hpv and cervical cancer research paper

REVIEW article

Involvement of human papillomaviruses in cervical cancer.

• 1 Department of Gynecology and Obstetrics, Qilu Hospital of Shandong University, Jinan, China
• 2 Department of Gynecology and Obstetrics, Zhongshan Hospital of Xiamen University, Xiamen, China

Human papillomaviruses (HPV) are the first viruses to have been acknowledged to prompt carcinogenesis, and they are linked with cancers of the uterine cervix, anogenital tumors, and head and neck malignancies. This paper examines the structure and primary genomic attributes of HPV and highlights the clinical participation of the primary HPV serotypes, focusing on the roles that HPV-16 and 18 play in carcinogenesis. The mechanisms that take place in the progression of cervical neoplasia are described. The oncogenic proteins E6 and E7 disrupt control of the cell cycle by their communication with p53 and retinoblastoma protein. Epidemiological factors, diagnostic tools, and management of the disease are examined in this manuscript, as are the vaccines currently marketed to protect against viral infection. We offer insights into ongoing research on the roles that oxidative stress and microRNAs play in cervical carcinogenesis since such studies may lead to novel methods of diagnosis and treatment. Several of these topics are surfacing as being critical for future study. One particular area of importance is the study of the mechanisms involved in the modulation of infection and cancer development at cervical sites. HPV-induced cancers may be vulnerable to immune therapy, offering the chance to treat advanced cervical disease. We propose that oxidative stress, mRNA, and the mechanisms of HPV infection will be critical points for HPV cancer research over the next decade.

Introduction

Human papillomaviruses (HPVs) are minute viruses that carry deoxyribonucleic acid (DNA) and are part of the Papillomaviridae family. They are ubiquitous and able to adjust to their hosts. They have the ability to hide efficiently from immune reactions. More than 200 types of HPV have been established and classified into 29 genera, and the majority of them impact humans. These viruses mainly target differentiating squamous epithelium, and they are linked to cutaneous infections, affecting nearly every part of human skin and causing mucosal infections. HPV infection is a risk factor for malignancy of the uterine cervix as it has a pivotal role in carcinogenesis via the activation of its genomic products ( Cubie , 2013 ).

The genome of all papillomaviruses has 3 dissimilar areas, known as the upstream regulatory region (URR), the first area, and the second area. The URR is also known as the long control region (LCR) or the non-coding region (NCR) and comprises about 10% of the complete genome ( IARC, 1995 ). The first area fills about half of the genome and is split into two large and several small reading frames: E1–E2 and E4–E7 are the large reading frames ( IARC, 1995 ), and E6 and E7 contain the small reading frames, which participate in the progression of cervical cancer ( Cubie et al., 2012 ). The second area fills the rest (40%) of the genome and contains the genes L1 and L2 ( IARC, 1995 ).

HPV Classification

While HPV is frequently linked to incidents of cervical cancer, it is not the only medical condition with which the virus has been associated. There are many HPVs that induce different lesions, and they can cause overlapping outcomes. HPV serotypes are genetically different from each other, and the typical classification system indicates that a certain HPV type has to have a full genome in which the L1 nucleotide sequence varies from that in any other HPV genome by at least 10%. HPV types are assigned numerically in chronological order based on the date of their discovery ( Cubie et al., 2012 ).

There are currently 39 genera in the family Papillomaviridae. The HPVs are contained in five of those genera (alphapapillomaviruses, betapapillomaviruses, gammapapillomaviruses, mupapillomaviruses, and nupapillomaviruses) (Figure 1 ). In 2012, all the different HPVs were established and designated as either group 1 (carcinogenic to humans) carcinogens, group 2A carcinogens (probably carcinogenic to humans), or group 2B carcinogens (possibly carcinogenic to humans) by the International Agency for Research on Cancer (IARC) (Figure 1 ). The group-1 HPVs (HPV16, HPV18, HPV31, HPV33, HPV35, HPV39, HPV45, HPV51, HPV52, HPV56, HPV58, and HPV59) are considered to be hazardous in high-pressure liquid chromatography. There is little research suggesting HPV68 as high risk, so it is placed in group 2A as probably carcinogenic. Of all of the cervical cancers, 96% can be linked to one of the 13 HPV types in groups 1 and 2A ( Arbyn et al., 2014 ). Additional alpha papillomaviruses (HPV26, HPV30, HPV34, HPV53, HPV66, HPV67, HPV 69, HPV70, HPV73, HPV82, HPV85, and HPV97) have been linked to infrequent incidences of cervical cancer and are thought to be group 2B carcinogens. Because fewer cases of cervical cancer are associated with the group 2B HPVs, it is more difficult to assess their carcinogenicity. Nevertheless, research has shown that markers of HPV-induced carcinogenesis, including E6 mRNA, elevated the expression of p16 and reduced the expression of cyclin D1, p53, and Rb. This pattern has been observed in cervical cancers related to all of the HPV carcinogen groups ( Arbyn et al., 2014 ). If the 2.6% of cervical cancer cases linked to group 2B HPV-type carcinogens are grouped with the 96% of cases attributable to group 1 and 2a type carcinogens, a total of 98.7% of all cervical cancers are HPV-positive cancers. Additional data have demonstrated that HPV68, HPV26, HPV66, HPV67, HPV73, and HPV82, although rare, are found with greater frequency in women with cervical cancer than in those with normal cervical cytology; therefore, an update to the carcinogen classification system should be considered ( Arbyn et al., 2014 ; Halec et al., 2014 ).

FIGURE 1. HPV classification based on the nucleotide sequence of the capsid protein L1 gene ( Burd, 2016 ).

Epidemiology

Anogenital infection is the most frequent sexually transmitted infection (STI) in the United States; approximately 6.2 million people (most frequently adolescents and young adults) are afflicted with this type of infection annually. Clinical evaluations have demonstrated that the occurrence of STI in adolescent girls is typically about 30% and can escalate to 64% in certain populations. A separate evaluation stated that at 4 years after their first sexual intercourse experience, more than 50% of the young female population was afflicted with a cervical HPV infection ( Brianti et al., 2017 ). The same study also documented that HPV may be transmitted via non-penetrative sexual behavior, but the probability of this is lower than that from obtaining the infection via penetrative intercourse. Aside from sexual history, evaluations in the United States have documented that patients aged younger than 25 years are also at risk of infection. The occurrence seems lower after this age in most studies, with the exception of one cohort study in Costa Rica that discovered that the occurrence increases once again after 40 years of age. In addition, men and women appear to have close HPV infection rates. Figure 2 shows the occurrence of HPV infection based on patient age.

FIGURE 2. Prevalence of high-risk HPV infection among females undergoing cervical screening. HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial ( Kitchener et al., 2006 ). Compiled using information from Kitchener et al. (2006) .

The identification of high-risk HPV in virgins, neonates, and children offers proof that sexual interaction is not the only method of HPV transmission. Low- and high-risk HPV serotypes can be circulated through non-sexual methods, including touching others, communal bathing, and touching contaminated fomites ( Brianti et al., 2017 ). It seems that the transfer of high-risk HPV from mother to infant occurs during parturition as the neonate goes down the infected birth canal. This more frequently happens in mothers with exceptionally large amounts of HPV DNA, especially in those with HPV-16, than in those with less DNA. Moreover, there has been a report of two mothers with both HPV-16 and 18 infections who gave birth to neonates with identical co-infections ( Cason et al., 1998 ).

Pregnancy appears to escalate the chance of contracting genital HPV infections. This was shown in a study in which 52.5% of mothers tested positive for HPV DNA in the third trimester of pregnancy, as opposed to 17.5% after parturition ( Brianti et al., 2017 ). A physiological explanation for this could be that the hormone profile in pregnancy escalates the transcription of HPV genes because of the communication between glucocorticoids and their response elements in the non-coding area of HPV-16. Furthermore, pregnant women are in a state of immunosuppression. HPV infections can also be transferred throughout pregnancy through the placenta and amniotic fluid. One study demonstrated that HPV DNA was in 75% of amniotic fluids obtained from mothers who tested positive for cervical HPV DNA ( Cason et al., 1998 ).

Worldwide, cervical cancer is the second most common malignancy in women, impacting about 35 of every 100,000 women ( Cubie, 2013 ). Attention given to the link between HPV and cancer was significantly raised when HPV types 16 and 18 were detected in cervical cancers and preneoplastic dysplasia, the lesions that can make a woman susceptible to malignancy of the uterine cervix. HPV DNA has been determined to be present in more than 99% of cervical cancer cases; however, the most frequent high-risk serotypes are different among countries, ethnicities, and socioeconomic statuses. In a study featuring over 30,000 cervical cancers, IARC showed that of the most frequent HPV serotypes that lead to cervical malignancy (16, 18, 58, 33, 45, 31, 52, 35, 59, 39, 51, and 56), HPV 16 induces more than 50% of cervical cancers, while HPV 16 and 18 together lead to over 70% of cases across the globe ( Burd, 2016 ). HPV serotypes 18 and 45 are implicated in the more aggressive cervical adenocarcinomas ( Cubie, 2013 ).

It has been discovered that long-term infection with high-risk HPV serotypes is the greatest risk factor in the progression from precursor lesions to cervical cancer. Persistence is typically defined as the identification of identical high-risk HPV types at >2 visits that are separated by 4–6 months ( Dunne and Markowitz, 2006 ). In fact, studies have shown that such persistent infections can increase the likelihood of developing high-grade precursors of cervical malignancy more than tenfold ( Dunne and Markowitz, 2006 ).

Pathophysiology

Cervical canal and associated malignancies.

The cervix, which is located between the vagina and the uterus, is a canal with two openings: the superior internal os that goes into the uterus and the inferior external os that goes into the vaginal cavity. The histology of the cervical canal is characterized by simple columnar secretory epithelium, as opposed to the vaginal cavity, which is lined by stratified non-keratinizing squamous epithelium. The epithelia that line the endocervix and exocervix join at the transition zone, or squamocolumnar junction, correlating to the area of the cervix at the external os ( Livolsi, 2002 ).

The squamocolumnar junction is a crucial cytological landmark since it is the area that is the most vulnerable to HPV infection, and it is the place in which over 90% of lower genital tract malignancies initiate ( Burd, 2016 ). HPV is recognized as inducing cervical dysplasia and cervical intraepithelial neoplasia (CIN), which typically develop into cervical cancer due to an ongoing infection with high-risk HPV ( Narisawasaito and Kiyono, 2007 ).

Since the transition zone includes two kinds of epithelial cells (glandular and squamous cells), two different forms of cancers can occur in the cervix. An unregulated rapid increase of glandular cells in the endocervix generates an adenocarcinoma in 10–20% of cases, although the incidence seems to be on the rise in recent years ( Brianti et al., 2017 ). A squamous cell malignancy is the cause of squamous cell carcinoma. The latter is much more frequent (occurring in 80–90% of cases) and is typically asymptomatic in its first stages, but can cause coital and pelvic pain and deviant vaginal bleeding and discharge as it progresses ( Brianti et al., 2017 ).

Life Cycle of HPV

Cervical carcinogenesis is strongly associated with the events that happen in the life cycle of the virus, as shown in Figure 3 . In a stratified squamous epithelium, the cells creating the basal layer act as stem cells, and thus they undergo cell division when they replace the cells released from the surface layer. When a basal cell divides via mitosis, two daughter cells are created: one rises and changes into a terminally differentiated cell and the other cell stays in the basal layer to retain the pool of dividing cells. The initial targets of the virus are the basal cells that are vulnerable via microwounds. HPV virions proceed into the cells by interacting with certain receptors, such as alpha-6 integrin, which binds HPV-16 ( Narisawasaito and Kiyono, 2007 ). Viral DNA replication starts in the basal layers, generating 50–100 copies of the genome in every cell. This is followed by the expression of the E1 and E2 proteins that are required for the replication procedure and for the separation of recently synthesized DNA, therefore guaranteeing that infected stem cells stay in the lesion for an extended period of time. The virus mostly uses host equipment to perform DNA replication, with the exception of the E1 helicase ( Narisawasaito and Kiyono, 2007 ). Early gene products, such as E5–E7, are believed to produce a favorable environment for replication to take place by encouraging DNA replication in the host cell and halting apoptosis ( Narisawasaito and Kiyono, 2007 ).

FIGURE 3. Human papillomavirus (HPV) life cycle and cancer. Cartoon depicting normal stratified cervical epithelium (left), HPV-infected epithelium (center), and HPV-induced cancer (right). Epithelial layers are indicated on the far left, and HPV life cycle stages are indicated on the far right. Episomal genomes are shown as orange circles and integrated genomes are shown as orange stripes. (Left) Normal keratinocyte differentiation: basal cells divide and daughter cells migrate upward, beginning the differentiation process. As differentiation proceeds, cells exit the cell cycle. Fully keratinized squames slough off from the apical surface. (Middle) Productive HPV infection: HPV virions gain access to basal cells via microwounds. The viral genomes migrate to the nucleus, where they are maintained at ˜100 copies/cell. As daughter cells begin differentiation, viral genomes are amplified. Cell nuclei are retained and chromatin is activated to support viral DNA replication. (Right) Cancer: viral genomes often integrate into the host genome and E6/E7 expression is increased, leading to enhanced proliferation and the accumulation of cellular mutations. Cellular differentiation is lost, and cancerous cells invade into the dermal layer as well as into neighboring tissues ( Langsfeld and Laimin, 2016 ).

As the infected basal cells move up and differentiate, the viral late genes L1 and L2 are transcribed, thus prompting the vegetative stage of the life cycle distinguished by dramatic amplification of the genome ( Narisawasaito and Kiyono, 2007 ). It appears that control over the expression of late genes depends on the state of differentiation of the host cell ( Howley, 2006 ). Once the cell reaches the outermost layer of the epithelium, the newly synthesized viral DNA is encapsulated to form new virions, which are released, and the life cycle is then repeated. As HPVs do not induce complete lysis in host cells, new virions are deposited in squames that are continuously shed ( Hikita and Kozako, 2001 ). It is intriguing that the virus is greatly hidden from the host immune system, since the immunogenic virions are put together only in the outer portions of the epithelium. In addition, viral proteins E6 and E7 act to ensure that the infection remains asymptomatic by deactivating interferon regulatory factor ( Narisawasaito and Kiyono, 2007 ).

Squamous epithelial cells infected by HPV undergo koilocytosis to become cells called koilocytes. Compared to normal cells, these cells have a larger, darker, and asymmetrically outlined nucleus encompassed by an area of transparent space, termed a perinuclear halo, and they appear to be vacuolated. This alteration suggests minor cellular dysplasia and shows a highly replicative viral state. When the dysplasia is moderate or severe, the cells are small and multiply on the uppermost portion of the epithelium, creating a potentially carcinogenic lesion if it is severe ( Camilleri and Bundell, 2013 ).

Role of HPV in Cervical Carcinogenesis

While HPV is the greatest risk factor for cervical cancer, many researchers propose that the specific integration of viral DNA in the host cell does not frequently happen, and in the majority of the time, HPV infection is removed quite speedily by the immune system. While viral DNA can lead to fast neoplastic alteration of infected cells once it is incorporated, the existence of HPV DNA in the cell by itself is not enough to induce cancer, as additional genetic and epigenetic occurrences are likely needed ( Narisawasaito and Kiyono, 2007 ).

Two main oncogenic protein products of the HPV virus are E6 and E7; they act by modifying the control of the cell cycle and by regulating apoptosis. The incorporation of viral DNA disrupts the activity of the E2 protein. The E2 protein is recognized as having the ability to repress the transcription of E6 and E7, and thus its interruption causes dysregulated expression of these oncoproteins. Combined, these proteins are able to immortalize cells, so that cells retain their mitotic ability to generate clones that also have the immortalized phenotype and do not experience terminal differentiation ( Howley, 2006 ). The immune response is a key factor in the fight against HPV infection and cervical carcinogenesis. However, HPV is able to promote immune evasion through the expression of the E5 oncogene, which is responsible for modulation of several immune mechanisms, including antigen presentation and inflammatory pathways ( de Freitas et al., 2017 ).

E7 Oncoprotein

The major characteristic of E7 that enables it to enhance neoplastic change is its interaction and subsequent inactivation of pRb. The phosphorylation state of pRb is modified based on the phase of the cell cycle, as it is dephosphorylated in G0 and G1 phases. It is phosphorylated during the S-phase and stays phosphorylated until later in the M-phase when it takes on a hypophosphorylated appearance again due to the action of a certain phosphatase ( Howley, 2006 ).

When dephosphorylated, pRb and its associated proteins inhibit transcription factors, such as E2F, by binding to them, thereby repressing the expression of genes whose products stimulate DNA synthesis and enhancing the progression of the cell cycle. In contrast, when pRb is phosphorylated by G1 cyclin D kinases (CDKs), it cannot bind to E2F and its inhibitory impact is thereby removed, enabling the cell to move to the S-phase. Thus, it is a regulator of the G1/S checkpoint. The identification of damaged DNA results in the activation of p53, which then initiates p21, a CDK inhibitor. This p21 links to and limits cyclin E-CDK2. Thus, pRb cannot be phosphorylated. As a result, pRb can inhibit E2F and halt the G1/S transition ( Shackelford et al., 1999 ).

