2007 JASN IMPACT FACTOR 7.111	HOME   AUTHOR INFO   EDITORIAL BOARD   SUBSCRIBE   FEEDBACK   ALERTS   HELP
advanced	CURRENT ISSUE	ARCHIVES	JASN Express	ONLINE SUBMISSION

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morath, C. Articles by Zeier, M. Search for Related Content PubMed PubMed Citation Articles by Morath, C. Articles by Zeier, M.

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.

Correspondence to Dr. Christian Morath, Department of Nephrology, University of Heidelberg, Bergheimerstr. 56 a, 69 115 Heidelberg, Germany. Phone: 49-6221-9112-0; Fax: 49-6221-9112-79; E-mail: christian_morath{at}med.uni-heidelberg.de

Eberhard Ritz : Feature Editor

	Introduction

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
An increased incidence of malignant tumors in transplant recipients was recognized as early as in the 1970s, and this effect was ascribed to the administration of immunosuppressive medication (1,2). In the early days of transplantation medicine, however, the clinician faced fulminant acute rejection episodes and severe infections; malignancy after transplantation represented only a minor problem. With longer graft survival and older donors (as well as recipients) and with the introduction of more potent immunosuppressive medication, malignancy represents a major burden in transplantation medicine. The overall incidence of malignancy after renal transplantation has been reported as being 3 to 5 times higher compared with the general population (3,4). However, an increased frequency is not found for all types of cancer (Figure 1). According to the Cincinnati Transplant Tumor Registry and other reports, the most frequent types of tumors are posttransplant lymphoproliferative disorder (PTLD) and squamous cell carcinoma (lip, cervix, vulva, skin) (5,6).

View larger version (18K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Ratio observed/expected malignancies in graft recipients (76).

	Epidemiology

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

Incidence and type of cancer after renal transplantation vary between centers, countries, and time periods (11). Some of this variation is accounted for by the impact of competing causes of death. For instance, according to a report from the Glasgow transplant program, during the first 14 yr of the program (1969 to 1982), 40% of patient deaths were attributed to infection, 23% to cardiovascular disease, and 10% to malignancies. During the subsequent 14 yr, deaths resulting from infection decreased substantially, and the relative and absolute frequency of death from cardiovascular disease and malignancy increased concomitantly (9,11).

In single-center reports from Glasgow and Leiden, death due to malignancy was found in 15% and 14% of kidney graft recipients, respectively (9,12). In contrast, only 2.6% of renal allograft recipients in Japan were reported to have developed a malignancy between 1970 and 1995 (13).

	Pathogenesis

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
Malignancy after transplantation can develop in three different ways:

• De novo occurrence in the recipient
  
• Recurrent malignancy in the recipient
  
• Transmission of malignancy from the donor
  

	De Novo Occurrence of Malignancy in the Recipient

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
Immunosuppression and Malignant Transformation
In renal transplant recipients, the frequency of two types of malignancies stands out: skin cancer and lymphoproliferative disease. The spectrum for the latter ranges from benign PTLD 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 literature, malignancies of the lymphoproliferative system occur mostly within the first three yr after renal transplantation. The high overall risk of malignancy in heavily immunosuppressed patients is primarily due to the development of NHL. It has been claimed that the introduction of new and more potent immunosuppressive regimens is associated with an increased incidence of cancer after renal transplantation (14), but this statement is not supported by solid epidemiologic evidence. There are conflicting reports on whether the introduction of cyclosporine was followed by a higher frequency of malignant tumors (15,16). It has also been reported that malignancies are more frequent in patients on triple drug regimens that include cyclosporine, azathioprine, and corticosteroids (17). There is little dispute that the development of lymphomas is particularly increased in patients receiving polyclonal or monoclonal antibodies for induction or rescue therapy. This is true for recipients of both renal and cardiac allografts (18). In an analysis of the United Network of Organ Sharing (UNOS), the risk of malignancy was particularly high in patients who received a combination of monoclonal antibodies, tacrolimus, and mycophenolate mofetil. In patients receiving this immunosuppressive regimen the overall risk of any type of cancer compared with the matched background population was increased by a factor of 5.11, and the risk of PTLD (with the above reservations) was higher by a factor of 27.2 (19).

The hypothesis that the action of immunosuppressive drugs is responsible for the increased incidence of tumors in transplant recipients is supported by the observation that patients also develop tumors if they receive immunosuppressive therapy for conditions other than transplantation, e.g., rheumatoid arthritis, systemic lupus erythematodes (SLE), or dermatomyositis. An increased frequency of lymphoproliferative disease in these patients has been attributed to the administration of immunosuppressive agents, such as methotrexate, cyclosporine, or azathioprine (20–22).

