Human papillomavirus in cervical cancer and oropharyngeal cancer: One cause, two diseases

Abstract

Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017;123:2219–2229. © 2017 American Cancer Society.

INTRODUCTION

Anogenital human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States, with a prevalence of 70 million cases and an incidence of 14 million cases per year.1-3 Fifteen high-risk (HR) HPV genotypes can lead to cancer of the cervix, anus, penis, vagina, vulva, and oropharynx.4 Among these, the HPV-16 and HPV-18 subtypes are by far the most prevalent in cancers, accounting for approximately 70% of cervical cancers, with other HR-HPV subtypes (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82) accounting for the rest.5 HPV-16 accounts for approximately 95% of HPV-positive oropharyngeal cancers (OPCs).6 The persistent low-risk genotypes HPV-6 and HPV-11 cause most anogenital warts and respiratory papillomatosis but are rarely associated with cancer.4

Although virtually all cervical cancers are HPV-induced, OPC has 2 distinct etiologies: tobacco and alcohol consumption or HPV infection, which may coexist.7 OPC is a subset of head and neck squamous cell cancers (HNSCCs), including tumors arising from the oral cavity, oropharynx, larynx, hypopharynx, and sinonasal tract. Anatomically, OPC is limited to the base of the tongue, tonsils, posterior pharyngeal wall, and soft palate.8

The profound epidemiologic shift from carcinogen-induced to HPV-associated OPC in many Western countries has catalyzed the recognition of 2 distinct clinical cohorts. HPV-positive patients with OPC tend to be younger, with a median age at diagnosis of 54 years; have less exposure to tobacco and alcohol; and have higher socioeconomic status and education, with better performance status and improved overall outcomes compared with their HPV-negative counterparts.9, 10 Such findings have created new opportunities for improved therapy and primary prevention for these HNSCCs.

EPIDEMIOLOGY

Cervical Cancer

Cervical cancer is the second most common cancer in women, with an estimated 500,000 diagnoses of cervical cancer occurring each year, globally resulting in >250,000 deaths.1 Nearly all cervical cancers are HPV-associated, including cervical squamous cell carcinomas (70%), cervical adenocarcinomas (CA) (25%), or mixed histology tumors.4, 11 Exceedingly rare non-HPV-associated histologies, including cervical neuroendocrine, small cell, and large cell carcinomas, collectively represent <1% of newly diagnosed cases.12

Papanicolaou (Pap) smear implementation in the 1950s dramatically decreased the incidence of cervical squamous cell cancer in the industrialized world, but the CA rate continues to rise, particularly in young women.13 Despite increased detection in the United States, the risk of invasive CA and related mortality has increased.13 Improved histologic classification and increased prevalence of oncogenic HPV infections may contribute to this rise.14 Also, because “cytologic screening” preferentially detects and removes squamous lesions, observed rates of CA might increase without a change in risk factors.15

Disproportionate numbers of cervical cancer deaths occur in developing nations, where resources to implement widespread, effective screening and treatment programs are lacking. Greater than 85% of cases worldwide are from developing nations.5 The highest estimated incidence rates are in Sub-Saharan Africa, Melanesia, Latin America and the Caribbean, South Central Asia, and Southeast Asia.4 In the United States, more than 12,000 cervical cancers are diagnosed annually, with approximately 4000 attributed deaths and a median age at diagnosis of 49 years.16

There is an inverse correlation between age after sexual debut and cervical HPV prevalence in many countries; however, in some poor areas, HPV prevalence is high across all age groups.17 A U-shaped prevalence curve also occurs, with 1 peak in women aged <30 years and another in women ages 55 to 64 years.18 This second peak may be explained by new sexual exposures or latent HPV reactivation; a strong association exists between new sexual partners and HPV incidence, even in older women.19 Approximately one-half of new infections occur among females ages 15 to 24 years in the United States.20 Rates can be expected to decrease in coming decades with increased use of routine HPV vaccination, as discussed below.