The E7 protein can link to the hypophosphorylated form of pRb, thus disturbing the complex generated between pRb and E2F. This causes an early movement of the cell into the S-phase, thus leading to DNA synthesis and, lastly, cell division. Interestingly, the actual production of E7 and its effects on targets that include pRb are necessary for the replication and completion of the full life cycle of HPV ( Hikita and Kozako, 2001 ).

The E7 oncoprotein was observed to modulate the DNA methylation mechanism to control pathways of cellular propagation, and may bring about epigenetic changes through the Rb family of tumor suppressor proteins ( Sen et al., 2018 ). A study showed that DNA methyl transferase DNMT1 could be linked by HPV-16 E7 both in vitro and in vivo to initiate its enzymatic actions ( Yin et al., 2016 ). The E7 oncoprotein can directly bind to DNMT1 and induce gene silencing by hypermethylation ( Sen et al., 2018 ). E7 can form a tight complex with Rb resulting in release of E2F, which then binds to DNMT1, causing hypermethylation of CpG islands ( Duenas-Gonzalez et al., 2005 ).

E6 Oncoprotein

The E6 protein mainly shows its neoplastic impact on HPV-infected cells by encouraging the ubiquitin-dependent proteosomal degradation of p53 ( Narisawasaito and Kiyono, 2007 ), a tumor suppressor gene product that prevents the buildup of destructive mutations that can cause cancer to develop. Such mutations can be due to DNA damage by physical and chemical mutagens, as well as errors that occur during DNA replication. Upon the identification of abnormal DNA and p53 activation, the cell cycle is halted, enabling DNA repair to happen prior to the cell splitting. In particular situations, including when the DNA cannot be repaired, apoptosis can be initiated for programmed cell death ( Hikita and Kozako, 2001 ).

The concentration of p53 in cells with E6, including cervical cancer cells, is about 2–3 times lower than in healthy cells. Its half-life is also substantially decreased. As a result, the typical response of p53 to DNA damage does not occur. DNA mutations remain in the genome unrepaired and are carried from one cellular generation to the next, ending up with a buildup over time leading to genomic fluctuations ( Howley, 2006 ). Thus, apart from the lack of checkpoint surveillance for DNA damage in cancer cells, these cells also have an intrinsic tendency to favor mutagenesis ( Hikita and Kozako, 2001 ).

The binding of E6 to p53 is not automatic; it is regulated by E6-associated protein (E6AP), an E3 ubiquitin protein ligase. E6AP is in a group of proteins similar to the E6-AP carboxyl terminus (HECT) E3 ligases that act in the identification of substrates via ubiquitylation machinery aimed at proteosomal degradation. Interestingly, the presence of E6 increases the turnover of E6AP, probably as a result of its enhanced enzymatic activity in the HPV-infected cellular environment ( Howley, 2006 ).

The mechanism of E6 mediated gene silencing has been reported ( Sen et al., 2018 ). The mechanism involves degradation of p53 and release of specificity protein 1 (Sp1) transcription activator, which binds to the promoter of DNMT1 and upregulates the expression of this gene. Then, the elevated amount of DNMT1 leads to hypermethylation of DNA.

E5 Oncoprotein

E5 was proposed to be classified as a viroporin, a channel protein able to modulate ion homeostasis, vesicle trafficking, virion production, and viral genome entry ( Wetherill et al., 2012 ). In HPV16 infected cells, E5 oncoprotein plays a key role in cell growth and impairs several signal transduction pathways. Furthermore, pro-carcinogenic activities are also performed by HPV16 E5, including the stimulation of EGF-mediated cell proliferation, the inhibition of apoptosis induced by tumor necrosis factor ligand (TNFL) and CD95 ligand (CD95L) ( de Freitas et al., 2017 ), and the modulation of genes involved in cell adhesion and cell motility ( Kivi et al., 2008 ). All of these are activities that indirectly intervene in the host’s immune system.

Immune Avoidance in HPV Infection, Squamous Intraepithelial Lesions (SIL), and Cervical Cancer

Human papillomaviruses has a few mechanisms to evade the immune system: it downregulates interferon expression and upregulates interleukin (IL)-10 and transforming growth factor (TGF)-β1, producing a local immunosuppressive environment; along with altered tumor surface antigens, this environment establishes an immunosuppressive network that blocks the antitumor immune response ( Torres-Poveda et al., 2014 ). In patients with high-risk HPV infections of the cervix and with SIL, the presence of IL-10 and TGF-β1 might initially create conditions that encourage an immunosuppressive microenvironment in the lesion, which could negatively affect the cellular immune response ( Sasagawa et al., 2012 ; Torres-Poveda et al., 2014 ). Such a microenvironment can encourage the persistence of viruses and lead to cervical cancer ( Stanley et al., 2007 ). In serum and cervical tissues from patients with high-risk HPV infections, low-grade SIL, high-grade SIL, and cervical cancer ( Giannini et al., 1998 ; Stanley et al., 2007 ), the cytokines IL-10 and TGF-β1 have been detected. The levels of these cytokines are correlated with lesion severity ( Bermudez-Morales et al., 2008 ). A previous review indicated that local immunosuppression distinguishes cervical cancer, and this immunosuppression is dependent on Th2/Th3 cytokines. These data accord with cervical biopsy findings in which there is a pattern of Th2/Th3 cytokine expression in cervical cancer tissues that is non-existent in the normal cervix, indicating that HPV infection initiates immunosuppressive cytokine transcription to avoid eliciting a response from the host immune system ( Sheu et al., 2001 ; Alcocer-Gonzalez et al., 2006 ).

Interleukin-10, a powerful immunosuppressive cytokine, and TGF-β1 promote each other’s expression. They also promote the production of HPV-16 E6 and E7 proteins, which induce the TGF-β1 and IL-10 genes, establishing a vicious cycle ( Peralta-Zaragoza et al., 2006 ). CD3 expression is downregulated by IL-10 and TGF-β1, and this has a crucial role in the activation of T-cells. Lastly, IL-10 and TGF-β1 enlist Treg cells, which cause serious peripheral tolerance. Therefore, we hypothesize that IL-10 and TGF-β1 promote immune system avoidance via establishment of an immunosuppressive state in the cervixes of HPV-infected women. These findings will be especially pertinent to HPV vaccine production and the development of novel targeted immunotherapies for women who have LGSIL, HGSIL, and cervical cancer ( Peralta-Zaragoza et al., 2012 ).

As research on the immune system and HPV-associated cervical cancer progresses, there are more questions than answers. Researchers have shown that T-lymphocytes isolated from patients with cervical lesions and cervical cancer are only partially activated and that there are lowered expression levels of a few signal transduction molecules that take part in the full activation of T-lymphocytes. Therefore, it is of special interest to evaluate if type Th1 cytokines can counteract the expression of these molecules and if researchers can produce completely functional HPV-specific T-lymphocytes.

Areas of Current Research

Research is now closing in on the role oxidative stress plays in HPV-mediated carcinogenesis. Reactive oxygen species prompt DNA damage and regulate the viral life cycle. Evaluations have suggested a link between the oxidative status of infected cells and their prolonged existence or further development of lesions. Reactive oxygen species also have pro-survival and anti-apoptotic effects on infected cells, and they increases the expression of the E6 and E7 genes (Figure 4A ). This seems to be an encouraging area to examine, in particular to establish the impacts of oxidative stress on chemotherapy reactions and resistance and the prospective use of markers of oxidative stress for diagnostic purposes ( Marco, 2013 ).

FIGURE 4. Schematic model of HPV-driven carcinogenesis. (A) A multistep molecular mechanism of host-viral interaction ( Senapati et al., 2016 ). The initial outcome of carcinogenesis is modulated by both viral (high-risk versus low-risk HPV types, HPV integration) and host factors (inflammatory response, oxidative stress). Inflammatory response upon initial infection such as IFN response plays role in reducing episomal HPV resulting clearance of infection. Integration of HPV is (initiated with DNA damage. The IFN induced loss of episomal HPV and down-regulation of E2 leads to the selection of cells with integrated HPV genomes expressing higher levels of E6 and E7. Once the early genes E6 and E7 are expressed, TLR9 down regulated and IFN response impaired, resulting a conducive milieu for immune evasion and persistent infection. Up regulation of E6/E7 increases genetic instability and chromosomal rearrangements that increase the risk of integration. Overexpression of E6/E7 leads to deregulation of the cell cycle via p53 and Rb degradation, deregulation of oncogenes and miRNAs expression. Epigenetic and genetic modification in viral and host genome leads to the deregulation of E6 and E7 oncogenes, and host tumor suppressor genes that lead to carcinogenesis. Oxidative modification of TFs also leads to altered gene expression and carcinogenesis. (B) Schematic model of the interaction between microRNAs and factors involved in malignant transformation caused by HPVE6 and E7 expression in cervical cancer cell ( del Mar Diaz-Gonzalez et al., 2015 ). E6 disrupts the expression of miR-23b, miR-218, and miR-34a via p53 degradation and their expression is transactivated by the binding of p53 to consensus sites in the promoter regions, affecting the expression of cell cycle regulators, such as E2, cyclin D1, CDK4, CDK6, E2F1, E2F3, E2F5, Bcl-2, SIRT1, p18, uPA, and LAMBD3. In the overexpression of miR-15/16 cluster byE7, E2F1 transactivates the c-Myb expression and represses the c-Myc expression, and then the microRNA cluster regulation is controlled by binding of c-Myc or c-Myb to promoter region of microRNA cluster. The increased expression of miR-15a/miR-16-1 induces the inhibition of cell proliferation, survival, and invasion. The down regulation of miR-203 by E7 is mediated by MAPK/PKC pathway.)

Micro-RNAs (miRNAs), which are short strands of non-coding RNA that normally have a short half-life and alter gene expression post-transcriptionally, appear to have a role in cervical carcinogenesis. Their deregulation is linked with the initiation, development, and spread of human tumors, such as cervical cancer, which shows elevated and lowered levels of oncogenic and tumor-suppressive miRNAs, respectively. The E6 and E7 proteins can regulate miRNAs (Figure 4B ). Thus, it is helpful to establish exactly how they will be utilized as prognostic biomarkers by contrasting the miRNA profiles of healthy and modified cells. Further, additional studies may potentially discover another type of cervical cancer treatment using RNA modification therapy ( Gómez-Gómez et al., 2013 ).

The E6 and E7 oncoproteins interact with and/or modulate the expression of many proteins involved in epigenetic regulation, including DNA methyltransferases, histone modifying enzymes, and subunits of chromatin remodeling complexes, thereby influencing the host cell transcription program. Furthermore, HPV oncoproteins modulate expression of cellular micro RNAs. Most of these epigenetic actions participate in a complex dynamic interplay involved in the maintenance of persistent infection, cell transformation, and development of invasive cancer by a considerable deregulation of tumor suppressor proteins and oncogenes ( Durzynska et al., 2017 ; Sen et al., 2018 ).

Recently, a detailed analysis of the Cancer Genome Atlas (TCGA) cervical cancer gene expression, DNA methylation, and somatic mutation profile was reported ( Banister et al., 2017 ). A subset of tumors, which no longer express HPV E6/E7 oncogenes (HPV-inactive), were identified. These tumors have gene expression, DNA methylation and somatic mutation signatures different from HPV-active tumors, and are more similar to other, viral-independent, cancers. Implications for cervical cancer progression and opportunities for targeted therapy have been discussed ( Banister et al., 2017 ).

Autophagy is the physiological cellular route that accounts for removal, degradation, and recycling of damaged organelles, proteins, and lipids in lysosomal vacuoles. In addition to this scavenger function, autophagy plays a fundamental role during viral infections and cancers and is, therefore, frequently exploited by viruses to their own benefit. Recently, a link between HPV and autophagy has clearly emerged, leading to a possibility for development of novel anti-viral strategies aimed at restraining HPV infectivity ( Mattoscio et al., 2018 ). How the oncogenic HPV16 virus can usurp autophagy has been described, including highlighting similarities and differences with mechanisms adopted by other oncoviruses ( Mattoscio et al., 2018 ).

Cytology and Histology

The commencement of screening programs over the last several decades has achieved its goal of lowering the occurrence and mortality of cervical cancer ( Martinhirsch and Wood, 2011 ). The Papanicolaou smear is the most frequently used and easiest method to evaluate the cervix for dysplastic cellular modifications. During the procedure, the vagina is held open with a speculum, and a specimen of cells is obtained from the squamocolumnar junction by inserting and rotating a spatula through the external os. The smear is fixed onto a slide, properly stained, and viewed under a microscope to see the morphology of the epithelial cells. A colposcope enables the immediate observation of the cervix with magnified epithelium and the ability to perform a biopsy ( Cubie, 2013 ). It has been estimated that 40–50% of cervical cancers are diagnosed in women who undergo routine cervical cytology screening and that four out of five women diagnosed with cancer had not been tested in the previous 5 years ( Cubie, 2013 ).

Liquid-based cytology has enabled the optimization of the quality and regularity of specimens by producing identical cell layers and lowering the amount of low-quality specimens. The existence of koilocytes is typical of a productive HPV infection, whereas a consistent infection reveals itself as causing extreme alterations in the nucleus, mitotic figures, and aggregates of pyknotic cells. Various classification techniques are utilized for these observations (see Table 1 ), but the Bethesda classification is typically the one that is selected and offers two categories: (1) low-grade squamous epithelial neoplasia (LSIL) that surrounds specimens with asymmetrical, large cells and well-defined nuclei and (2) high-grade squamous epithelial neoplasia (HSIL) for specimens identified by poorly differentiated and underdeveloped, small cells with definitive cytoplasmic borders that are arranged in sheets and syncytial groups ( Cubie, 2013 ).

TABLE 1. Classification of cervical intraepithelial lesions.

The histological assessment of samples offers more precise data regarding the HPV infection by detailing characteristics that include basal hypertrophy, a surplus of surface keratinization, and the overall disturbance of the epithelium. Cervical intraneoplasia lesions are graded according to the fraction of epithelium that exhibits abnormalities ( Cubie, 2013 ).

There are different biomarkers that can determine the existence and level of HPV infection and degree of cervical malignancy. The biomarkers can be separated into three groups. The first one contains HPV DNA, RNA, and proteins, which are highly sensitive and specific to diagnose CIN 2 or more extensive lesions in women who are 30 years of age or older and to identify adenocarcinoma. The second one includes cellular biomarkers that are associated with E6 and E7 proteins changing some pathways that regulate the cell cycle. For example, since the silencing of pRb produces a rise in the CDK inhibitor p16, the overexpression of this molecule can be determined by immunostaining or enzyme-linked immunosorbent assay (ELISA) and thus serves as a marker of cellular transformation. The third group contains epigenetic biomarkers that reveal DNA methylation and show if DNA has been activated or silenced. The state of methylation of the L1 gene appears to be associated with the diagnosis of CIN 2 ( Tornesello et al., 2013 ). Table 2 summarizes the different types of biomarkers used in the detection of cervical cancer lesions.

TABLE 2. HPV infection biomarkers.

Cervical cancer prognosis and the proper treatment for the condition are based on the stage of the cancer, which is decided by the level of invasion and how far the tumor has extended. While cervical cancer is staged based on International Federation of Obstetrics and Gynecology guidelines, it is classified into three sub-groups for treatment ( Duenasgonzalez et al., 2014 ). The earliest stages (IA 1 –IIA 1 ) show tumors on the upper 1/3 of the vagina that measure <4 cm and are treated via conization with sufficient excision margins for IA 1 and conization and simple/radical hysterectomy with pelvic lymphadenectomy for IIA 2 . Patients with small-volume macroscopic disease (IIA 1 –IB 1 ) receive radical hysterectomies, while radical trachelectomy with lymphadenectomy is utilized to retain fertility ( Martinhirsch and Wood, 2011 ). Intermediate stages (IB 2 –IVA) require primary chemoradiation ( Duenasgonzalez et al., 2014 ), whereas advanced stages (IVB) and those with ongoing incurable disease are given systemic chemotherapy, including cisplatin, carboplatin, paclitaxel, topotecan, and gemcitabine ( Scatchard et al., 2012 ).

Research is now closing in on novel molecular targets for cervical cancer therapeutics, including the utilization of epidermal growth factor receptor (EGFR) antagonists, such as panitumumab, and multitargeted tyrosine kinase inhibitors, such as imatinib and sunitinib ( Candelaria et al., 2009 ; Duenasgonzalez et al., 2014 ). In addition, epigenetic therapy seems to be a potential and efficient type of therapy for cervical cancer ( Dueñasgonzález et al., 2005 ). Investigations on the effects of adding the antiangiogenesis agent bevacizumab to chemotherapy used in advanced or recurrent disease are also being carried out ( Tewari et al., 2014 ).

The HPV vaccine is a vital method of protection against cervical cancer, particularly when combined with a healthy sexual lifestyle and the proper use of contraceptives. There has been a rise in backing the vaccination of men against HPV; it is a practical choice for two reasons. Since HPV serotypes 16 and 18 are connected to 70% of anal cancers and precancerous lesions of the penis, the HPV vaccine can limit the occurrence of these conditions, particularly in homosexual men who are at a high risk of anal dysplasia. The vaccination is also pertinent for heterosexuals who participate in anal intercourse. It has been determined that 35.9% of women and 42.3% of men 18–44 years of age have anal intercourse with people of the opposite sex ( Copen et al., 2016 ). In addition, vaccination of men is also a secondary way to protect against HPV-induced cervical cancer in women. Regrettably, populations in low-income countries are not as likely to receive the HPV vaccination due to its high cost. Further, the majority of women in these areas are not able to be regularly screened, although Pap smear screening has increased approximately 5% during the last 5 years ( Katz and Wright, 2006 ). The low rates of screening result in an overall higher mortality rate from cervical cancer in developing countries.

