). Fifteen tumors were donor-transmitted (malig- strategies targeting B cells (61), including local or systemic nancies that existed in the donor at the time of transplantation), administration of specific anti-CD24-, anti-CD21-, and anti- and six tumors were donor-derived (de novo tumors that de- CD20- (rituximab) B cell antibodies, were successful with a velop in transplanted hematogenous or lymphoid cells of the follow-up of several months (62,63). There are also reports of donor). Donor-derived tumors have been reported in allografts successful antiviral treatment with acyclovir, valacyclovir, or obtained from donors with bronchial carcinoma, breast cancer, ganciclovir in EBV-induced lymphoproliferative disease (64). and malignant melanoma (6,57). In some patients, cessation of In patients who do not respond to these therapies or in severe immunosuppression led to rejection of the donor-derived ma- disease, a treatment regimen including cyclophosphamide, lignancy without further therapy. In most patients, however, doxorubicin, vincristine, and prednisone (CHOP) is recom- specific anti-tumor therapy was necessary, i.e. surgery, chemo- mended (65). therapy, radiation, to induce remission. Transplant recipients with premalignant skin lesions should be referred to a dermatologist for active treatment and close Management of the Allograft Recipient with a follow-up. Skin cancers should be completely removed. Sec- Preexisting Malignancy ondary prevention includes the use of topical or systemic When a patient is considered for the transplant waiting list, retinoids in patients with actinic keratoses and squamous-cell the question arises whether a history of malignant disease is a carcinoma and reduction of immunosuppression when possible. contraindication to renal transplantation. One retrospective Posttransplant Kaposi sarcoma is particularly interesting be- analysis comprised 913 renal allograft recipients with a total of cause it is the tumor with the highest relative risk compared 939 preexisting cancers (58), illustrating that more often than with the background population (53). The clinical course is not the nephrologist must deal with this problem in today’s often aggressive, with a mortality rate of 34% within 3 yr of aging dialysis population. There is consensus that a 2-yr wait- diagnosis. Involvement of visceral organs is an indicator of ing period should be interposed between the successful treat- severe disease. Aggressive forms of gastrointestinal involvement of cancer and transplantation. A waiting period is not ment may be diagnosed during endoscopy. Reduction of im- required for the following tumors: incidentally discovered re- munosuppression leads to complete remission in 30% of the nal cell carcinoma, any type of in situ carcinoma, and basal cell patients. Localized lesions may be treated surgically or by local carcinoma of the skin. Because of a high likelihood of recur- radiation (66). rence even beyond the second year after treatment, a waiting Immunotherapy of melanoma (67), colorectal cancer (68), period of more than 2 yr is advisable in patients with a history and renal cell carcinoma (69) is currently under investigation in of malignant melanoma, breast cancer, and colorectal carci- nontransplant patients. Whether these treatment modalities will noma. The issue of recurrence was addressed in a retrospective be useful in organ transplantation awaits further studies. 1586 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1582–1588, 2004

Table 3. Protocol for screening of patients after transplantationa

History and physical examination to exclude disseminated or localized organ involvement by PTLD (every 3 mo during the first year after transplantation, subsequently at yearly intervals) Skin examination by dermatologist (every 6 mo in high-risk patients, otherwise yearly) Ultrasonography or CT scan of the native kidney (at yearly intervals) Gynecologic examination, including PAP smear and ultrasonography of female reproductive organs (at yearly intervals) In selected cases PSA and digital rectal examination (male Ͼ 50 yr, at yearly intervals) Fecal occult blood testing (age Ͼ 50 yr, at yearly intervals) Abdominal ultrasound and serum ␣-fetoprotein levels (in carriers of hepatitis B or C virus) Cystoscopy (de novo hematuria, particularly when history of cyclophosphamide treatment)

a According to Kasiske et al. (75) and others.