Most cervical HPV infections are asymptomatic, and >90% of detected infections clear within 2 years,21 presumably because of cell-mediated immune mechanisms. The degree of protection from natural antibodies and the duration of immunity after infection remain uncertain; only 50% to 60% of women develop serum antibodies to HPV postinfection.22 The development of antibodies to HPV-16 virus-like particles after infection may have a modest protective effect.23 Those who do not clear the infection are at risk for developing cervical precancer and cancer.

OPC

In contrast to cervical cancer, the incidence of HPV-positive OPC continues to steadily rise, with a 3-fold increase from 1988 to 2004 reported in the United States.24 In the last 20 years in the United States, HPV detection in OPC tumor specimens increased from 16% to 73%.24 An estimated 70% to 80% of OPCs are now attributed to HPV in the United States and western Europe, with substantially lower proportions of HPV-positive OPC reported in other regions.25 In the United States, the oropharynx has now surpassed the cervix as the most common site of HPV-related cancer.26 In Sweden, a doubling in tonsil cancer incidence each decade from 1970 to 2007 led to reports of an “epidemic of virus-induced carcinoma.”27, 28 At this rate, in the next few years in Europe, the number of HPV-associated OPCs will also outnumber cervical cancers.24 Similar trends have been noted in other high-income countries. By comparison, because of decreased incidence of smoking in the United States, HPV-negative, smoking-related OPC incidence has declined by 50%.2

Approximately 85,000 newly diagnosed OPCs occur per year among both sexes worldwide, with 22,000 HPV-positive OPCs and a male-to-female ratio of approximately 4:1.29 In fact, this number may underestimate the total number of OPCs because sizable numbers of OPCs arise in the base of the tongue and may have been coded as “tongue-not otherwise specified” in the previous International Classification of Disease, Ninth Revision site classification system.30 These count for oral cavity cancers rather than OPCs. Male predominance, although not fully understood, may be largely due to a higher prevalence of oral HPV-16 infections in men than in women (for example, the 3-fold to 5-fold higher prevalence in the United States).31 This higher rate may reflect reduced seroconversion rates among men versus women after genital HPV infection, resulting in greater protection among women against subsequent oral infections.32 A 50% risk reduction against future HPV-16 infections was detected among unvaccinated women who had high HPV-16 antibody titers versus HPV-16 seronegative women.33, 34 Unvaccinated men do not appear to have the same reduced risk of future HPV-16 infection with prior HPV-16 seropositivity.35 Also, transmissibility of oral HPV may be greater for men performing oral sex on women, possibly because of higher vaginal/cervical HPV copy numbers.36

It is noteworthy that a similar male-to-female predominance exists in non-HPV-related head and neck cancers, although this may reflect the 5:1 worldwide smoking prevalence among men versus women.6 However, in high-income countries, including the United States and Western Europe, women smoke at nearly the same rate as men; and, worldwide, alcoholism is nearly equivalent in both sexes.37, 38 Here, the HPV-negative OPC prevalence disparity is poorly understood, because risk factors apply equally to both sexes in affluent nations.

By comparison, the developing world features a relatively low proportion of OPCs (ranging from 1%-10% of HNSCCs) and has remained stable over time.39 In the developed world, a high and variable proportion of OPC accounts for 15% to 30% of HSNCC, whereas the overall HNSCC incidence has remained stable or has even declined over the same period.9 These demographic trends prompted researchers to seek further risk factors that contribute to OPC incidence.

RISK FACTORS AND PROTECTIVE FACTORS

The principal risk factor for cervical cancer and HPV-positive OPC is sexual behavior. Women acquire cervical HPV through genital skin-to-skin contact, usually but not necessarily during sexual intercourse with an infected partner.32 Higher risk is associated with early age at sexual exposure, multiple sexual partners, and having partners who have had multiple partners.19 The risk of HPV-positive OPC is primarily influenced by the lifetime number of oral sexual partners, with an overall risk of 5.7 for ≥6 lifetime oral sex partners.26, 40 An increase in HPV-related OPC has been described among younger white men,33 but differences in oral sexual behaviors explain this age-related and race-related prevalence, because younger populations more frequently engage in oral sex.34 Once adjusting for these behavioral trends, neither white race nor younger age are independently associated with oral HPV-16 infection.35 It is noteworthy that partners of patients with HPV-related oropharyngeal tumors do not seem to have more frequent oral HPV infections, downplaying the role of oral-to-oral transmission.36

