Urothelial carcinoma of donor origin in a kidney transplant patient
© The Author(s). 2016
Received: 14 June 2016
Accepted: 14 September 2016
Published: 18 October 2016
Malignancy after transplantation is an uncommon multifactorial occurrence. Immunosuppression to prevent graft rejection is described as a major risk factor in malignancy development in the post-transplant state. Donor-derived malignancy is a rare reported complication. Herein, we review our patient history and discuss diagnostic strategies and the implications of immunosuppression for donor-derived malignancy.
This is a 69-year-old man with post-renal-transplant urothelial carcinoma determined to be of donor origin. His course was complicated by BK virus at six years post-transplant; urothelial carcinoma was identified nine years post-transplant. Cystectomy was performed, but because of immunosuppression and underlying chronic kidney disease, the patient was considered ineligible for adjuvant chemotherapy. Two years after resection, screening MRI demonstrated retroperitoneal lymphadenopathy and a right upper pole mass in the transplanted kidney. Urine cytology confirmed the presence of malignant cells; FISH showed 2-8 copies of the X chromosome and no Y chromosome consistent with female origin of the malignant cells. CT-guided renal mass and paraaortic lymph node biopsies demonstrated that about 50 % of cells had an XY complement, while the remainder showed a XX genotype by chromosomal SNP microarray analysis. Immunosuppression was discontinued and the donor kidney removed. X/Y FISH of the urothelial carcinoma identified in the explanted kidney confirmed that the malignant cells were of female donor origin. Follow-up at 3, 6 and 12 months after discontinuation of immunosuppression and surgery demonstrated normalization of the lymphadenopathy and absence of new lesions.
Immunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment in our case.
KeywordsPost-transplant malignancy Immunosuppression Solid organ transplantation Urothelial carcinoma
According to the Organ Procurement and Transplantation Network (OPTN), there were 17,878 kidney transplants in 2015 in the United States with 5628 of them obtained from living-donors . In order for the graft to survive in the host, the recipient’s immune response to alloantigens from the graft is modulated. Otherwise, rejection would cause tissue damage and graft organ failure. Immunosuppressive drugs have made such immunomodulation feasible with 1-year graft-survival rates of 80 to 90 % . However, such treatment comes at the expense of increased incidence of infection and malignancy. The most common cancers in this scenario are non-melanoma skin cancer, non-Hodgkin lymphoma and lung, liver and kidney in recipients of those organs . Development of malignancy is multifactorial in this context. Commonly cited etiologies for new malignancy include decreased immunosurveillance secondary to immunosuppressive drugs, infections with oncogenic viruses, and other host-specific risk factors such as age, comorbidities and smoking and alcohol use. The risk of donor-derived transmission of disease is generally considered negligible .
Immunosuppression controls not only anti-graft but also anti-cancer immunity, and as such is most commonly implicated while the specific immunosuppression regimen is less important. A 2010 clinical trial of cadaveric kidney transplant recipients with a 20-year follow-up period randomly allocated patients to azathioprine and prednisolone, cyclosporine monotherapy, or cyclosporine monotherapy followed by azathioprine and prednisolone after the first 3 months of post-transplant. No specific immunosuppressive drug combination was more detrimental than another . Instead, factors such as increasing age and smoking status were associated with increased risk of malignancy in a multivariate analysis. This study however, did not include patients exposed to newer calcineurin inhibitors, such as tacrolimus, the mammalian target of rapamycin (mTOR) inhibitor, sirolimus or the antiproliferative agent mycophenolate mofetil.
We report on a patient that was treated with decreased immunosuppression and surgical removal of transplant kidney for management of donor-derived high-grade urothelial carcinoma.
A 69-year-old Caucasian male with a past medical history of hypertension and end-stage renal disease (ESRD) secondary to IgA nephropathy was managed with peritoneal dialysis (PD) for 1.5 years. His sister consented to provide a kidney and transplantation was performed in 2004. His post-transplant course was uncomplicated and immunosuppression was maintained with tacrolimus and sirolimus. In October 2010, he developed BK viremia and nephropathy, which was treated with leflunomide and a decrease in the tacrolimus dose. His course was further complicated by multiple cutaneous squamous carcinomas and a cutaneous basal cell carcinoma treated with Mohs surgery. In February 2013, he developed gross hematuria, which prompted further work-up. Masses identified by cystoscopy were sampled by transurethral resection and pathology showed high-grade invasive urothelial carcinoma of the bladder. In April 2013, he underwent radical cystectomy, prostatectomy and left pelvic lymphadenectomy (pT3pN0) with the discovery of an incidental adenocarcinoma of the prostate (Gleason 3 + 3 pT2c). Both native kidneys and ureters were removed and an ileal conduit created. He did not receive adjuvant chemotherapy because of the immunosuppression (prednisone, tacrolimus and sirolimus, which was later switched to mycophenolate mofetil) and chronic kidney disease.
