HPV Infection and Associated Cancers

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7th Aug 2017 Health Reference this

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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 to 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].

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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 discuss 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 some 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]. Adenocarcinoma (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 one’s 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 <15% of all cases of vaginal cancer patients are diagnosed before 50 years and about 10% of these occur before 40 years [66-69]. Over 90% of all vaginal cancer cases tend to be SCCs and mostly occur in the upper region of the posterior wall of the vagina while ACs accounts for only 5% [66-68]. At diagnosis, the median age associated with SCCs is approximately 69 years even though this malignancy is detected in the third and fourth decades [70].

The vagina is a 7.5-centimetre dilatable tubular structure which extends to the vulva from the cervix [71].A lot of the neoplasms associated with cancer of the vagina are SCCs even though melanoma and AC, which are largely associated with utero diethylstilbestrol (DES) exposure do rarely occur [28, 71]. The incidence of SCC of the vagina is reducing currently owing to the stoppage of DES prescription in pregnancy in many countries [71]. Primary vaginal cancer accounts for 1-2% of all genital cancers associated with women and over 80% are metastases from the cervix and vulva [72, 73]. Primary vaginal ACs are diagnosed in women younger than 20 years whereas primary SCCs often occur in women who are at least 65 years old [70]. Secondary vaginal cancer is more prevalent than primary vaginal cancer and usually occurs as an extension from the cervix, endometrium or vulva [70].

Vaginal intraepithelial neoplasia (VaIN) may precede vaginal cancer even though the natural progression of VaIN have not been completely described [28]. Two retrospective studies of several VaIN treatment procedures including surgical excision, topical agents, laser ablation and radiation therapy, reported that about 5% of cases progress to invasive carcinoma of the vagina [74, 75]. However, prospective trials establishing the most efficient treatment procedure is extremely sparse in the literature [71]. Nonetheless, surgical resection is the most commonly applied method of treating vain because it removes the diseased tissue and obtain histologic diagnosis of the entire lesion [71]. Depending on the severity of infection, surgical can be minimal as a wide local excision or extensive as a total vaginectomy which recurs at a rate of 18% [76, 77]. VaIN is usually related to a previous or current neoplasia in the lower portion of the genital tract [28]. Two studies therefore shows that about 50-90% of VaIN patients have a history of or current intraepithelial neoplasia or cervical and/or vulvar carcinoma [76, 78].

Having at least 5-lifetime sexual partners, early sexual debut (before 17 years), prior history of genital warts, current smoker at diagnosis, low socioeconomic status, prior abnormal cytology, prior hysterectomy [79-80], hrHPV infection and immunosuppression [81] are common risk factors associated with vaginal cancer. About 33% of women who report vaginal cancer would report a prior history and/or treatment for an anogenital tumor typically of the cervix [70]. In addition, women with a prior treatment for a high-grade CIN have a 4-fold higher risk of developing invasive cancer of the vagina [82].

Diagnosing vaginal cancer is sometimes difficult because patients have painless discharge and bleeding from the vagina and lesions are usually missed on visual inspection [28]. Also, there are chances that if a lesion is inconspicuous and is in found the lower two-thirds of the vagina, diagnosis may be missed because lesions can be obscured by the blade of the speculum and in such instances, examination under anesthesia is most recommended [71]. When symptoms are present, a complete examination involving cytology, speculum examination, colposcopy, digital palpation and biopsy of any noticeable lesion should be performed and the speculum slowly rotated as it is withdrawn from the vagina to ensure a visualization of the complete vaginal mucosa [71]. This is particularly important because invasion and the size of a tumor are the main prognostic pointers [83, 84].