A relationship between the intensity of immunosuppression and an increased incidence of tumors has been shown most convincingly for skin cancer. The established risk factors for basal cell and squamous cell cancer, such as exposure to 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 cell carcinoma may also be related to the increased prevalence of human papilloma virus (HPV) in transplant patients. Presumably because of immunosuppression, it is found in almost 90% of allograft recipients (26). Viral proteins E6 and E7 of HPV inhibit the tumor suppressor gene p53 and are thought to be involved in the induction of carcinoma in this high-risk population. In addition, exposure of the skin to ultraviolet radiation causes DNA mutations by formation of thymidine 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 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, e.g., anti-Thy 1.2 or anti-asialo GM-1, was associated with increased tumor colonization (30). However, this was not true for all immunomodulatory antibodies. For instance, anti-CD4 monoclonal antibody (keliximab) did not interfere with the immune response against malignant cells in mice (30). The recently introduced immunosuppressive agent rapamycine (Sirolimus) is believed to combine immunosuppressive action with antitumor effects (31).

These clinical and experimental observations are compatible with the notion that the increased frequency of malignancies in allograft recipients results mainly from immunosuppression. But this simple concept does not explain that the excess tumor incidence in kidney recipients is restricted to certain malignancies, such as skin tumors and lymphoma. It would therefore appear that immunosuppression alone is not sufficient for tumor development: additional risk factors, such as the patient’s genetic background, viral co-infection, or sun exposure apparently play also a role (Table 1).

Genetic Factors
Genetic factors are known to predispose to the development of malignancies, and this appears to apply also to transplanted patients. According to one study, patients who had an invasive carcinoma before transplantation had a much higher risk (RR 2.38) of developing a second invasive carcinoma de novo after transplantation (32). Some rare primary renal diseases (particularly von Hippel-Lindau disease) are associated with an intrinsically higher risk of developing renal cell carcinoma with an aggressive clinical course. When such patients receive a renal allograft, the frequency of renal cell carcinoma increases further (35). The risk of carcinoma is also markedly increased in patients with Wiskott-Aldrich syndrome or Drash syndrome. In transplant recipients with these rare syndromes, an excessive frequency of lymphoma and Wilms’ tumor was noted (36,37).

The hypothesis that genetic predisposition plays a role in the genesis of posttransplant malignancies is also supported by the observation that patients with malignancies after transplantation often have more than one type of tumor. Patients with as many as three different types of tumor have been reported (38). In patients with two malignancies, the most common secondary malignancy is a skin tumor. In a retrospective study by London et al. (39), skin tumors were found in 10 of 70 renal allograft recipients who had other types of malignancies.

Chronic Viral Infections
Certain viral infections predispose transplant recipients to specific types of malignancies (Table 2). Epstein-Barr virus (EBV) is frequently associated with lymphoma, and human herpes virus 8 (HHV 8) is frequently associated with Kaposi sarcoma (40). NHL results from abnormal lymphoid cell proliferation after aggressive or prolonged immunosuppression. Some 98% of cases with PTLD are associated with latent EBV infection. EBV is a herpes virus that infects most adults and establishes an asymptomatic B cell infection via T cell–mediated suppression of viral growth (41). T-cell surveillance is impaired by cyclosporine, and it is even more disturbed by antibodies directed against T cells, e.g. OKT3 or ATG. In vitro studies showed that coincubation of EBV-infected B cells with OKT3 or ATG resulted in increased B cell proliferation and immortalization (42). Such a mechanism is also likely to play a role in vivo. Schmidtko et al. (42) described EBV-associated PTLD after renal transplantation in primates, and this was particularly prominent in animals receiving an aggressive immunosuppressive conditioning regimen. The animal data are in good agreement with a large multicenter study of transplanted patients in which a higher rate of NHL was found in patients after the administration of antilymphocyte antibodies (18). Cathomas et al. (42) reported an association of Kaposi sarcoma with HHV 8 infection in a series of 18 renal transplant recipients. It is of note that almost all of these patients had received monoclonal or polyclonal antibodies as induction or rescue therapy for steroid-resistant rejection (43).

Polyoma virus, which has recently attracted considerable clinical attention, is a double-stranded DNA virus that induces acute interstitial nephritis in renal transplant recipients (45). It causes not only acute renal dysfunction, but is also tumorigenic by transforming cells mainly by the action of the middle T antigen (46,47).

At this point, some comments on the mechanism of virus-induced tumor formation may be appropriate. For any virus to induce uncontrolled cell proliferation in vivo, at least 3 processes must take place (48,49):

1. The virus must uncouple the mechanisms controlling progress of the cell cycle and cell division.
   
2. The virus must prevent the host cell from undergoing apoptosis.
   
3. The proliferating cell, bearing viral-derived antigens on its surface, must escape the attention of the host immune system.
   

