Human Papillomavirus and Its Testing Assays, Cervical Cancer Screening, and Vaccination

CHAPTER FOUR

Human Papillomavirus and Its Testing Assays, Cervical Cancer Screening, and Vaccination Yusheng Zhu*,1, Yun Wang†, Julie Hirschhorn†, Kerry J. Welsh{, Zhen Zhao{, Michelle R. Davis§, Sarah Feldman§ *Pennsylvania State University Hershey Medical Center, Hershey, PA, United States † Medical University of South Carolina, Charleston, SC, United States { National Institute of Health, Bethesda, MD, United States § Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Molecular Biology, Pathogenesis, and Epidemiology of HPV 2.1 Molecular Biology of HPV 2.2 Pathogenesis of HPV 2.3 Epidemiology of HPV Infection and HPV-Associated Cancers 3. Principles and Methods for HPV Testing 3.1 Qiagen Hybrid Capture 2 High-Risk HPV DNA Test 3.2 Cervista HPV HR and HPV 16/18 Genotyping Test 3.3 Cobas HPV Assay 3.4 Aptima HPV Assay and Aptima HPV 16 18/45 Genotype Assay 3.5 Clinical Performance of HPV Assays 4. Cervical Cancer Screening 4.1 The Current Cervical Cancer Screening Guidelines 4.2 Future Directions of Cervical Cancer Screening 5. HPV Vaccines and the Impact on Cervical Cancer Screening 5.1 Immunogenicity of HPV 5.2 Vaccine Efficacy 5.3 Potential Impact of HPV Vaccine on Cervical Cancer Screening Acknowledgments References

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Abstract Human papillomavirus (HPV) was found to be the causative agent for cervical cancer in the 1980s with almost 100% of cervical cancer cases testing positive for HPV. Since then,

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many studies have been conducted to elucidate the molecular basis of HPV, the mechanisms of carcinogenesis of the virus, and the risk factors for HPV infection. Traditionally, the Papanicolaou test was the primary screening method for cervical cancer. Because of the discovery and evolving understanding of the role of HPV in cervical dysplasia, HPV testing has been recommended as a new method for cervical cancer screening by major professional organizations including the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology. In order to detect HPV infections, many sensitive and specific HPV assays have been developed and used clinically. Different HPV assays with various principles have shown their unique advantages and limitations. In response to a clear causative relationship between high-risk HPV and cervical cancer, HPV vaccines have been developed which utilize virus-like particles to create an antibody response for the prevention of HPV infection. The vaccines have been shown in long-term follow-up studies to be effective for up to 8 years; however, how this may impact screening for vaccinated women remains uncertain. In this chapter, we will review the molecular basis of HPV, its pathogenesis, and the epidemiology of HPV infection and associated cervical cancer, discuss the methods of currently available HPV testing assays as well as recent guidelines for HPV screening, and introduce HPV vaccines as well as their impact on cervical cancer screening and treatments.

1. INTRODUCTION Human papillomaviruses (HPVs) are a group of about 200 related viruses. More than 40 HPV types can cause sexually transmitted diseases through direct sexual contact such as vaginal, anal, and oral sex. Low-risk HPVs transmitted by sex may result in condylomata acuminata (skin warts) on or around the genitals, anus, mouth, or throat, while high-risk HPVs (hrHPVs) are responsible for HPV-induced cervical, anogenital, oropharyngeal, and other rarer cancers. The HPV genome is incorporated into the host genome, and in particular, the incorporation of E6/E7 genes and subsequent host expression maintains a transformed phenotype which has been linked to oncogenesis. HPV DNA testing is primarily used for the detection of highrisk type of HPV infections to screen for cervical cancer. Various HPV testing methods with different principles have been developed and some of them have been approved for clinical use. Major professional organizations have provided recommendation of using HPV testing for cervical cancer screening. In order to prevent HPV infections and subsequent HPVassociated cancers, HPV vaccines have been developed and used in many countries.

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2. MOLECULAR BIOLOGY, PATHOGENESIS, AND EPIDEMIOLOGY OF HPV HPVs are nonenveloped viruses, which consist of an icosahedral capsid containing histone-associated dsDNA. About 200 genotypes have been identified to date, which are differentiated by their genetic sequences encoding the outer capsid protein. HPV infects epithelium of skin and mucosal origins and commonly induces benign self-limiting lesions, but is also known to be potentially oncogenic pathogens associated with cervical, anogenital, and oral cancers. HPV infection is currently one of the most common sexually transmitted infections in the world, and the treatment and prevention cost incurred represents significant economic burdens in many countries. In this section, we will review the molecular biology of HPV, its pathogenesis, and their epidemiologic associations with cervical cancer and others.

2.1 Molecular Biology of HPV 2.1.1 Molecular Structure of HPV HPVs are small (55–60 nm in diameter) viruses, which consist of an icosahedral capsid and a circular virus dsDNA with approximately 8000 base pairs [1]. The capsid contains two structural proteins: the major capsid protein (L1) and the minor capsid protein (L2). HPV virions contain 360 copies of the L1 protein and up to 72 copies of the L2 protein, which assemble into an T ¼ 7 icosahedral lattice structure, with 72 pentameric capsomeres connecting with each other via interlocking arms and disulfide bridging (Fig. 1A) [2]. Each pentameric capsomere contains five monomers of the L1 protein with one L2 monomer being at the central opening of each capsomere (Fig. 1A) [2]. In addition, the L1 protein alone or in combination with L2 can self-assemble into virus-like particles (VLPs) in mammalian or nonmammalian expression systems, which represents a promising prophylactic vaccine against HPV infections [3]. Within the icosahedral capsids, viral genomes are associated with cellular histones, forming chromatin-like structures. 2.1.2 HPV Genome HPV viral genomes harbor an average of eight open reading frames (ORFs), which encodes genes for early (E) and late (L) proteins, as well as a

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Fig. 1 Schematic representation of human papillomaviruses (HPV) structure. (A) HPV capsid is composed of the L1 and L2 proteins to form 72 pentameric capsomeres as a T ¼ 7 icosahedral lattice. The dashed frame indicates a pentameric capsomere composed of five units of L1 and one unit of L2 proteins. (B) Within in HPV capsid, the circular dsDNA is bound to histones to form chromatin-like structure. The virus genome consists of open reading frames encoding several early (E) proteins and two late (L) proteins, as well as an upstream regulatory region (URR) as indicated in the dashed frame.

noncoding region, also known as the upstream regulatory region (URR) (Fig. 1B) [1]. The URR of HPV genomes contains transcriptional and replication regulatory elements and serves as binding sites for a variety of transcription activators (e.g., SP1 [4], Oct-1 [4], AP-1 [5], nuclear factor-1 [6], liver-enriched transcriptional activator protein [7], and TEF-1 [8]), transcription repressors (e.g., YY1 [8,9], liver-enriched inhibitory protein [7]), and virus proteins E1 and E2 [10,11]. The ORFs encode various virus proteins and can be further categorized into early and late regions based on their spatial–temporal expression patterns during the virus life cycle as well as their roles in viral replication and virion assembly, respectively. The early transcription region is downstream of URR and encodes six early proteins (E1–E7) that are required for viral replication. The late transcription region is responsible for the production of the two structural proteins (L1 and L2) necessary for virion assembly. 2.1.3 Functions of Viral Proteins According to their functions, the early proteins can be subdivided into two regulatory proteins involved in replication and transcription (E1 and E2), three oncogenes proteins (E5, E6, and E7), and E4, which contributes to virion production and exhibits an expression pattern similar to the late

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proteins. The late proteins (L1 and L2) play essential roles in virus assembly and infection process. The major functions of individual early and late proteins are depicted later and summarized in Table 1. Both the E1 and E2 proteins are expressed at early and intermediate stages of the viral life cycle [1]. E1 is an ATP-dependent DNA helicase, which is responsible for the extrachromosomal replication and amplification Table 1 The Functions of the HPV Early and Late Proteins, Their Expression, and Targeted Protein During Virus Life Cycle Virus Protein Main Function Major Target

E1

Initiate episomal replication Coordinate assembly of replisome

DNA replication factors

E2

Regulate early gene transcription Interact with E1 to initiate DNA replication

Transcriptional factors

E4

Virus DNA replication, maturation, assembly, and release

E5

EGFR, MHC, etc. Minor oncoprotein Induce cell fusion to evoke aneuploidy Enhance transforming activities of E6 and E7

E6

Major oncoprotein (cell immortalization) Interrupt multiple apoptotic signal pathways Increase telomerase activity Destabilize host chromosome

p53, PDZ, E6AP, Bak, Bad, TNFR-1, FADD, TRAIL, etc.

E7

Major oncoprotein (cell immortalization) Stimulate G1/S progression Destabilize host chromosome

pRB, E2F, p21, p27, CDK/cyclin A, etc.

L1

Major capsid structural protein Self-assembly into virus-like particles Initiate cell attachment

L2

Minor capsid structural protein Coassembly with L1 protein Mediate internalization and transport

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of virus episome in the nucleus of infected cells in a tightly controlled manner [12]. E1 assembles into a double-hexamer enzymatically active form at the origin of viral DNA (vDNA) replication (ori), where unwinds the ori and DNA replication fork to initiate the replication [13]. E1 also interacts with the host cellular DNA replication factors to orchestrate the assembly of a functional replisome necessary for bidirectional replication of the viral genome [14]. Similarly, E2 is an essential regulatory protein that is involved in multiple processes of HPV life cycle. The full-length E2 protein functions primarily as a transcriptional regulator via recruiting cellular transcriptional activators or suppressors to the E2-binding motifs within URR to activate or repress the transcription of the downstream early genes. However, the shorter forms of E2 can either compete the E2-binding motif or form dimer with the full-length E2 to repress virus transcriptional processes [15,16]. Additionally, E2 recruits E1 at the viral ori to initiate DNA replication [13]. The E4 gene is located within the E2 ORF, and E1–E4 protein is primarily translated from a spliced mRNA that includes E1 initiation codon and adjacent sequences [17]. The E4 proteins are expressed at the later stage of HPV life cycle and aggregate into cytoplasmic and nuclear inclusion granules [17]. The structures and functions of the E4 proteins are dynamically modified by various protein kinases (e.g., protein kinase A and C, cyclindependent kinase, and MAP kinases) [18] or proteases [19,20] when the infected cells enter cell cycles of S and G2 phases or exit cell cycles and undergo terminal differentiation [21]. The E4 proteins participate in virus genome amplification via multiple mechanisms, including the association of the E4 proteins with cytoplasmic cyclin A/CDK2 leading to G2 arrest and the direct interaction with the E2 proteins [22]. Therefore, the E4 proteins can serve as a biomarker of active virus infection or an indicator of disease severity with the infection of hrHPV types [23]. Alternatively, the E4 proteins can be coexpressed with the L1 protein from the same bicistronic message, and thus involved in virus assembly and maturation [17]. Moreover, studies have suggested that the E4 proteins may assemble into amyloid-like fibers upon cleavage by protease calpain, and subsequently, disrupt associated cellular keratin network and the formation of the cornified envelope to facilitate efficient virus release and transmission [24]. The E6 and E7 proteins are the main HPV oncoproteins, which provide the primary transforming activities of hrHPV via inducing mitotic aberrations and interrupting multiple apoptotic pathways to facilitate stable maintenance of viral episomes and prevent differentiating of infected cells [25].