In the era where therapeutic reactivation of the immune system against cancer has gained significant momentum, this case points out how surgical removal of the primary donor-derived malignancy and tapering of immunosuppression to allow the body to mount a response proves to be effective therapy for at least 1 year follow-up. It is also the first documented case known to the authors to demonstrate donor-derived origin in post-transplant urothelial carcinoma by FISH.
Reduction of immunosuppression, the initial intervention provided to this patient, has been previously described in the management of aggressive squamous cell carcinomas  and aggressive undifferentiated epithelioid tumor  in kidney transplant recipients. Unlike these tumor types, renal cell and urinary tract carcinoma incidence did not vary significantly during the functional life of the transplant versus after transplant failure and subsequent decreased immunosuppression based on retrospective data from the Australia and New Zealand Dialysis and Transplant Registry .
Our patient additionally underwent removal of the graft after prolonged discussion of preferred renal replacement therapy and risks and benefits of a surgical approach were addressed.
However, decrease and/or modification of immunosuppression and, ultimately, removal of the primary malignancy, if arising in the transplanted organ, might not always be feasible as patients might be reluctant to return to dialysis.
He had a history of prior complications associated with an immunosuppressed state including BK viremia in 2010 and urothelial carcinoma that warranted surgical resection in 2013.
The oncogenic potential of BK virus remains controversial . BK virus is considered to cause a subclinical primary infection, and then establishes a latent infection in the kidney and urinary tract, amongst other tissues. When it reactivates, it can cause hemorrhagic cystitis, ureteric stenosis and nephritis. It has also been associated with the development of bladder and kidney cancer, as its viral sequence and T antigen (TAg) has been detected in urothelial carcinoma cells . TAg binds and inactivates p53 and pRb, resulting in aberrant cell cycle regulation [11, 12]. In contrast, Rollison et al. concluded that BK virus did not play a major role in the pathogenesis of bladder carcinoma, as only 5.5 % of the bladder cancer samples of 76 patients with urothelial carcinoma were BK positive by polymerase chain reaction (PCR) and none of them showed TAg expression. These cases were not specifically post-transplant, however, and immune state was not reported . It is beyond our scope to postulate if the prior BK viremia had any impact on the development of donor-derived urothelial carcinoma in our patient. However, he did not have any other known risk factors  as he had only been a smoker for 2 years, less than half a pack per day- and had quit more than 40 years prior to the malignancy diagnosis.
The transmission frequency of malignancy by donors, deceased or living, is considered to be less than 1 % [4, 15]. Living donors are regularly screened and in “good health”, consequently diagnosis is frequently made only after donation. Of note, these cancers are considered donor-derived and not donor-transmitted, as the cancer was technically derived from the donor cells, but not clinically present at the time of transplant . There have been at least two case reports of donor-derived urothelial carcinoma in kidney transplant recipients. Both received deceased donor kidneys, had malignancy and metastatic disease diagnosed within 1 year of transplantation, and management included paclitaxel-based chemotherapy. In the first patient, diagnosis of donor-derived malignancy was construed secondary to tempo of disease, lack of native urothelial involvement and inconclusiveness of histocompatibility testing of the tumor; this patient demonstrated no signs of disease over the 3 year follow-up period after halting immunosuppression, removal of the transplanted kidney and chemotherapy . The second patient received the same treatments, but unfortunately passed away from parietal hemorrhage during chemotherapy; interestingly, the liver recipient from the same donor was also found to have disease, biopsy-proven malignant nodules, once the state organ procurement was advised of the neoplasm transmission, whereas the recipient of the other kidney did not . In contrast, our patient developed donor-derived malignancy 11 years after transplantation from a living-related donor and had a sustained response 1 year after stopping immunosuppression and removal of the transplant with no chemotherapy with no current evidence of disease.
Once the clinical suspicion is present, assessment of molecular features of the tumor and/or the presence of XY or XX chromosomes discordant with the recipient’s sex, as in our case, enable the diagnosis. Male donor-derived cells in the basal layer and invasive areas of squamous cell carcinomas of three female kidney transplant recipients has been previously published ; however, to our knowledge; this is the first case of high grade urothelial carcinoma of donor-derived origin which is confirmed by FISH. No studies for the presence of BK virus were performed on the explant as management would not be affected.
Immunosuppression is a major risk factor for development of malignancy in transplant recipients. Donor-derived malignancy can arise and current molecular studies allow an accurate diagnosis. Withdrawal of immunosuppression and surgical resection of the transplant kidney proved an effective treatment with ongoing surveillance and the caveat of return to PD for ESRD management. Continuous communication amongst treatment teams and the patient allowed a good outcome.