1.15 Vulvar Cancer

The vulva comprises of the exterior female genital organs including the labia minor, labia majora, mons pubis, clitoris, vaginal vestibule which contains the Bartholin and skene glands as well as the urethral meatus [71].Cancer of the vulva accounts for about 5% of cancers of the female lower genital tract [43, 44]. It is an invasive growth of the vulva and sometimes the visible portion of the female genital organ [85]. The labia majora is the most susceptible site accounting for more than 50% of all cases [86, 87], seconded by the labia minora [88]. However, the clitoris is very infrequently affected [89].  The most prevalent morphologic type of vulvar cancer is SCC, however, a few women also report other relatively rare types including melanoma and sarcoma as well as other undifferentiated carcinomas [32]. Most women with vulvar dysplasia rarely show signs and symptoms and diagnosis is only made with a high degree of suspicion [71].

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Relatively rare cancer, ASR associated with cancer of the vulvar vary between 1.0 and 1.8 per 100000 women [64]. Fewer incident cases are associated with countries with comparatively small populations and relatively populous countries report a higher number of incident cases [88]. E.g. Scotland reports about 100 incident cases annually [86] whereas USA reports about 5000 cases [44]. The average age at diagnosis of vulvar cancer is 65 years but this age is projected to reduce by 2025 [89]. Over a decade ago, the incidence of vulvar cancer increased approximately by 10% within populations of women at most 50 years [89].

Risk factors associated with cancer of the vulvar include; persistent HPV infection, vulvar dystrophy (lichen sclerosus) and cigarette smoking [28]. Several studies also reported cervical cancer [90], CIN [88], immune-deficiency syndromes [91] and VIN [92] as significant risk factors.  VIN is a considered a precursor lesion to cancer of the vulvar [92]. However, the literature suggests a low rate of development to invasive carcinoma of the vulvar [93]. There is a worldwide increase in the incidence of VIN partly due to the increasing prevalence in young women [89, 94].

1.16 Oropharyngeal Cancer

Oropharyngeal cancers are malignancies located at where the pharynx and oral cavity merge, in the lingual and palatine tonsils, the soft palate, the posterior pharyngeal wall and the posterior one-third (base) of the tongue [95]. According to the World health organization (WHO), oropharyngeal cancer is the eleventh most prevalent worldwide and accounts for about 450000 new cases annually [96] even though there regional variations in incidence rates [95]. However, widely established in the literature is increasing incidence rates of oropharyngeal cancer in developing countries [97]. Globally, countries with the highest incidence rates associated with oropharyngeal cancer include Hungary, Romania, France and Slovakia [97, 98]. In these countries oropharyngeal cancer is most common in men [97]. According to the oral cancer foundation, there is a rising incidence of oral cancer amongst 25 to 50-year olds [99].

HPV causes clinically as well as epidemiologically different forms of oropharyngeal squamous cell carcinoma (OPSCC) [100-104]. These OPSCC forms are broadly grouped into two namely: HPV-positive and HPV-negative [105]. HPV-positive OPSCCs are strongly related to sexual behavior [100-104, 106] while HPV-negative OPSCCs have risk factors associated with tobacco and alcohol use [105, 106]. It is also important to note that, HPV-positive OPSCC patients have better survival when compared to their negative counterparts [107-109]. The reason for this result is thoroughly debated in the literature.

Several risk factors have been attributed to the development of oropharyngeal cancer. It is estimated that, about 75-90% of oropharyngeal cancers are directly linked to lifestyle choices and are therefore preventable [110-113]. According to the National Cancer institute, a diet low in fruits and vegetables, chewing of betel quid (a stimulant widely used in Asia), Plummer-Vinson syndrome are asbestos exposure are risked factors for oropharyngeal cancer [114]. In addition, the most important risk factors associated with oropharyngeal cancer are tobacco use (including chewing tobacco, smokeless tobacco and snuff), alcohol consumption and mucosal infection with HPV [110-113]. However, smoking marijuana is not linked to an increased risk of developing oropharyngeal cancer [112].

