Journal of Obstetrics and Gynaecology

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Human papillomavirus and cervical cancer

Kehinde Sharafadeen Okunade

To cite this article: Kehinde Sharafadeen Okunade (2019): Human papillomavirus and cervical
cancer, Journal of Obstetrics and Gynaecology, DOI: 10.1080/01443615.2019.1634030

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Published online: 10 Sep 2019.

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JOURNAL OF OBSTETRICS AND GYNAECOLOGY
https://doi.org/10.1080/01443615.2019.1634030

REVIEW ARTICLE

Human papillomavirus and cervical cancer

Kehinde Sharafadeen Okunade
Department of Obstetrics and Gynaecology, College of Medicine, University of Lagos/Lagos University Teaching Hospital, Lagos, Nigeria

ABSTRACT KEYWORDS
Cervical cancer is by far the most common HPV-related disease. About 99.7% of cervical cancer cases Cervical cancer; high-risk
are caused by persistent genital high-risk human papillomavirus (HPV) infection. Worldwide, cervical HPV; HPV vaccines;
cancer is one of the most common cancers in women with an estimated 528,000 new cases reported screening; triaging
in 2012. Most HPV infections clear spontaneously but persistent infection with the oncogenic or high-
risk types may cause cancer of the oropharynx and anogenital regions. The virus usually infects the
mucocutaneous epithelium and produces viral particles in matured epithelial cells and then causes a
disruption in normal cell-cycle control and the promotion of uncontrolled cell division leading to the
accumulation of genetic damage. There are currently two effective prophylactic vaccines against HPV
infection, and these comprise of HPV types 16 and 18, and HPV types 6, 11, 16 and 18 virus-like par-
ticles. HPV testing in the secondary prevention of cervical cancer is clinically valuable in triaging low-
grade cytological abnormalities and is also more sensitive than cytology as a primary screening. If these
prevention strategies can be implemented in both developed and developing countries, many thou-
sands of lives could be saved.

Introduction due to chronic HPV infection (Harro et al. 2001). Cervical can-
cer is the fourth most common cancer in women worldwide
Human papillomavirus (HPV) is the commonest viral infection
and it accounts for an estimated 570,000 new cases with
of the reproductive tract and is one of the most common
about 85% occurring in the less developed regions. In 2018,
causes of sexually transmitted infection worldwide (Burd
an estimated 311,000 deaths were attributed to cervical can-
2003). Even though it is sexually transmitted, HPV transmis-
cer, accounting for 7.5% of all female cancer deaths with
sion does not require penetrative sexual intercourse. Skin-to-
almost 90% these deaths occurring in the less developed
skin genital contact is a well-established mode of transmis-
regions (GLOBOCAN 2012; Bray et al. 2018). In these develop-
sion. Over 70% of sexually active women and men will be
ing countries, cervical cancer may constitute up to 25% of all
infected at some point in their lives and some may even be
female cancer deaths (Jin et al. 1999) and is only preceded
infected on more than one occasion (GLOBOCAN 2012). The
peak period for acquiring HPV infection is shortly after by breast cancer as the most common cause of cancer
becoming sexually active. The infection usually clears up deaths in women worldwide (Bray et al. 2018).
spontaneously within a few months after the acquisition with
about 90% clearing within 2 years. There are over 200 HPV Basic virology of HPV
types recognised based on DNA sequence data showing gen-
omic differences, and many of these are harmless. HPV can HPV is a member of the Papovaviridae family. It is a relatively
infect basal epithelial cells of the mucocutaneous membrane, small, non-enveloped virus of about 55 nm diameter. It has
and it is associated with a variety of clinical conditions that an icosahedral capsid with 72 capsomers and these contain
range from innocuous lesions to cancer. Most of these infec- at least two capsid proteins, L1 and L2. Each capsomer is a
tions are benign or non-oncogenic, causing lesions such as pentamer of the major capsid protein, L1 (Baker et al. 1991).
cutaneous warts on the hands, feet and anogenital regions. Each virion capsid contains about 12 copies of the minor
Warts are areas of hypertrophied skin filled with keratin and capsid protein, L2 (Sapp et al. 1995). The HPV genome con-
are mainly a cosmetic nuisance; generally, they resolve spon- sists of a single molecule of double-stranded, circular DNA
taneously within 1–5 years. Only a small proportion of infec- (Favre 1975) with all open reading frame (ORF) protein-cod-
tions with certain types of HPV can persist and progress to ing sequences confined to one strand. There are three func-
cancer such as oropharyngeal, cervical, vulvar, vaginal and tional regions in the genome (Figure 1, Stanley et al. 2007):
penile cancer (Burd 2003). the first is a ‘non-coding upstream regulatory region’ also
Cervical cancer is by far the most common HPV-related referred to as the long control region (LCR), or the upper
disease (Burd 2003). Nearly, all cases of cervical cancer are regulatory region (URR). This region contains the highest

