Renal transplant recipients are at increased risk for the development of a malignant neoplasm. Polyomavirus-associated urothelial carcinoma is a rare tumor that occurs in renal transplant recipients, with approximately 41 cases reported since 2002. It accounts for 27–31% of all post-transplant urothelial carcinomas and develops at an average of 8.5 years after transplantation. Histologically, it shows high-grade urothelial carcinoma (95.1%) with a high frequency of glandular differentiation and micropapillary structures (58.5%) and positive immunohistochemistry for polyomavirus large T antigen, p53 (92.9%), and p16 (100%). We encountered a case of BK polyomavirus (BKPyV)-associated urothelial carcinoma of the bladder diagnosed 54 months after kidney transplantation. Histologically, it was a high-grade urothelial carcinoma with micropapillary features, and immunohistochemically, it was diffusely positive for polyomavirus large T antigen, p16, and p53. BKPyV DNA and mRNA for BKPyV large T antigen have been identified in tissues using real-time polymerase chain reaction. The same sequence of the BKPyV VP1 genome hypervariable region was detected in both transplanted kidney tissue with polyomavirus nephropathy and urothelial carcinoma tissue, suggesting that polyomavirus-associated urothelial carcinoma developed in a background of persistent polyomavirus nephropathy. This case showed typical histological features and was detected and treated at an earlier stage than has been reported. It is important to keep in mind that polyomavirus-associated urothelial carcinoma can develop early after transplantation and might be associated with polyomavirus nephropathy. Because of its rapidly progressive nature, careful follow-up with urine cytology and cystoscopy is necessary. We report this case with a literature review.

Organ transplant recipients are at increased risk of malignancy, which is associated with immunosuppressive states and carcinogenic mechanisms associated with viral infections. In kidney transplant recipients, the incidence of cancer of the urinary tract is 4–10 times higher than that in the general population [1]. BK polyomavirus (BKPyV), which was originally identified in a patient with ureteral stenosis, is present asymptomatically in 80–90% of adults. In 30–40% of renal transplant recipients, BKPyV is activated, and its activation results in polyomavirus nephropathy [2]. BKPyV reactivation cases have an increased risk for the development of urothelial carcinoma (UC) [3].

Since the first report of polyomavirus-associated UC in a transplant patient in 2002, about 40 cases of BKPyV and one case of JC polyomavirus (JCPyV) have been reported to date [4‒20]. It was reported that polyomavirus-associated UC accounted for 27–31% of cases of post-transplantation UC [15, 20]. Immunohistochemistry showed that simian virus 40 (SV40) polyomavirus large T antigen (SV40T), which cross-reacts with large T antigen of BKPyV and JCPyV, was diffusely positive on tumor cells. Polyomavirus-associated UC is highly malignant and has a poor prognosis compared to that of non-polyomavirus-related UC [20]. The relationship between polyomavirus infection and the development of a tumor has been investigated, and the mechanism by which polyomavirus DNA is integrated into the UC genome has been elucidated [14]. In this article, we report a case of polyomavirus-associated UC of the bladder in a kidney transplantation patient after BKPyV nephropathy, with a literature review.

A 65-year-old Japanese woman with an unknown primary disease and a 13-year history of hemodialysis received an ABO-compatible kidney transplantation from a deceased 52-year-old donor who died of cerebral hemorrhage. She had a history of Hashimoto’s disease and an abdominal aortic aneurysm. The preoperative standard flow cytometry crossmatch test yielded a weakly positive result, and anti-HLA class I antibody (B37) was detected. The antibody was considered to be a preformed donor-specific antibody (DSA). Induction immunosuppressive therapy included tacrolimus, mycophenolate mofetil (MMF), methylprednisolone, everolimus, and basiliximab, in addition to rituximab. Renal biopsies at 1 and 3 months after transplantation revealed active antibody-mediated rejection (g1, ptc1), and methylprednisolone pulse therapy was performed. Decoy cells were continuously identified in urine for 3 months after transplantation. Thirteen months after transplantation, renal biopsy showed polyomavirus nephropathy (pvl2, ci1, class 2) with serum BKPyV DNA (1.6 × 104 copies) (Fig. 1a–c). As BKPyV nephropathy was confirmed, the dose of MMF was reduced. One year and 6 months after transplantation, the patient still had BKPyV nephropathy (pvl1, ci1, class 2); hence, administration of MMF was discontinued. At 48 months after transplantation, BKPyV nephropathy (pvl1, ci3, class 2) and calcineurin inhibitor-induced arteriolopathy (aah3) were observed, and the dose of tacrolimus was reduced. After that, atypical cells suggesting UC were observed in urine in addition to decoy cells (Fig. 1d). Fifty-four months after transplantation, a papillary tumor was found by cystoscopy (Fig. 1e), and the patient underwent transurethral resection of the bladder tumor.

