HPV Infection and Associated Cancers

HPV Infection and Associated Cancers 1.0 Introduction Human papillomavirus (HPV) is a sexually transmitted virus that is spread through genital and skin-to-skin contact [1]. Its infection is the most common sexually transmitted infection in the world [1] and accounts for 561200 representing 5.2% of all cancer cases worldwide [2, 3]. Over 290 million HPV infections are recorded worldwide annually [4] and the prevalence of HPV vary from 14% to over 90% [5]. Currently, over 170 HPV-types have been identified and designated with numbers [6-8] and at least forty are transmitted through genital contact [9]. The virus can also be transmitted through skin-to-skin sexual contact (regardless of penetration), mucous membranes or bodily fluids, oral sex and mutual masturbation (genital fondling) [10]. HPV affects only humans [11]. When the HPV virus comes in contact with human cells, it may bring about changes to the cell called lesions which may lead to the development of tumors [6]. High-risk HPV-types (hrHPV) (aka oncogenic HPV-types) are able t o incorporate themselves into the cell DNA and transform its behavior in a way that results in cancer whereas low-risk HPV-types (aka non-oncogenic HPV-types) do not cause cancer [10]. HPV infection is most common in young men and women in their teens and early 20s [11]. Authors of the HPV Infection and Transmission among Couples through Heterosexual activity (HITCH) cohort study reported an HPV infection of more than 56% in young adults in relatively new sexual relationships and more than half (44%) were infected with oncogenic HPV-types. In the early 2000s, about 6.2 million new cases of HPV infection were recorded in America of which 74% occurred in 15 to 24-year olds [12].   A systematic review of more than 40 studies by Dunne et al (2006) showed that HPV prevalence estimates vary from 1.3% to 72.9% amongst studies of multiple sites and 56% of them reported a prevalence of more than 20% [13]. Most HPV infections are asymptomatic and usually resolve on their own over the course of weeks [14]. For example, HPV-5 may cause infections that may linger for a very long time in an infected person without showing any clinical symptoms [9]. However, when an HPV infection does not resolve naturally, it may result in malignancies including genital warts (small or large, raised or flat or even shaped-like-a-cauliflower bumps or groups of bumps around the genital region) [9] and precancerous lesions [15]. While HPV-1/2 causes common warts (usually found on the hands, feet and sometimes knees and elbows), HPV-6/11 causes Recursive Respiratory Papillomatosis (RRP) (when warts are formed on the larynx [16] or other sites on the respiratory tract) [17, 18]. These warts recur very often and obstruct breathing [17]. Another major symptom of HPV infection is that it is strongly related to cancer, specifically cancer of the cervix, vagina, vulva, oropharynx, anus and penis [2, 3] (For details refer to Section 1.1). One common feature of these cancers involves the transmission of HPV infection to the stratified epithelial tissue (a multilayered cell with every cell in direct contact with a basement membrane that separates it from a connective underlying tissue) [2, 14 -15]. The first section of this chapter of this thesis, section 1.1, briefly introduces all cancers associated with and attributable to HPV infection as reported in [2, 3]. Definition of HPV-associated and HPV-attributable cancers are also given in the same section. This is particularly important as a clear inclusion or exclusion criteria is set for cancers of the cervix, vagina, vulva, anus and penis as defined by their causal methods which are HPV-inspired or otherwise. Subsections 1.11 to 1.16 are devoted to respectively discussing all six cancers. In these subsections, actual definitions of cancer of the cervix, vagina, vulva, anus and penis will be provided as well as their composition by specific anatomical region. The relationship between HPV and these cancers will also be provided in these subsections as well as a brief history. Section 1.2 will provide a detailed discussion regarding international trends in the incidence rates of these HPV-associated cancers. Section 1.3 will disc uss the behavior of the incidence rates in Canada as established in Canadian literature and will, therefore, show why this thesis seeks to explore the behavior of incidence rates of HPV-associated cancers in Canada using Canada-wide data. Finally, section 1.4 will itemize the research questions in this thesis. 