HPV Vaccines

There are currently two available vaccines against HPV, Gardasil ® made by Merck Frost, and Cervarix ® made by GlaxoSmithKline. Both vaccines contain virus-like particles (VLPs) produced with a recombinant DNA platform. They both have the L1 protein portion of the viral capsids ( Katz and Wright, 2006 ). These types of VLPs generate strong reactions from the immune system and produce antibody titers that are much greater than those prompted by natural infection ( Dawar et al., 2007 ).

Quadrivalent Vaccine

Gardasil ® is a quadrivalent vaccine because it targets four HPV serotypes, namely 6, 11, 16, and 18. The L1 capsid proteins are produced in yeast cells ( Saccharomyces cerevisiae ) and mixed with an aluminum adjuvant. The vaccine is suggested for both males and females who are 9–26 years of age, and it is given in three doses at 0, 2, and 6 months. Gardasil ® can safeguard against continuous HPV infection, precancerous lesions of the cervix, vulva, and vagina, and genital warts linked to serotypes 11, 16, and 18 in females who are 16–26 years of age who have not experienced a prior infection ( Mello, 2013 ).

Bivalent Vaccine

Cervarix ® is a bivalent vaccine that provides protection against the two serotypes HPV 16 and 18. The VLPs in this preparation are generated in insect cells with baculovirus and an adjuvant with ASO 4 and monophosphoryl lipid A via bacterial cell walls ( Dawar et al., 2007 ; Mello, 2013 ). The vaccine is designed for girls and women 10–25 years of age and is given in three doses at 0, 1, and 6 months. Randomized, controlled, and double-blind studies with women between 15 and 25 years of age showed that the vaccine is effective in averting precursor lesions of cervical cancer associated with HPV 16 and 18 in women without prior infection ( Mello, 2013 ).

Upon viewing the variation of antibody titer with the amount of time following the administration of the Gardasil ® vaccine, it is important to recognize that the variation in titer values after the Cervarix ® vaccine has an identical profile, with the exception of two variations. First, at 24 months following the vaccination with Gardasil ® , 96% of the patients were positive for HPV types 6, 11, and 16 antibodies, and 68% tested positive for type 18. Seropositivity is achieved in 100% of patients for HPV-16 and HPV-18 antibodies at 51–53 months following the vaccination. Second, the plateau achieved with Gardasil ® is close to the titers that are spontaneously prompted by types 6 and 18 and is increased for types 11 and 16, while the plateau of Cervarix ® is greater than that induced by the naturally occurring infection ( Dawar et al., 2007 ).

Nine-Valent Vaccine

The non-avalent vaccine, which represents a new vaccine generation, has been recently approved by Merck EMA ( Eisele et al., 2013 ; Joura et al., 2015 ; Schiller and Müller, 2015 ). The new vaccine increases the coverage from the four original types included in Gardasil ® to five more oncogenic types (HPV 31, 33, 45, 52, and 58). Coverage of the additional types may increase type-specific protection from approximately 70 to 90% of cervical cancer-causing HPV infections. In 2013, Merck announced that they had achieved the pre-specified endpoints of their large phase three efficacy trial ( Herrero et al., 2015 ). When compared with the quadrivalent vaccine, the non-avalent vaccine was non-inferior in inducing antibodies to the four shared VLPs and reduced the moderate and high-grade cervical dysplasia attributable to the five additional VLP types by 96%. The seven oncogenic types included in the new vaccine (HPV 16, 18, 31, 33, 45, 52, and 58) cause most HPV infections that quickly progress to high-grade precursors of cervical cancer. Eventually, the non-avalent vaccine could lead to longer intervals between screenings for cervical cancer in women who have been vaccinated against HPV, resulting in significant cost savings to cervical cancer prevention programs ( Printz, 2015 ; Schiller and Müller, 2015 ).

Vaccine Efficacy

The bivalent vaccine was evaluated in a phase III study sponsored by GlaxoSmithKline called the Papilloma Trial Against Cancer in Young Adults ( Paavonen et al., 2009 ; Luckett and Feldman, 2016 ; St Laurent et al., 2018 ). In this multinational prospective double-blind placebo-controlled trial, the vaccine was 92.9% effective in preventing CIN 2 in 18,000 women ages 15–25 with either normal cervical cytology or low grade cervical dysplasia (Table 3 ). The vaccine was 52.8% effective in preventing these lesions as well as 33.6% effective in preventing high risk CIN 3 lesions in patients with a history of HPV infection (Table 3 ).

TABLE 3. Efficacy of HPV vaccines available.

The qHPV vaccine was evaluated in a series of Merck sponsored trials: Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) trials (FIS Group, 2007 ; Garland et al., 2007 ). In the first smaller trial, qHPV vaccine was 100% effective against CIN 2/3 in HPV naive women (Table 3 ). The follow-up trial, FUTURE II, was a larger phase III double-blinded, multinational prospective, placebo-controlled trial of over 12,000 women. Qualified study subjects were between the ages of 15–26 without a history of abnormal Papanicolaou smears and had less than four lifetime sexual partners. In this group, qHPV vaccine was 98% efficacious against a composite of CIN 2/3, HPV 16/18 infection, as well as adenocarcinoma in situ (AIS) in women ages 15 to 26. Additionally, the vaccine was 42% effective against HPV 16 and 79% effective against HPV 18 (Table 3 ). In the same group, qHPV vaccine was, respectively, 57 and 45% effective against HPV 16 and 18 associated CIN 2/3, preventing approximately 17% of all CIN 2 lesions (Table 3 ). Importantly, the qHPV vaccine demonstrated limited cross-protection, 32.5%, against CIN 2/3 and AIS in the FUTURE trials (Table 3 ). The efficacy of the 9vHPV vaccine was evaluated in a phase IIb-III double-blinded, randomized international non-inferiority trial supported by Merck ( Luckett and Feldman, 2016 ; St Laurent et al., 2018 ). In 14,215 low risk women ages 16–26 randomized to a 3-dose regimen of either 9vHPV vaccine or qHPV, the 9vHPV vaccine was 96% effective at preventing high-grade CIN, AIS, high-grade VAIN, vulvar cancer, and vaginal cancer associated with the nine HPV subtypes targeted by the 9vHPV vaccine. 9vHPV was 96% effective at preventing persistent infections related to the same HPV-types. However, analysis of women including those with prior HPV infection showed no difference in cervical, vaginal, or vulvar disease between the two vaccines ( Luckett and Feldman, 2016 ).

Contraindications and Side Effects

The vaccine is contraindicated in patients with allergies to any of its components, and, while it does not seem to escalate the occurrence of miscarriage, pregnant women should not receive the vaccination ( Schiller et al., 2012 ; Mello, 2013 ; Schiller and Müller, 2015 ). Additionally, patients with direct hypersensitivity to yeast cannot be Gardasil ® vaccine recipients. The vaccine is not contraindicated for patients with immunosuppressive conditions or patients with prior HPV infections, but immunogenicity cannot be assured for the former group. Additional vaccines can be given prior to, during, and following the HPV vaccination ( Mello, 2013 ). Side effects that have been reported for the quadrivalent vaccine are: (1) pain, swelling, and redness at the injection site and headache in more than 10% of recipients; (2) bruising, itching, fever, and nausea in more than 0.1%; (3) urticaria in less than 0.1%; and (4) bronchospasm in less than 0.01% ( Kitchener et al., 2006 ; Burd, 2016 ).

Future Challenges

Despite the development of preventive vaccines that target high-risk HPV types, their usage rates remain low. Increased public health efforts are required to improve HPV vaccine usage in the United States. In the case of less-developed countries in which the number of cervical cancer cases is high, single-dose vaccines need to be developed. Furthermore, basic scientific research is required to aid in understanding the factors that regulate the development of cancer after HPV infection. Discovery of the factors that mediate this progression, such as disruption of signaling, pathway differentiation, and changes in epigenetic chromatin dynamics, will provide significant insight into the mechanisms of development of other cancers. In the future, research efforts will be most advantageous when broken up into three areas ( Langsfeld and Laimin, 2016 ): (i) understanding how HPV infections develop into cancer, specifically, how the viruses communicate with host chromatin remodeling processes, DNA repair, and differentiation pathways; (ii) examining of HPV infections and oropharynx cancers, since they appear to be different from cancers of the anogenital tract; and (iii) evaluating the effects of immunomodulation in HPV infection and the development of immune therapies for women currently infected with HPV. We believe that the exploration of these aspects is of great urgency for HPV research in the next 10 years.

Medical developments will continue; novel tests, markers, and evidence will increase our capability to distinguish between minor HPV infections and precancerous and cancerous disease. The main goal is to have an easy, strong, and cost-efficient system in place that will provide better patient care.

Author Contributions

YZ and XH provided ideas and chaired the projects. XW and YZ designed the research and were associated with data analysis. XW performed the other works and wrote the manuscript.

This work was supported by the National Key R&D Program of China (2016YFC1302900 and 2016YFC1302901), the National Natural Science Foundation of China (NSFC, 81572559), the Key Research Project of Shandong Province (2017CXGC1210), and the National Science and Technology Project of China (2015BAI13B05).

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Alcocer-Gonzalez, J. M., Berumen, J., Tamez-Guerra, R., Bermudez-Morales, V., Peralta-Zaragoza, O., Hernandez-Pando, R., et al. (2006). In vivo expression of immunosuppressive cytokines in human papillomavirus-transformed cervical cancer cells. Viral Immunol. 19, 481–491. doi: 10.1089/vim.2006.19.481

PubMed Abstract | CrossRef Full Text | Google Scholar

Arbyn, M., Tommasino, M., Depuydt, C., and Dillner, J. (2014). Are 20 human papillomavirus types causing cervical cancer? J. Pathol. 234, 431–435. doi: 10.1002/path.4424

Banister, C. E., Liu, C., Pirisi, L., Creek, K. E., and Buckhaults, P. J. (2017). Identification and characterization of HPV-independent cervical cancers. Oncotarget 8, 13375–13386. doi: 10.18632/oncotarget.14533

Bermudez-Morales, V. H., Gutierrez, L. X., Alcocer-Gonzalez, J. M., Burguete, A., and Madrid-Marina, V. (2008). Correlation between il-10 gene expression and hpv infection in cervical cancer: a mechanism for immune response escape. Cancer Invest. 26, 1037–1043. doi: 10.1080/07357900802112693

Brianti, P., De Flammineis, E., and Mercuri, S. R. (2017). Review of HPV-related diseases and cancers. New Microbiol. 40, 80–85.

Google Scholar

Burd, E. M. (2016). Human papillomavirus laboratory testing: the changing paradigm. Clin. Microbiol. Rev. 29, 291–319. doi: 10.1128/CMR.00013-15

Camilleri, G., and Bundell, R. (2013). The Mechanisms of HPV-Induced Carcinogenesis and the HPV Vaccine. Saarbrücken: Lambert Academic Publishing, 83–100.

Candelaria, M., Ariasbonfill, D., Chávezblanco, A., Chanona, J., Cantú, D., Pérez, C., et al. (2009). Lack in efficacy for imatinib mesylate as second-line treatment of recurrent or metastatic cervical cancer expressing platelet-derived growth factor receptor alpha. Int. J. Gynecol. Cancer 19, 1632–1637. doi: 10.1111/IGC.0b013e3181a80bb5

Cason, J., Rice, P., and Best, J. M. (1998). Transmission of cervical cancer-associated human papilloma viruses from mother to child. Intervirology 41:213. doi: 10.1159/000024939

Copen, C. E., Chandra, A., and Febo-Vazquez, I. (2016). Sexual behavior, sexual attraction, and sexual orientation among adults aged 18-44 in the united states: data from the 2011-2013 national survey of family growth. Nat. Health Stat. Rep. 88, 1–14.

PubMed Abstract | Google Scholar

Cubie, H. A. (2013). Diseases associated with human papillomavirus infection. Virology 445, 21–34. doi: 10.1016/j.virol.2013.06.007

Cubie, H. A., Cuschieri, K. S., and Tong, C. Y. W. (2012). “Papillomaviruses and polyomaviruses,” in Medical Microbiology. 18th Edn, eds D. Greenwood, M. Barer, R. Slack, and W. Irving (London: Churchill Livingstone Elsevier).

Dawar, M., Deeks, S., and Dobson, S. (2007). Human papillomavirus vaccines launch a new era in cervical cancer prevention. Can. Med. Assoc. J. 177, 456–461. doi: 10.1503/cmaj.070771

de Freitas, A. C., de Oliveira, T. H. A., Barros, M. R. Jr., and Venuti, A. (2017). hrHPV E5 oncoprotein: immune evasion and related immunotherapies. J. Exp. Clin. Cancer Res. 36:71. doi: 10.1186/s13046-017-0541-1

del Mar Diaz-Gonzalez, S., Deas, J., Benitez-Boijseauneau, O., Gomez-Ceron, C., Bermudez-Morales, V. H., Rodriguez-Dorantes, M., et al. (2015). Utility of microRNAs and siRNAs in cervical carcinogenesis. Biomed. Res. Int. 2015:374924. doi: 10.1155/2015/374924

Dueñasgonzález, A., Lizano, M., Candelaria, M., Cetina, L., Arce, C., and Cervera, E. (2005). Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol. Cancer 4, 1–24. doi: 10.1186/1476-4598-4-1

Duenas-Gonzalez, A., Lizano, M., Candelaria, M., Cetina, L., Arce, C., and Cervera, E. (2005). Epigenetics of cervical cancer. An overview and therapeutic perspectives. Mol. Cancer 4:38. doi: 10.1186/1476-4598-4-38

Duenasgonzalez, A., Serranoolvera, A., Cetina, L., and Coronel, J. (2014). New molecular targets against cervical cancer. Int. J. Womens Health 6, 1023–1031. doi: 10.2147/IJWH.S49471

Dunne, E. F., and Markowitz, L. E. (2006). Genital human papillomavirus infection. Clin. Infect. Dis. 43, 624–629. doi: 10.1086/505982

Durzynska, J., Lesniewicz, K., and Poreba, E. (2017). Human papillomaviruses in epigenetic regulations. Mutat. Res. Rev. Mutat. Res. 772, 36–50. doi: 10.1016/j.mrrev.2016.09.006

Eisele, P., Munshi, I., Ferguson, C., and Holko, J. (2013). Merck’s Investigational 9-Valent HPV Vaccine, V503, Prevented 97 Percent of Cervical, Vaginal and Vulvar Pre-Cancers Caused by Five Additional HPV Types. Phase III Study. Available at: http://www.mercknewsroom.com/news-release/research-and-developmentnews/mercks-investigational-9-valent-hpv-vaccine-v503-prevente

Garland, S. M., Hernandez-Avila, M., Wheeler, C. M., Perez, G., Harper, D. M., and Leodolter, S. (2007). Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N. Engl. J. Med. 356, 1928–1943. doi: 10.1056/NEJMoa061760

Giannini, S. L., Al-Saleh, W., Piron, H., Jacobs, N., Doyen, J., Boniver, J., et al. (1998). Cytokine expression in squamous intraepithelial lesions of the uterine cervix: implications for the generation of local immunosuppression. Clin. Exp. Immunol. 113, 183–189. doi: 10.1046/j.1365-2249.1998.00639.x

Gómez-Gómez, Y., Organista-Nava, J., and Gariglio, P. (2013). Deregulation of the miRNAs expression in cervical cancer: human papillomavirus implications. Biomed. Res. Int. 2013:407052. doi: 10.1155/2013/407052

Group, F. I. S. (2007). Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N. Engl. J. Med. 356, 1915–1927. doi: 10.1056/NEJMoa061741

Halec, G., Alemany, L., Lloveras, B., Schmitt, M., Alejo, M., Bosch, F. X., et al. (2014). Pathogenic role of the eight probably/possibly carcinogenic HPV types 26, 53, 66, 67, 68, 70, 73 and 82 in cervical cancer. J. Pathol. 234, 441–451. doi: 10.1002/path.4405

Herrero, R., González, P., and Markowitz, L. E. (2015). Present status of human papillomavirus vaccine development and implementation. Lancet Oncol. 16:e206–16. doi: 10.1016/S1470-2045(14)70481-4

CrossRef Full Text | Google Scholar

Hikita, M., and Kozako, M. (2001). Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 20:7888.

Howley, P. M. (2006). Warts, cancer and ubiquitylation: lessons from the papillomaviruses. Trans. Am. Clin. Climatol. Assoc. 117, 113–126.

IARC. (1995). Working Group on the Evaluation of Carcinogenic Risks to Humans. Geneva: World Health Organization.

