Cervical cancer is the fourth most common malignancy in females worldwide, and a leading cause of death in the United Kingdom (UK). The human papillomavirus (HPV) is the strongest risk factor for developing cervical intraepithelial neoplasia and cancer. Across the UK, the national HPV immunisation programme, introduced in 2008, has been successful in protecting against HPV-related infections. Furthermore, the National Health Service (NHS) implemented the cytology-based cervical cancer screening service to all females aged 25 to 64, which has observed a decline in cervical cancer incidence. In the UK, there has been an overall decline in age-appropriate coverage since April 2010. In 2019, the COVID-19 pandemic disrupted NHS cancer screening and immunisation programmes, leading to a 6.8% decreased uptake of cervical cancer screening from the previous year. Engagement with screening has also been associated with social deprivation. In England, incidence rates of cervical cancer were reported to be 65% higher in the most deprived areas compared to the least, with lifestyle factors such as cigarette consumption contributing to 21% of cervical cancer cases.
1. Introduction
Cervical cancer is a highly prevalent disease amongst females, associated with significant morbidity and mortality worldwide. It is the fourth most common malignancy to affect women globally and responsible for approximately 850 deaths per annum in the United Kingdom (UK). Cancer Research UK reported 3200 new cervical cancer cases in the UK annually between 2016 and 2018, with peak incidence rates among females aged 30 to 34. There are several associated risk factors, with the human papillomavirus (HPV) infection being a major causative factor, contributing to approximately 99.7% of all cases. Other factors have also been reported to increase cervical cancer risk, including smoking, immunosuppression, poor sexual health, and screening non-attendance. Regardless of the advances in the primary and secondary prevention of cervical cancer, a significant portion of patients present with or develop metastatic disease, mainly within the first 2 years of completing primary treatment. Surgical resection and/or radiotherapy may potentially be curative for selected cases with locally recurrent or limited metastatic disease. However, for the vast majority of patients, palliative chemotherapy represents the only treatment. Yet, there is a significant unmet clinical need for effective second-line therapeutic strategies. Technologies of proteomics, such as mass spectrometry and protein array analysis, have advanced the dissection of the underlying molecular signaling events in gynaecological oncology [8]. Moreover, proteomics analysis of cervical cancer can uncover new therapeutic targets, which can reduce the emergence of drug resistance and improve the prognosis [9]. This review aims to address the epidemiology of cervical cancer, HPV pathogenesis and transmission, and current programmes within the National Health Service (NHS) for prevention and early identification of this disease. Detailed analysis into screening uptake, risk factors, and future developments are crucial in reducing the burden of cervical cancer in the UK.
Cervical cancer is a devastating malignancy of the cervix, with squamous cell carcinomas reported to be more prevalent than adenocarcinomas. The year 2020 recorded an estimated 604,000 new cases of cervical cancer and 324,000 deaths globally, with almost 90% of these cases occurring in low- and middle-income countries. The NHS first aimed to tackle the burden of this disease by introducing a national cervical screening programme in 1988, which has since seen a significant reduction in over a third of cases in England. Cervical cancer screening is available from the age of 25, as the disease is rare among younger individuals. A large multi-centre study in the UK reported that screening individuals between the ages of 20 to 24 years old had little or no effect on the rates of cervical cancer. Interestingly, 9% of new diagnoses are in those aged 75 years and older, but this demographic is not currently screened as part of the programme. The screening programme invites all people with a cervix between the ages of 25 and 64, to undergo screening for cervical cancer every 3 or 5 years, depending on age. Since then, the incidence rates have remained stable over the last decade [
14]. Moreover, incidence rates of cervical cancer in England have been compared with countries such as Portugal, exploring differences between organised and opportunistic screening methods on cervical cancer incidence and mortality. Despite both England and Portugal observing a decline in mortality, Portugal adopts an opportunistic screening programme that has reported higher rates of cervical cancer cases compared to organised screening methods in England.
In the UK, it is important to note that cases have been reported to be 65% higher in areas of deprivation. There are several risk factors associated with this malignancy, HPV infection identifying as the strongest causative factor. HPV types, particularly HPV 16 and 18, are found to be highly prevalent in the UK general population. The HPV is a sexually transmitted infection that increases the risk of an individual to develop cervical cancer. Multiple sexual partners, early sexual intercourse, and smoking are established behavioural risk factors for developing cervical cancer, which may be more commonly seen in areas of higher social deprivation. Other than sexual transmission, other modes of disease conveyance include vertical transmission from mother to infant and through fomites, such as clothing, although the role of fomites in the transmission of infection is not fully understood. In May 2018, the World Health Organisation (WHO) proposed the ‘Cervical Cancer Elimination Initiative’, which aims to eradicate cervical cancer globally through more rigorous vaccination and screening methods. As HPV-associated malignancy may be preventable, understanding the pathogenesis of the HPV infection in developing invasive cancers will form the basis of preventing and treating most cases, thus, significantly improving the outcome of these patients.