1.2 International Trends in HPV-associated Cancers

Epidemiological data on HPV-associated cancers in Asia have been far more limited [115]. Asia contains more than half of the world’s population and show staggering diversity in incidence rates associated with HPV-related cancer prevalence [32]. Incidence rates are produced from data from population-based cancer registries (PBCRs) which usually collect information on incident cases in a country even though most Asian countries lack such registries [116]. In the Asia pacific region, the few countries have PBCRs also faces acute challenges in producing incidence data of quality [115]. In countries with cancer registration schemes (e.g. Singapore, India, Thailand, Vietnam, Malaysia, Myanmar, Indonesia, Philippines and Mongolia), this is the most ideal source of incidence data [116]. However, in Japan, China and Korea, incidence rates are estimated from mortality data using models that relate incidence to mortality by gender and age group [116].

Globally, geographical differences in the distribution of risk factors associated with HPV-related cancers lead to varying incidence rates [35]. Knowledge of the patterns and availability of data on these ever-changing incidence rates and the burden associated with HPV-cancers is critical in taking decisions (especially regarding resource allocation) to fight these malignancies [32]. This section therefore examines the global behavior of incidence rates associated with cancers of the vagina, anus, oropharynx, vulva, cervix and penis. Subsections 1.21.1 to 1.21.6 presents a continental picture of these behaviors by cancer type and are discussed next.

1.21 Trends in Asia

1.21.1 Cervical Cancer Trends

Cervical cancer is the prevalent cancer among women in the Asia Pacific region (after cancer of the breast) with about 255000 incident cases (12.4% of all cancers) [33]. Incidence rates in the region closely mirror estimated world averages and account for about 51.6% of total global cervical cancer cases and 50.3% of cervical cancers deaths [116]. The highest incidence rates (per 100000 population) are reported in Melanesian populations including Solomon Island (42.8), Papua New Guinea (40.4), Cambodia (38.7), Fiji (33.4), India (30.7) and the least reported in Japan (8.0) and china (6.8) [33].

Major variations in cervical cancer incidence are also reported among sub-regions making the Asia Pacific region [33, 35 and 116]. Two big countries, China and India, contribute about 85% of the total population in the region, with China reporting a cervical cancer ASR of 6.8 per 100000 and 30.7 per 100000 women in India in the year 2000 [117]. However it is important to note that, there are significant variations in cervical cancer incidence within each of these countries [116]. Worthy of mention is the fact that estimated incidence rates (per 100000 women) associated with microscopically diagnosed cervical cancer between 2001 and 2002 by districts revealed high rates in Pondicherry (39.2), Villipuram (31.1), Cuddalore (29.9) and Thiruvallur (28.6) in the Tamil Nadu district in southern India and Aizawl (30.1) and Mamit (29.6) in the Mizoram district of North-eastern India [118]. In Chennai (India), Osaka (Japan) and Hong Kong (China), there has been a dramatic reduction in cervical incidence since 2002 [116]. In Shanghai (China), cervical cancer incidence dropped from 26.7 to 2.5 per 100000 women from 1972 to 1974 and also 1993 to 1994 [119]. In the Chinese South-eastern city of Qidong, cervical incidence rate was 4.2 per 100000 in 1978 to 1982, however this value has been reducing at 4.7% per annum for 20 years while mortality rates are increasing among women younger than 45 years of age [120].

According to the Korean Central Cancer Registry Program (KCCRP), incidence rates associated with cervical cancer decreased in the years 1993-2002 and the ASRs were 19.0, 178.8 and 15.1 per 100000 women between 1993-1995, 1996-1998 and 1999-2002 respectively [121]. Parkin et al (2008), in determining the future burden of cervical cancer in Asia, projects that, irrespective of population growth, aging and changing risks, the number of incident cases will rise to 415000 by the year 2025 (a 62% increment) with an age profile such that 52% of cases will be at least 55 years compared to the current 41%, assuming current incident rates will apply in the future [116].

