Human papilloma viruses and cancer in the post-vaccine era

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1 REVIEW /j x Human papilloma viruses and cancer in the post-vaccine era E. Galani and C. Christodoulou Metropolitan Hospital Medical Oncology, Athens, Greece Abstract Human papilloma viruses (HPV) are strong human carcinogens, in fact today they are considered as the second most frequent carcinogen. In the middle of the 1970s the hypothesis that cervical cancer may arise from viruses was established and in the 1990s the relationship between HPV and cervical neoplasia was confirmed. HPV infections are the most common sexually transmitted infections. Specific subtypes of human papilomaviruses are now considered as the etiological agents in nearly all cases of cervical cancer and cervical epithelial neoplasia. Approximately new cases and deaths of cervical cancer occur each year, with the majority taking place in developing countries. Cervical cancer remains among the three leading causes of cancer deaths among women below the age of 45. Human papilomaviruses are classified into two groups: high-risk (oncogenic) types and low risk types. HPV types 16, 18, 45 and 31 are considered to be the most important oncogenic types. Subtypes 16 and 18 are the causative agents of more than 50% of cervical precancerous lesions, and more than 70% of cervical cancer cases. High risk subtypes are also implicated with anal, perianal and oropharyngeal carcinomas. Recently, the prophylactic bivalent HPV 16/18 and the quadrivalent HPV 6/11/16/18/ vaccines have been approved. The development of prophylactic vaccines against human papilomavirus has been hailed as one of the most significant advances of recent years and it is expected to reduce dramatically the mortality of human papilomavirus associated cancers, but has also given rise to some of the most intense scientific debates. Keywords: Cancer, cervical cancer, human papillomavirus, human papillomavirus related cancers, review, vaccines, virus Clin Microbiol Infect 2009; 15: Corresponding author and reprint requests: E. Galani, Metropolitan Hospital Medical Oncology, Kronou 12, Athens 17561, Greece Introduction Approximately new cases of cervical cancer are diagnosed annually and approximately women worldwide die from the disease each year. The majority (c. 80%) of these cases and deaths occur in developing countries. In approximately 60% of all countries, mainly in less developed regions, cervical cancer dominates as the first or second most frequent malignancy, often afflicting relatively young females. Although cervical cancer is considered to be a preventable disease, it remains one of the three leading cancers among women below the age of 45 years in up to 90% of all countries, including developed and less developed regions [1]. In the 1990s, molecular biology technology and epidemiological studies established the relationship between some specific subtypes of human papilloma virus (HPV) persistent infections and cervical cancer. Historically, in the middle of the 1970s, the hypothesis that cervical cancer may arise from infections with the virus found in condylomata acuminate was established [2,3]. In 1976, it was reported that koilocytic cells found in cervical smears of patients with dysplastic lesions characterize the pathological change in HPV infection [4]. Today, it is well known that infection with high-risk HPV subtypes can cause cervical cancer. More than 95% of cervical cancer biopsies contain HPV genomes; however, this does not necessarily imply that all of these tumours are caused by these infections [5]. HPV and Cervical Cancer HPV are now considered to be the aetiological agents in almost all cases of invasive cervical cancer and cervical intraepithelial neoplasia (CIN). Indeed, based on epidemiological, clinical and laboratory-based evidence, HPV has been identified as the necessary cause of cervical cancer (i.e. cervical cancer does not and will not develop in the absence of the persistent presence of HPV DNA) [6]. This association is Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases

2 978 Clinical Microbiology and Infection, Volume 15 Number 11, November 2009 CMI Cervical dysplasia Carcinoma in situ Invasive cervical cancer HPV-infected females stronger than that between cigarette smoking and lung cancer; however, the development of cervical cancer subsequent to HPV infection is not inevitable. It has been estimated that, for every one million women who are infected, only 10% or will develop pre-cancerous cervical cell changes (cervical dysplasia). Among these, approximately 8% (8000) will develop early cancer confined to the outer layers of the cervical cells (carcinoma in situ) and approximately 1600 of these women will go on to develop invasive cervical cancer. Moreover, mortality rates are significantly lower than the incidence of cervical cancer (Fig. 1). It is estimated that, worldwide, the ratio of mortality to incidence is 55%. The Virus HPV are non-enveloped viruses composed of a doublestranded, closed circular DNA genome. HPV is genetically stable, unlike other viruses such as influenza. Genetic studies indicate that the biology of HPV has remained essentially the same for over years [7]. HPV infections are the most common sexually transmitted infections. Both men and women can be affected; they can be asymptomatic carriers, transmitters, or can be infected with HPV. HPV transmission may occur even with skin-to-skin genital contact. Common risk factors include the number of sexual partners, an early age at first intercourse, and any previous sexually transmitted disease. The parameters of sexual behaviour, in general, reflect the risk of HPV infection. Studies have shown that the risk of a given woman for cervical cancer can be predicted by her own sexual behaviour or by her husband s/partner s sexual behaviour. A woman s risk of developing cervical cancer has been shown to be related to the presence of HPV in the penis or the urethra of her husband/sexual partner. It is estimated that a women s life-time risk of acquiring one or more genital HPV infections is at least 75%. Male circumcision protects males from HPV infection and their wives or sexual partners from developing cervical cancer. Additional proposed risk factors for developing cervical cancer (which have been inconsistently documented in related studies) are the prolonged use of oral contraceptives, high parity, and cigarette smoking. Possible factors include dietary habits, in particular diets poor in fruits and vegetables, as well as coinfection with other sexually transmitted pathogens, such as Chlamydia trachomatis and herpes simplex virus type 2 [8], and co-infection with more than one HPV type [9]. Moreover, HIV infection and other immunosuppressive situations are related to an increased risk of disease persistence and progression, indicating a theoretical background for longterm viral persistence in a latent form that eventually evolves when immune guarding allows for it. Viral Oncogenic Potential FIG. 1. Natural history of oncogenic human papilloma virus (HPV) infection. Over 200 papilloma virus types have been described, approximately 100 of which infect humans and are there-

