Vaccination and Screening Programmes Have Brought the Elimination of Cervical Cancer Within Reach

Cervical cancer screening and immunisation programmes have had an impressive impact on prevention and survival rates; Dr Adeola Olaitan outlines progress to date, and examines additional refinements to the process that can lead to further improvements

Background

Cervical cancer is potentially preventable through a policy of education, vaccination, and screening and, when indicated, treatment of precursor lesions. It is estimated that screening prevents 70% of cervical cancer deaths a year^1,2 and, since the introduction of call/recall screening in England in 1988, cervical cancer rates have declined. Cervical cancer prevention was further impacted by the introduction of a school vaccination programme against high-risk human papillomavirus (HPV) types for girls in 2008, with boys between the ages of 12 and 13 included from 2018.³ It is expected that the implementation of a primary HPV screening programme from 2019 will lead to a further decline in rates of the disease.⁴

History of the Screening Programme

Cervical screening was made possible when George Nicholas Papanicolaou, a Greek scientist, discovered that cells from the human cervix can be collected and mounted on a glass slide.⁵ The publication of a landmark book in collaboration with Dr Herbert Traut in 1943, Diagnosis of uterine cancer by the vaginal smear,⁶ paved the way for cervical screening. The procedure, known as the Pap test or cervical smear, quickly became the gold standard in screening for cervical cancer. First introduced in England in 1964, cervical cancer screening was opportunistic and was initially subject to little regulation.⁷

The National Health Service Cervical Screening Programme was launched in 1988, with clear guidelines about eligibility for screening and criteria for treatment. The Department of Health issued a circular requiring district health authorities to start a computerised call/recall system. Women age 20–64 years were invited to participate in cervical cancer screening every 3–5 years. The cervical cytology call/recall system is operated at a local level by health authorities in compliance with national policy, with safeguards and quality control embedded into the system. The introduction of screening has led to a 60–70% reduction in mortality from cervical cancer.¹

Changes in Screening Age

Studies demonstrated that screening women aged 20–24 years had little or no impact on rates of invasive cervical cancer up to age 30, which prompted questions around the optimal timing for screening implementation.⁸ There were also concerns that young women with low-grade premalignant lesions that had the potential to resolve spontaneously were being overtreated, as well as a recognition of subsequent pregnancy morbidity, such as preterm labour and low birthweight, following excisional procedures.⁹

The Advisory Committee on Cervical Cancer Screening increased the initial age of screening from 20 to 25 years in 2003.⁷ In England, the first invitation to screening is at 24.5 years, with the first invitation at 25 years of age in Wales and Northern Ireland.^10,11 Scotland increased their age of first invitation to 25 years in 2016.¹² Between the ages of 25 and 49 years, women are invited for screening every 3 years. From 50–64 years, invitations are every 5 years. Women over 65 years are invited only if they have not been screened in the past, or if they have had recent abnormal cytology test results. Women aged 65 years or over whose last three consecutive adequate tests were negative are removed from the screening programme but can request screening if they wish to have it.²

Infection and Cervical Cancer

Modifications to cervical cancer screening were made possible because of a greater understanding of the aetiology of cervical cancer. The role of infection in cervical carcinogenesis was first postulated in the 1950s, when it was thought that herpes simplex virus was the causative agent. Between 1977 and 1987, zur Hausen, a German scientist, challenged this theory, and published Condylomata accuminata and human genital cancer in 1976, postulating that cervical cancer is caused by human papillomavirus (HPV).¹³

HPV is a double-stranded DNA virus belonging to the Papillomaviridae family that infects squamous epithelia, including the skin and mucosae of the upper respiratory and anogenital tracts. It is the most common sexually transmitted infection worldwide, and it is estimated that most sexually active individuals will be infected with HPV at least once in their lifetime.¹⁴ More than 90% of exposed individuals will achieve immune-mediated spontaneous clearance of the virus within 2 years of exposure.¹⁵ HPV infection is most prevalent in young individuals following onset of sexual activity and, in most countries, declines after the age of 35.¹⁴

More than 200 types of HPV have been identified.¹⁶ Genital HPV is acquired through intimate skin-to-skin contact, not just penetrative sexual intercourse, and carries a lifetime risk of infection of up to 80% in exposed individuals.¹⁷ Most HPV infections are asymptomatic and self-limiting. However, persistent high-risk HPV infection occurs in 10–15% of women, and is associated with an increased risk of pre-cancerous cervical lesions and cervical cancer.¹⁸

HPV causes more than 95% of cervical cancers, with HPV 16 and 18 the most oncogenic.¹⁴ HPV 16 is implicated in about 60% of cervical cancers, and type 18 in about 10%.¹⁹ Other high-risk types include 31, 33, 45, 52, and 58, which together contribute to about 15% of cervical cancers globally.²⁰

Introduction of HPV Vaccination

There are three commercially available HPV vaccines for the prevention of cervical cancer in the western world: Cervarix (GlaxoSmithKline), Gardasil, and Gardasil9 (Merck). Cervarix, a bivalent vaccine, prevents acquisition of HPV 16 and 18 infection.²¹ Gardasil, in addition to protecting against HPV 16 and 18, also protects against HPV 6 and 11.³ HPV 6 and 11 are responsible for about 10% of low-grade cervical lesions and about 90% of genital warts.³ Gardasil 9, approved in 2014, protects against HPV 6 and 11, and seven high-risk HPV types (HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58).