1.1 HPV-associated Cancers When most people think of an HPV infection, they might think of cervical cancer. However, one must be careful because they is a growing subset of non-cervical cancers extensively established as strongly linked to HPV infection and the proportion of these cancers vary by anatomical site [3]. These cancers include cancer of the oropharynx as well as those in the genital region (i. e. vagina, anus, vulva and penis) [19]. Current data reveal that HPV-infection is associated with 12%-63% of oropharyngeal cancers, 40%-64% of vaginal cancers, 40%-51% of vulvar cancers, 36%-40% of penile cancers and 90%-93% of anal cancers [3, 20] and 100% of cervical cancer cases are attributable to HPV [21]. The difference in HPV-attributable proportions for these non-cervical cancers partly results from inherent differences in the methods of detecting cancer, differences in geographic locations in HPV-attributable populations [22]. Other potential reasons for differences in HPV proportions are because som e studies report on individuals currently having a detectable infection while others report on individuals who have ever had a detectable infection and also there are differences in the HPV strain tested for by different studies [23]. An HPV-associated cancer is a specific cellular type of cancer that is diagnosed in a particular part of the human body where HPV is found [9]. The virus is often found in the vulva, vagina, cervix, rectum, anus and oropharynx [23, 24]. Several studies including [24] have shown that the incidence rates of HPV-associated anal and rectal cancers are similar, so from-here-on-in, rectal cancer will be assumed to have an analogous incidence distribution as anal cancer. Cancer-based registries (CBRs) identify diagnosed cases by using the International Classification of Diseases for Oncology, 3rd revision (ICD-O-3) codes for HPV-associated groups: cancers of the anus (C20-C21), vulva (C51), vagina (C52), cervix (C53), penis (C60) and oropharynx (C019, C024, C028, C090-C099, C102, C108, C140, C142 and C148) [25, 26]. An HPV-attributable cancer is a cancer that is possibly caused by HPV [9]. HPV causes all cervical cancers and cancers of the vulva, penis, vagina, anus, rectum and oropharynx as shown above. The epidemiology and histology of HPV-associated cancers of the cervix, anal, penile, vaginal, vulvar and oropharynx are discussed next in subsections 1.11 to 1.16. 1.11 Cervical Cancer Cervical cancer is a major global public health threat: it is the fourth most prevalent cancer in women, with approximately 500000 new cases annually [27, 28]. Almost all cervical cancers occur at the junction of the endocervix and the ectocervix, at a junction called the transformation zone [28, 29]. According to the International Federation of Gynecology and Obstetrics (FIGO), any vaginal lesion that relates to the ectocervix should also be treated as cervical cancer [29]. Before puberty, this junction is found on the visible vaginal portion of the cervix (i.e. the ectocervix) and is fairly stable [30]. Within young women as well as women on oral contraceptives, the visible transformation zone is called ectopy, which regresses into the endocervix with increasing age and the commencement of sexual intercourse [31]. The main morphological type of cervical cancer associated with HPV is squamous cell carcinoma (SCC) which accounts for about 60% of all cervical cancer cases [28]. Adenoc arcinoma (AC) and adenosquamous carcinoma (ASC) are the next common types while neuroendocrine or small cell carcinomas, primary cervical lymphoma, cervical sarcoma, and rhabdomyosarcoma are rare [28]. There are geographical differences in the cervical cancer incidence rates [28]. GLOBOCAN 2012 examined the burden of cervical cancer amongst countries by estimating age-standardized incidence rates (ASR) by country, and a global ASR of 14 per 100000 women of all ages was reported [32]. Over 85% of the global burden of cervical cancer occurs in developing countries, where it accounts for 13% of all female cancers [33, 34]. Most countries in South America and sub-Saharan Africa report an ASR associated with cervical cancer of more than 50 per 100000 women [28]. In contrasts, cervical cancer rates are generally less than 7 per 100000 women in western Europe, western Asia, New Zealand, the Middle East and Australia and these geographical differences in cervical cancer incidence rates closely reflect the availability of cervical precancer screening programs [28]. Comprehensive national screening programs for cervical cancer and dysplasia have a great impact in managing cervical cancer incidence [35]. The Papanicolaou (pap) smear screening test, which detects cytological abnormalities of the cervical transformation zone reduced cervical cancer incidence by more than 70% in developed countries [36]. Risk factors associated with cervical cancer include early sexual debut, multiple sexual partners [37], smoking [38], a history of sexually transmitted diseases (STDs) [39] and chronic immunosuppression with Human Immunodeficiency Virus (HIV) infection [40]. Circumcision of male sexual partners is protective for women [41]. Cervical cancer is preventable by avoiding HPV, the causative agent or through the identification and treatment or pre-invasive lesions by histopathologists [30]. These precursor lesions to cervical cancer are called cervical intraepithelial neoplasia (CIN) or, specifically, squamous intraepithelial lesions (SIL) a term used to identify where abnormal cells develop [30]. Lesions from Low-grade CIN mostly relapse while those of high grade require comprehensive treatment [42]. For high-grade CIN, the rate of progression to invasive cancer if left untreated is approximately 30%-50% with 30 years, however, proper treatment drastically reduces this risk to under 1% [42]. 