A REVIEW OF CERVICAL CANCER INCIDENCE AND HPV INFECTION

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1 A REVIEW OF CERVICAL CANCER INCIDENCE AND HPV INFECTION Ngo Van Toan, Nguyen Duc Hinh, Luu Thi Hong, Vu Hong Thang, Bui Van Nhon Hanoi Medical University This review was carried out to provide information regarding incidence and Human Papilloma Virus (HPV) infection worldwide as well as in Vietnam. Cervical is second most common in women in less developed regions of globe. An estimation of new cases occurred in women from low - and middle-income countries in 2012, comprising 84% of all new cases of worldwide that year. In 2012, approximately women died from ; more than 85% of se deaths occurred in low - and middle - income countries. There are more than 100 types of HPV, of which at least 13 are -causing. Cervical is caused by sexually acquired infections from certain types of HPV. Two types of HPV (strains 16 and 18) cause 70% of all s and preous lesions. Keywords: Cervical, incidence, HPV I. INTRODUCTION develop active intervention programs, Cervical occurs in tissues of number of cases will increase cervix ( organ connecting uterus and by an additional 25% in next 10 years vagina). It is usually a slow-growing worldwide [1]. In England, since 1970s, that may not present with symptoms but can incidence rate has been be found with regular Pap tests (a procedure decreasing (it reduced 63% during in which cells are scraped from cervix and 1987 and 66% during , compared looked at under a microscope). Cervical to 1970 s) [1]. Developing countries must is almost always caused by human implement better screening papillomavirus (HPV) infection. Among more programs to see a similar reduction in than 100 types of HPV, several types can cases. The objective of this review was to cause. The most common provide information regarding types that lead to are HPV 16 incidence and HPV infection worldwide and 18. Over past 40 years, incidence and specifically in Vietnam. of has reduced significantly in developed countries due to implementation of screening programs. In developing countries, incidence rate has remained stable or increased. If developing countries do not II. CONTENTS 1. Incidence rate 1.1. Cervical incidence rates worldwide Cervical Corresponding author: Ngo Van Toan, Hanoi Medical University ngovantoan57@yahoo.com Received: 04 November 2016 Accepted: 10 December 2016 is second most common kind of among women worldwide after breast. There were about 528,000 new cases worldwide and women died of [1]. More than 1

2 80% of infected and affected women live in Almost all cases were in developing countries. Cervical is women aged 30 and above. The age- fourth leading cause of death among women standardized incidence rate of globally. About 20% of new cases worldwide among white women was from 8.2 to 8.8 were In cases per 100,000 women, while in black Sub-Sahara countries, re are about 34.8 women it was per 100,000 women, new cases of s per 100,000 and among Asian women it was per women and 22.5 deaths due to 100,000 women [5-9]. diagnosed in India [2]. per 100,000 women per year [3; 4]. Approximately 6,000 new In contrast, re were 6.6 new cases of cases are diagnosed annually in South Africa s per 100,000 women and 2.2 (SA) [1]. Accurate contemporary data on deaths due to per 100,000 incidence has not been women per year in North America [1]. In available since 1999 Cancer Registry was United States, age - standardized rate published. Many cases were presumed to still of s was 9.6 cases per 100,000 be undiagnosed due to poor screening programs women during period of [1]. and more than half of all patients diagnosed The global survival rate of five each year are expected die from disease. years after being diagnosed was 72%. There The World Health Organization estimated were about 4,100 women that died due to cer- age-standardized incidence rate for SA to be vical in 2003 in United States [1] per women [1]. The current Cervical was sixth most common prevalence of pre - invasive disease in among female s in European countries, with 58,400 new cases in 2012 [1]. The highest incidence rate of was in Rumania and lowest was in Switzerland [1]. Cervical was twelfth most common among women in England with an incidence rate of 10 cases per 100,000 women annually [1]. The difference in incidence rates of between developed and developing countries was due to a lack of access to screening, early detection and treatment programs in developing countries. In addition, or factors such as traditional practices, poor hygiene, and unsafe sex also contributed to high incidence rates in developing countries. Cervical incidence is closely related to a woman s age. 2 SA is unknown. Data from studies published in SA suggest important regional differences across country, and an overall increase in prevalence of cytological abnormalities when compared with historical data. Because of low sensitivity of cytology, we can assume that true prevalence of pre invasive disease is underestimated. Moreover, a single test done by cytology, even if done completely correct, will probably identify fewer than half of all existing pre-invasive disease when measured against greater yield obtained by colposcopy and directed biopsy. The incidence rate of in Senegal was quite high at 19.4 cases per women [10]. This rate was 1.5 times higher than breast incidence and more than 3 times higher than liver incidence among women in country [10].

