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."

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."

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.

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."

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."

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."

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."

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.

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."

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.

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."

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."

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.

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.

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."

[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.

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; 9.3% were positive for low-risk types and 34.7% for high-risk types.

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.

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.

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.

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.

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."

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.

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."

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.

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."

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):464-9. Epub 2006 Nov 15. "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)."

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."

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"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" (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.

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cast 08-22-08