Fig. 1.

Polyomavirus nephropathy in an allograft kidney 13 months after transplantation (a–c). a Interstitial mononuclear inflammation with intranuclear inclusions in tubular epithelial cells (HE ×40). b Immunohistochemistry of simian virus 40 large T antigen (SV40T) revealed the presence of large T antigen of BK polyomavirus (BKPyV) in tubular epithelial cells (SV40T ×40). c Immunohistochemistry revealed the presence of BKPyV VP1 in tubular epithelial cells, showing virion production (BKPyV VP1 ×40). d Urine cytology 48 months after renal transplantation revealed high-grade urothelial carcinoma (UC) cells (Papanicolaou ×40). e Cystoscopy 48 months after renal transplantation revealed a papillary tumor of the urinary bladder. Tumor tissue obtained by transurethral resection of bladder tumor (TUR-BT) was closely examined histopathologically (f–m). f High-grade UC contained micropapillary structures (HE ×40). g High-grade UC had invaded the submucosal stroma (HE ×40). h UC in situ was also found (HE ×40). i UC was shown to be diffusely positive for SV40T in immunohistochemistry (SV40T ×40). j UC did not express BKPyV VP1, and BKPyV was not considered to form a virion (BKPyV VP1 ×40). k Polyomavirus-associated UC was shown to be diffusely positive for p53 in immunohistochemistry (p53 ×40). l Polyomavirus-associated UC was shown to be diffusely positive for p16 (p16 ×40). m Polyomavirus-associated UC was shown to be diffusely positive for Ki-67 (Ki-67 ×40).

Fig. 1.

Polyomavirus nephropathy in an allograft kidney 13 months after transplantation (a–c). a Interstitial mononuclear inflammation with intranuclear inclusions in tubular epithelial cells (HE ×40). b Immunohistochemistry of simian virus 40 large T antigen (SV40T) revealed the presence of large T antigen of BK polyomavirus (BKPyV) in tubular epithelial cells (SV40T ×40). c Immunohistochemistry revealed the presence of BKPyV VP1 in tubular epithelial cells, showing virion production (BKPyV VP1 ×40). d Urine cytology 48 months after renal transplantation revealed high-grade urothelial carcinoma (UC) cells (Papanicolaou ×40). e Cystoscopy 48 months after renal transplantation revealed a papillary tumor of the urinary bladder. Tumor tissue obtained by transurethral resection of bladder tumor (TUR-BT) was closely examined histopathologically (f–m). f High-grade UC contained micropapillary structures (HE ×40). g High-grade UC had invaded the submucosal stroma (HE ×40). h UC in situ was also found (HE ×40). i UC was shown to be diffusely positive for SV40T in immunohistochemistry (SV40T ×40). j UC did not express BKPyV VP1, and BKPyV was not considered to form a virion (BKPyV VP1 ×40). k Polyomavirus-associated UC was shown to be diffusely positive for p53 in immunohistochemistry (p53 ×40). l Polyomavirus-associated UC was shown to be diffusely positive for p16 (p16 ×40). m Polyomavirus-associated UC was shown to be diffusely positive for Ki-67 (Ki-67 ×40).

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Histological examination of the bladder tumor revealed high-grade invasive UC (pT1 with pTis) (Fig. 1f–h). Micropapillary structures were observed, and cellular atypia was found to be prominent. Immunohistochemistry demonstrated diffusely positive results for SV40T, p53, p16, and high Ki-67 labeling index (Fig. 1i, 1k–m). BKPyV VP1 antigen was found to be positive in BKPyV nephropathy tissues at 13 months post-transplant but negative in the bladder tumor (Fig. 1c, j).