1.21.2 Anal Cancer Trends

Incidence rates associated with anal cancer in Asia are generally low, not higher than 1 per 100000 [119, 122 and 123]. However rates are slightly higher in Hawaii (white ethnicity) – 1.5 per 100000 [120]. In most Asian populations, anal cancer is more prevalent in men than in women. [119]. Only a few studies have reported the prevalence and incidence rates of HPV-associated anal cancers in Asia including India [124], China [125-127], Taiwan [125, 128] and Thailand [125].

High anal cancer incidence is extensively associated with some risk groups – men who have sex with other men (MSM) and HIV infected people [129, 130]. In Japan, even though there is a low prevalence of HIV in MSM (0.018%) in the overall population, the number of incident cases increased from 314 in 2001 to about 724 in 2012, which is further projected to increase to 10.4% in 2014 [131, 132]. However there are no data available on HPV-associated anal cancer infection in Japan [131]. Elsewhere, studies indicate that there is an increase in incidence rates of HPV-associated anal intraepithelial neoplasia (AIN) in Asian MSM [133].

Being a rare cancer, trends in the incidence of anal cancer in other Asian countries as well as among Asian ethnic groups have previously not been studied [134].

1.21.3 Penile Cancer Trends

Penile cancer is a rare malignancy with prevalence and incidence rates being typically low in Asia [119, 122 and 123]. ASRs of penile cancer in Asia are generally less than 1 per 100000 men [134]. A very low penile cancer incidence (0.04 per 100000) is reported in Jewish populations who commonly practice circumcision at birth [3]. Southeast Asia records the highest incidence rates for penile cancer: Lampang (1.6 per 100000), Thailand (Songhkla – 2.2 per 100000), Chiang Mai (1.7 per 100000) and in Vietnam (Hanoi – 2.2 per 100000 between 1993-1997). Penile cancer in Asia relatively uncommon and literature on it is sparse and really haven’t been explored in the Asia Pacific region [134].

1.21.4 Vaginal Cancer Trends

Incidence rates associated with cancer of the vagina In the Asian Pacific region are very low and never exceed 1 per 100000 [122, 123]. Generally, cancer of the vagina is highly infrequent in Asia and the highest incidence rate is recorded is India (Chennai: 0.8 per 10000 women) [122].

1.21.5 Vulvar Cancer Trends

This is a highly uncommon malignancy [64] and for the purposes of this thesis, no relevant studies were found in the literature.

1.21.6 Oropharyngeal Cancer Trends

Globally, incidence rates associated with oropharyngeal cancers differ significantly and are highest in regions where alcohol consumption and tobacco use are common [119]. In 2002, approximately 209000 (52% of the world’s total) cases and 125000 (59% of the world’s total) deaths occurred in Asia [119]. It is important to note that the male-to-female occurrence ratio varies from approximately 3:1 in Sri Lanka to 1:1 in Philippines and Mongolia [135]. In the Asia Pacific region, incidence rates associated with HPV-oropharyngeal cancers are generally low and below 10 per 100000 [119, 135]. The highest incidence rates are reported in Papua New Guinea – 42.2 in males and 27.0 in females, Sri Lanka – 31.4 in males and 11.2 in females, Solomon Islands – 37.0 in males and 22.5 in females and India – 22.4 in males and 9.3 in females [135].

The Indian subcontinent is associated with a high incidence of oropharyngeal cancer [127]. Very high ASRs of microscopically diagnosed cancers were reported in the Andhra Pradesh, Kerala and Tamil Nadu districts between 2001 and 2002. Also oropharyngeal cancer is more prevalent in males and females in Southern States and along the west coast when compared to other regions within India [119]. Tobacco exposure usually arises from smoking, but in India, the use of smokeless tobacco in various forms, with or without other elements is public practice and beedi rather than cigarette smoking is not unusual among rural populations [136]. In addition, rural women tend to chew (i.e. smokeless) instead of smoking tobacco even though this practice may differ in the Mizoram state [137, 138]. All these factors influences the differences in the incidence associated with oropharyngeal cancer at different sites of the oropharynx through the use of tobacco in India [119].

