Screening HPV and Cervical Cancer in the UK: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Stergios Boussios

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. 

  • HPV
  • cervical cancer
  • epidemiology
  • risk factors
  • cervical cancer screening
  • HPV vaccination

1. Epidemiology of Cervical Cancer

Cervical cancer is a devastating malignancy of the cervix, with squamous cell carcinomas reported to be more prevalent than adenocarcinomas [1][2]. 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 [3][4]. 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 [5]. Cervical cancer screening is available from the age of 25, as the disease is rare among younger individuals [6]. 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 [7]. 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 [6]. 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 [8]. Since then, the incidence rates have remained stable over the last decade [6]. 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 [9]. 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 [9].
In the UK, it is important to note that cases have been reported to be 65% higher in areas of deprivation [6]. There are several risk factors associated with this malignancy, HPV infection identifying as the strongest causative factor [10]. HPV types, particularly HPV 16 and 18, are found to be highly prevalent in the UK general population [11]. The HPV is a sexually transmitted infection that increases the risk of an individual to develop cervical cancer [12]. 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 [13]. 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 [14]. 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 [15]. 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.

2. Introduction of HPV

2.1. HPV Subtypes

HPVs belong to the Papillomaviridae family, which are small, non-enveloped, double-stranded DNA viruses, and the most common viral culprit of reproductive tract infections [4][16][17]. The genome of HPV is circular and estimated to be eight kilobase pairs in size, with most encoding eight proteins that can be divided into either ‘early’ or ‘late’ regions [17]. The ‘early’ region contains six proteins (E1, E2, E4, E5, E6, and E7), which are responsible for HPV genome replication and immune modulation [17][18]. The ‘late’ region consists of L1 and L2 capsid proteins, which have been reported to play a role in the transmission of the virus [16]. Not all HPV types have oncogenic potential, with more than 200 HPV subtypes identifiable as either low or high-risk based on their degree of oncogenicity [17][18][19]. Low-risk HPVs, such as HPV 6, 11, 42, 43, and 44, are classified as such due to commonly only causing benign epithelial lesions, such as verrucae, warts, and papillomas [17][19]. On the other hand, high-risk HPVs (hrHPV), including HPV 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70, are strongly linked to the development of cervical, anal, penile, vulval, vaginal, and oropharyngeal cancers [17][19]. Approximately 40 HPVs are specifically related to the anogenital region, with HPV 16 and 18 considered the most potent hrHPVs, responsible for almost half of high-grade cervical pre-malignancies [4]. Specifically in the UK, a 2014 study reported that hrHPV types 16 and 18 were highly prevalent (83%) in women under the age of 30, whilst other hrHPV types (31, 33, 45, 52, and 58) were detected in 16.1% of hrHPV-positive cervical cancers regardless of age [11].

2.2. HPV Transmission

HPV is primarily spread through direct skin-to-skin or skin-to-mucosa contact [20]. Sexual activity (including vaginal, anal, or oral intercourse) with an individual who has active HPV infection, is the most common mode of transmission [21]. Additionally, there is non-sexual horizontal transmission of HPV through skin, mouth, or fomite contact, which are less common [20][22]. Regarding cervical cancer, some risk factors are associated with its sexually transmitted nature, such as sexual intercourse from an early age and having multiple sexual partners [23][24]. HPV infection is highly prevalent, with one study estimating that women in the United States (US), who have similar interventions to the UK, carry a lifetime risk of infection between 53.6% and 95%, thus, making it a priority to reduce the burden of this disease [25].

3. Pathophysiology of HPV-Related Malignancy

Ninety percent of HPV-induced cell changes in the cervix regress spontaneously and HPV is cleared from the body, without any oncogenic consequences [19]. However, when a hrHPV infection evades the immune system, which is particularly common among immunocompromised patients, dyskaryosis and cervical intraepithelial neoplasia (CIN) can occur [26]. CIN is a pre-malignant abnormal collection of cells that, if untreated, may progress to become invasive carcinoma [27]. 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 [16][28]. 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 [29][30]. 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 [31][32]. E6 targets TP53 for degradation via the ubiquitin pathway, thus, preventing apoptosis [31][32]. E7 targets the retinoblastoma family members RB1, RBL1, and RBL2, which, consequently, drives the oncogenic process [31][33]. 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 [34]. 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 [35]. In the epithelial midzone and superficial zones, further viral replication of the genome and expression of L1, L2, and E4 genes take place [16][31]. L1 and L2 enclose the viral genomes to form progeny virions in the nucleus, which then go on to form new infections [31][36]. 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 [37][38]. Therefore, targeting L1 with self-assembled virus-like particles (VLPs) has become an integral part of developing successful HPV vaccines [37][38].