DNA was extracted and analyzed for BKPyV, JCPyV, and SV40 from formalin-fixed paraffin-embedded allograft kidney tissues, showing polyomavirus nephropathy at 13 months and 48 months after transplantation, and from formalin-fixed paraffin-embedded UC tissues obtained by transurethral resection of the bladder tumor at 54 months after transplantation [21]. As a result, only BKPyV DNA was detected in all specimens (1,170 and 33.1 copies/cell of BKPyV nephropathy, 45.5 copies/cell of bladder cancer), while JCPyV and SV40 DNA were under the detection limit (Fig. 2a). Moreover, RNA was extracted from UC tissues to investigate mRNA expression of BKPyV large T antigen. BKPyV large T antigen mRNA expression was verified by real-time reverse transcriptase polymerase chain reaction (8,160 copies/cell) (Fig. 2b). Sequences of the BKPyV VP1 genome hypervariable region in polyomavirus nephropathy tissues 13 months and 48 months after transplantation and in UC tissue 54 months after transplantation were compared with BKPyV types I–IV [22]. Each sequence obtained from the tissue samples matched each other identically and was assigned to BKPyV type I (Fig. 2c).

Fig. 2.

a Polyomavirus (BKPyV, JCPyV, SV40) DNA was examined using real-time PCR in polyomavirus nephropathy tissues 13 months and 48 months after transplantation and in UC tissue 54 months after transplantation. Only BKPyV DNA was detected in the three samples. b BKPyV large T antigen mRNA expression in UC tissues was identified using real-time reverse transcriptase PCR. The right column shows the control without the addition of reverse transcriptase. c Sequences of the BKPyV VP1 genome region were compared with BKPyV types I–IV in polyomavirus nephropathy tissues 13 months and 48 months after transplantation and in UC tissue 54 months after transplantation [22]. Dot (.) indicates the identical nucleotide to BKPyV type I, and only differences were detailed. Each sample showed the same sequence as that of BKPyV type I. PCR, polymerase chain reaction.

Fig. 2.

a Polyomavirus (BKPyV, JCPyV, SV40) DNA was examined using real-time PCR in polyomavirus nephropathy tissues 13 months and 48 months after transplantation and in UC tissue 54 months after transplantation. Only BKPyV DNA was detected in the three samples. b BKPyV large T antigen mRNA expression in UC tissues was identified using real-time reverse transcriptase PCR. The right column shows the control without the addition of reverse transcriptase. c Sequences of the BKPyV VP1 genome region were compared with BKPyV types I–IV in polyomavirus nephropathy tissues 13 months and 48 months after transplantation and in UC tissue 54 months after transplantation [22]. Dot (.) indicates the identical nucleotide to BKPyV type I, and only differences were detailed. Each sample showed the same sequence as that of BKPyV type I. PCR, polymerase chain reaction.

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These results suggested that the patient developed UC expressing BKPyV DNA with a background of persistent BKPyV nephropathy. Administration of tacrolimus was discontinued, and 8 courses of Baccile Calmette-Guerin bladder infusion therapy (80 mg) were administered. Ten-month follow-up including urine cytology and cystoscopy showed no signs of recurrence or distant metastasis. DSA measurement yielded negative results, and the transplant protocol biopsy showed no evidence of BKPyV nephropathy or strong suspicion of rejection.

Here we report a case of BK polyomavirus-associated UC of the bladder after BKPyV nephropathy in a transplanted kidney. Histologically, it was a high-grade UC with micropapillary features, and SV40T, p16, and p53 were diffusely positive in immunohistochemistry. BKPyV DNA and BKPyV large T antigen mRNA were identified in tissues by using real-time polymerase chain reaction. This case was histologically typical and was detected and treated at an early stage (pT1 with pTis). Early detection of the cancer was possible because of the frequent urine cytology and cystoscopy when atypical cells were detected in the urine cytology. It is important to keep in mind that this cancer can develop early after transplantation in association with polyomavirus nephropathy. Although the treatment in this case seemed to be successful, the rapidly progressive nature of the tumor requires careful follow-up with urine cytology and cystoscopy.