In Singapore, HPV-associated oropharyngeal cancer inci

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 to 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 discuss 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 some 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]. Adenocarcinoma (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 one’s 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 <15% of all cases of vaginal cancer patients are diagnosed before 50 years and about 10% of these occur before 40 years [66-69]. Over 90% of all vaginal cancer cases tend to be SCCs and mostly occur in the upper region of the posterior wall of the vagina while ACs accounts for only 5% [66-68]. At diagnosis, the median age associated with SCCs is approximately 69 years even though this malignancy is detected in the third and fourth decades [70].

The vagina is a 7.5-centimetre dilatable tubular structure which extends to the vulva from the cervix [71].A lot of the neoplasms associated with cancer of the vagina are SCCs even though melanoma and AC, which are largely associated with utero diethylstilbestrol (DES) exposure do rarely occur [28, 71]. The incidence of SCC of the vagina is reducing currently owing to the stoppage of DES prescription in pregnancy in many countries [71]. Primary vaginal cancer accounts for 1-2% of all genital cancers associated with women and over 80% are metastases from the cervix and vulva [72, 73]. Primary vaginal ACs are diagnosed in women younger than 20 years whereas primary SCCs often occur in women who are at least 65 years old [70]. Secondary vaginal cancer is more prevalent than primary vaginal cancer and usually occurs as an extension from the cervix, endometrium or vulva [70].

Vaginal intraepithelial neoplasia (VaIN) may precede vaginal cancer even though the natural progression of VaIN have not been completely described [28]. Two retrospective studies of several VaIN treatment procedures including surgical excision, topical agents, laser ablation and radiation therapy, reported that about 5% of cases progress to invasive carcinoma of the vagina [74, 75]. However, prospective trials establishing the most efficient treatment procedure is extremely sparse in the literature [71]. Nonetheless, surgical resection is the most commonly applied method of treating vain because it removes the diseased tissue and obtain histologic diagnosis of the entire lesion [71]. Depending on the severity of infection, surgical can be minimal as a wide local excision or extensive as a total vaginectomy which recurs at a rate of 18% [76, 77]. VaIN is usually related to a previous or current neoplasia in the lower portion of the genital tract [28]. Two studies therefore shows that about 50-90% of VaIN patients have a history of or current intraepithelial neoplasia or cervical and/or vulvar carcinoma [76, 78].

Having at least 5-lifetime sexual partners, early sexual debut (before 17 years), prior history of genital warts, current smoker at diagnosis, low socioeconomic status, prior abnormal cytology, prior hysterectomy [79-80], hrHPV infection and immunosuppression [81] are common risk factors associated with vaginal cancer. About 33% of women who report vaginal cancer would report a prior history and/or treatment for an anogenital tumor typically of the cervix [70]. In addition, women with a prior treatment for a high-grade CIN have a 4-fold higher risk of developing invasive cancer of the vagina [82].

Diagnosing vaginal cancer is sometimes difficult because patients have painless discharge and bleeding from the vagina and lesions are usually missed on visual inspection [28]. Also, there are chances that if a lesion is inconspicuous and is in found the lower two-thirds of the vagina, diagnosis may be missed because lesions can be obscured by the blade of the speculum and in such instances, examination under anesthesia is most recommended [71]. When symptoms are present, a complete examination involving cytology, speculum examination, colposcopy, digital palpation and biopsy of any noticeable lesion should be performed and the speculum slowly rotated as it is withdrawn from the vagina to ensure a visualization of the complete vaginal mucosa [71]. This is particularly important because invasion and the size of a tumor are the main prognostic pointers [83, 84].