4. Other Risk Factors

4.1. Smoking

Whilst the relationship between HPV infection and cervical cancer is well-established, it is important to acknowledge other possible risk factors. Both squamous cell and adenocarcinoma of the cervix have similar risk factors, with cigarette smoking being a particularly strong risk factor for squamous cell carcinomas [39]. The large European Prospective Investigation into Cancer and Nutrition (EPIC) study recruited over 521,000 participants across 10 European countries, which revealed a significant two-fold increase in CIN and invasive cervical cancer risk with greater pack-years of smoking, whilst time since quitting reduced risk by two-fold [40]. The association between smoking and cervical cancer risk has been debated, but it is thought to have a multi-faceted role in cervical carcinogenesis [41]. Smoking has been thought to either increase the risk of HPV infection or decrease the clearance, leading to an increased risk of cervical malignancy [42][43]. One study discovered that benzo[a]pyrene, a carcinogenic component of cigarettes, enhanced HPV persistence, thus, increasing HPV 16 and 18 titres [44]. Other studies have supported the hypothesis that smoking promoted carcinogenesis by suppressing cell-mediated immunity against HPV infection [45][46]. Therefore, the pathophysiology of cigarette smoking in cervical carcinogenesis seems to be a multifactorial mechanism that requires further research to understand the complexity of this phenomenon.

4.2. Oral Contraceptive Pill

The oral contraceptive pill (OCP) is the most common form of contraceptive alongside barrier protection in the UK, due to its high efficacy [47]. Whilst the National Institute for Health and Care Excellence (NICE) states that OCP use increases cervical cancer risk, the association is not well-established and has been the subject of debate among clinicians [48][49]. Several systematic reviews and meta-analyses concluded that there was no evidence to suggest that OCP use was associated with increased risk, whilst others concluded that hormonal contraceptives have the potential to affect the HPV-dependent pathway of carcinogenesis due to the cervix being an oestrogen-sensitive organ [50][51][52][53][54]. A recent systematic review and meta-analysis found that OCP use is significantly associated with cervical cancer, particularly adenocarcinomas [49]. Perhaps individuals taking the OCP may be less likely to use concomitant barrier protection, thus, becoming more susceptible to acquiring the HPV infection. Several longitudinal studies found that barrier methods, such as condom use, showed a statistically significant protective effect against the HPV infection and CIN development [55][56][57]. The International Agency for Research on Cancer (IARC) announced that the OCP was a risk factor for developing cervical cancer, stating the increased risk is due to long-term use of more than 5 years [58]. More research into the possible carcinogenic properties of OCP must be conducted to gain a clearer understanding.

4.3. Immunosuppression

It is well-known that immunosuppressed individuals are at an increased risk of developing many cancers, such as colorectal, liver, and stomach cancers [59]. These high-risk patients include but are not exclusive to those with immunodeficiency disorders and organ transplantation [60]. Patients with a cervix who are taking immunosuppressive medication post-organ transplantation are at an elevated risk of cervical cancer due to their vulnerability to HPV infections, driving the mechanism of oncogenesis [61]. A 2009 study from the Netherlands reported that renal transplant recipients were at a two-to-six-fold increase of CIN and a three-fold increased risk of cervical carcinoma compared to the immunocompetent population [62]. These findings were also supported by recent studies conducted in Brazil and China [63][64]. Furthermore, women living with human immunodeficiency virus (HIV) are also thought to be at risk due to the inability to clear the HPV infection effectively [65]. There is evidence that HIV-infected individuals are significantly more vulnerable to presenting with abnormal cervical cytology compared to non-HIV individuals [66]. Furthermore, an association between increased susceptibility to invasive cervical cancers with diminishing CD4 count has been observed [67]. Therefore, these high-risk patients should be warned of possible complications of immunosuppression and be provided vigilant screening with more regular follow-ups compared with the general population. This is supported by NICE guidelines, which offer screening within a year of transplantation, and for HIV-positive individuals, cervical screening, or colposcopy is offered at diagnosis and annually thereafter [68].