3 Cervical is a common for over three years), increased rates of among women in developing countries in Asia. in indigenous women reflects Worldwide, poorer access to cytology screening region comprising Asia Oceania covers a vast and diverse area geographically and ethnically, programs [12; 13]. supporting In contrast, in Thailand and Phillipines, around 60 percent of world s population re have not been significant reductions in and contributing to just over half of global incidence and mortality rates, despite burden of [11]. cytology programs that se India, in particular, has one of highest countries have had in place for decades [14]. reported incidence and mortal- This perhaps reflects fact that ity rates in region. These higher rates re- organized programs in se countries are not flect an overall lack of widespread screening reaching and treatment facilities, as well as a greater appropriate populations. As proportion of persistent HPV infections, as screening indicated by very high rates of sophisticated in more affluent and urbanized in older women. Asia-Pacific countries such as Singapore, Across Asia Pacific region, examples of successful cytology programs are rar limited [14]. In Australia and New Zealand, where long-standing and highly effective cytology programs have been in existence for several decades, incidence and mortality rates high proportiontions programs have of become more Hong Kong, Taiwan and Iran, incidence and mortality rates have begun to decline. Assisting furr with decline in se States is fact that programs in se countries are rolled out on a national level [9; 15-17]. have declined According to estimates, incidence rate significantly [12; 13]. In Australia in 2003, of in Indonesia was about 100 age-standardized incidence of cases per 100,000 women [18]. Cervical was 7.0 cases per 100, 000 women and was most common malignancy mortality rate was 2.2 cases per 100,000 among women in Indonesia, comprising up to women [12]. It is noteworthy, however, that 22.5% of all cases reported in govern- notwithstanding success of National mental hospitals re [18]. However, this Cervical Screening Program in general number population, indigenous women in Australia because only 25-30% of all sick people in were over four times more likely to die of Indonesia enter se medical facilities [18]. of cases was likely an underestimation, than non-indigenous women in Cervical is a major health problem ; incidence was 4 - in Indonesia since most patients present in 5 fold higher in indigenous women over later stages of disease, in low resource same time period [12]. Whilst overall for settings where no screening programs are Australian population, estimated lifetime available. The association of high-risk screening participation rate strains of HPV (notably strains 16, 18, 31 and was 88 per cent (62% for over two years, 73% 45) with among female 3