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E5 is the minor oncoprotein, which not only induces cell fusion to generate tetraploid cells with chromosomal instability but also enhances the immortalization potential of E6 and E7 [26]. The oncogenic activities of these oncoproteins and their contribution to the development of HPV-induced cervical intraepithelial neoplasia (CIN) are discussed in more detail in Section 2.2. The L1 and L2 proteins are HPV capsid structural proteins and expressed at the late stages of the viral life cycle [1]. The L1 protein (55 kDa) is the major capsid protein, which contributes to 80% of total viral protein [27]. The L1 monomers arrange into 72 pentameric capsomeres with the aid of up to 72 L2 monomers to form the T7 icosahedral capsid, which encapsulates the virus genome to form intact HPV [28]. The L1 protein can also spontaneously self-assemble into empty VLPs, which are indistinguishable from the icosahedral capsid of the native intact HPV [29]. The L2 protein (74 kDa) is the minor capsid protein, which constitutes 2%–8% of total viral protein. Although L2 alone does not form VLPs, it can coassemble with L1 into VLP [2]. L2 in combination with L1 can facilitate the genome encapsidation via direct binding of DNA to their putative DNA-binding regions [2]. Additionally, these two structural proteins play dynamic roles in the infectious processes. The initial cell attachment is mediated via the L1 protein interaction with heparin sulfate proteoglycan (HSPG) on the extracellular basement membrane, which leads to the conformational changes causing the exposure and cleavage of L2 by cellular furin protease that allows the virion to bind cell surface receptor [30]. Following virions internalization via a micropinocytosis-like process and virion dissociation, the L2 protein in complex with the vDNA passes through early endosome to late endosome and escape the vesicular compartment [31]. Subsequently, the L2 protein aids vDNA to traverse the cytoplasm to travel to the host cell nucleus via its interaction with cytoskeletal proteins [32]. The final nuclear entry step is carried out with the guide of the specific peptide signals located on L2, which enables the entry of vDNA through nuclear pores or the association of vDNA with the nuclear matrix during mitosis [33,34]. 2.1.4 HPV Life Cycle HPV life cycle including initial virus infection, genome maintenance, productive replication, and packaging is strictly associated with the differentiation of infected epithelial cells and is tightly orchestrated by the

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Uppermost layer Upper layer

Basal layer Normal epithelium Assembled virus Uncoated virus Uninfected cells Infected cells

Infect undifferentiated basal membrane virus attachment

Enter basal cells virus uncoating and genome maintenance

Basal cells proliferate, migrate, and differentiate virus productive replication

Cell terminal differentiation virus packaging and release

Expression of E1, E2, E6, E7 Expression of E4, L1, L2

Fig. 2 Epithelial cell differentiation and virus protein expression during HPV life cycle. HPV infects cervical epithelium and attaches to the HSPG on the undifferentiated cells in the basal cell layer. Once the virus enters cells via endocytosis, early HPV genes are expressed and the viral DNA is replicated at a low level from the episomal DNA. As the infected cells proliferate, differentiate, and migrate to the upper layers of epithelium where viral genome is productively replicated and the late genes are expressed. Finally, the virus is assembled in the terminal differentiated cells in the superficial zone, and the virus life cycle is completed with external release of progeny virions with keratinocytes peeled from uppermost layer.

expression of virus proteins to ensure virus replication and immune evasion [35]. The HPV life cycle is illustrated in Fig. 2. HPV life cycle initiates from virus infection of the basal layer of stratified epithelium. HPV invades damaged epithelium through attaching to the HSPG on the basal membrane, where the virus enters the host cells via clathrin-mediated endocytosis, caveolar endocytosis, or other types of endocytosis [36]. Following virus internalization and uncoating, HPV genomic DNA is released and transported into host cell nucleus, where the E1and E2-mediated viral genome episomal replication is maintained at a low level [37]. As the infected cells divide, the daughter cells carrying virus DNA migrate to the upper cell layers and start to differentiate. At the stratified epithelium, E6 and E7 inactivate cell apoptotic pathways and thus reactivate cell division cycle of the differentiation-initiated cells in order to provide necessary host DNA replication machinery to ensure productive virus replication [38]. Following virus genome amplification, the infected cells switch to terminal differentiation stage, where the cells stop expressing E6 and E7 but increase the production of the E4 protein and late capsid proteins L1 and L2, which facilitate the maturation and release of progeny virions and enable the virion packaging [39]. At the uppermost layer of

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the epithelium, the viral genomic DNA and the capsid protein assemble into progenitor virions, and then progeny virions are released externally with peeled keratinocytes to complete the life cycle of HPV [39]. 2.1.5 HPV Classification To date, 49 HPV species with up to 198 genotypes have been established according to the International Committee on Taxonomy of Viruses [40]. HPVs display prodigious diversity at the levels of epithelial tropism, genotype, and pathogenicity, which are employed as classification criteria, respectively. Historically, HPVs were categorized according to the tissue location where they were first isolated and their epithelium tropism into four major groups including cutaneous, mucosal, cutaneous and/or mucosal, and cutaneous associated with epidermodysplasia verruciformis [41]. Recently, an international standardization and classification system of HPV types has been established based on the taxonomic scheme developed by the International Committee on Taxonomy of Viruses with five major phylogenetic groups, including alpha-, beta-, gamma-, mu-, and nu-papillomavirus [40]. Different HPVs sharing at least 60%–70% similarity within their nucleotide sequence coding for the capsid protein L1 are classified into the same genera with different numbers that indicates their types [40]. Clinically, HPVs are often grouped into low-risk and high-risk categories according to their epidemiologic association with cancer [42]. Infection of hrHPV (e.g., HPV type 16, 18, 31) can result in cervical dysplasia (precancer); invasive cervical cancer; and the cancers of vulva, vagina, penis, anus, and oropharynx [42,43]. In contrast, low-risk HPV (e.g., HPV type 6, 11) only causes skin warts on or around the genitals or anus, low-grade mild dysplasia, and respiratory papillomatosis [44,45]. The classification of common HPVs according to their risk for cancer, virus phylogeny, and epithelia tropism [41,46,47] is listed in Table 2. Of note, although the majority of hrHPVs are alpha-papillomavirus and cause mucosal lesions, viruses with related phylogeny often exhibit distinct pathologies and result in divergent epithelial lesions.

2.2 Pathogenesis of HPV HPV infections are generally transient and spontaneously cleared by immune system. Nevertheless, a prolonged persistent infection with hrHPV as a result of evasion from immune surveillance can lead to increased risk of developing HPV-mediated precancerous lesion and invasive cancer. CIN is

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Table 2 Classification of Common HPV According to Risk for Cancer, Genus, and Epithelia Tropism [41,46,47] Epithelia Tropism Risk for Cancer Genus

Cutaneous Mucosal

Cutaneous Cutaneous With Epidermodysplasia and/or Verruciformis Mucosal

16, 18, 26a, 30a, 31, 33, 34, 35, 39, 45, 51, 52, 53a, 56a, 58, 59, 66a, 67, 68, 69a, 73, 82

High

Alpha

Low

Alpha

2, 3, 10, 6, 11, 13, 32, 42, 7, 40, 43, 49 27, 28, 29, 44, 54, 71, 72, 74, 61, 62, 91 81, 83, 84, 86, 87, 57, 94 89, 90

Beta

76

5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 25, 36, 37, 38, 47, 49, 75, 80, 92, 93, 96

Gamma 4, 48, 50, 60, 65, 88, 95

a

Mu

1, 63

Nu

41

Also found in benign lesions.

the most common clinically significant manifestation of persistent genital HPV infections, which can be classified cytohistologically into different grades depicting the extent of cervical epithelium affected by dysplastic cells. Oncoproteins of hrHPV are responsible for the mitotic aberration, cellular transformation, and cervical carcinogenesis through their interaction and modulation of multiple host cellular regulatory protein complexes that are important in the cell cycle, senescence, apoptosis, and maintenance of chromosomal stability. 2.2.1 The Fate of HPV Infection Primary HPV infection is naturally controlled or cleared within 12–18 months after first detection in approximately 90% of cases via host’s immune

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responses [48]. While intraepithelial dendritic cells are responsible for the first-line nonspecific innate immunity upon HPV infection [49], effective immunity primarily depends on cell-mediated adaptive immune response to the early proteins, mainly HPV-specific CD4 + T helper (Th) and CD8 + cytotoxic T lymphocytes that are targeted at the E2, E6, and E7 proteins [50]. Additionally, a slow and week humoral response is evoked by the major capsid protein L1 to produce specific antibodies, mainly IgG, in patients with acute or persistent HPV infections [51]. However, HPV possesses unique lifestyle that enables the virus effectively to evade immune recognition and to induce persistent infections without detectable symptoms or complications of the host. First of all, HPV infection does not induce cytolysis of infected cells to evoke subsequent inflammatory response. Despite the active virus replication and assembly occurring at the superficial layer of epithelium, infected cells are naturally programmed to apoptosis [52]. In contrast to necrosis, apoptotic cell death does not elicit inflammation nor releases any danger signals that activate dendritic cells and initiate immune responses to virus antigens around the dying cells [53]. Furthermore, the absence of viremia greatly contributes to HPV immune escape. HPV infection is exclusively intraepithelial, and HPV life cycle is organized to produce a limited viral antigen synthesis in undifferentiated cells [54]. During asymptomatic shedding of HPV from the surface of infected squamous epithelia, only minimal amounts of free virus invade vascular and lymphatic system, and thus result in limited immune response [55]. Moreover, the E6 and E7 proteins of the hrHPVs downregulate the local production of interferon [56], inhibit the expression of toll-like receptor 9 (TLR9) and TLR9-mediated interferon antivirus response for HPV infection [57], and reduce the attraction of antigenpresenting cells to the infect region [58]. Also, the E5 protein disrupts HPV-mediated antigen processing and presentation [59]. These mechanisms employed by HPV collectively facilitate the evasion of innate immune response and delay the activation of adaptive immunity in response to HPV infection. Failure to develop effective immune response to clear HPV infection results in a balance between viral replication and immune tolerance and allows its continued presence in immunocompetent hosts. The majority of persistent HPV infections ultimately regress following a virus-specific CD4 + and CD8+ T cell-mediated immune response, although a small percentage of infections last for a long time and eventually progress to invasive malignances, particular in women infected with hrHPV [60].

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2.2.2 HPV-Mediated Progression From Infection to Cervical Cancer HPV infection is established upon the virus gains initial entry to the basal cell layer through microabrasions in the cervical epithelium. Following the infection with HPV, the virus genome can maintain at low copies as a nonintegrated episomal DNA without inducing any morphological changes in the squamous epithelium. The latent infection can be reactivated with productive replication of virus DNA in differentiated postmitotic suprabasal layer. During normal HPV life cycle, the expression of viral oncogenes in these cells is under tight controls, which leads to the proliferation of squamous epithelia into benign tumors. The high-level oncoproteins are expressed only in the superficial layer, where the cells are destined to be lost from the cervical squamous epithelium, thus do not cause cancer. Nevertheless, the normal virus life cycle can be interrupted when the integration of high-risk virus DNA into host genome occurs, which results in the loss of negative-feedback control of virus E6 and E7 expression by the regulatory E1 and E2 proteins as well as host cell chromosomal instability. Consequently, these oncoproteins are highly expressed throughout the epithelium, which are responsible for the accumulation of genomic mutations, a loss of apoptosis and growth suppression, cellular transformation, and subsequent neoplastic progression characterized by different degrees of abnormal histological changes in the nuclei of infected epithelial cells. Over time, with a persistent hrHPV infection at cervical lesion, dysplastic cells may penetrate the basement membrane and lead to the development of an invasive cervical cancer. 2.2.3 Classification of HPV-Associated CIN CIN is a preinvasive lesional continuum, which is referred to as a potential premalignant transformation and abnormal growth of cervical squamous intraepithelial cells. The minimal criteria justifying a diagnosis of CIN are the presence of some degree of nuclear abnormality including nuclear enlargement and pleomorphism through the full thickness of the epithelium [61]. According to the proportion of the cervix epithelium that is occupied by dysplastic cells, CIN can be histologically subdivided into three different grades [62]. In cases of CIN1 (mild dysplasia), dysplastic cells constitute up to the basal one-third of the epithelium with cytoplasmic maturation remained within the upper 2/3 of the epithelium. In CIN2 (moderate dysplasia), the abnormality is confined to the basal two-third of the epithelium, while in CIN3 (server dysplasia), the dysplasia spans more than 2/3 and up to the full thickness of the epithelium with little or no cytoplasmic