Forty cases of BK polyomavirus-associated UC including the present case have been reported since the first report by Geetha in 2002 (Table 1) [4]. A case of JCPyV-associated UC has also been reported recently [23]. Polyomavirus-associated UC is characterized by diffuse positivity for SV40T antigen and accounts for 27–31% of cases of post-transplantation UC [15, 20]. The urinary bladder is the most common site (n = 23 of 39, 73.1%), but an allograft kidney and ureter are also frequent sites (n = 12 of 41, 29.3%). The average age of onset is 8.5 years after transplantation, and cases are accompanied by proceeding polyomavirus viremia (n = 28 of 32, 87.5%) and polyomavirus nephropathy (n = 21 of 28, 75.0%). Histologically, most cases are high-grade UC (n = 39 of 41, 95.1%), and 59.0% (n = 23 of 39) of cases contain a glandular or micropapillary variant. Shirohi reported that 81% of cases showed more than 1 variant morphologic pattern [17]. Although two cases were diagnosed as collecting duct carcinoma, differentiating it from poorly differentiated UC with glandular differentiation is not easy. In immunohistochemistry, p53 was diffusely positive in 26 (92.9%) of 28 cases. p16 was positive in 15 of 15 cases (100%) retrieved. Of the cases, 53.8% (n = 21 of 39) had advanced-stage disease at the time of diagnosis (pT3 or higher). Mortality is as high as 33.3% (n = 13 of 39). However, there was a unique case in which distant metastasis disappeared when an immunosuppressant was withdrawn after transplant nephrectomy, suggesting that the removal of immunosuppression may be a treatment option [19]. Since large T antigens are highly immunogenic, immune checkpoint inhibitors are assumed to be effective.

Table 1.