4 patients in Indonesia is now widely accepted, lowest in Thai Nguyen province (4.1 cases per as se strains of HPV have been detected in 100,000 women during ) and Thua almost all patients and are Thien Hue province (5.8 cases per 100,000 much less common in women without women in 2008) [20]. [18; 19]. Viet Nam has a population of million The distribution of HPV strains in Indonesia women aged 15 years and older who are at is largely unknown. HPV 18 has been reported risk of developing, and this to play more of a role in spread of poses a major public health problem for re than HPV 16 [18], at a rate that is country. Current estimates indicate that every higher than that reported in or geographical year 5174 women are diagnosed with areas worldwide. The viral origin for and 2472 die from disease, with an and its high morbidity and mortality estimated age - standardized incidence rate of figures give cause for development of a 11.5 cases per 100,000 women [20]. However, vaccine against HPV. To design vaccines suit- se statistics were derived by modeling able for Indonesian female population, an based on data obtained from some of inventory of HPV prevalence is essential. treatment centers and may not reflect 1.2. The incidence rate of in Vietnam Up to now, studies on incidence rate of actual rates in country. Reports from registries operating in country s two major cities, Hanoi and Ho Chi Minh City, in Vietnam have been rela- published nearly 15 years back show signifi- tively limited. The Program for Cancer Control cant regional variations in inci- has conducted studies looking at rates of cer- dence. The age - standardized incidence rate vical in cities and provinces across of in Hanoi, a city situated in country since Results have shown that Norrn Vietnam, was only 6.5 cases per estimated crude rate of 100,000 women, in stark contrast to high was 13.1 cases per 100,000 women in 2000 incidence rate in Ho Chi Minh City, situated in and 12.7 cases per 100,000 women in Sourn Vietnam, where rate was 26 The age - standardized rate of cases per 100,000 women [21; 22]. No recent was 17.3 cases per 100,000 women in 2000 data and 13.6 cases per 100,000 women in mortality The incidence rate of is population - based registries in Hanoi different between regions and provinces. The and Ho Chi Minh City. To develop a public rate was highest in Ho Chi Minh City (19.7 health strategy for prevention cases per 100,000 women in ), and to monitor its health impacts, Vietnam followed by Can Tho City (17.7 cases per must have quality data on 100,000 women in ), n Hanoi incidence and mortality in population. Post City (10.5 cases per 100,000 women during -treatment ) and finally Hai Phong (8.3 cases determined, as this is an important indicator of per 100,000 women in 2008). The rate was quality of treatment services in country. 4 on has been survival incidence published rates must and from also be

5 Both primary and secondary prevention preous lesions and invasive strategies are highly effective against [24; 25], compared with cytology -. Primary prevention via HPV based screening in women older than 30. Re- vaccine is still out of bounds for national cently, this finding has also been confirmed in program of Vietnam, principally due to its high cost. However, secondary prevention through screening is an important public health measure that Vietnam should invest in. The guiding principle of secondary India, developing country with a low human immunodeficiency virus (HIV). Over last 20 years, widespread HIV epidemic has increased overall burden of HPV infec- prevention of is that tion in sub - Saharan Africa. Accurate current disease should be detected through system- knowledge about hrhpv prevalence in devel- atic screening of all women within a certain oping countries is essential for cost analysis age group, and that all women found to have and planning for regionally tailored national pre - ous lesions should be treated. prevention and screening programs. Cervical precursors are classified as Cervical Intraepilial Neoplasia (CIN) 1, CIN 2 or CIN 3 depending on extent of disease in epilium. Whereas most CIN 1 lesions are due to transient HPV infection and do not progress furr, a large number of CIN 2 and CIN 3 lesions will progress to invasive s if left untreated [23]. In Vietnam, re is paucity of data regarding population prevalence of CIN 2 and CIN 3 - information that is necessary to understand disease burden in country, to formulate prevention strategies, and to design future interventions related to screening Human papillomavirus: etiological agent of Molecular epidemiological studies have conclusively established causal association between high - risk HPV genotypes and. The relative risk of developing from high - risk HPV strains is in hundreds - fold and far greater than association between cigarette smoking and lung. In fact, is first to be 100 percent attributable to an infection [24; 25]. Papillomaviruses are a very heterogeneous group of viruses. They are widely distributed throughout nature, infecting not only humans but also or higher 2. HPV infection and The identification of high-risk HPV (hrhpv) types ( strains of HPV that cause ) offers prospect of improving screening programmes through vertebrates such as dogs, horses, and cattle. In general, y are highly species-specific, with each animal species having its own papillomavirus [for example, bovine papillomaviruses (BPV) of cattle is different from introduction of hrhpv - based screening tests. HPV in humans]; re is no known crossing Studies from developed countries provide of papillomaviruses between species. convincing evidence that hrhpv DNA - based Sequence analysis of cloned HPVs shows screening algorithms are cost - effective and that y are highly conserved and that clinically genome is not prone to mutation, in contrast to sensitive for detection of 5