Persistent HPV infection can progress to cancer over a period of decades, if untreated.21 In cervical HPV, persistence is associated with infection with HR-HPV and multiple types of HPV, along with older age. Cigarette smoking increases the risks of dysplastic changes in cervical cancer and of OPC, with an increase up to 3-fold in the risk of squamous cell cervical cancer, but not of CA, depending on pack-years smoked.19, 41 Immunocompromised status also increases the risk for cervical dysplasia, as well as for latent reactivation of HPV-DNA at genital sites. Patients with human immunodeficiency virus (HIV) have a 5-fold higher risk of acquiring HPV-associated cervical cancer than those without HIV, with a likely component of persistent infection or latent reactivation.42 Moreover, because concurrent HIV infection increases the risk that cervical dysplasia will progress to cancer, invasive cervical cancer is now considered an acquired immunodeficiency syndrome-defining illness.43 Reproductive factors, such as combined estrogen and progesterone oral contraceptive use; high parity; and other sexually transmitted infections, such as chlamydia and herpes simplex virus type 2, are less strongly associated cervical cancer risk factors.42

Protective reproductive factors, independent of HPV status, include use of an intrauterine device, intercourse with circumcised partners, and consistent condom use for cervical cancer.42 Conflicting evidence exists regarding whether male circumcision protects against HPV infection in men, but several studies have reported that it is protective.44 An 80% risk reduction of cervical HPV infection was detected in women whose male partners used condoms,45 and condom use for 6 months resulted in a 20% greater clearance rate of cervical intraepithelial neoplasia (CIN) in women who already were infected.46

In OPC, a remote history of tonsillectomy can reduce the risk of HPV-positive tonsillar cancer and improve overall survival when within 1 year of tonsil carcinoma diagnosis.8 However, the overall risk of OPC, including nontonsillar sites, appears unaffected by this procedure.47 Recently, a novel genetic locus in the human leukocyte antigen (HLA) region was associated with a reduced risk of HPV-positive OPC (HLA-DRB1*1301-HLA-DQA1*0103-HLA-DQB1*0603).48 This protective effect may involve increased immune targeting of HPV-infected cells through major histocompatibility complex haplotype binding of HPV peptides and resultant strong CD4-positive T-cell response.48

In the cervix, low folate status may increase cancer risk. A common chromosomal fragile site sensitive to folate deficiency correlates with an HPV-16 DNA integration site49 and with 3 HPV-18 DNA integration sites in cervical tissue.50 Higher folate levels protected against HPV infections and were associated with eradicating infection in HPV-positive women in a 2-year prospective study.51 Folate and vitamin B12 at high concentrations independently protect against the development of CIN-2 and CIN-3, possibly through methylation of the HPV E6 promoter and enhancer, which is involved in cervical carcinogenesis.52

In addition, specific cervical microbial profiles are associated with the risk of CIN 2 or greater, suggesting the usefulness of combined approaches, including probiotics and vitamin supplementation along with vaccination (reviewed below), to reduce the overall risk of cervical cancer.53

BIOLOGY OF INFECTION AND CARCINOGENESIS

HPV is an epitheliotrophic, double-stranded DNA oncovirus.54 After sexual transmission, HPV infects traumatized epithelium, where basement membrane is exposed (Fig. 1), or, potentially, the naturally discontinuous epithelium of the oropharynx (Fig. 2), also susceptible to mechanical trauma. Infected basal cells differentiate to fill the disrupted area, resulting in active papillomavirus infection.56 During replication, HPV synthesizes 6 early proteins (E1 through E7) and 2 late capsid proteins (L1 and L2).54 The oncogenicity of HR-HPV is attributed primarily to the immortalizing and transforming properties of HPV oncoproteins E6 and E7, which are selectively retained and expressed during all stages of carcinogenic progression. E6 and E7 have multiple functions, most notably the inactivation tumor-suppressor proteins p53 and retinoblastoma protein (pRb), respectively, leading to loss of cell cycle and DNA damage control.57, 58 One outcome of the inhibition of pRb by E7 is an increase in p16INK4A (cyclin-dependent kinase inhibitor 2A/multiple tumor suppressor 1) protein levels, which can be used as a surrogate marker for oncogenic HPV infection.59 Suppressing E6/E7 in cervical cancer cell lines leads to growth arrest or apoptosis, and E6 and E7 mutants lacking these activities fail to contribute to keratinocyte immortalization.60

