Evidence of BK Polyomavirus Infection in Urothelial but not Renal Tumors from a Single Center Cohort of Kidney Transplant Recipients.

Emerging evidence indicates that reactivation of BK polyomavirus (BKPyV) in the kidney and urothelial tract of kidney transplant recipients (KTRs) may be associated with cancer in these sites. In this retrospective study of a single center cohort of KTRs (n = 1307), 10 clear cell renal cell carcinomas and 5 urinary bladder carcinomas were analyzed from 15 KTRs for the presence of BKPyV infection through immunohistochemistry and fluorescent in situ hybridization (FISH). Three of these patients had already exhibited biopsy-proven polyomavirus-associated nephropathies (PyVAN). Although the presence of BKPyV large-T antigen was evident in the urothelium from a kidney removed soon after PyVAN diagnosis, it was undetectable in all the formalin-fixed and paraffin-embedded (FFPE) blocks obtained from the 10 kidney tumors. By contrast, large-T antigen (LT) labeling of tumor cells was detected in two out of five bladder carcinomas. Lastly, the proportion of BKPyV DNA-FISH-positive bladder carcinoma nuclei was much lower than that of LT-positive cells. Taken together, our findings further strengthen the association between BKPyV reactivation and cancer development in KTRs, especially bladder carcinoma.

Can Epstein-Barr virus play a role in upper urinary tract urothelial carcinomas?

INTRODUCTION: Upper urinary tract urothelial carcinomas are very rare tumours with different biological behaviours. The Epstein-Barr virus, which is the first known oncogenic virus, is being investigated for various malignant tumours. It is known that this virus is associated with nasopharyngeal carcinoma, as well as multiple haematological malignancies, head and neck and gastric cancers. We aimed to determine the presence of the Epstein-Barr virus in upper urinary tract urothelial carcinomas using chromogenic in situ hybridisation (CISH). MATERIALS AND METHODS: A total of 44 upper urinary tract urothelial carcinomas from two different centres were included. Demographic data and survival rates were obtained from hospital records. One demonstrative paraffin block from each case was stained using Epstein-Barr encoded RNA (EBER) with an automated CISH procedure. The positivity of EBER was statistically analysed for prognostic factors. RESULTS: Among all patients, 38 were male and 6 were female. The mean age of the patients was 65.93 years. At the time of the study, 15 patients had died and 29 were alive. EBER-CISH positivity was found in 13 patients. Four showed strong EBER-CISH expression and nine showed weak expression. EBER-CISH positivity was not statistically related to any of the prognostic factors or to overall survival. DISCUSSION: Although EBER-CISH positivity showed no significant relation with prognostic factors, it was observed in one-third of all cases. Therefore, we think that the Epstein-Barr virus may have a role in the pathogenesis of upper urinary tract urothelial carcinomas. This finding needs to be supported by larger studies.

Targeting IL-11 in the treatment of BK virus-associated haemorrhagic cystitis-A promising new approach.

The BK polyomavirus (BKPyV) has pathogenic relevance especially in immunocompromised patients. No causal therapy has been established yet. Therefore, new therapeutic targets need to be identified in experimental studies. A 3D organotypic cell culture model with primary urothelial cells and fibroblasts was used as infection model. The detection of virus replication was performed with quantitative polymerase chain reaction (qPCR), and immunohistochemistry (IHC) was also used for analysis. Interleukin levels were measured by enzyme-linked immunosorbent assay (ELISA). Interestingly, the signal transducer and activator of transcription 3 (STAT3) pathway seems to be activated during infection with BKPyV, for example phosphorylated STAT3 is significantly (P < 0.0001) elevated on day 6 following infection. Therefore, we performed ELISAs for involved interleukins in STAT3 pathway. Interleukin 11 (IL-11) was significantly (P = 0.026) elevated at day 9. Subsequently, 3D cultures were treated with IL-11 neutralizing antibody. At day 9 following infection, the median virus replication rate is 4.4 × 106 copies/ml. The difference to replication rate without treatment was significantly lower at day 6 (P < 0.0001) and at day 9 (P < 0.0001), respectively. STAT3 pathways seem to be involved during BKPyV infection and need further investigation in experimental studies. A very promising target for treatment might be IL-11.

Glibenclamide inhibits BK polyomavirus infection in kidney cells through CFTR blockade.

BK polyomavirus (BKPyV) is a ubiquitous pathogen in the human population that is asymptomatic in healthy individuals, but can be life-threatening in those undergoing kidney transplant. To-date, no vaccines or anti-viral therapies are available to treat human BKPyV infections. New therapeutic strategies are urgently required. In this study, using a rational pharmacological screening regimen of known ion channel modulating compounds, we show that BKPyV requires cystic fibrosis transmembrane conductance regulator (CFTR) activity to infect primary renal proximal tubular epithelial cells. Disrupting CFTR function through treatment with the clinically available drug glibenclamide, the CFTR inhibitor CFTR172, or CFTR-silencing, all reduced BKPyV infection. Specifically, time of addition assays and the assessment of the exposure of VP2/VP3 minor capsid proteins indicated a role for CFTR during BKPyV transport to the endoplasmic reticulum, an essential step during the early stages of BKPyV infection. We thus establish CFTR as an important host-factor in the BKPyV life cycle and reveal CFTR modulators as potential anti-BKPyV therapies.

Bovine papillomavirus E5 oncoprotein upregulates parkin-dependent mitophagy in urothelial cells of cattle with spontaneous papillomavirus infection: A mechanistic study.

This study aimed to provide mechanistic insights into mitophagy pathway associated with papillomavirus infection in urothelial cells of cattle. The elimination of mitochondria via autophagy, termed mitophagy, is an evolutionarily conserved mechanism for mitochondrial quality control and homeostasis. PINK1/parkin-mediated mitophagy, a ubiquitin-dependent selective autophagy of dysfunctional mitochondria, has been described here, for the first time, in urothelial cells from 25 bladder cancers in cattle infected by bovine papillomavirus (BPV). The expression of BPV-2 and BPV-13 E5 oncoprotein was detected by RT-PCR. Abnormal mitochondria delimited by expanding phagophores, were peculiar ultrastructural features of neoplastic urothelial cells. High levels of mitochondrial phosphorylated PINK1/parkin were observed in neoplastic urothelial cells infected by BPVs. Phosphoparkin interacted with mitofusin 2 (Mfn2) and ubiquitin (Ub), which confirmed that Mfn2 is a parkin receptor at the mitochondrial level, where parkin interacted also with Ub. Furthermore, parkin established a complex that was comprised of optineurin, p62, LC3, laforin, and embryonic stem cell-expressed Ras (ERAS), that interacted with BPV E5 oncoprotein, and Bag3, which, in turn, regulated the formation of a complex composed of Hpc70/Hsp70, CHIP, an HSC70-interacting E3 ubiquitin ligase. It is conceivable that ERAS is involved in mitophagosome maturation via phosphatidylinositol 3-kinase (PI3K) pathway. Bag3, in association with Hsc70/Hsp70, may contribute to the transport and degradation of CHIP-ubiquitinated cargo as this complex recognises ubiquitinated cargos and transports them to aggresomes to be degraded. Furthermore, Bag3 may be involved in mitophagosome formation as it interacted with synaptopodin 2, which is known to play a role in mitophagosome biogenesis.

Novel 3D organotypic urothelial cell culture model for identification of new therapeutic approaches in urological infections.

PURPOSE: 3D organotypic cell cultures offer the possibility to study cell growth in a more in vivo like situation. To our knowledge no 3D culture of primary urothelial cells has been established yet. BK Polyomavirus (BKPyV), replicating in urothelial cells, may cause haemorrhagic cystitis in immunocompromised patients. PRIMARY ENDPOINTS OF THIS STUDY: Establishment of a 3D organotypic cell culture of primary urothelial cells and fibroblasts; use of this model as infection model for archetype BKPyV; description of first parts of viral life cycle with identification of therapeutic targets. METHODS: This is an experimental study. Primary urothelial cells were purchased from CellnTec, Bern, Switzerland; fibroblasts were isolated from the ureter of patients with no urothelial malignancy in their medical history. As main methods we used quantitative real-time PCR and immunohistochemistry. Outcomes were analysed using SPSS 23.0. RESULTS: We were able to develop a 3D organotypic culture for primary urothelium. An infection with archetype BKPyV was established in this model with virus replication rates up to 6.41 × 108 copies/ml on day 9 following Infection. Interestingly, proliferation rate of the urothelial cells is significantly (p = 0.049 at day 6 following infection) elevated while cells are losing differentiation under infection. Phosphorylated STAT3 is also significantly elevated (p < 0.0001) during infection. CONCLUSIONS: The established of urothelial 3D cultures is a new method to study several urothelial diseases. The archetype BKPyV infection model is novel and the first method to study archetype viral life cycle. The STAT3 pathway might be an interesting target for the development of a causal therapy.

FUNDC1-mediated mitophagy in bovine papillomavirus-infected urothelial cells.

E5 protein, the major oncoprotein of the bovine Deltapapillomavirus genus, has been detected in 17 of the 19 urothelial cancers by molecular and morphological procedures. In 10 urothelial cancers, the oxygen sensitive subunit HIF-1α, which is upregulated by hypoxia, was overexpressed. Mitophagy, the selective autophagic removal of dysfunctional mitochondria, was upregulated in hypoxic neoplastic cells infected by BPVs which was mediated by FUNDC1, a mitochondrial outer-membrane protein. The FUNDC1 receptor was amplified by PCR, and amplicon sequencing showed a 100% homology with bovine FUNDC1 sequences deposited in GenBank (accession number: NM_001104982). Both transcripts and protein levels of FUNDC1 were significantly decreased in hypoxic neoplastic cells relative to healthy, non-neoplastic cells. FUNDC1 interacted with the LC3 protein, a marker of autophagosome (mitophagosome) membrane, the Hsc70/Hsp70 chaperone, and Bag3 co-chaperone. Bag3 may play a role in mitophagosome formation together with the Synpo2 protein, and may be involved in the degradation of Hsc70/Hsp70-bound CHIP-ubiquitinated cargoes, in association with its chaperone. Ultrastructural findings revealed the presence of mitochondria exhibiting severe fragmentation and loss of cristae, as well as numerous mitochondria-containing autophagosomes. Total and phosphorylated GTPase dynamin-related protein 1 (DRP1), which plays a crucial role in mitochondrial fission, a pre-requisite for mitophagy, was overexpressed at the mitochondrial level. Total and phosphorylated mitochondrial fission factor (Mff), mitochondrial fission protein 1 (Fis1), mitochondrial dynamics 51 (MiD51), and MiD49, which are DRP1 receptors responsible and/or co-responsible for its mitochondrial recruitment were overexpressed.

Bovine papillomavirus E5 oncoprotein expression and its association with an interactor network in aggresome-autophagy pathway.

E5 protein, the major oncoprotein of bovine Deltapapillomavirus (BPV), was found to be expressed in 18 of 21 examined urothelial cancers of cattle. E5 oncoprotein was found to interact with p62 which was degraded through the autophagosome-lysosome pathway as well as LC3-II and appeared to be involved in the phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α). Autophagy was morphologically documented by transmission electron microscope (TEM) through the detection of double-membrane autophagosomes and autolysosomes. Overexpression of Bag3 known to mediate selective autophagy was also demonstrated. Furthermore, Bag3 and BPV E5 oncoprotein were seen to co-localize with dynein and 14-3-3γ, which suggested that Bag3 could be involved in inducing the retrograde transport of BPV E5 along microtubules to aggresomes, perinuclear sites with high autophagic flux. Electron dense perinuclear structures consistent with aggresomes were also documented by TEM in urothelial cancer cells. Finally, Bag3 was found to also interact with synaptopodin 2 (Synpo2), which would seem to contribute to cargo degradation as it has been shown to facilitate autophagosome formation. This study provides mechanistic insights into the potential role(s) of autophagy in BPV disease, which can help to develop future treatment and control measures for BPV infection. Activation of autophagy correlates positively with BPV infection and may play a role in biological behavior of bladder cancer as urothelial carcinomas of cattle are known to be characterized by a relatively low rate of metastasis.

Chaperone-assisted selective autophagy in healthy and papillomavirus-associated neoplastic urothelium of cattle.

Chaperone-assisted selective autophagy (CASA) is a newly-described selective tension-induced macroautophagy pathway mediated by Bag3 that is believed to be essential for mechanotransduction in skeletal muscle and to be an important regulator of the immune system. We investigated CASA machinery both in healthy and in fifteen papillomavirus-associated neoplastic bovine urothelium. The components of CASA complex, that comprises the molecular chaperones HspA8/Hsc70 and Hsp8B/Hsp22 and the cochaperones Bag3 and STUB1/CHIP, were studied by molecular, microscopic and submicroscopic investigations. CASA complex was found to be constitutively expressed in healthy bovine urothelium; its expression increased in urothelial cancers of cattle, namely thirteen papillary carcinomas and two papillary urothelial neoplasm of low malignant potential (PUNLMPs). We suggest that basal levels of CASA are important in the healthy urothelium which interfaces with the community of urinary microbiota thus representing an important epithelial cell-autonomous mechanism of antibacterial defense. Co-immunoprecipitation studies using an antibody against bovine papillomavirus E5 protein revealed that the oncoprotein co-localized with CASA complex in urothelial cancer cells. This suggests that infection by BPV E5 could influence cell behaviour by interfering with basal autophagy processes although this study did not conclusively show that this interaction increased the expression of CASA proteins. In neoplastic urothelium, CASA could be involved in regulating fundamental cellular processes such adhesion, migration, and proliferation and so might influence the biological behaviour of urothelial tumors in cattle.

Carcinoma of the urethra.

Primary carcinomas of the urethra are rare and poorly understood lesions; hence, their clinical and pathologic spectrum is not completely defined. We analyzed a series of 130 primary urethral tumors and classified 106 of them as primary urethral carcinomas. The age at diagnosis of patients with primary urethral carcinomas ranged from 42 to 97 years (mean, 69.4 years; median, 70 years). There were 73 male and 33 female patients with a ratio of 2.2:1. In male patients, the tumors most frequently developed in the bulbous-membranous segment of the urethra. In female patients, the entire length of the urethra was typically involved. Microscopically, they were poorly differentiated carcinomas with hybrid squamous and urothelial features and developed from precursor intraepithelial conditions such as dysplasia and carcinoma in situ, which were frequently present in the adjacent urethral mucosa. High-risk human papilloma virus infection could be documented in 31.6% of these tumors. Follow-up information was available for 95 patients. Twenty-three patients died of the disease with a mean and median survival of 39 and 21 months, respectively. Urethral carcinomas are aggressive tumors with a high propensity for regional and distant metastases with mean and median survival of 39 and 21 months, respectively. Our observations have important implications for the management of patients with primary carcinoma of the urethra by defining them as a unique entity linked to human papilloma virus infection.

DNA detection of JC and BK virus in archival urine cytospin slides.

To identify decoy cells, cytological examination was performed in urine cytospin slides. Decoy cells are related to Polyomaviruses (JC virus [JCV] and BK virus [BKV]), which are recognized worldwide due to potential infection and morbidity in kidney transplant recipients. Cytologically, it is difficult to evaluate the cytopathic effect of JCV and BKV in urine of patients with urothelial neoplasia. For this reason, there is a need for molecular approaches. To evaluate the incidence of BKV and JCV DNA in archival slides of urine cytospin material with benign and malignant characteristics. A total of 176 urine specimens were used for cytological examination of neoplastic or decoy cells. The samples were analyzed for the presence of JCV and BKV, by polymerase chain reaction (PCR) in DNA Isolated from archival slides of urine cytospin material. A typical samples (n = 48) were compared with the remaining 128 samples without atypia/neoplasia for the presence of JCV or BKV DNA. A statistically nonsignificant result was observed correlating the presence of JCV or BKV. The results show that DNA Isolated from archival slides of urine cytospin material can be used for detection of BKV and JCV.

Donor-derived, metastatic urothelial cancer after kidney transplantation associated with a potentially oncogenic BK polyomavirus.

BK polyomavirus has been linked to urothelial carcinoma in immunosuppressed patients. Here, we performed comprehensive genomic analysis of a BK polyomavirus-associated, metachronous, multifocal and metastatic micropapillary urothelial cancer in a kidney transplant recipient. Dissecting cancer heterogeneity by sorting technologies prior to array-comparative genomic hybridization followed by short tandem repeat analysis revealed that the metastatic urothelial cancer was of donor origin (4-year-old male). The top 50 cancer-associated genes showed no key driver mutations as assessed by next-generation sequencing. Whole genome sequencing and BK polyomavirus-specific amplification provided evidence for episomal and subgenomic chromosomally integrated BK polyomavirus genomes, which carried the same unique 17-bp deletion signature in the viral non-coding control region (NCCR). Whereas no role in oncogenesis could be attributed to the host gene integration in chromosome 1, the 17-bp deletion in the NCCR increased early viral gene expression, but decreased viral replication capacity. Consequently, urothelial cells were exposed to high levels of the transforming BK polyomavirus early proteins large tumour antigen and small tumour antigen from episomal and integrated gene expression. Surgery combined with discontinuation of immunosuppression resulted in complete remission, but sacrificed the renal transplant. Thus, this report links, for the first time, BK polyomavirus NCCR rearrangements with oncogenic transformation in urothelial cancer in immunosuppressed patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Zika virus infects renal proximal tubular epithelial cells with prolonged persistency and cytopathic effects.

Zika virus (ZIKV) infection can cause fetal developmental abnormalities and Guillain-Barré syndrome in adults. Although progress has been made in understanding the link between ZIKV infection and microcephaly, the pathology of ZIKV, particularly the viral reservoirs in human, remains poorly understood. Several studies have shown that compared to serum samples, patients' urine samples often have a longer duration of ZIKV persistency and higher viral load. This finding suggests that an independent viral reservoir may exist in the human urinary system. Despite the clinical observations, the host cells of ZIKV in the human urinary system are poorly characterized. In this study, we demonstrate that ZIKV can infect renal proximal tubular epithelial cells (RPTEpiCs) in immunodeficient mice in vivo and in both immortalized and primary human renal proximal tubular epithelial cells (hRPTEpiCs) in vitro. Importantly, ZIKV infection in mouse kidneys caused caspase-3-mediated apoptosis of renal cells. Similarly, in vitro infection of immortalized and primary hRPTEpiCs resulted in notable cytopathic effects. Consistent with the clinical observations, we found that ZIKV infection can persist with prolonged duration in hRPTEpiCs. RNA-Seq analyses of infected hRPTEpiCs revealed a large number of transcriptional changes in response to ZIKV infection, including type I interferon signaling genes and anti-viral response genes. Our results suggest that hRPTEpiCs are a potential reservoir of ZIKV in the human urinary system, providing a possible explanation for the prolonged persistency of ZIKV in patients' urine.

Archetype and Rearranged Non-coding Control Regions in Urothelial Bladder Carcinoma of Immunocompetent Individuals.

BACKGROUND: Polyomaviruses (PyVs) are potential transforming viruses. Despite their involvement in human tumours still being debated, there is evidence to suggest a role for PyVs in bladder carcinoma (BC). Therefore, a possible association between PyVs and BC was investigated. MATERIALS AND METHODS: Urine, blood and fresh bladder tissue specimens were collected from 29 patients with BC. PyV prevalence, non-coding control region (NCCR) organization and genotypic analysis were assessed. RESULTS: Data showed a significant prevalence of John Cunningham (JC) PyV in BC tissues and in urine with respect to BKPyV, while simian virus 40 was not revealed. A BKPyV rearranged NCCR sequence was isolated, whereas a JCPyV archetypal structure was consistently retained. A prevalence of European genotypes was observed. CONCLUSION: Our data would suggest a JCPyV involvement in cancer progression and a BKPyV association with BC pathogenesis in immunocompetent patients. However, further work is necessary to better understand the exact role of PyVs in urothelial carcinogenesis.

Mincle, an Innate Immune Receptor, Is Expressed in Urothelial Cancer Cells of Papillomavirus-Associated Urothelial Tumors of Cattle.

BACKGROUND: Mincle, macrophage-inducible C-type lectin, is a member of C-type lectin receptors. It plays an important role in anti-mycobacterial and anti-fungal immunity. Furthermore it senses dead cells through its primary ligand SAP130. MATERIALS AND FINDINGS: We examined ten urothelial tumors of the urinary bladder of cattle. Eight of them expressed E5 cDNA of bovine papillomaviruses type 2 (BPV-2) and type 13 (BPV-13) that belong to Deltapapillomavirus genus. Two of them were not examined for detection of E5 cDNA. Mincle expression appeared to occur in urothelial neoplastic cells only. No mincle expression was detected in urothelial cells from healthy cattle. Mincle expression was characterized by a membranous pattern in papillary urothelial cancers; isolated and/or clustered urothelial cells showing a strong cytoplasmic immunoreactivity were primarily seen in invasive urothelial cancers. CONCLUSION: This is the first study about the expression of mincle in veterinary oncology and the first report which describes the expression of functional mincle receptor in neoplastic cells in medical literature. As it has been shown that urothelial cancer cells have the ability to function as antigen-presenting cells (APCs), it is conceivable that mincle expression is involved in the presentation of cancer cell antigens to cells of the immune system. Furthermore, since expression of mincle contributes to the control of Mycobacterium bovis BCG infection, this study has exciting clinical implications in comparative medicine keeping in mind that Bacillus Calmette-Guérin (BCG) immunotherapy is currently the most effective treatment of non-muscle invasive bladder cancer in man. Mincle expression in urothelial tumor cells warrants further study to better understand the role, if any, of this receptor in bladder cancer. Future studies will provide insights in the role of mincle receptor of urothelial cancer cells in antitumor immunotherapy.

The oncogenic potential of BK-polyomavirus is linked to viral integration into the human genome.

It has been suggested that BK-polyomavirus is linked to oncogenesis via high expression levels of large T-antigen in some urothelial neoplasms arising following kidney transplantation. However, a causal association between BK-polyomavirus, large T-antigen expression and oncogenesis has never been demonstrated in humans. Here we describe an investigation using high-throughput sequencing of tumour DNA obtained from an urothelial carcinoma arising in a renal allograft. We show that a novel BK-polyomavirus strain, named CH-1, is integrated into exon 26 of the myosin-binding protein C1 gene (MYBPC1) on chromosome 12 in tumour cells but not in normal renal cells. Integration of the BK-polyomavirus results in a number of discrete alterations in viral gene expression, including: (a) disruption of VP1 protein expression and robust expression of large T-antigen; (b) preclusion of viral replication; and (c) deletions in the non-coding control region (NCCR), with presumed alterations in promoter feedback loops. Viral integration disrupts one MYBPC1 gene copy and likely alters its expression. Circular episomal BK-polyomavirus gene sequences are not found, and the renal allograft shows no productive polyomavirus infection or polyomavirus nephropathy. These findings support the hypothesis that integration of polyomaviruses is essential to tumourigenesis. It is likely that dysregulation of large T-antigen, with persistent over-expression in non-lytic cells, promotes cell growth, genetic instability and neoplastic transformation.

Simultaneous immunostaining with anti-S100P and anti-SV40 antibodies revealed the origin of BK virus-infected decoy cells in voided urine samples.

BACKGROUND: Methods for determining the origin of BK virus (BKV)-infected cells (decoy cells) in clinical urine samples have not been established although they could enhance the diagnosis of BKV infection in immunocompromised patients. METHODS: We performed simultaneous immunostaining with anti-S100P (a urothelial marker) and anti-SV40 antibodies in 66 clinical urine samples exhibiting SV40 positivity and a decoy-cell appearance on Papanicolaou staining. The clinical voided urine samples included seven cases of renal transplantation, 47 cases of cancer therapy and 12 cases of non-neoplastic disease. SurePath(™) liquid-based cytology was used for the urine samples. RESULTS: BKV-infected cells were categorized as SV40(+)/S100P(+) and SV40 (+)/S100p(-). SV40(+)/S100P(-) cells were found in 55 cases (83.4%); nine cases (13.6%) carried both SV40(+)/S100P(-) and SV40(+)/S100P(+) cells. The former were identified as BKV infection in renal tubules and the latter in both the renal tubules and urothelial epithelia. The remaining two cases (3.0%) had only SV40(+)/S100P(+) cells of urothelial origin. CONCLUSION: Simultaneous immunostaining with anti-S100P and anti-SV40 is a useful method for determining the origin of BKV-infected cells in clinical urine samples from immunocompromised patients such as renal transplantation recipients.

Human papillomavirus infection and pathogenesis in urothelial cells: a mini-review.

Several recent studies described that high-risk human papillomavirus (HPV) infection could have a potential role in the development of malignancies other than cervical cancer, such as laryngeal carcinoma, penile carcinoma, and anal carcinoma. However, the etiological role of HPV infection in the pathogenesis of urinary tract has not been clarified. Many epidemiological studies demonstrated that HPV infections frequently occur in the external genitalia through sexual contact; however, it was reported that HPV infection could also occur in the urinary tract, including the urethra and urinary bladder. Some morphological changes of cells associated with HPV infection and mild atypical cells, suspected to be intraneoplasia, were seen in HPV-positive samples obtained from the urinary tract. Some clinical studies and meta-analysis have indicated that HPV infection is likely to have a certain etiological correlation with the development of bladder carcinoma, although its prevalence may vary according to HPV type, study population, region, histological type, detection methods, and other variables. According to the results of previous studies, the prevalence of HPV greatly widely varies in cases of bladder carcinoma. Further research by case-control or large-scales studies is thus required to reach a more definite conclusion.

Complex of molecular genetic and immunohistochemical methods for detection of human papillomavirus in the bladder cancer epithelium.

A battery of tests for detection human papillomavirus DNA, mRNA corresponding to viral oncogenes, and viral oncoprotein E7 in cancer bladder urothelium was piloted in 35 samples of bladder cancer. DNA of human papillomavirus type 16 (causes cervical cancer) was found in 16 (46%) samples; E6/E7 oncogene transcript and E7 oncoprotein of human papillomavirus type 16 were detected in 10 and 7 human papillomavirus DNA-positive samples, respectively. These findings attest to association of bladder cancer with human papillomavirus in Russia.