1.15 Vulvar Cancer

The vulva comprises of the exterior female genital organs including the labia minor, labia majora, mons pubis, clitoris, vaginal vestibule which contains the Bartholin and skene glands as well as the urethral meatus [71].Cancer of the vulva accounts for about 5% of cancers of the female lower genital tract [43, 44]. It is an invasive growth of the vulva and sometimes the visible portion of the female genital organ [85]. The labia majora is the most susceptible site accounting for more than 50% of all cases [86, 87], seconded by the labia minora [88]. However, the clitoris is very infrequently affected [89].  The most prevalent morphologic type of vulvar cancer is SCC, however, a few women also report other relatively rare types including melanoma and sarcoma as well as other undifferentiated carcinomas [32]. Most women with vulvar dysplasia rarely show signs and symptoms and diagnosis is only made with a high degree of suspicion [71].

Relatively rare cancer, ASR associated with cancer of the vulvar vary between 1.0 and 1.8 per 100000 women [64]. Fewer incident cases are associated with countries with comparatively small populations and relatively populous countries report a higher number of incident cases [88]. E.g. Scotland reports about 100 incident cases annually [86] whereas USA reports about 5000 cases [44]. The average age at diagnosis of vulvar cancer is 65 years but this age is projected to reduce by 2025 [89]. Over a decade ago, the incidence of vulvar cancer increased approximately by 10% within populations of women at most 50 years [89].

Risk factors associated with cancer of the vulvar include; persistent HPV infection, vulvar dystrophy (lichen sclerosus) and cigarette smoking [28]. Several studies also reported cervical cancer [90], CIN [88], immune-deficiency syndromes [91] and VIN [92] as significant risk factors.  VIN is a considered a precursor lesion to cancer of the vulvar [92]. However, the literature suggests a low rate of development to invasive carcinoma of the vulvar [93]. There is a worldwide increase in the incidence of VIN partly due to the increasing prevalence in young women [89, 94].

1.16 Oropharyngeal Cancer

Oropharyngeal cancers are malignancies located at where the pharynx and oral cavity merge, in the lingual and palatine tonsils, the soft palate, the posterior pharyngeal wall and the posterior one-third (base) of the tongue [95]. According to the World health organization (WHO), oropharyngeal cancer is the eleventh most prevalent worldwide and accounts for about 450000 new cases annually [96] even though there regional variations in incidence rates [95]. However, widely established in the literature is increasing incidence rates of oropharyngeal cancer in developing countries [97]. Globally, countries with the highest incidence rates associated with oropharyngeal cancer include Hungary, Romania, France and Slovakia [97, 98]. In these countries oropharyngeal cancer is most common in men [97]. According to the oral cancer foundation, there is a rising incidence of oral cancer amongst 25 to 50-year olds [99].

HPV causes clinically as well as epidemiologically different forms of oropharyngeal squamous cell carcinoma (OPSCC) [100-104]. These OPSCC forms are broadly grouped into two namely: HPV-positive and HPV-negative [105]. HPV-positive OPSCCs are strongly related to sexual behavior [100-104, 106] while HPV-negative OPSCCs have risk factors associated with tobacco and alcohol use [105, 106]. It is also important to note that, HPV-positive OPSCC patients have better survival when compared to their negative counterparts [107-109]. The reason for this result is thoroughly debated in the literature.

Several risk factors have been attributed to the development of oropharyngeal cancer. It is estimated that, about 75-90% of oropharyngeal cancers are directly linked to lifestyle choices and are therefore preventable [110-113]. According to the National Cancer institute, a diet low in fruits and vegetables, chewing of betel quid (a stimulant widely used in Asia), Plummer-Vinson syndrome are asbestos exposure are risked factors for oropharyngeal cancer [114]. In addition, the most important risk factors associated with oropharyngeal cancer are tobacco use (including chewing tobacco, smokeless tobacco and snuff), alcohol consumption and mucosal infection with HPV [110-113]. However, smoking marijuana is not linked to an increased risk of developing oropharyngeal cancer [112].

