This review was carried out to provide information regarding cervical cancer incidence and Human Papilloma Virus (HPV) infection worldwide as well as in Vietnam. Cervical cancer is the second most common cancer in women in less developed regions of the globe. An estimation of 445 000 new cases occurred in women from low - and middle-income countries in 2012, comprising 84% of all new cases of cervical cancer worldwide that year. In 2012, approximately 270 000 women died from cervical cancer; more than 85% of these deaths occurred in low - and middle - income countries. There are more than 100 types of HPV, of which at least 13 are cancer-causing. Cervical cancer is caused by sexually acquired infections from certain types of HPV. Two types of HPV (strains 16 and 18) cause 70% of all cervical cancers and precancerous cervical lesions.
JOURNAL OF MEDICAL RESEARCH 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 cervical cancer incidence and Human Papilloma Virus (HPV) infection worldwide as well as in Vietnam Cervical cancer is the second most common cancer in women in less developed regions of the globe An estimation of 445 000 new cases occurred in women from low - and middle-income countries in 2012, comprising 84% of all new cases of cervical cancer worldwide that year In 2012, approximately 270 000 women died from cervical cancer; more than 85% of these deaths occurred in low - and middle - income countries There are more than 100 types of HPV, of which at least 13 are cancer-causing Cervical cancer is caused by sexually acquired infections from certain types of HPV Two types of HPV (strains 16 and 18) cause 70% of all cervical cancers and precancerous cervical lesions Keywords: Cervical cancer, incidence, HPV I INTRODUCTION develop active intervention programs, the Cervical cancer occurs in tissues of the number of cervical cancer cases will increase cervix (the organ connecting the uterus and by an additional 25% in the next 10 years vagina) It is usually a slow-growing cancer worldwide [1] In England, since the 1970s, the that may not present with symptoms but can cervical cancer incidence rate has been be found with regular Pap tests (a procedure decreasing (it reduced 63% during 1985 - in which cells are scraped from the cervix and 1987 and 66% during 2009 - 2011, compared looked at under a microscope) Cervical to the 1970’s) [1] Developing countries must cancer is almost always caused by human implement better cervical cancer screening papillomavirus (HPV) infection Among more programs to see a similar reduction in cancer than 100 types of HPV, several types can cases The objective of this review was to cause cervical cancer The most common provide the information regarding cervical types that lead to cervical cancer are HPV 16 cancer incidence and HPV infection worldwide and 18 Over the past 40 years, the incidence and specifically in Vietnam of cervical cancer has reduced significantly in developed countries due to implementation of cervical cancer screening programs In developing countries, the cervical cancer incidence rate has remained stable or increased If developing countries not II CONTENTS Incidence rate 1.1 Cervical cancer incidence rates worldwide Cervical Corresponding author: Ngo Van Toan, Hanoi Medical University Email: ngovantoan57@yahoo.com Received: 04 November 2016 Accepted: 10 December 2016 JMR 105 E1 (7) - 2016 cancer is the second most common kind of cancer among women worldwide after breast cancer There were about 528,000 new cases worldwide and 260.000 women died of cervical cancer [1] More than JOURNAL OF MEDICAL RESEARCH 80% of infected and affected women live in the Almost all cervical cancer cases were in developing countries Cervical cancer is the women aged 30 and above The age- fourth leading cause of death among women standardized incidence rate of cervical cancer 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, there are about 34.8 women it was 6.3 - 11.2 per 100,000 women, new cases of cervical cancers per 100,000 and among Asian women it was 3.6 - 6.5 per women and 22.5 deaths due to cervical cancer 100,000 women [5 - 9] diagnosed in India [2] per 100,000 women per year [3; 4] Approximately 6,000 new cervical cancer In contrast, there were 6.6 new cases of cases are diagnosed annually in South Africa cervical cancers per 100,000 women and 2.2 (SA) [1] Accurate contemporary data on deaths due to cervical cancer per 100,000 cervical cancer incidence has not been women per year in the North America [1] In available since the 1999 Cancer Registry was the United States, the age - standardized rate published Many cases were presumed to still of cervical cancers was 9.6 cases per 100,000 be undiagnosed due to poor screening programs women during the period of 1996 - 2000 [1] and more than half of all patients diagnosed The global survival rate of cervical cancer five each year are expected die from the