HPV immunisation using a three-dose schedule of Cervarix was introduced in England in 2008.²² Routine vaccination was offered to schoolgirls aged 12–13 years, with a catch-up programme for females aged 14–18 years in 2008–10.²² The administered vaccine was changed to Gardasil in September 2012²² and, in March 2014, the Joint Committee on Vaccination and Immunisation revised its existing recommendation to change from a three-dose to a two-dose schedule for girls who were under 15 years of age when vaccination was initiated.²³

The HPV immunisation programme has contributed to a decline in the incidence of cervical cancer in women born after September 1995, as demonstrated by an observational study²⁴ that used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts who were not eligible for HPV vaccination. It found a substantial reduction in cervical cancer and incidence of cervical intraepithelial neoplasia (CIN) 3 in young women following the introduction of the HPV immunisation programme in England, particularly in those offered the vaccine at age 12–13 years.²⁴

Is HPV Testing Alone Sufficient?

Although rare, HPV-independent cervical cancers do exist, and there is concern that relying exclusively on HPV detection as the initial screening tool may lead to some precursor lesions being missed. The literature suggests that up to 5% of cervical cancers are HPV independent.²⁵ These tumours are associated with a worse prognosis, and with lymph node metastasis,²⁵ illustrating the importance of public health education alongside a screening programme. An awareness of the symptoms of cervical cancer, such as post-coital or post-menopausal bleeding or an offensive vaginal discharge, should lead to early presentation. It is important for healthcare practitioners to appreciate that HPV testing is a screening test in an asymptomatic population, and that women with symptoms should be referred for investigations and a biopsy.

HPV-induced Cervical Carcinogenesis

The HPV genome consists of three regions. The Long Control Region (LCR) regulates gene expression and replication, the Early I region encodes for proteins that are required for HPV gene expression, replication and survival, and the Late (L) region encodes for viral structural proteins.²⁶ The virus gains access to host cells by infecting the basal epithelial layer of the cervix. Following infection, early proteins E1, E2, E4, E5, E6, and E7 are produced; E6 and E7 are the key oncoproteins that promote viral DNA replication and prevent apoptosis via interactions with tumour suppression proteins.²⁶ Subsequently, late capsid proteins L1 and L2 are produced, which allow formation of progeny virions in host nuclei cells—these replicate the viral life cycle.²⁶ (See Figure 1.)

Introduction of Liquid-based Cytology

Liquid-based cytology was introduced in 2008 with the aim of improving diagnostic accuracy.²⁸

Liquid-based cytology has advantages over conventional smears: fewer artefacts arise from the airdrying process, and there are less background elements to obscure details, leading to improved viewing and a reduced number of unsatisfactory smears.²⁸

There are disadvantages, however. Liquid-based cytology is associated with increased costs and can reduce or alter background extracellular material, and alter cell morphology. Despite this, its sensitivity has been shown to be equivalent to that of conventional techniques, and it is superior in high-risk populations. Liquid-based cytology allows an HPV test to also be performed on the sample so it can be used to triage screening results.²⁸

Introduction of HPV as Primary Screening

In 2013, Public Health England (PHE) established pilot sites in Sheffield, Liverpool, Manchester, Bristol, Norfolk, and Northwest London²⁹ for baseline high-risk HPV testing and early recall; these demonstrated a substantial increase in detection of the precursor lesion of cervical cancer, CIN, and for cervical cancer than that found with liquid-based cytology.²⁹

The UK National Screening Committee recommended a switch to high-risk HPV primary screening in January 2016, and this was implemented in 2019.^30,31

Colposcopy and Treatment of Cervical Intraepithelial Neoplasia

Cervical screening identifies women at high risk of specified cervical abnormalities. High-risk HPV positive women with cytological abnormalities are referred for colposcopy. The role of colposcopy is to make a diagnosis to inform a treatment decision. This is based on pattern recognition, aided by targeted biopsies of the abnormal areas.

Women with low-grade disease (CIN1) can be managed by observation as there is a high chance of spontaneous resolution. CIN2 may also be managed conservatively, after taking into consideration the size and characteristics of the lesion and the woman’s wishes. Evidence shows that conservative management is a reasonable and effective strategy in appropriately selected women with CIN2.³² Treatment is usually recommended for women with CIN3 because of the risk of progression to cancer.

Large loop excision of the transformation zone is the commonest treatment modality in the UK.³³ It is usually well tolerated as an outpatient procedure. Major complications are rare and include haemorrhage, visceral injury, infection, cervical stenosis, or incompetence. Other modalities include laser ablation of the excision, needle excision, and knife cone biopsy.

Conclusion

HPV testing is highly specific, but lacks sensitivity.³⁴ Attention is turning to molecular testing for more accurate detection of women at risk of cervical cancer. The WID-CIN (Women’s cancer risk Identification-Cervical Intraepithelial Neoplasia) test, a DNA methylation signature consisting of 5000 CpG sites, helps to identify the majority of high-risk HPV-positive women with current CIN3+ lesions. A positive WID-CIN test result, with the absence of cytologic abnormalities, is likely to indicate a significantly increased risk of developing CIN3+ in the near future.³⁵

This, or other similar molecular tests may offer more sensitive and—more importantly—specific screening methods in the future, further reducing cervical cancer rates.

The UK National Screening Committee is expected to publish a review on recommendations for cervical cancer care in 2023 that could provide greater insights into testing, as well as a further review of different age cohorts who participate in screening programmes.

There has been tremendous progress in strategies for prevention of cervical cancer over the past 40 years, and the elimination of cervical cancer is now within reach. For this to happen, high coverage through the vaccination programme must be maintained. Women must be made aware that screening remains important, even if they have been vaccinated. The emergence of molecular tests is likely to finesse screening even further, potentially leading to more lives saved.