HPV is implicated in bladder cancer

With state of the art detection techniques, human papillomavirus (HPV) has been detected in nearly 100% of cervical cancers. HPV infection is more common in smokers (and passive smokers) for non-causal socioeconomic reasons. This resulted in false blame of smoking due to confounding. Bovine papillomavirus is known to cause bladder cancer in cattle. It is possible that HPV can also cause bladder cancer in man.

High frequency of human papillomavirus detection in urinary bladder cancer. AM Agliano, A Gradilone, P Gazzaniga, M Napolitano, R Vercillo, L Albonici, G Naso, V Manzari, L Frati, A Vecchione. Urol Int 1994;53(3):125-129. In 46 transitional carcinomas and 10 non-neoplastic normal urinary samples, "HPV16 and/or HPV18 genomes were detected in 23 of 46 (50%) bladder carcinomas and in none of 10 (0%) non-neoplastic urinary samples."

Agliano - Urol Int 1994 abstract / PubMed

HPV and p53 in urinary bladder carcinoma. GP Mincione, L Messerini, C Saltutti, V Di Cello, A Dominici, E Giannelli, G Baroni, A Calzolari. Pathologica 1994 Jun;86(3):244-246. 1 if 18 urothelial carcinomas was positive for HPV type 31/33/51 and for p53 protein.

Mincione - Pathologica 1994 abstract / PubMed

Transitional cell carcinoma of the bladder: low incidence of human papillomavirus DNA detected by the polymerase chain reaction and in situ hybridization. A Lopez-Beltran, E Munoz. Histopathology 1995 Jun;26(6):565-569. "Of the 76 cases investigated, PCR analysis showed positive signals in seven (9.2%) of cases--six for HPV 16 DNA, and one for HPV 16 DNA and HPV 6 DNA. Four (5.2%) were also reactive for HPV 16/18 DNA using in situ hybridization."

Lopez-Beltran - Histopathology 1995 abstract / PubMed

Detection of human papillomavirus DNA sequences in cancer of the urinary bladder by in situ hybridisation and polymerase chain reaction. V Gopalkrishna, AN Srivastava, S Hedau, JK Sharma, BC Das. Genitourin Med 1995 Aug;71(4):231-233. One of 10 transitional cell carcinomas of the urinary bladder was positive for HPV 16 by ISH, and 2 were positive by PCR.

Gopalkrishna - Genitourin Med 1995 abstract / PubMed

Presence of human papilloma virus in transitional cell carcinoma in Jewish population in Israel. Z Smetana, T Keller, S Leventon-Kriss, M Huszar, A Lindner, S Mitrani-Rosenbaum, E Mendelson, S Smetana. Cell Mol Biol (Noisy-le-grand) 1995 Dec;41(8):1017-1023. "HPV capsid antigen was demonstrated in 19 out of 110 cases (17.3%). HPV-DNA sequences, determined by in situ DNA-DNA hybridization at high stringency wash were present in 24 cases (21.8%). 16(14.5%) cases proved to be HPV6/11 and 8 (7.3%) were HPV 16/18 positive. Four (3.6%) of the HPV 6/11 positive specimens cross hybridized with HPV 31/33/35 at low stringency conditions. Sixteen samples known to be positive by in situ hybridization were reconfirmed by polymerase chain reaction (PCR). When the PCR was performed on the 43 negative cases, an additional 4(9.3%) HPV positive cases were revealed: two proved to be HPV 6/11 and two HPV 16/18."

Smetana - Cell Mol Biol (Noisy-le-grand) 1995 abstract / PubMed

Human papillomavirus infection and transitional cell carcinoma of the bladder. Immunohistochemistry and in situ hybridization. A Lopez-Beltran, AL Escudero, JC Carrasco-Aznar, L Vicioso-Recio. Pathol Res Pract 1996 Feb;192(2):154-159. "25 (32.8%) out of 76 bladder carcinoma specimens reacted with HPVcAg. Twelve (15.7%) out of 76 cases were positive for HPV 16/18-DNA using non-isotopic in situ hybridization. Sixteen cases had koilocytosis. No positive signals were found for HPV 6/11 or 31/33/35-DNA probes."

Lopez-Beltran - Pathol Res Pract 1996 abstract / PubMed

The aetiological significance of human papillomavirus in bladder cancer. NR Boucher, JH Scholefield, JB Anderson. Br J Urol 1996 Dec;78(6):866-869. "Fifty-five formalin-fixed, paraffin-embedded bladder tumour specimens were analysed for the presence of HPV infection using Southern blotting DNA hybridization and radiolabelled probes for HPV DNA types 6/11 and 16. RESULTS: Despite the detection of HPV DNA type 6, 11 and 16 in positive control samples and the successful detection of HPV DNA in anogenital cancer using the same technique, no HPV DNA was found in any of the bladder tumour specimens examined."

Boucher - Br J Urol 1996 abstract / PubMed

Detection and typing of human papillomavirus in cervical cancer in the Thai. P Bhattarakosol, A Poonnaniti, S Niruthisard. J Med Assoc Thai 1996 Dec;79 Suppl 1:S56-S64. By PCR using L1-consensus primers, "82 out of 100 (82%) samples were positive for HPV-DNA. Among the positive samples, 50 samples (61%) were typed by dot hybridization technique (DH). HPV-16 was the dominant type (42.68%), followed by HPV-18 (20.73%) and HPV-33 (3.66%). There were double infection of HPV-16 and 18 in 5 (6.1%) samples. None of HPV-6 and 11 were detected in this study."

Bhattarakosol - J Med Assoc Thai 1996 abstract / PubMed

Transitional cell and uncommon urothelial carcinoma of renal pelvis/ureter and bladder: low incidence of human papilloma virus. JS Wang, HH Tseng, SL Lin, SP Hsieh. Zhonghua Yi Xue Za Zhi (Taipei) 1997 Mar;59(3):151-157. By ISH, 3 of 8 bladder SCCs were positive for HPV, two of which were actually cervical cancer invasions. "HPV was not detected in any of the 51 bladder TCC, 48 renal pelvic/ ureter TCC, 5 bladder adenocarcinoma, 3 bladder small cell carcinoma, and 2 bladder undifferentiated carcinoma."