CONTACT Kehinde Sharafadeen Okunade [email protected] Department of Obstetrics and Gynaecology, College of Medicine, University of Lagos/
Lagos University Teaching Hospital, Lagos, Nigeria
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 K. S. OKUNADE

Figure 1. Genome organisation of HPV (Stanley et al 2007).

degree of variation in the viral genome and contains the p97 Cervical cancer arises at the transformation zone, which is
core promoter along with enhancer and silencer sequences the region between the squamous epithelium of the ectocer-
that control ORFs transcription in the regulation of DNA repli- vix and the columnar epithelium of the endocervix, where
cation (Apt et al. 1996). The second is called the ‘early region continuous metaplastic changes occur. The period of greatest
(E)’ and it consists of ORFs E1, E2, E4, E5, E6 and E7, which metaplastic activity coincides with the greatest risk of HPV
are involved in viral replication and tumorigenesis. The third infection and this occurs at puberty and the first pregnancy
is referred to as the ‘late region (L)’ and this encodes the L1 and subsequently declines slowly after the occurrence
and L2 ORFs for the viral capsid. The E6, E7 and L1 ORFs of a of menopause.
new or unknown HPV type should be 90% or less homolo-
gous to the corresponding sequences of known HPV types
The link between genital HPV infections and
(Torrisi et al. 2000).
cervical cancer
In the past three to four decades, the natural history of cer-
Epidemiology of genital HPV infection
vical cancer has been well studied, and persistent infection of
The worldwide prevalence of high-risk HPV infection is 10.4% the cervix with certain types of HPV has been reported as a
(de Sanjose et al. 2003) and it can be as high as 36.5% in necessary causative factor for its occurrence (Walboomers
some developing countries (Bao et al. 2008; Okunade, et al. 1999). The link between HPV and cervical squamous
Nwogu, et al. 2017). Several epidemiologic studies have cell carcinoma has become well established since the early
clearly shown that the risk of contracting genital high-risk 80s. The magnitude of the association between HPV and
HPV infection and cervical cancer is influenced by sexual squamous cell carcinoma of the cervix is higher than that for
activity (Erickson et al. 2013; ACOG 2017). An individual is at the association between smoking and lung cancer (Franco
increased risk of having HPV infection if he or she has had 1995). About 30 HPV types that are transmitted through sex-
multiple sexual partners at any time or if he or she has a ual contact and infect primarily the cervix, vagina, vulva,
partner who has had multiple sexual partners. Having sexual penis and anus have been identified. One or more of these
activity at an early age as well as having a history of other HPV types has been implicated in 99.7% of cases of squa-
sexually transmitted infections, genital warts, or cervical or mous cell carcinoma of the cervix (Walboomers et al. 1999).
penile cancer in an individual or sexual partner may also HPV is a family of closely related viruses with each desig-
increase the risk of becoming infected with HPV. In addition nated as a type based on their nucleic acid sequencing and
to sexual activity, age is an important determinant of the risk then numbered in the order of discovery. More than 200 HPV
of HPV infection (Burk et al. 1996; Adam et al. 2000). The types are known to exist (Burd 2003; Unger and Eliav 2004)
infection is most common among sexually active young with 15 types associated with cervical cancer. Genital HPV
women between the age of 18 and 30 years with a sharp types can be grouped as high-risk (oncogenic) and low-risk
decline in prevalence after the age of 30 years. Although, cer- (non-oncogenic) HPV types based on this association with
vical cancer is more common in older women of 35 years cervical cancer and its precursor lesions. Low-risk or non-
and above, thus suggesting that the infection occurs at a oncogenic HPV types include types 6, 11, 42, 43 and 44 while
younger age with a slow progression to cancer at an older the high-risk or oncogenic HPV types include types 16, 18,
age. Persistence of HPV infection is commoner with the high- 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73 and 82
risk or oncogenic types and this plays an important role in (Walboomers et al. 1999). Low-risk subtypes are also occa-
the development of invasive cancer of the cervix (Burd 2003). sionally found in cervical carcinomas. The virus usually infects
 JOURNAL OF OBSTETRICS AND GYNAECOLOGY 3

the mucocutaneous epithelium and produces viral particles independent of HPV infection for high-grade cervical disease
in matured epithelial cells and then causes a disruption in (Adam et al. 2000). Smoking shows little or no relationship to
normal cell-cycle control and the promotion of uncontrolled low-grade cervical disease (Burd 2003).
cell division leading to the accumulation of genetic damage
(Unger and Eliav 2004). Adenocarcinomas of the cervix are
also less commonly related to HPV infection and are age
Increasing parity
dependent (Andersson et al. 2001). Almost 90% of adenocar- Having an increasing number of full-term pregnancies is a
cinoma of the cervix in women younger than 40 years of age significant independent risk factor for persistent HPV infec-
are related to HPV infection, whereas it was observed in only tion and cervical cancer (Juneja et al. 2003; Shields et al.
43% of adenocarcinomas in those aged 60 years and older. 2004). The possible mechanisms proposed for this are the
Most HPV-induced cervical changes are transient with 90% increased hormone levels and impaired immune response of
regressing spontaneously within 12–36 months (Moscicki pregnancies (Appleby et al. 2006). In multiparous women, the
et al. 1993; Ostor 1993; Chua and Hjerpe 1996; Syrj€anen transformation zone remains longer on the ectocervix and
1996; Ho et al. 1998). However, various other factors such as this facilitates its direct exposure to the virus and other
the individual’s genetic predisposition, i.e. polymorphic genes potential cofactors (Autier et al. 1996). However, the most
of the major histocompatibility complex, as well as a particu- plausible mechanism is the local tissue damage occurring
lar polymorphism in the p53 gene involved in the clearance during vaginal childbirth or cellular oxidative stress with the
and maintenance of HPV infection (de Araujo Souza and Villa increased likelihood of DNA damage and HPV integration
2003), genetic variation within different HPV type, coinfection (Castle 2004; Williams et al. 2011).
with more than one type of HPV, frequency of reinfection,
hormone levels and immune response may alter an individu-
al’s ability to clear the infection. Therefore, the detection of Prevention of HPV-associated cervical cancer
high-risk HPV is necessary but may not be enough for the The natural history of cervical cancer offers unique opportu-
development of cervical cancer. Whether a woman will nities for prevention of the disease (Denny 2012).
develop cervical cancer depends on several factors that act Conventionally, Pap smear and liquid-based cytology (LBC),
in conjunction with oncogenic HPV types in a process that combined with treatment of cervical pre-cancerous lesions
leads to cervical cancer. These factors or modifiers of HPV and early-stage cancer, has been successful in preventing up
activities include: to 80% of invasive cervical cancer cases in the developed
world (Gichangi et al. 2003; Kivistik et al. 2011). Cervical can-
Suppressed primary immune response cer screening involves testing for HPV infection and cervical
cancer precursor lesions among women who have no symp-
Immune response to HPV infection is cell-mediated and thus toms. When screening detects cervical pre-cancerous lesions,
conditions that impair cell-mediated responses such as renal treatment can easily be instituted, and cancer avoided.
transplantation or HIV disease increase the risk of acquisition Screening can also detect early-stage cervical cancer at a
and progression of HPV (Cubie et al. 2000; Torrisi et al. 2000; time when treatment has a high potential for cure. Currently,
Calore et al. 2001). Studies have consistently shown a higher primary approaches to HPV prevention include both risk
prevalence of HPV infection and cervical cancer precursors in reduction and development of vaccines against HPV infec-
HIV infected women (Conely et al. 2002; Harris et al. 2005; tion. Furthermore, the risk of contracting HPV may also be
Singh et al. 2009). decreased with the use of latex condoms and spermicides.
However, these are not totally reliable, since HPV infection
may be transmitted through contact with other parts of the
Long-term use of oral contraceptives
body, such as the external genitalia, or anus, that are not
This is a significant risk factor for high-grade cervical disease protected by a condom (Burd 2003).
according to some studies (Brisson et al. 1994; Adam et al.
2000). This is because the upstream regulatory region of
HPV testing
high-risk HPV contains sequences which are similar to the
responsive elements of glucocorticoid that can be induced This is a laboratory test in which cells from the cervix are
by steroid hormones such as progesterone which is the tested for DNA from certain types of HPV that are known to
active component of oral contraceptives and dexamethasone. cause cervical cancer. This may be done alone (primary HPV
screening) or in combination with cervical cytology (hybrid
HPV screening). These two screening strategies are meant to
Cigarette smoking minimise unnecessary follow-up visits and invasive proce-
The suppression of local immune response induced by smok- dures without compromising the detection of disease.
ing and the mutagenic activity of tobacco components have
been demonstrated in cervical cells and this may contribute
Hybrid screening
to HPV persistence or to malignant changes in the cervix
(Philips and Ni She 1993; Yang et al. 1996; Villa 1997). It This is the concomitant cervical cytology and HPV testing.
appears that smoking is the most important risk factor This test is usually done using the sample of cells removed
4 K. S. OKUNADE

during a Pap smear test or LBC. HPV testing is done if the 12 months with referral back to colposcopy if results show
results of a Pap smear test show certain abnormal cervical ASCUS or greater or repeat HPV DNA testing at 12 months
cells (reflex testing). When both the HPV test and Pap test with referral back to colposcopy if high-risk HPV types
are done using cells from the sample removed during a Pap are detected.
test, it is called a Pap Smear/HPV co-testing. Large-scale stud-
ies to evaluate management options for women with abnor-
mal Pap smear results have been conducted and these Primary HPV screening
studies indicate the potential utility of HPV DNA testing in HPV DNA testing alone without a Pap smear test may also be
the management of women with Pap smear results of used for screening in women aged 25 years and older (Qiao
Atypical Squamous Cells of Undetermined Significance et al. 2008; Wright et al. 2015). It is as effective as a hybrid
(ASCUS) (Saslow et al. 2012; ACOG 2013; Massad et al. 2013). screening strategy that uses cytology in women aged
Based on the results of these studies, screening strategy 25–29 years and co-testing in those at 30 years or older
options that include testing for high-risk HPV DNA as an (Wright et al. 2015). However, HPV primary screening requires
adjunct to cytology have been developed to triage and less screening frequency (every 5 years). This involves direct
monitor ASCUS patients. These improvements in cytologic referral to colposcopy for women who test positive for HPV
screening through LBC, as well as the introduction of HPV types 16/18 and cytology for those who test positive for any
DNA testing, greatly facilitate the identification of women at of the other high-risk HPV types (Huh et al. 2015). The
risk for cervical cancer. There are three recommended International Agency for Research on Cancer (IARC) and the
options in the management of women with ASCUS (Massad World Health Organisation (WHO) have endorsed HPV testing
et al. 2013) and these include. as the primary screening method for cervical cancer. Several
developed countries are now changing to HPV primary
screening (Leinonen et al. 2012; Ronco et al. 2014; Huh et al.
Repeat cervical cytology
2015). Until recently, the major obstacles to the use of HPV
In this approach, ASCUS patients would undergo cytology at testing in cervical cancer prevention in most resource-
4–6-month intervals until two negative results are obtained constraint settings such as Africa and other developing coun-
after which the patient can be returned to routine cytologic tries are the need for expensive laboratory infrastructure and
screening. If any repeat cytology shows ASCUS or greater, the 4–7 hours’ time to process the test. However, the devel-
referral to colposcopy is recommended. opment of rapid molecular methods for the detection of HPV
DNA is a milestone in cervical cancer screening in these low-
resource settings as these may make the test more feasible
Immediate colposcopy
in the future and reduce the huge infrastructural require-
This is the usual approach in immunocompromised women ments (Catarino et al. 2015). Following a positive HPV testing,
such as those infected with HIV (Holcomb et al. 1999). If this various types of secondary screenings have been described,
is used, women with biopsy-confirmed cervical intraepithelial however, indications and intervals of repeat testing and rec-
neoplasia (CIN) are treated as per standard protocol using ommendations for referral for colposcopic examinations are
excision or coagulation techniques. If biopsy is negative for still subject to discussion and variations in different parts of
CIN, patients will undergo repeat cytology at 12 months. In the world (Cardenas-Turanzas et al. 2008).
postmenopausal women who have ASCUS and clinical or
cytologic evidence of atrophy, a 6-week course of intravagi-
HPV vaccination
nal oestrogen is recommended if there are no contraindica-
tions to oestrogen use. Repeat cytology is performed after One of the major prevention strategies for cervical cancer is
completion of the oestrogen regimen and if this is negative, the vaccination against HPV infection among adolescents
the test is repeated in 4–6 months. If the repeat test shows prior to their first sexual exposure (ACOG 2017). HPV vaccines
ASCUS or greater, the patient is referred to colposcopy. are composed of virus-like particles (VLPs), which contains
Immunosuppressed women with ASCUS should be referred the major and minor HPV capsid antigens but lacking viral
directly to colposcopy. DNA. The vaccines are produced by expressing the L1 or L1
and L2 ORFs in eukaryotic cells. These proteins then self-
assemble into VLPs which are highly immunogenic. There is
HPV DNA testing
no cross-protection among the HPV types due to the high
This is the most preferred approach especially if LBC is used level of antigenic specificity of HPV capsid antigens and thus
or if specimens are co-collected for HPV DNA testing. If HPV protection against each HPV type requires vaccination with
DNA testing is negative for high-risk HPV types, the patient VLPs of that type. Optimal vaccines would contain a cocktail
undergoes repeat cytology testing at 12 months. However, of VLPs of the most common high-risk HPV subtypes. There
direct referral to colposcopy is recommended for women are currently two commonly used vaccines (bivalent and
who test positive for any of the high-risk HPV types. If the quadrivalent) which protect against both HPV 16 and 18,
biopsy confirms CIN, patients are treated per standard proto- which are known to cause at least 70% of cervical cancers. In
col for the management of CIN. If the biopsy does not con- addition, the quadrivalent vaccine also protects against HPV
firm CIN, then cytology should be repeated at 6 and types 6 and 11 which cause anogenital warts. Both vaccines
 JOURNAL OF OBSTETRICS AND GYNAECOLOGY 5

are more effective if administered prior to exposure to HPV have a role in the future screening of women for high-risk
and thus, it is preferable to administer them before first sex- HPV especially type 16 which accounts for more than 50% of
ual activity. The WHO recommends vaccination for girls aged all cervical cancer cases (Schiffman et al. 2007; Li et al. 2011;
9–13 years as this is the most cost-effective public health Schiffman and Wentzensen 2013). The E6/E7 oncoproteins
measure against cervical cancer (Burd 2003; WHO 2009, are overexpressed after HPV invasion into the host cervical
2014). Some countries have started to vaccinate boys as the cells in the form of HPV DNA or viral integration into the
vaccination prevents genital cancers in males as well as host’s genome and are closely related to the development of
females, and the quadrivalent vaccine also prevents genital cervical cancers (Munagala et al. 2011). In a recent pilot
warts in males and females. These vaccines may provide study, HPV16 E6/E7 oncoprotein test has a satisfactory diag-
some cross-protection against other less common HPV types nostic value for cervical cancer screening and demonstrated
which cause invasive cervical cancer. Recently, a nonavalent a better sensitivity than cytological test and better specificity
vaccine against HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58, than HPV DNA testing (Zhang et al. 2018).
which has shown a better impact compared to the bivalent
and quadrivalent vaccine, has been approved by the US
Food and Drug Administration (FDA) and is now commer- Conclusions
cially available (Capra et al. 2017). At present, vaccination Molecular and epidemiologic studies have solidified the asso-
against HPV is not recommended as a replacement for cer- ciation between high-risk strains of genital HPV and squa-
vical cancer screening and in countries where the vaccine is mous cell carcinoma of the cervix. The incidence of cervical
introduced, cervical screenings still need to be developed or cancer and its associated mortality have declined in recent
further strengthened (Okunade, Sunmonu, et al. 2017). years, largely due to the widespread implementation of
However, in most developing countries, there is still a gener- screening programmes. Screening for cervical cancer remains
ally low level of awareness of the existence and availability of an important public health and economic concern through-
these HPV vaccines (Okunade, Sunmonu, et al. 2017) com- out the world. Large-scale studies to evaluate management
pared to the developed countries with well-organised cervical options for women with abnormal Pap smear results have
cancer screening and HPV vaccination programmes. Several been conducted and these studies highlighted the potential
other barriers to accessing these vaccines that exist in most utilisation of HPV DNA testing in the management of women
resource-constraint countries are the prohibitive cost which is with ASCUS Pap smear results. From these studies, screening
out of the reach of the poor, the poor vaccine delivery strategies that include testing for high-risk HPV DNA as an
efforts, ineffective health system capabilities, inaccessibility to adjunct to cytology have been developed for the triage and
medical care, low awareness and knowledge of HPV and cer- surveillance of women with ASCUS. Several other studies,
vical cancer, and failure to recognise cervical cancer as a such as the ATHENA study (Saslow et al. 2012), have also
major health concern (Ezenwa et al. 2013; Perlman et al.
examined and confirmed the role of HPV DNA testing as pri-
2014; Agida et al. 2015; Okunade, Sunmonu, et al. 2017).
mary screening for cervical precursor lesions. In addition to
Other recommended preventive interventions against HPV
the changes in screening strategies, HPV 16 testing through
infections that are appropriate for both boys and girls are
measurement of HPV E6/E7 oncoprotein levels and effective
education about safe sexual practices including delayed
therapeutic HPV vaccines that have the potential to contrib-
onset of sexual activity; promotion and provision of condoms
ute significantly to the control and prevention of cervical
for those already engaged in sexual activity; male circumci-
cancer are also currently being developed for future use.
sion; and warnings about tobacco smoking.