1.12 Anal Cancer Anal cancer or squamous carcinoma of the anus and anal canal is a rare malignancy accounting for only 2% of all gastrointestinal cancers [43, 44] and about 4% of cancers associated with the lower gastrointestinal tract [45]. Anal cancers emerge from anal mucosa when glandular elements associated with the gastrointestinal tract develops into squamous mucosa [28]. Research has shown that a greater proportion of anal cancer cases are attributable to continuous infection with hr-HPV (HPV-16/18) [46]. The global ASR associated with anal cancer is shown to be 1.0 per 100000 [32]. Risk factors for HPV-associated cancer of the anus are generally associated with sexual activity [46, 47]. Reporting at least 10 sexual partners in ones lifetime increases the risk of developing anal cancer [48]. Elsewhere, receptive anal intercourse with two or more partners and HIV infection [49], a history of sexually transmitted infections (STIs) (e.g. gonorrhea, chlamydia trachomatis, herpes simplex virus 2) [48], genital warts [50] and smoking [51] have also been shown to increase the risk of developing HPV-associated anal cancer. 1.13 Penile Cancer Another rare malignancy associated with HPV infection is penile cancer. It accounts for less than 1% of all male cancers [3, 43 and 52]. It is an abnormal growth found in the tissues or on the skin of the penis and about 95% of all cases of penile cancer are SCC [53]. It mostly results from a series of epithelial modifications (precursor lesions) which often progress quickly from low-grade lesions to high-grade lesions and finally invasive carcinoma [53]. The frequency of SCC being preceded by premalignant lesions is still unknown [54-57]. Although SCC is the most prevalent penile neoplasia, several histological types of different growth patterns, clinical aggressiveness and HPV association have been reported [58]. An HPV infection is found in basaloid (warty penile SCCs (39%) and 76%, mixed warty-basaloid (82%) [55]. DNA of HPV has also been identified in about of 30%-40% and about 70%-100% of invasive penile cancer tissues [54]. Variations in histological subtypes of penile cancer vis-à  -vis the rate of HPV-positivity is an indication that HPV may be a cofactor in the carcinogenesis of certain variants of penile SCC [59]. This therefore points to higher incidence associated with penile cancer in regions with higher prevalence of HPV and vice versa [60]. Geographical differences in study populations result in variations in incidence rates associated with penile cancer [32]. In North America and Europe, SCC of the penis accounts for less than 1% of cancers associated with men [43]. In developed countries, the ASR of penile cancer is between 0.1 and 0.5 per 100000 men [32].   However, for developing countries including Malawi, Uganda, Brazil, Vietnam, Paraguay, Columbia and India, the penile cancer accounts for more than 10% of reported cancers [32]. The associated ASR is at least 2.0 per 100000 men is reported in these countries [32, 43-44]. The incidence of penile cancer suggests the presence of risk factors [28]. Risk factors essentially are associated with chronic inflammation and HPV infection, compromised genital hygiene [61-63]. Circumcision is reported to have a 3-fold decrease in penile cancer risk [62]. Cancer of the penis is classically associated with old age and is generally reported in men with low socioeconomic status [52]. Smoking is also an independent risk factor associated with penile cancer [62, 63]. Though not an Acquired Immune Deficiency Syndrome (AIDS)-defining cancer, the risk of developing penile cancer in HIV-positive men is 8 times higher than in HIV-negative men. Men with penile cancer are most likely to report protracted penile rash, penile injury, prior history of genital warts and phimosis (the inability of an uncircumcised penis to fully retract the foreskin) [62]. 1.14 Vaginal Cancer HPV-associated vaginal cancer is a rare malignancy with an ASR between 0.2 and 0.7 per 100000 in most countries [64]. It is associated with older women, with incidence peaking around the sixth and seventh decades of life [65]. Several studies have shown that