Malignancy remains a major cause of late morbidity and mortality in kidney transplant recipients, largely due to chronic immunosuppression and impaired tumor immune surveillance. Mammalian target of rapamycin inhibitors have antiproliferative and antiangiogenic properties and are frequently used in recipients considered to be at increased oncologic risk. However, their protective effect against de novo malignancy is not absolute. Here, we report 2 cases of severe malignancies that developed in kidney transplant recipients after conversion from calcineurin inhibitors to sirolimus following polyomavirus-associated nephropathy. The first patient, a 55-year-old man, developed prostate adenocarcinoma 6 years after transplant and 4 years after conversion to sirolimus. The diagnosis was established during evaluation for severe anemia and graft dysfunction. The second patient, a 35-year-old woman, developed primary central nervous system posttransplant lymphoproliferative disorder 4 years after transplant and 2 years after conversion to sirolimus. Histopathologic examination confirmed an aggressive lymphoma without detectable Epstein-Barr virus infection. These cases illustrate that mammalian target of rapamycin inhibitor-based immunosuppression does not eliminate the risk of solid or hematologic malignancy. Cumulative immunosuppressive exposure, viral complications, and delayed conversion may contribute to persistent oncogenic risk. Careful long-term oncologic surveillance and individualized immunosuppressive management remain essential in kidney transplant recipients.

Key words : BK virus nephropathy, Immunosuppression, Oncogenesis, Posttransplant lymphoproliferative disorder, Transplant oncology

Introduction
Malignancy is a leading cause of late morbidity and mortality in kidney transplant recipients, with an overall cancer risk 2- to 4-fold higher than shown in the general population.¹ Chronic immunosuppression impairs immune surveillance and promotes oncogenesis through reduced tumor immunosurveillance, direct oncogenic drug effects, and increased susceptibility to oncogenic viral infections.² Calcineurin inhibitors have been associated with increased cancer risk due to their pro-oncogenic and pro-angiogenic properties.³ In contrast, mammalian target of rapamycin (mTOR) inhibitors exert antiproliferative and antiangiogenic effects by inhibiting the phosphatidylinositol 3-kinase/Akt/mTOR pathway, a key regulator of cell growth and tumor progression.⁴ These properties have led to their preferential use in transplant recipients at increased oncologic risk or after diagnosis of de novo malignancy.⁵ However, the oncologic benefit of mTOR inhibitors remains incomplete and appears influenced by cumulative immunosuppressive exposure, timing of conversion, and underlying viral complications.⁶ BK virus infection, in particular, has been associated not only with graft dysfunction but also with potential oncogenic mechanisms through chronic inflammation and viral-mediated cellular dysregulation.⁷ Here, we report 2 cases of severe neoplastic complications occurring in kidney transplant recipients after conversion to sirolimus for BK virus nephropathy, highlighting the persistent risk of malignancy despite mTOR-based immunosuppression. All procedures were conducted in accordance with the ethical standards of the institutional research committee and with the 1975 Helsinki Declaration and its later amendments. Written informed consent was obtained from both patients for publication of this report and accompanying images.

Case Report

Case 1
A 55-year-old man with end-stage kidney disease secondary to immunoglobulin A nephropathy underwent living-donor kidney transplant in 2019. Initial maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and corticosteroids. In 2021, he developed biopsy-proven BK virus nephropathy with plasma viremia of 113 000 copies/mL. Tacrolimus was discontinued and replaced with sirolimus (target trough level, 6-8 ng/mL). The dose of mycophenolate mofetil was reduced. In January 2025, the patient was admitted for progressive graft dysfunction. Laboratory evaluation showed serum creatinine of 511 µmol/L and hemoglobin of 5.3 g/dL. The patient also reported chronic gastrointestinal symptoms and fatigue. Investigations for severe anemia revealed prostate adenocarcinoma confirmed by histopathologic examination. Staging showed no distant metastasis at diagnosis. The malignancy occurred 6 years after transplant and 4 years after conversion to sirolimus. This case illustrates the development of de novo solid malignancy despite prolonged exposure to an mTOR inhibitor.