Figure 1

The cervicovaginal lifecycle of human papillomaviruses is illustrated. To initiate infection, human papillomavirus (HPV) binds to heparin sulfate proteoglycans on the basement membrane through breaks in the epithelium, leading to infection of cells in the basal epithelial layer.55 Uninfected epithelium is represented on the left and HPV-infected epithelium is illustrated on the right. Viral genomes are maintained as episomal DNA in infected cell nuclei, with viral gene expression changing as the infected cells move toward the epithelial surface. The late phase of the productive lifecycle occurs in the upper, terminally-differentiated epithelial layers and progenitor virions are released from these uppermost layers (red hexagons). Viral E6 and E7 expression deregulates cell cycle control, pushing differentiating cells into S-phase, allowing viral genome amplification in cells that normally would have exited the cell cycle. Progression to high-grade neoplasia represents an abortive infection, in which E6 and E7 expression becomes deregulated and the normal virus-producing life cycle cannot be completed. CIN indicates cervical intraepithelial neoplasia.

Figure 2

Human papillomavirus (HPV) in oropharyngeal carcinogenesis is illustrated. The molecular pathology of HPV-associated oropharyngeal cancer remains uncertain. HPV-positive head and neck tumors, which express E6 and E7, have a predilection for the reticular crypt epithelium of palatine and lingual tonsils. Discontinuities in the epithelial layer, exposing the basement membrane, may facilitate viral entry, whereas nearby lymphoid tissue may influence HPV carcinogenesis with increased cytokine release. Precancerous lesions have not been unequivocally identified in the oropharynx, in contrast to cervical tissue, perhaps related to the difficulty in sampling the deep tonsillar crypts. Much of the HPV detected in oropharyngeal cancers is episomal, although integrated HPV-DNA has been detected in tonsil crypt epithelium.

Persistent HPV infection will cause cancer precursor lesions called squamous intraepithelial lesions, which are graded into 3 progressive risk groups (CIN-1, CIN-2, and CIN-3) based on the proportion of abnormally affected epithelium.61 A small percentage of CIN-1 lesions can evolve into CIN-2 and CIN-3 lesions, with continuous proliferation and increased chromosomal instability. By comparison, no OPC precursor lesions have been definitively identified and the multistep process of oropharyngeal carcinogenesis has yet to be elucidated. Instead, in HPV-positive OPC, immunohistochemistry (IHC) of p16 is currently used as a surrogate HPV biomarker.10 Current diagnostic algorithms advocate screening by p16 IHC followed by detection of HPV-DNA using either consensus polymerase chain reaction or in situ hybridization (ISH).10

Particular HR-HPV types will specifically infect mucosal surfaces. In the cervix, HPV-induced high-grade dysplasia preferentially occurs in the transformation zone: a small ring of tissue at the opening of the cervix (the os), where the stratified squamous epithelium of the ectocervix transitions to the simple columnar epithelium of the endocervix.15 In the oral cavity, HPV preferentially induces cancers in the oropharynx for unknown reasons.10 However, possible explanations may include: 1) the oropharynx uniquely possesses transitional mucosa, similar to the cervix, with easily accessible metaplastic basal epithelial cells9; 2) the oropharyngeal epithelium is naturally attenuated with a discontinuous basement membrane, potentially allowing greater susceptibility to HPV infection62; 3) the deep invaginations of the tonsillar crypts may function as a reservoir for HPV9; and 4) the lymphoid tissue crypts may favor persistent HPV infection by allowing tumors to evade immune surveillance with their strong lymphoepithelial expression of programmed death-ligand 1 (PD-L1) to suppress T-cell responses to HPV.10

TREATMENT

Cervical Cancer

Treatment for early stage cervical cancer is surgical and often includes modified radical hysterectomy with pelvic lymphadenectomy.63 Cervical cancers are generally radiosensitive and can be treated with primary radiation therapy (RT) when surgical options do not exist. External-beam RT can be boosted by brachytherapy to deliver total doses of 80 to 85 Gy to cervical tumors.63 Concurrent chemotherapy with either cisplatin alone or with 5-fluorouracil is usually administered with external-beam RT.63 Fertility-preserving treatment by conization or extrafascial hysterectomy can be used for small, localized lesions. Adjuvant RT after surgery is recommended when intermediate-risk factors are present, for example, lymphovascular invasion.64 With HR features, including positive surgical margins, patients should receive adjuvant chemotherapy-RT with a platinum-based agent, such as single-agent cisplatin.65

Persistent, recurrent, or metastatic cervical cancer requires first-line treatment with platinum-based combination chemotherapy, such as cisplatin plus paclitaxel or topotecan plus paclitaxel, with bevacizumab, a recombinant, humanized monoclonal antibody against vascular endothelial growth factor.66 Advanced cervical cancer at presentation is characterized by early treatment failure, deterioration of quality of life, and a median overall survival of 7 to 12 months.67

Immunotherapy is an emerging strategy using the immune system to fight cancer. Nivolumab, a programmed death 1 (PD-1) inhibitor, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of patients with recurrent or metastatic, platinum-refractory HNSCC.68 Pembrolizumab, a monoclonal antibody against PD-L1 (the ligand for the immune checkpoint regulator PD-1 present on activated T-cells), has now entered a phase 2 study after producing a 12.5% overall response rate in a population of patients with advanced, heavily pretreated cervical cancer.69 Ipilimumab, a monoclonal cytotoxic T-lymphocyte–associated protein 4 antibody, is undergoing investigation in phase 2 trials evaluating the tolerability and efficacy of checkpoint inhibition in persistent, recurrent disease.70

Vaccines are also being used to treat recurrent, persistent cervical cancer by modulating T-cell immunity and activating the immune system to destroy cells that display tumor-associated antigens.71 A Listeria-based vaccine, ADXS11-001, demonstrated an 11% response rate in a phase 2 investigation among patients with recurrent or refractory cervical cancer.72

OPC

Treatment for OPC is the same regardless of HPV status or p16 positivity, despite improved outcomes in HPV-positive OPC. Patients with early stage OPC can be treated with either primary surgery and/or definitive RT.10 However, patients with OPC often present with advanced-stage disease necessitating multimodality treatment, including notoriously morbid concurrent cisplatin-based chemoradiotherapy or surgery, followed by adjuvant RT with or without chemotherapy.8, 73 Many studies are currently underway to de-escalate therapy for HPV-associated OPC, given its much improved prognosis.8 Before determining eligibility for such trials, patient HPV status is now required.

Recently, targeted therapy has begun to replace cytotoxic chemotherapy. Cetuximab, an epidermal growth factor receptor inhibitor, demonstrated improved locoregional control and overall survival when combined with RT compared with RT alone, especially in p16-positive and HPV ISH-positive subgroups, with similar toxicity profiles for both groups.74 In the EXTREME study, cetuximab also demonstrated a survival benefit when combined with standard platinum-fluorouracil chemotherapy in a p16-positive population. A large phase 3 trial with cetuximab plus RT-based versus cisplatin-based chemoradiotherapy in patients with p16-positive OPC is ongoing, and the results are pending.8

Many groups have now considered omitting chemotherapy in HPV-positive patients who are at low risk for distant metastatic disease because RT alone may be sufficient for treatment. Dose-reduction has lowered the RT dose to a total volume of <60 gray with altered fractionation.8 Transoral surgery as an alternative treatment platform offers good survival and good functional and quality-of-life outcomes with an added benefit of more precise pathologic staging.8 A large, prospective phase 2 trial (Eastern Cooperative Oncology Group 3311) is currently evaluating whether transoral surgery alone would be indicated for patients who have early stage, low-volume disease and whether lower doses of postoperative RT would suffice for intermediate-risk tumors.8

Similar to cervical cancer responses, immunomodulation of the PD-1/PD-L1 immune checkpoint exhibits great therapeutic potential, especially in the “inflamed” variant of HPV-associated OPC.8 Pembrolizumab yielded a 23.7% response rate in the KEYNOTE-012 trial, with durable and complete responses in both HPV-associated and HPV-negative tumors and a pronounced overall survival of 10 months.8 Just recently, nivolumab demonstrated a survival advantage in patients with platinum-refractory HNSCC compared with standard single-agent therapy.75 Durvalumab, an anti-PD-L1 antibody, also has reported activity in OPC. De-escalation in HPV-associated OPC will lead to less toxicity, which is important for this younger population with a presumed longer life expectancy.8

COMPARATIVE PROGNOSIS

There is a 28% reduced risk of death and a 49% reduced risk of disease recurrence for patients who have HPV-positive OPC versus those with non-HPV OPC.9 Key biologic differences may explain why HPV-related OPC responds better to treatment than non-HPV OPC: 1) In cancers caused by HPV, the virus silences p53 but leaves the gene that produces it “intact”; by contrast, in HPV-negative cancers, the gene is mutated, probably through exposure to carcinogens like tobacco or alcohol, and produces an “ineffective” version of the protein. Chemotherapy or RT may somehow reactivate p53 in HPV-positive cancers, turning the powerful protein back on to fight the tumor.76 Numerous studies have reported an inverse correlation between HPV-DNA and p53 mutations.77 2) Patients with HPV-positive cancer are generally younger and healthier than their HPV-negative counterparts, with better performance status, no smoking history, and fewer comorbidities.9 3) More genetic heterogeneity exists in HPV-negative tumors than in HPV-positive tumors, including a wider range of somatic mutations.76 An HPV-negative tumor may have an increased likelihood of a mutation that causes resistance to therapy. 4) HPV persistence in the tonsils may promote an antitumor immune response to viral-specific tumor antigens after chemotherapy or RT.9 5) HPV-positive tumors have higher radiosensitivity, perhaps because of an intact apoptotic response after RT.9 6) HPV-OPC may be detected earlier, because 51% of patients initially present with a neck mass versus 18% of patients with HPV-negative OPC, which is less likely to metastasize to cervical lymph nodes.78 7) HPV-negative OPC demonstrates greater locoregional progression than HPV-positive OPC, thus making HPV-negative OPC more refractory to treatment.79

Why does HPV-positive OPC respond better to treatment than HPV-positive cervical cancer when the etiologic agent is the same? Although much has yet to be elucidated regarding the natural history of these diseases, key pathologic differences may provide clues. 1) Immunologically, the oropharynx may respond better because of its wealth of lymphoid/immune tissue, with potentially enhanced recognition and immune stimulation against viral-specific tumor antigens.9 2) In contrast, the cervical microbiome composition may be more favorable to the persistence of HPV. For example, concurrent bacterial vaginosis, a condition characterized by Lactobacillus species depletion, overgrowth of anaerobic species, and higher vaginal pH, has been associated with delayed HPV clearance and CIN.80 3) HPV-positive OPC presents more obviously, most commonly with a palpable neck mass,78 compared with cervical cancer, which is usually asymptomatic or has generalizable abnormal bleeding or discharge. More advanced HPV-positive OPC will spread locoregionally to the neck, allowing earlier detection than advanced cervical cancer, which spreads internally and more distally. 4) Aside from initial stage at diagnosis, staging in general between cervical cancer and OPC is not comparable. For example, OPC stage IVA has not yet metastasized, whereas stage IVA cervical cancer has already spread into adjacent organs, such as the rectum or bladder. 5) Epidemiologically, 85% of cervical cancers occur in the developing world5 versus a majority of HPV-positive OPC occurring in the United States and Europe. With increased access to superior care in industrialized nations, the HPV-positive OPC population may have an economic advantage in terms of better treatment. In addition, they may present with better nutritional status and less comorbidities than women from developing countries.

SCREENING

In cervical cancer screening, Pap smears can detect the mild morphologic changes in cervical epithelium accompanying early HPV infections. Low-grade dysplastic lesions, which are simply manifestations of productive HPV infection, exhibit abnormalities only in the deepest (basal) layer of epithelium. Co-screening with HPV-DNA testing can now identify high-grade CIN with greater sensitivity than Pap smears with acceptable rates of specificity for women aged >30 years, permitting increased intervals for screening. Over the next decade, HPV-based screening will likely gradually replace cytology as a primary screening modality, because it has been approved by the FDA since 2014 for this indication. In the near future, inexpensive, successful HPV-DNA testing could be incorporated as a practical and economically viable solution into screening for women in the developing world.81 Moreover, compared with cytology, HPV-DNA testing is more sensitive for detecting adenocarcinoma and may reduce CA incidence as well as cervical squamous cell cancer.82

Currently, no effective OPC screening program exists because there are no identified OPC precursor lesions. A “Pap-test equivalent” using a cytology brush to collect oropharyngeal cell samples was only useful in a study that detected invasive OPC in the presence of accessible lesions and had limited utility for populations without visible lesions or clinical disease.83 HPV-detection methods are available, such as salivary DNA testing, but the causal relation between HPV-DNA detected in the oropharynx and subsequent development of OPC is poorly understood.

Evaluation and diagnosis of OPC, as always, should begin with a thorough history and physical head and neck examination, paying special attention to symptoms of persistent sore throat, chronic dysphagia, persistent odynophagia, and otalgia.84 Physical examination should include inspection of the tonsillar complex, inspection and palpation at the tongue base, and careful cervical lymphadenopathy evaluation.78 IHC for p16 with polymerase chain reaction and ISH to detect HPV-DNA represent the currently used HPV surrogate biomarkers for testing tumor tissues. Alternative HPV-DNA testing methods are under intensive study, such as molecular monitoring and surveillance of somatic mutations and/or HPV genes from saliva and plasma to facilitate precision care.8

PRIMARY PREVENTION

Until recently, secondary cancer prevention using Pap tests has been the main cervical cancer preventive strategy.81 Because virtually all cervical cancers and rising proportions of OPCs are attributable to HPV infection, primary prevention with vaccination against HPV could effectively reduce the incidence of these and other HPV-associated cancers.6

Three prophylactic vaccines are currently available and FDA-approved: Cervarix (GlaxoSmithKline, Brentford, UK), a bivalent vaccine designed to prevent HPV type 16 and 18 infections; Gardasil (Merck, Kenilworth, NJ), a quadrivalent vaccine targeting HPV subtypes 6, 11, 16, and 18; and Gardasil 9 (Merck), a 9-valent vaccine targeting HPV subtypes 6, 11, 16, 18, 31, 33, 45, 52, and 58. The addition of HPV subtypes 31, 33, 45, 52, and 58 to Gardasil 9 results in a vaccine targeting the HPVs that cause 90% of cervical cancers worldwide.85

All 3 vaccines can be administered in 3 intramuscular doses given over 6 months, but Gardasil-9 was recently approved by the FDA for a 2-dose regimen. Individuals younger than 15 years in Europe may receive 2 doses of any HPV vaccine. These protein-based, noninfectious vaccines are comprised of multiple pentameric subunits of the L1 virion protein that self-assemble into virus-like particles, inducing high levels of neutralizing and protective antibodies.81

Published clinical vaccine efficacy trials for cervical cancer demonstrated high levels of protection against incident persistent infection and disease caused by the HPV types in the respective vaccines with overall good toleration.81 HPV vaccines have also demonstrated efficacy against vaginal, vulvar, and anal HPV-16/HPV-8 among women and for HPV-associated external genital lesions and anal HPV among men who are sexually active with men.86 FDA-approved vaccinations are now available for females ages 9 to 26 years for the prevention of vulvar and vaginal cancer, cervical cancer, genital warts, and anal cancer and males for the prevention of genital warts and anal cancer.

Only 1 study to date has reported HPV vaccine efficacy against oral infection.33 In young Costa Rican women, the bivalent vaccine reduced the prevalence of oral HPV-16/HPV-18 infection by 93.3% compared with the control arm approximately 4 years after vaccination.33 In addition, by effectively reducing the incidence and transmission of anogenital HPV, the vaccine should also indirectly reduce the incidence and sexual transmission of oral HPV and thereby decrease the incidence of HPV-positive OPC. However, considering the long (approximately 30-year) latency from exposure to disease, the incidence of HPV-positive OPCs will not begin to decline until the year 2060.73

Despite their efficacy in preventing incident infection and disease, the vaccines do not influence clearance of prevalent HPV-16/HPV-18 infections and/or CIN.81 However, therapeutic vaccines designed to induce regression of existing HPV-associated lesions are in development.87

Biologically active compounds have demonstrated antiviral potential and warrant further investigation in human trials. For example, carrageenan, a seaweed extract and gelling agent in sexual lubricant, prevents HPV infection in cellular and mouse models.56 In primates, the use of a carrageenan-based gel versus sterile surgical lubricant jelly for an internal digital examination resulted in a 24-fold reduction in detectable infectious events after epithelium disruption (using Pap smears) and inoculation with HPV-16 pseudovirions.15 Clinical efficacy trials are underway. Also, a phase 2 clinical trial is currently investigating a mushroom extract, active hexose-correlated compound (AHCC), to treat preclinical cervical cancer lesions.88 AHCC reportedly increases natural killer cell activity and primes the toll-like receptor signaling pathway in the gut.89 Concurrent cisplatin enhances AHCC efficacy in murine models90 and AHCC alone prevented hepatocellular carcinoma recurrence while prolonging survival postoperatively without adverse side effects in patients with HCC.91

CONCLUSION

HPV-associated cervical cancers and OPCs share common risk factors and biologic features (Table 1).6, 24 However, notable differences are apparent, particularly in susceptibility to treatment, screening strategies, and understanding the natural history of premalignancy. Several key questions remain, especially with regard to HPV-associated OPC, including the identification of precursor lesions and understanding the multistep progression from infection to cancer.82 In the future, widespread screening programs and prophylactic vaccinations to reduce disease burden will be paramount. Meanwhile, other approaches may be used to manage the residual risk of developing cervical cancer from strains not covered by the vaccines and to manage HR-HPV-related CIN ≥2 lesions. Simple strategies, such as micronutrient supplementation and probiotic therapies, may offer economic solutions to alter the natural history of HR-HPV and protect against HR-HPV-related lesions. Antiviral drugs or therapeutic vaccines to effectively treat HPV infection and premalignant neoplastic lesions with minimal morbidity are urgently needed worldwide. Finally, further understanding of HPV as a uniquely powerful human carcinogen remains of utmost importance for reaching these goals.

Table 1. Common Risk Factors and Biologic Features Shared by Human Papillomavirus-Associated Cervical and Oropharyngeal Cancer

Characteristic	HPV-Associated Cervical Cancera	HPV-Associated OPCa
HPV16/18 positive	70%	90%
E6/E7 expression	Yes	Yes
p53 and pRb wild type	Yes	Yes
Median age at detection	49 y	54 y
Age at peak virus prevalence	20 y	25-30 y and 55-60 y
Latency period	30 y	10-30 y
Sex ratio	100% Women	70% Men
Premalignant lesions	Well documented	Uncertain
Sexually transmitted	Yes	Yes
Other risk factors	Multiple vaginal-sex partners, partners with many partners, early age of coitarche, cigarette smoking, long-duration oral contraceptive use, multiple live births, immunocompromised status, and low folate levels	High number of lifetime vaginal-sex partners (>25) and ≥6 lifetime oral-sex partners, female partner with anogenital HPV-associated SCC, cigarette smoking, alcohol use, immunocompromised status, male sex
Susceptibility to chemo/Rx	Moderate	High
Screening tests
Cytology	Yes	No
Virologic	Yes	No
5-Year survival rate	68%	85-90%
Vaccine efficacy evidence	Strong	Weak

• Abbreviations: Chemo/Rx, chemotherapy drugs; HPV, human papillomavirus; OPC, oropharyngeal cancer; SCC, squamous cell carcinoma; y, years.
• ^a Cervical cancer is >99% HPV positive, whereas OPC is from 20% to 70% HPV positive (see Dayyani F, Etzel CJ, Liu M, Ho CH, Lippman SM, Tsao AS. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC) [serial online]. Head Neck Oncol. 2010;2:156; and Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29:4294-430124).

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.