1.2 International Trends in HPV-associated Cancers

Epidemiological data on HPV-associated cancers in Asia have been far more limited [115]. Asia contains more than half of the world’s population and show staggering diversity in incidence rates associated with HPV-related cancer prevalence [32]. Incidence rates are produced from data from population-based cancer registries (PBCRs) which usually collect information on incident cases in a country even though most Asian countries lack such registries [116]. In the Asia pacific region, the few countries have PBCRs also faces acute challenges in producing incidence data of quality [115]. In countries with cancer registration schemes (e.g. Singapore, India, Thailand, Vietnam, Malaysia, Myanmar, Indonesia, Philippines and Mongolia), this is the most ideal source of incidence data [116]. However, in Japan, China and Korea, incidence rates are estimated from mortality data using models that relate incidence to mortality by gender and age group [116].

Globally, geographical differences in the distribution of risk factors associated with HPV-related cancers lead to varying incidence rates [35]. Knowledge of the patterns and availability of data on these ever-changing incidence rates and the burden associated with HPV-cancers is critical in taking decisions (especially regarding resource allocation) to fight these malignancies [32]. This section therefore examines the global behavior of incidence rates associated with cancers of the vagina, anus, oropharynx, vulva, cervix and penis. Subsections 1.21.1 to 1.21.6 presents a continental picture of these behaviors by cancer type and are discussed next.

1.21 Trends in Asia

1.21.1 Cervical Cancer Trends

Cervical cancer is the prevalent cancer among women in the Asia Pacific region (after cancer of the breast) with about 255000 incident cases (12.4% of all cancers) [33]. Incidence rates in the region closely mirror estimated world averages and account for about 51.6% of total global cervical cancer cases and 50.3% of cervical cancers deaths [116]. The highest incidence rates (per 100000 population) are reported in Melanesian populations including Solomon Island (42.8), Papua New Guinea (40.4), Cambodia (38.7), Fiji (33.4), India (30.7) and the least reported in Japan (8.0) and china (6.8) [33].

Major variations in cervical cancer incidence are also reported among sub-regions making the Asia Pacific region [33, 35 and 116]. Two big countries, China and India, contribute about 85% of the total population in the region, with China reporting a cervical cancer ASR of 6.8 per 100000 and 30.7 per 100000 women in India in the year 2000 [117]. However it is important to note that, there are significant variations in cervical cancer incidence within each of these countries [116]. Worthy of mention is the fact that estimated incidence rates (per 100000 women) associated with microscopically diagnosed cervical cancer between 2001 and 2002 by districts revealed high rates in Pondicherry (39.2), Villipuram (31.1), Cuddalore (29.9) and Thiruvallur (28.6) in the Tamil Nadu district in southern India and Aizawl (30.1) and Mamit (29.6) in the Mizoram district of North-eastern India [118]. In Chennai (India), Osaka (Japan) and Hong Kong (China), there has been a dramatic reduction in cervical incidence since 2002 [116]. In Shanghai (China), cervical cancer incidence dropped from 26.7 to 2.5 per 100000 women from 1972 to 1974 and also 1993 to 1994 [119]. In the Chinese South-eastern city of Qidong, cervical incidence rate was 4.2 per 100000 in 1978 to 1982, however this value has been reducing at 4.7% per annum for 20 years while mortality rates are increasing among women younger than 45 years of age [120].

According to the Korean Central Cancer Registry Program (KCCRP), incidence rates associated with cervical cancer decreased in the years 1993-2002 and the ASRs were 19.0, 178.8 and 15.1 per 100000 women between 1993-1995, 1996-1998 and 1999-2002 respectively [121]. Parkin et al (2008), in determining the future burden of cervical cancer in Asia, projects that, irrespective of population growth, aging and changing risks, the number of incident cases will rise to 415000 by the year 2025 (a 62% increment) with an age profile such that 52% of cases will be at least 55 years compared to the current 41%, assuming current incident rates will apply in the future [116].

