BK Virus: Beyond Nephropathy Metastatic BK Virus-Induced, Donor-Derived Bellini’s Carcinoma in a Kidney Allograft Recipient: Boosting Rejection to Treat the Cancer

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Dear Editors, BK virus (BKV), present in 80-90% of the population, establishes a lifelong persistent infection in the kidney and urinary tract after a subclinical primary infection. It can reactivate and cause de novo infection in immunocompromised kidney transplant recipients (KTRs) lacking neutralizing antibodies against the donor strain 1 , causing nephropathy (BKVAN) in 4-8% of cases. Persistent BKV infection increases the risk of urothelial carcinoma and collecting duct carcinoma (CDC) 2 .A 73-year-old KTR was admitted for asthenia, acute kidney injury (creatinine 320 µmol/L), inflammatory syndrome (CRP 130 mg/L), and anaemia (Hb 75 g/L). He was followed for a KT performed 9 years earlier, complicated by biopsy-proven BKVAN at month 10. Mycophenolate mofetil was switched to everolimus (3-8 ng/mL), then to leflunomide, and tacrolimus to ciclosporin (80-120 ng/mL). The viral load decreased over 5 months and BKV was never detected again in the blood. At admission, MRI revealed a hypovascular mass in the graft with central necrosis and retroperitoneal inflammation. Biopsy confirmed a tumour composed of irregular tubular structures, trabeculae and single cells (Figure 1). The nuclei had a high mitotic index. Necrotic changes were observed. This tumour proliferation infiltrated between nontumour and dysplastic premalignant tubules. Immunohistochemistry showed diffuse positivity of tumour cells for PAX8, CK7, INI1, fumarate hydratase, and SDHB, and focal positivity for GATA3 (Figure 1B), but negativity for CK20, p504S, p63, or ALK. Only tumour cells showed strong nuclear staining with anti-SV40 large T-antigen (Figure 1), leading to the diagnosis of BKV-associated CDC. No metastases were initially found, and transplantectomy was performed. On pathological examination, the tumour invaded the surgical margins of the transplantectomy. Immunosuppressive therapy was tapered by withdrawing leflunomide and reducing tacrolimus trough levels, but not entirely discontinued in order to minimize the risk of donor-specific alloimmunization. Two months later, PET/CT showed iliac, retroperitoneal, pelvic lymph node metastases, and a right ischiopubic bone metastasis. Bulk HLA genotyping of the biopsy revealed that the tumour was not of recipient origin. Immunosuppression was completely withdrawn to stimulate the allo-immune anti-tumoral response, and the patient achieved complete metastatic regression within three months. At 2 years, he remained recurrence-free. This is a very rare case of metastatic donor-derived BKV-induced CDC in a KTR, successfully managed without chemotherapy nor immunotherapy. Bellini's CDC is a rare (<1%) and aggressive variant of renal cell carcinoma 2 . It has been hypothesized that CDC could be linked to BKV in transplanted patients 3 . No other specific risk factor have been identified. The tumorigenesis induced by BKV is known. Polyomaviruses encode 2 viral oncogenes, the small and the large T-antigen 4,5 . They can inactivate tumour suppressor genes p53 and pRb. Deletion of p53 and pRB leads to gene instability and replication errors that contribute to oncogenesis.cell growth, genetic instability and neoplasic transformation 6 7 . The high levels of large Tantigen expression in tumour nuclei is visualized by SV40 staining in immunohistochemistry.Microdissected samples of neoplasic cells usually contain DNA sequences specific for segments of BK-polyomavirus large T-antigen and VP1 genes. On the contrary, no BKV DNA sequences are detected in microdissected normal renal parenchyma 8 . Donor-derived tumours in KTRs are rare (<0.1%) and may arise from donor cells predisposed to oncogenesis. Key oncogenic drivers occur as early as late childhood and early adolescence. Then, late events during transplantation and under immunosuppression, such as BKV infection and genomic integration, may promote further oncogenesis in donor renal cells 9 . These donor-derived tumours offer a unique treatment opportunity: withdrawal of immunosuppression led to spontaneous alloimmune tumour rejection by enabling the immune system to target the graft through alloimmune and antitumour responses. Ortega et al reported remission of a metastatic donor-derived urothelial tumour after transplantectomy and immunosuppression withdrawal 10 .Meier et al achieved similar success in a metastatic Bellini carcinoma by boosting the antitumour immune response with IL-2 immunotherapy 3 (Table 1). This case highlights the specificity of urological tumours in KTRs. Identifying donor-derived malignancies may refine treatment strategies, reducing reliance on aggressive therapies. The clinical history reported in this case suggests pragmatic management, although this is by no means a recommendation. Firstly, given the very unfavourable prognosis of these tumours, it seems legitimate to perform surgery and completely stop immunosuppression. The two expected benefits of surgery are the removal of the largest possible tumour mass, and the avoidance of symptomatic toxic graft rejection. The addition of immunotherapy or chemotherapy should be discussed on a case-by-case basis, after evaluating the efficacy of the initial treatment. Given BKV's oncogenic potential, long-term monitoring should extend beyond the risk of nephropathy to include surveillance for malignancy. Options could include annual urinary cytology screening, early invasive urological evaluation in the event of haematuria and potentially biannual imaging of the graft.

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