disease years after being diagnosed was 72% There The World Health Organization estimated the were about 4,100 women that died due to cer- age-standardized incidence rate for SA to be vical cancer in 2003 in the United States [1] 26.6 per 100 000 women [1] The current Cervical cancer was the sixth most common prevalence of pre - invasive cervical disease in cancer among female cancers in European countries, with 58,400 new cases in 2012 [1] The highest incidence rate of cervical cancer was in Rumania and the lowest was in Switzerland [1] Cervical cancer was the twelfth most common cancer among women in England with an incidence rate of 10 cases per 100,000 women annually [1] The difference in incidence rates of cervical cancer between developed and developing countries was due to a lack of access to screening, early detection and treatment programs in developing countries In addition, other factors such as traditional practices, poor hygiene, and unsafe sex also contributed to high incidence rates in developing countries Cervical cancer incidence is closely related to a woman’s age SA is unknown Data from studies published in SA suggest important regional differences across the country, and an overall increase in the prevalence of cytological abnormalities when compared with historical data Because of the low sensitivity of cytology, we can assume that the true prevalence of pre invasive disease is underestimated Moreover, a single test done by cervical cytology, even if done completely correct, will probably identify fewer than half of all existing pre-invasive cervical disease when measured against the greater yield obtained by colposcopy and directed biopsy The incidence rate of cervical cancer in Senegal was quite high at 19.4 cases per 100.000 women [10] This rate was 1.5 times higher than breast cancer incidence and more than times higher than liver cancer incidence among women in the country [10] JMR 105 E1 (7) - 2016 JOURNAL OF MEDICAL RESEARCH Cervical cancer is a common cancer for over three years), the increased rates of among women in developing countries in Asia cervical cancer in indigenous women reflects Worldwide, poorer access to cervical cytology screening the region comprising Asia Oceania covers a vast and diverse area geographically and ethnically, programs [12; 13] supporting In contrast, in Thailand and the Phillipines, around 60 percent of the world’s population there have not been significant reductions in and contributing to just over half of the global incidence and mortality rates, despite the burden of cervical cancer [11] cervical cytology programs that these India, in particular, has one of the highest countries have had in place for decades [14] reported cervical cancer incidence and mortal- This perhaps reflects the fact that the ity rates in the region These higher rates re- organized programs in these countries are not flect an overall lack of widespread screening reaching and treatment facilities, as well as a greater appropriate populations As cervical cancer proportion of persistent HPV infections, as screening indicated by the very high rates of cervical sophisticated in more affluent and urbanized cancer in older women Asia-Pacific countries such as Singapore, Across the Asia Pacific region, examples of successful cervical cytology programs are rather 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 the more Hong Kong, Taiwan and Iran, cervical cancer incidence and mortality rates have begun to decline Assisting further with the cervical cancer decline in these States is the fact that the programs in these countries are rolled out on a national level [9; 15 - 17] have declined According to estimates, the incidence rate significantly [12; 13] In Australia in 2003, the of cervical cancer in Indonesia was about 100 age-standardized incidence of cervical cancer - 190 cases per 100,000 women [18] Cervical was 7.0 cases per 100, 000 women and the cancer was the 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 cancer cases reported in govern- notwithstanding the success of the National mental hospitals there [18] However, this Cervical Screening Program in the 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 these medical facilities [18] of cervical cancer cases was likely an underestimation, cervical cancer than non-indigenous women in Cervical cancer is a major health problem 2001-2004; cervical cancer incidence was - in Indonesia since most patients present in the fold higher in indigenous women over the later stages of the disease, in low resource same time period [12] Whilst overall for the settings where no screening programs are Australian population, the estimated lifetime available The association of the high-risk cervical cancer screening participation rate strains of HPV (notably strains 16, 18, 31 and was 88 per cent (62% for over two years, 73% 45) JMR 105 E1 (7) - 2016 with cervical cancer among