4.4. Sexual Behavioural Factors

Various aspects of sexual behaviours have been associated with increased cervical cancer risk, due to a higher chance of acquiring HPV infection [69]. Firstly, early age of sexual intercourse is a known risk factor, with one study reporting a 2.4-fold increase in developing invasive cervical cancer in girls aged 16 or younger [23]. Similarly, a large epidemiological study revealed that first sexual intercourse aged 14 or below compared to 25 and above reported a relative risk of 3.52 [69]. The current age of consent for sexual intercourse in the UK is 16 years old, therefore, offering the HPV vaccination before this age can provide adequate protection against the infection [70]. Furthermore, a meta-analysis investigated the significance of having multiple sexual partners in the development of cervical malignancies, which found that this was an independent risk factor, regardless of HPV status [24]. In contrast, a recent study did not find correlation between sexual behavior and HPV infection. As such, the interpretation of HPV-related head and neck cancer as a sexually transmitted disease should be treated with caution [71].

5. Current NHS Programmes—HPV Vaccination

The NHS vaccination programme currently offers the first HPV vaccine dose to children aged 12 to 13 years, with their second dose 6 to 24 months later [72]. These vaccinations are provided free of charge by the NHS for girls born after 1 September 1991 and boys born after 1 September 2006 [72]. Previously, there was a longstanding vaccination programme exclusively for girls until its extension to both sexes in September 2019 [72]. This was due to beliefs of herd immunity and indirect protection for boys against the HPV infection [73]. This does not equally safeguard men who have sex with men (MSM), and this population was, therefore, still unprotected from HPV-associated cancer risk [73]. Since early 2018, the NHS offers eligible MSM, who are 45 years old and under, free HPV vaccinations [72]. If an individual is eligible for the HPV vaccine, but does not opt for vaccination when offered, it remains available on the NHS at no cost to the individual until their 25th birthday [72]. It is important to note that three doses of the vaccine are recommended for immunocompromised persons and those who received their first dose at 15 years of age or older [74].
As shown in Figure 1, Cervavix, Gardasil, and Gardasil-9 are the three HPV vaccines approved by the Food and Drug Administration (FDA), designed with L1 VLPs to induce neutralising antibodies against the capsid protein [37][38][71][75][76]. The nine-valent HPV vaccine (Gardasil-9) is the current vaccine of choice and covers nine types of HPV: 6, 11, 16, 18, 31, 33, 45, 52, and 58 [77][78]. It will be implemented throughout 2022 as stock of the previous quadrivalent Gardasil vaccine becomes exhausted [79]. Gardasil-9 is a non-infectious recombinant vaccine that contains purified L1 proteins [80]. Studies report that vaccination protects against HPV infection for at least ten years, with some estimating longer lasting protection, although the long-term efficacy of Gardasil-9 is yet to be confirmed [81][82]. Research using simulation models found hypothetical evidence that without regular cervical screening, Gardasil-9 vaccination decreases the lifetime risk of cervical cancer and mortality by seven-fold [83]. It is important to note that despite being deemed to be effective in reducing cervical cancer by up to 88%, the vaccine does not protect against all HPV types culpable of cervical cancer development [84]. Consequently, it remains imperative that individuals who enrol in the immunisation programme, also receive regular cervical screening.
Figure 1. Timeline of HPV vaccination programme implementation and adjustments.

