Cervical cancer is a devastating malignancy of the cervix, with squamous cell carcinomas reported to be more prevalent than adenocarcinomas [10,11]. 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 [2,12]. 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 [13]. Cervical cancer screening is available from the age of 25, as the disease is rare among younger individuals [14]. 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 [15]. 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 [14]. 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 [16]. 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 [17]. 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 [17].

In the UK, it is important to note that cases have been reported to be 65% higher in areas of deprivation [14]. There are several risk factors associated with this malignancy, HPV infection identifying as the strongest causative factor [18]. HPV types, particularly HPV 16 and 18, are found to be highly prevalent in the UK general population [19]. The HPV is a sexually transmitted infection that increases the risk of an individual to develop cervical cancer [20]. 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 [21]. 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 [22]. 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 [23]. 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.

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 [12,24,25]. 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 [25]. The ‘early’ region contains six proteins (E1, E2, E4, E5, E6, and E7), which are responsible for HPV genome replication and immune modulation [25,26]. The ‘late’ region consists of L1 and L2 capsid proteins, which have been reported to play a role in the transmission of the virus [24]. 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 [25,26,27]. 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 [25,27]. 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 [25,27]. 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 [12]. 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 [19].

HPV is primarily spread through direct skin-to-skin or skin-to-mucosa contact [28]. Sexual activity (including vaginal, anal, or oral intercourse) with an individual who has active HPV infection, is the most common mode of transmission [29]. Additionally, there is non-sexual horizontal transmission of HPV through skin, mouth, or fomite contact, which are less common [28,30]. 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 [31,32]. 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 [33].

Ninety percent of HPV-induced cell changes in the cervix regress spontaneously and HPV is cleared from the body, without any oncogenic consequences [27]. However, when a hrHPV infection evades the immune system, which is particularly common among immunocompromised patients, dyskaryosis and cervical intraepithelial neoplasia (CIN) can occur [34]. CIN is a pre-malignant abnormal collection of cells that, if untreated, may progress to become invasive carcinoma [35]. 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 [24,36]. 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 [37,38]. 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 [39,40]. E6 targets TP53 for degradation via the ubiquitin pathway, thus, preventing apoptosis [39,40]. E7 targets the retinoblastoma family members RB1, RBL1, and RBL2, which, consequently, drives the oncogenic process [39,41]. 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 [42]. 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 [43]. In the epithelial midzone and superficial zones, further viral replication of the genome and expression of L1, L2, and E4 genes take place [24,39]. L1 and L2 enclose the viral genomes to form progeny virions in the nucleus, which then go on to form new infections [39,44]. 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 [45,46]. Therefore, targeting L1 with self-assembled virus-like particles (VLPs) has become an integral part of developing successful HPV vaccines [45,46].

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 [47]. 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 [48]. The association between smoking and cervical cancer risk has been debated, but it is thought to have a multi-faceted role in cervical carcinogenesis [49]. Smoking has been thought to either increase the risk of HPV infection or decrease the clearance, leading to an increased risk of cervical malignancy [50,51]. One study discovered that benzo[a]pyrene, a carcinogenic component of cigarettes, enhanced HPV persistence, thus, increasing HPV 16 and 18 titres [52]. Other studies have supported the hypothesis that smoking promoted carcinogenesis by suppressing cell-mediated immunity against HPV infection [53,54]. 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.

The oral contraceptive pill (OCP) is the most common form of contraceptive alongside barrier protection in the UK, due to its high efficacy [55]. 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 [56,57]. 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 [58,59,60,61,62]. A recent systematic review and meta-analysis found that OCP use is significantly associated with cervical cancer, particularly adenocarcinomas [57]. 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 [63,64,65]. 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 [66]. More research into the possible carcinogenic properties of OCP must be conducted to gain a clearer understanding.

It is well-known that immunosuppressed individuals are at an increased risk of developing many cancers, such as colorectal, liver, and stomach cancers [67]. These high-risk patients include but are not exclusive to those with immunodeficiency disorders and organ transplantation [68]. 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 [69]. 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 [70]. These findings were also supported by recent studies conducted in Brazil and China [71,72]. 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 [73]. There is evidence that HIV-infected individuals are significantly more vulnerable to presenting with abnormal cervical cytology compared to non-HIV individuals [74]. Furthermore, an association between increased susceptibility to invasive cervical cancers with diminishing CD4 count has been observed [75]. 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 [76].

Various aspects of sexual behaviours have been associated with increased cervical cancer risk, due to a higher chance of acquiring HPV infection [77]. 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 [31]. 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 [77]. 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 [78]. 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 [32]. 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 [79].

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 [80]. These vaccinations are provided free of charge by the NHS for girls born after 1 September 1991 and boys born after 1 September 2006 [80]. Previously, there was a longstanding vaccination programme exclusively for girls until its extension to both sexes in September 2019 [80]. This was due to beliefs of herd immunity and indirect protection for boys against the HPV infection [81]. This does not equally safeguard men who have sex with men (MSM), and this population was, therefore, still unprotected from HPV-associated cancer risk [81]. Since early 2018, the NHS offers eligible MSM, who are 45 years old and under, free HPV vaccinations [80]. 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 [80]. 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 [82].

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 [45,46,79,83,84]. 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 [85,86]. It will be implemented throughout 2022 as stock of the previous quadrivalent Gardasil vaccine becomes exhausted [87]. Gardasil-9 is a non-infectious recombinant vaccine that contains purified L1 proteins [88]. 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 [89,90]. 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 [91]. 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 [92]. Consequently, it remains imperative that individuals who enrol in the immunisation programme, also receive regular cervical screening.