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maturation observed, which sometimes are also known as cervical carcinoma in situ. Recently, a modified CIN grading system has been adapted in histological diagnosis, which classifies CIN into to low-grade CIN (CIN1) and high-grade CIN (CIN2 and CIN3) [63]. Alternatively, the squamous intraepithelial lesion (SIL) can be divided into two tiers using the Bethesda classification system to ensure a uniform analysis with clear terminology for making a cervical cytological diagnosis and reporting Pap smear results [64]. Similar to the modified CIN grading system, the low-grade SIL (LSIL) reflects productive, largely transient HPV infection and associated cellular alterations, including those in CIN1, whereas the high-grade SIL (HSIL) represents a precancerous lesion, including the histological abnormalities observed in CIN2 and CIN3. Of note, the prognosis of cervical abnormalities varies significantly according to their classification, which together with HPV types and HLA-restricted HPV-specific immune responses determines the disease outcome [65–67]. LSIL (CIN1) is often spontaneously resolved via immune clearance and reverts to a normal state without treatment. On the contrary, HISL (CIN2, 3) is less likely to regress without appropriate intervention, which is especially the case for the lesions associated with persistent hrHPV infection, and at a great risk of progression to invasive cervical cancer if left untreated [67]. The correspondence of cytohistological changes and their clinical outcomes of HPV-associated cervical lesions between these two classification systems are summarized in Table 3. 2.2.4 The Role of Oncogenic Proteins in HPV-Induced Cervical Carcinogenesis The E6 and E7 proteins are the major oncoproteins that differentially regulate cell proliferation, apoptosis, and senescence in infected epithelium. They impair apoptosis-mediated elimination of virus-infected cells and enable uncontrolled growth of differentiating cells, thus contribute to the persistent infections and cellular immortalization and transformation in HPV-infected cervical epithelium. E6 and E7 exert their oncogenic activities mainly through interaction with different host regulatory protein complexes listed in Table 2. The E6 proteins from HPV-16 and HPV-18 mainly interrupt the normal functions of tumor suppressor p53. The E6 proteins are able to hijack the ubiquitin ligase E6-associated protein (E6AP) and p53, which lead to ubiquitin-mediated p53 degradation [68]. Additionally, the formation of E6/E6AP/p53 complex inhibits p53-dependent cell cycle arrest and apoptotic pathway via interrupting its sequence-specific DNA

Table 3 The Correspondence of Cytohistological Changes and Clinical Outcome of HPV-Associated Cervical Lesions Between Cervical Intraepithelial Neoplasia (CIN) and Bethesda Classification Systems CIN Cytoplasmic Bethesda Classification Dysplastic Involvement Maturation Modified CIN Classification Clinical Outcome

CIN1 (mild dysplasia)

Basal 1/3 epithelium

Upper 2/3 epithelium

Low-grade CIN LSIL (CIN1)

Spontaneous regress

CIN2 (moderate dysplasia)

Basal 2/3 epithelium

Upper 1/3 epithelium

High-grade HSIL CIN (CIN2, 3)

Unlikely regress; progress to invasive cervical cancer if untreated

CIN3 (severe dysplasia)

>Basal 2/3 to full thickness of epithelium

Little to none

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binding and abrogating transactivation of p53-responsive genes [68]. The E6 proteins also inhibit p53-independent extrinsic and intrinsic apoptotic pathways through the interaction with serval proteins involved in death receptors signaling pathway (e.g., TNFR-1, FADD, TRAIL) [69–71] and proapoptotic Bcl2 members (e.g., Bak and Bax) [71,72], respectively. The oncogenic activities of the E6 proteins can also be attributed to the increase of telomerase activity via inducing the expression of telomerase reverse transcriptase to ensure infinite proliferative life span of infected cells, the degradation of proteins involved in maintaining chromosomal stability, as well as the increased tolerance of genomic instability. On the other hand, the hrHPV E7 proteins can efficiently induce postmitotic epithelial cells to bypass the G1 phase and enter the S phase via stimulating proteasomemediated degradation of retinoblastoma tumor suppressor (pRB), which subsequently activates E2F-mediated transcription of S phase-specific genes and potentiates the proapoptotic activity of p53 [73,74]. Additionally, the E7 proteins have been shown to retain the DNA synthesis competent state in differentiated keratinocytes via abrogating cyclin-dependent kinase inhibitors (p21 and p27) to maintain the activity of CDK2/cyclin A complex [75]. Intriguingly, the E7 proteins can either trigger or inhibit apoptosis dependent on the cell and viral types as well as the specific stages of the virus life cycle [71,76,77]. In addition, the E7 proteins have been reported to facilitate vDNA integration [78], induce mitotic aberrations, and abrogate cell cycle checkpoints to induce genomic instability [79], and compromise cellmediated HPV-specific immune responses [80], which collectively contribute to the malignant progression of cervical lesions. Recent studies also suggest that the induction of epigenetic alteration and aberrant expression of miRNA by the E6 and E7 proteins may contribute to the cervical carcinogenesis [81]. Compared to E6 and E7, the E5 protein is a weak oncogenic protein, but it plays important roles in multiple events during the early stage of HPVassociated cervical cancer by enhancing the oncogenic activities of the E6 and E7 proteins, although it does not directly contribute to the malignant progression and the maintenance of transformed phenotype [82]. E5 has been reported to induce the formation of tetraploid cells with increased chromosomal instability, particularly in the presence of cell cycle checkpoint inhibitors like HPV-16 E6 and E7 [83]. Additionally, the E5 protein downregulates MCH I- and II-mediated antigen presentation which enables infected cells to escape from immunosurveillance and subsequent viral persistence, and thus facilitates the induction of cell transformation by the E6

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and E7 proteins and increases the probability of malignant progression [59,84]. Moreover, the E5 protein favors the proliferation of infected cells via stimulating DNA synthesis in differentiated epithelial cells [85], enhancing the activation of EFGR in keratinocytes [86], and downregulating the gap-junction-mediated growth suppression of transformed cells by adjacent normal cells [87]. Finally, the E5 protein also facilitates virus integration and episomal loss that are critical events in the early stage of HPV-associated cervical cancer. It has been shown that an endogenous antiviral response through the stimulation of IRF-1 and IFN-β can be activated by the E5 protein, which leads to the loss of episomal E2 DNA and impaired inhibitory regulation of oncogene expression [88].

2.3 Epidemiology of HPV Infection and HPV-Associated Cancers HPV infections are the most common sexually transmitted infections in the world, and the treatment and prevention cost incurred represents significant economic burdens in many countries [89]. Approximately 70% of sexually active men and women will encounter at least one infection during their lifetime [89]. HPVs have been established as the principal cause of cervical cancer and also suggested as a relevant factor for a growing incidence of other anogenital cancers and a subset of head and neck cancers worldwide [89]. Multiple risk factors are responsible for HPV infection and progression and contribute to the geography, age, and sex-specific incidence patterns of HPV-associated cancers. 2.3.1 Risk Factors for HPV Infection, Persistence, and Malignant Progression Many risk factors collaboratively contribute to the HPV infection, persistence, and carcinogenesis. HPV infections are primarily related to sexual behavior, especially the number of recent or lifetime partners and the age at sexual debut [90]. Circumcision and regular use of condom were associated with reduced risk for oncogenic HPV infection and HPV-associated cancer in both men and their sexual partners [91,92]. Additionally, individuals with compromised immune system, such as patients with HIV or receiving immunosuppressive treatment, are at greater risk of HPV infection [93]. The risks of developing persistent HPV infection and HPV-associated cancer are mostly associated with the HPV type. Infections with low-risk HPVs (HPV types 6, 11, etc.) usually clear up without any intervention

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or develop only benign or low-grade cervical cell abnormalities, genital warts, or laryngeal papillomas [67]. In contrast, hrHPVs (HPV types 16, 18, etc.) often cause persistent infection which can progress to invasive cancer if left untreated [67]. hrHPV types are detected in 99% of cervical cancer patients with about 50% associated with HPV type 16. The rate can increase up to 70% when coinfected with HPV type 18 [94]. The global HPV prevalence in women with normal cervical cytology is 11%–12% according to hybrid capture and PCR-based HPV DNA detection, which increases in proportion to the severity of the cervical lesion [95]. Furthermore, other environmental factors, including multiparty [96], long-term oral contraceptives [97], tobacco use [98], and coinfection with other sexually transmitted agents [99,100], are consistently identified as cofactors likely to influence the risk of progression from cervical HPV infection to high-grade CIN and invasive cervical cancer. Additionally, HPV-associated cancers also exhibit some socioeconomic status and race/ethnic-related geography disparity as described later. 2.3.2 Geography-, Age-, and Sex-Related Incidences of HPV-Associated Cancers In 2008, a total of 610,000 cancers are attributable to HPV infection worldwide with 86.9% are cervical cancers [89,101]. Cervical cancer is the fourth most common cancer among women worldwide, and it is the second most common female cancer in women with ages between 15 and 44 years in the world with an estimated 527,624 new cases and 265,672 deaths in 2012 [89]. The majority of cervical cancer cases are squamous cell carcinoma developed from high-grade CIN [102]. Additionally, growing evidence suggests a strong association between HPV infection and cancers of the anus, vulva, vagina, penis, and oropharynx [103]. More importantly, the incidence of HPV-associated cancers displays geographic location-, age-, and sex-specific distribution patterns. A distinct geographical distribution of HPV-associated cancers has been attributed independently to socioeconomic and race disparities [104]. In general, lower education and higher poverty are associated with higher incidence of penile, cervical, and vaginal invasive cancers, whereas higher education is associated with higher incidence of vulvar cancer, anal cancer, and oropharyngeal cancers [104]. According to the 2016 Human Papillomavirus and Related Diseases Report [105], the incidence of cervical cancer is significantly higher in less developed countries than that in developed countries. The highest age-standardized rate (ASR) of cervical cancer was

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observed in Africa and the lowest was in Oceania [105]. Not surprisingly, the incidences of penile cancer strongly correlate with those of cervical cancer, which are higher in developing countries, accounting for up to 10% of male cancers in some parts of Africa, South America, and Asia [105]. Similar to cervical cancer, the majority of vaginal cancer cases (68%) occur in less developed countries [105]. Conversely, about 60% of all vulvar cancer cases occur in developed countries located in Europe and America and Australia has the highest ASR of anal cancer [105]. In addition to socioeconomic status, sexual behavior, innate genetic differences, or circulating intratypic HPV variants may contribute to the differences in HPV infection and associated diseases across racial/ethnic groups in the United States and other countries [106,107]. It has been reported that Hispanic women have higher rates of cervical cancer compared to non-Hispanic women [108]. On the contrary, the incidence of vulvar, anal, and oropharyngeal cancers in Whites and non-Hispanics was higher than that in other racial/ethnic groups. Rates of vaginal cancer were the highest among Blacks [109]. Asian and pacific island race had the lowest incidence of HPV and exhibited a lower probability of acquiring new HPV infections [107]. The incidence of HPV-associated cancers is generally higher in sexually active population. However, some of these cancers may exhibit an agespecific distribution pattern. The cervical cancer risk is strongly related to age with higher incidence in women between the late teens and mid1930s in the United States [110]. A bimodal peak pattern of HPV-associated cervical cancer has also been reported in some countries, with a second peak among individuals older than 45 years, possibly due to immunosenescence, hormonal changes at menopause, and reactivation of latent infections [111–113]. In contrast, invasive vaginal cancer is diagnosed rarely in women under 45 years with the peak incidence of carcinoma in situ observed between ages 55 and 70 [114]. The two types of vulvar cancer, basaloid/ warty lesions and keratinizing, are more common in young women and older women, respectively [115]. Penile cancer is rare and most confined to uncircumcised men between 50 and 70 years of age, indicating that circumcision might have strong protective effect against HPV infection-related penile caner [116]. In addition, a sexual preference has been observed in HPV-associated cancer at specific locations related to sexual activities. Women generally have higher incidences of anal cancer than men, although elevated incidence is observed in men who have sex with men and/or immunodeficiency disorders [117]. On the contrary, higher incidence and mortality of pharyngeal

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cancer occur in men [118]. Therefore, implementation of specific preventive strategies is necessary to effectively reduce the burden of HPVassociated cancers in targeted populations.