Of particular interest is the escape from apoptosis, which is a requirement for sustained growth after transformation of the host cell by oncogenic viruses. A class of proteins, FLIPs (FADD l Like Interleukin 1B converting enzyme-like protease Inhibited Proteins), interfere with the initiation of apoptosis at the level of death receptors (50). Some FLIPs are encoded by class herpes viruses, e.g., herpes virus Saimiri (HVS) or HHV 8. So-called viral FLIPs (vFLIPs) inhibit apoptosis through several apoptosis-reducing receptors (CD95, TNF-R1, TRAMP/DR3, and TRAIL-R1) that presumably share common 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 susceptible primates and induces stable growth transformation of human T cells in vitro. HHV 8 is associated with Kaposi sarcoma and multicentric Castleman disease.

Another important pathway for virus-induced malignancy is interference with the p53 tumor suppressor gene (52). P53 induces cell cycle arrest or apoptosis in response to DNA damage. Small DNA viruses use distinct mechanisms to counter p53. They either bind directly to p53 and inhibit p53-mediated transcriptional activation, or they promote the degradation of p53 via the ubiquitin pathway.

Geographical Differences
A survey of the literature shows that the relative frequency of malignancy after renal transplantation varies widely between different geographical regions. In Japan, tumors of digestive organs (50%)—liver, stomach, colon, rectum—are the most frequently observed posttransplant tumors, in good agreement with the generally high prevalence of GI cancers in this country. In contrast, the frequency of skin cancer and lymphoma is low in Japan (13). In the United Kingdom, the most frequent posttransplant malignancies are lymphoma, renal cell carcinoma, carcinoma of the digestive system, and bronchial carcinoma (39). In Saudi Arabia, the most frequent malignancies are Kaposi sarcoma, lymphoma (particularly in children), 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 spinocellular carcinoma, is extremely high. The most favored explanation for this unique Australian experience is that a fair-skinned Caucasoid population is exposed to excessive ultraviolet light (54). In South East Asia, where hepatitis B and C infections are endemic, the frequency of liver cancer after renal transplantation is high (55).

	Transmission of Malignancy from the Donor

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
Transmission of a tumor via (micro)metastases of an undiagnosed malignancy in the donor is rare, but this possibility must also be considered in the differential diagnosis of malignancy after transplantation. According to data from the Organ Procurement and Transplantation Network/UNOS, a total of 21 donor-related malignancies was reported in 108,062 transplant recipients (56). Fifteen tumors were donor-transmitted (malignancies that existed in the donor at the time of transplantation), and six tumors were donor-derived (de novo tumors that develop in transplanted hematogenous or lymphoid cells of the donor). Donor-derived tumors have been reported in allografts obtained from donors with bronchial carcinoma, breast cancer, and malignant melanoma (6,57). In some patients, cessation of immunosuppression led to rejection of the donor-derived malignancy without further therapy. In most patients, however, specific anti-tumor therapy was necessary, i.e. surgery, chemotherapy, radiation, to induce remission.

	Management of the Allograft Recipient with a Preexisting Malignancy

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
When a patient is considered for the transplant waiting list, the question arises whether a history of malignant disease is a contraindication to renal transplantation. One retrospective analysis comprised 913 renal allograft recipients with a total of 939 preexisting cancers (58), illustrating that more often than not the nephrologist must deal with this problem in today’s aging dialysis population. There is consensus that a 2-yr waiting period should be interposed between the successful treatment of cancer and transplantation. A waiting period is not required for the following tumors: incidentally discovered renal cell carcinoma, any type of in situ carcinoma, and basal cell carcinoma of the skin. Because of a high likelihood of recurrence even beyond the second year after treatment, a waiting period of more than 2 yr is advisable in patients with a history of malignant melanoma, breast cancer, and colorectal carcinoma. The issue of recurrence was addressed in a retrospective study of 1297 renal allograft recipients with a history of malignancy (59). For tumors diagnosed and treated before transplantation, the frequency of recurrence after transplantation was 21%. For tumors diagnosed and treated after transplantation the respective figure was 33%. Among tumors diagnosed and treated before transplantation, the frequency of recurrence after transplantation was highest for breast cancer, symptomatic renal cell cancer, sarcoma, bladder cancer, and multiple myeloma (59).

	Management of the Allograft Recipient with De Novo Malignancy after Transplantation

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
When a patient develops a malignancy de novo after renal transplantation, the question arises whether it is useful to reduce or stop immunosuppression. The underlying idea is that this move might allow rejection of the malignancy by the recipient’s recovering immune system. If immunosuppression is stopped, particularly early after transplantation, graft monitoring at short intervals is necessary; otherwise fulminant rejection may be discovered too late, with the potential consequence of graft rupture. Removal of the graft is often advisable.

Successful reduction or cessation of immunosuppression was reported in transplanted patients who developed NHL and Kaposi sarcoma (60). Despite this the rate of death remained high in patients with posttransplant lymphoma. Therapeutic strategies targeting B cells (61), including local or systemic administration of specific anti-CD24-, anti-CD21-, and anti-CD20- (rituximab) B cell antibodies, were successful with a follow-up of several months (62,63). There are also reports of successful antiviral treatment with acyclovir, valacyclovir, or ganciclovir in EBV-induced lymphoproliferative disease (64). In patients who do not respond to these therapies or in severe disease, a treatment regimen including cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is recommended (65).