Joura, E. A., Giuliano, A. R., Iversen, O.-E., Bouchard, C., Mao, C., Mehlsen, J., et al. (2015). A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N. Engl. J. Med. 372, 711–723. doi: 10.1056/NEJMoa1405044

Katz, I. T., and Wright, A. A. (2006). Preventing cervical cancer in the developing world. N. Engl. J. Med. 354:1110. doi: 10.1056/NEJMp068031

Kitchener, H. C., Almonte, M., Wheeler, P., Desai, M., Gilham, C., Bailey, A., et al. (2006). HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br. J. Cancer 95:56. doi: 10.1038/sj.bjc.6603210

Kivi, N., Greco, D., Auvinen, P., and Auvinen, E. (2008). Genes involved in cell adhesion, cell motility and mitogenic signaling are altered due to HPV 16 E5 protein expression. Oncogene 27, 2532–2541. doi: 10.1038/sj.onc.1210916

Langsfeld, E., and Laimin, L. A. (2016). Human papillomaviruses: research priorities for the next decade. Trends Cancer 2, 234–240. doi: 10.1016/j.trecan.2016.04.001

Livolsi, V. A. (2002). Blaustein’s pathology of the female genital tract, 5th ed. Hum. Pathol. 33, 1149–1149. doi: 10.1016/S0046-8177(02)70046-4

Luckett, R., and Feldman, S. (2016). Impact of 2-, 4- and 9-valent HPV vaccines on morbidity and mortality from cervical cancer. Hum. Vaccin. Immunother. 12, 1332–1342. doi: 10.1080/21645515.2015.1108500

Marco, F. D. (2013). Oxidative stress and HPV carcinogenesis. Viruses 5, 708–731. doi: 10.3390/v5020708

Martinhirsch, P. L., and Wood, N. J. (2011). Cervical cancer. Clin. Evid. 2011, 1186–1187.

Mattoscio, D., Medda, A., and Chiocca, S. (2018). Human papilloma virus and autophagy. Int. J. Mol. Sci. 19:1775. doi: 10.3390/ijms19061775

Mello, C. F. (2013). Vaccination against human papillomavirus. Einstein 11, 547–549. doi: 10.1590/S1679-45082013000400027

Narisawasaito, M., and Kiyono, T. (2007). Basic mechanisms of high-risk human papillomavirus-induced carcinogenesis: roles of E6 and E7 proteins. Cancer Sci. 98, 1505–1511. doi: 10.1111/j.1349-7006.2007.00546.x

Paavonen, J., Naud, P., Salmeron, J., Wheeler, C. M., Chow, S. N., Apter, D., et al. (2009). Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374, 301–314. doi: 10.1016/S0140-6736(09)61248-4

Peralta-Zaragoza, O., Bermudez-Morales, V., Gutierrez-Xicotencatl, L., Alcocer-Gonzalez, J., Recillas-Targa, F., and Madrid-Marina, V. (2006). E6 and E7 oncoproteins from human papillomavirus type 16 induce activation of human transforming growth factor beta1 promoter throughout Sp1 recognition sequence. Viral Immunol. 19, 468–480. doi: 10.1089/vim.2006.19.468

Peralta-Zaragoza, O., Bermudez-Morales, V. H., Perez-Plasencia, C., Salazar-Leon, J., Gomez-Ceron, C., and Madrid-Marina, V. (2012). Targeted treatments for cervical cancer: a review. Onco Targets Ther. 5, 315–328. doi: 10.2147/ott.s25123

Printz, C. (2015). FDA approves gardasil 9 for more types of HPV. Cancer 121, 1156–1157. doi: 10.1002/cncr.29374

Sasagawa, T., Takagi, H., and Makinoda, S. (2012). Immune responses against human papillomavirus (HPV) infection and evasion of host defense in cervical cancer. J. Infect. Chemother. 18, 807–815. doi: 10.1007/s10156-012-0485-5

Scatchard, K., Forrest, J. L., Flubacher, M., Cornes, P., and Williams, C. (2012). Chemotherapy for metastatic and recurrent cervical cancer. Cochrane Database. Syst. Rev. 10:Cd006469. doi: 10.1002/14651858.CD006469.pub2

Schiller, J. T., Castellsagué, X., and Garland, S. M. (2012). A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine 30(Suppl. 5), F123–F138. doi: 10.1016/j.vaccine.2012.04.108

Schiller, J. T., and Müller, M. (2015). Next generation prophylactic human papillomavirus vaccines. Lancet Oncol. 16:e217–25. doi: 10.1016/S1470-2045(14)71179-9

Sen, P., Ganguly, P., and Ganguly, N. (2018). Modulation of DNA methylation by human papillomavirus E6 and E7 oncoproteins in cervical cancer. Oncol. Lett. 15, 11–22. doi: 10.3892/ol.2017.7292

Senapati, R., Senapati, N. N., and Dwibedi, B. (2016). Molecular mechanisms of HPV mediated neoplastic progression. Infect. Agent Cancer 11:59. doi: 10.1186/s13027-016-0107-4

Shackelford, R. E., Kaufmann, W. K., and Paules, R. S. (1999). Cell cycle control, checkpoint mechanisms, and genotoxic stress. Environ. Health Perspect. 107(Suppl. 1), 5–24.

Sheu, B. C., Lin, R. H., Lien, H. C., Ho, H. N., Hsu, S. M., and Huang, S. C. (2001). Predominant Th2/Tc2 polarity of tumor-infiltrating lymphocytes in human cervical cancer. J. Immunol. 167, 2972–2978. doi: 10.4049/jimmunol.167.5.2972

St Laurent, J., Luckett, R., and Feldman, S. (2018). HPV vaccination and the effects on rates of HPV-related cancers. Curr. Probl. Cancer doi: 10.1016/j.currproblcancer.2018.06.004 [Epub ahead of print].

Stanley, M. A., Pett, M. R., and Coleman, N. (2007). HPV: from infection to cancer. Biochem. Soc. Trans. 35, 1456–1460. doi: 10.1042/bst0351456

Tewari, K. S., Sill, M. W., Penson, R. T., Huang, H., Ramondetta, L. M., Landrum, L. M., et al. (2014). Improved survival with bevacizumab in advanced cervical cancer. N. Engl. J. Med. 370, 734–743. doi: 10.1056/NEJMoa1309748

Tornesello, M. L., Buonaguro, L., Giorgirossi, P., and Buonaguro, F. M. (2013). Viral and cellular biomarkers in the diagnosis of cervical intraepithelial neoplasia and cancer. BioMed. Res. Int. 2013:519619. doi: 10.1155/2013/519619

Torres-Poveda, K., Bahena-Roman, M., Madrid-Gonzalez, C., Burguete-Garcia, A. I., Bermudez-Morales, V. H., Peralta-Zaragoza, O., et al. (2014). Role of IL-10 and TGF-beta1 in local immunosuppression in HPV-associated cervical neoplasia. World J. Clin. Oncol. 5, 753–763. doi: 10.5306/wjco.v5.i4.753

Wetherill, L. F., Holmes, K. K., Verow, M., Muller, M., Howell, G., Harris, M., et al. (2012). High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors. J. Virol. 86, 5341–5351. doi: 10.1128/JVI.06243-11

Yin, F. F., Wang, N., Bi, X. N., Yu, X., Xu, X. H., Wang, Y. L., et al. (2016). Serine/threonine kinases 31(STK31) may be a novel cellular target gene for the HPV16 oncogene E7 with potential as a DNA hypomethylation biomarker in cervical cancer. Virol. J. 13:60. doi: 10.1186/s12985-016-0515-5

Keywords : human papillomaviruses, cervical cancer, HPV-induced carcinogenesis, HPV genotype, HPV vaccine

Citation: Wang X, Huang X and Zhang Y (2018) Involvement of Human Papillomaviruses in Cervical Cancer. Front. Microbiol. 9:2896. doi: 10.3389/fmicb.2018.02896

Received: 25 April 2018; Accepted: 12 November 2018; Published: 28 November 2018.

Reviewed by:

Copyright © 2018 Wang, Huang and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Youzhong Zhang, [email protected]

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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• http://orcid.org/0000-0003-0589-2696 Andreina Fernandes 1 ,
• http://orcid.org/0000-0001-9395-0627 David Viveros-Carreño 2 ,
• http://orcid.org/0000-0003-0063-3871 Jorge Hoegl 3 ,
• Maira Ávila 1 and
• http://orcid.org/0000-0003-0093-0438 Rene Pareja 2 , 4
• 1 Laboratorio de Genética Molecular , Instituto de Oncología y Hematología , Caracas , Bolivarian Republic of Venezuela
• 2 Department of Gynecologic Oncology , Instituto Nacional de Cancerologia , Bogota , Colombia
• 3 Obstetrics and Gynecology. Division of Gynecological Oncology , Hospital General del Este "Dr. Domingo Luciani" , Caracas , Bolivarian Republic of Venezuela
• 4 Clínica ASTORGA , Medellín , Colombia
• Correspondence to Dr Rene Pareja, Department of Gynecologic Oncology, Instituto Nacional de Cancerologia, Bogota, Colombia; ajerapener{at}gmail.com

Cervical cancer is the fourth most frequent cancer in women worldwide, representing nearly 8% of all female cancer deaths every year. The majority of cases of cervical cancer are caused by human papillomavirus (HPV); however, up to 5% of tumors are not associated with HPV-persistent infection and, moreover, the new WHO Female Genital Tumors classification subdivided cervical squamous and adenocarcinomas into HPV-associated and HPV-independent tumors. Based on this new information, the aim of this review is to provide an overview of HPV-independent cervical cancer, evaluating diagnostic techniques, molecular profiles, and clinical outcomes. The HPV-independent tumors are characterized by a differentiated molecular profile with lower proliferative activity, a p53 immunostaining, a decreased expression of cyclin-dependent kinase inhibitor proteins, such as p16, p14, and p27, and alterations in PTEN, p53, KRAS, CTNNB1, ARID1A, and ARID5B . HPV-independent tumors are associated with both adenocarcinomas and squamous histologic subtypes, with lymph node involvement in the early stages, more distant metastasis, and generally worse oncological outcomes. Thus far, no specific therapeutic strategies have been developed based on HPV status; however, with advancing knowledge of differences in the molecular profiles and possible targetable alterations, novel approaches may offer potential options in the near future. Investigators should report on clinical outcomes, evaluating the overall response rates to specific treatments, and consider new biomarkers to establish more accurate prognostics factors.

• cervical cancer
• adenocarcinoma

https://doi.org/10.1136/ijgc-2021-003014

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INTRODUCTION

Cervical cancer is the fourth most frequent cancer in women, with 604 127 new cases in 2020 and more than 341 831 deaths, representing nearly 8% of all female cancer deaths every year. 1 Of the estimated incidence and mortality from cervical cancer, approximately 84% of all cases and 88% of all deaths occurred in low- and middle-income countries. 2 Human papillomavirus (HPV) is a sexually transmitted virus that, if it establishes a persistent infection with high-risk genotypes, such as HPV 16 and 18, there is high association with cervical cancer. 3 Both of the HPV sub-types jointly cause 70–75% of all cervical cancers and 40–60% of its precursor lesions. 2

Epidemiological studies report that almost all cases of cervical cancer are caused by HPV 3 ; however, approximately 5% of tumors are not associated with HPV-persistent infection. 4 In 2009, zur Hausen stated that although more than 95% of cervical cancer biopsies contain high-risk HPV genomes, this does not necessarily imply that all of these tumors are caused by the infection. 5 A meta-analysis involving 40 679 women with cervical cancer from 229 studies, that used broad-spectrum consensus polymerase chain reaction (PCR) assays based on the primers MY09/11, PGMY09/11, GP5+/6+, SPF10, SPF1/GP6+, or L1C1/L1C2, reported that 10.6% (8.4–13.9%) of cases were HPV-negative and this percentage varied with geographic location. 6

In 2020, the WHO updated the Female Genital Tumors classification (5th edition) and recognized that a proportion of cervical cancers are not associated with HPV infection, especially adenocarcinomas. 7 Based on this statement the Tumor Editorial Board subdivided the cervical squamous lesions into HPV-associated and HPV-independent tumors, and adenocarcinomas into HPV-associated, including (1) usual type: villoglandular variant; (2) mucinous type: mucinous not otherwise specified (NOS) adenocarcinoma, intestinal adenocarcinoma, signet-ring cell adenocarcinoma, and stratified mucin-producing adenocarcinoma, and HPV-independent tumors, including (1) gastric type adenocarcinoma; (2) clear cell adenocarcinoma; (3) mesonephric adenocarcinoma; and (4) endometrioid adenocarcinoma. 7

The aim of this review is to provide an overview of HPV-independent cervical cancer, evaluating diagnostic techniques, molecular profiles, and clinical outcomes.

HPV Tests: Screening and Genotyping

HPV-independent cervical cancers are clinically relevant due to their biological behavior and possible worst prognosis. HPV-negative status may be associated with different potential scenarios: (1) HPV-independent (true negative) cancers, such as some subtypes of adenocarcinomas and a few cases of squamous carcinoma; (2) loss of the HPV genome during the integration process; (3) presence of viral genotypes not included in the molecular tests; (4) failure in detection of the diagnostic method employed; or (5) misclassification of cancers as primary cervical (metastases or primary uterine corpus neoplasms). 4 8 9

The WHO initiative on preventive strategies for eradication of cervical cancer include HPV vaccination in combination with the implementation of effective screening programs with HPV-based testing for risk estimation of CIN3 +, and the proper management of pre-invasive lesions and cervical cancer. 10 11 Therefore, it is important to select an appropriate and validated test in terms of clinical accuracy, reproducibility, and cost-effectiveness before screening implementation. 12–14 In general, molecular tests are widely used in epidemiological studies, during HPV surveillance, and in monitoring the impact of HPV vaccination. 15

HPV testing is a highly sensitive technique with high negative predictive value (97.9–99.3%) 12 16 ; however, the optimal performance of an HPV test depends on a large number of factors such as sample collection, nucleic acid extraction methodology, primers, and use of internal controls. 17 The most commonly used methods to detect the HPV genome are based on PCR and the use of hybridization probes targeting the L1 gene, as this is the most conserved gene in the HPV genotypes. 18 These tests are highly sensitive and specific ( Table 1 ); however, they may not be capable of detecting HPV genomes that do not specifically bind to the designed primers and probes, and therefore a viral genotype that diverges in genomic sequence from the designed primer/probe sequences may escape amplification and/or hybridization and remain undetected. 19–21

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HPV test FDA approved for cervical cancer screening 16 17 24

There are currently commercial tests approved by the US Food and Drug Administration for cervical cancer screening based on viral DNA amplification and mRNA amplification. Another group include signal amplification systems ( Table 1 ). Signal amplification methods have a lower sensitivity than DNA amplification methods and may cause false negatives, especially in cases where the viral load is low. In addition, the absence of an internal control increases the proportion of false negatives, likely due to degradation of the viral genome. 22 23 Most PCR-based tests only amplify the L1 region of the virus. Therefore, PCR false negatives may be associated with the loss of this region during the viral integration process 24 ; whereas the E6/E7 mRNA expression evaluation could be associated with the presence of a high-grade lesion or cervical cancer, since it is known that the E6/E7 mRNA proportion increases after integration of the viral genome into host cells. 24

Due to variations in the methodological approaches used to detect HPV, different primers, and diverse sensitivities and specificities, Petry et al 25 recommend the use of an additional PCR-based test as a part of the differential diagnosis of possible HPV-negative cervical cancer. However, when HPV detection fails by the conventional methodologies, other molecular techniques such as high-throughput sequencing can be used to identify the specific genotype in case of HPV infection. Likewise, if the cDNA is sequenced, the data can show whether there is transcriptional activity of the virus, which is fundamental in both the initiation and maintenance of the malignant phenotype. 26 27 The evidence shows that in cases of re-testing of suspected HPV-independent tumors, especially those performed with deep sequencing, between 48–57% of cervical cancer samples with a negative result by PCR remain truly negative 28 both in cases of adenocarcinomas and squamous cell carcinomas.

Molecular Profile of HPV-Independent Tumors

The HPV carcinogenesis associated with the development of cervical cancer is well described 3 ; however, the mechanism associated with HPV-independent cancers is unclear. 29 Several studies have evaluated the differential gene expression between the HPV-associated and HPV-independent cervical cancers. 4 30 31 There are differences in the expression of markers between HPV-positive and HPV-independent tumors, evaluating cell proliferation markers such as PCNA 32 and Ki67 33 ; tumor suppressor proteins such as p53, 33–37 p16, 35–38 p14, p21, and p27 36 ; and proto-oncogenes such as epidermal growth factor receptor (EGFR), 33 c-myc, 34 and c-Erb-2. 33

The HPV-independent tumors have a lower proliferative activity, suggesting that the viral infection induces an increased cellular proliferation. 32 Additionally, HPV-independent tumors show p53 nuclear immunostaining, and thus a useful marker in the differentiation of the viral independent tumors. 33–36 Nicolás et al 37 reported that tumors with an HPV-negative result showed a high rate of p53 abnormal (p53abn) immunostaining pattern, suggesting a mutational phenotype associated with the capacity of tumor deregulation, with increased growth potential and metastasis. Finally, HPV-positive tumors show increased expression of cyclin-dependent kinase (CDK) inhibitor proteins, such as p16, p14, and p27, 36 as a surrogate marker of HPV infection. 38

With the development and implementation of novel molecular techniques, the comparison of genetic profiles between HPV-associated and HPV-independent tumors has been possible. 4 30 31 39 40 WIG-1 is a p53-regulated gene that encodes a transcription factor. WIG-1 can interact with heterogeneous nuclear ribonucleoprotein (hnRNP A2/B1), RNA helicase A, and double strand RNA (dsRNA), which plays an important role in RNA and protein stabilization. 41 WIG-1 is frequently amplified in tumors, including cervical cancer. 39 WIG-1 mRNA expression was higher in the HPV-independent cervical cancer cell lines (C33-A and HT-3) than in the HPV-positive cell lines, suggesting a possible role of WIG-1 in HPV-negative cervical carcinogenesis. The authors reported statistically significant higher WIG-1 protein staining intensity in HPV-independent cervical cancer tumors compared with HPV-associated tumors, both in squamous (p=0.002) and in adenocarcinomas (p=0.049). 39

Differences in expression levels of miRNAs—a class of small non-coding RNA molecules that regulate key cellular processes—between high risk-HPV E6/E7 mRNA positive and high risk-HPV E6/E7 mRNA negative cervical cancer tissue samples have been evaluated. While miR-9 was downregulated, 40 miR-21 and miR-155 31 were upregulated in high risk-HPV E6/E7 mRNA negative cancer tissue samples. The miRNA regulation mechanism involves high risk-HPV E6/E7 proteins; therefore, the absence of these proteins could be deregulating the expression of miR9, miR21, and miR155, impacting regulation of metastasis, cell proliferation, inflammation-associated carcinogenesis, and tumor metabolism. 31 40

The Cancer Genome Atlas (TCGA) Research Network 4 reports that HPV-independent cervical cancer encompassed a distinct subgroup within the CpG island hypermethylated (CIMP)-low cluster, with a lower mean promoter methylation, typically observed on healthy epithelial tissue. Functional epigenetic analysis showed differential subnetworks for HPV-associated and HPV-independent tumors, with one common subnetwork centered around Forkhead Box A2 ( FOXA2 ) gene (high DNA-methylation and low gene expression in HPV-positive cases). HPV-independent tumors also have a lower activation of NF-κB, p53, and MAPK signaling, a significantly higher epithelial-mesenchymal transition (EMT) mRNA score, and a lower frequency of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) mutagenesis signature, and are characterized by mutations in KRAS, ARID1A, and PTEN .