Screening of the Allograft Recipient for Periodic screening of feces for occult blood is advisable Malignancy because colonic carcinoma is more frequent after renal trans- Regular tumor screening is advisable when a patient is plantation. Patients with a history of ureterosigmoidostomy considered for renal transplantation and especially after trans- should undergo colonoscopy at least 10 yr after renal transplantation (Table 3) (75). The rising age of patients on the plantation because of the risk of late colonic carcinoma (74). waiting list in conjunction with the increasing length of time For other solid organ cancers (prostate, breast), guidelines patients spend on the waiting list enhances the risk that ma- published for screening and prevention of solid organ cancers lignancy will escape detection so that recipients with preexist- in the general population should be strictly applied to trans- ing tumors will receive transplants. plant recipients. History and physical examination, with attention to symptoms suggesting organ involvement by PTLD, should be per- Outlook formed every 3 mo during the first year after transplantation Early diagnosis and treatment of posttransplant malignancies and at least yearly thereafter. is an important challenge in transplantation medicine. An even Screening to detect skin tumors is most important. Periodic greater challenge is the prevention of malignancies. Documen- inspection of the entire skin, with emphasis on sun-exposed tation of tumors arising de novo after transplantation as well as areas, by a dermatologist is mandatory (at least at yearly elucidation of their relationship with particular immunosup- intervals). In high-risk patients (e.g., those who have previ- pressive treatment regimens is a first step in this direction. ously been diagnosed with squamous cell carcinoma), more This overview attempted to summarize the available evi- frequent controls are indicated (at least every 6 mo). Primary dence in this area. As even more potent immunosuppressive prevention of skin cancers includes avoidance of sun exposure, drugs enter the transplant field, it will be important to monitor use of protective clothing, and use of effective sunscreen by the their tumor-inducing potential. Reduction of life-threatening patient, according to the European Best Practice Guidelines infection had been a goal in the past decades. In the future, the (70). Compliance is a universal problem. According to a study reduction of posttransplant malignancies must be another target from Leeds, only 54% of patients remembered that they had in the effort to improve immunosuppression in graft recipients. received any advice concerning cancer prevention, and only 30% of patients knew why extra precautions against sunlight were necessary (71). Acknowledgment Yearly gynecologic examinations are mandatory to exclude The critical advice of Professor Eberhard Ritz during the prepara- tion of the manuscript is gratefully acknowledged. vulvar, perineal, and uterine malignancies. In women without hysterectomy, transvaginal ultrasonography is recommended. Multicystic transformation of contracted kidneys in patients References with primary renal disease is a precancerous condition. Ultrasono- 1. Penn I: Malignancies associated with renal transplantation. Urol- graphic examination of the recipient’s kidney should be per- ogy 10: 57–63, 1977 formed at least at yearly intervals. Urologic examination is indi- 2. Penn I: Second malignant neoplasms associated with immuno- cated in patients with a history of analgesic nephropathy who suppressive medications. Cancer 37: 1024–1032, 1976 3. Birkeland SA, Lokkegaard H, Storm HH: Cancer risk in patients develop microhematuria. Another high-risk group includes those on dialysis and after renal transplantation. Lancet 355: 1886– patients who received cyclophosphamide for treatment of vascu- 1887, 2000 litis, especially in those patients where the cumulative dose ex- 4. Peto J: Cancer epidemiology in the last century and the next ceeds 20 g (72). Some authors also recommend urologic exami- decade. Nature 411: 390–395, 2001 nation in patients who have been treated with azathioprine for 5. Penn I: Cancers in renal transplant recipients. Adv Ren Replace more than 10 yr (73). Ther 7: 147–156, 2000 J Am Soc Nephrol 15: 1582–1588, 2004 Malignancy and Immunosuppression — A Historical Perspective 1587

