A review of cervical cancer incidence and HPV infection

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.

Corresponding author: Ngo Van Toan, Hanoi Medical

University

Email: ngovantoan57@yahoo.com

Received: 04 November 2016

Accepted: 10 December 2016

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 world-wide 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

Cervical cancer occurs in tissues of the

cervix (the organ connecting the uterus and

vagina) It is usually a slow-growing cancer

that may not present with symptoms but can

be found with regular Pap tests (a procedure

in which cells are scraped from the cervix and

looked at under a microscope) Cervical

cancer is almost always caused by human

papillomavirus (HPV) infection Among more

than 100 types of HPV, several types can

cause cervical cancer The most common

types that lead to cervical cancer are HPV 16

and 18 Over the past 40 years, the incidence

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 do not

develop active intervention programs, the number of cervical cancer cases will increase

by an additional 25% in the next 10 years worldwide [1] In England, since the 1970s, the cervical cancer incidence rate has been decreasing (it reduced 63% during 1985

-1987 and 66% during 2009 - 2011, compared

to the 1970’s) [1] Developing countries must implement better cervical cancer screening programs to see a similar reduction in cancer cases The objective of this review was to provide the information regarding cervical cancer incidence and HPV infection worldwide and specifically in Vietnam

II CONTENTS

1 Incidence rate

1.1 Cervical cancer incidence rates worldwide

Cervical cancer is the second most common kind of cancer among women world-wide after breast cancer There were about 528,000 new cases worldwide and 260.000 women died of cervical cancer [1] More than

80% of infected and affected women live in the

developing countries Cervical cancer is the

fourth leading cause of death among women

globally About 20% of new cases worldwide

were diagnosed in India [2] In

Sub-Sahara countries, there are about 34.8

new cases of cervical cancers per 100,000

women and 22.5 deaths due to cervical cancer

per 100,000 women per year [3; 4]

In contrast, there were 6.6 new cases of

cervical cancers per 100,000 women and 2.2

deaths due to cervical cancer per 100,000

women per year in the North America [1] In

the United States, the age - standardized rate

of cervical cancers was 9.6 cases per 100,000

women during the period of 1996 - 2000 [1]

The global survival rate of cervical cancer five

years after being diagnosed was 72% There

were about 4,100 women that died due to

cer-vical cancer in 2003 in the United States [1]

Cervical cancer was the sixth most common

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

Almost all cervical cancer cases were in women aged 30 and above The age-standardized incidence rate of cervical cancer among white women was from 8.2 to 8.8 cases per 100,000 women, while in black women it was 6.3 - 11.2 per 100,000 women, and among Asian women it was 3.6 - 6.5 per 100,000 women [5 - 9]

Approximately 6,000 new cervical cancer cases are diagnosed annually in South Africa (SA) [1] Accurate contemporary data on cervical cancer incidence has not been available since the 1999 Cancer Registry was published Many cases were presumed to still

be undiagnosed due to poor screening programs and more than half of all patients diagnosed each year are expected die from the disease The World Health Organization estimated the age-standardized incidence rate for SA to be 26.6 per 100 000 women [1] The current prevalence of pre - invasive cervical disease in

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 3 times higher than liver cancer incidence among women in the country [10]

Cervical cancer is a common cancer

among women in developing countries in Asia

Worldwide, the region comprising Asia

Oceania covers a vast and diverse area

geographically and ethnically, supporting

around 60 percent of the world’s population

and contributing to just over half of the global

burden of cervical cancer [11]

India, in particular, has one of the highest

reported cervical cancer incidence and

mortal-ity rates in the region These higher rates

re-flect an overall lack of widespread screening

and treatment facilities, as well as a greater

proportion of persistent HPV infections, as

indicated by the very high rates of cervical

cancer in older women

Across the Asia Pacific region, examples of

successful cervical cytology programs are

rather limited [14] In Australia and New

Zea-land, where long-standing and highly effective

cytology programs have been in existence for

several decades, incidence and mortality rates

of cervical cancer cases have declined

significantly [12; 13] In Australia in 2003, the

age-standardized incidence of cervical cancer

was 7.0 cases per 100, 000 women and the

mortality rate was 2.2 cases per 100,000

women [12] It is noteworthy, however, that

notwithstanding the success of the National

Cervical Screening Program in the general

population, indigenous women in Australia

were over four times more likely to die of

cervical cancer than non-indigenous women in

20012004; cervical cancer incidence was 4

-5 fold higher in indigenous women over the

same time period [12] Whilst overall for the

Australian population, the estimated lifetime

cervical cancer screening participation rate

was 88 per cent (62% for over two years, 73%

for over three years), the increased rates of cervical cancer in indigenous women reflects poorer access to cervical cytology screening programs [12; 13]