3 CMI Galani and Christodoulou Human papilloma viruses and cancer 979 ΣεIρα FIG. 2. Human papilloma virus (HPV) types characterized as oncogenic and their relative contribution to cervical cancer development. Values are shown as percentages, with data estimates derived from Arbyn and Dillner [27]. 0 HPV16 HPV16+18 HPV HPV HPV HPV HPV HPV HPV HPV HPV HPV fore classified as HPV. There are approximately types of HPV specifically infecting the genital area and these are classified into two groups: high-risk (or oncogenic) types and low-risk types [10]. The most important oncogenic types have now been fully characterized. Munoz et al. [11], in a pooled analysis of all cancer types, found HPV types 16, 18, 45 and 31 to be the most important of the ongogenic types. The most recent designations of the International Agency for Research in Cancer, along with their relative impact on the causes of cervical cancer, are depicted in Fig. 2. Globally, types 16 and 18 together are the causative agent of more than 50% of cervical pre-cancerous lesions (high-grade dysplasias), more than 70% of all cases of cervical squamous cell carcinoma and adenocarcinoma, and 25% of low-grade cervical lesions. Squamous cell carcinoma is the typical lesion, whereas adenocarcinoma represents 10 15% of cervical cancers, particularly in the developed world. HPV and Other Cancers Because HPV expresses a predilection for transitional zones, it is also implicated in other cancers. High-risk HPV types are implicated in penile, vulvar, vaginal, anal and oropharyngeal carcinomas. Specifically, approximately 50% of vulvar squamous cell carcinomas [12] and 30 50% of penile carcinomas [13,14] are HPV-related. In general, HPV-positive vulva and penile neoplasms appear to have a better prognosis compared to the HPV-negative tumours [14]. By contrast to penile and vulvar cancers, carcinomas of the vagina are HPV-positive in 60 90% of cases [12]. The same appears to be true for anal and perianal cancers. Furthermore, it is now well established that 20 75% of oropharyngeal cancers are HPV-positive. HPV-related oropharyngeal carcinoma is associated with better clinical outcome as compared with the non-hpv-related oropharyngeal cancer. In cervical cancer, the number of high-risk types is restricted to types. HPV Epidemiology Worldwide, HPV 16 is the most common type implicated in cervical cancer, with a prevalence ranging from 47.7% in sub- Saharan Africa to 69.7% in Europe/North America [15]. HPV 18 is the second most common cause of cervical cancer, with a prevalence ranging from 12.6% in Central/South America to 25.7% in Southern Asia [15]. HPV 18 is more frequently the cause of cervical adenocarcinoma than HPV- 16. The two most common low-risk HPVs, genotypes 6 and 11, cause genital warts or condylomata accuminata and lowgrade intraepithelial lesions. HPV 6 and 11 are found in over 90% of anogenital warts [16] and these are not associated with oncogenesis in the cervix [11]. They also cause recurrent respiratory papillomatosis.