Liu et al 30 identified 17 differentially expressed genes between HPV-positive and HPV-negative tumors. Following mRNA and protein level determinations, the authors reported seven genes with significantly higher expression in HPV-negative cervical cancer cells and tissues than in HPV-positive cervical cancer and normal cells or tissues. Particularly, MEX3A, an RNA binding gene, and TTYH3, a chloride-channel-responsive gene, correlated with shorter overall survival of patients with HPV-independent cervical cancer, representing a possible new therapeutic target.

Based on the expression of HPV E6/E7 oncogenes, Banister et al 42 classified cervical tumors into HPV-active and HPV-inactive, based on the transcriptional state of the mRNA. The HPV-inactive group is associated with lower DNA methylation levels and therefore overexpression of several genes. According to the non-synonymous and synonymous mutation profile, the cancer driver genes PTEN, p53, CTNNB1, AKT, ARID1A, and ARID5B tend to be mutated, independently of the APOBEC pathway, suggesting that HPV-inactive tumors use alternative pathways to sustain tumor growth; additionally, the expression of inflammatory associated genes is decreased.

Clinical Outcomes of HPV-Independent Tumors

Currently, the proposed first-line treatment for early stages of cervical cancer (stage IA1 with lymph vascular space invasion to IB2 and IIA1 International Federation of Gynecology and Obstetrics (FIGO) 2018) is an open radical hysterectomy with pelvic lymph node assessment. 43 44 Adjuvant treatment with chemoradiotherapy may be necessary based on pathologic findings. For advanced stages (stage IB3, IIA2 to IVA FIGO 2018) the standard treatment is concomitant platinum-based chemoradiotherapy, and for metastatic disease (IVB FIGO 2018) platinum-based therapy with bevacizumab. 43–45

Primary treatment of cervical cancer is based on clinical, imaging, and pathological results. However, there is no specific treatment based on histological type, genomic alteration or HPV status defined in the current guidelines. Several studies have reported that patients with HPV-independent tumors could have a worse prognosis than HPV-associated tumors; however, the clinical impact of HPV detection to determine treatment is still not clear. 46–49 There is no prospective evidence evaluating the outcomes of patients with HPV-independent cervical cancer.

A retrospective cohort study of 136 patients 50 with cervical cancer, including squamous cell carcinoma and adenocarcinoma, showed that of 14 initially HPV-independent tumors, determined by the Hybrid Capture system (Qiagen, USA), only eight were confirmed by PCR. These patients had a worse disease-free survival (51.9 vs 109.9 months; p=0.010) and this was considered a prognostic factor even after multivariate analysis. The authors found that despite being more common in adenocarcinomas, these poor outcomes were also demonstrated in non-keratinizing squamous histological types. 51

Some additional retrospective studies analyzed the association between HPV negativity and oncological outcomes. In a study including 248 patients—108 patients who underwent surgery and 140 patients treated with chemoradiation—Chong et al 52 reported that 18.5% of cervical cancers were HPV-independent and those tumors were associated in a multivariate analysis with poorer disease-free survival when compared with HPV-associated tumors (HR 3.97, 95% CI 1.84 to 8.58; p=0.0005). Several reports have demonstrated a similar pattern in patients with HPV-associated head and neck squamous cell carcinoma, showing greater radiosensitivity and better prognosis, and this is strongly related to the molecular differences between HPV-associated and HPV-independent tumors. 53 Another retrospective analysis included 214 tumors, 37 classified as squamous cell carcinoma, adenocarcinoma, adenosquamous, or neuroendocrine. Using reverse hybridization for HPV genotyping and p16 immunostaining, the authors found a 10% rate of HPV-independent tumors. Patients with HPV-independent tumors had higher rates of lymph node invasion (67% vs 36%, p<0.01) and worse disease-free survival (59.8 vs 132.2 months, p<0.01) and overall survival (77.0 vs 153.8 months, p=0.01) compared with women with HPV-associated tumors. However, only advanced FIGO stage and lymph node metastases after multivariate analysis were associated with a poor prognosis.

A recent retrospective multicenter study evaluating prognostic biomarkers analyzed 464 cases with IB endocervical adenocarcinomas using the International Endocervical Adenocarcinoma Criteria and Classification system and no molecular tests. They identified on multivariate analysis that the HPV-independent status was associated with worse recurrence-free survival (HR 2.31, CI 95% 1.02 to 5.46; p=0.05). The other associated factors for this cohort were the lymph vascular invasion and the presence of lymph node metastasis. 54

Finally, in a re-testing study 55 including FIGO stage I–IV of 37 initially HPV-negative samples (corresponding to 14% of all the analyzed tumors), including squamous cell carcinoma and adenocarcinomas, only half were confirmed as HPV-independent. These tumors had a worse cancer-specific survival at 5 years (27% vs 69%, p=0.009) and a lower recurrence rate, although this was non-significant (27% vs 50%, p=0.061). A systematic review and meta-analysis was recently published exploring the value of HPV status in patients with cervical cancer. 56 The analysis of 17 retrospectives studies including 2838 patients showed that the oncological outcomes of patients with HPV-associated cancers were different. The overall survival was higher in this population (HR 0.610, 95% CI 0.457 to 0.814; p=0.001), as was the disease-free survival (HR 0.362, 95% CI 0.252 to 0.519; p<0.001), compared with HPV-independent cancer patients. This review has some limitations, given the lack of a registered protocol, the absence of a methods section, and the performance of meta-analysis even when high heterogeneity was present. It also has to be mentioned that the methods for HPV detection and the source of tissue varied through the different primary studies.

The American Joint Committee on Cancer (AJCC) 57 in its 9th edition, within the key modifications for cervical cancer, suggested defining HPV status as associated or independent, considering the evidence describing worse oncologic outcomes in the HPV-independent tumors. Despite the modest evidence that defines pathological and clinical characteristics of these tumors, the determination of HPV status prior to the start of treatment could be a useful tool for discussion of disease prognosis and potentially for establishing closer surveillance in these patients. It also encourages further research with the aim of determining carcinogenesis and biological behavior that might lead to personalized treatment and improved oncological outcomes.

Etiology of HPV-Independent Tumors

Thus far, it is difficult to explain the development of HPV-independent tumors, but the ‘hit and run viral theory’ could explain the absence of the viral genome in these cases. Viruses associated with human cancers promote an inflammatory process, change the microenvironment and cellular metabolism, and are associated with genomic instability. The ‘hit and run theory’ proposes that once a viral infection has caused sufficient cellular alteration, expression of viral proteins or viral infection is no longer required for tumor maintenance, and, consequently, the virus may be lost during cancer progression ( Figure 1 ). 58 59

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Schematic representation of the hypothetical hit and run mechanism. Created with BioRender.com. Adapted from Ferreira et al 59 and Niller et al. 60

It has been proposed that the E6/E7 oncogenes start the process of carcinogenesis, but as the mutations accumulate over time, transcription of the viral genes is no longer necessary and therefore they are lost. 59 Additionally, it has been proposed that the ‘hit and run’ theory of oncogenesis may also leave permanent traces through epigenetic dysregulation. Chromatin remodeling may expose hotspots for viruses to impair transcriptional regulation, DNA repair, and permanent epigenetic alterations in the infected cell, as E7 HR-HPV oncoprotein that stimulates DNA methyltransferase 1 (Dnmt1) activity. 60 During the ‘hit and run’ process, the transient but regular presence of viral genomes or parts thereof in a pre-invasive stage of the respective tumor would be considered; thus the initial persistent infection with HPV in pre-invasive lesions could be the necessary hit for the development of HPV-independent cervical cancer after the viral run. 60 The existence of HPV-independent pre-invasive lesions has not been established thus far. However, it was recently reported that two of three HPV-independent pre-invasive cervical lesions showed diffuse p16 ink4a staining, similar to the pattern shown in HPV-associated lesions. The authors excluded somatic or germline mutations in the RB gene or the CDKN2A gene encoding the p16 ink4a protein, 61 which could suggest the action of the ‘hit-and-run’ mechanism.

NEW PERSPECTIVES

With the development of new technologies for HPV detection, the detection rate of HPV-negative cases has decreased. 9 However, several studies continue reporting HPV-independent cervical cancer through different methodologies, including deep sequencing, both in cases of adenocarcinomas and squamous cell carcinomas ( Table 2 ). Additionally, the distinctive molecular profile of these HPV-independent tumors provides information regarding the presence of tumors with a different biological behavior, mediated by the alteration of signaling pathways independent of viral infection, and highlighting alterations in PTEN, KRAS, p53, CTNNB1, ARID1A, and ARID5B . 4 42 With these data, further investigations based on the evaluation of these proteins as tumor markers in cases of HPV-independent cervical cancer could have some implications for treatment.

HPV-independent cervical cancer reports

A patient with cervical cancer with an HPV-negative test may constitute a biologically distinct subgroup, which may be associated with advanced FIGO stage and a poor prognosis, and may require a different therapeutic strategy. 24 42 62 It is well known that in HPV-independent oropharyngeal cancer, the response rate to chemotherapy and radiation treatment is lower than in HPV-associated cases. 53 Therefore, the lower progression-free survival and overall survival of HPV-independent cervical tumors may be associated with low responses to current standard treatment. However, to date there are no current data to support this hypothesis. Banister et al 42 proposed that, due to the somatic mutations shown by HPV-independent tumors, PI3K/mTOR inhibitors and tyrosine kinases inhibitors (dasatinib) may improve the response rate in these patients.

The lower expression of inflammatory associated genes 42 suggest that HPV-independent cervical cancers may have a worse response rate to checkpoint inhibitors-based immunotherapy, such as programmed death protein 1/programmed cell death ligand 1 (PD1/PD-L1) inhibitors. The KEYNOTE-028 trial 63 and CHECKMATE-358 trial 64 demonstrated that patients with HPV-associated cervical cancer (squamous cell type) had improved outcomes due to an elevated proportion of TCD8 + infiltrating lymphocytes (TILSs) and PD-L1. 65 66 However, Chen et al 67 reported no significant difference in PD-L1 expression among different histologic types of endocervical adenocarcinomas.

CONCLUSIONS

HPV-independent cervical cancer constitutes a unique biological entity with a different molecular profile when compared with HPV-associated tumors. The absence of p16 and the presence of founder mutations in genes such as p53, KRAS, ARID1A, and PTEN characterize the HPV-independent tumors; thus the WHO recommends the use of HPV testing and p16 immunostaining for differentiation between HPV-associated and HPV-independent cervical cancer. HPV-independent tumors are associated with both adenocarcinomas and squamous histologic subtypes, with lymph node involvement in early stages, more distant metastasis, and generally worse oncological outcomes. However, there is no prospective information available that evaluates different interventions according to HPV status that will lead to changing clinical practice yet, and there is no specific treatment based on HPV status. There is need for future research, encouraging investigators to report on clinical outcomes, evaluating the overall response rates to specific treatments, and to consider new biomarkers to establish more accurate prognostics factors.

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• Siegel RL , et al
• Weiderpass E ,
• Bruni L , et al
• Schiffman M ,
• Doorbar J ,
• Wentzensen N , et al
• Cancer Genome Atlas Research Network
• Albert Einstein College of Medicine
• Analytical Biological Services
• zur Hausen H
• Howell-Jones R ,
• Li N , et al
• WHO Classification of Tumours Editorial Board
• Franceschi S ,
• Howell-Jones R , et al
• Perkins RB ,
• Simelela PN
• Snijders PJF ,
• Meijer CJLM , et al
• de Sanjose S ,
• de Sanjose S
• Oštrbenk Valenčak A ,
• Gimpelj Domjanič G , et al
• Chrysostomou AC ,
• Kostrikis LG
• Abreu ALP ,
• Gimenes F , et al
• Arroyo LS ,
• Bzhalava D , et al
• Arroyo Mühr LS ,
• Bzhalava D ,
• Lagheden C , et al
• Tsakogiannis D ,
• Gartzonika C ,
• Levidiotou-Stefanou S
• Kocjan BJ ,
• Oštrbenk A , et al
• Sheng Y , et al
• Liebrich C ,
• Luyten A , et al
• Johansson H ,
• Ekström J , et al
• Bzhalava Z ,
• Hortlund M , et al
• Lagheden C ,
• Lei J , et al
• Jiang W , et al
• Kim J , et al
• Shikano K ,
• Ito K , et al
• Schmidt M ,
• Frankowski A , et al
• Brewer CA ,
• Wilczynski SP , et al
• Kiyokawa T ,
• Kondo T , et al
• Nicolás I ,
• Marimon L ,
• Houghton O ,
• Jamison J ,
• Wilson R , et al
• Thoppe SR , et al
• Hu X , et al
• Sedaghat Y ,
• Sabripour M , et al
• Banister CE ,
• Pirisi L , et al
• Frederick P ,
• Planchamp F , et al
• Tewari KS ,
• Penson RT , et al
• Studer HU , et al
• Nagata K , et al
• Jeannel D , et al
• Rodríguez-Carunchio L ,
• Soveral I ,
• Steenbergen RDM , et al
• Cheung TH ,
• Chung TK , et al
• Han HS , et al
• Kimple RJ ,
• Blitzer GC , et al
• Stolnicu S ,
• Hoang L , et al
• Karlsson MG ,
• Sorbe B , et al
• Zhu L-X , et al
• Olawaiye AB ,
• Washington MK , et al
• Gaglia MM ,
• Ferreira DA ,
• Niller HH ,
• Minarovits J
• Regauer S ,
• Frenel J-S ,
• Le Tourneau C ,
• O'Neil B , et al
• Naumann RW ,
• Hollebecque A ,
• Meyer T , et al
• Mezache L ,
• Paniccia B ,
• Nyinawabera A , et al
• Andersen AS ,
• Koldjaer Sølling AS ,
• Ovesen T , et al

Supplementary materials

Supplementary data.

This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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Twitter @AndreFernandes2, @dviverosc, @oncohoegl, @RParejaGineOnco

Contributors AF, DV and RP designed the research; DV, JH and MA searched and reviewed the data; AF, DV, JH, MA wrote the paper; RP made the editorial revision. All the authors reviewed the manuscript and approved the final version.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer reviewed.

Linked Articles

• Editorial Human papillomavirus-independent cervical cancer: what are the implications? Samantha H Batman Kathleen M Schmeler International Journal of Gynecologic Cancer 2021; 32 8-8 Published Online First: 29 Nov 2021. doi: 10.1136/ijgc-2021-003250
• Letter Correspondence on "Human papillomavirus-independent cervical cancer" by Fernandes et al Sigrid Regauer Olaf Reich Karl Kashofer International Journal of Gynecologic Cancer 2022; 32 581-581 Published Online First: 15 Feb 2022. doi: 10.1136/ijgc-2022-003368

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• HPV vaccine: the key...

HPV vaccine: the key to eliminating cervical cancer inequities

Linked research.

Effect of the HPV vaccination programme on incidence of cervical cancer and grade 3 cervical intraepithelial neoplasia by socioeconomic deprivation in England

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• Peer review
• Trisha L Amboree , postdoctoral fellow 1 ,
• Joslyn Paguio , advocate for patients with cervical cancer 2 ,
• Kalyani Sonawane , associate professor 3
• 1 The University of Texas MD Anderson Cancer Center, Houston, TX, USA
• 2 Patient author, The Cervivor Advocacy Group, CA, USA
• 3 MUSC Hollings Cancer Center, Charleston, SC 29464, USA
• Correspondence to: K Sonawane sonawane{at}musc.edu

Programmes must ensure equitable access for all eligible groups

The human papillomavirus (HPV) vaccine protects individuals from HPV strains that cause cancer. Evidence of its effectiveness in eliminating invasive cervical cancers is growing. 1 2 3 4 In a linked paper, Falcaro and colleagues (doi: 10.1136/bmj-2023-077341 ) provide further evidence for the impact of HPV vaccination in eliminating invasive cancers. 5 They also answered the vexed question of whether national HPV vaccination programmes magnify or narrow cervical cancer inequities.