Literature review: Polyomavirus-associated UC in renal transplant recipients

Reference No.AuthorsAgeSexYears after transplantVirusViremiaPolyomavirus nephropathySitesHistologyTumor gradeEtiology of native kidney failureClinical outcomep16p53Cytology
Geetha et al. 2002 59 BKPyV N.A. N.A. UB HGUC pT3N1M1 N.A. Died of metastasis N.A. (+) (+) 
Roberts et al. 2008 40 BKPyV N.A. Yes UB HGUC with squamous differentiation pT3 N.A. Alive N.A. N.A. (−) 
Hill et al. 2009 46 BKPyV Yes Yes UB HGUC with micropapillary features pT2 with pTis CKD due to tuberculosis Alive N.A. (+) (+) 
Pino et al. 2013 38 BKPyV N.A. Yes UB HGUC pT1 with pTis ADPKD Alive N.A. N.A. (+) 
Bialasiewicz et al. 2013 55 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis Hypertensive nephropathy Died of metastasis N.A. N.A. (+) 
Bialasiewicz et al. 2013 75 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis Hypertensive nephropathy Alive N.A. N.A. (+) 
Alexiev et al. 2013 38 BKPyV Yes Yes UB HGUC with glandular differentiation pT3a N.A. Alive (+) (+) N.A. 
Alexiev et al. 2013 60 11 BKPyV N.A. No UB HGUC with micropapillary features pT1 N.A. Alive (+) (+) (+) 
10 van Aalderen et al. 2013 56 BKPyV Yes N.A. UB HGUC with sarcomatoid features pT3M1 Polycystic kidney disease Died of metastasis N.A. N.A. (+) 
11 McDaid et al. 2013 64 BKPyV Yes Yes Allograft renal pelvis HGUC with papillary differentiation pT4 N.A. Alive (+) (+) (+) 
12 Li et al. 2013 59 BKPyV Yes Yes Allograft renal pelvis HGUC pTX Hypertensive nephropathy Alive N.A. N.A. N.A. 
13 Oikawa et al. 2014 47 BKPyV N.A. Yes Allograft ureter HGUC pT2 Diabetes mellitus Alive N.A. N.A. (+) 
14 Kenan et al. 2015 54 BKPyV Yes No Allograft renal pelvis HGUC with glandular differentiation pT3 with pTisNX Hypertensive nephropathy Alive N.A. N.A. (+) 
15 Yan et al. 2016 33 10 BKPyV Yes No UB HGUC with micropapillary features pT2bN0M1 Reflux nephropathy Died of metastasis (+) N.A. N.A. 
15 Yan et al. 2016 50 10 BKPyV Yes No UB/ureter HGUC with micropapillary features pT2aN0 Hypertensive nephropathy Alive (+) N.A. N.A. 
15 Yan 2016 31 18 BKPyV Yes Yes UB HGUC pT2NX Obstructive Alive (+) N.A. N.A. 
15 Yan et al. 2016 71 BKPyV No No UB HGUC with glandular differentiation pT2N0 Diabetes mellitus Alive (+) N.A. N.A. 
16 Kenan et al. 2017 62 BKPyV Yes Yes Allograft medulla to cortex HGUC with glandular differentiation pT1bN0M0 Diabetes mellitus Alive N.A. N.A. N.A. 
17 Sirohi et al. 2018 56 10 BKPyV Yes N.A. UB HGUC with sarcomatoid, signet ring cell pT3NX N.A. Died of metastasis N.A. (+) N.A. 
17 Sirohi et al. 2018 69 BKPyV N.A. N.A. Allograft collecting duct carcinoma pT1aN0 N.A. Died of unrelated causes N.A. (+) N.A. 
17 Sirohi et al. 2018 41 BKPyV N.A. N.A. Allograft collecting duct carcinoma pT3 ADPKD N.A. N.A. N.A. N.A. 
17 Sirohi et al. 2018 79 BKPyV Yes N.A. Ureter HGUC with sarcomatoid, micropapillary, glandular pT3NX N.A. Alive with disease N.A. (+) N.A. 
17 Sirohi et al. 2018 37 11 BKPyV Yes N.A. UB HGUC with micropapillary, glandular pT4aN1 Reflux nephropathy Alive N.A. (+) N.A. 
17 Sirohi et al. 2018 53 BKPyV No N.A. UB HGUC with micropapillary features pT3aN0 Hypertensive nephropathy Died of metastasis N.A. (-, null) N.A. 
17 Sirohi et al. 2018 69 11 BKPyV Yes N.A. UB HGUC with glandular differentiation pT3aNX IgA nephropathy Recurrence N.A. (wild type) N.A. 
17 Sirohi et al. 2018 42 BKPyV N.A. N.A. UB HGUC with glandular differentiation pT3aNX Diabetes mellitus Alive with disease N.A. (+) N.A. 
17 Sirohi et al. 2018 68 BKPyV Yes N.A. UB HGUC pT2aN0 ESRD Alive N.A. (+) N.A. 
18 Bertz et al. 2020 66 BKPyV N.A. N.A. UB/allograft HGUC with micropapillary features pT4 with pTisNX ESRD N.A. N.A. (+) N.A. 
18 Bertz et al. 2020 47 17 BKPyV No No UB HGUC with micropapillary features pT3 with pTisN0M1 ESRD Died of unrelated causes N.A. (+) N.A. 
18 Bertz et al. 2020 59 10 BKPyV N.A. N.A. Allograft renal pelvis HGUC with clear cell carcinoma pT2 with pTisNX ADPKD Died of metastasis N.A. (+) N.A. 
18 Bertz et al. 2020 44 18 BKPyV No No UB HGUC with villoglandular pattern pT1 with pTis IgA nephropathy Died of metastasis N.A. (+) N.A. 
19 Wang et al. 2020 57 BKPyV Yes Yes Allograft HGUC pTXM1 CKD Alive N.A. (+) N.A. 
19 Wang et al. 2020 61 BKPyV Yes Yes Allograft HGUC with glandular differentiation pT3N1 ADPKD Alive N.A. (+) N.A. 
19 Wang et al. 2020 76 12 BKPyV Yes Yes UB HGUC with glandular differentiation pT4N2M0 Lupus nephritis Died of metastasis N.A. (+) N.A. 
20 Chu et al. 2020, (n = 6) 62.0 (34–72) M/F = 4/2 11.1 (8.8–19.1) BKPyV Yes(6) Yes(5) UB(5)/allograft(1) HGUC(6) pT1(1)T2(2)T3(1)T4(2) N.A. Died of metastasis(3) 6/6 (+) 6/6 (+) N.A. 
23 Querido et al. 2019 57 JCPyV Yes Yes UB HGUC pT4M1 ESRD Died of metastasis (+) (+) N.A. 
★ The present case 69 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis ESRD Alive (+) (+) (+) 