References

  1. Zhang, S.; Xu, H.; Zhang, L.; Qiao, Y. Cervical cancer: Epidemiology, risk factors and screening. Chin. J. Cancer. Res. 2020, 32, 720–728.
  2. Green, J.; Berrington de Gonzalez, A.; Sweetland, S.; Beral, V.; Chilvers, C.; Crossley, B.; Deacon, J.; Hermon, C.; Jha, P.; Mant, D.; et al. Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20-44 years: The UK National Case-Control Study of Cervical Cancer. Br. J. Cancer 2003, 89, 2078–2086.
  3. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. Cancer. J. Clin. 2021, 71, 209–249.
  4. World Health Organization. Cervical Cancer. 2022. Available online: https://www.who.int/news-room/fact-sheets/detail/cervical-cancer (accessed on 9 January 2023).
  5. Pesola, F.; Sasieni, P. Impact of screening on cervical cancer incidence in England: A time trend analysis. BMJ. Open. 2019, 9, e026292.
  6. Cervical Cancer Incidence Statistics. Cancer Research UK. 2015. Available online: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/cervical-cancer/incidence (accessed on 19 December 2022).
  7. Tota, J.; Franco, E.L. Effectiveness of cervical cancer screening at different ages. Womens Health 2009, 5, 613–616.
  8. Cervical Screening: Programme Overview. GOV.UK. 2021. Available online: https://www.gov.uk/guidance/cervical-screening-programme-overview (accessed on 31 December 2022).
  9. Mendes, D.; Mesher, D.; Pista, A.; Baguelin, M.; Jit, M. Understanding differences in cervical cancer incidence in Western Europe: Comparing Portugal and England. Eur. J. Public Health 2018, 28, 343–347.
  10. Schiffman, M.H.; Castle, P. Epidemiologic Studies of a Necessary Causal Risk Factor: Human Papillomavirus Infection and Cervical Neoplasia. J. Natl. Cancer. Inst. 2003, 95, E2.
  11. Mesher, D.; Cuschieri, K.; Hibbitts, S.; Jamison, J.; Sargent, A.; Pollock, K.G.; Powell, N.; Wilson, R.; McCall, F.; Fiander, A.; et al. Type-specific HPV prevalence in invasive cervical cancer in the UK prior to national HPV immunisation programme: Baseline for monitoring the effects of immunisation. J. Clin. Pathol. 2015, 68, 135–140.
  12. Wang, X.; Huang, X.; Zhang, Y. Involvement of Human Papillomaviruses in Cervical Cancer. Front. Microbiol. 2018, 9, 2896.
  13. Dempsey, A.F. Human Papillomavirus: The Usefulness of Risk Factors in Determining Who Should Get Vaccinated. Rev. Obstet. Gynecol. 2008, 1, 122–128.
  14. Jayasinghe, Y.; Garland, S.M. Genital warts in children: What do they mean? Arch. Dis. Child. 2006, 91, 696–700.
  15. World Health Organization. Cervical Cancer Elimination Initiative. 2022. Available online: https://www.who.int/initiatives/cervical-cancer-elimination-initiative (accessed on 9 January 2023).
  16. Graham, S. Human papillomavirus: Gene expression, regulation and prospects for novel diagnostic methods and antiviral therapies. Future. Microbiol. 2010, 5, 1493–1506.
  17. Jendoubi-Ferchichi, M.; Satouri, L.; Ghoul, F.; Malek-Mellouli, M.; Derbel, A.M.; Makni, M.K.; Reziga, H.; Baba, A.; Zili, M.; Segondy, M.; et al. Phylogeny and Classification of Human Papillomavirus (HPV)16 and HPV18 Variants Based on E6 and L1 genes in Tunisian Women with Cervical Lesions. Asian Pac. J. Cancer Prev. 2018, 19, 3361–3366.
  18. Williams, V.M.; Filippova, M.; Soto, U.; Duerksen-Hughes, P.J. HPV-DNA integration and carcinogenesis: Putative roles for inflammation and oxidative stress. Future Virol. 2011, 6, 45–57.
  19. Burd, E.M. Human Papillomavirus and Cervical Cancer. Clin. Microbiol. Rev. 2003, 16, 1–17.
  20. Petca, A.; Borislavschi, A.; Zvanca, M.E.; Petca, R.C.; Sandru, F.; Dumitrascu, M.C. Non-sexual HPV transmission and role of vaccination for a better future (Review). Exp. Ther. Med. 2020, 20, 186.
