sign in sign up
<<
Home , Inverted papilloma, Penile cancer

ANTICANCER RESEARCH 35: 2513-2520 (2015)

Review The Role of Human in Urological Malignancies

ISABEL HEIDEGGER1, WEGENE BORENA2 and RENATE PICHLER1

1Department of Urology and 2Division of Virology, Department of , Microbiology and Social Medicine, Medical University Innsbruck, Innsbruck, Austria

Abstract. Human papillomavirus (HPV) is associated with reading frames encode early (E) and late (L) genes required of the cervix uteri, , , vagina, anus and for viral genome replication (5,6). Among them E6 and E7 oropharynx. However, the role of HPV infection in urological are the major oncoproteins altering the function of critical tumors is not yet clarified. HPV appears not to play a major host cellular proteins. HPV E6 leads to the degradation of causative role in renal and testicular carcinogenesis. the tumor suppressor p53, while HPV E7 degrades the tumor However, HPV infection should be kept in mind regarding suppressor RB (7) (Figure 1). cases of , as well as in a sub-group of patients In generally, HPVs cause different types of diseases with with squamous differentiation. ranging from benign lesions to invasive tumors (8). Mucosal Concerning the role of HPV in penile cancer , it is HPVs are distinguished by their potential to cause malignant a recognized risk factor proven in a large number of studies. progression: Low-risk HPVs (types 6, 11, 40, 42, 43, 44, 54, This short review provides an update regarding recent 61, 70, 72 and 81) which cause low-grade lesions such as literature on HPV in urological malignancies, thereby, also benign , respiratory , as well as a proportion discussing possible limitations on HPV detection in of low-grade cervical intra-epithelial , vulvar and urological cancer. vaginal intra-epithelial neoplasms grade 1 and anal intraepithelial neoplasia grade 1 (9). However, high-risk Human papillomavirus (HPV) infections are one of the most HPVs, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, common sexually transmitted infections worldwide. More 58, 59 and 66 gained notoriety by being the primary than 200 genotypes of HPV have been identified, among causative agents of , especially them 40 different HPV genotypes infect the anogenital tract in women. Furthermore, high-risk HPV infection is a causal (1, 2). In generally, HPVs are a large family of agent in 5% of all , including cancer of the anus, desoxyribonucleic acid (dsDNA) that infect human tonsils, tongue, larynx and head and neck (2, 10). epithelial cells and use the epithelial cellular machinery to Besides gynecological, cutaneous and oral squamous replicate (3, 4). They have a diameter of approximately 55 carcinomas, HPV are also discussed in the pathogenesis of nm and a double-stranded circular DNA genome comprising urological cancer, including penile, prostate, bladder, testis almost 8,000 nucleotide base pairs. There exist five major and renal cancer. For example, high-risk (HR) and low-risk HPV: Alpha papillomavirus, beta papillomavirus, gamma (LR) HPV was detected in prepuces of asymptomatic boys papillomavirus, mu papillomavirus and nu papillomavirus. and men undergoing with different prevalence Alpha-HPVs infect mucosal tissue whereas beta-, gamma-, depending on the HPV detection method utilized (11, 12). nu- and mu-subtypes infect cutaneous sites. The HPV open Figure 2 and 3 represent the results of in situ hybridization (ISH) with confirmed LR-HPV positivity in condyloma acuminatum (Figure 2) and episomal, integrative pattern of LR-HPV in preputial in asymptomatic men Correspondence to: Renate Pichler, MD, FEBU, Medical University (Figure 3) undergoing circumcision. Innsbruck, Department of Urology, Anichstreet 35, A-6020 Innsbruck, In this short review, we provide an overview concerning Austria. Tel: +43 (0)51250482156, Fax:+43 (0)51250428365, e-mail: HPV infection in the epidemiology of urological [email protected] malignancies. We critically review the ongoing literature and Key Words: HPV, prostate cancer, renal cell , bladder give an update on the current knowledge of HPV in all cancer, , penile cancer, review. urological cancer entities.

0250-7005/2015 $2.00+.40 2513 ANTICANCER RESEARCH 35: 2513-2520 (2015)

Figure 1. High-risk oncoproteins E6 and E7 interact with the cell cycle thereby inhibiting the progress from G1 to S phase. Abbreviations: G0= Gap 0, G 1=Gap 1, S= Synthesis, G 2=Gap 2, M= Mitosis, E6= HPV oncoprotein E6, p53= Protein 53, p21=Protein 21, CDK= Cyclin dependent kinases, E7= HPV oncoprotein E7, pRB= Retinoblastoma protein.

HPV in Penile Cancer carcinomas (18). In contrast to the PCR studies, Senba et al. used the ISH method for HPV detection and found 81.5% HPV of the penis accounts for 0.5% of all positivity in patients with penile cancer (19). cancers in men (13). Emerging evidence suggests that penile A meta-analysis (of 31 studies) examining the prevalence cancer follows two etiological pathways: those related to HPV of HPV subtypes in invasive penile tumors found that HPV- infection and those related to other factors, including , 16 was the most common HPV type (60.2%), followed by chronic , and (13). The findings HPV-18 (13.3%) and HPV types 6/11 (8.13%) (20). of an essential impact of HPV in penile cancer incidence are Furthermore, serological studies support the role of HPV based on a large number of studies evaluating the impact of infection in penile cancer. Data from Bjorge et al. support HPV incidence and penile cancer. In summary, HPV DNA has the concept that HPV seropositivity is associated with higher been detected in 14%-100% of invasive penile carcinomas risk of developing penile cancer (21). depending on the number of patient samples, on the method In summary, most studies found a significant number of used for HPV detection [polymerase chain reaction (PCR) penile cancer cases to be associated with HPV infection. A versus ISH], as well as on the type of tumor tissue storage more detailed proper concerning of the role of HPV in penile (fresh versus paraffin-embedded tissue). A quantitative review carcinogenesis might help planning intervention strategies of studies using PCR methods for HPV DNA detection found such as vaccination against HPV infection. HPV presence in 45.4% of invasive penile tumors after adjusting for PCR primer, histological subtype, and year and HPV in Prostate Cancer geographical location of the study (14). In contrast to this, another study also using PCR found HPV present in 100% of Prostate cancer is the leading cause of cancer in men and the warty and 80% of basaloid tumors, but in only about one-third second cause of cancer mortality among men in European of keratinizing and verrucous tumors (15). Heideman et al. countries (22). detected HPV DNA in 55% of penile cancer (16), while Several serological- and tissue-based studies were another work from Chaux et al. measured HPV by real-time undertaken to elucidate differences in HPV presence in PCR in 35% of cases (17). However, a small study including benign and malignant prostate tissue with contradictory 31 patients measured HPV DNA in more than 80% of penile results. Briefly, most studies found no difference in HPV

2514 Heidegger et al: HPV in Urological Malignancies (Review)

Figure 2. Condyloma acuminatum 2, human papillomavirus (×10) (own data). Arrow, episomal pattern.

Figure 3. Episomal and integrative pattern of (×20) of the preputial epithelium in an asymptomatic man (own data). Thin arrow, integrative pattern. Thick arrow, episomal pattern.

2515 ANTICANCER RESEARCH 35: 2513-2520 (2015) expression patterns between cancerous and non-cancerous cancer. Again, depending on the method used for HPV prostate (reviewed in (23)). Tachezy et al. for example detection (ISH versus PCR) either high or rare incidence of detected HPV DNA in 2% of both prostate and HPV has been detected in tumor samples (33). Khoury et al. prostate cancer, moreover no difference in the seroprevalence for example interrogated data from 3,775 malignant rates for HPV 16 E6 and E7 oncoproteins between prostate neoplasms in the Cancer Genome Atlas database for the cancer and non-cancerous prostate was found in this study presence of viral sequences using RNA-Seq analysis. One of (24). Data of Ghasemian et al. also did not describe a the main findings in this study was the absence of transcribed significant role of HPV infection in prostatic disease in DNA viral transcripts in some of the most prevalent human Iranian patients (25). The Prostate Cancer Prevention Trial cancer types, including (34). Grce et al. also conducted a large prospective investigation of HPV types 16, found no HPV DNA positivity in analyses of 28 renal cell 18, and 31 in relation to risk of prostate cancer, including carcinomas by PCR using, two sets of consensus primers and 1232 patients. In line with previous studies, no associations specific primer pairs for HPV types 16, 18, and 33 (35). In were observed for weak or strong HPV-16, HPV-18 or HPV- addition, no positive staining for HPV DNA was found in any 31 seropositivity and risk of prostate cancer (26). histological type in a study of 62 renal tumors (40 clear cell, However, there also exist several studies that found a nine papillary, and three chromophobe renal cell carcinomas, differences in HPV expression between prostate cancer and one collecting duct carcinoma, duo urothelial carcinomas of benign prostate: Already 15 years ago Serth et al. described the renal pelvis and seven ), supporting the significantly higher (p=0.02) copy numbers of HPV-16-E6 notion that HPV does not seem to play a role in the sequences in prostate cancer compared to prostate , development of benign and malignant renal tumors. In this indicating that oncogenic HPV-16 might contribute to the study, signal-amplified colorimetric ISH was performed on development of a subset of prostate tumors (27). In line with microarray sections using biotinylated probes for HPV this finding, Dillner et al. also revealed a positive correlation subtypes 6, 11, 16 and 18 (36). between HPV seropositivity and prostate cancer risk (28). In In contrast to these findings, Salehipoor et al. confirmed January 2015, an Indian study including 96 prostate cancer high-risk HPV DNA positivity (types 16 and 18) in and 55 benign prostate tissue samples found HPV infection approximately 14.3% of tissue in 41% of prostate tumor biopsies and 20% of benign specimens analyzed by nested PCR (37). Using ISH, Kamel prostate tissue samples (29). Moreover, they showed that a et al. investigated 56 renal cell carcinomas for the presence significant proportion of HPV-infected (74%) cases had a of HPV DNA (subtypes 6, 11, 16, 18, 31 and 33) and high Gleason score (29). concluded that the presence of HPV DNA in these tumors Another recent study investigated the prevalence of HPV implicated HPV viral infection in the etiology of kidney infection and the prognostic impact for overall survival in a cancer as HPV positivity was found in 52% (38). cohort of 150 patients with primary prostate cancer (30). The results regarding HPV incidence in renal cell Thereby, they found that overall survival was significantly carcinoma remain controversial possibly depending on the associated with the nuclear expression of E7 protein and HPV DNA detection method used. other clinicopathological factors, such as age greater than 72 years, high nuclear grade, capsule infiltration, and high HPV in Testicular Cancer Gleason score at diagnosis; on multivariate analysis, all except capsule infiltration were significantly independent Testicular cancer is a common in men of younger prognostic factors for worse survival of patients with primary age. In 1984, Newell et al. suggested for the first time that prostate cancer (30). testicular cancer might have a viral etiology since it exhibits In summary, the HPV link to prostate cancer is still similar characteristics to Hodgkin's lymphoma, arguing that questionable and hotly debated by researchers. Further the similar geographical distribution of both cancer types studies are needed to address this issue. would point to viral etiology as the causative agent for testicular cancer (39, 40). The viral theory was supported by HPV in Renal Cell Carcinoma certain characteristics of testicular cancer itself, including young age, as well as the increase in overexpression of wild- Renal cell cancer is a very rare neoplasm, thus only few type p53 in many cases (41). In a large epidemiological study, studies evaluated the pathogenetic role of HPV on renal cell only 6% of patients with testicular cancer tested positive for carcinogenesis. Different studies have shown that HPV type 16 (42). To investigate the transforming activity of immunosuppressed renal allograft recipients seem to be at the E6 and E7 genes in vivo, Kondoh et al. conducted an high risk for infection with virus HPV-related de novo experiment with transgenic mice carrying HPV-16 E6 and E7 urogenital malignancies (31, 32). However, there is still open reading frames; they obtained five transgenic founders controversy regarding the exact prevalence of HPV in kidney and established three transgenic lineages, confirming testicular

2516 Heidegger et al: HPV in Urological Malignancies (Review) tumors of germ cell origin in mice of all three lineages. These DNA (48). No recent trial proved any relationship between results suggest that E6 and E7 of HPV-16 have transforming HPV infection and risk of cancer recurrence and progression. activity in vivo and preferential effects on germ cells in the Using urine samples for HPV detection by highly sensitive testis (43). In contrast to these findings, HPV genotype 16 and PCR assays, HPV presence in bladder cancer cases (6.1%) 18 were not detectable in a study performed by Rajpert-De was similar to the control group (3.6%) (60). No positive Meyts et al (44). Using real-time PCR employing GP5+/GP6+ signals for high-risk HPV (types 16 and 18) were confirmed consensus HPV primers to examine the presence of HPV by different studies n method using ISH for HPV detection sequences in testicular (n=61) and normal (61-63). Alexander et al. investigated 42 cases of squamous (n=23), none of the specimens displayed the presence of HPV cell carcinoma and 27 cases of urothelial cancer with DNA (45). A recent study confirmed that 155 patients with squamous differentiation. HPV DNA and protein were not testicular cancer had a high prevalence of semen infection with detected in any case of bladder cancer by ISH at the DNA HPV (using fluorescence ISH) that worsened after level and immunohistochemistry at the protein level (64). radiotherapy and , probably through their In summary, although many trials demonstrated a possible immunosuppressive action and the effect of a higher relationship between bladder cancer and HPV infection, vulnerability induced by the tumor (46). convincing evidence regarding bladder carcinogenesis is still The role of HPV in testicular cancer needs to be analyzed lacking. Additional studies to investigate the carcinogenic further. potential of HPV and the possible role of HPV infection on cancer recurrence or progression are needed. HPV in Urothelial Cancer Summary The relationship between urothelial carcinogenesis and human papilloma virus is still poorly understood. The HPV is a recognized risk factor in penile cancer that has been prevalence of high-risk HPV in bladder cancer ranges demonstrated in a large number of studies. Concerning other between 3% and 50% (47-52). Li et al., for example, noticed urological malignancies, the role of HPV is not yet clear, that HPV prevalence varies by region, by type of HPV DNA however, in most studies HPV does not appear to be specimen, as well as by PCR primers used (53). The highest associated with risk of urological malignancies. Small patient prevalence of HPV positivity was found in Moroccan numbers, unicentric or retrospective study characteristics may patients, with an incidence of 52.4% (HPV-16 in 95.5% of partly explain the differences in HPV detection rates among cancer samples) (54). Although HPV DNA presence appears the studies. Moreover, the detection method used for HPV not to play a major causative role in bladder cancer in the measurement seems to be a challenging issue. In addition, it general population, HPV infection should be kept in mind in was recently shown for the first time that the HPV epigenetic a sub-group of patients such as those with rare urothelial signature is a better predictor of survival than HPV status carcinomas with squamous differentiation, neurogenic alone (65). Thus, further studies with larger patient collectives bladder, urothelial inverted papilloma or inverted papilloma and optimized detection methods are of great need. with atypia, and in Bilharzial bladder carcinogenesis (23, 49, 55). In these cases, HPV serology may pave the way for Conflicts of Interest better management and follow-up of patients and for optimal evaluation of HPV vaccination (56). However, how The Authors have no conflict of interest regarding this article vaccination may induce the regression of bladder tumors at such mucosal sites has not been sufficiently examined. References Interestingly, Domingos-Pereira et al. established an orthotopic model expressing HPV-16 antigen E7 as a model 1 de Villiers EM and Gunst K: Characterization of seven novel using an adjuvant E7 polypeptide. Subcutaneous and human papillomavirus types isolated from cutaneous tissue, but intravaginal vaccination induced a high number of intravesical also present in mucosal lesions. J Gen Virol 90: 1999-2004, 2009. E7+CD8+ T-cells, with confirmed tumor regression (57). 2 Moscicki AB, Schiffman M, Kjaer S, and Villa LL: Chapter 5: In contrast to these findings, urothelial carcinoma Updating the natural history of HPV and anogenital cancer. following renal transplantation does not seem to be 24 Suppl 3: S3-42-S3/51, 2006. associated with infection by HPV type 16 and 18 (58). 3 Doorbar J: Molecular biology of human papillomavirus infection Currently, only one Japanese study showed that patients with and cervical cancer. Clin Sci (Lond) 110: 525-541, 2006. 4 Stanley MA: Epithelial cell responses to infection with human HPV DNA positivity/p53 antibody had a significant worse papillomavirus. Clin Microbiol Rev 25: 215-222, 2012. survival rate, indicating a poor prognosis (59). Additionally, 5 Hebner CM and Laimins LA: Human papillomaviruses: basic the data of a pilot study suggested a positive trend in the mechanisms of pathogenesis and oncogenicity. Rev Med Virol correlation between tumor grade/stage and high-risk HPV 16: 83-97, 2006.

2517 ANTICANCER RESEARCH 35: 2513-2520 (2015)

6 Scheurer ME, Tortolero-Luna G, and Adler-Storthz K: Human 21 Bjorge T, Hakulinen T, Engeland A, Jellum E, Koskela P, papillomavirus infection: biology, epidemiology, and prevention. Lehtinen M, Luostarinen T, Paavonen J, Sapp M, Schiller J, Int J Gynecol Cancer 15: 727-746, 2005. Thoresen S, Wang Z, Youngman L, and Dillner J: A prospective, 7 Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, seroepidemiological study of the role of human papillomavirus and Stanley MA: The biology and life-cycle of human in esophageal cancer in Norway. Cancer Res 57: 3989-3992, papillomaviruses. Vaccine 30 Suppl 5: F55-F70, 2012. 1997. 8 Duensing S and Munger K: Mechanisms of genomic instability 22 Center MM, Jemal A, Lortet-Tieulent J, Ward E, Ferlay J, in human cancer: insights from studies with human Brawley O, and Bray F: International variation in prostate cancer papillomavirus oncoproteins. Int J Cancer 109: 157-162, 2004. incidence and mortality rates. Eur Urol 61: 1079-1092, 2012. 9 Lacey CJ, Lowndes CM, and Shah KV: Chapter 4: Burden and 23 Tolstov Y, Hadaschik B, Pahernik S, Hohenfellner M, and management of non-cancerous HPV-related conditions: HPV- Duensing S: Human papillomaviruses in urological 6/11 disease. Vaccine 24 Suppl 3: S3-35-S3/41, 2006. malignancies: a critical assessment. Urol Oncol 32: 46-27, 2014. 10 Cuzick J, Arbyn M, Sankaranarayanan R, Tsu V, Ronco G, 24 Tachezy R, Hrbacek J, Heracek J, Salakova M, Smahelova J, Mayrand MH, Dillner J, and Meijer CJ: Overview of human Ludvikova V, Svec A, Urban M, and Hamsikova E: HPV papillomavirus-based and other novel options for cervical cancer persistence and its oncogenic role in prostate tumors. J Med in developed and developing countries. Vaccine 26 Virol 84: 1636-1645, 2012. Suppl 10: K29-K41, 2008. 25 Ghasemian E, Monavari SH, Irajian GR, Jalali Nodoshan MR, 11 Heidegger I, Pichler R, Muller B, Klocker H, Oswald D, Haid Roudsari RV, and Yahyapour Y: Evaluation of human B, Zelger B, Horninger W, and Oswald J: Is real-time PCR the papillomavirus infections in prostatic disease: a cross-sectional correct method to evaluate the incidence of human study in Iran. Asian Pac J Cancer Prev 14: 3305-3308, 2013. papillomavirus in prepuces of asymptomatic boys and men? 26 Sutcliffe S, Viscidi RP, Till C, Goodman PJ, Hoque AM, Hsing World J Urol 32: 1199-1204, 2014. AW, Thompson IM, Zenilman JM, De Marzo AM, and Platz EA: 12 Klinglmair G, Pichler R, Zelger B, Dogan HS, Becker T, Human papillomavirus types 16, 18, and 31 serostatus and Esterbauer J, Riccabona M, Loidl W, Horninger W, and Oswald J: prostate cancer risk in the Prostate Cancer Prevention Trial. Prevalence of the human papillomavirus (HPV) expression of the Cancer Epidemiol Biomarkers Prev 19: 614-618, 2010. inner prepuce in asymptomatic boys and men. World J Urol 2012. 27 Serth J, Panitz F, Paeslack U, Kuczyk MA, and Jonas U: 13 Bleeker MC, Heideman DA, Snijders PJ, Horenblas S, Dillner Increased levels of human papillomavirus type 16 DNA in a J, and Meijer CJ: Penile cancer: epidemiology, pathogenesis and subset of prostate cancers. Cancer Res 59: 823-825, 1999. prevention. World J Urol 27: 141-150, 2009. 28 Dillner J, Knekt P, Boman J, Lehtinen M, Af G, V, Sapp M, 14 Backes DM, Kurman RJ, Pimenta JM, and Smith JS: Systematic Schiller J, Maatela J, and Aromaa A: Sero-epidemiological review of human papillomavirus prevalence in invasive penile association between human-papillomavirus infection and risk of cancer. Cancer Causes Control 20: 449-457, 2009. prostate cancer. Int J Cancer 75: 564-567, 1998. 15 Rubin MA, Kleter B, Zhou M, Ayala G, Cubilla AL, Quint WG, 29 Singh N, Hussain S, Kakkar N, Singh SK, Sobti RC, and and Pirog EC: Detection and typing of human papillomavirus DNA Bharadwaj M: Implication of high risk Human papillomavirus in penile carcinoma: evidence for multiple independent pathways HR-HPV infection in prostate cancer in Indian population- A of penile carcinogenesis. Am J Pathol 159: 1211-1218, 2001. pioneering case-control analysis. Sci Rep 5: 7822, 2015. 16 Heideman DA, Waterboer T, Pawlita M, Delis-van Diemen P, 30 Pascale M, Pracella D, Barbazza R, Marongiu B, Roggero E, Nindl I, Leijte JA, Bonfrer JM, Horenblas S, Meijer CJ, and Bonin S, and Stanta G: Is human papillomavirus associated with Snijders PJ: Human papillomavirus-16 is the predominant type prostate cancer survival? Dis Markers 35: 607-613, 2013. etiologically involved in penile squamous cell carcinoma. J Clin 31 Brown MR, Noffsinger A, First MR, Penn I, and Husseinzadeh Oncol 25: 4550-4556, 2007. N: HPV subtype analysis in lower genital tract neoplasms of 17 Chaux A, Cubilla AL, Haffner MC, Lecksell KL, Sharma R, female renal transplant recipients. Gynecol Oncol 79: 220-224, Burnett AL, and Netto GJ: Combining routine morphology, 2000. (INK4a) immunohistochemistry, and in situ hybridization for 32 Bobrowska K, Kaminski P, Cyganek A, Jabiry-Zieniewicz J, the detection of human papillomavirus infection in penile Bablok L, Durlik M, and Fiedor P: Multiple neoplastic lesions carcinomas: a tissue microarray study using classifier of the lower genital tract in a human papilloma virus-infected performance analyses. Urol Oncol 32: 171-177, 2014. kidney-pancreas allograft recipient: a case report. Transplant 18 Ferrandiz-Pulido C, Masferrer E, de T, I, Lloveras B, Hernandez- Proc 37: 2093-2095, 2005. Losa J, Mojal S, Salvador C, Morote J, Cajal S, Pujol RM, Garcia- 33 Wang JS, Tseng HH, Lin SL, and Hsieh SP: Transitional cell and Patos V, and Toll A: Identification and genotyping of human uncommon urothelial carcinoma of renal pelvis/ and papillomavirus in a Spanish cohort of penile squamous cell bladder: low incidence of human papilloma virus. Zhonghua Yi carcinomas: correlation with pathologic subtypes, p16(INK4a) Xue Za Zhi (Taipei) 59: 151-157, 1997. expression, and prognosis. J Am Acad Dermatol 68: 73-82, 2013. 34 Khoury JD, Tannir NM, Williams MD, Chen Y, Yao H, Zhang J, 19 Senba M, Kumatori A, Fujita S, Jutavijittum P, Yousukh A, Thompson EJ, Meric-Bernstam F, Medeiros LJ, Weinstein JN, Moriuchi T, Nakamura T, and Toriyama K: The prevalence of and Su X: Landscape of DNA virus associations across human human papillomavirus genotypes in penile cancers from northern malignant cancers: analysis of 3,775 cases using RNA-Seq. J Thailand. J Med Virol 78: 1341-1346, 2006. Virol 87: 8916-8926, 2013. 20 Miralles-Guri C, Bruni L, Cubilla AL, Castellsague X, Bosch FX, 35 Grce M, Furcic I, Hrascan R, Husnjak K, Krhen I, Marekovic Z, and de Sanjose S: Human papillomavirus prevalence and type Zeljko Z, and Pavelic K: Human papillomaviruses are not associated distribution in penile carcinoma. J Clin Pathol 62: 870-878, 2009. with renal carcinoma. Anticancer Res 17: 2193-2196, 1997.

2518 Heidegger et al: HPV in Urological Malignancies (Review)

36 Hodges A, Talley L, and Gokden N: Human Papillomavirus 52 Mvula M, Iwasaka T, Iguchi A, Nakamura S, Masaki Z, and DNA and P16INK4A are not detected in renal tumors with Sugimori H: Do human papillomaviruses have a role in the immunohistochemistry and signal-amplified in situ hybridization pathogenesis of bladder carcinoma? J Urol 155: 471-474, 1996. in paraffin-embedded tissue. Appl Immunohistochem Mol 53 Li N, Yang L, Zhang Y, Zhao P, Zheng T, and Dai M: Human Morphol 14: 432-435, 2006. papillomavirus infection and bladder cancer risk: a meta- 37 Salehipoor M, Khezri A, Behzad-Behbahani A, Geramizadeh B, analysis. J Infect Dis 204: 217-223, 2011. Rahsaz M, Aghdaei M, and Afrasiabi MA: Role of viruses in renal 54 Berrada N, Al Bouzidi A, Ameur A, Abbar M, El Mzibri M, cell carcinoma. Saudi J Kidney Dis Transpl 23: 53-57, 2012. Ameziane-El-Hassani R, Benbacer L, Khyatti M, Qmichou Z, 38 Kamel D, Turpeenniemi-Hujanen T, Vahakangas K, Paakko P, Amzazi S, and Attaleb M: Human papillomavirus detection in and Soini Y: Proliferating cell nuclear antigen but not p53 or Moroccan patients with bladder cancer. J Infect Dev Ctries 7: human papillomavirus DNA correlates with advanced clinical 586-592, 2013. stage in renal cell carcinoma. Histopathology 25: 339-347, 1994. 55 Shigehara K, Sasagawa T, Kawaguchi S, Nakashima T, 39 Newell GR, Mills PK, and Johnson DE: Epidemiologic Shimamura M, Maeda Y, Konaka H, Mizokami A, Koh E, and comparison of cancer of the testis and Hodgkin's disease among Namiki M: Etiologic role of human papillomavirus infection in young males. Cancer 54: 1117-1123, 1984. bladder carcinoma. Cancer 117: 2067-2076, 2011. 40 Yousif L, Hammer GP, Blettner M, and Zeeb H: Testicular 56 Badawi H, Ahmed H, Ismail A, Diab M, Moubarak M, Badawy cancer and viral infections: a systematic literature review and A, and Saber M: Role of human papillomavirus types 16, 18, meta-analysis. J Med Virol 85: 2165-2175, 2013. and 52 in recurrent cystitis and cancer among 41 Gray A, Guillou L, Zufferey J, Rey F, Kurt AM, Jichlinski P, Egyptian patients. Medscape J Med 10: 232, 2008. Leisinger HJ, and Benhattar J: Persistence of parvovirus B19 57 Domingos-Pereira S, Derre L, Warpelin-Decrausaz L, Haefliger DNA in testis of patients with testicular germ cell tumours. J JA, Romero P, Jichlinski P, and Nardelli-Haefliger D: Gen Virol 79 ( Pt 3): 573-579, 1998. Intravaginal and subcutaneous immunization induced vaccine 42 Strickler HD, Schiffman MH, Shah KV, Rabkin CS, Schiller JT, specific CD8 T cells and tumor regression in the bladder. J Urol Wacholder S, Clayman B, and Viscidi RP: A survey of human 191: 814-822, 2014. papillomavirus 16 antibodies in patients with epithelial cancers. 58 Xiao J, Zhu X, Hao GY, Zhu YC, Ma LL, Zhang YH, and Tian Eur J Cancer Prev 7: 305-313, 1998. Y: Association between urothelial carcinoma after renal 43 Kondoh G, Murata Y, Aozasa K, Yutsudo M, and Hakura A: Very transplantation and infection by human papillomavirus types 16 high incidence of germ cell tumorigenesis (seminomagenesis) in and 18. Transplant Proc 43: 1638-1640, 2011. human papillomavirus type 16 transgenic mice. J Virol 65: 3335- 59 Furihata M, Inoue K, Ohtsuki Y, Hashimoto H, Terao N, and Fujita 3339, 1991. Y: High-risk human papillomavirus infections and overexpression 44 Rajpert-De Meyts E, Hording U, Nielsen HW, and Skakkebaek of p53 protein as prognostic indicators in transitional cell NE: Human papillomavirus and Epstein-Barr virus in the etiology carcinoma of the urinary bladder. Cancer Res 53: 4823-4827, 1993. of testicular germ cell tumours. APMIS 102: 38-42, 1994. 60 Polesel J, Gheit T, Talamini R, Shahzad N, Lenardon O, Sylla 45 Bertazzoni G, Sgambato A, Migaldi M, Grottola A, Sabbatini B, La Vecchia C, Serraino D, Tommasino M, and Franceschi S: AM, Nanni N, Farinetti A, Iachetta F, Giacobazzi E, Pecorari M, Urinary human polyomavirus and papillomavirus infection and and Bonetti LR: Lack of evidence for an association between bladder cancer risk. Br J Cancer 106: 222-226, 2012. seminoma and human papillomavirus infection using GP5+/GP6+ 61 Lu QL, Lalani e, and Abel P: Human papillomavirus 16 and 18 consensus primers. J Med Virol 85: 105-109, 2013. infection is absent in urinary bladder carcinomas. Eur Urol 31: 46 Garolla A, Pizzol D, Bertoldo A, Ghezzi M, Carraro U, Ferlin 428-432, 1997. A, and Foresta C: Testicular cancer and HPV semen infection. 62 Boucher NR, Scholefield JH, and Anderson JB: The aetiological Front Endocrinol (Lausanne) 3: 172, 2012. significance of human papillomavirus in bladder cancer. Br J 47 Cai T, Mazzoli S, Meacci F, Nesi G, Geppetti P, Malossini G, Urol 78: 866-869, 1996. and Bartoletti R: Human papillomavirus and non-muscle 63 Reyes MC, Park KJ, Lin O, Ioffe O, Isacson C, Soslow RA, invasive urothelial bladder cancer: potential relationship from a Reuter VE, and Fine SW: Urothelial carcinoma involving the pilot study. Oncol Rep 25: 485-489, 2011. gynecologic tract: a morphologic and immunohistochemical 48 Moonen PM, Bakkers JM, Kiemeney LA, Schalken JA, study of 6 cases. Am J Surg Pathol 36: 1058-1065, 2012. Melchers WJ, and Witjes JA: Human papilloma virus DNA and 64 Alexander RE, Hu Y, Kum JB, Montironi R, Lopez-Beltran A, p53 mutation analysis on bladder washes in relation to clinical Maclennan GT, Idrees MT, Emerson RE, Ulbright TM, Grignon outcome of bladder cancer. Eur Urol 52: 464-468, 2007. DG, Eble JN, and Cheng L: p16 expression is not associated 49 Khaled HM, Bahnassi AA, Zekri AR, Kassem HA, and Mokhtar with human papillomavirus in urinary bladder squamous cell N: Correlation between p53 mutations and HPV in bilharzial carcinoma. Mod Pathol 25: 1526-1533, 2012. bladder cancer. Urol Oncol 21: 334-341, 2003. 65 Feber A, Arya M, de Winter P, Saqib M, Nigam R, Malone PR, Tan 50 Agliano AM, Gradilone A, Gazzaniga P, Napolitano M, Vercillo WS, Rodney S, Lechner M, Freeman A, Jameson C, Muneer A, R, Albonici L, Naso G, Manzari V, Frati L, and Vecchione A: Beck S, and Kelly JD: Epigenetics Markers of Metastasis and HPV- High frequency of human papillomavirus detection in urinary Induced Tumorigenesis in Penile Cancer. Clin Cancer Res 2014. bladder cancer. Urol Int 53: 125-129, 1994. 51 Tekin MI, Tuncer S, Aki FT, Bilen CY, Aygun C, and Ozen H: Human papillomavirus associated with bladder carcinoma? Received January 26, 2015 Analysis by polymerase chain reaction. Int J Urol 6: 184-186, Revised February 8, 2015 1999. Accepted February 10, 2015

2519