female JOURNAL OF MEDICAL RESEARCH patients in Indonesia is now widely accepted, lowest in Thai Nguyen province (4.1 cases per as these strains of HPV have been detected in 100,000 women during 2006 - 2010) and Thua almost all cervical cancer patients and are Thien Hue province (5.8 cases per 100,000 much less common in women without cervical women in 2008) [20] cancer [18; 19] Viet Nam has a population of 30.77 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 cervical cancer, and this to play more of a role in the spread of cervical poses a major public health problem for the cancer there than HPV 16 [18], at a rate that is country Current estimates indicate that every higher than that reported in other geographical year 5174 women are diagnosed with cervical areas worldwide The viral origin for cervical cancer and 2472 die from the disease, with an cancer and its high morbidity and mortality estimated age - standardized incidence rate of figures give cause for the development of a 11.5 cases per 100,000 women [20] However, vaccine against HPV To design vaccines suit- these statistics were derived by modeling able for the Indonesian female population, an based on data obtained from some of the inventory of HPV prevalence is essential cancer treatment centers and may not reflect 1.2 The incidence rate of cervical cancer in Vietnam Up to now, studies on the incidence rate of the actual rates in the country Reports from cancer registries operating in the country’s two major cities, Hanoi and Ho Chi Minh City, cervical cancer in Vietnam have been rela- published nearly 15 years back show signifi- tively limited The Program for Cancer Control cant regional variations in cervical cancer inci- has conducted studies looking at rates of cer- dence The age - standardized incidence rate vical cancer in cities and provinces across the of cervical cancer in Hanoi, a city situated in country since 2008 Results have shown that Northern Vietnam, was only 6.5 cases per the estimated crude rate of cervical cancer 100,000 women, in stark contrast to the 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 2010 Southern Vietnam, where the rate was 26 The age - standardized rate of cervical cancer 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 2010 mortality The incidence rate of cervical cancer is population - based cancer 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 cervical cancer prevention cases per 100,000 women in 2009 - 2010), and to monitor its health impacts, Vietnam followed by Can Tho City (17.7 cases per must have quality data on cervical cancer 100,000 women in 2008 - 2009), then Hanoi incidence and mortality in the population Post City (10.5 cases per 100,000 women during -treatment 2004 - 2008) and finally Hai Phong (8.3 cases determined, as this is an important indicator of per 100,000 women in 2008) The rate was the quality of treatment services in the country on cervical has cancer been survival incidence published rates must and from also JMR 105 E1 (7) - 2016 the be JOURNAL OF MEDICAL RESEARCH Both primary and secondary prevention precancerous lesions and invasive cervical strategies are highly effective against cervical cancer [24; 25], compared with cytology - cancer Primary prevention via the HPV based screening in women older than 30 Re- vaccine is still out of bounds for the national cently, this finding has also been confirmed in program of Vietnam, principally due to its high cost However, secondary prevention through cervical cancer screening is an important public health measure that Vietnam should invest in The guiding principle of secondary India, the developing country with a low human immunodeficiency virus (HIV) Over the last 20 years, the widespread HIV epidemic has increased the overall burden of HPV infec- prevention of cervical cancer is that the 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 - cancerous lesions should be treated prevention and screening programs Cervical cancer precursors are classified as Cervical Intraepithelial Neoplasia (CIN) 1, CIN or CIN depending on the extent of the disease in the epithelium Whereas most CIN lesions are due to transient HPV infection and not progress further, a large number of CIN and CIN lesions will progress to invasive cancers if left untreated [23] In Vietnam, there is paucity of data regarding the population prevalence of CIN and CIN - information that is necessary to understand the disease burden in the country, to formulate prevention strategies, and to design future interventions related to cervical cancer screening 2.1 Human papillomavirus: the etiological agent of cervical cancer Molecular epidemiological studies have conclusively established the causal association between high - risk HPV genotypes and cervical cancer The relative risk of developing cervical cancer from high - risk HPV strains is in the hundreds - fold and far greater than the association