  21. Manini, I.; Montomoli, E. Epidemiology and prevention of Human Papillomavirus. Ann. Ig. 2018, 30, 28–32.
  22. Sabeena, S.; Bhat, P.; Kamath, V.; Arunkumar, G. Possible non-sexual modes of transmission of human papilloma virus. J. Obstet. Gynaecol. Res. 2017, 43, 429–435.
  23. Louie, K.S.; de Sanjose, S.; Diaz, M.; Castellsagué, X.; Herrero, R.; Meijer, C.J.; Shah, K.; Franceschi, S.; Muñoz, N.; Bosch, F.X.; et al. Early age at first sexual intercourse and early pregnancy are risk factors for cervical cancer in developing countries. Br. J. Cancer 2009, 100, 1191–1197.
  24. Liu, Z.C.; Liu, W.D.; Liu, Y.H.; Ye, X.H.; Chen, S.D. Multiple Sexual Partners as a Potential Independent Risk Factor for Cervical Cancer: A Meta-analysis of Epidemiological Studies. Asian Pac. J. Cancer Prev. 2015, 16, 3893–3900.
  25. Chesson, H.W.; Dunne, E.F.; Hariri, S.; Markowitz, L.E. The Estimated Lifetime Probability of Acquiring Human Papillomavirus in the United States. Sex. Transm. Dis. 2014, 41, 660–664.
  26. Dugué, P.A.; Rebolj, M.; Hallas, J.; Garred, P.; Lynge, E. Risk of cervical cancer in women with autoimmune diseases, in relation with their use of immunosuppressants and screening: Population-based cohort study. Int. J. Cancer 2015, 136, E711–E719.
  27. Balasubramaniam, S.D.; Balakrishnan, V.; Oon, C.E.; Kaur, G. Key Molecular Events in Cervical Cancer Development. Medicina 2019, 55, 384.
  28. Song, D.; Li, H.; Li, H.; Dai, J. Effect of human papillomavirus infection on the immune system and its role in the course of cervical cancer. Oncol. Lett. 2015, 10, 600–606.
  29. Horvath, C.A.; Boulet, G.A.; Renoux, V.M.; Delvenne, P.O.; Bogers, J.P.J. Mechanisms of cell entry by human papillomaviruses: An overview. Virol. J. 2010, 7, 11.
  30. Richards, R.M.; Lowy, D.R.; Schiller, J.T.; Day, P.M. Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection. Proc. Natl. Acad. Sci. USA 2006, 103, 1522–1527.
  31. Crosbie, E.J.; Einstein, M.H.; Franceschi, S.; Kitchener, H.C. Human papillomavirus and cervical cancer. Lancet 2013, 382, 889–899.
  32. Shimada, M.; Yamashita, A.; Saito, M.; Ichino, M.; Kinjo, T.; Mizuki, N.; Klinman, D.M.; Okuda, K. The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation. Sci. Rep. 2020, 10, 14195.
  33. White, E.A.; Münger, K.; Howley, P.M. High-Risk Human Papillomavirus E7 Proteins Target PTPN14 for Degradation. mBio 2016, 7, e01530-16.
  34. Venuti, A.; Paolini, F.; Nasir, L.; Corteggio, A.; Roperto, S.; Campo, M.S.; Borzacchiello, G. Papillomavirus E5: The smallest oncoprotein with many functions. Mol. Cancer 2011, 10, 140.
  35. Graham, S.V. The human papillomavirus replication cycle, and its links to cancer progression: A comprehensive review. Clin. Sci. 2017, 131, 2201–2221.
  36. Fay, N.; Panté, N. Nuclear entry of DNA viruses. Front. Microbiol. 2015, 6, 467.
  37. Wang, J.W.; Roden, R.B.S. Virus-like particles for the prevention of human papillomavirus-associated malignancies. Expert. Rev. Vaccines 2013, 12, 129–141.
  38. Kirnbauer, R.; Booy, F.; Cheng, N.; Lowy, D.R.; Schiller, J.T. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc. Natl. Acad. Sci. USA 1992, 89, 12180–12184.
  39. International Collaboration of Epidemiological Studies of Cervical Cancer; Appleby, P.; Beral, V.; Berrington de González, A.; Colin, D.; Franceschi, S.; Goodhill, A.; Green, J.; Peto, J.; Plummer, M.; et al. Carcinoma of the cervix and tobacco smoking: Collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int. J. Cancer 2006, 118, 1481–1495.
  40. Roura, E.; Castellsagué, X.; Pawlita, M.; Travier, N.; Waterboer, T.; Margall, N.; Bosch, F.X.; de Sanjosé, S.; Dillner, J.; Gram, I.T.; et al. Smoking as a major risk factor for cervical cancer and pre-cancer: Results from the EPIC cohort. Int. J. Cancer 2014, 135, 453–466.