Case 2
A 35-year-old female patient with headache and decreased visual acuity presented to our hospital in April 2017. She had undergone kidney transplant in November 2013 from a deceased donor because of glomerular nephropathy secondary to Alport syndrome. She received for induction polyclonal antibodies with bolus of methylprednisolone and underwent a maintenance therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. The posttransplant period was complicated by a recurrent pyelonephritis because of urinary reflux on graft. Creatinine levels were about 100 and 300 µmol/L, respectively, at year 1 and year 2. In March 2015, graft biopsy showed BK nephropathy and anticalcineurin nephrotoxicity with creatinine level of 300 µmol/L. For this reason, tacrolimus was stopped and switched to sirolimus; mycophenolate mofetil dose was also reduced, and residual rate of sirolimus was about 8 mg/mL. The pathological examination confirmed the diagnosis of acinar adenocarcinoma of the prostate (Figure 1). On general neurologic examination, no abnormalities, a maximum Glasgow coma score, no meningismus, and no focal neurology were documented. Additional physical examination proved unremarkable with no lymphadenopathy noted. Peripheral blood studies disclosed a leukocyte count of 7100/mm³, platelet count of 224 000, hemoglobin level of 9.1 g/dL, C-reactive protein level of 2 mg/dL, stable serum creatinine level of 292 µmol/L, with a clearance of 16 mL/min, and normal lactate dehydrogenase level of 250 U/L. Urgent computed tomography of the brain showed a contrast rim-enhancing lesion over the left frontal lobe. Magnetic resonance imaging of the brain showed 2 lesions (1 frontal and 1 occipital), suggesting an infectious etiology, particularly toxoplasmosis according to imaging characteristics of the lesions (Figure 2). With a history of long-term immunosuppressive therapy and the computed tomography findings, cerebral toxoplasmosis was highly suspected. The patient was treated with antibiotics; however, with worsening of cerebral edema and appearance of papillary edema, an emergency operation was performed. Histopathology showed a primary central nervous system lymphoma, with cells positive for B-cell marker CD20, CD3+, and Bcl²+ (Figure 3). Bone marrow biopsies showed no evidence of lymphoproliferative disease. Computed tomography showed no abnormalities in the neck, thorax, abdomen, and pelvis. Virology was negative for cytomegalovirus, herpes simplex virus, human herpes virus 8, and toxoplasmosis. Epstein-Barr virus polymerase chain reaction was negative on peripheral blood and on cerebrospinal fluid. Postoperatively, the patient’s brain pain decreased significantly, and the patient was continued on prednisone and sirolimus, but antibiotics and mycophenolate mofetil were stopped. The patient received chemotherapy that included high doses of methotrexate (3 g/m²), rituximab (375 mg/m²), and cytarabine. Brain magnetic resonance imaging showed progression of disease, and radiotherapy was proposed.

Discussion
These 2 cases illustrate that mTOR inhibitor therapy does not confer absolute protection against de novo malignancies in kidney transplant recipients. Epidemiologic studies have demonstrated that solid-organ transplant recipients remain at significantly increased risk of solid tumors, including prostate cancer, even when treated with mTOR inhibitors.⁸ Although retrospective analyses have suggested reduced incidence of certain skin cancers and Kaposi sarcoma under mTOR-based regimens, results are heterogeneous across cancer types.⁹ Prostate cancer is one of the most frequent malignancies in male transplant recipients and may present at a younger age compared with presentation in the general population.¹⁰ The pathogenesis likely reflects cumulative immunosuppression rather than a single drug effect. Primary central nervous system posttransplant lymphoproliferative disorder represents a rare but highly aggressive form of lymphoma.¹¹ This disease often presents several years after transplant and requires histopathologic confirmation because imaging findings are nonspecific.¹² Although many posttransplant lymphoproliferative disorders are related to Epstein-Barr virus, virus-negative cases are increasingly recognized and may involve alternative oncogenic pathways.¹³ The history of BK virus nephropathy in both of our patients may have contributed to impaired immune regulation and chronic inflammatory stimulation. Emerging evidence suggests that viral infections in transplant recipients can create a pro-oncogenic microenvironment through genomic instability and altered immune signaling.⁷ Furthermore, timing of conversion to mTOR inhibitors appears critical. Early conversion may reduce cumulative exposure to calcineurin inhibitors, whereas late conversion after prolonged immunosuppression may not sufficiently reverse oncogenic risk.⁶ The complex interplay between immunosuppressive agents, viral infections, and host immune surveillance underscores the necessity of individualized risk assessment. Large registry analyses and consensus conferences emphasized that immunosuppressive minimization strategies must be carefully balanced against rejection risk.¹⁴ Observations in our case report reinforce the need for the following: (1) long-term oncologic surveillance, (2) early investigation of unexplained neurologic or systemic symptoms, (3) multidisciplinary management, and (4) individualized immunosuppressive strategies.

Conclusions
Although mTOR inhibitors have recognized antiproliferative properties, these agents do not eliminate the risk of de novo malignancy in kidney transplant recipients. Patients with prior viral complications and prolonged immunosuppressive exposure remain particularly vulnerable. Personalized immunosuppressive strategies and vigilant long-term follow-up are essential to optimize graft survival while minimizing oncologic risk.