Acknowledgements
Future perspectives
The author acknowledges the mentorship provided by Prof. Folasade
Therapeutic HPV vaccines Ogunsola, Deputy Vice-Chancellor, Development Services of the
University of Lagos, Lagos, Nigeria, Prof Rose Anorlu, Head of
There are currently no approved therapeutic vaccines against Department of Obstetrics and Gynaecology, College of Medicine of the
HPV in humans. However, there are many recent studies that University of Lagos and Phyllis Kanki, Harvard University School of Public
have generated promising vaccine candidates tested in clin- Health, Boston, MA, USA, throughout the preparation of this manuscript.
ical trials (Vici et al. 2016; Yang et al. 2016; Kim and Kim
2017). Despite the success of these vaccine candidates, there
Disclosure statement
still remains the concern that conventional expression meth-
ods when fully developed might result in very expensive The author declared no conflict of interest.
products (Giorgi et al. 2010; Rybicki 2014) that will be
inaccessible to the resource-constraint countries who have
Funding
the highest incidences of cervical cancer.
The work reported in this publication was supported by the Fogarty
International Center and National Institute of Mental Health, of the
Measurement of HPV oncoprotein levels National Institutes of Health under Award Numbers D43TW010543 and
D43TW010134. The content is solely the responsibility of the authors and
Measuring the levels of HPV E6/E7 oncoproteins is now a does not necessarily represent the official views of the National Institutes
potential biomarker for high-risk HPV infection and this may of Health.
6 K. S. OKUNADE

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