Transplant recipients with premalignant skin lesions should be referred to a dermatologist for active treatment and close follow-up. Skin cancers should be completely removed. Secondary prevention includes the use of topical or systemic retinoids in patients with actinic keratoses and squamous-cell carcinoma and reduction of immunosuppression when possible.

Posttransplant Kaposi sarcoma is particularly interesting because it is the tumor with the highest relative risk compared with the background population (53). The clinical course is often aggressive, with a mortality rate of 34% within 3 yr of diagnosis. Involvement of visceral organs is an indicator of severe disease. Aggressive forms of gastrointestinal involvement may be diagnosed during endoscopy. Reduction of immunosuppression leads to complete remission in 30% of the patients. Localized lesions may be treated surgically or by local radiation (66).

Immunotherapy of melanoma (67), colorectal cancer (68), and renal cell carcinoma (69) is currently under investigation in nontransplant patients. Whether these treatment modalities will be useful in organ transplantation awaits further studies.

	Screening of the Allograft Recipient for Malignancy

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
Regular tumor screening is advisable when a patient is considered for renal transplantation and especially after transplantation (Table 3) (75). The rising age of patients on the waiting list in conjunction with the increasing length of time patients spend on the waiting list enhances the risk that malignancy will escape detection so that recipients with preexisting tumors will receive transplants.

Screening to detect skin tumors is most important. Periodic inspection of the entire skin, with emphasis on sun-exposed areas, by a dermatologist is mandatory (at least at yearly intervals). In high-risk patients (e.g., those who have previously been diagnosed with squamous cell carcinoma), more frequent controls are indicated (at least every 6 mo). Primary prevention of skin cancers includes avoidance of sun exposure, use of protective clothing, and use of effective sunscreen by the patient, according to the European Best Practice Guidelines (70). Compliance is a universal problem. According to a study from Leeds, only 54% of patients remembered that they had received any advice concerning cancer prevention, and only 30% of patients knew why extra precautions against sunlight were necessary (71).

Yearly gynecologic examinations are mandatory to exclude vulvar, perineal, and uterine malignancies. In women without hysterectomy, transvaginal ultrasonography is recommended.

Multicystic transformation of contracted kidneys in patients with primary renal disease is a precancerous condition. Ultrasonographic examination of the recipient’s kidney should be performed at least at yearly intervals. Urologic examination is indicated in patients with a history of analgesic nephropathy who develop microhematuria. Another high-risk group includes those patients who received cyclophosphamide for treatment of vasculitis, especially in those patients where the cumulative dose exceeds 20 g (72). Some authors also recommend urologic examination in patients who have been treated with azathioprine for more than 10 yr (73).

Periodic screening of feces for occult blood is advisable because colonic carcinoma is more frequent after renal transplantation. Patients with a history of ureterosigmoidostomy should undergo colonoscopy at least 10 yr after renal transplantation because of the risk of late colonic carcinoma (74).

For other solid organ cancers (prostate, breast), guidelines published for screening and prevention of solid organ cancers in the general population should be strictly applied to transplant recipients.

	Outlook

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 
Early diagnosis and treatment of posttransplant malignancies is an important challenge in transplantation medicine. An even greater challenge is the prevention of malignancies. Documentation of tumors arising de novo after transplantation as well as elucidation of their relationship with particular immunosuppressive treatment regimens is a first step in this direction.

This overview attempted to summarize the available evidence in this area. As even more potent immunosuppressive drugs enter the transplant field, it will be important to monitor their tumor-inducing potential. Reduction of life-threatening infection had been a goal in the past decades. In the future, the reduction of posttransplant malignancies must be another target in the effort to improve immunosuppression in graft recipients.

	Acknowledgments

 
The critical advice of Professor Eberhard Ritz during the preparation of the manuscript is gratefully acknowledged.

	References

Top Introduction Epidemiology Pathogenesis De Novo Occurrence of... Transmission of Malignancy from... Management of the Allograft... Management of the Allograft... Screening of the Allograft... Outlook References

 

1. Penn I: Malignancies associated with renal transplantation. Urology 10: 57–63, 1977
2. Penn I: Second malignant neoplasms associated with immunosuppressive medications. Cancer 37: 1024–1032, 1976[CrossRef][Medline]
3. Birkeland SA, Lokkegaard H, Storm HH: Cancer risk in patients on dialysis and after renal transplantation. Lancet 355: 1886–1887, 2000[CrossRef][Medline]
4. Peto J: Cancer epidemiology in the last century and the next decade. Nature 411: 390–395, 2001[CrossRef][Medline]
5. Penn I: Cancers in renal transplant recipients. Adv Ren Replace Ther 7: 147–156, 2000[Medline]
6. Zeier M, Hartschuh W, Wiesel M, Lehnert T, Ritz E: Malignancy after renal transplantation. Am J Kidney Dis 39: E5, 2002[CrossRef][Medline]
7. Yang TC, Shu KH, Cheng CH, Wu MJ, Lian JD: Malignancy following renal transplantation. Zhonghua Yi Xue Za Zhi (Taipei) 61: 281–288, 1998
8. Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, Wolfe RA, Jones E, Disney AP, Briggs D, McCredie M, Boyle P: Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 354: 93–99, 1999[CrossRef][Medline]
9. Briggs JD: Causes of death after renal transplantation. Nephrol Dial Transplant 16: 1545–1549, 2001[Free Full Text]
10. Bouwes Bavinck JN, Hardie DR, Green A, Cutmore S, MacNaught A, O’Sullivan B, Siskind V, Van Der Woude FJ, Hardie IR: The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation 61: 715–721, 1996[Medline]
11. Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK: Long-term survival in renal transplant recipients with graft function. Kidney Int 57: 307–313, 2000[CrossRef][Medline]
12. Arend SM, Mallat MJ, Westendorp RJ, van der Woude FJ, van Es LA: Patient survival after renal transplantation; more than 25 years follow-up. Nephrol Dial Transplant 12: 1672–1679, 1997[Abstract/Free Full Text]
13. Hoshida Y, Tsukuma H, Yasunaga Y, Xu N, Fujita MQ, Satoh T, Ichikawa Y, Kurihara K, Imanishi M, Matsuno T, Aozasa K: Cancer risk after renal transplantation in Japan. Int J Cancer 71: 517–520, 1997[CrossRef][Medline]
14. Penn I: Post-transplant malignancy: the role of immunosuppression. Drug Saf 23: 101–113, 2000[CrossRef][Medline]
15. Vogt P, Frei U, Repp H, Bunzendahl H, Oldhafer K, Pichlmayr R: Malignant tumours in renal transplant recipients receiving cyclosporin: survey of 598 first-kidney transplantations. Nephrol Dial Transplant 5: 282–288, 1990
16. Shuttleworth D, Marks R, Griffin PJ, Salaman JR: Epidermal dysplasia and cyclosporine therapy in renal transplant patients: a comparison with azathioprine. Br J Dermatol 120: 551–554, 1989[CrossRef][Medline]
17. Penn I, First MR: Development and incidence of cancer following cyclosporine therapy. Transplant Proc 18: 210–215, 1986[Medline]
18. Opelz G, Henderson R: Incidence of non-Hodgkin lymphoma in kidney and heart transplant recipients. Lancet 342: 1514–1516, 1993[CrossRef][Medline]
19. Cherikh WS, Kauffmann HM, Delmonico FL: A multivariate analysis of discharge immunosuppression and post-transplant malignancy [Abstract]. Am J Transplant 1 [Suppl 1]: 353, 2001
20. Beauparlant P, Papp K, Haraoui B: The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum 29: 148–158, 1999[CrossRef][Medline]
21. Kamel OW, van de Rijn M, LeBrun DP, Weiss LM, Warnke RA, Dorfman RF: Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol 25: 638–643, 1994[CrossRef][Medline]
22. Arellano F, Krupp P: Malignancies in rheumatoid arthritis patients treated with cyclosporin A. Br J Rheumatol 32 Suppl 1: 72–75, 1993
23. Dreno B: Skin cancers after transplantation. Nephrol Dial Transplant 18: 1052–1058, 2003[Free Full Text]
24. Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN: Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis 36: 167–176, 2000[Medline]
25. Fortina AB, Caforio AL, Piaserico S, Alaibac M, Tona F, Feltrin G, Livi U, Peserico A: Skin cancer in heart transplant recipients: frequency and risk factor analysis. J Heart Lung Transplant 19: 249–255, 2000[CrossRef][Medline]
26. Berg D, Otley CC: Skin cancer in organ transplant recipients: Epidemiology, pathogenesis, and management. J Am Acad Dermatol 47: 1–17, 2002; quiz, 18–20
27. Farag SS, VanDeusen JB, Fehniger TA, Caligiuri MA: Biology and clinical impact of human natural killer cells. Int J Hematol 78: 7–17, 2003[Medline]
28. Seaman WE, Sleisenger M, Eriksson E, Koo GC: Depletion of natural killer cells in mice by monoclonal antibody to NK-1.1. Reduction in host defense against malignancy without loss of cellular or humoral immunity. J Immunol 138: 4539–4544, 1987[Abstract]
29. Rushfeldt C, Sveinbjornsson B, Seljelid R, Smedsrod B: Early events of hepatic metastasis formation in mice: role of Kupffer and NK-cells in natural and interferon-gamma-stimulated defense. J Surg Res 82: 209–215, 1999[CrossRef][Medline]
30. Herzyk DJ, Gore ER, Polsky R, Nadwodny KL, Maier CC, Liu S, Hart TK, Harmsen AG, Bugelski PJ: Immunomodulatory effects of anti-CD4 antibody in host resistance against infections and tumors in human CD4 transgenic mice. Infect Immun 69: 1032–1043, 2001[Abstract/Free Full Text]
31. Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK: Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 8: 128–135, 2002[CrossRef][Medline]
32. Danpanich E, Kasiske BL: Risk factors for cancer in renal transplant recipients. Transplantation 68: 1859–1864, 1999[CrossRef][Medline]
33. Pommer W, Bronder E, Klimpel A, Helmert U, Greiser E, Molzahn M: Urothelial cancer at different tumour sites: role of smoking and habitual intake of analgesics and laxatives. Results of the Berlin Urothelial Cancer Study. Nephrol Dial Transplant 14: 2892–2897, 1999[Abstract/Free Full Text]
34. Kliem V, Kolditz M, Behrend M, Ehlerding G, Pichlmayr R, Koch KM, Brunkhorst R: Risk of renal cell carcinoma after kidney transplantation. Clin Transplant 11: 255–258, 1997[Medline]
35. Goldfarb DA, Neumann HP, Penn I, Novick AC: Results of renal transplantation in patients with renal cell carcinoma and von Hippel-Lindau disease. Transplantation 64: 1726–1729, 1997[CrossRef][Medline]
36. Cleper R, Davidovitz M, Krause I, Bar Nathan N, Ash S, Schwarz M, Mor C, Eisenstein B: Unexpected Wilms’ tumor in a pediatric renal transplant recipient: suspected Denys-Drash syndrome. Transplant Proc 31: 1907–1909, 1999[CrossRef][Medline]
37. Fischer A, Binet I, Oertli D, Bock A, Thiel G: Fatal outcome of renal transplantation in a patient with the Wiskott-Aldrich syndrome. Nephrol Dial Transplant 11: 2077–2079, 1996[Free Full Text]
38. Gomez E, Portal CG, Seco MA, Alvarez-Grande J: Multiple solid malignancies in a renal transplant patient. Nephrol Dial Transplant 14: 803–804, 1999[Free Full Text]
39. London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP: Risk of neoplasia in renal transplant patients. Lancet 346: 403–406, 1995[CrossRef][Medline]
40. Lye WC: Successful treatment of Epstein-Barr virus-associated T-cell cutaneous lymphoma in a renal allograft recipient: case report and review of the literature. Transplant Proc 32: 1988–1989, 2000[CrossRef][Medline]
41. Bird AG, McLachlan SM, Britton S: Cyclosporin A promotes spontaneous outgrowth in vitro of Epstein-Barr virus-induced B-cell lines. Nature 289: 300–301, 1981[CrossRef][Medline]
42. Schmidtko J, Wang R, Wu CL, Mauiyyedi S, Harris NL, Della Pelle P, Brousaides N, Zagachin L, Ferry JA, Wang F, Kawai T, Sachs DH, Cosimi BA, Colvin RB: Posttransplant lymphoproliferative disorder associated with an Epstein-Barr-related virus in cynomolgus monkeys. Transplantation 73: 1431–1439, 2002[CrossRef][Medline]
43. Cathomas G, Tamm M, McGandy CE, Itin PH, Gudat F, Thiel G, Mihatsch MJ: Transplantation-associated malignancies: restriction of human herpes virus 8 to Kaposi’s sarcoma. Transplantation 64: 175–178, 1997[CrossRef][Medline]
44. Harwood CA, Surentheran T, McGregor JM, Spink PJ, Leigh IM, Breuer J, Proby CM: Human papillomavirus infection and non-melanoma skin cancer in immunosuppressed and immunocompetent individuals. J Med Virol 61: 289–297, 2000[CrossRef][Medline]
45. Nickeleit V, Klimkait T, Binet IF, Dalquen P, Del Zenero V, Thiel G, Mihatsch MJ, Hirsch HH: Testing for polyomavirus type BK DNA in plasma to identify renal-allograft recipients with viral nephropathy. N Engl J Med 342: 1309–1315, 2000[Abstract/Free Full Text]
46. Ichaso N, Dilworth SM: Cell transformation by the middle T-antigen of polyoma virus. Oncogene 20: 7908–7916, 2001[CrossRef][Medline]
47. Benjamin TL: Polyoma virus: old findings and new challenges. Virology 289: 167–173, 2001[CrossRef][Medline]
48. Thomson BJ: Viruses and apoptosis. Int J Exp Pathol 82: 65–76, 2001[CrossRef][Medline]
49. Hay S, Kannourakis G: A time to kill: viral manipulation of the cell death program. J Gen Virol 83: 1547–1564, 2002[Abstract/Free Full Text]
50. Scaffidi C, Schmitz I, Krammer PH, Peter ME: The role of c-FLIP in modulation of CD95-induced apoptosis. J Biol Chem 274: 1541–1548, 1999[Abstract/Free Full Text]
51. Muller M, Wilder S, Bannasch D, Israeli D, Lehlbach K, Li-Weber M, Friedman SL, Galle PR, Stremmel W, Oren M, Krammer PH: p53 activates the CD95 (APO-1/Fas) gene in response to DNA damage by anticancer drugs. J Exp Med 188: 2033–2045, 1998[Abstract/Free Full Text]
52. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 100: 57–70, 2000[CrossRef][Medline]
53. al-Sulaiman MH, al-Khader AA: Kaposi’s sarcoma in renal transplant recipients. Transplant Sci 4: 46–60, 1994[Medline]
54. Kimlin MG, Parisi AV, Wong JC: Quantification of personal solar UV exposure of outdoor workers, indoor workers and adolescents at two locations in Southeast Queensland. Photodermatol Photoimmunol Photomed 14: 7–11, 1998[Medline]
55. Luengrojanakul P, Vareesangthip K, Chainuvati T, Murata K, Tsuda F, Tokita H, Okamoto H, Miyakawa Y, Mayumi M: Hepatitis C virus infection in patients with chronic liver disease or chronic renal failure and blood donors in Thailand. J Med Virol 44: 287–292, 1994[Medline]
56. Myron Kauffman H, McBride MA, Cherikh WS, Spain PC, Marks WH, Roza AM: Transplant tumor registry: donor related malignancies. Transplantation 74: 358–362, 2002[CrossRef][Medline]
57. Detry O, Detroz B, D’Silva M, Pirenne J, Defraigne JO, Meurisse M, Honore P, Michel P, Boniver J, Limet R, et al.: Misdiagnosed malignancy in transplanted organs. Transpl Int 6: 50–54, 1993[CrossRef][Medline]
58. Penn I: The effect of immunosuppression on pre-existing cancers. Transplantation 55: 742–747, 1993[Medline]
59. Penn I: Evaluation of transplant candidates with pre-existing malignancies. Ann Transplant 2: 14–17, 1997
60. Penn I: Incidence and treatment of neoplasia after transplantation. J Heart Lung Transplant 12: S328–S336, 1993[Medline]
61. Boye J, Elter T, Engert A: An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 14: 520–535, 2003[Abstract/Free Full Text]
62. Fischer A, Blanche S, Le Bidois J, Bordigoni P, Garnier JL, Niaudet P, Morinet F, Le Deist F, Fischer AM, Griscelli C, et al.: Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation. N Engl J Med 324: 1451–1456, 1991[Abstract]
63. Stephan JL, Le Deist F, Blanche S, Le Bidois J, Peuchmaur M, Lellouch-Tubiana A, Hirn M, Griscelli C, Fischer A: Treatment of central nervous system B lymphoproliferative syndrome by local infusion of a B cell-specific monoclonal antibody. Transplantation 54: 246–249, 1992[Medline]
64. Pirsch JD, Stratta RJ, Sollinger HW, Hafez GR, D’Alessandro AM, Kalayoglu M, Belzer FO: Treatment of severe Epstein-Barr virus-induced lymphoproliferative syndrome with ganciclovir: two cases after solid organ transplantation. Am J Med 86: 241–244, 1989[CrossRef][Medline]
65. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment. Nephrol Dial Transplant 17[Suppl 4]:31-33: 35–36, 2002
66. Gotti E, Remuzzi G: Post-transplant Kaposi’s sarcoma. J Am Soc Nephrol 8: 130–137, 1997[Medline]
67. Weber JS, Aparicio A: Novel immunologic approaches to the management of malignant melanoma. Curr Opin Oncol 13: 124–128, 2001[CrossRef][Medline]
68. Safa MM, Foon KA: Adjuvant immunotherapy for melanoma and colorectal cancers. Semin Oncol 28: 68–92, 2001[CrossRef][Medline]
69. Rosenberg SA: Progress in human tumour immunology and immunotherapy. Nature 411: 380–384, 2001[CrossRef][Medline]
70. European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV. 6.2. Cancer risk after renal transplantation. Skin cancers: prevention and treatment. Nephrol Dial Transplant 17 [Suppl 4]: 31–36, 2002
71. Seukeran DC, Newstead CG, Cunliffe WJ: The compliance of renal transplant recipients with advice about sun protection measures. Br J Dermatol 138: 301–303, 1998[CrossRef][Medline]
72. Vlaovic P, Jewett MA: Cyclophosphamide-induced bladder cancer. Can J Urol 6: 745–748, 1999[Medline]
73. Biggs AW: Carcinoma of the bladder in a renal transplant patient. J Urol 109: 417–418, 1973[Medline]
74. Baysal C, Gur G, Gursoy M, Ustundag Y, Demirhan B, Boyacioglu S, Bilgin N: Colonoscopy findings in renal transplant patients with abdominal symptoms. Transplant Proc 30: 754–755, 1998[CrossRef][Medline]
75. Kasiske BL, Vazquez MA, Harmon WE, Brown RS, Danovitch GM, Gaston RS, Roth D, Scandling JD, Singer GG: Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation. J Am Soc Nephrol 11 [Suppl 15]: S1–S86, 2000
76. Birkeland SA, Storm HH, Lamm LU, Barlow L, Blohme I, Forsberg B, Eklund B, Fjeldborg O, Friedberg M, Frodin L, et al.: Cancer risk after renal transplantation in the Nordic countries, 1964–1986. Int J Cancer 60: 183–189, 1995[Medline]

