Case of the Month - SV-40 Associated Invasive Urothelial Carcinoma

Authors
Deepika Sirohi, MD (Fellow) and Daniel J. Luthringer, MD (Faculty)

Subject: Urologic Pathology


Clinical History

66 year-old female, status post orthoptopic heart transplant 8 years ago for ischemic cardiomyopathy; presented with recent onset of urgency, frequency and dysuria of 6 weeks duration. She had multiple comorbidities significant amongst which were end stage renal disease and immunosuppressant therapy for heart transplant. Cystoscopic examination showed areas of papillary projections throughout the bladder and a transurethral resection was performed. For evaluation of end stage renal failure, a renal biopsy was performed 4 years ago.


Figures


Figure 1: H&E stain, 200x. High grade papillary urothelial carcinoma with villoglandular features


Figure 2: H&E stain, 200x. Urothelial carcinoma in situ


Figure 3: H&E stain, 100x and 200x. Invasive urothelial carcinoma with micropapillary features



Figure 4: H&E stain, 100x and 200x. Invasive urothelial carcinoma with signet ring cell features



Figure 5: H&E, 400x; SV40, 400x. Renal biopsy from 4 years ago, demonstrating characteristic viral cytopathic changes of polyoma virus with nuclear enlargement and basophilic ground glass appearance. SV40 immunostains shows nuclear positivity in lining renal tubular epithelial cells.



Figure 6: SV40, 100x. SV40 immunostains shows nuclear positivity in invasive and surface in situ urothelial carcinoma from the current transurethral resection specimen.


Diagnosis

SV-40 associated invasive urothelial carcinoma, high grade with elements of micropapillary carcinoma and signet ring (mucinous) differentiation arising in a background of urothelial carcinoma in situ and surface papillary carcinoma with features of villoglandular differentiation.


Discussion

Human polyomaviruses are unenveloped DNA viruses that include the BK, JC and SV40 viruses. Most individuals acquire the infection during childhood that persists in a latent form. Shedding of the virus in urine is frequently seen in immunosuppressive states such as after organ transplant, chemotherapy and HIV infection. It is commonly diagnosed by urine cytology with the characteristic viral cytopathic changes of enlarged nuclei with basophilic ground glass appearance. However, urine cytology also happens to be a common cause of diagnostic error as the viral cytopathic changes can mimic malignant urothelial cell.

Like many viruses, the role of BKV in oncogenesis has been postulated, with a putative role in urothelial carcinoma, ependymoma and mesothelioma. Studies have shown increased risk of urothelial carcinoma in renal transplant and BK viruric recipients with the latter cohort also showing a more rapid onset of malignancy. BK viruria, however is not always present. Literature review of reported cases of SV40 positive urothelial carcinomas occurring in post-transplant setting have been mostly high grade tumors with variant morphology, such as micropapillary or adenocarcinoma, presenting at high stage as seen in this case and have adverse outcomes.

It is thought that BKV reactivation promotes dysplastic changes in the urothelium, though by itself is not sufficient for oncogenic transformation due to continuous cell death associated with lytic viral replication. With passage of time and acquisition of other mutations, the uncoupling of early and late viral genes prevents virion assembly and promotes oncogenesis. The exact role of BKV in causation of urothelial carcinoma is uncertain at present and an alternate explanation is that the positivity could be a consequence rather than cause of neoplastic transformation with the replicating cells providing a better milieu for viral replication.


References
1. Roberts ISD, Besarani D, Mason P, Turner G, Friend PJ, Newton R. BK virus and bladder cancer in renal transplant recipients. British Journal of Cancer. 2008;99(9):1383 – 1386
2. Borislav A. Alexiev, Parmjeet Randhawa, Eduardo Vazquez Martul, Gang Zeng, Chunqing Luo, Emilio Ramos et al. BK virus–associated urinary bladder carcinoma in transplant recipients: report of 2 cases, review of the literature, and proposed pathogenetic model. Human Pathology. 2013; 44:908–917
3. Wang HH, Liu KL, Chu SH, Tian YC, Lai PC, Chaing YJ. BK virus infection in association with posttransplant urothelial carcinoma. Transplantation Proceedings. 2009; 41:165–166
4. Vajdic CM, McDonald SP, McCredie MR, van Leeuwen MT, Stewart JH, Law M et al. Cancer incidence before and after kidney transplantation. JAMA 2006;296:2823– 2831