Chronic kidney disease
Eastern Cooperative Oncology Group
End stage renal disease
Fluorescence in situ hybridization
mammalian target of rapamycin
Organ Procurement and Transplantation Network
Polymerase chain reaction
Single nucleotide polymorphism
Availability of data and materials
RMMO saw patient in clinic; wrote case and created first draft. HAD was involved in the conception of this case report, followed patient, helped with literature review and was critical in the development of the manuscript. DJW and CAS specifically reviewed the technical description and accuracy of cytogenetic studies of all samples, also reviewed the manuscript. All authors read and approved the final manuscript.
RMMO is a third year fellow in Hematology and Oncology in the Medical University of South Carolina.
DJW is a Professor in the Department of Pathology & Laboratory Medicine, and Director of Cytogenetics and Molecular Genetics Laboratories in the Medical University of South Carolina.
CAS is an Associate Professor in the Department of Pathology and Laboratory Medicine, and the Medical Director of Cytogenetics and Genomics Laboratories in the Medical University of South Carolina.
HAD is Professor of Medicine & Gilbreth Chair in Clinical Oncology. Faculty at the Division of Hematology & Oncology in the Medical University of South Carolina.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
Ethics approval and consent to participate
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- OPTN. Transplants by Donor Type. 2016. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/##.
- Morris PJ. Transplantation—A Medical Miracle of the 20th Century. N Engl J Med. 2004;351(26):2678–80.View ArticlePubMedGoogle Scholar
- AlBugami M, Kiberd B. Malignancies: pre and post transplantation strategies. Transplant Rev (Orlando). 2014;28(2):76–83.View ArticleGoogle Scholar
- Engels EA, et al. Cancers among US organ donors: a comparison of transplant and cancer registry diagnoses. Am J Transplant. 2014;14(6):1376–82.View ArticlePubMedGoogle Scholar
- Gallagher MP, et al. Long-term cancer risk of immunosuppressive regimens after kidney transplantation. J Am Soc Nephrol. 2010;21(5):852–8.View ArticlePubMedPubMed CentralGoogle Scholar
- Moloney FJ, et al. Maintenance versus reduction of immunosuppression in renal transplant recipients with aggressive squamous cell carcinoma. Dermatol Surg. 2004;30(4 Pt 2):674–8.PubMedGoogle Scholar
- Waldman AH, et al. Revision of immunosuppression in a solid organ transplant recipient leads to complete remission of metastatic undifferentiated carcinoma. JAAD Case Rep. 2015;1(6):S8–S11.View ArticlePubMedPubMed CentralGoogle Scholar
- van Leeuwen MT, et al. Effect of reduced immunosuppression after kidney transplant failure on risk of cancer: population based retrospective cohort study. BMJ. 2010;340:c570.View ArticlePubMedPubMed CentralGoogle Scholar
- Abend JR, Jiang M, Imperiale MJ. BK virus and human cancer: innocent until proven guilty. Semin Cancer Biol. 2009;19(4):252–60.View ArticlePubMedPubMed CentralGoogle Scholar
- Geetha D, et al. Bladder carcinoma in a transplant recipient: evidence to implicate the BK human polyomavirus as a causal transforming agent. Transplantation. 2002;73(12):1933–6.View ArticlePubMedGoogle Scholar
- Tognon M, et al. Oncogenic transformation by BK virus and association with human tumors. Oncogene. 2003;22(33):5192–200.View ArticlePubMedGoogle Scholar
- Reploeg MD, Storch GA, Clifford DB. BK Virus: A Clinical Review. Clin Infect Dis. 2001;33(2):191–202.View ArticlePubMedGoogle Scholar
- Rollison DE, et al. Lack of BK virus DNA sequences in most transitional-cell carcinomas of the bladder. Int J Cancer. 2007;120(6):1248–51.View ArticlePubMedGoogle Scholar
- Burger M, et al. Epidemiology and risk factors of urothelial bladder cancer. Eur Urol. 2013;63(2):234–41.View ArticlePubMedGoogle Scholar
- Ison MG, et al. Donor-derived disease transmission events in the United States: data reviewed by the OPTN/UNOS Disease Transmission Advisory Committee. Am J Transplant. 2009;9(8):1929–35.View ArticlePubMedGoogle Scholar
- Ison MG, Nalesnik MA. An update on donor-derived disease transmission in organ transplantation. Am J Transplant. 2011;11(6):1123–30.View ArticlePubMedGoogle Scholar
- Milks K, Krishnan S, Caserta M, Stratta RJ, Tchelepi H. Incidental Discovery of a Donor-Derived Urothelial Carcinoma Following Kidney Transplantation. Int J Transplant Res Med. 2015;1:006.Google Scholar
- Ferreira GF, et al. Urothelial carcinoma transmission via kidney transplantation. Nephrol Dial Transplant. 2010;25(2):641–3.View ArticlePubMedGoogle Scholar
- Verneuil L, et al. Donor-derived stem-cells and epithelial mesenchymal transition in squamous cell carcinoma in transplant recipients. Oncotarget. 2015;6(39):41497–507.PubMedPubMed CentralGoogle Scholar