Women from lower socioeconomic backgrounds share a disproportionately greater burden of cervical cancer incidence and mortality. 6 Notably, socioeconomic inequities in cervical cancer are reported across high, middle, and low income countries. 7 8 9 Falcaro and colleagues’ findings underscore the importance of the HPV vaccine as an effective tool for reducing inequalities in cervical cancer, making a clear case for equitable access to the vaccine.

In their nationwide study, Falcaro and colleagues found that HPV vaccination reduced cervical cancer risk and grade 3 cervical intraepithelial neoplasia by 83.9% (95% confidence interval 63.8% to 92.8%) and 94.3% (92.6% to 95.7%), respectively, in the contemporary birth cohort of women offered vaccination routinely at age 12-13 years in England. Invasive cervical cancers decreased by more than 80% in all socioeconomic groups among vaccinated girls and women, preventing an estimated 687 cervical cancers by mid-2020. Interestingly, vaccine effectiveness (the proportion of cervical cancers averted) was consistent regardless of socioeconomic status. This finding suggests that marginalized groups may benefit from the HPV vaccine despite poor social determinants of health or higher prevalence of risk factors such as smoking, alcohol consumption, and reduced uptake of cancer screening. 10 11 12 13 14

Vaccine equity

Foundational to the success of England’s universal HPV immunization programme was the consideration of equitable access. More than 100 countries have introduced HPV vaccination programmes, and inequities in vaccine access and availability are documented. 15 To successfully eliminate cervical cancers, policy makers must develop, implement, or redesign programmes to ensure equal access to the HPV vaccine for all individuals, regardless of their income. For example, the Vaccines for Children programme in the US provides free HPV vaccination to children from a low income household, as a result of which vaccine coverage in teenagers from such households is comparable to (and exceeds) coverage among teenagers from high income households. 16 Similarly, the national immunization programme in Australia, introduced in 2007 and providing free HPV vaccination to schoolchildren aged 12-13 years, led to rapid uptake and attainment of 80% vaccine coverage. 17 The human and monetary consequences of cervical cancer and treatment averted through HPV vaccination outweigh the costs of making it accessible to all age eligible individuals. 18

Another notable finding from Falcaro and colleagues’ study is the incremental effect of building up HPV vaccine coverage in successive birth cohorts. Typically, the effect of a public health programme is often not fully evident during the early phases due to lag time in population uptake. In England, for instance, HPV vaccine coverage (a proxy for herd protection from HPV) increased from 38.9% to 48.1% in individuals born between September 1990 and August 1993 to 70.8-75.7% in those born between September 1993 and August 1995 and to 80.9-88.0% in those born between September 1995 and August 2000. The reduction in cervical cancer risk in these three cohorts was incremental—35.5%, 71.3%, and 86.0%, respectively.

Inherently, these data also emphasize the importance of attaining the 90% coverage target recommended by the World Health Organization. 19 Currently, HPV vaccine coverage is below target in many countries despite being offered for several years. 20 Inequities in vaccine access, hesitancy, and variation in the extent to which healthcare providers recommend vaccination create a major challenge to target attainment in countries with existing HPV vaccine programmes. 21 22 23 24 Additionally, upstream factors (finances, health system capacity, supply, and vaccine prioritization) can deter introduction and scale-up in countries with no programmes. 25 To overcome the challenges of reaching target coverage and to maximize population herd immunity, collective efforts of government, community stakeholders, and healthcare professionals in these countries will be necessary.

In conclusion, the HPV vaccine is the key to eliminating cervical cancer inequalities. An equity driven approach is critical for the success of HPV vaccination programmes.

Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: Dr. Sonawane has consulted Value Analytics Labs on unrelated projects.

Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf .

Provenance and peer review: Commissioned; not externally peer reviewed.

• Elfström KM ,
• Palmer TJ ,
• Kavanagh K ,
• Cuschieri K ,
• Falcaro M ,
• Castañon A ,
• Skorstengaard M ,
• Thamsborg LH ,
• Lorenzoni V ,
• Amboree TL ,
• Damgacioglu H ,
• Sonawane K ,
• Montealegre JR ,
• Deshmukh AA
• Vaccarella S ,
• Lortet-Tieulent J ,
• Saracci R ,
• De Vries E ,
• Sierra MS ,
• Georges D ,
• Pappas-Gogos G ,
• Douglas E ,
• Currin LG ,
• Linklater KM ,
• NCD Global Health Research Group ,
• Association of Pacific Rim Universities (APRU)
• Khanduri A ,
• Pingali C ,
• Elam-Evans LD ,
• Brotherton J ,
• Macartney K ,
• Rosettie KL ,
• Sparks GW ,
• ↵ World Health Organization. Human papillomavirus vaccines: WHO position paper, December 2022. Weekly Epidemiological Record, WER No 50, 2022, 97, 645-72.
• ↵ World Health Organization. HPV immunization coverage estimates among primary target cohort (9-14 years old girls) (%). Retrieved from The Global Health Advisory. WHO, March 31 2023. https://www.who.int/data/gho/data/indicators/indicator-details/GHO/girls-aged-15-years-old-that-received-the-recommended-doses-of-hpv-vaccine
• Sabeena S ,
• Arunkumar G
• Watson-Jones D
• Guillaume D ,
• Waheed DE ,
• Schleiff M ,
• Muralidharan KK ,
• Vorsters A ,

Cervical cancer

Affiliations.

• 1 Department of Gynaecological Oncology, Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia, WA, Australia; Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Crawley, Western Australia, WA, Australia. Electronic address: [email protected].
• 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, TX, USA.
• 3 Medical Oncology Department, Gynaecological Tumour Unit, Vall d'Hebron University Hospital, Vall d'Hebron, Institute of Oncology (VHIO), Barcelona, Spain.
• 4 Department Obstetrics and Gynaecology, University of Cape Town, Cape Town, South Africa; South African Medical Research Council, Gynaecological Cancer Research Centre, Tygerberg, South Africa.
• PMID: 30638582
• DOI: 10.1016/S0140-6736(18)32470-X

Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300 000 deaths worldwide. High-risk subtypes of the human papilloma virus (HPV) are the cause of the disease in most cases. The disease is largely preventable. Approximately 90% of cervical cancers occur in low-income and middle-income countries that lack organised screening and HPV vaccination programmes. In high-income countries, cervical cancer incidence and mortality have more than halved over the past 30 years since the introduction of formal screening programmes. Treatment depends on disease extent at diagnosis and locally available resources, and might involve radical hysterectomy or chemoradiation, or a combination of both. Conservative, fertility-preserving surgical procedures have become standard of care for women with low-risk, early-stage disease. Advances in radiotherapy technology, such as intensity-modulated radiotherapy, have resulted in less treatment-related toxicity for women with locally-advanced disease. For women with metastatic or recurrent disease, the overall prognosis remains poor; nevertheless, the incorporation of the anti-VEGF agent bevacizumab has been able to extend overall survival beyond 12 months. Preliminary results of novel immunotherapeutic approaches, similarly to other solid tumours, have shown promising results so far.

Copyright © 2019 Elsevier Ltd. All rights reserved.

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• Chemoradiotherapy
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• Papillomavirus Vaccines / immunology
• Risk Factors
• Uterine Cervical Neoplasms* / diagnosis
• Uterine Cervical Neoplasms* / epidemiology
• Uterine Cervical Neoplasms* / prevention & control
• Uterine Cervical Neoplasms* / therapy
• Papillomavirus Vaccines

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Human papilloma virus articles from across Nature Portfolio

Human papilloma virus (HPV) is an infectious agent belonging to the virus family Papillomaviridae, members of which have tropism for cutaneous epithelium and mucosal epithelium. There are more than 120 different HPV types, with HPV-16 and HPV-18 having a strong association with cervical cancer.

Latest Research and Reviews

Concomitant human papillomavirus (HPV) vaccination and screening for elimination of HPV and cervical cancer

Here the authors report baseline results of a population-based trial testing concomitant human papillomavirus (HPV) vaccination and HPV-based screening of young women in Sweden and, using a transmission model, suggest that this approach may reduce high-risk HPV infections.

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Global evaluation of lineage-specific human papillomavirus capsid antigenicity using antibodies elicited by natural infection

Human Papillomaviruses (HPV) are classified in lineages based on their sequence. Here, the authors test neutralizing activity of sera from naturally infected women against vaccine-preventable HPV variants, delineating lineage-specific antibody responses.

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A prospective clinical trial of diathermy ablation for patients with high-grade cervical intraepithelial neoplasia from a single institution in Japan

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HPV16E1 downregulation altered the cell characteristics involved in cervical cancer development

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The role of keratinocyte subpopulations in the different phases of the viral cycle during HPV16 infection remains to be characterised. Here, single cell RNA sequencing of HPV16 infected and uninfected organoids identifies 12 distinct keratinocyte populations including an HPV-reprogrammed keratinocyte subpopulation that is linked to cancer.

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News and Comment

A refined view of tumour-associated B cells

Wieland et al. report that the tumour microenvironment of human papillomavirus (HPV)-positive head and neck squamous cell carcinomas contains HPV-specific B cells that actively secrete HPV-specific antibodies.

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Toll of vaccine hesitancy

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Benevolent viruses in skin cancer

Strickley, Messerschmidt et al. show that beta human papilloma virus (β-HPV) infection itself is not causal in cutaneous squamous cell carcinoma (SCC) development in the context of immunosuppression — instead, the loss of β-HPV-mediated T cell immunity promotes SCC.

• Ulrike Harjes

TIL infusions effective in HPV-associated cancers

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JCVI defers decision on HPV

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Cervical Cancer Research

For some people with early-stage cervical cancer, a surgical procedure called a simple hysterectomy may be a safe and effective alternative to treatment with a radical hysterectomy, results from the SHAPE trial show.

It may be worthwhile for some individuals between ages 65 and 69 to get tested for HPV, findings from a Danish study suggest. Specifically, the testing may help prevent cervical cancer among those who haven’t had cervical cancer screening for at least 5 years.

One dose of the HPV vaccine was highly effective in protecting young women against infection from high-risk HPV types, a study in Kenya found. A single dose would make HPV vaccines more accessible worldwide, reducing cervical cancer’s global burden.

The rates of timely cervical cancer screening fell between 2005 and 2019, researchers found, and disparities existed among groups of women. The most common reason for not receiving timely screening was lack of knowledge about screening or not knowing they needed screening.

Fewer women with early-stage cervical cancer are having minimally invasive surgery, including robotic, as part of their treatment, a new study shows. The shift toward more open surgeries follows the release of results from the LACC trial in 2018.

Widespread HPV vaccine use dramatically reduces the number of women who will develop cervical cancer, according to a study of nearly 1.7 million women. Among girls vaccinated before age 17, the vaccine reduced cervical cancer incidence by 90%.

Updated cervical cancer screening guidelines from the American Cancer Society recommend HPV testing as the preferred approach. NCI’s Dr. Nicolas Wentzensen explains the changes and how they compare with other cervical cancer screening recommendations.

In a new study, an automated dual-stain method using artificial intelligence improved the accuracy and efficiency of cervical cancer screening compared with the current standard for follow-up of women who test positive with primary HPV screening.

More than a decade after vaccination, women who had received a single dose of the HPV vaccine continued to be protected against infection with the two cancer-causing HPV types targeted by the vaccine, an NCI-funded clinical trial shows.

Women with cervical or uterine cancer who received radiation to the pelvic region reported side effects much more often using an online reporting system called PRO-CTCAE than they did during conversations with their clinicians, a new study shows.

A research team from NIH and Global Good has developed a computer algorithm that can analyze digital images of the cervix and identify precancerous changes that require medical attention. The AI approach could be valuable in low-resource settings.

A new test can help to improve the clinical management of women who screen positive for HPV infection during routine cervical cancer screening, an NCI-led study has shown.

FDA has approved pembrolizumab (Keytruda) for some women with advanced cervical cancer and some patients with primary mediastinal large B-cell lymphoma (PMBCL), a rare type of non-Hodgkin lymphoma.

By comparing the genomes of women infected with a high-risk type of human papillomavirus (HPV), researchers have found that a precise DNA sequence of a viral gene is associated with cervical cancer.

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified novel genomic and molecular characteristics of cervical cancer that will aid in subclassification of the disease and may help target therapies that are most appropriate for each patient.

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HPV vaccine slashes cervical cancer rates across society

16 May 2024

The NHS HPV vaccination programme is preventing the highest number of cervical cancer cases in the most deprived groups, according to our latest study of data from England .

The findings, which reflect the fact that more deprived groups have higher rates of cervical cancer, show that the HPV vaccine is reaching people from all backgrounds.

In 2021, the same research team, led by Professor Peter Sasieni, found that offering the HPV vaccine to girls aged between 12 and 13 prevents almost 9 in 10 cervical cancers . Still, some scientists had been concerned that differing levels of vaccine uptake could be increasing cervical cancer inequalities.

There’s more work to do to address those inequalities, but it’s now clear the HPV vaccine is a big part of the solution. Sasieni’s team at Queen Mary University of London estimates that it has prevented more than three times as many cases in the most deprived group in England (around 190) than in the least (around 60).

Our research highlights the power of HPV vaccination to benefit people across all social groups. Historically, cervical cancer has had greater health inequalities than almost any other cancer and there was concern that HPV vaccination may not reach those at the greatest risk. Instead, this study captures the huge success of the school-based vaccination programme in helping to close these gaps and reach people from even the most deprived communities. In the UK, the elimination of cervical cancer as a public health problem in our lifetime is possible with continued action to improve access to vaccination and screening for all.

More work to do to prevent cervical cancer

Around 3,300 people are diagnosed with cervical cancer in the UK every year.* Research has shown that the HPV vaccine, combined with cervical screening, can bring that number right down.   

However, the percentages of eligible people receiving an HPV vaccine and attending screening have both fallen in the wake of the COVID pandemic.   

And, although this research shows that the HPV vaccine is preventing cervical cancer in all socioeconomic groups, rates are still higher in people from deprived backgrounds.  

That’s why we’re calling on the government to do more to ensure that as many young people as possible get the HPV vaccination. We’re also pushing for better reporting on uptake by deprivation and ethnicity, along with more research, to help us understand how to reach those most at risk.  

Our scientists helped to prove the link between HPV and cervical cancer 25 years ago . That discovery made it clear that we could use HPV vaccines to prevent cervical cancer. It also helped improve cervical cancer screening.

Thanks to these scientific developments, cervical cancer rates in the UK have fallen by almost a third since the early 1990s.**

Who is eligible for the HPV vaccine?

After decades of research, the HPV vaccination programme was first introduced for girls aged 12-13 in England in 2008. Since September 2019, the vaccine has also been available to boys of the same age. Anyone who missed their vaccine can request it through the NHS up to the age of 25.   

The vaccine is also available to men who have sex with men and some transgender people up to the age of 45 through sexual health and HIV clinics.  

We encourage people to take up the HPV vaccine if they are eligible. If you are concerned that you or your child has missed out on the HPV vaccine, you can contact your child’s school nurse, school immunisation service or GP surgery to find out more.

Gem’s story

36-year-old Gem Sofianos, from London, found out that she had cervical cancer after a screening appointment in 2015.

The HPV vaccination programme launched after Gem had left school. Now she’s a strong advocate that eligible people should take up the offer of the vaccine, as well as cervical screening.

Gem said: “If I had been offered the vaccine when I was younger, I wouldn’t have hesitated to take it up. My younger sister was given the HPV vaccine in the first rollout at school. It gives me comfort knowing that she and others are protected against HPV, and therefore less likely to develop cervical cancer.”

Gem was 28 when she was diagnosed. “I was young and healthy and hadn’t experienced any symptoms, so to be told I had cervical cancer took me completely by surprise. It was a lot to take in.”

Because Gem’s cancer was caught early, she had surgery a month later and the treatment was successful. Gem is now free from cancer, but she still attends regular screening.

“I still suffer from the aftermath of my diagnosis,” she said, “and I hope one day we live in a world where cervical cancer is eliminated. With advances in research and more people getting the HPV vaccine, this could be a reality.”

* Based on the average annual number of new cases of cervical cancer (ICD10 C53) diagnosed in the United Kingdom in the years 2017-2019.

* Based on the percentage change in incidence rates from 14 cases per 100,000 women in the UK between 1991-1993 to 10 cases per 100,000 women between 2017-2019.

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Prevention Strategies and Early Diagnosis of Cervical Cancer: Current State and Prospects

Viktor v. kakotkin.

1 Scientific and Educational Cluster MEDBIO, Immanuel Kant Baltic Federal University, A. Nevskogo St., 14, 236041 Kaliningrad, Russia

Ekaterina V. Semina

Tatiana g. zadorkina.

2 Kaliningrad Regional Centre for Specialised Medical Care, Barnaulskaia Street, 6, 236006 Kaliningrad, Russia

Mikhail A. Agapov

Associated data.

Data sharing not applicable. No new data were created or analysed in this study. Data sharing is not applicable to this article.