Reference No.AuthorsAgeSexYears after transplantVirusViremiaPolyomavirus nephropathySitesHistologyTumor gradeEtiology of native kidney failureClinical outcomep16p53Cytology
Geetha et al. 2002 59 BKPyV N.A. N.A. UB HGUC pT3N1M1 N.A. Died of metastasis N.A. (+) (+) 
Roberts et al. 2008 40 BKPyV N.A. Yes UB HGUC with squamous differentiation pT3 N.A. Alive N.A. N.A. (−) 
Hill et al. 2009 46 BKPyV Yes Yes UB HGUC with micropapillary features pT2 with pTis CKD due to tuberculosis Alive N.A. (+) (+) 
Pino et al. 2013 38 BKPyV N.A. Yes UB HGUC pT1 with pTis ADPKD Alive N.A. N.A. (+) 
Bialasiewicz et al. 2013 55 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis Hypertensive nephropathy Died of metastasis N.A. N.A. (+) 
Bialasiewicz et al. 2013 75 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis Hypertensive nephropathy Alive N.A. N.A. (+) 
Alexiev et al. 2013 38 BKPyV Yes Yes UB HGUC with glandular differentiation pT3a N.A. Alive (+) (+) N.A. 
Alexiev et al. 2013 60 11 BKPyV N.A. No UB HGUC with micropapillary features pT1 N.A. Alive (+) (+) (+) 
10 van Aalderen et al. 2013 56 BKPyV Yes N.A. UB HGUC with sarcomatoid features pT3M1 Polycystic kidney disease Died of metastasis N.A. N.A. (+) 
11 McDaid et al. 2013 64 BKPyV Yes Yes Allograft renal pelvis HGUC with papillary differentiation pT4 N.A. Alive (+) (+) (+) 
12 Li et al. 2013 59 BKPyV Yes Yes Allograft renal pelvis HGUC pTX Hypertensive nephropathy Alive N.A. N.A. N.A. 
13 Oikawa et al. 2014 47 BKPyV N.A. Yes Allograft ureter HGUC pT2 Diabetes mellitus Alive N.A. N.A. (+) 
14 Kenan et al. 2015 54 BKPyV Yes No Allograft renal pelvis HGUC with glandular differentiation pT3 with pTisNX Hypertensive nephropathy Alive N.A. N.A. (+) 
15 Yan et al. 2016 33 10 BKPyV Yes No UB HGUC with micropapillary features pT2bN0M1 Reflux nephropathy Died of metastasis (+) N.A. N.A. 
15 Yan et al. 2016 50 10 BKPyV Yes No UB/ureter HGUC with micropapillary features pT2aN0 Hypertensive nephropathy Alive (+) N.A. N.A. 
15 Yan 2016 31 18 BKPyV Yes Yes UB HGUC pT2NX Obstructive Alive (+) N.A. N.A. 
15 Yan et al. 2016 71 BKPyV No No UB HGUC with glandular differentiation pT2N0 Diabetes mellitus Alive (+) N.A. N.A. 
16 Kenan et al. 2017 62 BKPyV Yes Yes Allograft medulla to cortex HGUC with glandular differentiation pT1bN0M0 Diabetes mellitus Alive N.A. N.A. N.A. 
17 Sirohi et al. 2018 56 10 BKPyV Yes N.A. UB HGUC with sarcomatoid, signet ring cell pT3NX N.A. Died of metastasis N.A. (+) N.A. 
17 Sirohi et al. 2018 69 BKPyV N.A. N.A. Allograft collecting duct carcinoma pT1aN0 N.A. Died of unrelated causes N.A. (+) N.A. 
17 Sirohi et al. 2018 41 BKPyV N.A. N.A. Allograft collecting duct carcinoma pT3 ADPKD N.A. N.A. N.A. N.A. 
17 Sirohi et al. 2018 79 BKPyV Yes N.A. Ureter HGUC with sarcomatoid, micropapillary, glandular pT3NX N.A. Alive with disease N.A. (+) N.A. 
17 Sirohi et al. 2018 37 11 BKPyV Yes N.A. UB HGUC with micropapillary, glandular pT4aN1 Reflux nephropathy Alive N.A. (+) N.A. 
17 Sirohi et al. 2018 53 BKPyV No N.A. UB HGUC with micropapillary features pT3aN0 Hypertensive nephropathy Died of metastasis N.A. (-, null) N.A. 
17 Sirohi et al. 2018 69 11 BKPyV Yes N.A. UB HGUC with glandular differentiation pT3aNX IgA nephropathy Recurrence N.A. (wild type) N.A. 
17 Sirohi et al. 2018 42 BKPyV N.A. N.A. UB HGUC with glandular differentiation pT3aNX Diabetes mellitus Alive with disease N.A. (+) N.A. 
17 Sirohi et al. 2018 68 BKPyV Yes N.A. UB HGUC pT2aN0 ESRD Alive N.A. (+) N.A. 
18 Bertz et al. 2020 66 BKPyV N.A. N.A. UB/allograft HGUC with micropapillary features pT4 with pTisNX ESRD N.A. N.A. (+) N.A. 
18 Bertz et al. 2020 47 17 BKPyV No No UB HGUC with micropapillary features pT3 with pTisN0M1 ESRD Died of unrelated causes N.A. (+) N.A. 
18 Bertz et al. 2020 59 10 BKPyV N.A. N.A. Allograft renal pelvis HGUC with clear cell carcinoma pT2 with pTisNX ADPKD Died of metastasis N.A. (+) N.A. 
18 Bertz et al. 2020 44 18 BKPyV No No UB HGUC with villoglandular pattern pT1 with pTis IgA nephropathy Died of metastasis N.A. (+) N.A. 
19 Wang et al. 2020 57 BKPyV Yes Yes Allograft HGUC pTXM1 CKD Alive N.A. (+) N.A. 
19 Wang et al. 2020 61 BKPyV Yes Yes Allograft HGUC with glandular differentiation pT3N1 ADPKD Alive N.A. (+) N.A. 
19 Wang et al. 2020 76 12 BKPyV Yes Yes UB HGUC with glandular differentiation pT4N2M0 Lupus nephritis Died of metastasis N.A. (+) N.A. 
20 Chu et al. 2020, (n = 6) 62.0 (34–72) M/F = 4/2 11.1 (8.8–19.1) BKPyV Yes(6) Yes(5) UB(5)/allograft(1) HGUC(6) pT1(1)T2(2)T3(1)T4(2) N.A. Died of metastasis(3) 6/6 (+) 6/6 (+) N.A. 
23 Querido et al. 2019 57 JCPyV Yes Yes UB HGUC pT4M1 ESRD Died of metastasis (+) (+) N.A. 
★ The present case 69 BKPyV Yes Yes UB HGUC with micropapillary features pT1 with pTis ESRD Alive (+) (+) (+) 

F, female; M, male; BKPyV, BK polyomavirus; JCPyV, JC polyomavirus; HGUC, high-grade urothelial carcinoma; N.A., not available; UB, urinary bladder; UC, urothelial carcinoma; CKD, chronic kidney disease; ADPKD, autosomal dominant polycystic kidney disease; ESRD, end-stage renal disease; IgA, immunoglobulin A.

In polyomavirus-associated UC, BKPyV DNA has been reported to be integrated into the UC genome [14]. The breakpoint of the viral genome is nonrandom and tends to assemble with large and small T antigens [19]. In this case, BKPyV VP1 antigen was not detected by IHC; it might be because the breakpoint of the BKPyV genome is on the VP1 antigen as previously reported [16]. Large T antigen of BKPyV is translated and expressed in polyomavirus-associated UC. Large T antigen is thought to directly contribute to oncogenesis by binding to and inactivating p53 and pRB, resulting in inhibition of p53-mediated apoptosis and pRB-mediated cell cycle arrest. In UC genomes, the genes for p53, Rb, and p16 are not mutated, but compensatory overexpression of p53 and p16 in response to large T antigen was detected using immunohistochemistry [17, 18]. There have been few reports on comparison of the genomes of BKPyV in transplanted kidney tissue and UC tissue, so it is significant that we have demonstrated the same viral sequence between two polyomavirus nephropathy tissues and UC tissue.

We reported a case of BK polyomavirus-associated UC of the bladder after BKPyV nephropathy in a transplanted kidney. The same sequence of the BKPyV VP1 genome hypervariable region was detected in both transplanted kidney tissue with polyomavirus nephropathy and UC tissue, suggesting that polyomavirus-associated UC developed in a background of persistent polyomavirus nephropathy. Early detection of the cancer is important because of its rapidly progressive nature. We could manage the patient successfully with frequent urine cytology and cystoscopy when atypical cells were detected in the urine cytology. It is important to keep in mind that this cancer can develop early after transplantation in association with polyomavirus nephropathy.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. This study was approved by the Ethical Review Board of Sapporo City General Hospital (R03-060–901).

The authors have no conflicts of interest to declare.

There are no funding sources associated with this case report.

S.I., K.M., Y.F., and T.T. designed the study and prepared the manuscript. T.D., H.S., H.H., and Y.T. provided clinical information. K.T., H.K., and T.S. performed viral DNA and mRNA analysis.

The data that support the findings of this study are openly available.

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