3. PRINCIPLES AND METHODS FOR HPV TESTING There are over about 200 different genotypes of HPV with around 40 of these types able to infect the anogenital mucosa of humans. Of these 40 types, 14 (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) are considered high risk (HR) for the development of cervical cancer and/or precursor legions. HPV-16 is associated with approximately 60% of cervical cancers, while HPV-18 is associated with 15% of cervical cancers. In 2002, guidelines began inclusion of recommendations for testing HR HPV types as a screening tool for patient management [119,120]. In 2012, the guidelines of a variety of organizations across the county including American College of Obstetricians and Gynecologists (ACOG), American Society for Clinical Pathology (ASCP), American Cancer Society (ACS), and American Society for Colposcopy and Cervical Pathology (ASCCP) were updated to be consistent in recommending routine Pap and HPV cotesting in women 30 years of age or greater [121]. The indicated use for HPV DNA testing and genotyping was indicated for two scenarios starting with the first approval in 1999. The first indication is as a screening tool for patients observed to have atypical squamous cells of undetermined significance (ASCUS) Pap test results. However, it should be noted that results from HPV screening were not at the time intended to prevent women from continuing to colposcopy. The second indication was for women 30 years of age or greater to evaluate for the presence of hrHPV types. The results of the HPV test in combination with cytology results and clinical assessment were used to guide patient management. These remained the indicated guidelines for all of the Food and Drug Administration (FDA)-approved assays (Table 4) until April 2014, when the Roche Cobas® 4800 HPV test was FDA-approved HPV test for women 25 and older to be used alone to assess the need to undergo additional diagnostic testing for cervical cancer. The features of all the FDA-approved current HPV assays are summarized in Table 4 and discussed in details later.

3.1 Qiagen Hybrid Capture 2 High-Risk HPV DNA Test In 1999, Qiagen Corporation was the first to obtain FDA approval for a hrHPV DNA test [123]. The Qiagen Hybrid Capture 2 High-Risk HPV

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Table 4 Features of the High-Risk HPV FDA-Cleared Assays Feature

Qiagen HC2

Cervista

Cobas

Aptima

FDA approval

2003

2009

2011

2011

Technology

DNA:RNA hybrid probe, signal amplification

Invader® chemistry, signal amplification

Target amplification, real-time PCR

Target amplification, TMA

Nucleic acid DNA starting material

DNA

DNA

RNA

Target(s)

L1, E6, E7

L1

E6, E7

Sample type ThinPrep (4 mL); (volume) STM

ThinPrep (2 mL)

ThinPrep (1 mL)

ThinPrep (1 mL)

Requires prealiquot

No

No

Yes

No

Options for automation

Semiautomated and automated

Manual and automated

Automated

Automated

Internal control

None

Human Human genomic genomic (HIST2H2BE) (β-globin)

Multigene

HPV-16/18 None genotype identification

Yes (separate reaction)

Yes (integrated) Yes, plus HPV-45 (separate reaction)

1250–7500 Copies/ reaction

300–2400 Copies/mL

LOD at clinical cutoff

5000 Copies/ reaction

Cross reactivity with LR HPV types

6, 11, 42, 53, 54, 55, 67, 70 58, 61, 62, 66a, 67, 69, 70, 73, 81, 82/82v, 84, 86

Intended use ASCUS, cotesting

Expanded test menu available

Process only

ASCUS, cotesting

CT/NG (Chlamydia No trachomatis/Neisseria gonorrhoeae)

20–240 Copies/ reaction

6, 42, 54, 55, 62, 26, 62, 67, 70, 89 82

ASCUS, ASCUS, cotesting, cotesting primary screening (approved 2014) CT/NG, HSV (Herpes simplex virus) 1/2

CT/NG, TV (Trichomonas vaginalis)

a Studies involving the classification of the HPV-66 type are limited and conflicting [122]; starting around 2005 HPV-66 was reclassified from low-risk to high-risk in a number of national guidelines.

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DNA test (HC2 HR HPV) utilizes a cocktail of RNA probes recognizing HPV HR types that will then hybridize to the DNA material obtained from a woman’s cervical cells. The DNA:RNA hybrid molecules are then captured on the surface of an antibody-coated microplate. Numerous alkaline phosphatase-conjugated antibodies can bind to each DNA:RNA hybrid molecule resulting in signal amplification that is then detected with a chemiluminescent substrate. The intensity of the light emitted is detected by a luminometer, and the intensity of the light indicates the presence or absence of the HPV target. The package insert describes 13 high-risk (HR) types detected by this test including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. The Qiagen assay does not include an internal control. The assay can be semiautomated using the Rapid Capture® System or fully automated using the QIAensemble™ system. The Qiagen assay remained the only FDA-approved test on the market for the next 6 years.

3.2 Cervista HPV HR and HPV 16/18 Genotyping Test In 2009, the FDA-approved two tests manufactured by Third Wave Technologies (Hologic), the Cervista® HPV HR and Genfind® DNA extraction kit, and the Cervista® HPV-16/18 genotyping test. Both of these tests utilize the Invader® chemistry for the detection of 14 hrHPV types. The Invader® chemistry uses two isothermal reactions to detect the HPV DNA target. The first isothermal reaction consists of an Invader oligonucleotide and DNAspecific target probe that both bind at the same time to the target DNA sequence. The binding of both probes results in a structure that is then recognized by the Cleavase® enzyme, which is a proprietary enzyme. Recognition by Cleavage causes a cut in an overlapping flap of the target-specific probe that is then released. Each overlapping flap that is released binds to a FRET cassette creating the second isothermal reaction. The binding of the overlapping flap to the FRET cassette creates a structure again recognized by Cleavase® that will emit a fluorescent signal. Each copy of target HPV DNA results in a total of 106- to 107-fold signal amplification per hour due to the two isothermal reactions. The same 13 HR types are looked as with the Qiagen assay, but HPV-66 was added. The Cervista® HPV HR test cannot distinguish between the 14 HPV types present. Use of the Cervista® HPV16/18 genotyping test is able to determine the presence of the 16, 18, or both 16 and 18 genotypes as a separate reaction. The human genomic internal control used for the Cervista assay is the human histone 2 gene (HIST2H2BE). The assay can be semiautomated or fully automated using the Cervista high-throughput automation system.

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3.3 Cobas HPV Assay In 2011, the Cobas® HPV assay, manufactured by Roche, was FDA approved. This assay in a single reaction provides results for the HPV-16, HPV-18, and a pooled result of the 12 additional HR HPV types. Primers are designed to amplify HR HPV DNA from the L1 region of the HPV genome and with detection of HR HPV by fluorescent probes binding to HPV DNA. The assay uses four fluorescent dyes for the probes with the dyes recognizing HPV-16, HPV-18, the pool of 12 other HR HPV types, and finally the β-globin gene. The β-globin target serves as the human genomic internal control used for the Cobas® assay. Based on real-time PCR technology, complementary probes bind to the target DNA and the probes are cleaved due to the 5ʹ–3ʹ nuclease activity of the polymerase. Once the reporter dye is separated from the quencher (probe), it is free to emit fluorescence when excited by the proper spectrum of light. Full automation of the assay is accomplished using the Cobas® 4800 instrument. In 2014, the Cobas® 4800 HPV test became the first HPV test approved by the FDA as a first-line screen for cervical cancer risk in women 25 and older.

3.4 Aptima HPV Assay and Aptima HPV 16 18/45 Genotype Assay Also in 2013, the Aptima HPV assay and Aptima HPV-16/18/45 genotype assays manufactured by Hologic were approved by the FDA. The three steps involved in this assay are performed in a single reaction tube and focus on amplification of the E6/E7 viral oncogenes of HPV. The first step involves target capture. The second step utilizes transcription-based NA amplification (TMA) method. Reverse transcription involving two enzymes MMLV reverse transcriptase and T7 RNA polymerase generates a DNA copy of the target mRNA sequence containing a promoter sequence for the T7 RNA polymerase. The T7 RNA polymerase can then bind and product many copies of the HPV RNA amplicon from the DNA copy template. The third step is detection by hybridization protection assay, which uses a singlestranded DNA probe with chemiluminescent labels complementary to the amplicon. A selection reagent can differentiate between hybridized and unhybridized probes by inactivating the label on the unhybridized probes. Light is emitted from the RNA:DNA hybrid and results are determined based on the analyte signal to cutoff. Collected in ThinPrep liquid cytology specimens. Detects messenger RNA overexpressed by the E6 and E7 oncogenes in 14 hrHPV types. Full automation of these assays is accomplished on

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the TIGRIS DTS system and later approved for the Panther System in 2013. The APTIMA HPV-16/18/45 genotype assay is a separate reaction used to specifically identify the HPV-16, HPV-18, or HPV-45 type.

3.5 Clinical Performance of HPV Assays An analysis of the last 2 years of CAP Proficiency surveys for the hrHPV ThinPrep methodology reveals that an average of 7% of laboratories use the Qiagen HC2 assay, 10% use Cervista®, 37% use Cobas®, and 46% use the Aptima® assay. There is higher use today of the Cobas® and Aptima® assays. One reason may be comparable levels of sensitivity across the assays, but increased specificity with the newer assays. A large contributor to the increased specificity of the Cervista®, Cobas®, and Aptima® assays has to do with lower levels of cross-reactivity with low-risk HPV types [124–128]. Cross-reactivity between low-risk and high-risk HPV genotypes is highest in the Qiagen HC2 assay with an estimated 5%–10% false-positive result due to cross-reactivity with low-risk HPV genotype(s) [129,130]. Another potential reason that users have switched toward the Cobas® and Aptima® assays is the required sample volume, which in the newer assays is 1 mL from the ThinPrep vial vs 4 or 2 mL.

4. CERVICAL CANCER SCREENING Historically cervical cancer screening recommendations have changed relatively rapidly since the introduction of the Pap test reflecting emerging data and understanding of the pathogenesis of cervical cancer. Prior to 1980 the ACS recommended a Pap test “as part of a regular checkup” [119]. From 1980 to 1987 the recommendation for cervical cancer screening was for annual Pap smears with cervical cytology for women over the age 20 (younger if sexually active) and if two negative Pap tests, this could be spaced to every 3 years. This was revised in 1987 to recommend yearly Pap testing for women 18 years and older with spacing of screening at the discretion of the provider. Up to this point, the majority of screening recommendations were based on expert opinion. In 2002, following the ASCUS–LSIL triage group randomized control trial adding reflex HPV testing for abnormal cytology, screening parameters again changed, increasing in complexity with new agebased variations with the addition of HPV cotesting in women over the age of 30 [119,131,132]. In 2012, the ACS, ASCCP, and the ASCP developed a set of guidelines with the goal of providing unified, evidence-based recommendations aimed

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at detecting precancerous lesions while simultaneously reducing the risk of overtreatment [131]. Despite general agreement among 11 national and international organizations around these guidelines, there remain challenges in uptake and adherence. In a study by Teoh et al. looking at provider adherence to the 2012 guidelines, in a cross-sectional survey, 12.1% of providers were not aware of the changes made in these guidelines and only 5.7% were able to answer questions correctly regarding the information in the 2012 guidelines [133]. Despite evidence-based recommendations, providers and patients have been slow to change practice, often opting to continue annual testing. Since that time, additional changes have been made to screening recommendations after the FDA approved the Cobas HPV test in April of 2014 for use in primary HPV testing [134]. This section will review the most up to date recommendation from major organizations as well as the evidence behind these recommendations to guide clinical screening practice. This section will include recommendations and evidence for onset, interval, modality, and duration of screening and will also address screening in special populations. Finally, it will review areas in need of further study to improve screening programs to further reduce the incidence of cervical cancer.