Cervical cancer ranks third among all new cancer cases and causes of cancer deaths in females. The paper provides an overview of cervical cancer prevention strategies employed in different regions, with incidence and mortality rates ranging from high to low. It assesses the effectiveness of approaches proposed by national healthcare systems by analysing data published in the National Library of Medicine (Pubmed) since 2018 featuring the following keywords: “cervical cancer prevention”, “cervical cancer screening”, “barriers to cervical cancer prevention”, “premalignant cervical lesions” and “current strategies”. WHO’s 90-70-90 global strategy for cervical cancer prevention and early screening has proven effective in different countries in both mathematical models and clinical practice. The data analysis carried out within this study identified promising approaches to cervical cancer screening and prevention, which can further enhance the effectiveness of the existing WHO strategy and national healthcare systems. One such approach is the application of AI technologies for detecting precancerous cervical lesions and choosing treatment strategies. As such studies show, the use of AI can not only increase detection accuracy but also ease the burden on primary care.

1. Introduction

It was in 1996 that the World Health Association, the European Research Organization on Genital Infection and Neoplasia and the National Institutes of Health Consensus Conference on Cervical Cancer recognised the role of human papillomavirus (HPV) in cervical cancer development [ 1 ]. According to the degree of association with invasive tumours, HPV genotypes have been subdivided into those posing high oncogenic risk, low oncogenic risk and undetermined risk. High oncogenic risk (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) is related to an increased risk of developing cervical cancer [ 2 ]. Low oncogenic risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, 89) is associated, in most cases, with no disease or benign epithelial lesions, such as anogenital and oropharyngeal warts [ 3 ]. Finally, undetermined risk HPVs (3, 7, 10, 27, 28, 29, 30, 32, 34, 55, 57, 62, 67, 69, 71, 74, 77, 83, 84, 85, 86, 87, 90, 91) include individuals whose oncogenicity has not yet been fully defined [ 4 , 5 ]. There are World Health Organization (WHO) strategies for cervical cancer prevention and screening, yet the annual cervical cancer incidence and mortality rates still force the global community to explore ways to improve current approaches for its prevention and early detection [ 1 ].

In 2018, according to WHO, the number of new cervical cancer cases was 569,847 (third most common among oncological diseases), and the number of deaths from the disease was 311,365 (accounting for one-third of all cancer deaths in females), exceeding colorectal cancer deaths in females and males combined (310,394). In 2020, at the peak of the COVID-19 pandemic, these numbers were 604,127 (third) and 341,831 (third), respectively [ 6 , 7 ]. However, the incidence varies widely, ranging from 4.1 per 100,000 women in West Asia to 40.1 per 100,000 women in East Africa, with mortality rates varying from 1.6 per 100,000 women in Australia and New Zealand to 28.6 per 100,000 women in East Africa [ 7 , 8 , 9 ].

Several problems hinder a considerable and steady reduction in new cases and overall mortality from cervical cancer. These are limited opportunities for primary prevention in low- and middle-income countries (in June 2020, only 107 [55%] WHO member countries were vaccinated against HPV, while the global estimated immunisation rate was about 15% of the adequate level), and there is difficulty in providing early screening for precancerous cervical lesions [ 9 , 10 , 11 ]. Nowadays, the most common ways to ensure the timely and effective treatment of precancerous cervix lesions include studying targeted treatment strategies, identifying early molecular markers and determining the effect of vaginal microbiota on virus clearance [ 12 , 13 , 14 ]. One of the least studied areas for improving screening programs is the application of artificial intelligence to ensure high-quality screening in regions lacking qualified specialists [ 15 ].

This study explores major problems of cervical cancer prevention strategies in several regions with varying incidence and mortality rates.

2. Materials and Methods

An analysis of data published in the National Library of Medicine (Pubmed database) over the past five years has made it possible to assess the effectiveness of various approaches proposed by the national healthcare systems of the study regions. The search was conducted using the following keywords: “cervical cancer prevention”, “cervical cancer screening”, “barriers to cervical cancer prevention”, “premalignant cervical lesions” and “current strategies”. At the final stage, we searched and analysed publications focusing on new approaches to cervical cancer screening and prevention, which can further increase the effectiveness of the existing WHO strategy and national healthcare systems.

3. Current Cervical Cancer Prevention Strategies

In order to reduce the global cervical cancer incidence rate and decrease the social significance of this problem, in 2020, WHO adopted a global strategy to accelerate the elimination of cervical cancer. The strategy takes into account the existing differences in the capabilities of national healthcare systems [ 16 ]. The strategy sets the following target indicators (the 90-70-90 targets): 90% of girls vaccinated against HPV by the age of 15; 70% of women having undergone primary screening by the age of 35 and, for the second time, 45; 90% of women with precancerous cervical lesions and 90% of women with invasive cancer timely treated. The World Health Organization and other guidelines recommend HPV testing, including the Pap test, which is now considered a secondary procedure [ 1 ]. In the event of a positive or abnormal result, the HPV-DNA test procedure will involve colposcopy and a related biopsy [ 1 , 5 ]. Conversely, if HPV tests and cytological examination results are discordant, repeating the HPV-DNA test one year later and at 12–24 months (in the case of negative results or colposcopy in women who have tested positive) is recommended. Finally, in cases of CIN2 histological diagnoses, patients should be offered a surgical solution followed by a targeted follow-up over time [ 1 ].

According to the numerical model provided by the strategy developers, the implementation of the strategy can decrease the median incidence rate by 42% by 2045 and 97% by 2120 [ 16 ].

As the full worldwide implementation of this global strategy is difficult to achieve, it is reasonable to consider current national strategies for cervical cancer prevention and early detection.

3.1. Countries with Low Incidence and Mortality Rates

Australia is a representative example of an effective national cervical cancer prevention strategy with cervical cancer incidence and mortality rates at 5.6 and 1.6 cases per 100,000, respectively, as estimated in GLOBOCAN [ 7 ]. The key feature of its HPV immunisation programme is vaccinating both girls and boys with tetravalent and nonavalent vaccines [ 17 , 18 ]. Australian highly standardised cervical pre-cancer screening programme ( Figure 1 ) differs from the strategy developed by WHO [ 1 , 19 ].

The Australian model of early screening of precancerous cervical lesions (Reprinted from Ref. [ 15 ] (do not require permission)). LBC stands for liquid-based cytology; ASC-UC, atypical squamous cells of undetermined significance; ASC-H, atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions; LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion.

Despite the national strategy’s proven effectiveness, the country actively seeks ways to improve it within the ‘Pathways-Cervix’ project [ 19 ]. Some of the proposed revisions are listed below.

3.2. Countries with High Incidence and Mortality Rates

Eastern and Southern Africa both have the highest cervical cancer incidence and mortality rates. Thus, the effect of implementing the WHO strategy should be most profound in its countries [ 1 , 7 , 16 ]. We provide an analysis of the available data on the region’s current cervical cancer prevention strategies below.

According to GLOBOCAN 2020, the incidence and mortality rates in the Southern African Region were 36.4 and 20.6 per 100,000 women, respectively [ 7 ]. At the same time, Cari van Schalkwyk et al. from South Africa stated that the activities carried out in the country within the framework of the WHO global strategy prevented approximately 8600 cases of cervical cancer over the past 20 years [ 20 ]. They emphasise that WHO’s strategies focus on reducing incidence and mortality rates in the long term (targets set for 2045 and 2120). At the same time, given the current incidence rate, there is a need to search for ways to enhance existing prevention strategies affecting epidemiological indicators in the coming years and decades [ 20 , 21 ]. According to van Schalkwyk et al., the following issues are the major barriers to achieving acceptable incidence and mortality rates in the near future:

• The use of bivalent vaccines against HPV rather than polyvalent ones [ 20 , 21 ];
• Lower vaccine effectiveness in HIV-infected females [ 20 , 22 , 23 ];
• Persistent HPV infection in at least 15% of patients treated for precancerous cervical lesions [ 20 , 24 ];
• The use of LBC rather than HPV-DNA testing as a primary screening method [ 20 , 25 ].

According to estimates, amendments to the national cervical cancer prevention strategy in South Africa made in response to the above issues can contribute to the achievement of WHO-recommended levels in 10–12 years [ 20 ].

As discussed, the countries of East Africa show the highest cervical cancer incidence and mortality rates [ 7 ]. Healthcare systems and prevention strategies differ across countries in this region. However, individual publications provide a general understanding of how the WHO global strategy is implemented there [ 26 , 27 , 28 ]. For example, Corrado et al. from Uganda report that visual inspection with acetic acid (VIA) has an extremely low positive predictive value (PPV) of about 16%. as a method of primary screening for precancerous cervical lesions. At the same time, they note that its effectiveness does not depend much on the experience of the specialist or the location of the test (at a specialised centre or “at home”) [ 26 ]. Mchome et al. from Tanzania provided statistical data from the CONCEPT study, without referring explicitly to a national cervical cancer prevention strategy or describing HPV vaccination coverage [ 27 ]. In the country, 18.9% of women have HPV [ 27 ]. Describing an attempt at screening for precancerous cervical lesions in northwestern Ethiopia, Destaw et al. cited disappointing statistics: out of 493 women selected for the study, only 76 (16.4%) were screened (VIA) [ 28 ]. The authors do not provide data on the existence of a national strategy for cervical cancer prevention, indicating insufficient awareness of the disease and a low literacy rate as the main factors impeding adequate screening [ 28 ].

3.3. Countries with Intermediate Incidence and Mortality Rates

Jingfen Zhu et al. from China pointed out that despite China’s rather low cervical cancer incidence and mortality rates (10.2 and 5.3 per 100,000, respectively) compared to the above regions, the prevention and early detection of precancerous lesions in this country are acute problems [ 7 , 29 ]. China accounts for 11.9% of the global cervical cancer mortality rate, with the number of new cases per day reaching 12.3% of the global number in 2017 [ 30 , 31 ]. Jingfen Zhu names the high cost of vaccines as the main obstacle to mass HPV vaccination in the country [ 24 ]. In 2009, to achieve the cervical pre-cancer screening targets, China initiated the National Cervical Cancer Screening Program in Rural Areas (NACCSPRA). It involves DNA-HPV testing in some provinces, as well as extensive cytology and colposcopy coverage [ 29 ]. By 2019, the measures allowed engaging approximately 120 million women in the screening (21.4% of the required number). However, recent mathematical models reflect a continuing trend towards a growth in the incidence rate in the coming years. This could be due to an increase in the early detection of cervical cancer and quite a low uptake of preventive measures in females [ 30 , 32 ]. According to Jingfen Zhu et al., the main reason for the low effectiveness of screening in China is insufficient funding for the NACCSPRA programme, hindering the development of information systems, ways of promoting public awareness and the expansion of public engagement [ 30 ].

Indirect data show that, in 2020, the cervical cancer incidence and mortality rate in Russia were 14.1 and 6.1 cases per 100,000, respectively (the International Agency for Research on Cancer, November 2022) [ 33 , 34 ]. According to Tatarinova et al., the cervical cancer detection rate during active screening does not exceed 40%. It is impossible to keep track of participation in primary prevention programmes despite the presence of a national strategy for early screening of precancerous cervical diseases [ 34 , 35 ]. The main problems impeding the widespread implementation of the WHO strategy in Russia are as follows [ 36 ]:

• No HPV vaccination in the national immunisation schedule;
• No domestic HPV vaccine is allowed for use;
• No binding national standards on the early screening of precancerous cervical lesions.

3.4. Problems Common to Current National Strategies

It is generally accepted that state revenues determine a country’s ability to follow WHO’s global strategy to accelerate the elimination of cervical cancer [ 1 , 7 , 16 ], yet some problems are common to all countries.

According to recent reports by the WHO and the United Nations Children’s Fund (UNICEF), in 2019, less than a third of girls lived in countries with mandatory HPV vaccinations on national schedules. Moreover, even among them, many were not immunised regardless of the state’s revenue level [ 37 , 38 ]. Jacqueline Spayne et al. estimated that, in 2018, 15-year-old girls vaccinated against HPV accounted for only 12.5% of the global cohort (61 million); up to 7000 of them, almost all from low-income countries (LICs), run a high risk of dying from cervical cancer [ 38 ].

One of the major problems in primary prevention, inherent in not only low-income but also middle- (MICs) and high-income (HICs) countries, is the low awareness among both women and men of the disease and its prevention [ 39 , 40 , 41 ]. For instance, a survey of young sexually active men in the United States conducted by Jennifer A. Sledge et al. shows that only 64% of them had heard of the infection caused by HPV, while 86% did not know of the vaccines against HPV for women [ 42 ]. A survey among Korean adult men, conducted by Hae Won Kim et al., indicated that the majority of respondents, half of them married, were not familiar with the ways to effectively prevent the disease or understand its social significance [ 40 ]. Raising the population’s awareness of cervical cancer prevention and early detection requires not only scaling the use of modern digital technologies but also the active engagement of men [ 41 , 42 , 43 , 44 ].

Another equally important issue is switching from the screen-and-treat principle to the screen, triage and treat principle when managing patients with cervical abnormalities, including pre-cancer abnormalities [ 1 , 45 , 46 ]. Van Nghiem et al. from the USA argued that the “screen-and-treat” (see-and-treat) strategy makes it possible to reduce the number of women who drop out when colposcopy is required on the one hand; on the other hand, it entails excessive treatment and may be economically unviable in some cases [ 46 ]. Despite the fact that it significantly increases the burden on primary care and the number of invasive procedures, this approach to the treatment of precancerous cervical lesions has become common in LICs as they lack funds for high-quality triage [ 47 , 48 ]. Considering different situations across regions, the wider adoption of the “screen, triage and treat” strategy requires its modification with a view toward optimizing follow-up schedules and establishing clear indications for the mandatory invasive treatment of cervical diseases [ 1 , 19 , 48 , 49 ].

4. Prospects for Improving Primary Prevention

Table 1 shows the main challenges faced by countries that try to achieve the goals of the WHO strategy for cervical cancer prevention.

Problems facing countries with different revenue levels in implementing the Global Strategy to Accelerate the Elimination of Cervical Cancer as a Public Health Problem.

The data analysis indicates that the common causes of failure to implement the principles of the strategy are the need for large-scale public investments for preventive healthcare, the heavy burden on primary care and the lack of HPV vaccines in MICs and LICs. One of the most affordable ways to implement the primary prevention of cervical cancer is increasing public awareness of its contribution to female cancer deaths and the potential reversibility of precancerous changes in the cervix, yet there is room for development in all countries regardless of their revenues.

Although the targets of the WHO strategy are still far from being achieved, some countries continue to search for other ways to improve primary cervical cancer prevention. The literature review shows that most authors found the following measures promising beyond achieving the “90-70-90” targets:

• Studying the effectiveness of HPV vaccination in women over 35 years of age [ 70 , 71 , 72 ];
• Increasing vaccination uptake in men [ 19 , 73 , 74 ];
• Developing new HPV vaccines to expand preventive vaccination in MICs and LICs [ 75 , 76 ]

5. Prospects for Improving Secondary Prevention (Screening)

Although primary cervical cancer prevention can have a significant impact on the incidence rate in the long term, it does not reduce the incidence rate in women who are at risk right now. Even representatives of countries with the lowest cervical cancer incidence and mortality rates recognise the need to improve the “screen, triage and treat” strategy [ 19 ]. Table 2 shows the promising areas of secondary prevention according to Velentzis et al. from Australia.

Promising ways to enhance secondary cervical cancer prevention according to Australia’s Scientific Advisory Committee (SAC) (Adapted from Ref. [ 15 ] (do not require permission)).

Several more actively studied ways to improve the “screen, triage, and treat” approach will be considered below.

5.1. Acceptability of Self-Sampling for Pre-Cancer Screening: Screen and Triage

Although the first reports on developing methods for self-collection for cervical screening date back to 1982, there were no further reports over the next 18 years on its effectiveness or implementation in healthcare [ 77 , 78 ]. For instance, in 1982, Noguchi wrote that the Kato technique for the cervical smear collection with a subsequent cytological study had similar results to the classical method of obtaining materials. However, no convincing statistical evidence was provided [ 77 ]. The next reports on the possibilities of vaginal smear self-collection, now for HPV testing, came at the beginning of the 21st century [ 78 , 79 ]. For example, in 2000, Sellors studied the collection of vulvar, vaginal and urethral samples for HPV detection by using a hybrid capture II assay (Digene Corp., Silver Spring, Md.) [ 78 ]. The results show that the sensitivity for self-collected samples ranged from 44.8% to 86.2%, and the specificity ranged from 53.5% to 69.7%. For the samples collected by physicians, the sensitivity was 98.3%, and the specificity was 52.1% [ 78 ]. In 2001, Gravitt et al. reported a high consistency of PCR results for HPV detection in cervical cancer patients when comparing self-collected and clinician-administered samples [ 79 ], yet at the end of the first decade of the twenty-first century, self-sampling was not a common method. Less than ten years ago, the global community again directed attention to the possibility of expanding cervical cancer screening via the self-collection of samples. Lazcano-Ponce et al. presented data on successful HPV screening in more than 100 thousand women using self-collected samples. However, the authors did not compare the effectiveness of this technique and the classical method [ 80 ]. Duke et al. from Canada calculated that self-sampling caused a fivefold increase in the intensity of screening compared to the classical approaches. However, the authors did not provide data on either the method’s sensitivity or specificity [ 81 ]. Comparing two vaginal self-collection methods and clinician-assisted sampling, Haguenoer et al. demonstrated a high efficiency of self-sampling and a high correspondence of its results to those obtained from the classical sampling (from 90 to 97%) [ 82 ]. The beginning of the COVID-19 pandemic coincided with an increase in the number of publications on self-sampling effectiveness. In addition, WHO officially recommended self-sampling as part of the cervical cancer prevention strategy [ 1 , 16 ]. Over the past three years, at least 80 papers have been published on this topic. There are ongoing investigations comparing the results of HPV testing of samples obtained via self-collection with the results of VIA, as well as population-based studies on the possibilities of implementing this technique in LICs and MICs or using it among the socially disadvantaged groups in HICs [ 83 , 84 , 85 ].

Currently, the most active research area is the detection of not only HPV DNA copies but also markers of malignancy in self-collected samples. For instance, back in 2014, Verhoef et al. concluded that it was possible to use DNA methylation-based triage on self-sampled specimens [ 86 ]. The study, having high statistical power, showed the similar effectiveness of molecular and cytology triage before referral for colposcopy [ 86 ]. Hesselink presented similar data showing the MAL-m1/miR-124-2 sensitivity for the detection of CIN3+ of up to 87.8% [ 87 ]. In 2022, authors from China presented data on the triage performance and predictive value of human gene methylation panels (ZNF671/ASTN1/ITGA4/RXFP3/SOX17/DLX1), including a combination of HPV16/18 genotyping, studied on self-collected samples [ 88 ]. To date, WHO does not regulate the use of such technologies for the early screening and prevention of cervical cancer, but further research in this direction looks promising.

5.2. Digital Technologies for Detection of Precancerous Cervical Lesions: Screen and Triage

Today, the use of digital technologies in cervical cancer screening can ease the burden on primary care. In 2018, Ravikumar et al. reported on enhancing Clinical Decision Support Systems (CDSS) intended to assist primary care clinicians in making decisions based on electronic medical records [ 52 ]. The introduction of this system to determine the tactics of patient treatment after cervical cancer screening made it possible to improve the care recommendation accuracy up to 94% [ 52 ].

Using artificial intelligence to interpret primary screening results is of particular interest for screening programme enhancement. In 2020, Elima Hussain et al. reported the completion of a training dataset for the automated assessment of Pap test results but did not submit a finished product [ 89 ]. In 2021, Li X et al. from China presented a neural network capable of replacing medical laboratory scientists in interpreting liquid-based cytology results in the future, potentially solving the problem of personnel shortages in MICs and LICs [ 90 ]. In the same year, Anabik Pal et al. from the USA presented a similar development with a diagnostic accuracy of 84.55% [ 91 ]. Pirovano et al. presented the results of machine learning on liquid-based cytology samples. The accuracy of abnormal smears detection was 95.2%, with only 66.8% accuracy on severity classification (LSIL and HSIL) [ 92 ]. As part of a study on the effectiveness of their automatic model, Xiangyu Tan et al. conducted a retrospective analysis of the accuracy of the system using the training dataset of 13,775 ThinPrep cytological test (TCT) images. Its sensitivity for ASCUS, LSIL and HSIL was 89.3%, 71.5%, and 73.9%, respectively, while the specificity of the proposed system in determining smear abnormalities was only 34.8% [ 15 ].

Another application of artificial intelligence in cervical pre-cancer detection is digital colposcopy using artificial intelligence to facilitate the work of a primary care physician. Liming Hu et al. in 2019 showed that their “deep learning”-based algorithm ensured a fairly accurate detection of CIN2 + by analysing cervical images. However, the authors were cautious in interpreting the study’s results [ 93 ]. Studying the possibility of using a machine learning algorithm for smartphone-based visual inspection after acetic acid (VIA), Bae et al. approached the possible introduction of digital technologies in limited-resource settings. However, the small size of the studied group does not allow us to draw conclusions on the potential of the proposed tool [ 94 ]. Xue et al. also suggested using artificial intelligence to improve the accuracy of cervical biopsy during colposcopy [ 95 ]. AI-guided colposcopy can be implemented in regions lacking highly qualified specialists [ 95 ]. Another approach increasingly employed to improve the quality of diagnostics using digital technologies is a cross-modal integration of data obtained during colposcopy, cytology and HPV testing [ 96 , 97 ].

5.3. Studying Vaginal Microbiome as an Integral Part of HPV Pathogenesis: Screen and Triage

The term “microbiome” was coined by Lederberg and McCray in 2001 to define a set of all microorganisms sharing one living space and interacting with the surrounding host tissues (human organism) [ 98 ]. For a long period of time, the only pathological conditions associated with a change in the composition of the normal vaginal microbiota (except for sexually transmitted infections) were bacterial vaginosis ( Gardnerella vaginalis ) and vaginal candidiasis [ 99 , 100 ]. Later, studies have shown that the state of the vaginal microbiome is a dynamic indicator influenced by many factors, such as sexual activity, hormonal disorders, hygienic habits, lactation, stress, diabetes, diet, region of residence and ethnicity [ 101 , 102 , 103 ]. In 2011, Ravel et al. performed the pyrosequencing of barcoded 16S rRNA genes of the vaginal samples of 396 women to cluster the “normal” female microbiome into 5 groups [ 104 ]. They presented their findings in the form of a heat map of log10-transformed proportions of microbial taxa found in vaginal bacterial communities ( Figure 1 in the original article) [ 104 ]. The first group included the types of microbiomes in which L. crispatus prevailed; the second type included L. gasseri ; the third included L. inners . The fourth type of microbiomes was characterised by the predominance of L. jensenii . All other microbiomes were assigned by the authors to the fifth type [ 104 ]. This approach made it possible to change the perception of the “normal” vaginal microflora. The fundamental mechanisms of bacterial microbiome’s effect on the processes in the cervix epithelium in the case of an HPV infection have not been studied sufficiently. According to the latest data, L. iners is not capable of producing D-lactic acid and reactive oxygen species, albeit Lactobacillus species usually produce lactic acid, H 2 O 2 and antimicrobial peptides such as bacteriocins and biosurfactants that inhibit the growth of bacteria and viruses and regulate vaginal homeostasis [ 101 , 105 ]. According to the results of the studies by Petrova et al. and Rampersaud et al., L. iners produces L-lactic acid and inerolysin (a pore-forming toxin cytolysin capable of damaging the cells of the vaginal mucosa), both contributing to pathogenic proliferation and infections [ 106 , 107 ]. Major research conducted in recent years confirms the role of microbiome in virus clearance and oncogenesis [ 108 , 109 ].

In 2017, Di Paola et al. found that Gardnerella , Prevotella , Megasphoera and Atopobium were present at sampling in 43% of women in the persistence group and only in 7% in the clearance group when examining the microbiome from women with high-risk HPV persistence [ 110 ]. They assumed that Atopobium spp and sialidase gene from Gardnerella vaginalis were independent markers of HPV persistence [ 110 ]. In 2020, based on a meta-analysis, Norenhag et al. [ 111 ] linked microbiota dominated by non-lactobacillus flora or L. Iners to a three to five times higher risk of dysplasia/cervical cancer for any prevalent HPV and two to three times higher risk of high-risk HPV, compared with L. crispatus . In 2021, Kang GU et al. reported that the microbiota composition in invasive cervical cancer and CIN is significantly different from the microbiome of healthy women. The authors suggested that Gardnerella and Streptococcus may be involved in carcinogenesis [ 112 ]. In 2020, Mitra et al., in a study of the effect of vaginal microbiome on spontaneous CIN2 regression and HPV clearance, obtained data suggesting that the predominance of non-lactobacillus flora ( Prevotella , Atopobium and Gardnerella ) was associated with virus persistence, and the predominance of L. crispatus and L. gasseri was associated with more frequent regression and clearance [ 14 ]. In the same year, Mei Yang et al. found that Trichomonas vaginalis and HPV16 co-infection were associated with a 1.71-fold increase in CIN 2-3 risk [ 113 ]. The results of a study published at the end of 2022 are interesting as well: Miriam Dellino et al. suggested that the long-term administration of oral Lactobacillus crispatus can restore eubiosis in women with HPV infections and hence achieve viral clearance. Total HPV clearance was shown in 9.3% of patients undergoing follow-up only, compared to 15.3% of patients in the group taking long-term (median 12 months (range 9–14 months)) oral Lactobacillus crispatus M247 ( p = 0.34) [ 114 ]. Despite the percentage of HPV-negative patients assessed with the HPV-DNA test at the end of the study period (being similar to the control group), further research studies in this direction seem promising.

A further study of the effect of vaginal microbiome on HPV clearance and persistence, as well as carcinogenesis, opens up new opportunities for both molecular-based triage and the treatment of patients with HPV or abnormal changes in the cervical epithelium.

6. Conclusions

At the moment, the ability of countries to achieve the targets of the WHO global strategy to accelerate the elimination of cervical cancer is limited by the level of their socioeconomic wellbeing.

To increase the effectiveness of primary prevention measures, researchers from different countries propose the following:

• Raising awareness of HPV risks and the virus’s role in oncogenesis among not only females but also males;
• Inclusion of HPV vaccination of boys in national immunisation schedules;
• Development of new HPV vaccines to expand vaccination to MICs and LICs.

To increase the effectiveness of secondary prevention measures (early screening for precancerous cervical lesions), the following is proposed.

• A more intensive study into the effectiveness of the analysis of self-collected samples;
• Search for molecular markers of carcinogenesis in self-collected samples;
• Using artificial intelligence to detect abnormalities in samples for PAP testing;
• Using artificial intelligence in guided cervical biopsies to improve the accuracy of histology;
• Development of diagnostic and therapeutic approaches for treatments based on vaginal microbiome analysis.

Funding Statement

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Data availability statement, conflicts of interest.

The authors declare no conflict of interest.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Time Between HPV Tests for Cervical Cancer Might Be Safely Extended

By Dennis Thompson HealthDay Reporter

WEDNESDAY, May 22, 2024 (HealthDay News) -- HPV testing to prevent cervical cancer might not have to happen as often as currently recommended, a new study says.

Current standards require women to undergo human papillomavirus (HPV) screening every five years. Nearly all cervical cancers are caused by HPV .

But researchers found that waiting eight years for follow-up HPV screening after a woman test negative for the virus is safe and effective.

The safety of an eight-year interval is the same as that of the standard three-year interval between a Pap smear, researchers report.

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“These findings should provide assurance that the five-year interval recommended for HPV screening is even safer than the three-year interval for cytology [Pap] screening,” said researcher Anna Gottschlich , an assistant professor at Wayne State School of Medicine, in Michigan.

During the past two decades, the United States has been transitioning from Pap smears to HPV-based screening for cervical cancer, researchers said in background notes.

The U.S. Preventive Services Task Force currently recommends that women routinely get a Pap smear every three years, HPV screening every five years, or combined Pap and HPV screening every five years.

Each year, about 11,500 U.S. women are diagnosed with cervical cancer and about 4,000 women die from it, according to the U.S. Centers for Disease Control and Prevention.

But these advanced screening methods have led the World Health Organization to call for the global elimination of cervical cancer by 2030, researchers said.

For the study, researchers analyzed data from a Canadian HPV screening trial conducted between January 2008 and December 2016, with an average 14-year follow up.

They found that the risk of women developing a precancerous lesion of the cervix was 3.2 cases per 1,000 within eight years of a single negative HPV test, and 2.7 per 1,000 within eight years of two negative HPV tests.

That was similar to women’s three-year risk following a single negative Pap test (3.3 per 1,000) or two negative Pap tests (2.5 per 1,000), researchers noted.

After six years -- a year longer than current five-year guidelines -- HPV screens showed lower risk after one (2.5 per 1,000) and two (2.3 per 1,000) negative tests.

The findings were published May 21 in the journal Cancer Epidemiology, Biomarkers & Prevention .

“HPV screening performs better than [Pap smears] by detecting more precancer earlier, which can then be treated earlier,” Gottschlich said in a journal news release. “We saw that in our study population, even those who had only one negative HPV test were at very low risk for the development of cervical precancer for many years after the negative test.”

These results might lead to changes in screening guidelines, but that depends on each country and their specific population, Gottschlich noted.

For example, countries will need to make sure that their health systems are good at following up with patients, as a longer screening interval means that some will forget they are due for their next check-up, the researchers noted.

More information

The U.S. Centers for Disease Control and Prevention has more on cervical cancer screening .

SOURCE: American Association for Cancer Research, news release, May 22, 2024

Copyright © 2024 HealthDay . All rights reserved.

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New study shows continued high effectiveness of HPV vaccination in England

by British Medical Journal

The human papillomavirus (HPV) vaccination program in England has not only been associated with a substantial reduction in cervical disease, but has done so in all socioeconomic groups, finds a study published by The BMJ .

Although women living in the most deprived areas are still at higher risk of cervical disease than those in less deprived areas, the results show that well-planned and executed public health interventions can both improve health and reduce health inequalities.

HPV is one of the most common sexually transmitted infections. Many countries, including the UK, now offer routine vaccination to girls and boys at age 12–13 to protect them against strains that can cause cancer in later life.

In England, the HPV vaccination program began in 2008, with catch-up vaccination for 14–18-year-olds from 2008–10. But because cervical cancer rates have always been higher in the most deprived groups, there is concern that HPV vaccination could benefit those at greatest risk of cervical cancer the least.

To address this, researchers analyzed cancer data from NHS England for vaccinated and unvaccinated women aged 20–64 years resident in England between January 2006 and June 2020 to examine whether the already high HPV vaccination effectiveness continued in an additional year of follow-up, from July 2019–June 2020.

The team used the index of multiple deprivation, which divides local areas into five equal groups from the most to the least deprived, to assess the effect of the vaccination program by social and economic deprivation.

Between 1 January 2006 and 30 June 2020 there were 29,968 diagnoses of cervical cancer and 335,228 of grade 3 precancerous cervical lesions (CIN3) in women aged 20–64 years.

In the group of women offered vaccination at age 12–13, rates of cervical cancer and CIN3 in the additional year of follow-up were, respectively, 84% and 94% lower than in the older unvaccinated group. Overall, the researchers estimate that by mid-2020, HPV vaccination had prevented 687 cancers and 23,192 CIN3s. The highest rates remained among women living in the most deprived areas, but the HPV vaccination program had a large effect in all five levels of deprivation.

For example, the greatest numbers of cervical cancer cases were prevented in women in the most deprived areas (192 and 199 for first and second fifths, respectively) and the fewest in women in the least deprived fifth (61 cancers prevented).

The number of women with CIN3 prevented was also high across all deprivation groups but greatest among women living in the more deprived areas: 5,121 and 5,773 for first and second fifths, respectively, compared with 4,173 and 3,309 in the fourth and fifth fifths, respectively.

For women offered catch-up vaccination at age 14–18, CIN3 rates decreased more in those from the least deprived areas than from the most deprived areas. However, for cervical cancer, the strong downward gradient from high to low deprivation seen in the older unvaccinated cohort was no longer present among those offered the vaccine.

This is an observational study so no firm conclusions can be drawn about cause and effect, and individual-level data on vaccination status were not available. However, randomized controlled trials have shown conclusively that the vaccine works in preventing HPV infection and in preventing CIN3 in women free of HPV at the time of vaccination.

What's more, the authors say this was a well-designed study based on high-quality population-based cancer registry data, making it "powerful and less prone to biases from unobserved confounders than an analysis based on individual-level data on HPV vaccination status."

As such, they conclude, "The HPV vaccination program in England has not only been associated with a substantial reduction in incidence of cervical neoplasia in targeted cohorts, but also in all socioeconomic groups ."

They add, "Cervical screening strategies for women offered vaccination should carefully consider the differential effect both on rates of disease and on inequalities that are evident among women offered catch-up vaccination."

The HPV vaccine is key to eliminating cervical cancer inequities, say US researchers in a linked editorial.

They point to the importance of attaining the 90% coverage target recommended by the World Health Organization, but acknowledge several challenges such as vaccine hesitancy, finances, health system capacity, supply, and variation in the extent to which health care providers recommend vaccination.

To overcome the challenges of reaching target coverage and to maximize population herd immunity, "collective efforts of government, community stakeholders, and health care professionals in these countries will be necessary," they conclude.

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Preventing HPV-Associated Cancers

What to know.

Vaccines protect against the types of HPV that most often cause cervical, vaginal, vulvar, and anal precancers and cancers. Cervical cancer also can be prevented or found early through regular screening and follow-up treatment.

HPV vaccine

Vaccines protect against the types of human papillomavirus (HPV) that most often cause cervical, vaginal, vulvar, penile, and anal precancers and cancers, as well as the types of HPV that cause most oropharyngeal cancers. The vaccine used in the United States also protects against the HPV types that cause most genital warts.

HPV Vaccine: Ask About It for Your Child

In this video, a family physician and a pediatrician explain why they made sure their children got HPV vaccine at age 11 or 12.

Cervical cancer screening tests

Cervical cancer also can be prevented or found early through regular screening and follow-up treatment. Learn about cervical cancer screening test options.

• The Pap test (or Pap smear) looks for precancers (cell changes on the cervix that might become cervical cancer if they are not treated appropriately).
• The HPV test looks for the virus that can cause these cell changes.

If your doctor finds any abnormal results from a cervical cancer screening test, make sure to follow up in case you need treatment or further tests.

Currently, screening tests for other types of HPV-associated cancers are not recommended.

Learn how to lower your cancer risk and what CDC is doing to prevent and control cancer.

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