between cigarette smoking and lung cancer In fact, cervical cancer is the first cancer 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 other higher HPV infection and cervical cancer The identification of high-risk HPV (hrHPV) types (the strains of HPV that cause cervical cancer) offers the prospect of improving cervical screening programmes through the vertebrates such as dogs, horses, and cattle In general, they 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]; there 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 they are highly conserved and that the clinically genome is not prone to mutation, in contrast to sensitive for JMR 105 E1 (7) - 2016 the detection of JOURNAL OF MEDICAL RESEARCH other viruses like the human immunodefi- squamous cell carcinomas, 80 to 85 percent of ciency virus (HIV) The 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 the viral Phylogenetically, HPVs are within the alpha DNA, transcription of the 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 In contrast, the proteins making up the major viral capsid) HPV genotypes and 11 are closely related Much of the natural host immune response is and in the same species, species 10 directed to conformational epitopes on the L1 2.2 HPV infection protein displayed on the outer surface of the intact virion [26] Moreover, the L1 protein, HPV specifically infects the epithelial cells when expressed via recombinant yeast or viral of the skin or mucosa Either through minor vectors, folds and self - assembles into empty abrasions of the squamous epithelium or capsids or viral-like particles (VLPs), which through entry at the transformation zone in the antigenically and morphologically resemble cervix, viral particles infect basal cellular lay- wild virus, forming the basis of current prophy- ers It is here that a small amount of the 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 the large number of HPVs, there is tropism of infection for different tissues by various genotypes; i.e., skin types (e.g., HPV - 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 the virus enters the supra basal compartment, where the keratinocytes lose their ability to replicate but initiate terminal differentiation As the epithelium is shed, the full virions become ready to infect the next host various 30s, 40s, 50s, 60s, 70s) Around 40 It is because of this complex interaction genotypes are able to infect the genital tract with the differentiating keratinocyte, that HPV Of these, some have oncogenic potential cannot be propagated in vitro in cell lines, in (established high risk strains include strains contrast to other 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 others 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 the ‘necessary’ CP6108) Within the high - risk group, HPV cause for the development of cervical cancer genotypes 16 and 18 impart the greatest [29 - 31] The International Agency for Research degree of risk, with these 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 cervical cient evidence that they cause cervical cancer: JMR 105 E1 (7) - 2016 JOURNAL OF MEDICAL RESEARCH 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 the development of cervical in Vietnam to look at the overall HPV preva- cancer [32] Considering the broad interest in lence in the country’s female population No HPV vaccines, it is important to verify the study has been done to date that documents prevalence of the various types of HPV world- HPV genotype prevalence, especially of the wide, especially the high-risk strains Despite high risk types, either in the healthy female the medical importance of identifying high-risk population or among cervical cancer patients HPV strains, and the high incidence rate of To understand how potentially impact the HPV cervical cancer, there is a lack of information vaccine could be in the country, the distribu- on the incidence of the most common HPV tion of high risk HPV genotypes among both genotypes cervical cancer patients and those with CIN To determine HPV genotypes, the and CIN lesions must be determined amplified PCR products were run in 1.5% Knowledge regarding the prevalence of the 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 the useful- lengths, the genotypes of the virus were ness of various HPV detection technologies as analyzed by electrophoresis and visualized by cervical cancer screening tests an ultraviolet light trans - illuminator Bands of Worldwide, the risk of cervical cancer has appropriate size were identified by comparison increased in parallel with the incidence of with DNA molecular weight markers that are certain genotypes of HPV [32] Therefore, the made from a set of known DNA fragments presence of these genotypes indicates a The adequacy of the DNA in each specimen significant risk factor for the development of for PCR amplification was determined by the cervical cancer HPV infects cutaneous and