Wang - Zhonghua Yi Xue Za Zhi (Taipei) 1997 abstract / PubMed

Human papillomavirus 16 and 18 infection is absent in urinary bladder carcinomas. QL Lu, el-N Lalani, P Abel. Eur Urol 1997;31(4):428-432. "Thirty-one samples of formalin-fixed paraffin-embedded bladder carcinomas (4 adenocarcinomas, 5 squamous cell and 22 transitional cell carcinomas) were examined using non-isotopic ISH with biotin-labelled DNA probes of HPV 16 and 18 subtypes;" none were positive.

Lu - Eur Urol 1997 abstract / PubMed

Human papillomavirus and schistosomiasis associated bladder cancer. K Cooper, Z Haffajee, L Taylor. Mol Pathol 1997 Jun;50(3):145-148. "Twenty five archival samples of bladder squamous cell carcinoma associated with Schistosoma haematobium were subjected to non-isotopic in situ hybridisation and the polymerase chain reaction for the detection of human papillomavirus 6, 11, 16, 18, 31, and 33 genotypes. RESULTS: Using these two techniques, none of the 25 cases was shown to harbour human papillomavirus DNA."

Cooper - Mol Pathol 1997 full article / PubMed Central

A review of more than 27 laboratory/clinical studies of bladder cancer in the general population (A Lopez-Beltran, AL Escudero. Human papillomavirus and bladder cancer. Biomed & Pharmacother 1997;51(6-7):252-257) found high-risk HPV DNA in from 2.5% to 81% of cancers, with HPV-16 the most common. It was found in both papillary and invasive cancers.

Lopez-Beltran - Biomed Pharmacother 1997 abstract / PubMed

Prevalence of six types of human papillomavirus in inverted papilloma and papillary transitional cell carcinoma of the bladder: an evaluation by polymerase chain reaction. KW Chan, KY Wong, G Srivastava. J Clin Pathol 1997 Dec;50(12):1018-1021. In 10 inverted papillomas and 20 papillary transitional cell carcinomas, "HPV type 18 was found in 60% and 30% of cases of inverted papilloma and papillary transitional cell carcinoma of the bladder, respectively. These tumours were rarely associated with HPV types 6, 11, 16, 31, and 33."

Chan - J Clin Pathol 1997 full article / PubMed Central

Lack of evidence for a role of human papillomaviruses in transitional cell carcinoma of the bladder. O Aynaud, P Tranbaloc, G Orth. J Urol 1998 Jan;159(1):86-9; discussion 90. "HPV-6 DNA was detected in the condylomatous tumor. However, no HPV DNA was detected in the 57 bladder cancers by Southern blot hybridization and polymerase chain reaction."

Aynaud - J Urol 1998 abstract / PubMed

Prevalence of papillomavirus, Epstein-Barr virus, cytomegalovirus, and herpes simplex virus type 2 in urinary bladder cancer. P Gazzaniga, R Vercillo, A Gradilone, I Silvestri, O Gandini, M Napolitano, L Giuliani, A Fioravanti, M Gallucci, AM Agliano. J Med Virol 1998 Aug;55(4):262-267). EBV and HPV were each found in about one-third of 35 biopsies, and 20% had more than one viral infection. "To our knowledge, this is the first report concerning the association of EBV, CMV and HSV-2 with bladder cancer. This finding may raise the question of whether such viral infection may contribute to development and progression of some types of urological malignancies in humans."

Gazzaniga - J Med Virol 1998 abstract / PubMed

Detection of human papillomavirus DNA in urinary bladder carcinoma by in situ hybridisation. C De Gaetani, G Ferrari, E Righi, S Bettelli, M Migaldi, P Ferrari, GP Trentini. J Clin Pathol 1999 Feb;52(2):103-106. "HPV DNA was identified by the in situ hybridisation technique in 17 of 43 cases of bladder cancer; 12 of these were serum antibody positive and 10 had had multiple biopsies. Fifteen of the cases that were negative for HPV DNA by in situ hybridisation had positive serum serology when tested by ELISA. In 14 cases, the HPV was either types 16/18 or types 31/33/35, both of which carry high oncogenic risk." Discussion of methodologies: The rates of HPV detection in bladder cancer vary widely because no single ideal method has been determined yet. Southern blotting can be confused by viral DNA deletions and rearrangements. In situ hybridization (ISH) keeps the tissue architecture intact and can demonstrate infection in specific cells; its detection rate depends upon the specificity of the probes used. Some studies found HPV only in inactive episomal form, suggesting that its presence was only coincidental, while others found active transcription. "Some of the discrepancies reported in the literature on the association of HPVs to bladder cancer have been considered to be related to geographical differences, DNA preparation and amplification, as well as sample fixation." Serum antibodies to HPV by enzyme linked immunosorbent assay (ELISA) have been compared by various cancers. Such studies may suffer from high rates of both false positives and false negatives. HPV can also be missed simply because the biopsy didn't get the right spot.

De Gaetani - J Clin Pathol 1999 abstract / PubMed
De Gaetani / J Clin Pathol 1999 Full Article (pdf, 5pp)
De Gaetani - J Clin Pathol 1999 Full Article / PubMed Central

Human papillomavirus associated with bladder carcinoma? Analysis by polymerase chain reaction. MI Tekin, S Tuncer, FT Aki, CY Bilen, C Aygun, H Ozen. Int J Urol. 1999 Apr;6(4):184-186. 2/42 fresh biopsy specimens (4.8%) were positive for HPV 16 or 18.

Tekin - Int J Urol. 1999 abstract / PubMed

Low frequency of human papillomavirus infection in initial papillary bladder tumors. M Simoneau, H LaRue, Y Fradet. Urol Res 1999 Jun;27(3):180-184. "We investigated a total of 187 newly diagnosed superficial papillary bladder tumors for the presence of L1-HPV DNA by the polymerase chain reaction method and hybridization with specific probes for HPV 6, 11, 16, 18, 33. HPV DNA was detected in 16 (8.5%) of the 187 specimens tested, although in a low copy number compared with SiHa cervical cancer cells used as control. HPV type 16 was observed in eight tumors while HPV type 6 and type 11 were each observed in three tumors. Two tumor specimens contained two types of HPV: one tumor hybridized with type 6 and 16 and the other with type 11 and 18."

Simoneau - Urol Res 1999 abstract / PubMed

[The detection of high risk human papillomaviruses in papillary transitional cell carcinoma of urinary bladder.] Z Yu, T Xia, Z Xue. Zhonghua Wai Ke Za Zhi 1999 Jun;37(6):369-371. 36.5% of 52 cases were HPV-positive.

Yu - Zhonghua Wai Ke Za Zhi 1999 abstract / PubMed

[The study on relation of human papillomavirus and P53 expression with bladder transitional cell carcinoma]. T Chen, QS Kong, H Cao, MY Yi, XZ Li, W Zhu, CP Liu, CW Shan. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2000 Dec;14(4):345-348. 75 cases. "The positive rates of HPV types 6, 11, 16 and 18 were 6.7%, 5.3%, 33.3% and 6.7%, respectively. The positive rate of low risk HPV type (6/11) was 9.3% (7/75), and that of high risk HPV types (16/18) was 34.7% (26/75). There were 8 cases with two or three HPV types mixed infection, accounting for 10.6%, HPV types 6,11,16,18 in tumor metastasis group were significantly higher than that in non-metastasis group. The positive rates of HPV 16, 18 types in G3 were significantly higher than that in G1 and G2. HPV type 16 was the main type in bladder cancer. Positive rate of P53 expression was 44%."

Chen - Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 2000 abstract / PubMed

Investigation of human papillomavirus in transitional cell carcinomas of the urinary bladder in South Africa. M Sur, K Cooper, U Allard. Pathology 2001 Feb;33(1):17-20. In 91 archival samples of bladder transitional cell carcinoma, 1 was positive by PCR and 0 by non-isotopic in situ hybridisation (NISH), for HPV types 6, 11, 16, 18, 31, and 33.

Sur - Pathology 2001 abstract / PubMed

Human papilloma virus infection and overexpression of p53 protein in bilharzial bladder cancer. HM Khaled, A Raafat, N Mokhtar, AR Zekri, H Gaballah. Tumori 2001 Jul-Aug;87(4):256-261. 46% of 52 cases were positive for HPV.

Khaled - Tumori 2001 abstract / PubMed

Human papillomavirus 6/11, 16/18 and 31/33/51 are not associated with squamous cell carcinoma of the urinary bladder. PJ Westenend, JA Stoop, JG Hendriks. BJU Int 2001 Aug;88(3):198-201. 0/16 were positive for HPV.

Westenend - BJU Int 2001 abstract / PubMed

p53 codon 72 polymorphism and its association with bladder cancer. N Soulitzis, G Sourvinos, DN Dokianakis, DA Spandidos. Cancer Lett 2002 May 28;179(2):175-183. HPV was found in 6/50 patients.

Soulitzis - Cancer Lett 2002 abstract / PubMed

Correlation between p53 mutations and HPV in bilharzial bladder cancer. HM Khaled, AA Bahnassi, AR Zekri, HA Kassem, N Mokhtar. Urol Oncol 2003 Sep-Oct;21(5):334-341. In 99 cases of bilharzial bladder cancer [BBC] in Egypt, "HPV-DNA was detected in 48.97% of the cases the majority of which [64.6%] were of type 16."

Khaled - Urol Oncol 2003 abstract / PubMed

Does human papillomavirus play a role in the development of bladder transitional cell carcinoma? A comparison of PCR and immunohistochemical analysis. S Youshya, K Purdie, J Breuer, C Proby, MT Sheaf, RT Oliver, S Baithun. J Clin Pathol 2005 Feb;58(2):207-210. "The two methods produced contrasting results, with 47 of the 78 samples positive for HPV antigen and none positive for HPV DNA. HPV DNA was not detected in the 20 additional paraffin wax embedded TCCs or in the 20 paired unfixed samples. In contrast, HPV DNA was amplified by PCR from all six of the paraffin wax embedded cervical carcinoma and anogenital wart control samples."

Youshya - J Clin Pathol 2005 full article / PubMed Central

Sensitive detection of human papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies. H Yang, K Yang, A Khafagi, Y Tang, TE Carey, AW Opipari, R. Lieberman, PA Oeth, W Lancaster, HP Klinger, AO Kaseb, A. Metwally, H Khaled, DM Kurnit. PNAS 2005 May 24;102(21):7683-7688. HPV 16/18 was detected in 27/27 schistosomiasis-associated bladder cancers. HPV was found in only 2/10 patients with schistosomiasis infection but without cancer.

Yang / PNAS 2005 full article

Correlation between human papillomavirus infection and bladder transitional cell carcinoma. MR Barghi, A Hajimohammadmehdiarbab, SM Moghaddam, B Kazemi. BMC Infect Dis 2005 Nov 8;5:102. In bladder tissue specimens of 59 patients with transitional cell carcinoma of bladder compared with 20 bladder samples of cases with non-neoplastic disorders by PCR, "HPV DNA was detected in 21 (35.6%) samples, while it was present in only one sample (5%) in the control group (P = 0.008). HPV18 was the most common type of virus with the incidence rate of 17/21(81%)."

Barghi / BMC Infect Dis 2005 full article
Barghi - BMC Infect Dis 2005 full article / PubMed Central

Association of human herpesvirus type 6 DNA with human bladder cancer. AL Escudero, RJ Luque, A Quintero, J Alvarez-Kindelan, MJ Requena, R Montironi, A Lopez-Beltran. Cancer Lett 2005 Dec 8;230(1):20-24. "HHV-6 type B DNA was present in 5 men (6.8%) out of the 74 tumors investigated; two of them had associated HPV-16 DNA in the same specimen. In one case that had associated urothelial carcinoma in situ, both HHV-6B and HPV-16 DNA were present."

Escudero - Cancer Lett 2005 abstract / PubMed

Human papilloma virus and p53 expression in bladder cancer in Egypt: relationship to schistosomiasis and clinicopathologic factors. A Helal Tel, MT Fadel, NK El-Sayed. Pathol Oncol Res 2006;12(3):173-178. 64/114 (56.1%) tumors were schistosomiasis-associated, 1 of which was positive for HPV 16/18.

Helal - Pathol Oncol Res 2006 abstract / PubMed

Meta-analysis of studies analyzing the relationship between bladder cancer and infection by human papillomavirus. J Gutiérrez, A Jiménez, J de Dios Luna, MJ Soto, A Sorlózano. J Urol. 2006 Dec;176(6 Pt 1):2474-81; discussion 2481. Meta-analysis of 44 observational studies published until July 2005. "In 39 studies the investigators determined the presence of human papillomavirus DNA, and found a prevalence of between 0% and 100% and significant homogeneity analysis (p <0.001). Pooled estimation of the presence of the infection was 16.0% (95% CI 12.8 to 19.1). Pooled OR estimation was 2.3 (95% CI 1.3 to 4.1) with no significant publication bias. In 7 studies human papillomavirus infection was studied by detecting the antigen or antibodies and a prevalence of between 14% and 60% was found with significant homogeneity analysis (p <0.001). Pooled estimation of the prevalence of infection was 32.4% (95% CI 17.0 to 47.8). Pooled OR estimation was 2.9 (95% CI 1.7 to 5.3). CONCLUSIONS: Finding a relationship between bladder cancer and human papillomavirus depends on the method used. In the literature examined there are insufficient cases and samples compared to controls and studies rely on a combination of various microbiological techniques in the same patient and sample, making it difficult to draw any definite conclusion."

Gutiérrez - J Urol 2006 abstract / PubMed

Human papilloma virus DNA and p53 mutation analysis on bladder washes in relation to clinical outcome of bladder cancer. PM Moonen, JM Bakkers, LA Kiemeney, JA Schalken, WJ Melchers, JA Witjes. Eur Urol 2007 Aug;52(2):464-468. In 107 pateints, "The prevalence of all-type and high-risk HPV infection in malignancies of the bladder was 15.2% and 8.1%, respectively. In high-grade tumours this prevalence was 18.2% and 10.6%, respectively. In grade 1, 2 and 3 tumours the infection rate of high-risk HPV types was 0%, 3.3%, and 10.6%, respectively (trend test: p=0.221)."

Moonen - Eur Urol 2007 abstract / PubMed

Role of human papillomavirus types 16, 18, and 52 in recurrent cystitis and urinary bladder cancer among Egyptian patients. H Badawi, H Ahmed, A Ismail, M Diab, M Moubarak, A Badawy, M Saber. Medscape J Med 2008;10(10):232. 20 bladder cancer patients, 24 with recurrent cystitis, 16 with both bladder cancer and cystitis, and 20 healthy controls. HPV-16 and HPV-18 DNA was detected in 44.1% of bladder cancer cases versus 11.1% of cystitis cases. "There was a significant association of transitional cell carcinoma (TCC) with HPV-16 in 69.2% and 61.1%" by serology and bladder tissue biopsies, respectively. "Multiple HPV types 16, 18, and 52 were significantly higher than single types (79.2% and 20.8%, respectively)."

Badawi - Medscape J Med 2008 full article / PubMed Central

[Detection of oncoprotein E7 HPV16 in the cancer and normal urinary bladder urothelium]. GM Volgareva, LE Zavalishina, DA Golovina, IuIu Andreeva, VD Ermilova, NL Cheban, DA Kuevda, OB Trofimova, O Shipulina, LS Pavlova, AN Petrov, VB Matveev, AA Shtil', GA Frank. Arkh Patol 2009 Jan-Feb;71(1):29-30. "Oncoprotein E7 HPV16 was detected by immunohistochemical staining with specific polyclonal antiserum [Fiedler et al., 2004] in 7 out of the 24 (29.2%) studied bladder cancer specimens."

Volgareva - Arkh Patol 2009 abstract / PubMed

Koilocytosis: correlations with high-risk HPV and its comparison on tissue sections and cytology, urothelial carcinoma. S Aggarwal, VK Arora, S Gupta, N Singh, A Bhatia. Diagn Cytopathol 2009 Mar;37(3):174-177. High risk HPV was found in 14 of 33 (42%) bladder carcinomas. 11 of 13 specimens with koilocytosis were HPV-positive.

Aggarwal - Diagn Cytopathol 2009 abstract / PubMed

Investigation of human papillomavirus in bladder cancer in a series of Tunisian patients. W Ben Selma, S Ziadi, R Ben Gacem, K Amara, F Ksiaa, M Hachana, M Trimeche. Pathol Res Pract 2010 Nov 15;206(11):740-743. None of 119 urothelial carcinomas, five squamous carcinomas, and one adenocarcinoma of the bladder were positive for HPV by any of three PCR primers. "[H]owever, the question of whether other subtypes of HPV contribute to bladder carcinogenesis remains to be clarified."

Ben Selma - Pathol Res Pract 2010 abstract / PubMed

Human papillomavirus and non-muscle invasive urothelial bladder cancer: potential relationship from a pilot study. T Cai, S Mazzoli, F Meacci, G Nesi, P Geppetti, G Malossini, R Bartoletti. Oncol Rep 2011 Feb;25(2):485-489. "HR-HPV DNA in tissue was found in 27 of 78 (34.6%) tumour samples and in 6 of 59 (10.1%) specimens from TUR-P, with a statistically significant difference (p=0.0009; dF=1; χ2=10.98). HR-HPV DNA in urine was found in 36 of 78 (46.1%) samples obtained from patients, whereas in only 8 of 59 (13.5%) samples from controls (p<0.0001: dF=1; χ2=16.37). A statistical significant difference in terms of HR-HPV frequency between high-grade and low-grade urothelial bladder cancer, was found (p=0.032; RR=0.52-95% CI 0.27-0.93; OR=0.34-95% CI 0.13-0.90)."

Cai - Oncol Rep 2011 abstract / PubMed

Epidermal growth factor receptor expression in urinary bladder cancer. DS Naik, S Sharma, A Ray, S Hedau. Indian J Urol 2011 Apr;27(2):208-214. 30 urothelial carcinomas. "No cases were positive for HPV-18, whereas HPV-16 was detected in 10% cases." Those two types were the only ones sought.

Naik - Indian J Urol 2011 full article / PubMed Central
Naik / Indian J Urol 2011 full article

Etiologic role of human papillomavirus infection in bladder carcinoma. K Shigehara, T Sasagawa, S Kawaguchi, T Nakashima, M Shimamura, Y Maeda, H Konaka, A Mizokami, E Koh, M Namiki. Cancer 2011 May 15;117(10):2067-2076. "HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6-45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2-17.0) were associated with HPV infection. ISH analysis indicated that high-risk HPV DNA was localized in the nuclei of tumor cells of all HPV-positive samples. p16-INK4a and mcm-7 were expressed in 94% and 89% of HPV-positive carcinoma cells, respectively. HPV-L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma."

Shigehara - Cancer 2011 abstract / PubMed

Association between urothelial carcinoma after renal transplantation and infection by human papillomavirus types 16 and 18. J Xiao, X Zhu, GY Hao, YC Zhu, LL Ma, YH Zhang, Y Tian. Transplant Proc 2011 Jun;43(5):1638-1640. 90 cases of urothelial carcinoma among 3780 patients, compared to 30 nontransplanted patients with bladder cancer. "Seven transplanted patients were HPV positive: HPV-16 was detected in 3 patients with bladder cancer (3/90; 3.3%), and HPV-18 in 2 patients with bilateral pelvic ureteral carcinoma (2/90; 2.2%), and 2 patients with bladder cancer (2/90; 2.2%). Only 2 cases from the control group were HPV positive (both HPV-18; 2/30; 5%). The difference between the RTR and control groups was not significant (P > .05)."

Xiao - Transplant Proc 2011 abstract / PubMed

Human Papillomavirus Infection and Bladder Cancer Risk: A Meta-analysis. N Li, L Yang, Y Zhang, P Zhao, T Zheng, M Dai. J Infect Dis 2011 Jul;204(2):217-223. "The prevalence of HPV in bladder cancer was estimated by pooling data from 52 studies, taking into consideration the heterogeneity from major related parameters including study region, histological type, HPV DNA specimen, publication calendar period, and detection method. Moreover, the association of HPV infection with bladder cancer was tested by a meta-analysis with 19 case-control studies. Results. An HPV prevalence of 16.88% (95% confidence interval [CI], 15.53%-18.31%) among the bladder cancer cases was revealed, most of whom were high-risk HPV types (15.82% [95% CI, 14.37%-17.36%]). The prevalence varied by region, types of HPV DNA specimen, and polymerase chain reaction primers used. A significantly increased risk of bladder cancer was shown for the positivity of overall HPV (odds ratio, 2.84 [95% CI, 1.39-5.80]), which was also influenced by HPV type, study region, HPV DNA specimen, and detection method."

Li - J Infect Dis 2011 abstract / PubMed

Role of human papillomavirus in the development of urothelial carcinoma. D Yavuzer, N Karadayi, T Salepci, H Baloglu, A Bilici, D Sakirahmet. Med Oncol 2011 Sep;28(3):919-923. None of 70 urothelial bladder carcinoma tissues were positive for HPV by nested PCR. Types tested for were not specified in the abstract.

Yavuzer - Med Oncol 2011 abstract / PubMed

Role of viruses in renal cell carcinoma. M Salehipoor, A Khezri, A Behzad-Behbahani, B Geramizadeh, M Rahsaz, M Aghdaei, MA Afrasiabi. Saudi J Kidney Dis Transpl 2012 Jan;23(1):53-57. 49 patients with RCC. "7 of 49 (14.29%) RCC tissue specimens had HPV DNA compared with none of 16 non-cancer control subjects. Regarding the HPV types, all the positive results were high-risk HPV types (type 16 in three and 18 in four patients)."

Salehipoor / Saudi J Kidney Dis Transpl 2012 full article landing

Association between the Evidence of Human Papilloma Virus Infection in Bladder Transitional Cell Carcinoma in Men and Cervical Dysplasia in their Spouses. MR Barghi, T Rahjoo, M Borghei, SM Hosseini-Moghaddam, D Amani, B Farrokhi. Arch Iran Med 2012 Sep;15(9):572-574. 82 male patients with bladder tumors and their spouses. "In 24 (29.3%) men, bladder tumor samples were positive for HPV infection. Of these, we found HPV-18 infection in 9 (37.5%), while 3 (12.5%) were infected with HPV-16. In the spouses of those men with HPV-infected bladder tumors, 4 (4.9%) cases had cellular dysplasia noted on their Pap smear tests. We found no dysplasia in those women whose husbands had bladder TCC, but no HPV infection (P = 0.006)."

Barghi - Arch Iran Med 2012 abstract - PubMed

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. RE Alexander, Y Hu, JB Kum, R Montironi, A Lopez-Beltran, GT Maclennan, MT Idrees, RE Emerson, TM Ulbright, DG Grignon, JN Eble, L Cheng. Mod Pathol 2012 Nov;25(11):1526-1533. "HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation."

Alexander - Mod Pathol 2012 abstract / PubMed

High-risk human papillomavirus DNA detected in primary squamous cell carcinoma of urinary bladder. JR Chapman-Fredricks, M Cioffi-Lavina, MA Accola, WM Rehrauer, MT Garcia-Buitrago, C Gomez-Fernandez, P Ganjei-Azar, M Jordŕ. Arch Pathol Lab Med 2013 Aug;137(8):1088-1093. 14 cases of primary bladder SCC. "Detection of HR-HPV by the in situ hybridization method was negative in all cases (0 of 14). However, in 3 of 14 cases (21.4%), the presence of HR-HPV DNA was detected with the Cervista HPV HR Invader assay, which was followed by identification of genotype." 2 were HPV 16 and one was HPV 35.

Chapman-Fredricks - Arch Pathol Lab Med 2013 abstract / PubMed

Human papillomavirus detection in Moroccan patients with bladder cancer. N Berrada, A Al-Bouzidi, A Ameur, M Abbar, M El-Mzibri, R Ameziane-El-Hassani, L Benbacer, M Khyatti, Z Qmichou, S Amzazi, M Attaleb. J Infect Dev Ctries 2013 Aug 15;7(8):586-592. 43 bladder tumors and 5 non-tumor samples. "52.4% of bladder cancer patients were positive for HPV. Subsequent DNA sequencing of positive cases of HPV revealed the presence of HPV16 in 95.5% of bladder tumor samples."

Berrada / J Infect Dev Ctries 2013 full article landing

Etiological correlation of human papillomavirus infection in the development of female bladder tumor. K Shigehara, S Kawaguchi, T Sasagawa, K Nakashima, T Nakashima, M Shimamura, M Namiki. APMIS 2013 Dec;121(12):1169-1176. 84 fenale patients. "HPV-DNA was detected in 5 (6.0%) of 84 eligible patients, and HPV16 was detected in 3 patients, and HPV6 and HPV52 was detected in one case, respectively. HPV-DNA was detected frequently in younger patients and in patients with a history of cervical cancer. In four high-risk HPV-positive cases, high-risk HPV-DNA was present in tumor tissues, and p16-INK4a was expressed moderately or strongly. Two cases had a past history of cervical cancer. In these 2 cases, the same HPV type (HPV16) was detected from bladder tumor and cervical cancer. High-risk HPV-DNA ISH signals and p16-INK4A expression were also detected widely in these cervical cancer tissues."

Shigehara - APMIS 2013 abstract / PubMed

Complex of molecular genetic and immunohistochemical methods for detection of human papillomavirus in the bladder cancer epithelium. DA Golovina, OB Trofimova, VD Ermilova, VB Matveev, GM Volgareva. Bull Exp Biol Med 2014 May;157(1):70-73. HPV16 was found in 16 (46%) of 35 bladder cancer 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."

Golovina - Bull Exp Biol Med 2014 abstract / PubMed

Genotyping of high-risk human papillomaviruses in p16/Ki-67-positive urothelial carcinoma cells: even a worm will turn. AS Advenier, JS Casalegno, Y Mekki, M Decaussin-Petrucci, F Mčge-Lechevallier, A Ruffion, E Piaton. Cytopathology 2015 Apr;26(2):106-113. 50 patients. "Co-expression of p16/Ki-67 was noted in 43 of 57 (75.4%) cases. In these, hr-HPVs 16, 31 and 70, and low risk HPV 84, were detected in the urine in four patients (8%). Upregulation of p16INK4a protein was confirmed on bladder biopsy or transurethral resection specimens, but PCR and ISH for hr-HPVs were both negative on the tissue sections."

Advenier - Cytopathology 2015 abstract / PubMed

Human papilloma virus is not detectable in samples of urothelial bladder cancer in a central European population: a prospective translational study. SC Schmid, L Thümer, T Schuster, T Horn, F Kurtz, J Slotta-Huspenina, J Seebach, M Straub, T Maurer, M Autenrieth, H Kübler, M Retz, U Protzer, JE Gschwend, D Hoffmann. Infect Agent Cancer 2015 Sep 21;10:31. No HPV-DNA was found in 109 bladder cancers, tested for 14 high risk and 35 low risk types.

Schmid - Infect Agent Cancer 2015 full article - PubMed Central
Schmid / Infect Agent Cancer 2015 full article

Low prevalence of HPV detection and genotyping in non-muscle invasive bladder cancer using single-step PCR followed by reverse line blot. R Pichler, W Borena, G Schäfer, C Manzl, Z Culig, S List, S Neururer, D Von Laer, L Heidegger, H Klocker, W Horninger, H Steiner, A Brunner. World J Urol 2015 Dec;33(12):2145-2151. 186 patients, 22 cervical carcinoma controls. "The presence of HPV-DNA by single-step PCR was detected in four (2.2 %) patients. HPV 16 and HPV 6 were positive in two (1.1 %) and one (0.6 %) patient, respectively In one case, no HPV genotype listed on the RLB assay could be identified. In the control group, the HPV infection rate was 100 %:"

Pichler - World J Urol 2015 abstract / PubMed

Molecular Typing for Detection of High-Risk HPV is a Useful Tool to Distinguish Primary Bladder Cancer from Secondary Involvement of Uterine Cervical Cancer in the Urinary Bladder. HL Kao, CR Lai, HL Ho, CC Pan. Histopathology 2016 Mar;68(4):513-519. "Paired bladder and cervix tumour specimens from 37 patients with cervical cancer with bladder involvement, four patients with bladder cancer with uterine cervical involvement, and two patients with double primaries were studied using quantitative multiplex PCR and CISH. 375 bladder cancers and 220 cervical cancers were analysed as controls. All cases of cervical cancer with bladder involvement showed concordant HR-HPV-positive pattern. The four cases of bladder cancer with uterine involvement were negative for HR-HPV. HR-HPV was detected in the cervical cancer but not in the bladder cancer of the patients with double primaries. HR-HPV was detected in 91.9% of cervical cancers but in none of the bladder cancers in the control group."

Kao - Histopathology 2016 abstract / PubMed

Loss of Cell Differentiation in HPV-Associated Bladder Cancer. DA Golovina, VD Ermilova, LE Zavalishina, YY Andreeva, VB Matveev, GA Frank, GM Volgareva. Bull Exp Biol Med 2016 May;161(1):96-98. 101 urothelial bladder cancers. "DNA of HPV16... was detected in 38 specimens, while mRNA of E6 and E7 oncogenes and E7 oncoprotein of HPV16 were observed in 13 specimens."

Golovina - Bull Exp Biol Med 2016 abstract / PubMed

Association Between Human Papillomavirus and Transitional Cell Carcinoma of the Bladder. P Abdollahzadeh, SH Madani, S Khazaei, S Sajadimajd, B Izadi, F Najafi. Urol J 2017 Nov 4;14(6):5047-5050. 67 transitional cell carcinomas and 30 controls. "22.4% of patients with TCC of bladder and 3.3% of control group were positive for HPV with a meaningful relation (P=.019). The prevalence of HPV was 4.3 fold higher in men than women."

Abdollahzadeh / Urol J 2017 full article

Defining the frequency of human papillomavirus and polyomavirus infection in urothelial bladder tumours. MA Llewellyn, NS Gordon, B Abbotts, ND James, MP Zeegers, KK Cheng, A Macdonald, S Roberts, JL Parish, DG Ward, RT Bryan. Sci Rep 2018 Jul 26;8(1):11290. 689 samples. "[I]n United Kingdom patients, the presence of HPV DNA sequences is extremely rare in UBC (<1% of cases). Polyomavirus DNA (predominantly BKV) is more common in UBC, but still only detectable in 7% of cases and in many of these cases at low copy number."

Llewellyn - Sci Rep 2018 abstract / PubMed

Human Papillomavirus in Urothelial Carcinoma of Bladder: An Indian study. UK Mete, S Shenvi, MP Singh, A Chakraborti, N Kakkar, RK Ratho, AK Mandal. Int J Appl Basic Med Res 2018 Oct-Dec;8(4):217-219. 50 patients, 10 controls; HPV-16 and HPV-18. "All cancerous specimens and control specimens were found to be negative by PCR for the presence of HPV DNA."

Mete - Int J Appl Basic Med Res 2018 full article / PubMed Central

Human papillomavirus and squamous cell carcinoma of the urinary bladder: DaBlaCa-10 study. KR Jřrgensen, S Hřyer, JK Jakobsen, TK Jensen, N Marcussen, G Wrist Lam, T Hasselager, PO Thind, BG Toft, T Steiniche, JB Jensen. Scand J Urol 2018 Oct - Dec;52(5-6):371-376. 50 SCC, 25 urothelial, 25 with squamous differentiation. "An overall H.P.V. prevalence of 12/100 (12%) was observed. H.P.V. was demonstrated in 9/50 (18%) of the S.C.C."

Jřrgensen - Scand J Urol 2018 abstract / PubMed

Is There any Association between Urothelial Carcinoma of the Bladder and Human Papillomavirus? A Case-Control Study. M Sarier, N Sepin, Y Keles, L Imir, M Emek, M Demir, E Kukul, A Soylu. Urol Int 2019 May 8:1-6. 69 cases, 69 non-cancer controls. "HPV-DNA was detected in 28.9% (20/69) of the patients in the case group and in 8.7% (6/69) of the patients in the control group. HPV-DNA positivity was significantly higher in the case group (OR 4.24; 95% CI 1.63-12.34)."

Sarier - Urol Int 2019 abstract / PubMed

Polyomaviruses Are Implicated in Bladder Cancer in Non-Immunodeficient Patients

Low frequency of human polyomavirus BKV and JCV DNA in urothelial carcinomas of the renal pelvis and renal cell carcinomas. A Knöll, R Stoehr, W Jilg, A Hartmann. Oncol Rep 2003 Mar-Apr;10(2):487-491. 83 renal cell carcinomas. "Human polyomavirus DNA was detected in renal pelvis samples with a frequency of 16% (BKV) and 15% (JCV), and in kidney samples with a frequency of 1% (BKV) and 23% (JCV), respectively. However, viral sequences were not present more often in tumors than in normal tissue. There was no integration of the potentially oncogenic viral large T-antigen in the tumors, and the viral concentration of both BKV and JCV was not higher in DNA extracted from tumors compared to normal tissue."

Knöll - Oncol Rep 2003 abstract / PubMed

Urothelial bladder carcinoma and viral infections: different association with human polyomaviruses and papillomaviruses. D Fioriti, V Pietropaolo, S Dal Forno, C Laurenti, F Chiarini, AM Degener. Int J Immunopathol Pharmacol 2003 Sep-Dec;16(3):283-238. 32 primary bladder neoplasias, vs 20 healthy tissue samples. "In the examined population the association bladder carcinoma-HPV, found by others, has not been confirmed. The high percentage of human polyomaviruses present in the samples is a statistically significant data (p=0.0087) and allows to presume that BKV and JCV may play a role in the aetiology of bladder tumor. In particular the polyomavirus BK, which is found in significative percentage both in single infection (p=0.0036) and in co-infections with other viral species (p=0.035), may be an important co-factor in the pathogenesis of bladder carcinoma."

Fioriti - Int J Immunopathol Pharmacol 2003 abstract / PubMed

Lack of BK virus DNA sequences in most transitional-cell carcinomas of the bladder. DE Rollison, WJ Sexton, AR Rodriguez, LC Kang, R Daniel, KV Shah. Int J Cancer 2007 Mar 15;120(6):1248-1251. 76 transitional cell carcinoma tissues and 46 paired adjacent normal urothelial tissues. "Seventy-three bladder tumors yielded >/=3,000 copies of ERV-3, 4 (5.5%) of which tested positive for BKV with average copy numbers of 7.9, 15.8, 0.4 and 0.3 per 1,000 cells. Paired normal tissue was available for 2 of these BKV-positive tumors, 1 of which was BKV-positive (14.6 copies/1,000 cells). No other normal tissues were BKV-positive by QPCR. The 6 BKV-positive tissues by QPCR were also positive by conventional PCR, but all stained negative for BKV T-Ag by immunohistochemistry."

Rollison - Int J Cancer 2007 abstract / PubMed

Association of human herpes, papilloma and polyoma virus families with bladder cancer. GI Panagiotakis, D Papadogianni, MN Chatziioannou, I Lasithiotaki, D Delakas, DA Spandidos. Tumour Biol 2013 Feb;34(1):71-79. "All cancerous specimens, including the control group, were found to be negative both by PCR and real-time qPCR for the presence of HPV DNA..." "EBV showed a higher prevalence in bladder cancer specimens compared to healthy tissue (p = 0.048), whilst BKV and JCV were detected only in tumour samples."

Panagiotakis - Tumour Biol 2013 abstract / PubMed

Potential relationship between BK virus and renal cell carcinoma. Y Bulut, E Ozdemir, HI Ozercan, EO Etem, F Aker, ZA Toraman, A Seyrek, F Firdolas. J Med Virol 2013 Jun;85(6):1085-1089. 50 renal cell carcinomas, 40 bladder transitional cell carcinomas, 45 controls with benign renal pathology, and 25 controls with benign bladder pathology. "The results of the nested PCR indicated that 23 (14.3%) of 160 samples were positive for BKV DNA. The relationship between the cancer and the presence of BKV DNA was significant (P < 0.05). The BKV DNA positivity was significantly associated with the histological diagnosis of renal cell carcinoma (P = 0.03), but not with that of bladder transitional cell carcinoma. The results of real-time RT-PCR showed that the mRNA of BKV VP1 was present in 69.5% of the BKV DNA positive samples. The levels of BKV mRNA were significantly higher in the renal cell cancer samples than in the control samples (P < 0.05)... The findings also indicated that the presence of BKV DNA resulted in a fivefold increase in the risk of development of renal cell carcinoma."

Bulut - J Med Virol 2013 abstract / PubMed

Bladder cancer and seroreactivity to BK, JC and Merkel cell polyomaviruses: the Spanish bladder cancer study. C Robles, R Viscidi, N Malats, DT Silverman, A Tardon, R Garcia-Closas, C Serra, A Carrato, J Herranz, J Lloreta, N Rothman, FX Real, S de Sanjose, M Kogevinas. Int J Cancer 2013 Aug 1;133(3):597-603. "Our results show a similar seroprevalence in cases and controls: 64/60% for BKV, 83/82% for MCV and 87/83% for JCV. However, among seropositive subjects, higher median seroreactivities were observed in cases compared to controls for BKV (0.84 vs. 0.70, p-value = 0.009) and MCV (1.81 vs. 0.65, p-value < 0.001). Increased bladder cancer risk was observed for BKV (OR = 1.4, 95%CI 1.04-1.8) and for MCV (OR = 1.5, 95%CI 1.2-1.9), when comparing highest to lowest seroreactivity tertiles. The associations of BKV and MCV with bladder cancer were independent of each other and neither smoking status nor disease stage and grade modified them."

Robles - Int J Cancer 2013 abstract / PubMed

The oncogenic potential of BK polyomavirus is linked to viral integration into the human genome. DJ Kenan, PA Mieczkowski, R Burger-Calderon, HK Singh, V Nickeleit. J Pathol 2015 Nov;237(3):379-389. "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 1) disruption of VP1 protein expression and robust expression of large T antigen; 2) preclusion of viral replication; and 3) 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."

Kenan - J Pathol 2015 abstract / PubMed

Survey for human polyomaviruses in cancer. T Toptan, SA Yousem, J Ho, Y Matsushima, LP Stabile, MT Fernández-Figueras, R Bhargava, A Ryo, PS Moore, Y Chang. JCI Insight 2016 Feb;1(2). Only "scattered positive cells" among 137 bladder cancers (129 transitional cell carcinomas, 8 other types) were positive for T-antigen by IHC.

Toptan - JCI Insight 2016 full article / PubMed Central

Defining the frequency of human papillomavirus and polyomavirus infection in urothelial bladder tumours. MA Llewellyn, NS Gordon, B Abbotts, ND James, MP Zeegers, KK Cheng, A Macdonald, S Roberts, JL Parish, DG Ward, RT Bryan. Sci Rep 2018 Jul 26;8(1):11290. 689 samples. "[I]n United Kingdom patients, the presence of HPV DNA sequences is extremely rare in UBC (<1% of cases). Polyomavirus DNA (predominantly BKV) is more common in UBC, but still only detectable in 7% of cases and in many of these cases at low copy number."

Llewellyn - Sci Rep 2018 abstract / PubMed

Chemicals and Bladder Cancer

Cancer in cattle that was blamed in carcinogens in bracken ferns turned out to be caused by bovine papillomavirus (BPV), which was the result of immunosuppression from the toxicity of the substances.


TP53 alterations and patterns of carcinogen exposure in a U.S. population-based study of bladder cancer. KT Kelsey, T Hirao, S Hirao, T Devi-Ashok, HH Nelson, A Andrew, J Colt, D Baris, JS Morris, A Schned, M Karagas. Int J Cancer 2005 Nov 10;117(3):370-375. In 330 bladder cancer cases in New Hampshire, "Tobacco smoking was not associated with TP53 alterations."

Kelsey - Int J Cancer 2005 abstract / PubMed

[Are human papillomaviruses responsible for the occurrence of bladder cancer]. Volgareva GM, Zavalishina LÉ, OB Trofimova, LI Korolenkova, AV Khachaturian, IuIu Andreeva, VD Ermilova, NL Cheban, DA Kuevda, OIu Shipulina, VA Glazunova, DA Golovina, AN Petrov, VB Matveev, GA Frank. Arkh Patol 2010 Jul-Aug;72(4):24-27. Case report. "The primary tumor removed in 2004 showed human papillomavirus (HPV) 16 DNA, mRNA corresponding to HPV16 oncogene E7, as well as HPV16 protein E7. The patient is a smoker who has been working at a chemical factory for over 20 years. During tumor recurrence in 2009, there was no DNA of high-risk HPV types in the cancer cells. HPV16 E7protein and cellular p 16(INK4alpha), an indicator of HPV-induced carcinogenesis, were not found. Colposcopy revealed no precancerous changes in the epithelium of the cervix uteri. The cervical epitheliocytes contained no high-risk HPV DNA, E7 and p16(INK4alpha) proteins."

Volgareva - Arkh Patol 2010 abstract

See Also:

Confounding By Infection - why studies that don't include full detection of HPV (and other causal infections) are defective, and falsely blame smoking and other non-causal associations.
Lies About Smoking and Cervical Cancer
HPV Causes Head and Neck Cancers
HPV Causes Oral Cancer
HPV is implicated in laryngeal cancer
HPV Causes Lung Cancer
HPVs Cause Skin Cancer
HPV Strains and Oncogenicity
HPV Is Implicated in Esophageal Cancer
The Lie That p53 Mutations Are the Mechanism Behind Lung Cancer - p53 mutations are a late event and are not causal
BK & JC Polyoma Viruses Cause Kidney Transplant Rejection


cast 05-19-19