6. Zeier M, Hartschuh W, Wiesel M, Lehnert T, Ritz E: Malignancy 25. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin after renal transplantation. Am J Kidney Dis 39: E5, 2002 G, Livi U, Peserico A: Skin cancer in heart transplant recipients: 7. Yang TC, Shu KH, Cheng CH, Wu MJ, Lian JD: Malignancy frequency and risk factor analysis. J Heart Lung Transplant 19: following renal transplantation. Zhonghua Yi Xue Za Zhi (Taipei) 249–255, 2000 61: 281–288, 1998 26. Berg D, Otley CC: Skin cancer in organ transplant recipients: 8. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Epidemiology, pathogenesis, and management. J Am Acad Der- Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs D, matol 47:1–17, 2002; quiz, 18–20 McCredie M, Boyle P: Cancer in patients on dialysis for end- 27. Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA: Biology stage renal disease: an international collaborative study. Lancet and clinical impact of human natural killer cells. Int J Hematol 354: 93–99, 1999 78: 7–17, 2003 9. Briggs JD: Causes of death after renal transplantation. Nephrol 28. Seaman WE, Sleisenger M, Eriksson E, Koo GC: Depletion of Dial Transplant 16: 1545–1549, 2001 natural killer cells in mice by monoclonal antibody to NK-1.1. 10. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, Mac- Reduction in host defense against malignancy without loss of Naught A, O’Sullivan B, Siskind V, Van Der Woude FJ, Hardie cellular or humoral immunity. J Immunol 138: 4539–4544, 1987 IR: The risk of skin cancer in renal transplant recipients in 29. Rushfeldt C, Sveinbjornsson B, Seljelid R, Smedsrod B: Early Queensland, Australia. A follow-up study. Transplantation 61: events of hepatic metastasis formation in mice: role of Kupffer 715–721, 1996 and NK-cells in natural and interferon-gamma-stimulated de- 11. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, fense. J Surg Res 82: 209–215, 1999 Port FK: Long-term survival in renal transplant recipients with 30. Herzyk DJ, Gore ER, Polsky R, Nadwodny KL, Maier CC, Liu graft function. Kidney Int 57: 307–313, 2000 S, Hart TK, Harmsen AG, Bugelski PJ: Immunomodulatory 12. Arend SM, Mallat MJ, Westendorp RJ, van der Woude FJ, van effects of anti-CD4 antibody in host resistance against infections Es LA: Patient survival after renal transplantation; more than 25 and tumors in human CD4 transgenic mice. Infect Immun 69: years follow-up. Nephrol Dial Transplant 12: 1672–1679, 1997 1032–1043, 2001 13. Hoshida Y, Tsukuma H, Yasunaga Y, Xu N, Fujita MQ, Satoh T, 31. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Ichikawa Y, Kurihara K, Imanishi M, Matsuno T, Aozasa K: Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch Cancer risk after renal transplantation in Japan. Int J Cancer 71: KW, Geissler EK: Rapamycin inhibits primary and metastatic 517–520, 1997 tumor growth by antiangiogenesis: involvement of vascular en- 14. Penn I: Post-transplant malignancy: the role of immunosuppres- dothelial growth factor. Nat Med 8: 128–135, 2002 sion. Drug Saf 23: 101–113, 2000 32. Danpanich E, Kasiske BL: Risk factors for cancer in renal 15. Vogt P, Frei U, Repp H, Bunzendahl H, Oldhafer K, Pichlmayr transplant recipients. Transplantation 68: 1859–1864, 1999 R: Malignant tumours in renal transplant recipients receiving 33. Pommer W, Bronder E, Klimpel A, Helmert U, Greiser E, cyclosporin: survey of 598 first-kidney transplantations. Nephrol Molzahn M: Urothelial cancer at different tumour sites: role of Dial Transplant 5: 282–288, 1990 smoking and habitual intake of analgesics and laxatives. Results 16. Shuttleworth D, Marks R, Griffin PJ, Salaman JR: Epidermal of the Berlin Urothelial Cancer Study. Nephrol Dial Transplant dysplasia and cyclosporine therapy in renal transplant patients: a 14: 2892–2897, 1999 comparison with azathioprine. Br J Dermatol 120: 551–554, 34. Kliem V, Kolditz M, Behrend M, Ehlerding G, Pichlmayr R, 1989 Koch KM, Brunkhorst R: Risk of renal cell carcinoma after 17. Penn I, First MR: Development and incidence of cancer follow- kidney transplantation. Clin Transplant 11: 255–258, 1997 ing cyclosporine therapy. Transplant Proc 18: 210–215, 1986 35. Goldfarb DA, Neumann HP, Penn I, Novick AC: Results of renal 18. Opelz G, Henderson R: Incidence of non-Hodgkin lymphoma in transplantation in patients with renal cell carcinoma and von kidney and heart transplant recipients. Lancet 342: 1514–1516, Hippel-Lindau disease. Transplantation 64: 1726–1729, 1997 1993 36. Cleper R, Davidovitz M, Krause I, Bar Nathan N, Ash S, 19. Cherikh WS, Kauffmann HM, Delmonico FL: A multivariate Schwarz M, Mor C, Eisenstein B: Unexpected Wilms’ tumor in analysis of discharge immunosuppression and post-transplant a pediatric renal transplant recipient: suspected Denys-Drash malignancy [Abstract]. Am J Transplant 1[Suppl 1]:353, 2001 syndrome. Transplant Proc 31: 1907–1909, 1999 20. Beauparlant P, Papp K, Haraoui B: The incidence of cancer 37. Fischer A, Binet I, Oertli D, Bock A, Thiel G: Fatal outcome of associated with the treatment of rheumatoid arthritis. Semin renal transplantation in a patient with the Wiskott-Aldrich syn- Arthritis Rheum 29: 148–158, 1999 drome. Nephrol Dial Transplant 11: 2077–2079, 1996 21. Kamel OW, van de Rijn M, LeBrun DP, Weiss LM, Warnke RA, 38. Gomez E, Portal CG, Seco MA, Alvarez-Grande J: Multiple Dorfman RF: Lymphoid neoplasms in patients with rheumatoid solid malignancies in a renal transplant patient. Nephrol Dial arthritis and dermatomyositis: frequency of Epstein-Barr virus Transplant 14: 803–804, 1999 and other features associated with immunosuppression. Hum 39. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP: Risk Pathol 25: 638–643, 1994 of neoplasia in renal transplant patients. Lancet 346: 403–406, 22. Arellano F, Krupp P: Malignancies in rheumatoid arthritis pa- 1995 tients treated with cyclosporin A. Br J Rheumatol 32 Suppl 1: 40. Lye WC: Successful treatment of Epstein-Barr virus-associated 72–75, 1993 T-cell cutaneous lymphoma in a renal allograft recipient: case 23. Dreno B: Skin cancers after transplantation. Nephrol Dial Trans- report and review of the literature. Transplant Proc 32: 1988– plant 18: 1052–1058, 2003 1989, 2000 24. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN: Clin- 41. Bird AG, McLachlan SM, Britton S: Cyclosporin A promotes ical risk factors associated with nonmelanoma skin cancer in spontaneous outgrowth in vitro of Epstein-Barr virus-induced renal transplant recipients. Am J Kidney Dis 36: 167–176, 2000 B-cell lines. Nature 289: 300–301, 1981 1588 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 1582–1588, 2004

42. Schmidtko J, Wang R, Wu CL, Mauiyyedi S, Harris NL, Della 61. Boye J, Elter T, Engert A: An overview of the current clinical use Pelle P, Brousaides N, Zagachin L, Ferry JA, Wang F, Kawai T, of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 14: Sachs DH, Cosimi BA, Colvin RB: Posttransplant lymphopro- 520–535, 2003 liferative disorder associated with an Epstein-Barr-related virus 62. Fischer A, Blanche S, Le Bidois J, Bordigoni P, Garnier JL, in cynomolgus monkeys. Transplantation 73: 1431–1439, 2002 Niaudet P, Morinet F, Le Deist F, Fischer AM, Griscelli C, et al.: 43. Cathomas G, Tamm M, McGandy CE, Itin PH, Gudat F, Thiel G, Anti-B-cell monoclonal antibodies in the treatment of severe Mihatsch MJ: Transplantation-associated malignancies: restric- B-cell lymphoproliferative syndrome following bone marrow tion of human herpes virus 8 to Kaposi’s sarcoma. Transplanta- and organ transplantation. N Engl J Med 324: 1451–1456, 1991 tion 64: 175–178, 1997 63. Stephan JL, Le Deist F, Blanche S, Le Bidois J, Peuchmaur M, 44. Harwood CA, Surentheran T, McGregor JM, Spink PJ, Leigh Lellouch-Tubiana A, Hirn M, Griscelli C, Fischer A: Treatment IM, Breuer J, Proby CM: Human papillomavirus infection and of central nervous system B lymphoproliferative syndrome by non-melanoma skin cancer in immunosuppressed and immuno- local infusion of a B cell-specific monoclonal antibody. Trans- competent individuals. J Med Virol 61: 289–297, 2000 plantation 54: 246–249, 1992 45. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, 64. Pirsch JD, Stratta RJ, Sollinger HW, Hafez GR, D’Alessandro Thiel G, Mihatsch MJ, Hirsch HH: Testing for polyomavirus AM, Kalayoglu M, Belzer FO: Treatment of severe Epstein-Barr type BK DNA in plasma to identify renal-allograft recipients virus-induced lymphoproliferative syndrome with ganciclovir: with viral nephropathy. N Engl J Med 342: 1309–1315, 2000 two cases after solid organ transplantation. Am J Med 86: 241– 46. Ichaso N, Dilworth SM: Cell transformation by the middle T- antigen of polyoma virus. Oncogene 20: 7908–7916, 2001 244, 1989 47. Benjamin TL: Polyoma virus: old findings and new challenges. 65. European best practice guidelines for renal transplantation. Sec- Virology 289: 167–173, 2001 tion IV: Long-term management of the transplant recipient. IV. 48. Thomson BJ: Viruses and apoptosis. Int J Exp Pathol 82: 65–76, 6.1. Cancer risk after renal transplantation. Post-transplant lym- 2001 phoproliferative disease (PTLD): prevention and treatment. 49. Hay S, Kannourakis G: A time to kill: viral manipulation of the Nephrol Dial Transplant 17[Suppl 4]:31-33: 35–36, 2002 cell death program. J Gen Virol 83: 1547–1564, 2002 66. Gotti E, Remuzzi G: Post-transplant Kaposi’s sarcoma. JAmSoc 50. Scaffidi C, Schmitz I, Krammer PH, Peter ME: The role of Nephrol 8: 130–137, 1997 c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 67. Weber JS, Aparicio A: Novel immunologic approaches to the 274: 1541–1548, 1999 management of malignant melanoma. Curr Opin Oncol 13: 124– 51. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li- 128, 2001 Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Kram- 68. Safa MM, Foon KA: Adjuvant immunotherapy for melanoma mer PH: p53 activates the CD95 (APO-1/Fas) gene in response and colorectal cancers. Semin Oncol 28: 68–92, 2001 to DNA damage by anticancer drugs. J Exp Med 188: 2033– 69. Rosenberg SA: Progress in human tumour immunology and 2045, 1998 immunotherapy. Nature 411: 380–384, 2001 52. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 70. European best practice guidelines for renal transplantation. Sec- 57–70, 2000 tion IV: Long-term management of the transplant recipient. IV. 53. al-Sulaiman MH, al-Khader AA: Kaposi’s sarcoma in renal 6.2. Cancer risk after renal transplantation. Skin cancers: preven- transplant recipients. Transplant Sci 4: 46–60, 1994 tion and treatment. Nephrol Dial Transplant 17[Suppl 4]: 31–36, 54. Kimlin MG, Parisi AV, Wong JC: Quantification of personal 2002 solar UV exposure of outdoor workers, indoor workers and 71. Seukeran DC, Newstead CG, Cunliffe WJ: The compliance of adolescents at two locations in Southeast Queensland. Photoder- renal transplant recipients with advice about sun protection mea- matol Photoimmunol Photomed 14: 7–11, 1998 sures. Br J Dermatol 138: 301–303, 1998 55. Luengrojanakul P, Vareesangthip K, Chainuvati T, Murata K, 72. Vlaovic P, Jewett MA: Cyclophosphamide-induced bladder can- Tsuda F, Tokita H, Okamoto H, Miyakawa Y, Mayumi M: cer. Can J Urol 6: 745–748, 1999 Hepatitis C virus infection in patients with chronic liver disease 73. Biggs AW: Carcinoma of the bladder in a renal transplant pa- or chronic renal failure and blood donors in Thailand. J Med tient. J Urol 109: 417–418, 1973 Virol 44: 287–292, 1994 74. Baysal C, Gur G, Gursoy M, Ustundag Y, Demirhan B, Boya- 56. Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, cioglu S, Bilgin N: Colonoscopy findings in renal transplant Marks WH, Roza AM: Transplant tumor registry: donor related malignancies. Transplantation 74: 358–362, 2002 patients with abdominal symptoms. Transplant Proc 30: 754– 57. Detry O, Detroz B, D’Silva M, Pirenne J, Defraigne JO, 755, 1998 Meurisse M, Honore P, Michel P, Boniver J, Limet R, et al.: 75. Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch Misdiagnosed malignancy in transplanted organs. Transpl Int 6: GM, Gaston RS, Roth D, Scandling JD, Singer GG: Recommen- 50–54, 1993 dations for the outpatient surveillance of renal transplant recip- 58. Penn I: The effect of immunosuppression on pre-existing can- ients. American Society of Transplantation. J Am Soc Nephrol cers. Transplantation 55: 742–747, 1993 11[Suppl 15]: S1–S86, 2000 59. Penn I: Evaluation of transplant candidates with pre-existing 76. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, malignancies. Ann Transplant 2: 14–17, 1997 Forsberg B, Eklund B, Fjeldborg O, Friedberg M, Frodin L, et 60. Penn I: Incidence and treatment of neoplasia after transplanta- al.: Cancer risk after renal transplantation in the Nordic coun- tion. J Heart Lung Transplant 12: S328–S336, 1993 tries, 1964–1986. Int J Cancer 60: 183–189, 1995