A chimeric bladder tumor in a renal transplant recipient: the oncogenic convergence of JC virus and PIK3CA mutation

Organ transplant recipients face a markedly elevated risk of developing cancer, with posttransplant malignancies accounting for up to 20% of long-term complications [1]. The most common malignancies developing after solid organ transplantation and directly attributable to the transplant procedure include Kaposi's sarcoma, post-transplant lymphoproliferative disorders, and non-melanoma skin cancers [2,3]. Less frequently, yet with an incidence higher than in the general population, urothelial carcinomas are also diagnosed [4]. The primary driver of this increased oncologic burden is chronic immunosuppressive therapy, both due to the direct oncogenic effects of immunosuppressive drugs and, more importantly, the impaired immune surveillance they induce [5]. For certain cancers with clearly increased incidence, oncogenic viruses play a decisive role, with immunosuppression facilitating viral persistence and chronic infection in predisposed individuals [6,7]. Post-transplant malignancies are categorized as either de novo tumors or chimeric tumors [8]. The latter are further subdivided, based on timing, into "donor-transmitted" tumors (DTTs), occurring within the first two years post-transplant, and "donor-derived" tumors, arising thereafter (DDTs) [9]. DTTs are rare and typically reflect undetected malignancies present in the donor. Despite stringent screening protocols, a residual risk of DTTs persists [10]. DDTs, in contrast, appear later and originate from donor cells that migrate and engraft in the recipient. These cells are not malignant per se but behave as tumor-initiating cells (TICs), leading to the development of recipient malignancies [11].Here, we report a highly unusual case of urothelial carcinoma diagnosed two years after kidney transplantation from a deceased donor. This stands out both for its rarity-a donorderived bladder carcinoma in a recipient of two renal transplants-and for the coexisting JC polyomavirus infection, allowing investigation of its potential role in post-transplant oncogenesis [12].The patient is a 59-year-old Caucasian male with a history of chronic glomerulonephritis (not histologically confirmed) that progressed to end-stage renal disease, initially treated with peritoneal dialysis. After two years, he underwent a first kidney transplantation from a deceased male donor (karyotype XY), with implantation in the right iliac fossa and immediate graft function. Immunosuppressive induction therapy included basiliximab, tacrolimus, mycophenolate, and steroids; maintenance therapy consisted of tacrolimus, mycophenolate, and steroids. Renal function remained stable for seven years. Subsequently, progressive renal deterioration prompted a biopsy of the transplanted kidney, which revealed polyomavirusassociated nephropathy due to JC virus (JCV). This histopathological diagnosis, coupled with a concurrent plasma JC virus viremia of 39,650 copies/mL, established JCPyV-associated nephropathy as the primary cause of graft dysfunction, leading to chronic kidney failure. Immunosuppressive therapy was modified with tapering and eventual discontinuation of tacrolimus, and everolimus was introduced for its antiviral potential. Two years after JC virus diagnosis, further investigations were conducted as part of a staging work-up to assess potential systemic involvement, although no focal neurological symptoms were documented at that time. Lumbar puncture revealed JC virus in cerebrospinal fluid (20 copies/mL), and urinary viral load was 26,582,889,960 copies/mL. Four years later, renal failure progressed to end-stage disease, necessitating hemodialysis via a native arteriovenous fistula. The patient was re-listed for kidney transplantation and, after three years on the waitlist, received a kidney from a deceased female donor (karyotype XX). The second graft was implanted in the left iliac fossa with immediate functional recovery. Induction immunosuppression included thymoglobulin, basiliximab, tacrolimus, mycophenolate, and steroids; maintenance therapy consisted of tacrolimus, mycophenolate, and steroids. At that time, JC virus viremia was detected at low levels (467 copies/mL), and routine post-transplant brain MRI was unremarkable. Renal function remained satisfactory for approximately six months, after which a rapid deterioration was observed. A graft biopsy showed no histological evidence of JC virus infection or acute rejection. During this phase, a concomitant Escherichia coli urinary tract infection was diagnosed and treated with antibiotics, resulting in only partial and transient improvement of renal function. Five months later, a repeat graft biopsy revealed cytological features consistent with JC virusassociated cytopathic effect. As a consequence, tacrolimus was discontinued and everolimus was reintroduced in an attempt to modulate immunosuppression. Despite these interventions, renal function continued to decline, and hemodialysis was resumed one year later. Notably, JC virus infection persisted throughout follow-up, with a progressive increase in viral replication. Plasma viral load reached a peak of 2,957,144 copies/mL, while cerebrospinal fluid viral load rose to 2,427,850 copies/mL approximately one year after the second transplant, without the manifestation of overt clinical neurological deficits. Two years after the second transplant and one year after dialysis resumed, the patient presented with macrohematuria. Cytological analysis revealed malignant urothelial cells. Ultrasound showed a bladder mass on the left lateral wall. Transurethral Resection of Bladder Tumor (TURBT) revealed multiple exophytic lesions and tissue protruding from the left ureteral orifice. Histopathology confirmed high-grade invasive urothelial carcinoma with angioinvasion. (FIGURE 2) Ureteroscopy was not performed to avoid upper tract tumor seeding. Abdominal CT showed diffuse bladder wall thickening. Given the bladder tumor location, wall infiltration, and absent residual renal f