Transitional Cell Carcinoma Arising Within a Pediatric Donor Renal Transplant in Association With BK Nephropathy

We describe the first known case of transitional cell carcinoma (TCC) arising within a renal graft from a pediatric donor. This occurred in the context of an en bloc 2-year-old pediatric kidney pair lost to BK nephropathy in a 64-year-old female recipient and supports previous reports of an association between BK replication and urologic malignancy. Standard immunosuppressive protocol was used, with rabbit antithymocyte globulin induction. Maintenance immunosuppression was mycophenolate mofetil, prednisone, and tacrolimus. She received extra doses of antithymocyte globulin with pulsed steroids twice in the first month after transplantation to empirically treat possible cellular rejection. Biopsy was not performed because of concerns of iatrogenic injury to the small pediatric kidneys. Five months after transplantation, urine cytology showed decoy cells, and plasma BK polymerase chain reaction tested positive at 88 million copies/mL. In response, her immunosuppression was reduced. The graft failed at 1 year after transplantation. One month before ultimate graft failure, she underwent her only allograft biopsy, which showed BK nephropathy. Five years after transplantation, she was admitted for a urinary tract infection, her third for that year. Urinalysis demonstrated the presence of macroscopic hematuria, which persisted beyond clearance of the urinary tract infection. Urine cytology demonstrated atypical urothelial cells suspicious for an epithelial malignancy. Computed tomographic scan revealed mild hydronephrosis of the upper pole renal transplant with an associated ureteric calculus. A magnetic resonance imaging scan demonstrated the presence of a mass suspicious for malignancy associated with the superior kidney, reinforcing the need for nephrectomy. The two renal transplants in the right iliac fossa were excised separately with a short segment of extrapelvic artery, vein, and ureter. The kidneys were removed through the old transplant incision using an extraperitoneal, extracapsular approach because of the concern for malignancy in the superior kidney. Histology revealed a pT4, grade 3 papillary TCC arising from the renal calyces, extensively involving the renal parenchyma (Fig. 1A, B). Although the tumor extended up to the renal capsule, the margins were free from tumor, and there was no obvious lymphovascular invasion. Immunohistochemical studies showed that the tumor was positive for large T antigen in keeping with BK infection (Fig. 1C), p53 (Fig. 1D), CK7, PAX8, p63 (focal), and p16 and negative for WT1 and CK20. The uninvolved renal parenchyma was negative for the large T antigen and showed global glomerulosclerosis and tubulointerstitial nephritis, in keeping with prior BK nephropathy, and focal and segmental glomerulosclerosis.FIGURE 1: A, bivalved superior nephrectomy specimen showing a 6-cm lobulated, solid, partially necrotic mass involving the pelvis, hilum, and renal parenchyma. B, malignant epithelial neoplasm with glandular and papillary differentiation invading renal parenchyma; a minor sarcomatoid component is not shown (hematoxylin-eosin, 400×). Inset: Malignant cells have hyperchromatic, pleomorphic nuclei. There are frequent mitoses, including atypical tripolar forms (arrow). C, all tumor cells stain strongly positive for the polyoma large T antigen. Stroma and surrounding renal parenchyma are negative. D, all tumor cells stain strongly positive for p53.It was elected not to give any further treatment for her TCC after nephrectomy, with plans for ongoing surveillance cystoscopy, urine cytology, and imaging. She remains well at 8-month follow-up. The chief points of interest in this case are the occurrence of TCC within a pediatric donor kidney and the association with BK virus replication. There have been no prior reports of TCC arising in such a young donor organ. TCC has been reported relatively frequently in the bladder of the recipient but very rarely in the allograft itself (1–4). In a world transplant tumor registry, there have been only five allograft TCCs ever reported: renal cell carcinomas in the allograft are much more common (1). In the general population, the median age at presentation is 65, much older than our donor of 2 years old with TCC 6 years after transplantation, giving a biologic 8-year-old kidney. High-dose immunosuppression may well have contributed to the development of TCC in this case but also predisposed the patient to the development of polyomavirus nephropathy. It has been proposed that viruses, particularly BK virus and human papillomavirus, can contribute to oncogenesis in TCC (5–7). BK and other polyomaviruses share the large T-cell antigen, which can bind and inactivate the p53 and retinoblastoma tumor suppressor proteins. Some in vitro and animal models have provided supporting data for a role of BK in TCC (5). It is tempting to speculate in this case that the carcinoma was driven by BK virus. All tumor cells were strongly positive for BK large T antigen and showed accumulation of p53, in keeping with BK large T-antigen binding to p53. The surrounding normal tissue was negative for these markers. Interestingly, others have similarly reported the paradoxical accumulation of stabilized p53 in BK-infected tissues (5). This differential expression of BK large T antigen between the tumor and normal surrounding urothelium supports a role for the virus in oncogenesis. This is particularly compelling given the occurrence of TCC in such a biologically young kidney from a 2-year-old donor. James McDaid 1 Evan A. Farkash2 David J.R. Steele3 Paulo N. Martins1 Camille N. Kotton4 Nahel Elias1 Dicken S.C. Ko1,5 Robert B. Colvin2 Martin Hertl1 1 Department of Surgery Division of Transplant Surgery Massachusetts General Hospital Harvard Medical School Boston, MA 2 Department of Pathology Massachusetts General Hospital Harvard Medical School Boston, MA 3 Division of Nephrology Massachusetts General Hospital Harvard Medical School Boston, MA 4 Infectious Diseases Division Massachusetts General Hospital Harvard Medical School Boston, MA 5 Department of Urology Massachusetts General Hospital Harvard Medical School Boston, MA