  41. Vaccarella, S.; Herrero, R.; Snijders, P.J.; Dai, M.; Thomas, J.O.; Hieu, N.T.; Ferreccio, C.; Matos, E.; Posso, H.; de Sanjosé, S.; et al. IARC HPV Prevalence Surveys (IHPS) Study Group. Smoking and human papillomavirus infection: Pooled analysis of the International Agency for Research on Cancer HPV Prevalence Surveys. Int. J. Epidemiol. 2008, 37, 536–546.
  42. Xi, L.F.; Koutsky, L.A.; Castle, P.E.; Edelstein, Z.R.; Meyers, C.; Ho, J.; Schiffman, M. Relationship between cigarette smoking and human papillomavirus type 16 and 18 DNA load. Cancer. Epidemiol. Biomark. Prev. 2009, 18, 3490–3496.
  43. Koshiol, J.; Schroeder, J.; Jamieson, D.J.; Marshall, S.W.; Duerr, A.; Heilig, C.M.; Shah, K.V.; Klein, R.S.; Cu-Uvin, S.; Schuman, P.; et al. Smoking and Time to Clearance of Human Papillomavirus Infection in HIV-Seropositive and HIV-Seronegative Women. Am. J. Epidemiol. 2006, 164, 176–183.
  44. Alam, S.; Conway, M.J.; Chen, H.S.; Meyers, C. The Cigarette Smoke Carcinogen Benzopyrene Enhances Human Papillomavirus Synthesis. J. Virol. 2008, 82, 1053–1058.
  45. Wei, L.; Griego, A.M.; Chu, M.; Ozbun, M.A. Tobacco exposure results in increased E6 and E7 oncogene expression, DNA damage and mutation rates in cells maintaining episomal human papillomavirus 16 genomes. Carcinogenesis 2014, 35, 2373–2381.
  46. Alam, S.; Bowser, B.S.; Conway, M.J.; Israr, M.; Ryndock, E.J.; Xi, L.F.; Meyers, C. Downregulation of Cdc2/CDK1 kinase activity induces the synthesis of noninfectious human papillomavirus type 31b virions in organotypic tissues exposed to benzopyrene. J. Virol. 2010, 84, 4630–4645.
  47. Combined Pill. Your Contraception Guide. nhs.uk. 2020. Available online: https://www.nhs.uk/conditions/contraception/combined-contraceptive-pill/ (accessed on 10 January 2023).
  48. National Institute for Health and Care Excellence. Contraception—Combined Hormonal Methods: Scenario: Combined Oral Contraceptive. 2022. Available online: https://cks.nice.org.uk/topics/contraception-combined-hormonal-methods/management/combined-oral-contraceptive/ (accessed on 20 December 2022).
  49. Asthana, S.; Busa, V.; Labani, S. Oral contraceptives use and risk of cervical cancer-A systematic review & meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol. 2020, 247, 163–175.
  50. Peng, Y.; Wang, X.; Feng, H.; Yan, G. Is oral contraceptive use associated with an increased risk of cervical cancer? An evidence-based meta-analysis. J. Obstet. Gynaecol. Res. 2017, 43, 913–922.
  51. Anastasiou, E.; McCarthy, K.J.; Gollub, E.L.; Ralph, L.; van de Wijgert, J.H.H.M.; Jones, H.E. The relationship between hormonal contraception and cervical dysplasia/cancer controlling for human papillomavirus infection: A systematic review. Contraception 2022, 107, 1–9.
  52. International Collaboration of Epidemiological Studies of Cervical Cancer; Appleby, P.; Beral, V.; Berrington de González, A.; Colin, D.; Franceschi, S.; Goodhill, A.; Green, J.; Peto, J.; Plummer, M.; et al. Cervical cancer and hormonal contraceptives: Collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 2007, 370, 1609–1621.
  53. Roura, E.; Travier, N.; Waterboer, T.; de Sanjosé, S.; Bosch, F.X.; Pawlita, M.; Pala, V.; Weiderpass, E.; Margall, N.; Dillner, J.; et al. The Influence of Hormonal Factors on the Risk of Developing Cervical Cancer and Pre-Cancer: Results from the EPIC Cohort. PLoS. ONE 2016, 11, e0147029.
  54. Ramachandran, B. Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis. Endocr. Relat. Cancer 2017, 24, R99–R108.
