DOI: 10.1111/tog.12279 2016;18:251–63
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Cervical cancer prevention and screening: the role of
human papillomavirus testing
a b,
Mehrnoosh Aref-Adib MBBS MA MRCOG, Theresa Freeman-Wang MBChB MRCOG *
a
ST6 Specialty Trainee in Obstetrics and Gynaecology, Whipps Cross University Hospital, Whipps Cross Road, London E11 1NR, UK
b
Consultant Gynaecologist, Whittington Hospital, Department of Women’s Health, Jenner Building, Magdala Avenue, London N19 5NF, UK
*Correspondence: Theresa Freeman-Wang. Email:
Accepted on 9 December 2015
Key content To understand the role of HR-HPV in the development of cervical
An organised screening programme has reduced the incidence of premalignancy and malignancy.
cervical cancer in the UK. To understand the potential of HPV vaccination and the uses of
Cervical screening aims to detect and treat premalignant, low- or HPV testing in reducing the burden of cervical cancer.
high-grade disease.
Ethical issues
Oncogenic or high-risk human papillomaviruses (HR-HPV)
HPV infection is common, so should women with only transient
account for over 99.7% of cervical cancer cases; the most common
HPV infection be informed of their diagnoses, given that
subtypes are HPV-16, 18, 31, 33 and 45.
HPV vaccination was introduced as part of the childhood vaccination
disclosures provide little benefit and may cause significant
emotional harm?
programme in 2008 and will probably save 400 lives per year.
HPV is related to other premalignant and malignant diseases of the
HPV testing is useful: in triage of women with borderline or low-
lower genital tract and oropharynx affecting males and females.
grade cytology; as a test of cure after treatment, in the management
Should boys therefore be also offered HPV vaccination?
of uncertainty, and in primary HPV screening.
Keywords: cervical cancer / cervical screening programme / HPV /
Learning objectives
HPV vaccination / human papillomavirus
To review the history of cervical screening and colposcopy.
Please cite this paper as: Aref-Adib M, Freeman-Wang T. Cervical cancer prevention and screening: The role of human papillomavirus testing. The Obstetrician &
Gynaecologist 2016;18:251–63. DOI: 10.1111/tog.12279
types of HPV have been identified and the viral genome has a
Introduction
common structure with three main areas: E (early) region, L
Cervical cancer presents a significant global health burden, (late) region and the genomic regulatory region (Figure 1).4
with an estimated 266 000 deaths and 528 000 new cases Genital HPV is acquired through intimate skin to skin
worldwide recorded in 2012.1 Approximately 85% of cervical contact, not just penetrative sexual intercourse and has a
cancer cases occur in developing countries, and they lifetime risk of infection of up to 80% in exposed
comprise 12% of all female cancers.1 Human individuals.5 The prevalence of HPV in women declines
papillomavirus (HPV) is necessary but not sufficient for with age6 but increases with increasing numbers of sexual
cervical cancer, and it is also a factor in vaginal, vulval, anal, partners. Most HPV infections are asymptomatic and self-
penile and oropharyngeal cancers.2 limiting. However, persistent HPV infection occurs in
This article reviews HPV in the context of the UK’s 10–15% of women and is associated with various forms of
National Health Service (NHS) Cervical Screening cancer.7 This association with cancer risk is used to stratify
Programme, describes its potential future application in persistent HPV into high- and low-risk types.3 Bouvard has
this programme, and highlights the efficacy of HPV further stratified these into HPV subtypes (Table 1).8
prevention via a vaccination programme. Subtypes 16 and 18 (HPV-16 and HPV-18) have been
found to be the most pathogenic of the high-risk HPV types.
Indeed, together they account for 70–80% of cervical cancers,
Human papillomavirus
40–50% of vulval and oropharyngeal cancers and 70–80% of
HPV is a double-stranded DNA virus that infects squamous anal cancers.8–10
epithelia, including the skin and mucosae of the upper Figure 2 describes the progression of HPV.11 Classically,
respiratory and anogenital tracts.3 To date, more than 120 the development of cancer from HPV has been described in
ª 2016 Royal College of Obstetricians and Gynaecologists 251
, HPV testing in cervical screening
HPV and cervical cancer
Worldwide, cervical cancer is the fourth most common
cancer in women. Furthermore, it is the most common
cancer in women aged 15–44 years, accounting for 9% of new
diagnoses.1 It is clear that HPV infection is causally related to
cervical cancer and its precursor lesions.14 Although HPV has
a high prevalence, the rate of cervical cancer is low, so other
factors are likely to influence disease progression.15
Compared to the risk in uninfected women, the risk of
developing squamous cell carcinoma of the cervix is about
400 times higher following infection with HPV-16 and about
250 times higher following infection with HPV-18.16 Seven
years is believed to be the minimum time span between
infection by HPV and the development of a premalignant
lesion with true malignant potential.17
The most common symptoms of cervical cancer include
intermenstrual, postcoital or postmenopausal bleeding.
Cervical cancer may also be associated with vaginal
discharge, dyspareunia or pelvic pain.18
Figure 1. Genomic structure of human papillomavirus. The viral
genome has a common structure with 3 main areas: E (early) region, L Cervical screening in the UK
(late) region and the genomic regulatory region.
In the UK, cervical screening using a smear test to detect
abnormal cytology, began in the 1960s. However, screening was
initially opportunistic and it was not until the introduction of a
Table 1. Bouvard table of HPV groups8 systematic call and recall programme in 1988 that cancer rates
began to decline.19 Since its introduction, screening has resulted
Group Definition HPV types
in a 60–70% reduction in mortality from cervical cancer.20 The
NHS Cervical Screening Programme (NHSCSP) offers screening
Group 1 Carcinogenic 16, 18, 31, 33, 35, 39, 45, 51,
to humans 52, 56, 58, 59 at different intervals, depending on a woman’s age. There are four
Group 2A Probably 68 programmes (Scottish, Welsh, Northern Irish and English)
carcinogenic within the UK with slight variations of practice.
to humans
Group 2B Possibly 53, 64, 65, 66, 67, 69, 70, 73, 82
Studies demonstrated that screening in women aged 20–24
carcinogenic years had little or no impact on rates of invasive cervical
to humans cancer up to age 30.21 There were also concerns of over-
Group 3 Not classifiable 6, 11 treatment in young women with low-grade premalignant
Group 4 Probably not
carcinogenic
lesions that would resolve spontaneously, as well as concern
related to subsequent pregnancy morbidity (preterm labour
HPV = human papillomavirus
and low birthweight) after excisional procedures.22
The Advisory Committee on Cervical Cancer Screening
increased the initial age of screening from 20 to 25 years in
four stages. Stage 1 is defined by HPV acquisition, which may 2003. This remains controversial. In England, Wales and
be followed by persistence (Stage 2). Stage 3 is premalignant Northern Ireland, the first invitation occurs at 24.5 years of
disease and the final stage is invasion leading to cancer age. Scotland will also be increasing their age of first
(Stage 4).12 invitation to 25 years in 2016.23 Between the ages of 25 and
Once integrated with the host cell genome, HPV can cause 49 years, subsequent invitations are distributed every 3 years.
genetic rearrangements including deletions, translocations From 50 to 64 years, women are invited every 5 years.
and activation of proto-oncogenes. However, although HPV Women over 65 years are invited only if they have not been
is necessary for transformation of the infected cell, it is not screened in the past or they have had recent abnormal
sufficient on its own and requires additional epigenetic cytology test results. Women aged 65 years or over whose last
events, including inflammation, altered immune response or three consecutive adequate tests were negative are removed
exposure to environmental factors.13 from the screening programme.24
252 ª 2016 Royal College of Obstetricians and Gynaecologists
The Obstetrician & Gynaecologist
Review
http://onlinetog.org
Cervical cancer prevention and screening: the role of
human papillomavirus testing
a b,
Mehrnoosh Aref-Adib MBBS MA MRCOG, Theresa Freeman-Wang MBChB MRCOG *
a
ST6 Specialty Trainee in Obstetrics and Gynaecology, Whipps Cross University Hospital, Whipps Cross Road, London E11 1NR, UK
b
Consultant Gynaecologist, Whittington Hospital, Department of Women’s Health, Jenner Building, Magdala Avenue, London N19 5NF, UK
*Correspondence: Theresa Freeman-Wang. Email:
Accepted on 9 December 2015
Key content To understand the role of HR-HPV in the development of cervical
An organised screening programme has reduced the incidence of premalignancy and malignancy.
cervical cancer in the UK. To understand the potential of HPV vaccination and the uses of
Cervical screening aims to detect and treat premalignant, low- or HPV testing in reducing the burden of cervical cancer.
high-grade disease.
Ethical issues
Oncogenic or high-risk human papillomaviruses (HR-HPV)
HPV infection is common, so should women with only transient
account for over 99.7% of cervical cancer cases; the most common
HPV infection be informed of their diagnoses, given that
subtypes are HPV-16, 18, 31, 33 and 45.
HPV vaccination was introduced as part of the childhood vaccination
disclosures provide little benefit and may cause significant
emotional harm?
programme in 2008 and will probably save 400 lives per year.
HPV is related to other premalignant and malignant diseases of the
HPV testing is useful: in triage of women with borderline or low-
lower genital tract and oropharynx affecting males and females.
grade cytology; as a test of cure after treatment, in the management
Should boys therefore be also offered HPV vaccination?
of uncertainty, and in primary HPV screening.
Keywords: cervical cancer / cervical screening programme / HPV /
Learning objectives
HPV vaccination / human papillomavirus
To review the history of cervical screening and colposcopy.
Please cite this paper as: Aref-Adib M, Freeman-Wang T. Cervical cancer prevention and screening: The role of human papillomavirus testing. The Obstetrician &
Gynaecologist 2016;18:251–63. DOI: 10.1111/tog.12279
types of HPV have been identified and the viral genome has a
Introduction
common structure with three main areas: E (early) region, L
Cervical cancer presents a significant global health burden, (late) region and the genomic regulatory region (Figure 1).4
with an estimated 266 000 deaths and 528 000 new cases Genital HPV is acquired through intimate skin to skin
worldwide recorded in 2012.1 Approximately 85% of cervical contact, not just penetrative sexual intercourse and has a
cancer cases occur in developing countries, and they lifetime risk of infection of up to 80% in exposed
comprise 12% of all female cancers.1 Human individuals.5 The prevalence of HPV in women declines
papillomavirus (HPV) is necessary but not sufficient for with age6 but increases with increasing numbers of sexual
cervical cancer, and it is also a factor in vaginal, vulval, anal, partners. Most HPV infections are asymptomatic and self-
penile and oropharyngeal cancers.2 limiting. However, persistent HPV infection occurs in
This article reviews HPV in the context of the UK’s 10–15% of women and is associated with various forms of
National Health Service (NHS) Cervical Screening cancer.7 This association with cancer risk is used to stratify
Programme, describes its potential future application in persistent HPV into high- and low-risk types.3 Bouvard has
this programme, and highlights the efficacy of HPV further stratified these into HPV subtypes (Table 1).8
prevention via a vaccination programme. Subtypes 16 and 18 (HPV-16 and HPV-18) have been
found to be the most pathogenic of the high-risk HPV types.
Indeed, together they account for 70–80% of cervical cancers,
Human papillomavirus
40–50% of vulval and oropharyngeal cancers and 70–80% of
HPV is a double-stranded DNA virus that infects squamous anal cancers.8–10
epithelia, including the skin and mucosae of the upper Figure 2 describes the progression of HPV.11 Classically,
respiratory and anogenital tracts.3 To date, more than 120 the development of cancer from HPV has been described in
ª 2016 Royal College of Obstetricians and Gynaecologists 251
, HPV testing in cervical screening
HPV and cervical cancer
Worldwide, cervical cancer is the fourth most common
cancer in women. Furthermore, it is the most common
cancer in women aged 15–44 years, accounting for 9% of new
diagnoses.1 It is clear that HPV infection is causally related to
cervical cancer and its precursor lesions.14 Although HPV has
a high prevalence, the rate of cervical cancer is low, so other
factors are likely to influence disease progression.15
Compared to the risk in uninfected women, the risk of
developing squamous cell carcinoma of the cervix is about
400 times higher following infection with HPV-16 and about
250 times higher following infection with HPV-18.16 Seven
years is believed to be the minimum time span between
infection by HPV and the development of a premalignant
lesion with true malignant potential.17
The most common symptoms of cervical cancer include
intermenstrual, postcoital or postmenopausal bleeding.
Cervical cancer may also be associated with vaginal
discharge, dyspareunia or pelvic pain.18
Figure 1. Genomic structure of human papillomavirus. The viral
genome has a common structure with 3 main areas: E (early) region, L Cervical screening in the UK
(late) region and the genomic regulatory region.
In the UK, cervical screening using a smear test to detect
abnormal cytology, began in the 1960s. However, screening was
initially opportunistic and it was not until the introduction of a
Table 1. Bouvard table of HPV groups8 systematic call and recall programme in 1988 that cancer rates
began to decline.19 Since its introduction, screening has resulted
Group Definition HPV types
in a 60–70% reduction in mortality from cervical cancer.20 The
NHS Cervical Screening Programme (NHSCSP) offers screening
Group 1 Carcinogenic 16, 18, 31, 33, 35, 39, 45, 51,
to humans 52, 56, 58, 59 at different intervals, depending on a woman’s age. There are four
Group 2A Probably 68 programmes (Scottish, Welsh, Northern Irish and English)
carcinogenic within the UK with slight variations of practice.
to humans
Group 2B Possibly 53, 64, 65, 66, 67, 69, 70, 73, 82
Studies demonstrated that screening in women aged 20–24
carcinogenic years had little or no impact on rates of invasive cervical
to humans cancer up to age 30.21 There were also concerns of over-
Group 3 Not classifiable 6, 11 treatment in young women with low-grade premalignant
Group 4 Probably not
carcinogenic
lesions that would resolve spontaneously, as well as concern
related to subsequent pregnancy morbidity (preterm labour
HPV = human papillomavirus
and low birthweight) after excisional procedures.22
The Advisory Committee on Cervical Cancer Screening
increased the initial age of screening from 20 to 25 years in
four stages. Stage 1 is defined by HPV acquisition, which may 2003. This remains controversial. In England, Wales and
be followed by persistence (Stage 2). Stage 3 is premalignant Northern Ireland, the first invitation occurs at 24.5 years of
disease and the final stage is invasion leading to cancer age. Scotland will also be increasing their age of first
(Stage 4).12 invitation to 25 years in 2016.23 Between the ages of 25 and
Once integrated with the host cell genome, HPV can cause 49 years, subsequent invitations are distributed every 3 years.
genetic rearrangements including deletions, translocations From 50 to 64 years, women are invited every 5 years.
and activation of proto-oncogenes. However, although HPV Women over 65 years are invited only if they have not been
is necessary for transformation of the infected cell, it is not screened in the past or they have had recent abnormal
sufficient on its own and requires additional epigenetic cytology test results. Women aged 65 years or over whose last
events, including inflammation, altered immune response or three consecutive adequate tests were negative are removed
exposure to environmental factors.13 from the screening programme.24
252 ª 2016 Royal College of Obstetricians and Gynaecologists