6 or viruses like human immunodefi- squamous cell carcinomas, 80 to 85 percent of ciency virus (HIV). The 8 kilobase circular which are adenocarcinomas which are more genome of HPV is made up of one early (E) difficult to detect on cytological screening. gene (necessary for replication of viral Phylogenetically, HPVs are within alpha DNA, transcription of non-structural early genus. HPV genotypes 16 and 18 are quite proteins E1, E2, E4, E5, E6 and E7, and as- distinct and are from separate species: HPV sembly of newly produced viral particles) and genotype 16 is from species 9, whereas HPV two late (L) genes (L1 and L2) (which code for genotype 18 is from species 7. In contrast, proteins making up major viral capsid). HPV genotypes 6 and 11 are closely related Much of natural host immune response is and in same species, species 10. directed to conformational epitopes on L HPV infection protein displayed on outer surface of intact virion [26]. Moreover, L1 protein, HPV specifically infects epilial cells when expressed via recombinant yeast or viral of skin or mucosa. Eir through minor vectors, folds and self - assembles into empty abrasions of squamous epilium or capsids or viral-like particles (VLPs), which through entry at transformation zone in antigenically and morphologically resemble cervix, viral particles infect basal cellular lay- wild virus, forming basis of current prophy- ers. It is here that a small amount of viral lactic vaccine candidates. genome is maintained, allowing for latency in Over 200 papillomaviruses are now recognized, and over 100 have been cloned [27; 28]. Of large number of HPVs, re is tropism of infection for different tissues by various genotypes; i.e., skin types (e.g., HPV 1-4, 10, 26-29, 37, 38, 46, 47, 49, 50, 57) and genital types (e.g., HPV 6, 11, 16, 18, some infected women. Full HPV infection only occurs when virus enters supra basal compartment, where keratinocytes lose ir ability to replicate but initiate terminal differentiation. As epilium is shed, full virions become ready to infect next host. various 30s, 40s, 50s, 60s, 70s). Around 40 It is because of this complex interaction genotypes are able to infect genital tract. with differentiating keratinocyte, that HPV Of se, some have oncogenic potential cannot be propagated in vitro in cell lines, in (established high risk strains include strains contrast to or viruses that are readily 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, cultured for diagnostic purposes. However, by 68, 73, 82; probable high risk strains include various molecular hybridization assays, HPV strains 26, 53, 66) whilst ors are low risk nucleic acid can be detected as DNA or RNA (established low risk strains include strains 6, in tissues or clinical samples. 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, High-risk HPV infection is necessary CP6108). Within high - risk group, HPV cause for development of genotypes 16 and 18 impart greatest [29-31]. The International Agency for Research degree of risk, with se now known formally on Cancer in Lyon lists 12 genotypes of HPV as human carcinogenic agents. HPV 16 and that are considered high - risk and have suffi- 18 contribute to around 70 per cent of cient evidence that y cause : 6