  55. Munk, A.C.; Gudlaugsson, E.; Ovestad, I.T.; Lovslett, K.; Fiane, B.; Hidle, B.v.; Kruse, A.J.; Skaland, I.; Janssen, E.A.; Baak, J.P. Interaction of epithelial biomarkers, local immune response and condom use in cervical intraepithelial neoplasia 2-3 regression. Gynecol. Oncol. 2012, 127, 489–494.
  56. Hogewoning, C.J.; Bleeker, M.C.; van den Brule, A.J.; Voorhorst, F.J.; Snijders, P.J.; Berkhof, J.; Westenend, P.J.; Meijer, C.J. Condom use promotes regression of cervical intraepithelial neoplasia and clearance of human papillomavirus: A randomized clinical trial. Int. J. Cancer 2003, 107, 811–816.
  57. Winer, R.L.; Hughes, J.P.; Feng, Q.; O’Reilly, S.; Kiviat, N.B.; Holmes, K.K.; Koutsky, L.A. Condom use and the risk of genital human papillomavirus infection in young women. N. Engl. J. Med. 2006, 354, 2645–2654.
  58. Moreno, V.; Bosch, F.X.; Muñoz, N.; Meijer, C.J.; Shah, K.V.; Walboomers, J.M.; Herrero, R.; Franceschi, S.; International Agency for Research on Cancer. Multicentric Cervical Cancer Study Group. Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: The IARC multicentric case-control study. Lancet 2002, 359, 1085–1092.
  59. Grulich, A.E.; van Leeuwen, M.T.; Falster, M.O.; Vajdic, C.M. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: A meta-analysis. Lancet 2007, 370, 59–67.
  60. Dugué, P.A.; Rebolj, M.; Garred, P.; Lynge, E. Immunosuppression and risk of cervical cancer. Expert. Rev. Anticancer. Ther. 2013, 13, 29–42.
  61. Hinten, F.; Meeuwis, K.A.; van Rossum, M.M.; de Hullu, J.A. HPV-related (pre)malignancies of the female anogenital tract in renal transplant recipients. Crit. Rev. Oncol. Hematol. 2012, 84, 161–180.
  62. Meeuwis, K.A.; van Rossum, M.M.; van de Kerkhof, P.C.; Hoitsma, A.J.; Massuger, L.F.; de Hullu, J.A. Skin cancer and (pre)malignancies of the female genital tract in renal transplant recipients. Transpl. Int. 2010, 23, 191–199.
  63. Klitzke, S.; Wender, I.O.; Salcedo, M.P.; Pessini, S.A. Cervical cancer screening abnormalities in immunosuppressed renal transplant women: Case-control study in Southern Brazil. Arch. Gynecol. Obstet. 2020, 302, 649–655.
  64. Chen, M.; Cui, Q.; Chen, M.; Xia, M.; Liu, D.; Chen, P.; Wang, C.; He, M. Risk of human papillomavirus infection and cervical intraepithelial lesions in Chinese renal transplant recipients. Front. Oncol. 2022, 12, 905548.
  65. Stelzle, D.; Tanaka, L.F.; Lee, K.K.; Ibrahim Khalil, A.; Baussano, I.; Shah, A.S.V.; McAllister, D.A.; Gottlieb, S.L.; Klug, S.J.; Winkler, A.S.; et al. Estimates of the global burden of cervical cancer associated with HIV. Lancet. Glob. Health 2021, 9, e161–e169.
  66. Massad, L.S.; Seaberg, E.C.; Wright, R.L.; Darragh, T.; Lee, Y.C.; Colie, C.; Burk, R.; Strickler, H.D.; Watts, D.H. Squamous cervical lesions in women with human immunodeficiency virus: Long-term follow-up. Obstet. Gynecol. 2008, 111, 1388–1393.
  67. Abraham, A.G.; D’Souza, G.; Jing, Y.; Gange, S.J.; Sterling, T.R.; Silverberg, M.J.; Saag, M.S.; Rourke, S.B.; Rachlis, A.; Napravnik, S.; et al. Invasive Cervical Cancer Risk Among HIV-Infected Women: A North American multicohort collaboration prospective study. J. Acquir. Immune. Defic. Syndr. 2013, 62, 405–413.
  68. Cervical Screening: Scenario: Cervical Screening. National Institute for Health and Care Excellence. 2022. Available online: https://cks.nice.org.uk/topics/cervical-screening/management/cervical-screening/ (accessed on 23 December 2022).
  69. International Collaboration of Epidemiological Studies of Cervical Cancer. Cervical carcinoma and sexual behavior: Collaborative reanalysis of individual data on 15,461 women with cervical carcinoma and 29,164 women without cervical carcinoma from 21 epidemiological studies. Cancer. Epidemiol. Biomarkers. Prev. 2009, 18, 1060–1069.
