Posttransplantation malignancy in a patient presenting with weight loss and changed bowel habits: a case report
© Schmitt et al; licensee BioMed Central Ltd. 2006
Received: 15 January 2006
Accepted: 04 May 2006
Published: 04 May 2006
Advancements in immunosuppressive therapy have significantly improved patient and graft survival following renal transplantation. This is paralleled by an increasing occurrence of posttransplantation malignancy.
We report on a patient who presented with a history reminding of colon cancer seven years after receiving a kidney transplant. Initial diagnostic imaging seemed to confirm this diagnosis showing a constricting colonic lesion. To our surprise, colonoscopy findings were unremarkable. Review of the imaging studies revealed that the tumor-like picture was caused by the renal graft impressing the intestine. The following search for malignancy in other locations resulted in the diagnosis of glioblastoma multiforme of which the patient died several weeks later.
Follow-up of renal transplant patients must include screening tests directed at tumor detection. Imaging studies and other tests in this patient group should be interpreted by physicians who are familiar with transplant related peculiarities.
Kidney transplantation is the treatment of choice for appropriate patients with chronic renal failure. With advancements in immunosuppressive therapy patient and graft survival have significantly improved over the last decades. This achievement of long-term organ acceptance, however, coincides with an increased occurrence of posttransplantation malignancy . We will present a renal transplant patient who was referred to us because of suspected colon cancer.
A 66 year old male patient who had received a renal transplant seven years earlier because of IgA nephropathy in his native kidneys was referred to us by his nephrologist. His graft had functioned well and his creatinine was stable at 130 μmol/l with an immunosuppressive regimen of cyclosporine, azathioprine, and prednisolone that he had received since his surgery. Over the past 6 months he reported a 6 kg weight loss and increasing nausea. He had also noted loose, darkish stools several times daily and significant night sweats but no fever. He denied having travelled outside of Germany in the past year. His nephrologists had noted small contracted native kidneys, an unremarkable graft and normal remaining abdominal structures in an ultrasound study. A gastroscopy, chest x-ray and urological evaluation were unremarkable. All tests conducted for infectious diseases were negative. The haemoglobin and hematocrit, liver enzymes, thyroid hormone levels and serum proteins were normal. His creatinine was unchanged and the C-reactive protein was 4 mg/dl. His nephrologists, who suspected an intestinal malignancy in this transplanted patient, referred him to our service for colonoscopy and further evaluation.
A significantly increased incidence of malignancy is well documented in renal transplant recipients if compared to the general population . With improvements in immunosuppressive regimens that prolong patient and graft survival, neoplastic disease has developed into a frequent long-term complication in kidney recipients. One study found that 40 percent of renal graft recipients had cancer after 20 years of immunosuppression . Many types of posttransplant cancers display a more malignant course than the same type of cancer in non-transplant patients. This aggressive behaviour of posttransplant malignancy contributes to the associated mortality causing 26 percent of deaths in patients surviving transplantation for at least 10 years .
One of the contributing factors to posttransplant cancer is the immunosuppressive therapy . The association of immunosuppressive therapy and cancer development is also known from non-transplant patients but the precise role of immunosuppressive drugs in carcinogenesis is not fully understood. There is experimental evidence that the inhibition of immunological responses, especially after giving anti-T cell antibodies, increases cancer susceptibility by interfering with the host's anti-cancer surveillance system [1, 4]. Accordingly, the amount of immunosuppression would be directly correlated to the risk of cancer. While this applies clinically to renal graft recipients on high-dose versus low-dose cyclosporine  it has also been demonstrated that cyclosporine is still carcinogenic in mice without an immune system . This is partly ascribed to a TGF-beta dependent mechanism as cancer progression could be inhibited by TGF-beta blockade . Similar effects have been reported for tacrolimus which also promoted cancer growth in immunodeficient mice . A direct carcinogenic potential has recently been highlighted for azathioprine which increases the risk of skin cancer through higher UVA radiation sensitivity and subsequent DNA mutations . In contrast to these cancer promoting side effects of calcineurin inhibitors and azathioprine, inhibitors of target-of-rapamycin (TOR), such as sirolimus and everolimus, seem to inhibit primary and metastatic tumor growth [9, 10]. TOR inhibitor treatment was associated with reduced TGF-beta levels and with attenuated VEGF signalling [9, 10]. A recent multivariate analysis including more than 30.000 kidney recipients showed a three times higher incidence rate of posttransplant malignancy in patients on calcineurin inhibitors as compared to patients on sirolimus or everolimus . Another study followed 15 renal transplant patients with Kaposi's sarcoma while they were switched from cyclosporine to sirolimus . Three months after the switch all Kaposi's sarcoma lesions had disappeared while no graft rejection occurred and the serum creatinine stayed stable . These and other studies indicate that TOR inhibitors have an equivalent immunosuppressive potency but a reduced risk of malignancy.
Guided by our patient's history we agreed with the referring nephrologist and suspected post-transplant malignancy. Considering the negative results of outpatient gastroscopy, x-ray and ultrasound together with reported changes in bowel habits, we wrongly assumed the colon as the most likely tumor location. This assumption seemed to be confirmed by the misinterpreted radiological findings. While the incidence of rectal cancer is decreased in transplant patients, the risk of colon cancer is significantly increased . A general odds ratio hierarchy of tumor risk in kidney transplanted patients shows in decreasing order: Non-melanoma skin cancer, thyroid and other endocrine tumors, oral cavity cancers, cervix and vaginal cancers, non-Hodgkin lymphoma, renal, ureteral, and bladder cancer, colorectal cancer, lung cancer, and brain tumors . Our patient's final diagnosis was glioblastoma multiforme, which together with other brain tumors has an odds ratio of 2.5 in transplant patients. Although we were not able to help our patient this case illustrates several aspects:
1. Transplant patients need a regular history, physical examination and screening tests directed at tumor detection (reviewed in reference 1).
2. The prevalence and the behaviour of specific types of cancers in transplant recipients are significantly different from the general population.
3. Post-transplant malignancy can only in part be explained by immunosuppression itself.
4. Imaging studies in transplant patients should be interpreted by physicians familiar with transplant related peculiarities.
Written consent was obtained from the Ethical Committee of the Charité Campus Berlin-Buch for publication of this study
- Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M: Malignancy in renal transplantation. J Am Soc Nephrol. 2004, 15 (6): 1582-8. 10.1097/01.ASN.0000126194.77004.9B.View ArticlePubMedGoogle Scholar
- London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP: Risk of neoplasia in renal transplant patients. Lancet. 346 (8972): 403-6. 10.1016/S0140-6736(95)92780-8. 1995, Aug 12
- Sheil AG, Disney AP, Mathew TH, Amiss N: De novo malignancy emerges as a major cause of morbidity and late failure in renal transplantation. Transplant Proc. 1993, 25 (1 Pt 2): 1383-4.PubMedGoogle Scholar
- 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 (12): 4539-44. 1987 Jun 15
- Dantal J, Hourmant M, Cantarovich D, Giral M, Blancho G, Dreno B, Soulillou JP: Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 351 (9103): 623-8. 10.1016/S0140-6736(97)08496-1. 1998 Feb 28
- Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K, Lagman M, Shimbo T, Suthanthiran M: Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 397 (6719): 530-4. 10.1038/17401. 1999 Feb 11
- Maluccio M, Sharma V, Lagman M, Vyas S, Yang H, Li B, Suthanthiran M: Tacrolimus enhances transforming growth factor-beta1 expression and promotes tumor progression. Transplantation. 76 (3): 597-602. 2003 Aug 15
- O'Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P: Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science. 309 (5742): 1871-4. 10.1126/science.1114233. 2005 Sep 16
- Luan FL, Ding R, Sharma VK, Chon WJ, Lagman M, Suthanthiran M: Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney Int. 2003, 63 (3): 917-26. 10.1046/j.1523-1755.2003.00805.x.View ArticlePubMedGoogle Scholar
- 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. 2002, 8 (2): 128-35. 10.1038/nm0202-128.View ArticlePubMedGoogle Scholar
- Kauffman HM, Cherikh WS, Cheng Y, Hanto DW, Kahan BD: Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies. Transplantation. 80 (7): 883-9. 10.1097/01.TP.0000184006.43152.8D. 2005 Oct 15
- Stallone G, Schena A, Infante B, Di Paolo S, Loverre A, Maggio G, Ranieri E, Gesualdo L, Schena FP, Grandaliano G: Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med. 352 (13): 1317-23. 10.1056/NEJMoa042831. 2005 Mar 31
- Ponticelli C, Passerini P: Gastrointestinal complications in renal transplant recipients. Transpl Int. 2005, 18 (6): 643-50. 10.1111/j.1432-2277.2005.00134.x.View ArticlePubMedGoogle Scholar
- 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 (2): 183-9. 1995 Jan 17
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2369/7/9/prepub