In contrast, in Thailand and the Phillipines, there have not been significant reductions in incidence and mortality rates, despite the cervical cytology programs that these countries have had in place for decades [14] This perhaps reflects the fact that the organized programs in these countries are not reaching high proportiontions of the appropriate populations As cervical cancer screening programs have become more sophisticated in more affluent and urbanized Asia-Pacific countries such as Singapore, 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]

According to estimates, the incidence rate

of cervical cancer in Indonesia was about 100

- 190 cases per 100,000 women [18] Cervical cancer was the most common malignancy among women in Indonesia, comprising up to 22.5% of all cancer cases reported in govern-mental hospitals there [18] However, this number was likely an underestimation, because only 25 - 30% of all sick people in Indonesia enter these medical facilities [18] Cervical cancer is a major health problem

in Indonesia since most patients present in the later stages of the disease, in low resource settings where no screening programs are available The association of the high-risk strains of HPV (notably strains 16, 18, 31 and 45) with cervical cancer among female

patients in Indonesia is now widely accepted,

as these strains of HPV have been detected in

almost all cervical cancer patients and are

much less common in women without cervical

cancer [18; 19]

The distribution of HPV strains in Indonesia

is largely unknown HPV 18 has been reported

to play more of a role in the spread of cervical

cancer there than HPV 16 [18], at a rate that is

higher than that reported in other geographical

areas worldwide The viral origin for cervical

cancer and its high morbidity and mortality

figures give cause for the development of a

vaccine against HPV To design vaccines

suit-able for the Indonesian female population, an

inventory of HPV prevalence is essential

1.2 The incidence rate of cervical

cancer in Vietnam

Up to now, studies on the incidence rate of

cervical cancer in Vietnam have been

rela-tively limited The Program for Cancer Control

has conducted studies looking at rates of

cer-vical cancer in cities and provinces across the

country since 2008 Results have shown that

the estimated crude rate of cervical cancer

was 13.1 cases per 100,000 women in 2000

and 12.7 cases per 100,000 women in 2010

The age - standardized rate of cervical cancer

was 17.3 cases per 100,000 women in 2000

and 13.6 cases per 100,000 women in 2010

The incidence rate of cervical cancer is

different between regions and provinces The

rate was highest in Ho Chi Minh City (19.7

cases per 100,000 women in 2009 - 2010),

followed by Can Tho City (17.7 cases per

100,000 women in 2008 - 2009), then Hanoi

City (10.5 cases per 100,000 women during

2004 - 2008) and finally Hai Phong (8.3 cases

per 100,000 women in 2008) The rate was

lowest in Thai Nguyen province (4.1 cases per 100,000 women during 2006 - 2010) and Thua Thien Hue province (5.8 cases per 100,000 women in 2008) [20]

Viet Nam has a population of 30.77 million women aged 15 years and older who are at risk of developing cervical cancer, and this poses a major public health problem for the country Current estimates indicate that every year 5174 women are diagnosed with cervical cancer and 2472 die from the disease, with an estimated age - standardized incidence rate of 11.5 cases per 100,000 women [20] However, these statistics were derived by modeling based on data obtained from some of the cancer treatment centers and may not reflect the actual rates in the country Reports from cancer registries operating in the country’s two major cities, Hanoi and Ho Chi Minh City, published nearly 15 years back show signifi-cant regional variations in cervical cancer inci-dence The age - standardized incidence rate

of cervical cancer in Hanoi, a city situated in Northern Vietnam, was only 6.5 cases per 100,000 women, in stark contrast to the high incidence rate in Ho Chi Minh City, situated in Southern Vietnam, where the rate was 26 cases per 100,000 women [21; 22] No recent data on cervical cancer incidence and mortality has been published from the population - based cancer registries in Hanoi and Ho Chi Minh City To develop a public health strategy for cervical cancer prevention and to monitor its health impacts, Vietnam must have quality data on cervical cancer incidence and mortality in the population Post -treatment survival rates must also be determined, as this is an important indicator of the quality of treatment services in the country

Both primary and secondary prevention

strategies are highly effective against cervical

cancer Primary prevention via the HPV

vaccine is still out of bounds for the national

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

prevention of cervical cancer is that the

disease should be detected through

system-atic screening of all women within a certain

age group, and that all women found to have

pre - cancerous lesions should be treated

Cervical cancer precursors are classified as

Cervical Intraepithelial Neoplasia (CIN) 1, CIN

2 or CIN 3 depending on the extent of the

dis-ease in the epithelium Whereas most CIN 1

lesions are due to transient HPV infection and

do not progress further, a large number of CIN

2 and CIN 3 lesions will progress to invasive

cancers if left untreated [23] In Vietnam, there

is paucity of data regarding the population

prevalence of CIN 2 and CIN 3 - 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 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

introduction of hrHPV - based screening tests

Studies from developed countries provide

convincing evidence that hrHPV DNA - based

screening algorithms are cost - effective and

clinically sensitive for the detection of

precancerous lesions and invasive cervical cancer [24; 25], compared with cytology -based screening in women older than 30 Re-cently, this finding has also been confirmed in India, the developing country with a low hu-man immunodeficiency virus (HIV) Over the last 20 years, the widespread HIV epidemic has increased the overall burden of HPV infec-tion in sub - Saharan Africa Accurate current knowledge about hrHPV prevalence in devel-oping countries is essential for cost analysis and planning for regionally tailored national prevention and screening programs

2.1 Human papillomavirus: the etiologi-cal agent of cervietiologi-cal cancer

Molecular epidemiological studies have conclusively established the causal associa-tion 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 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 papillo-maviruses (BPV) of cattle is different from HPV in humans]; there is no known crossing

of papillomaviruses between species

Sequence analysis of cloned HPVs shows that they are highly conserved and that the genome is not prone to mutation, in contrast to

other viruses like the human

immunodefi-ciency virus (HIV) The 8 kilobase circular

genome of HPV is made up of one early (E)

gene (necessary for replication of the viral

DNA, transcription of the non-structural early

proteins E1, E2, E4, E5, E6 and E7, and

as-sembly of newly produced viral particles) and

two late (L) genes (L1 and L2) (which code for

the proteins making up the major viral capsid)

Much of the natural host immune response is

directed to conformational epitopes on the L1

protein displayed on the outer surface of the

intact virion [26] Moreover, the L1 protein,

when expressed via recombinant yeast or viral

vectors, folds and self - assembles into empty

capsids or viral-like particles (VLPs), which

antigenically and morphologically resemble

wild virus, forming the basis of current

prophy-lactic vaccine candidates

Over 200 papillomaviruses are now

recog-nized, 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

1 - 4, 10, 26-29, 37, 38, 46, 47, 49, 50, 57)

and genital types (e.g., HPV 6, 11, 16, 18,

various 30s, 40s, 50s, 60s, 70s) Around 40

genotypes are able to infect the genital tract

Of these, some have oncogenic potential

(established high risk strains include strains

16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59,

68, 73, 82; probable high risk strains include

strains 26, 53, 66) whilst others are low risk

(established low risk strains include strains 6,

11, 40, 42, 43, 44, 54, 61, 70, 72, 81,

CP6108) Within the high - risk group, HPV

genotypes 16 and 18 impart the greatest

degree of risk, with these now known formally

as human carcinogenic agents HPV 16 and

18 contribute to around 70 per cent of cervical

squamous cell carcinomas, 80 to 85 percent of which are adenocarcinomas which are more difficult to detect on cytological screening Phylogenetically, HPVs are within the alpha genus HPV genotypes 16 and 18 are quite distinct and are from separate species: HPV genotype 16 is from species 9, whereas HPV genotype 18 is from species 7 In contrast, HPV genotypes 6 and 11 are closely related and in the same species, species 10

2.2 HPV infection

HPV specifically infects the epithelial cells

of the skin or mucosa Either through minor abrasions of the squamous epithelium or through entry at the transformation zone in the cervix, viral particles infect basal cellular lay-ers It is here that a small amount of the viral genome is maintained, allowing for latency in 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

It is because of this complex interaction with the differentiating keratinocyte, that HPV

cannot be propagated in vitro in cell lines, in

contrast to other viruses that are readily cultured for diagnostic purposes However, by various molecular hybridization assays, HPV nucleic acid can be detected as DNA or RNA

in tissues or clinical samples

High-risk HPV infection is the ‘necessary’ cause for the development of cervical cancer [29 - 31] The International Agency for Research

on Cancer in Lyon lists 12 genotypes of HPV that are considered high - risk and have suffi-cient evidence that they cause cervical cancer:

HPV strains 16, 18, 31, 33, 35, 39 45, 51, 52,

56, 58, and 59 Only one study has been done

in Vietnam to look at the overall HPV

preva-lence in the country’s female population No

study has been done to date that documents

HPV genotype prevalence, especially of the

high risk types, either in the healthy female

population or among cervical cancer patients

To understand how potentially impact the HPV

vaccine could be in the country, the

distribu-tion of high risk HPV genotypes among both

cervical cancer patients and those with CIN 2

and CIN 3 lesions must be determined

Knowledge regarding the prevalence of the

high - risk HPV genotypes in CIN 2+ lesions

will also help to gain insight into the

useful-ness of various HPV detection technologies as

cervical cancer screening tests

Worldwide, the risk of cervical cancer has

increased in parallel with the incidence of

certain genotypes of HPV [32] Therefore, the

presence of these genotypes indicates a

significant risk factor for the development of

cervical cancer HPV infects cutaneous and

mucosal epithelial cells of the ano - genital

tract, which can lead to a variety of diseases

with a range of severities The mildest form of

HPV disease is the low - grade intraepithelial

neoplasia (CIN1) These lesions can persist

and progress to high-grade disease (CIN2)

and invasive cervical cancer HPVs are also

found in cancers of the tonsils, anus, penis

and cancer of neck

High - risk HPV 16 and 18 are the most

common causes of cervical cancer,

account-ing for approximately two thirds of all cervical

carcinomas worldwide Of the two strains,

HPV-16 occurs most frequently Studies have

shown that the presence of even minimal

amounts of HPV DNA is associated with an increased risk of the development of cervical cancer [32] Considering the broad interest in HPV vaccines, it is important to verify the prevalence of the various types of HPV world-wide, especially the high-risk strains Despite the medical importance of identifying high-risk HPV strains, and the high incidence rate of cervical cancer, there is a lack of information

on the incidence of the most common HPV genotypes

To determine HPV genotypes, the amplified PCR products were run in 1.5% agarose gel stained by ethidium bromide Since all amplified products had different lengths, the genotypes of the virus were analyzed by electrophoresis and visualized by

an ultraviolet light trans - illuminator Bands of appropriate size were identified by comparison with DNA molecular weight markers that are made from a set of known DNA fragments The adequacy of the DNA in each specimen for PCR amplification was determined by the detection of the β - globin gene

In Vietnam, at present, cervical cancer screening activities in the country are mostly opportunistic Some of the country’s non-governmental voluntary organizations are conducting individual projects involving relatively small population Since 2007, the organization Program for Appropriate Techno-logy in Health (PATH) is conducting a cervical cancer vaccination and screening project in Thanh Hoa, Hue, and Can Tho provinces, in collaboration with the Vietnamese National Institute of Hygiene and Epidemiology and the Maternal and Child Health Department of the Ministry of Health The program, primarily relying on a ‘see and treat’ strategy using VIA

as the screening test, screened more than

38,000 women aged 30 to 49 years across

these three provinces from 2007 to February

2011 The Vietnamese Ministry of Health, with

technical assistance from international

organizations, has drafted the National

Population/Reproductive Health Strategy for

the period of 2011 - 2020, to be implemented

in 63 provinces/cities Each province/city

developed an action plan in 2011 that

extended for five years, from 2011 to 2015

Control of cervical cancer through effective

population - based cervical cancer screening

programs is a major goal of the country’s

national reproductive health teams The aim is

to screen 20% of women aged 30 - 54 years

by 2015 and to scale up the program by 2020

to achieve 50% coverage The National

Guidelines on Cervical Cancer Screening and

Treatment of Precancerous Lesions have also

been prepared and advocate that VIA and/or

cervical cytology will be offered to help screen

women aged 21 - 70 years

Several factors help to determine the

success of cervical cancer screening programs

The target population must be aware of these

programs, have positive perceptions abou

tpreventive health and accept screening as a

strategy to reduce cancer incidence Even

within the same country, these factors may

vary depending on the target population’s

ethnicity, religion, culture and literacy level A

study to evaluate the knowledge, attitudes and

practices (KAP) among women in the target

population, sampled systematically to

represent the population of the entire country,

could provide valuable information that would

help reorganize the country’s cervical cancer

screening program It is also essential to

evaluate the awareness, perception and

capacity of the medical professionals linked to cervical cancer screening and treatment programs in the country In Vietnam, such pro-fessionals include midwives, nurses, assistant physicians, obstetricians and gynecologists, and oncologists A KAP study in Vietnam should be done both with women in the coun-try, and with these healthcare professionals

III CONCLUSIONS

Cervical cancer is the second most com-mon cancer in women in less developed re-gions, with an estimated 445000 new cases in

2012 (representing 84% of the new cases 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 infection with certain types of HPV Two types of HPV (16 and 18) cause 70% of all cervical cancers and precancerous cervical lesions

Acknowlegment

We would like to express our thanks to UNFPA Vietnam, the Department of Maternal and Child Health and the Ministry of Health for their financial and technical support

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