4.1 The Current Cervical Cancer Screening Guidelines Although screening is a vital part of a successful prevention program, a complete program should include primary prevention with vaccination as well as management of abnormal screens with diagnostic testing such as colposcopy and biopsies and treatment of high grade or persistent abnormalities with ablative or excisional procedures. While management of screening abnormalities will not be discussed in this chapter, it is important to note that proper triage and treatment of abnormal results are critical to an effective prevention program. The goal of screening is to optimize the detection of precancerous lesions in healthy individuals at a time when the disease is treatable while limiting the harm of overtreating benign disease. Ten prominent organizations have published guidelines in the last 5 years to guide clinicians and improve screening practices. This has been led by the updated guidelines released by the ACS, ASCCP, and the ASCP. The ACS/ASCCP/ASCP guidelines were developed with the intent to provide an evidenced-based optimal screening strategy. These guidelines employed a rigorous process laid out by the Institute of Medicine to perform an unbiased review of the literature

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using the Grading Recommendations Assessment, Development, and Evaluation (GRADE) system. They also sought public evaluation and comment prior to submission to add strength and transparency to the guidelines. Because of the relative rarity of cervical cancer, in these guidelines, “benefit” was defined as a higher detection of high-grade dysplasia or higher (CIN3+) and a reduction in CIN3+ at subsequent rounds of screening. “Harm” was defined as an increased number of colposcopies. At the time of publication of the majority of the guidelines in 2012, primary screening with HPV testing was not recommended, based on the limitation number of studies with long-term follow-up, data on actual cancer prevention, and no clear recommendations for triaging an abnormal test [131,134–141]. Estimates of the number of colposcopies performed if all positive HPV tests were triaged to evaluation suggest an absolute increase in the number of colposcopies by 4%, such that the harm would outweigh the benefit [131]. However, following the publication of the ATHENA trial in 2015, experts from Society of Gynecologic Oncology (SGO)/ASSCP state that primary HPV may be an appropriate screening alternative in women ages 25–65 if managed according to the algorithms followed in the ATHENA trial [134]. In 2016 ACOG published an update to their guidelines now including primary HPV screening as an alternate screening strategy [135]. Table 5 outlines the screening recommendations currently available for each organization. 4.1.1 Screening Modalities In regards to modality of screening, there are currently five FDA-approved technologies available: conventional cytology, liquid-based cytology, cotesting with liquid-based cytology and HPV testing, HPV genotyping for triage, and primary hrHPV testing. The details of these assays have been discussed in Section 3. Conventional cytology uses cervical cells which are applied directly to a microscope slide following collection and subsequently interpreted. Liquid-based cytology utilizes cervical cells which are collected and then are suspended in a preservative media to allow for subsequent interpretation in a laboratory setting. In a meta-analysis by Arbyn et al. conventional cervical cytology and liquid-based cytology demonstrated similar sensitivities and specificities in individual studies though liquid-based cytology had a slightly lower pooled specificity when using atypical squamous cells of undetermined significance (ASCUS) as a cutoff [143]. A subsequent randomized control trial using CIN as a cutoff found no significant difference between detection of CIN1, 2, or 3 and found similar adjusted positive

Table 5 Cervical Cancer Screening Guidelines From Major Organizations Onset of Screening

Preferred Method of Screening

Definition of High-Risk Cessation of Screening Patients

Screening for High-Risk Patientsa Prior Hysterectomy

Organization

Date

ASCCP/ ASCP/ACS [131]

2012 21

Age 21–29: cytology q3yrs 65—if adequate prior Age 30–65: negative screeninga – Cytology with HPV cotesting q5yrs – Alternative q3yr cytology

NCCN guidelines panel for cervical cancer screening [139]

2012 21

Age 21–29: 65—if adequate prior – – Cytology q3yrs with reflex HPV screeninga (and no hx – (ASCUS, HPV + colpo, of prior abnormal ASCUS, HPV negative rescreen cytology) – with cytology in 3 years) – Continue screening – for women with Age 30–65: high-risk features – Cytology with HPV cotesting – May discontinue in q5yrs is preferred women with – Cytology w3yr is also acceptable life-threatening – Screening with HPV alone is conditions not recommended

USPSTF [136]

2012 21

Age 21–65: 65 High-grade precancerous Excluded Recommend screening with q3yr – Caveat: after lesions or cervical cancer cytology 65 may be indicated – DES exposure – If desired lengthening of if no prior screening – Immunocompromised screening interval may consider or for high-risk women HPV cotesting q5yrs “as a patients reasonable alternative” after age 30 – Recommends against primary HPV or HPV cotesting in women < 30 years

– – – –

Hx of CIN2 or more Excluded Hx of cervical cancer DES exposure Immunocompromised women

HIV infection Immunocompromised women DES exposure Women with prior treatment for CIN2 or greater

HPV Vaccination

No screening Continue routine screening as per Caveat: age-specific 1. Retention of cervix guidelines 2. Hx CIN2 or more requires 20 years of screening

Continue routine HIV, solid-organ transplant, or No screening screening as per long-term steroid use may need Caveat: more frequent screening 1. Retention of age-specific – HIV: q6months for 1 year cervix guidelines after diagnosis then annual 2. Hx CIN2 or more screening (does not specify requires 20 years of cytology vs HPV) screening – DES exposure: recommend more frequent screening, usually annually as determined by their physician No screening Continue routine Caveat: screening as per 1. Retention of age-specific cervix guidelines 2. Hx CIN2 or more requires 20 years of screening

AMAa

2014 21

Age 21–29: 65—if adequate prior Cytology q3yr negative screeninga Age 30–65: – Cytology with HPV cotesting q5yrs is preferred – Cytology q3yrs is an alternative

– HIV infection Not addressed – Immunocompromised women – DES exposure – Women with prior treatment for CIN2 or greater

No screening

WHO [140] 2014 30

Adolescent to age 30: 49 (or determined by Women with HIV – Primary prevention with HPV national standards) infection vaccination and education Age 30–49: Screen and treat at least once: – Options include – HPV testing and treatment for positive results (with or without triage) – If negative for HPV rescreen in minimum 5 years – Visual inspection with acetic acid (VIA) in women who have a visible transformation zone – Cytology – If negative for VIA or cytology rescreen in 3–5 years – Concomitant screening for HIV in endemic areas

ACP [138]

65—if adequate prior – High-grade Excluded No screening Age 21–65: Cytology q3yrs or HPV cotesting q5yrs beginning in negative screeninga Caveat: precancerous lesions or women age 30–65 – Ending screening cervical cancer – American Society of 1. Retention of prior to age 65 in – DES exposure Nephrology recommends cervix against screening women with women with – Immunocompromised life-limiting women (including end-stage renal disease on comorbid HIV) dialysis with limited life conditions is expectancy reasonable (limited evidence)

2015 21

For women with HIV: screen at Not addressed diagnosis – If negative test q3yrs – If treated for precancer lesion follow up in 1 year

Not addressed

Continue routine screening as per age-specific guidelines

Continue routine screening as per age-specific guidelines

Continued

Table 5 Cervical Cancer Screening Guidelines From Major Organizations—cont’d Organization

Date

Onset of Screening

Preferred Method of Screening

Definition of High-Risk Cessation of Screening Patients

Screening for High-Risk Patients

Prior Hysterectomy

HPV Vaccination

Not addressed

Not addressed

Not addressed

Not addressed

Age 21–25: 65—if adequate prior Not addressed Cytology q3yrs negative screeninga Age 25–65: – Option for q3yr primary HPV testing (triage for positive test: hr genotyping 16/18 1. If positive ! colposcopy 2. If “other high-risk types” ! cytology, if ASCUS + colposcopy 3. If negative ! repeat in 1 year Age 30–65: Cytology with HPV cotesting q5yr or q3yr cytology or primary HPV testing as above

Not addressed

Not addressed

Not addressed

ACOG US 2015 Not Alternative screening methods in Not addressed Pacific Islandaddressed resource poor settings: PB 624 [142] – VIA with subsequent cryotherapy if abnormal – HPV testing followed by treatment with cryotherapy if positive SGO/ ASCCPinterim clinical guidance [134]

2015 21

ACOG-PB 157 [135]

a

2016 21 except Age 21–29: cytology q3yrs 65—if adequate prior women Age 30–65: negative screeninga with HIV – Cytology with HPV cotesting q5yrs preferred – Q3 yr cytology is acceptable – Alternative screening strategy of primary hrHPV testing q3yrs beginning at age 25 if performed according to SGO/ASCCP interim guidance algorithms – Regardless of screening interval, annual well women visits recommended

– HIV infection – Recommend for HIV and No screening Continue routine – Immunocompromised immunosuppression: initiate Caveat: screening as per agewomen (i.e., solidscreening at the time of sexual 1. Retention of specific guidelines organ transplant) debut (regardless of mode of cervix – DES exposure HIV transmission) and no 2. Hx CIN2 or more – Women with prior later than 21 recommendation treatment for CIN2 + – Annual cytology for 3 years q3yr cytology for following diagnosis: if all 20 years negative may lengthen interval to q3yrs – For women 30 years + screening may be with cytology or cotesting. If one negative cotest may screen q3yrs – Low-grade abnormalities (LSIL or ASCUS/HPV +) should be evaluated with immediate colposcopy – For DES, recommend annual cytology

Adequate prior negative screening is defined as three consecutive negative cytology results or two negative cotests in the last 10 years with the most recent evaluation in the last 5 years. For women with a history of CIN2 or higher, routine screening should be continued for 20 years after regression or treatment even if extending beyond age 65. ASCCP, American Society for Colposcopy and Cervical Pathology; ASCP, American Society for Clinical Pathology; ACS, American Cancer Society; ACOG, American Congress of Obstetrics and Gynecology; SGO, Society of Gynecologic Oncology; AMA, American Medical Association; NCCN, National Comprehensive Cancer Network; USPSTF, United States Preventive Services Task Force; ACP, American College of Physicians; WHO, World Health Organization.

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predictive value ratios between conventional and liquid-based cytology, suggesting they are essentially equivalent modalities [143,144]. Several HPV tests have been approved to be used in combination with cytology for cotesting, and HPV genotyping for high-risk subtypes 16 and 18 has been approved following cotesting in the setting of negative cytology and a positive HPV cotest [138]. The most recently approved testing modality is hrHPV testing in which cervical cells are collected in a similar liquid media and DNA testing for hrHPV subtypes is performed. The FDA-approved Cobas HPV test detects HPV type 16 and 18 as well as 12 other high-risk subtypes in a pooled analysis. To date, the Cobas HPV test is the only FDAapproved HPV test to be used in primary HPV screening [134,138]. Any of the FDA-approved modalities may be used as outlined later based on clinic access, availability of pathologic analysis, and provider comfort with test interpretation. 4.1.2 Onset of Screening Among the 10 organizations, there is consensus among 9 of the organizations that screening should begin at the age of 21 regardless of sexual debut [131,134–141]. The incidence of cervical cancer in women under 20 is 1–2 cases per 1,000,000 females, and further, screening may not be preventative in this population as the incidence of cervical cancer in adolescents has remained unchanged despite initiation of screening, unlike the remainder of the population which has shown a 60% reduction in cervical cancer following the initiation of screening [131,135,138]. Furthermore, the incidence of HPV is highest following the initiation of sexual intercourse, but has been shown to resolve spontaneously in 85%–90% of young women within 2 years with the majority clearing within 8 months [135]. Thus, many organizations, in particular the US Preventive Service Task Force (USPSTF) and American College of Physicians (ACP), cite the increased harm of overtreatment in this age group and the associated pain, anxiety, cost of treatment, as well as the risk of preterm delivery from multiple cervical treatments [136,138]. The USPSTF also notes that the prevalence of CIN3 in women under 21 is estimated at 0.2%, while the false-positive cytology rate is reported at 3.1% again emphasizing the potential harm of early screening [136,137]. Overall, the consensus for adolescents is to focus on primary prevention with education and universal vaccination [131,134,137–140]. The updated ACOG guidelines only recommend screening prior to age 21 for women with HIV, regardless of the mode of transmission [135].

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4.1.3 Screening Modality and Interval for Women Age 21–29 All US organizations recommend screening women age 21–29 with cervical cytology (either with conventional or with liquid-based cytology) every 3 years [131,134,135,137–140]. While the 2012 guidelines recommend against HPV testing in this population either as primary testing or as cotesting [131,134,137–140], updated guidelines from ACOG reflecting the interim recommendations from SGO and the ASCCP suggest that primary hrHPV testing every 3 years with the FDA-approved Cobas test may be used as an alternative screening strategy for women age 25 and older [134,135]. The evidence for the screening interval of 3 years in this population comes from modeling studies [131,137]. The estimated lifetime cervical cancer risk in the absence of screening is 31–33 per 1000 women [137]. Modeling studies compared the lifetime cervical cancer risk between annual, every 2 years, and every 3 years screening interval and found that while the lifetime risk of cancer diagnosis is slightly decreased with annual screening (3 per 1000 for annual vs 4–6 per 1000 for every 2-year vs 5–8 per 1000 for every 3-year screening, respectively), the predicted lifetime risk of death due to cervical cancer is essentially unchanged at 0.03 vs 0.05 vs 0.05 per 1000 women [131,137,145]. In contrast, the risk of harm was significantly higher in the annual screening model with more than double the colposcopies compared to every 3 years [131]. There was no significant difference in the odds ratio of the risk of invasive cancer following the last negative cytology between a 2- and 3-year interval (OR 1.2, CI 0.65–2.21); however, there was a rise in cancer risk at intervals over 3 years, suggesting that a 3-year screening interval is the optimal balance between benefit and harm in this age group [131,146]. The available evidence regarding HPV testing has consistently demonstrated an improved sensitivity as compared to cytology (95% vs 40%–70%), a slightly lower rate of CIN3 following a negative test, but also a lower specificity (94% vs 97%, respectively) [131,147–149]. The 2012 guidelines noted that the harm of HPV testing in this population outweighed the benefit, suggesting that higher rates of largely transient infections with a higher sensitivity with HPV testing would lead to unnecessary procedures. The majority of data on primary HPV testing have been from large, European studies; however, the publication of the ATHENA trial in 2015 leads to the consideration of primary HPV as a viable screening option in the United States [147,150–152]. In the ATHENA trial, Wright and colleagues analyzed over 40,000 women over the age of 25 who received both primary HPV and cytology testing. The triaging strategy proposed in the ATHENA trial

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was for repeat screening in 3 years for HPV-negative patients, immediate colposcopy for HPV-16 or -18 positive patients, and for women with other HPV genotype positivity, reflex cytology was recommend with colposcopy if the results were ASCUS or greater. Women with negative triage cytology would have a repeat cotest in 1 year. At baseline, 10.5% of women were HPV positive with 6.4% demonstrating cytology abnormalities. The 3-year cumulative incidence rate for CIN3+ with a negative test was lowest with cotesting at 0.3% vs 0.38% with primary HPV vs 0.8% with cytology. HPV also improved detection of cancers, as well as adenocarcinoma in situ, compared to cytology alone [150]. While HPV was more prevalent in women 25–29, they also found an increased sensitivity for detection of CIN3+ over cytology in this age group. Both the hybrid cotesting strategy and primary HPV were associated with absolute increased number of colposcopies; however, there were a similar number of colposcopies per case of CIN3+ detected at 12.8 compared to 10.8 for cytology [150]. These data led to the FDA approval of the Cobas test (hrHPV test utilized in the ATHENA trial) and led to the updates in current recommendations to include primary hrHPV screening as an alternate screening strategy. Some important caveats are that there is no data supporting other HPV tests for primary testing, the exact triage algorithms must be followed as outlined in the ATHENA trial, as explained in the SGO/ASCCP interim guidance, and there are no cost-effectiveness or long-term follow-up studies to determine applicability and efficacy in clinical practice. 4.1.4 Screening Modality and Interval for Women Age 30–65 The ACS/ASCCP/ASP, ACOG, SGO, National Comprehensive Cancer Network (NCCN), and American Medical Association (AMA) recommend screening every 5 years with cervical cytology and HPV cotesting as the preferred method for women 30–65. Screening with cytology every 3 years is recognized as an acceptable alternative and as of 2016; ACOG, SGO, and the ASCCP recognize primary hrHPV testing every 3 years as another acceptable alternative [134,135]. There is a body of evidence that suggests that the addition of HPV testing results in an increased sensitivity and only slightly decreased specificity, resulting in an increased detection of CIN3 while providing a similar or lower cancer risk than screening cytology alone every 3 years [131,141,147,148]. Four European randomized control trials have compared cotesting to cytology screening, and in each trial, the cotesting arm showed an absolute increase in detection of CIN3 and an absolute decrease in cancer in the second round of screening [131,141,151–155]. The

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ARTISTIC trial, which included a longer follow-up period up to 6 years after the initial screen, found the cumulative rate of CIN2+ was 1.41% for negative cytology and 0.87% for negative HPV [154–156]. In a pooled analysis by Dillner et al. of seven European studies screening over 24,000 women, the cumulative incidence rate (CIR) of CIN3+ at 6 years following a negative baseline HPV test was 0.27% (CI 0.12%–0.45%) and was lower compared to the CIR of CIN3+ at 3 years following a negative baseline cytology 0.51% (0.23%–0.77%) [147]. This evidence supports the recommendation for increased screening intervals with cotesting and may even suggest the possibility of extended intervals with negative primary HPV testing though more data are needed [131,135,141,147,157,158]. Cotesting also has improved detection of adenocarcinoma compared to cytology and in the posttreatment surveillance of ACIS; hrHPV positivity has been shown to be the most significant independent predictor of recurrent or progressive disease [157,158]. A modeling study further supported increased screening intervals with HPV cotesting, demonstrating that over a 10-year study period, there was only a modest decrease in lifetime cancer risk (0.39%) with cotesting every 3 years compared to every 5 years (0.61%), while there was a significant increase in harm [131,137]. In a United States population-based study by Katki et al. looking at over 330,000 women, the 5-year cumulative incidence of cancer was 3.2 per 100,000 for negative cytology with HPV cotesting vs 7.5 per 100,000 with negative cytology alone [148]. These data suggest that with the added sensitivity of HPV cotesting, an extended screening interval allows for a minimal risk while decreasing the harm of increased colposcopies with shorter screening intervals. The USPSTF, on the other hand, recommends cytology every 3 years as the preferred modality of screening with HPV cotesting only for those wishing to extend the screening internal [136]. For the development of their guidelines the USPSTF performed a decision analysis to clarify screening intervals as well as to address the benefits and harm of over- vs underscreening [136]. While it is recognized that both modalities demonstrate a comparable balance between benefit and harm, the USPSTF suggests that HPV cotesting may prolong surveillance for women nearing the end of screening who test positive for HPV with otherwise negative cytology resulting in increased harm with minimal benefit [136]. This is based on data that upward of 11% of women age 30–34 years and 2.6% of women age 60–65 years will fall into the category of cytology negative, HPV positive who then require repeat evaluation in 1 year, potentially extending

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screening intervals [136,159]. At the time of publication, the USPSTF has not addressed the addition of primary hrHPV testing in screening practices. The ACP recognizes all published guidelines and suggests that either cytology every 3 years or cytology with HPV cotesting every 5 years are viable options for women age 30–65 [138]. The ACP does address the cost of screening, citing a lower cost with cytology but a cost benefit with increased screening intervals [138,160]. The ACP also warns against the significant increased cost of annual screening in a low-risk population [138]. Goldie et al. reviewed the cost-effectiveness and reduction in cancer risk of varying screening models in cytology alone every 1, 2, 3, or 4 years and cytology with HPV cotesting every 1, 2, 3, or 4 years and found that cotesting every 3 or 4 years had a 89%–91.3% reduction in cancer risk with a slightly higher incremental cost-effectiveness ratio than cytology alone every 3 years [160]. This study does not provide cost-effectiveness data for cotesting every 5 years as recommended in the guidelines, but ultimately the extended screening interval for cotesting provides a balance between the benefit of improved detection of dysplasia, cost-effectiveness, and harm of screening. In 2014 in response to the guidelines released by the USPSTF the AMA also petitioned for third-party payers to amend metrics to reflect these recommendations (as seen in Table 5). 4.1.5 Cessation of Screening In regards to exiting from screening, all US organizations recommend the discontinuation of screening at age 65 with adequate prior negative screening [131,135–139,141]. Adequate prior negative screening is defined as three consecutive negative cytology or two consecutive negative HPV results in the last 10 years with the most recent test within the last 5 years. All US guidelines agree that women with a history of CIN2+ should continue routine screening for at least 20 years following the initial increased period of surveillance even if this extends beyond age 65 as these women retain a 5- to 10-fold increase risk of cervical cancer compared to the general population [131,135–141]. The evidence for discontinuation of screening is based primarily on a single modeling study with a model of continued screening up to age 90 [137]. A prolonged screening model only resulted in the reduction of 1.6 cancer cases and 0.5 cancer deaths per 1000 women compared to an additional 127 colposcopies per 1000 women [131,137]. ACOG also suggests that vulvovaginal atrophy contributes to a higher rate of false-positive cytology which is supported by data from Sawaya et al. who reported that only 1 out of 110 postmenopausal women with abnormal

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cytology following a previously normal screen had dysplasia on biopsy (PPV 0.9%) [135,141,161]. The ACP does address the possibility of early discontinuation for women with life-limiting comorbidities given an estimated 10 years for disease progression, though evidence is limited [138]. The 2016 ACOG guidelines stress the importance of discontinuation of all screening modalities including primary HPV testing in women with prior negative screening. It has been reported that 19.6% of the new cases of cervical cancer are in women over the age of 65; however, most cases are in women who are unscreened or underscreened reflective of the slow disease progression [135]. Taking an accurate and thorough screening history is paramount prior to the discontinuation of screening to avoid underscreening patients with a history of prior abnormalities who may benefit from ongoing evaluation. 4.1.6 Screening Following Hysterectomy All US guidelines are in agreement recommending the discontinuation of screening, regardless of age, for a woman undergoing hysterectomy for benign disease without a history of CIN2+ [131,135–139,141]. These patients do not require adequate prior negative screening because the risk of vaginal cancer is so low (reported at 0.18 per 100,000 women), and additionally, the positive predictive value for vaginal cytology is poor. In a systematic review of 19 studies of patients undergoing total hysterectomy both with and without a history of CIN, for women without CIN, 1.8% had abnormal cytology and 0.12% had vaginal intraepithelial neoplasia (VAIN) on biopsy compared to women with a history of CIN2+, of whom 14.1% had abnormal cytology, 1.7% had VAIN, and one patient had vaginal cancer [135,141,162,163]. A patient who undergoes a supracervical hysterectomy should continue routine screening, and diagnostic cytology should still be performed for all symptomatic patients. The updated ACOG recommendations recommend against primary HPV testing in women without a cervix. 4.1.7 Screening for High-Risk Populations One of the limitations of the majority of the guidelines, including the ACS/ ASCCP/ASCP, AMA, SGO, the ACP, and the USPSTF, is they were developed specifically to guide screening for the general population and do not address screening for high-risk populations defined in these studies as patients with immunosuppression, diethylstilbestrol (DES) exposure, or patients with prior abnormal cytology with CIN2+ [131,136,138]. In the

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updated ACOG guidelines they do cite updated recommendations from the Panel on Opportunistic Infections in HIV-infected adults and adolescents on screening for women with HIV (Table 5) [135]. Immunosuppression increases the risk of persistent HPV infection in women with HIV and has been shown to expedite the progression to invasive cervical carcinoma from 15.7 years in the general population to 3.2 years in women with acquired immunodeficiency syndrome, and in a large North American cohort study, the incidence of invasive cervical cancer was 26 per 100,000 person-years in HIV-positive women compared to 6 per 100,000 person-years in their HIV-negative counterparts [164,165]. In regards to screening modality, a multicenter International study evaluating cytology, colposcopy, and HPV testing for HIV-positive women: the sensitivities of baseline cytology, HPV testing, cotesting, and colposcopy were similar for the detection CIN2+ at 93.3%, 91.3%, 86.8%, and 98.0%, while HPV testing demonstrating a significantly lower specificity at 47.7% compared to other modalities ranging from 62.9% to 76.7% [166]. While small studies in resource poor settings demonstrate the feasibility of self-collection of hrHPV for women with HIV, there is limited data currently available to support the use of primary HPV testing and primary HPV testing has not been approved or validated in high-risk populations [135]. Data suggest that following three negative annual cytology results for HIV-positive women with normal range CD4 counts, the 3-year risk of high-grade dysplasia is 1% making it reasonable to consider extended screening intervals up to 3 years which is reflected in the newest ACOG and CDC recommendations [167,168]. Screening recommendations for women with HIV have been extrapolated to apply to all women who are immunocompromised, but there are no evidence-based guidelines to direct this care. The American Society of Transplantation recommends annual cytology and pelvic examination for women with a history of solid-organ transplant, though these recommendations are based on limited evidence [169]. The updated ACOG guidelines recommend screening similar to women with HIV, and the NCCN suggests that women with immunosuppression may require more frequent screening, though an optimal interval is left to the discretion of the provider [135,139]. Data show an increased rate of cervical cancer following kidney transplant with a standardized incidence ratio of 2–5 [164,169]. The data regarding cervical cancer risk with autoimmune diseases remain mixed, though overall there does appear to be an increased risk of dysplasia. In a population-based cohort study of over 130,000 women with all

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autoimmune diseases, the crude incidence rates of severe dysplasia were highest with SLE and lowest in psoriasis, though still elevated compared to the general population [170]. SLE appears to confer a substantially elevated risk of high-grade dysplasia, with risks ranging from 1.5- to more than 8-fold higher than the general population [170,171]. A meta-analysis including eight studies on women with IBD on varying immune therapies demonstrated a modest increased risk of CIN2+ (OR 1.34, CI 1.23–1.46) [172]. These data are limited by the heterogeneity of the studies with varying immunosuppressive agents, though five of the studies independently suggest a small but statistically significant increase in cervical cancer with IBD [172]. No recommendations are made on the role of HPV testing in this population in any of the above guidelines. 4.1.8 Screening in a Resource Poor Setting Several of the guidelines discuss the challenges and barriers to screening; however, the World Health Organization (WHO) and ACOG specifically outline recommendations for screening in a resource poor setting [140,142]. More than 80% of cervical cancers occur in developing nations, and cervical cancer mortality is predicted to rise by 25% over the next 10 years in low- to middle-income countries [140,142]. ACOG produced a committee opinion in 2015 to help guide care, specifically in areas such as the US-affiliated Pacific Islands where only 55% of women had received cervical cancer screening in the 5 years prior to the development of the guidelines [142]. They suggest alternate options for screening when access, cost, and available personnel for test interpretation and treatment are limited. The WHO has produced evidence-based guidelines, endorsed in this committee opinion, for a “screen and treat” model for secondary prevention [140]. The WHO recommends initiation of secondary prevention with screening from age 30 to 49 with HPV testing or visual inspection with acetic acid (VIA). For primary HPV testing, when available, it is recommended either to triage HPV-positive tests with VIA or to cytology [140]. Success rates with VIA and treatment with cryotherapy have been reported up to 70% for eradication of CIN3 [55]. In regards to primary HPV testing in this population, a prospective study in rural India demonstrated a 50% reduction in cervical cancer mortality and advanced stage cervical cancer diagnosis with a single lifetime HPV test compared to controls [142,173]. This was reproduced in a South African study where HPV testing with subsequent cryotherapy showed a 77% reduction in CIN3+ compared to a 38% reduction with VIA and cryotherapy [142,174]. ACOG addresses some

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limitations of using primary HPV including increased cost compared to VIA and the role of triaging positive tests and increased visits which can be a major challenge in this population. It has been proposed that this may be circumvented with patient-collected HPV where promising data have suggested equivalent sensitivities to provider-collected samples [142].

4.2 Future Directions of Cervical Cancer Screening Although the guidelines are evidence based and generally in agreement on screening average-risk women—with onset at age 21, screening every 3–5 years if all normal results until age 65, there are several important areas of future investigation to optimize screening practices and further reduce the risk of cervical cancer. An effective strategy to prevent cervical cancer is multifactorial including primary prevention with vaccination, optimization of screening for average-risk women and proper utilization of new screening technologies, triage of patients risk for future dysplasia, and appropriate treatment of abnormal results. Data from 2015 have demonstrated a role for HPV testing as an alternative primary screening strategy which is supported by current guidelines. While the data on primary HPV testing appear promising in detecting and reducing CIN3+, without cost-effective data and long-term followup on the incorporation of triaging algorithms into clinical practice, generalization of the data remains limited. Primary HPV testing is an appropriate alternate option; though, ongoing research is needed on long-term outcomes and translation into a clinical practice. Several recent studies have compared cervical cancer screening approaches—specifically comparing primary cytology, primary HPV testing, and cotesting. Blatt et al. compared the efficacy of cotesting vs primary HPV and primary cytology among a retrospective cohort of greater than 250,000 women whose specimens were processed by Quest diagnostics [175]. They found that the negative predictive and positive predictive values were almost identical among the three options, although the sensitivity of cotesting at 98.8% was better than HPV alone (94%) over one round of testing. Since the 4% improvement in sensitivity resulted from double the number of initial tests (since two tests were by definition done on all patients), and presumably an increase number of downstream colposcopies, the cost of this approach must be considered as well by studying a programmatic approach over time which considers consecutive screening rounds.

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Choi et al. studied 1000 cervical cytology samples at Korea University Ansan Hospital which were obtained for screening. These samples were tested using liquid-based cytology, Hybrid Capture 2, and real-time HPV genetic PCR. Patients were then evaluated by colposcopy using standard clinical algorithms, and pathology results were used to calculate the clinical performance of each option. They found that “primary HPV screening alone was equivalent to that of cotesting for CIN2+.” They noted that primary HPV screening can be performed economically and with a simple algorithm, but due to its lower specificity may result in an increased referral for colposcopy for a subgroup of patients [176]. More data are needed in real clinical settings over time to provide overall programmatic costeffectiveness, especially as increased rates of HPV vaccination may alter the underlying prevalence of HPV and thus the specificity of primary HPV testing. There are also limited data guiding screening practices in “high-risk” women, in particular, women who are immunosuppressed. Data suggest that there is an increased risk of cervical cancer in women with HIV, and there appear to be a spectrum of risk associated with autoimmune diseases: specifically, women with SLE and IBD on immunomodulator therapy appear to have a modest increased risk for high-grade dysplasia and cervical cancer compared to the general population; however, the impact of duration and strength of immunomodulator therapy on cancer risks is not well defined. Optimal screening intervals and modalities are still not clear from the current literature in this population and warrants further investigation. Compliance with screening remains a major barrier to care across many populations, but in particular, in those high-risk populations as seen in women with HIV, solid-organ transplant, and in underserved communities. Also, while rapid advancements in research provide improved knowledge on prevention of cervical cancer, it is often difficult for providers across multiple specialties to remain abreast to changes and to educate their patients about the most current recommendations. A recent article by Kim et al. using population-based data from a state-wide registry in New Mexico studied the cost-effectiveness of “current screening practice” which includes both over- and underscreening women in real practice and found current practice to be less cost-effective than improved compliance with screening at 3-year intervals [177]. Similarly, the low vaccination rates in the United States preclude significant changes in screening recommendation for this population which is a barrier to care. Improving compliance with primary

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prevention, as has been suggested internationally, likely would optimize screening programs and further investigation is needed. Ultimately provider and patient education and improved compliance in prevention, screening, and treatment are critical for the uptake of evidence-based practices and the reduction of cervical cancer.

5. HPV VACCINES AND THE IMPACT ON CERVICAL CANCER SCREENING HPV vaccines consist of type-specific HPV L1 proteins that are capable of self-assembly into VLPs. VLPs do not contain vDNA, and thus are noninfectious. The FDA currently licenses three HPV vaccines. Cervarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is a bivalent vaccine that provides protection against HPV types 16 and 18, which are responsible for approximately 70% of cervical cancer cases. A quadrivalent HPV vaccine, Gardasil (Merck, Kenilworth, NJ) adds protection against HPV types 6 and 11, which cause the majority of genital warts, in addition to types 16 and 18. A 9-valent HPV vaccine, Gardasil 9 (Merck) was licensed by the FDA in 2014, and covers five additional strains of HPV to include HPV-31, -33, -45, -52, and -58. The addition of these five HPV types in the 9-valent vaccine is expected to increase cervical cancer protection to approximately 90% [178]. The vaccine VLP components are each generated and purified individually and then combined [28]. Cervarix uses the adjuvant AS04, which consists of aluminum hydroxide and monophosphoryl lipid A. The aluminum adjuvant aluminum hydroxyphosphate sulfate is used for the quadrivalent and 9-valent vaccines. Aluminum salt adjuvants promote strong antibody responses with generation of a primarily T-helper 2 immune response [179]. Monophosphoryl lipid A is an agonist of toll-like receptor 4 that promotes formation of antigen-specific interferon-gamma-producing CD4+ T cells, thus skewing toward a Th1 immune response; therefore, the AS04 adjuvant used in Cervarix has the potential to promote both Th1 and Th2 responses [180].

5.1 Immunogenicity of HPV Naturally acquired HPV genital infections are cleared due to cell-mediated immune responses. Antibodies against the type-specific HPV viral capsids may be generated; however, this only occurs in approximately 60% of women with incident HPV infection [51]. This is likely because natural

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HPV infection does not cause viremia, and viral particles do not localize to the vasculature and lymph nodes where acquired immunity is generated [181]. Unfortunately, the humoral immune responses that do get generated by natural HPV infection result in low antibody titers that may not persist. The specific role of humoral responses induced by naturally acquired HPV infection in preventing additional HPV infections is uncertain [51]. The intramuscular delivery of HPV vaccine VLPs results in antigen distribution to lymph nodes, enabling the induction of acquired immunity [181]. VLPs administered intramuscularly alone without adjuvant are immunogenic and induce high-specific antibody titers [181,182]. Several studies have been conducted examining antibody titers in clinical trial patients administered the vaccine. Nearly 100% of patients administered either the bivalent or the quadrivalent vaccine seroconvert with a significant increase in the geometric mean titers after the third dose [180,183–186]. It has been noted that the two companies manufacturing the vaccine used different assays for measuring antibody titers, and thus antibody titer results from the main clinical trials are not directly comparable [187]. However, higher mean geometric antibody titers have been reported for Cervarix in studies directly comparing it to the quadrivalent vaccine [188,189], a finding attributed to the enhanced immune activation caused by the adjuvant AS04 [187]. Immunogenicity of the 9-valent vaccine has also been evaluated. The 9-valent vaccine administered in three doses to 3066 boys and girls ages 9–15 years resulted in seroconversion and increases in titers to all of the HPV types included in the vaccine [190].

5.2 Vaccine Efficacy Proof of concept that a vaccine against hrHPV types could protect against type-specific HPV infection was first demonstrated by administration of a HPV-16 VLP vaccine or placebo to 2392 women ages 16–23 years, which showed a reduction in incident HPV-16 infection and CIN in women administered the vaccine [191]. Follow-up of this population for 8.5 years demonstrated that vaccine recipients did not develop HPV-16 infection or its associated cervical lesions [192]. Several phases II and III studies with multiple subanalyses have since been performed [28,187,193]. The major phase III trials are summarized in Table 6. Cervarix was evaluated by the Costa Rica Vaccine Trial (CVT) and Papilloma Trial Against Cancer in Young Adults (PATRICIA) trials, while Females United to Unilaterally Reduce Endo/Ectocervical disease (FUTURE) I and II evaluated Gardasil.

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Table 6 Summary of Phase III Clinical Trials of the HPV Vaccine Vaccine Trial Evaluated Participants Endpoint

CVT

Cervarix

7466

Development of persistent HPV-16/18

FUTURE I

Gardasil

5455

HPV-6/11/16/18 + genital warts and CIN1–3

FUTURE II

Gardasil

12,167

HPV-16/18 CIN2 +

PATRICIA

Cervarix

18,644

HPV-16/18 CIN2 +

V503-001

9vHPV

14,215

High-grade cervical, vulvar, or vaginal disease of any HPV type

CIN, cervical intraepithelial neoplasia; CVT, Costa Rica HPV trial; FUTURE, Females United to Unilaterally Reduce Endo/Ectocervical disease; PATRICIA, Papilloma Trial Against Cancer in Young Adults [194–198].

The FUTURE I, FUTURE II, and PATRICIA trials placed limitations on the number of lifetime sexual partners; however, prevalent infections with HPV determined by DNA detection, prior exposure demonstrated by serology, and abnormal cervical cytology at enrollment were not exclusion criteria. These criteria allowed the investigators to minimize the numbers of women with active infections or genital lesions, but still permit evaluation of vaccine efficacy in patients with current or prior HPV infection [187]. The trial vaccines were administered at times 0, 1–2 months, and at 6 months. The PATRICIA and FUTURE II trial endpoints included CIN grades II or III (CIN2+), adenocarcinoma in situ, or cervical cancer due to the vaccine subtypes [194,195]. FUTURE I also included vaccine subtype CIN1+, genital warts, and vaginal and vulvar intraepithelial neoplasia [196]. CVT had an endpoint of HPV-16 or -18 infection that was persistent after 1 year [197]. All four trials showed high efficacy against the HPV types targeted by the vaccine including persistent infection and cervical cytology in women who had never been infected by the HPV subtype targeted by the vaccine [194–197]. A recent study compared the 9-valent HPV vaccine to the quadrivalent vaccine and found that the 9-valent HPV vaccine prevented infection and associated cervical, vaginal, and vulvar disease caused by HPV types 31, 33, 45, 52, and 58 while preserving immune responses to types 6, 11, 16, and 18 [198]. However, the vaccines did not provide an effect for prevalent infection or cervical lesions present at the time of enrollment. Thus, the vaccine is considered most efficacious if administered prior to HPV infection. Given that HPV infection is usually

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acquired shortly after initiation of sexual activity, the series should ideally be administered before onset of sexual activity [28]. While the quadrivalent HPV vaccine has been demonstrated to have efficacy in women over age 26 [199], the public health benefit of vaccinating older women is limited due to the higher frequency of prevalent HPV infections in older women that are not impacted by vaccination. Analysis of HPV vaccine clinical trial data has demonstrated effectiveness at sites other than the cervix. Vaccinated women in the CVT trial had a 50% decrease in vulvar infection as well as an 84% reduction of anal infection due to HPV types 16 and 18 [200,201]. A vaccine efficacy of 93% was found for oral infection of HPV-16/18 4 years after vaccination [202]. The quadrivalent vaccine was shown to significantly reduce vaginal, vulvar, and perianal disease regardless of the associated HPV type [196], and has an efficacy of 99% for genital warts caused by vaccine subtypes in women ages 16–26 [183]. Vaccine efficacy has also been demonstrated in males. A trial of 4065 males age 16–26 administered the quadrivalent vaccine or placebo showed prevention of infection with the vaccine HPV subtypes and genital lesions [203]. The rates of anal intraepithelial neoplasia were significantly reduced in men who have sex with men in a trial of 602 men who were administered the quadrivalent vaccine or placebo [203]. Another study showed similar antibody responses in mid-adult men ages 27–45 compared to younger men, a finding of potential importance because men acquire new HPV infections with increasing age and HPV-associated cancers occur at an older age compared to women [204]. The HPV vaccine is recommended for administration in three doses scheduled at 0, 1–2, and 6 months for adolescents aged 11–12 years, although the vaccine series can be initiated at 9 years of age [135]. Catchup vaccination is recommended for females up to age 26, age 21 for most males, and age 26 for immunocompromised males or men who have sex with men. Immunogenicity studies and analyses of clinical trial patients who received less than three doses of the vaccine have been conducted. The antibody responses induced by two vaccine doses given at least 6 months apart were similar to those raised by three doses [205–207]; however, longevity of antibody responses with only two doses has not been sufficiently evaluated. HPV infection with vaccine subtypes is similar among the clinical trial participants who received three doses and one or two doses [200,208,209]. However, an investigation by Pollock et al. [210] did not find a significant decrease in CIN in partially immunized patients compared to unvaccinated patients. Others investigations concluded that all three doses

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of vaccine were needed to reduce the risk of high-grade histological abnormalities, although some protection was still obtained with fewer doses [211,212]. It was noted that the women who received fewer doses were older and more likely to be HPV infected compared to fully vaccinated patients, suggesting demographic and behavioral characteristics may be associated with partial vaccination [211,212]. Thus, the true effectiveness of fewer vaccine doses remains unknown. Cost-effectiveness studies have concluded that two-dose HPV vaccine schedules are the most cost-effective approach [213]. Indeed, two-dose vaccination schedules are recommended for girls ages 9–14 in certain countries and the WHO in part because of the cost-effectiveness [213]. Additional studies explored coadministration of the 9-valent vaccine with other vaccines including the meningococcal, Tdap (diphtheria, tetanus toxoids, and acellular pertussis), and poliomyelitis vaccines with good tolerance and no impact on antibody responses, which would allow for reduced clinic visits [190,214]. Unfortunately, HPV vaccination in the United States is significantly lower compared to other vaccines typically given to adolescents. Thirty-five percent of boys and 57% of girls had received at least one dose by 2013; however, only approximately 14% of boys and 38% of girls received all three of the recommended doses [215]. While HPV vaccine uptake has been improving since surveillance began in 2007, it is still substantially lower than the over 75% coverage for meningococcal conjugate, Tdap (tetanus toxoids, diphtheria, and pertussis), and varicella vaccines [215]. Barriers to HPV vaccination include the absence of a school requirement and the need for multiple doses. A number of strategies have resulted in increased HPV vaccination include school-based initiatives, selected marketing to target populations, physician education, and reminder systems [216]; however, the increase in vaccination rates by these various strategies was generally small. Caskey et al. [217] advocate for a “less is more” strategy for HPV vaccination by treating this vaccine in a similar manner to other adolescent vaccines; specifically, a recommendation should be made to vaccinate against HPV without a detailed discussion that possibly gives parents the notion that the HPV vaccine is different from other vaccines.

5.3 Potential Impact of HPV Vaccine on Cervical Cancer Screening HPV vaccination may potentially alter the epidemiology of cervical pathology that may eventually lead to changes in the strategy for cervical cancer screening. A reduction in the prevalence of hrHPV types is expected to

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cause a reduction in the positive predictive value of cervical cancer screening, potentially resulting in more abnormal results being false positives and overtreatment of patients [218]. Various strategies have been proposed to circumvent this problem, including initiation of screening at a later age and less frequent screening [216]. Shifting to HPV DNA testing as a firstline screening test has also been suggested since a decrease in the prevalence of hrHPV will result in fewer positives by this method [219]. However, a change in the epidemiology of cervical cancer from vaccination is not expected to occur for many decades due to the very long lag time between acquisition of HPV infection and development of malignancy [218]. Furthermore, vaccine uptake in the United States is currently suboptimal. Certain countries such as Australia have achieved high levels of HPV vaccination that has impacted the epidemiology of HPV infection and cervical lesions. Australia began offering a national HPV vaccination program in 2007 targeting girls ages 12–13 and catch-up vaccination to girls ages 14–26 [212,220]. Vaccination was offered in schools and community-based settings, and over 70% of the targeted women have received all three doses of the vaccine [212]. A reduction in the prevalence of infections with HPV vaccine subtypes was observed in both women administered the vaccine and an indication of herd immunity suggested by a lower infection prevalence in unvaccinated women [221,222]. Declines in high-grade cervical abnormalities were observed 3 and 5 years after implementation of the Australia national vaccination program [212,220]. Significant declines in genital warts were also observed in both women and men in the postvaccination time period; the decrease in warts in unvaccinated men is attributed to herd immunity [165]. Other countries with national HPV vaccine programs and high vaccine uptake such as Denmark and the United Kingdom have shown reduced prevalence of HPV vaccine subtype infection prevalence, genital warts, and cervical lesions [223–225]. A reduction in high-grade cervical lesions has even been demonstrated in the United States after vaccine introduction, where vaccine uptake remains suboptimal and there is a lack of immunization and screening registries [216]. The ACOG recommends cytology alone every 3 years for women ages 21–29 and combined cytology and HPV testing every 5 years for women ages 30–65 years [135]. Combined testing for HPV is specifically not recommended by ACOG in women under age 30 due to the high prevalence of hrHPV types that ultimately have a low overall risk of progression to cervical cancer [135]. Australia, which has at least 70% HPV vaccine coverage, is introducing a cervical cancer screening approach that will be based on

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HPV DNA testing at age 25 regardless of a woman’s vaccination status [211,226]. The basis of this recommendation is the declining prevalence of hrHPV in Australia and is expected to result in fewer referrals for colposcopy [226]. Current ACOG guidelines do not recommend a separate screening strategy for women who have been vaccinated [135]. First, the vaccine is relatively new and it is possible that the vaccine efficacy decreases with advancing age. Second, many women may have received catch-up vaccination after initiation of sexual activity, which does not protect against HPV infection acquired prior to vaccination. Finally, complete vaccination history may not always be available. Confusion with other vaccines may occur and patients may not receive all of the recommended doses. Thus, a modified screening approach for vaccinated women is not currently recommended at this time [135]. In summary, the clinical trial results demonstrate that the available HPV vaccines show high efficacy in preventing HPV vaccine subtype persistent infection, cervical lesions, genital lesions, and oral HPV infection. However, no protection is provided for prevalent HPV infections at the time of vaccination. Thus, the vaccine is ideally administered prior to initiation of sexual activity and has limited public health benefit in women over age 26 due to the high prevalence of HPV infection in older women. An effect on cervical cancer epidemiology by HPV vaccination is not anticipated for many years due to the long lag period between the acquisition of HPV infection and cervical cancer. However, countries with high vaccine uptake have demonstrated a reduction in infections due to HPV vaccine subtypes and associated cervical lesions that are anticipated to ultimately impact cervical cancer epidemiology. Changes to cervical cancer screening are not recommended in the United States at this time; however, certain countries such as Australia are shifting to HPV DNA testing as a sole screening mechanism due to a reduction in the prevalence of hrHPV subtypes. Future directions include evaluating the effectiveness of fewer doses to improve compliance and improving vaccine uptake.

ACKNOWLEDGMENTS Section 4, “Cervical Cancer Screening,” is adapted from a prior published article in Current Treatment Options in Oncology by M.R.D. and S.F. entitled “Making Sense of Cervical Cancer Screening” [227] with permission of Springer.

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