This article has been cited by other articles:

				C. Sommerer, T. Giese, S. Meuer, and M. Zeier Pharmacodynamic monitoring of calcineurin inhibitor therapy: Is there a clinical benefit? Nephrol. Dial. Transplant., October 15, 2008; (2008) gfn556v2. [Full Text] [PDF]

				M. Fischereder Cancer in patients on dialysis and after renal transplantation Nephrol. Dial. Transplant., August 1, 2008; 23(8): 2457 - 2460. [Full Text] [PDF]

				I. T. da Costa e Silva, L. C. de Lima Ferreira, F. S. Gimenez, R. A. G. Guimaraes, L. B. Fujimoto, C. R. B. Cabral, R. V. Mozzer, and L. de Souza Atala High-Resolution Anoscopy in the Diagnosis of Anal Cancer Precursor Lesions in Renal Graft Recipients Ann. Surg. Oncol., May 1, 2008; 15(5): 1470 - 1475. [Abstract] [Full Text] [PDF]

				C. Morath, W. Arns, V. Schwenger, A. Mehrabi, H. Fonouni, J. Schmidt, and M. Zeier Sirolimus in renal transplantation Nephrol. Dial. Transplant., September 1, 2007; 22(suppl_8): viii61 - viii65. [Abstract] [Full Text] [PDF]

				J. R. Chapman and J. M. Campistol Malignancy in renal transplantation: opportunities with proliferation signal inhibitors: Guest editors' introduction Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i1 - i3. [Full Text] [PDF]

				J. Dantal and E. Pohanka Malignancies in renal transplantation: an unmet medical need Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i4 - i10. [Abstract] [Full Text] [PDF]

				J. Pascual Post-transplant lymphoproliferative disorder--the potential of proliferation signal inhibitors Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i27 - i35. [Abstract] [Full Text] [PDF]

				J. M. Campistol, J. Albanell, W. Arns, I. Boletis, J. Dantal, J. W. de Fijter, S. A. Mortensen, H.-H. Neumayer, O. Oyen, J. Pascual, et al. Use of proliferation signal inhibitors in the management of post-transplant malignancies--clinical guidance Nephrol. Dial. Transplant., May 1, 2007; 22(suppl_1): i36 - i41. [Abstract] [Full Text] [PDF]

				A. Djamali, M. Samaniego, B. Muth, R. Muehrer, R. M. Hofmann, J. Pirsch, A. Howard, G. Mourad, and B. N. Becker Medical Care of Kidney Transplant Recipients after the First Posttransplant Year Clin. J. Am. Soc. Nephrol., July 1, 2006; 1(4): 623 - 640. [Abstract] [Full Text] [PDF]

				T. Pankhurst, A. J. Howie, D. Adu, D. M. A. Wallace, and G. W. Lipkin Incidental neoplasms in renal biopsies Nephrol. Dial. Transplant., January 1, 2006; 21(1): 64 - 69. [Abstract] [Full Text] [PDF]

				F. Togel, Z. Hu, K. Weiss, J. Isaac, C. Lange, C. Westenfelder, T. Stasko, M.D. Brown, J.A. Carucci, S. Euvrard, et al. Amelioration of Acute Renal Failure by Stem Cell Therapy--Paracrine Secretion Versus Transdifferentiation into Resident Cells: Administered Mesenchymal Stem Cells Protect against Ischemic Acute Renal Failure through Differentiation-Independent Mechanisms. Am J Physiol Renal Physiol E-pub February 15, 2005 J. Am. Soc. Nephrol., May 1, 2005; 16(5): 1153 - 1163. [Full Text] [PDF]

				S. Domhan, C. Morath, P. Schnulle, R. Waldherr, and M. Zeier A generalized seizure in a renal allograft recipient Nephrol. Dial. Transplant., April 1, 2005; 20(4): 834 - 836. [Full Text] [PDF]

				G. Stallone, A. Schena, B. Infante, S. Di Paolo, A. Loverre, G. Maggio, E. Ranieri, L. Gesualdo, F. P. Schena, and G. Grandaliano Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients N. Engl. J. Med., March 31, 2005; 352(13): 1317 - 1323. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend