Abstract
Human papillomavirus (HPV) is associated with cancer of the cervix uteri, penis, vulva, vagina, anus and oropharynx. However, the role of HPV infection in urological tumors is not yet clarified. HPV appears not to play a major causative role in renal and testicular carcinogenesis. However, HPV infection should be kept in mind regarding cases of prostate cancer, as well as in a sub-group of patients with bladder cancer with squamous differentiation. Concerning the role of HPV in penile cancer incidence, it is a recognized risk factor proven in a large number of studies. This short review provides an update regarding recent literature on HPV in urological malignancies, thereby, also discussing possible limitations on HPV detection in urological cancer.
Human papillomavirus (HPV) infections are one of the most common sexually transmitted infections worldwide. More than 200 genotypes of HPV have been identified, among them 40 different HPV genotypes infect the anogenital tract (1, 2). In generally, HPVs are a large family of desoxyribonucleic acid viruses (dsDNA) that infect human epithelial cells and use the epithelial cellular machinery to replicate (3, 4). They have a diameter of approximately 55 nm and a double-stranded circular DNA genome comprising almost 8,000 nucleotide base pairs. There exist five major HPV: Alpha papillomavirus, beta papillomavirus, gamma papillomavirus, mu papillomavirus and nu papillomavirus. Alpha-HPVs infect mucosal tissue whereas beta-, gamma-, nu- and mu-subtypes infect cutaneous sites. The HPV open reading frames encode early (E) and late (L) genes required for viral genome replication (5,6). Among them E6 and E7 are the major oncoproteins altering the function of critical host cellular proteins. HPV E6 leads to the degradation of the tumor suppressor p53, while HPV E7 degrades the tumor suppressor RB (7) (Figure 1).
In generally, HPVs cause different types of diseases ranging from benign lesions to invasive tumors (8). Mucosal HPVs are distinguished by their potential to cause malignant progression: Low-risk HPVs (types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72 and 81) which cause low-grade lesions such as benign warts, respiratory papillomas, as well as a proportion of low-grade cervical intra-epithelial neoplasms, vulvar and vaginal intra-epithelial neoplasms grade 1 and anal intraepithelial neoplasia grade 1 (9). However, high-risk HPVs, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66 gained notoriety by being the primary causative agents of carcinomas, especially cervical cancer in women. Furthermore, high-risk HPV infection is a causal agent in 5% of all cancers, including cancer of the anus, tonsils, tongue, larynx and head and neck (2, 10).
Besides gynecological, cutaneous and oral squamous carcinomas, HPV are also discussed in the pathogenesis of urological cancer, including penile, prostate, bladder, testis and renal cancer. For example, high-risk (HR) and low-risk (LR) HPV was detected in prepuces of asymptomatic boys and men undergoing circumcision with different prevalence depending on the HPV detection method utilized (11, 12). 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 epithelium in asymptomatic men (Figure 3) undergoing circumcision.
In this short review, we provide an overview concerning HPV infection in the epidemiology of urological malignancies. We critically review the ongoing literature and give an update on the current knowledge of HPV in all urological cancer entities.
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
Squamous cell carcinoma of the penis accounts for 0.5% of all cancers in men (13). Emerging evidence suggests that penile cancer follows two etiological pathways: those related to HPV infection and those related to other factors, including phimosis, chronic inflammation, and lichen sclerosus (13). The findings of an essential impact of HPV in penile cancer incidence are based on a large number of studies evaluating the impact of HPV incidence and penile cancer. In summary, HPV DNA has been detected in 14%-100% of invasive penile carcinomas depending on the number of patient samples, on the method used for HPV detection [polymerase chain reaction (PCR) versus ISH], as well as on the type of tumor tissue storage (fresh versus paraffin-embedded tissue). A quantitative review of studies using PCR methods for HPV DNA detection found HPV presence in 45.4% of invasive penile tumors after adjusting for PCR primer, histological subtype, and year and geographical location of the study (14). In contrast to this, another study also using PCR found HPV present in 100% of warty and 80% of basaloid tumors, but in only about one-third of keratinizing and verrucous tumors (15). Heideman et al. detected HPV DNA in 55% of penile cancer (16), while another work from Chaux et al. measured HPV by real-time PCR in 35% of cases (17). However, a small study including 31 patients measured HPV DNA in more than 80% of penile carcinomas (18). In contrast to the PCR studies, Senba et al. used the ISH method for HPV detection and found 81.5% HPV positivity in patients with penile cancer (19).
A meta-analysis (of 31 studies) examining the prevalence of HPV subtypes in invasive penile tumors found that HPV-16 was the most common HPV type (60.2%), followed by HPV-18 (13.3%) and HPV types 6/11 (8.13%) (20). Furthermore, serological studies support the role of HPV infection in penile cancer. Data from Bjorge et al. support the concept that HPV seropositivity is associated with higher risk of developing penile cancer (21).
In summary, most studies found a significant number of penile cancer cases to be associated with HPV infection. A more detailed proper concerning of the role of HPV in penile carcinogenesis might help planning intervention strategies such as vaccination against HPV infection.
HPV in Prostate Cancer
Prostate cancer is the leading cause of cancer in men and the second cause of cancer mortality among men in European countries (22).
Several serological- and tissue-based studies were undertaken to elucidate differences in HPV presence in benign and malignant prostate tissue with contradictory results. Briefly, most studies found no difference in HPV expression patterns between cancerous and non-cancerous prostate (reviewed in (23)). Tachezy et al. for example detected HPV DNA in 2% of both prostate adenoma and prostate cancer, moreover no difference in the seroprevalence rates for HPV 16 E6 and E7 oncoproteins between prostate cancer and non-cancerous prostate was found in this study (24). Data of Ghasemian et al. also did not describe a significant role of HPV infection in prostatic disease in Iranian patients (25). The Prostate Cancer Prevention Trial conducted a large prospective investigation of HPV types 16, 18, and 31 in relation to risk of prostate cancer, including 1232 patients. In line with previous studies, no associations were observed for weak or strong HPV-16, HPV-18 or HPV-31 seropositivity and risk of prostate cancer (26).
Condyloma acuminatum 2, human papillomavirus (×10) (own data). Arrow, episomal pattern.
Episomal and integrative pattern of (×20) of the preputial epithelium in an asymptomatic man (own data). Thin arrow, integrative pattern. Thick arrow, episomal pattern.
However, there also exist several studies that found a differences in HPV expression between prostate cancer and benign prostate: Already 15 years ago Serth et al. described significantly higher (p=0.02) copy numbers of HPV-16-E6 sequences in prostate cancer compared to prostate adenomas, indicating that oncogenic HPV-16 might contribute to the development of a subset of prostate tumors (27). In line with this finding, Dillner et al. also revealed a positive correlation between HPV seropositivity and prostate cancer risk (28). In January 2015, an Indian study including 96 prostate cancer and 55 benign prostate tissue samples found HPV infection in 41% of prostate tumor biopsies and 20% of benign prostate tissue samples (29). Moreover, they showed that a significant proportion of HPV-infected (74%) cases had a high Gleason score (29).
Another recent study investigated the prevalence of HPV infection and the prognostic impact for overall survival in a cohort of 150 patients with primary prostate cancer (30). Thereby, they found that overall survival was significantly associated with the nuclear expression of E7 protein and other clinicopathological factors, such as age greater than 72 years, high nuclear grade, capsule infiltration, and high Gleason score at diagnosis; on multivariate analysis, all except capsule infiltration were significantly independent prognostic factors for worse survival of patients with primary prostate cancer (30).
In summary, the HPV link to prostate cancer is still questionable and hotly debated by researchers. Further studies are needed to address this issue.
HPV in Renal Cell Carcinoma
Renal cell cancer is a very rare neoplasm, thus only few studies evaluated the pathogenetic role of HPV on renal cell carcinogenesis. Different studies have shown that immunosuppressed renal allograft recipients seem to be at high risk for infection with virus HPV-related de novo urogenital malignancies (31, 32). However, there is still controversy regarding the exact prevalence of HPV in kidney cancer. Again, depending on the method used for HPV detection (ISH versus PCR) either high or rare incidence of HPV has been detected in tumor samples (33). Khoury et al. for example interrogated data from 3,775 malignant neoplasms in the Cancer Genome Atlas database for the presence of viral sequences using RNA-Seq analysis. One of the main findings in this study was the absence of transcribed DNA viral transcripts in some of the most prevalent human cancer types, including kidney cancer (34). Grce et al. also found no HPV DNA positivity in analyses of 28 renal cell carcinomas by PCR using, two sets of consensus primers and specific primer pairs for HPV types 16, 18, and 33 (35). In addition, no positive staining for HPV DNA was found in any histological type in a study of 62 renal tumors (40 clear cell, nine papillary, and three chromophobe renal cell carcinomas, one collecting duct carcinoma, duo urothelial carcinomas of the renal pelvis and seven oncocytomas), supporting the notion that HPV does not seem to play a role in the development of benign and malignant renal tumors. In this study, signal-amplified colorimetric ISH was performed on microarray sections using biotinylated probes for HPV subtypes 6, 11, 16 and 18 (36).
In contrast to these findings, Salehipoor et al. confirmed high-risk HPV DNA positivity (types 16 and 18) in approximately 14.3% of renal cell carcinoma tissue specimens analyzed by nested PCR (37). Using ISH, Kamel et al. investigated 56 renal cell carcinomas for the presence of HPV DNA (subtypes 6, 11, 16, 18, 31 and 33) and concluded that the presence of HPV DNA in these tumors implicated HPV viral infection in the etiology of kidney cancer as HPV positivity was found in 52% (38).
The results regarding HPV incidence in renal cell carcinoma remain controversial possibly depending on the HPV DNA detection method used.
HPV in Testicular Cancer
Testicular cancer is a common neoplasm in men of younger age. In 1984, Newell et al. suggested for the first time that testicular cancer might have a viral etiology since it exhibits similar characteristics to Hodgkin's lymphoma, arguing that the similar geographical distribution of both cancer types would point to viral etiology as the causative agent for testicular cancer (39, 40). The viral theory was supported by certain characteristics of testicular cancer itself, including young age, as well as the increase in overexpression of wild-type p53 in many cases (41). In a large epidemiological study, only 6% of patients with testicular cancer tested positive for HPV type 16 (42). To investigate the transforming activity of the E6 and E7 genes in vivo, Kondoh et al. conducted an experiment with transgenic mice carrying HPV-16 E6 and E7 open reading frames; they obtained five transgenic founders and established three transgenic lineages, confirming testicular tumors of germ cell origin in mice of all three lineages. These results suggest that E6 and E7 of HPV-16 have transforming activity in vivo and preferential effects on germ cells in the testis (43). In contrast to these findings, HPV genotype 16 and 18 were not detectable in a study performed by Rajpert-De Meyts et al (44). Using real-time PCR employing GP5+/GP6+ consensus HPV primers to examine the presence of HPV sequences in testicular seminoma (n=61) and normal testicle (n=23), none of the specimens displayed the presence of HPV DNA (45). A recent study confirmed that 155 patients with testicular cancer had a high prevalence of semen infection with HPV (using fluorescence ISH) that worsened after radiotherapy and chemotherapy, probably through their immunosuppressive action and the effect of a higher vulnerability induced by the tumor (46).
The role of HPV in testicular cancer needs to be analyzed further.
HPV in Urothelial Cancer
The relationship between urothelial carcinogenesis and human papilloma virus is still poorly understood. The prevalence of high-risk HPV in bladder cancer ranges between 3% and 50% (47-52). Li et al., for example, noticed that HPV prevalence varies by region, by type of HPV DNA specimen, as well as by PCR primers used (53). The highest prevalence of HPV positivity was found in Moroccan patients, with an incidence of 52.4% (HPV-16 in 95.5% of cancer samples) (54). Although HPV DNA presence appears not to play a major causative role in bladder cancer in the general population, HPV infection should be kept in mind in a sub-group of patients such as those with rare urothelial carcinomas with squamous differentiation, neurogenic bladder, urothelial inverted papilloma or inverted papilloma with atypia, and in Bilharzial bladder carcinogenesis (23, 49, 55). In these cases, HPV serology may pave the way for better management and follow-up of patients and for optimal evaluation of HPV vaccination (56). However, how vaccination may induce the regression of bladder tumors at such mucosal sites has not been sufficiently examined. Interestingly, Domingos-Pereira et al. established an orthotopic model expressing HPV-16 antigen E7 as a model using an adjuvant E7 polypeptide. Subcutaneous and intravaginal vaccination induced a high number of intravesical E7+CD8+ T-cells, with confirmed tumor regression (57).
In contrast to these findings, urothelial carcinoma following renal transplantation does not seem to be associated with infection by HPV type 16 and 18 (58). Currently, only one Japanese study showed that patients with HPV DNA positivity/p53 antibody had a significant worse survival rate, indicating a poor prognosis (59). Additionally, the data of a pilot study suggested a positive trend in the correlation between tumor grade/stage and high-risk HPV DNA (48). No recent trial proved any relationship between HPV infection and risk of cancer recurrence and progression. Using urine samples for HPV detection by highly sensitive PCR assays, HPV presence in bladder cancer cases (6.1%) was similar to the control group (3.6%) (60). No positive signals for high-risk HPV (types 16 and 18) were confirmed by different studies n method using ISH for HPV detection (61-63). Alexander et al. investigated 42 cases of squamous cell carcinoma and 27 cases of urothelial cancer with squamous differentiation. HPV DNA and protein were not detected in any case of bladder cancer by ISH at the DNA level and immunohistochemistry at the protein level (64).
In summary, although many trials demonstrated a possible relationship between bladder cancer and HPV infection, convincing evidence regarding bladder carcinogenesis is still lacking. Additional studies to investigate the carcinogenic potential of HPV and the possible role of HPV infection on cancer recurrence or progression are needed.
Summary
HPV is a recognized risk factor in penile cancer that has been demonstrated in a large number of studies. Concerning other urological malignancies, the role of HPV is not yet clear, however, in most studies HPV does not appear to be associated with risk of urological malignancies. Small patient numbers, unicentric or retrospective study characteristics may partly explain the differences in HPV detection rates among the studies. Moreover, the detection method used for HPV measurement seems to be a challenging issue. In addition, it was recently shown for the first time that the HPV epigenetic signature is a better predictor of survival than HPV status alone (65). Thus, further studies with larger patient collectives and optimized detection methods are of great need.
Footnotes
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Conflicts of Interest
The Authors have no conflict of interest regarding this article
- Received January 26, 2015.
- Revision received February 8, 2015.
- Accepted February 10, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