4 980 Clinical Microbiology and Infection, Volume 15 Number 11, November 2009 CMI The prevalence in low-risk/general population females varies with age as well as geographically; a 15% median prevalence of oncogenic types in all females has been reported [17], although the prevalence in females aged >30 years is 9.2%. A peak is observed at or approaching age 25 years, with a subsequent decrease in prevalence and a possible second peak at or approaching age 55 years [18]. Pathophysiology of Carcinogenesis Persistent infection with one or more high-risk subtypes over time leads to the development and progression of CIN disease. The progressive development of cellular changes starts with infection of the basal cell layers of the epithelium. The entire process generally takes place over a period of years, although it may take place in only 1 2 years in some cases. CIN I changes can arise within 3 months of infection, whereas CIN II changes arise within 6 months, and CIN III changes within 1 2 years. Whether pathogen virulence factors or inherent host immune factors are decisive in the speed of the oncogenic process remains to be clarified. Abnormal infected cells and CIN I can also be termed lowgrade squamous intraepithelial lesions, whereas CIN II and CIN III can also be termed high-grade squamous intraepithelial lesions. The development of CIN I is not necessarily a precursor to cancer, and can be observed even with nononcogenic type HPV infection. Even CIN II changes can regress naturally. A substantial fraction of women with highrisk HPV DNA who are cytomorphologically normal will develop CIN II or CIN III within 4 years. By contrast, women negative for high-risk HPV DNA, even though cytologically abnormal (with atypical squamous cells of undetermined significance, or borderline or mild dysplasia) are unlikely to develop CIN II/III during a follow-up period of 2 years, and their cytology is likely to return to normal [6]. The E6 and E7 proteins of the oncogenic HPV are generally recognized as the dominant oncoproteins [19]. The major mechanisms through which HPV contributes to carcinogenesis include the activity of these two viral oncoproteins, which interfere with the critical cell cycle tumour suppressive proteins, p53 (E6) and retinoblastoma (Rb) protein (E7). Moreover, E6 and E7 oncoproteins are also associated with viral and host DNA methylation changes, many of which also occur in cancer types that are not related to HPV infection. The E6 and E7 interactions with the cellular proteins and with DNA methylation changes are associated with alterations in key cellular pathways that regulate genomic integrity, cell adhesion, the immune response, apoptosis and cell cycle control [20]. Vaccines for Prophylaxis Papilloma viruses possess a major capsid protein called L1 that has the ability to self-assemble in viral-like particles and to be expressed in eukaryotic cells [21]. Human papilloma viruses are localized in the epithelium and thus have minimal contact with the host immune system and, in general, the immune response can be low-grade and transient. With the development of the HPV viral-like particles, however, the first generation of prophylactic vaccines was feasible. Clinical trials of prophylactic bivalent HPV 16/18 and quadrivalent HPV 6/11/16/18 vaccines demonstrated that the vaccines were well tolerated, without serious adverse events, and were highly effective in preventing HPV infection. In June 2006, a quadrivalent vaccine was approved by the US Food and Drug Administration for the prevention of HPV 6/11/16/ 18-associated cervical cancer, adenocarcinoma in situ, cervical intraepithelial neoplasia, vulvar intraepithelial neoplasia, vaginal intraepithelial neoplasia and genital warts in women. A bivalent vaccine that protects against HPV 16 and 18 has also been approved in Europe. The development of prophylactic vaccines for HPV oncogenic types has been hailed as one of the most significant scientific advances of recent years, but has also given rise to some of the most intense scientific debates regarding the implementation, planning and cost-effectiveness of vaccination. Compulsory vaccination is still not implemented in certain countries of the Western world, and religious, ethical and political issues have been raised, understandably, because sexual behaviour and related policies are implicated [22]. One important issue regarding evaluation of prophylactic vaccine efficacy is that the major endpoint (i.e. a reduction in incidence of cervical cancer) can only be evaluated after decades of implementation of vaccination; thus, mathematical models (with all the resulting statistical inconsistencies and differences in modelling) have been incorporated, aiming to demonstrate vaccine effectiveness [23 25]. Long-term efficacy has been recently re-confirmed, extending to a 5-year period. Questions arise regarding vaccination of older females, with some studies supporting the idea that partial protection may be offered to a subset of HPV-negative females [26]. Moreover, vaccination of males has been discussed as a potential inducer of herd immunity by minimizing the pool by which females become infected; mathematical models, however, have shown that the impact of such an extended vaccination programme would be borderline, and definitely not cost-effective. Further questions regard the potential impact on HPV ecology (i.e. whether mass vaccination will lead to a higher incidence of other oncogenic HPV

5 CMI Galani and Christodoulou Human papilloma viruses and cancer 981 types). Another issue that has not been evaluated is that of the impact of mass vaccination on the overall incidence of other cancers, apart from cervical cancer, that are aetiologically related to HPV. Finally, a consistently raised issue is that of screening, which subsequently influences the planning of vaccination policies and impacts modelling. An aggressive screening approach may, for example, reveal a small minority of young patients with rapidly developing disease and would simultaneously identify a significant number of females with lesions that would regress naturally. Conclusions In summary, HPV today is considered to be the second most frequent human carcinogen, accounting for 5% of human cancers, 10% of cancers in women, and 15% of cancers in women in developing countries. The percentage of cases linked to HPV 16 and 18 subtypes is potentially preventable. 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