7 HPV strains 16, 18, 31, 33, 35, 39 45, 51, 52, amounts of HPV DNA is associated with an 56, 58, and 59. Only one study has been done increased risk of development of in Vietnam to look at overall HPV preva- [32]. Considering broad interest in lence in country s female population. No HPV vaccines, it is important to verify study has been done to date that documents prevalence of various types of HPV world- HPV genotype prevalence, especially of wide, especially high-risk strains. Despite high risk types, eir in healthy female medical importance of identifying high-risk population or among patients. HPV strains, and high incidence rate of To understand how potentially impact HPV, re is a lack of information vaccine could be in country, distribu- on incidence of most common HPV tion of high risk HPV genotypes among both genotypes. patients and those with CIN 2 To determine HPV genotypes, and CIN 3 lesions must be determined. amplified PCR products were run in 1.5% Knowledge regarding prevalence of agarose gel stained by ethidium bromide. high - risk HPV genotypes in CIN 2+ lesions Since all amplified products had different will also help to gain insight into useful- lengths, genotypes of virus were ness of various HPV detection technologies as analyzed by electrophoresis and visualized by screening tests. an ultraviolet light trans - illuminator. Bands of Worldwide, risk of has appropriate size were identified by comparison increased in parallel with incidence of with DNA molecular weight markers that are certain genotypes of HPV [32]. Therefore, made from a set of known DNA fragments. presence of se genotypes indicates a The adequacy of DNA in each specimen significant risk factor for development of for PCR amplification was determined by. HPV infects cutaneous and detection of β - globin gene. mucosal epilial cells of ano - genital In Vietnam, at present, tract, which can lead to a variety of diseases screening activities in country are mostly with a range of severities. The mildest form of opportunistic. Some of country s non- HPV disease is low - grade intraepilial governmental neoplasia (CIN1). These lesions can persist conducting and progress to high-grade disease (CIN2) relatively small population. Since 2007, and invasive. HPVs are also organization Program for Appropriate Techno- found in s of tonsils, anus, penis logy in Health (PATH) is conducting a and of neck. vaccination and screening project in voluntary individual organizations projects are involving High - risk HPV 16 and 18 are most Thanh Hoa, Hue, and Can Tho provinces, in common causes of, account- collaboration with Vietnamese National ing for approximately two thirds of all Institute of Hygiene and Epidemiology and carcinomas worldwide. Of two strains, Maternal and Child Health Department of HPV-16 occurs most frequently. Studies have Ministry of Health. The program, primarily shown that presence of even minimal relying on a see and treat strategy using VIA 7

8 as screening test, screened more than capacity of medical professionals linked to 38,000 women aged 30 to 49 years across se three provinces from 2007 to February programs in country. In Vietnam, such pro The Vietnamese Ministry of Health, with fessionals include midwives, nurses, assistant technical physicians, obstetricians and gynecologists, assistance organizations, has from drafted international screening and treatment National and oncologists. A KAP study in Vietnam Population/Reproductive Health Strategy for should be done both with women in coun- period of , to be implemented try, and with se healthcare professionals. in 63 provinces/cities. Each province/city developed an action plan in 2011 that III. CONCLUSIONS extended for five years, from 2011 to Cervical is second most com- Control of through effective mon in women in less developed re- population - based screening gions, with an estimated new cases in programs is a major goal of country s 2012 (representing 84% of new cases national reproductive health teams. The aim is worldwide that year). In 2012, approximately to screen 20% of women aged years women died from ; by 2015 and to scale up program by 2020 more than 85% of se deaths occurred in to achieve 50% coverage. The National low- and middle - income countries. There are Guidelines on Cervical Cancer Screening and more than 100 types of HPV, of which at least Treatment of Preous Lesions have also 13 are - causing. Cervical is been prepared and advocate that VIA and/or caused by sexually acquired infection with cytology will be offered to help screen certain types of HPV. Two types of HPV (16 women aged years. and 18) cause 70% of all s and Several factors help to determine preous lesions. success of screening programs. The target population must be aware of se Acknowlegment programs, have positive perceptions abou We would like to express our thanks to tpreventive health and accept screening as a UNFPA Vietnam, Department of Maternal strategy to reduce incidence. Even and Child Health and Ministry of Health for within same country, se factors may ir financial and technical support. vary depending on target population s ethnicity, religion, culture and literacy level. A REFERENCES study to evaluate knowledge, attitudes and 1. World Health Organization/ICO Infor- practices (KAP) among women in target mation Centre on HPV and Cervical Cancer population, to (2010). Human papilloma virus and related represent population of entire country, s in South Africa. Summary Report could provide valuable information that would (accessed 15 help reorganize country s November 2012). sampled systematically screening program. It is also essential to evaluate 8 awareness, perception and 2. IARC (2012). Global burden rises to 14.1m new cases in 2012: Marked increase

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