1.21.2 Anal Cancer Trends

Incidence rates associated with anal cancer in Asia are generally low, not higher than 1 per 100000 [119, 122 and 123]. However rates are slightly higher in Hawaii (white ethnicity) – 1.5 per 100000 [120]. In most Asian populations, anal cancer is more prevalent in men than in women. [119]. Only a few studies have reported the prevalence and incidence rates of HPV-associated anal cancers in Asia including India [124], China [125-127], Taiwan [125, 128] and Thailand [125].

High anal cancer incidence is extensively associated with some risk groups – men who have sex with other men (MSM) and HIV infected people [129, 130]. In Japan, even though there is a low prevalence of HIV in MSM (0.018%) in the overall population, the number of incident cases increased from 314 in 2001 to about 724 in 2012, which is further projected to increase to 10.4% in 2014 [131, 132]. However there are no data available on HPV-associated anal cancer infection in Japan [131]. Elsewhere, studies indicate that there is an increase in incidence rates of HPV-associated anal intraepithelial neoplasia (AIN) in Asian MSM [133].

Being a rare cancer, trends in the incidence of anal cancer in other Asian countries as well as among Asian ethnic groups have previously not been studied [134].

1.21.3 Penile Cancer Trends

Penile cancer is a rare malignancy with prevalence and incidence rates being typically low in Asia [119, 122 and 123]. ASRs of penile cancer in Asia are generally less than 1 per 100000 men [134]. A very low penile cancer incidence (0.04 per 100000) is reported in Jewish populations who commonly practice circumcision at birth [3]. Southeast Asia records the highest incidence rates for penile cancer: Lampang (1.6 per 100000), Thailand (Songhkla – 2.2 per 100000), Chiang Mai (1.7 per 100000) and in Vietnam (Hanoi – 2.2 per 100000 between 1993-1997). Penile cancer in Asia relatively uncommon and literature on it is sparse and really haven’t been explored in the Asia Pacific region [134].

1.21.4 Vaginal Cancer Trends

Incidence rates associated with cancer of the vagina In the Asian Pacific region are very low and never exceed 1 per 100000 [122, 123]. Generally, cancer of the vagina is highly infrequent in Asia and the highest incidence rate is recorded is India (Chennai: 0.8 per 10000 women) [122].

1.21.5 Vulvar Cancer Trends

This is a highly uncommon malignancy [64] and for the purposes of this thesis, no relevant studies were found in the literature.

1.21.6 Oropharyngeal Cancer Trends

Globally, incidence rates associated with oropharyngeal cancers differ significantly and are highest in regions where alcohol consumption and tobacco use are common [119]. In 2002, approximately 209000 (52% of the world’s total) cases and 125000 (59% of the world’s total) deaths occurred in Asia [119]. It is important to note that the male-to-female occurrence ratio varies from approximately 3:1 in Sri Lanka to 1:1 in Philippines and Mongolia [135]. In the Asia Pacific region, incidence rates associated with HPV-oropharyngeal cancers are generally low and below 10 per 100000 [119, 135]. The highest incidence rates are reported in Papua New Guinea – 42.2 in males and 27.0 in females, Sri Lanka – 31.4 in males and 11.2 in females, Solomon Islands – 37.0 in males and 22.5 in females and India – 22.4 in males and 9.3 in females [135].

The Indian subcontinent is associated with a high incidence of oropharyngeal cancer [127]. Very high ASRs of microscopically diagnosed cancers were reported in the Andhra Pradesh, Kerala and Tamil Nadu districts between 2001 and 2002. Also oropharyngeal cancer is more prevalent in males and females in Southern States and along the west coast when compared to other regions within India [119]. Tobacco exposure usually arises from smoking, but in India, the use of smokeless tobacco in various forms, with or without other elements is public practice and beedi rather than cigarette smoking is not unusual among rural populations [136]. In addition, rural women tend to chew (i.e. smokeless) instead of smoking tobacco even though this practice may differ in the Mizoram state [137, 138]. All these factors influences the differences in the incidence associated with oropharyngeal cancer at different sites of the oropharynx through the use of tobacco in India [119].

In Singapore, HPV-associated oropharyngeal cancer inci

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