detection of the β - globin gene mucosal epithelial cells of the ano - genital In Vietnam, at present, cervical cancer tract, which can lead to a variety of diseases screening activities in the country are mostly with a range of severities The mildest form of opportunistic Some of the country’s non- HPV disease is the low - grade intraepithelial governmental neoplasia (CIN1) These lesions can persist conducting and progress to high-grade disease (CIN2) relatively small population Since 2007, the and invasive cervical cancer HPVs are also organization Program for Appropriate Techno- found in cancers of the tonsils, anus, penis logy in Health (PATH) is conducting a cervical and cancer of neck cancer vaccination and screening project in voluntary individual organizations projects are involving High - risk HPV 16 and 18 are the most Thanh Hoa, Hue, and Can Tho provinces, in common causes of cervical cancer, account- collaboration with the Vietnamese National ing for approximately two thirds of all cervical Institute of Hygiene and Epidemiology and the carcinomas worldwide Of the two strains, Maternal and Child Health Department of the HPV-16 occurs most frequently Studies have Ministry of Health The program, primarily shown that the presence of even minimal relying on a ‘see and treat’ strategy using VIA JMR 105 E1 (7) - 2016 JOURNAL OF MEDICAL RESEARCH as the screening test, screened more than capacity of the medical professionals linked to 38,000 women aged 30 to 49 years across cervical these three provinces from 2007 to February programs in the country In Vietnam, such pro- 2011 The Vietnamese Ministry of Health, with fessionals include midwives, nurses, assistant technical physicians, obstetricians and gynecologists, assistance organizations, has from drafted international the cancer screening and treatment National and oncologists A KAP study in Vietnam Population/Reproductive Health Strategy for should be done both with women in the coun- the period of 2011 - 2020, to be implemented try, and with these 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 2015 Cervical cancer is the second most com- Control of cervical cancer through effective mon cancer in women in less developed re- population - based cervical cancer screening gions, with an estimated 445000 new cases in programs is a major goal of the country’s 2012 (representing 84% of the new cases national reproductive health teams The aim is worldwide that year) In 2012, approximately to screen 20% of women aged 30 - 54 years 270 000 women died from cervical cancer; by 2015 and to scale up the program by 2020 more than 85% of these 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 Precancerous Lesions have also 13 are cancer - causing Cervical cancer is been prepared and advocate that VIA and/or caused by sexually acquired infection with cervical cytology will be offered to help screen certain types of HPV Two types of HPV (16 women aged 21 - 70 years and 18) cause 70% of all cervical cancers and Several factors help to determine the precancerous cervical lesions success of cervical cancer screening programs The target population must be aware of these Acknowlegment programs, have positive perceptions abou We would like to express our thanks to tpreventive health and accept screening as a UNFPA Vietnam, the Department of Maternal strategy to reduce cancer incidence Even and Child Health and the Ministry of Health for within the same country, these factors may their financial and technical support vary depending on the target population’s ethnicity, religion, culture and literacy level A REFERENCES study to evaluate the knowledge, attitudes and World Health Organization/ICO Infor- practices (KAP) among women in the target mation Centre on HPV and Cervical Cancer population, to (2010) Human papilloma virus and related represent the population of the entire country, cancers in South Africa Summary Report could provide valuable information that would 2010 http://who.int/hpvcentre (accessed 15 help reorganize the country’s cervical cancer November 2012) sampled systematically screening program It is also essential to evaluate the awareness, perception and IARC (2012) Global cancer burden rises to 14.1m new cases in 2012: Marked increase JMR 105 E1 (7) - 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2016 ... are diagnosed annually in South Africa cervical cancers per 100,000 women and 2.2 (SA) [1] Accurate contemporary data on deaths due to cervical cancer per 100,000 cervical cancer incidence has... the of cervical cancer in Indonesia was about 100 age-standardized incidence of cervical cancer - 190 cases per 100,000 women [18] Cervical was 7.0 cases per 100, 000 women and the cancer was... types of HPV Two types of HPV (16 women aged 21 - 70 years and 18) cause 70% of all cervical cancers and Several factors help to determine the precancerous cervical lesions success of cervical cancer