inety percent of HPV-induced cell changes in the cervix regress spontaneously and HPV is cleared from the body, without any oncogenic consequences. However, when a hrHPV infection evades the immune system, which is particularly common among immunocompromised patients, dyskaryosis and cervical intraepithelial neoplasia (CIN) can occur. CIN is a pre-malignant abnormal collection of cells that, if untreated, may progress to become invasive carcinoma. The pathophysiology is not fully understood, but it is believed that micro-abrasions in the epithelial surface are the most probable route for HPVs to infect the epithelial basal layer. After the interaction of the HPV viral DNA with the host cell, the virus is then internalised and transported into the nucleus for further replication. E6 and E7 are proteins that possess strong oncogenic potential by interacting with tumour suppressor genes (TSGs), the tumour protein p53 (TP53), and retinoblastoma proteins (pRb), respectively. E6 targets TP53 for degradation via the ubiquitin pathway, thus, preventing apoptosis. E7 targets the retinoblastoma family members RB1, RBL1, and RBL2, which, consequently, drives the oncogenic process [
3. HPV rely on the replication system of the human cell, as they do not have their own. Accordingly, the intrinsically differentiated dormant cells must be induced to replicate again, which the viruses achieve with E6 and E7 activity. Additionally, E5 is considered a weak co-factor that can accelerate oncogene expression, although any significant effects on E6 and E7 are yet to be proven. Therefore, downregulation of these TSGs causes genomic instability, thus, driving the malignant transformation of an HPV-infected cell into an invasive cancer cell.
Basal epithelial cells have intimately related replication cycles to HPV, whereby early gene expression results in substantial amplification of viral DNA. In the epithelial midzone and superficial zones, further viral replication of the genome and expression of L1, L2, and E4 genes take place. L1 and L2 enclose the viral genomes to form progeny virions in the nucleus, which then go on to form new infections. Due to the non-enveloped nature of the virus, the capsid has a non-lipid membrane structure, in which L1 plays a vital role in its formation. Therefore, targeting L1 with self-assembled virus-like particles (VLPs) has become an integral part of developing successful HPV vaccines.
2. Current NHS Programmes—Cervical Cancer Screening
The NHS cervical screening (smear test) programme was first introduced in 1988 in the UK, which screened women aged 20 to 64 years of age every 3 to 5 years. Between 1988 and 1992, the UK observed a striking reduction in mortality and an increased coverage. However, due to evidence that screening women from age 20 had little or no effect on cancer risk, the NHS announced that women aged between 25 to 49 years were to be screened three-yearly, whilst women aged 50 to 64 years old would be invited to be screened every five years. Northern Ireland has since adopted the same screening method, whilst Wales and Scotland have decreased the testing frequency to five-yearly for all eligible age groups. The updated screening programme continues to be successful in decreasing incidence rates and mortality regarding cervical cancer.
Currently, the primary aim of the screening programme is to identify the HPV infection, thus, preventing cervical cancer. Various randomised controlled trials revealed that a cervical screening test detecting hrHPV DNA had greater sensitivity in recognising CIN than a cytology-based screening method, thus, providing significantly more protection against cervical cancer. Those who are informed of an abnormal result that are highly suggestive of CIN are referred to cytology to look for dyskaryosis. If present, those individuals will be invited for another screening in 12 months’ time. However, if dyskaryosis is reported on cytology, women will be offered a colposcopy, to ensure a further detailed examination of the cervix. Subsequently, women with severe dyskaryosis may be offered large loop excision of the cervical transformation zone (LLETZ) to remove abnormal cells, a procedure that has been hugely beneficial in reducing the overall mortality rate.
Data were collected from NHS Digital, where outcomes of the cervical screening programme are published annually. This includes data from the call and recall system that, according to the NHS, was minimally disrupted by the coronavirus pandemic. The date range for data collection for each year was from the 1st of April to the 31st of March of the following year. ‘Screened from invitation’ measures screening uptake within a specific year and provides an indication of short-term screening uptake, whereas coverage data represent a summary of screening uptake over a longer period. Age-appropriate coverage was calculated through the number of women in the 25 to 49 and 50 to 64 years age group, who, within the last 3.5 and 5.5 years, respectively, have had an adequate screening test as a percentage of the eligible population.
3. Conclusions
Understanding of the HPV infection is crucial in the prevention, detection, and management of a significant majority of cervical cancers in the UK. Current programmes in the UK, which include the enrolment of the HPV vaccines, organised screening, and detailed colposcopy procedures, are highly beneficial in improving the prognosis and mortality of these patients. Prominent risk factors including cigarette smoking, immunosuppression, the OCP, and sexual behaviour have been identified as significant risk factors. Public health initiatives to educate the general population on these modifiable risk factors will help reduce the burden of disease. Furthermore, critiquing the possible reasons for reduced uptake of current NHS programmes and considering methods to ensure maximal compliance will be key in moving closer to eliminating cervical cancer in the UK.
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