  70. Children and the Law. NSPCC Learning. 2022. Available online: https://learning.nspcc.org.uk/child-protection-system/children-the-law/ (accessed on 8 January 2023).
  71. Quabius, E.S.; Fazel, A.; Knieling, C.; Gebhardt, S.; Laudien, M.; Moore, C.; Kühnel, A.; Hoppe, F.; Mlynski, R.; Heinrichs, A.; et al. No association between HPV-status in tonsillar tissue and sexual behavior of the patients in a northern German population—Critical view of the link between HPV natural history and HPV-driven carcinogenesis. Papillomavirus. Res. 2020, 10, 100207.
  72. HPV Vaccine Overview. nhs.uk. 2019. Available online: https://www.nhs.uk/conditions/vaccinations/hpv-human-papillomavirus-vaccine/ (accessed on 8 January 2023).
  73. Bogaards, J.A.; Wallinga, J.; Brakenhoff, R.H.; Meijer, C.J.; Berkhof, J. Direct benefit of vaccinating boys along with girls against oncogenic human papillomavirus: Bayesian evidence synthesis. BMJ 2015, 350, h2016.
  74. HPV Vaccination Recommendations. Centers for Disease Control and Prevention. 2021. Available online: https://www.cdc.gov/vaccines/vpd/hpv/hcp/recommendations.html (accessed on 10 January 2023).
  75. HPV Vaccine to Change in September 2012. GOV.UK. 2011. Available online: https://www.gov.uk/government/news/hpv-vaccine-to-change-in-september-2012 (accessed on 10 January 2023).
  76. Information on HPV Vaccination. GOV.UK. 2022. Available online: https://www.gov.uk/government/publications/hpv-vaccine-vaccination-guide-leaflet/information-on-hpv-vaccination (accessed on 10 January 2023).
  77. Joura, E.A.; Giuliano, A.R.; Iversen, O.E.; Bouchard, C.; Mao, C.; Mehlsen, J.; Moreira, E.D., Jr.; Ngan, Y.; Petersen, L.K.; Lazcano-Ponce, E.; et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N. Engl. J. Med. 2015, 372, 711–723.
  78. Joura, E.A.; Garland, S.M.; Paavonen, J.; Ferris, D.G.; Perez, G.; Ault, K.A.; Huh, W.K.; Sings, H.L.; James, M.K.; Haupt, R.M.; et al. Effect of the human papillomavirus (HPV) quadrivalent vaccine in a subgroup of women with cervical and vulvar disease: Retrospective pooled analysis of trial data. BMJ 2012, 344, e1401.
  79. Human Papillomavirus (HPV): The Green Book, Chapter 18a. GOV.UK. 2022. Available online: https://www.gov.uk/government/publications/human-papillomavirus-hpv-the-green-book-chapter-18a (accessed on 10 January 2023).
  80. Shi, L.; Sings, H.L.; Bryan, J.T.; Wang, B.; Wang, Y.; Mach, H.; Kosinski, M.; Washabaugh, M.W.; Sitrin, R.; Barr, E. GARDASIL: Prophylactic human papillomavirus vaccine development--from bench top to bed-side. Clin. Pharmacol. Ther. 2007, 81, 259–264.
  81. Artemchuk, H.; Eriksson, T.; Poljak, M.; Surcel, H.M.; Dillner, J.; Lehtinen, M.; Faust, H. Long-term Antibody Response to Human Papillomavirus Vaccines: Up to 12 Years of Follow-up in the Finnish Maternity Cohort. J. Infect. Dis. 2019, 219, 582–589.
  82. Hoes, J.; Pasmans, H.; Schurink-van ’t Klooster, T.M.; van der Klis, F.R.M.; Donken, R.; Berkhof, J.; de Melker, H.E. Review of long-term immunogenicity following HPV vaccination: Gaps in current knowledge. Hum. Vaccin. Immunother. 2022, 18, 1908059.
  83. Petry, K.U.; Bollaerts, K.; Bonanni, P.; Stanley, M.; Drury, R.; Joura, E.; Kjaer, S.K.; Meijer, C.J.L.M.; Riethmuller, D.; Soubeyrand, B.; et al. Estimation of the individual residual risk of cervical cancer after vaccination with the nonavalent HPV vaccine. Hum. Vaccin. Immunother. 2018, 14, 1800–1806.
  84. Lei, J.; Ploner, A.; Elfström, K.M.; Wang, J.; Roth, A.; Fang, F.; Sundström, K.; Dillner, J.; Sparén, P. HPV Vaccination and the Risk of Invasive Cervical Cancer. N. Engl. J. Med. 2020, 383, 1340–1348.
More
©Text is available under the terms and conditions of the Creative Commons-Attribution ShareAlike (CC BY-SA) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback