Kelsey H. Jordan
Chloe M. Beverly Hery
Xiaochen Zhang
Electra D. Paskett- 1Division of Population Sciences, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States
- 2Division of Epidemiology, College of Public Health, The Ohio State University, Columbus, OH, United States
- 3Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, United States
- 4Division of Cancer Prevention and Control, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States
Objective: The oral-cervical human papillomavirus (HPV) infection/cancer relationship is not well established. Oral-cervical HPV studies were reviewed to assess dual-site occurrence, HPV type concordance, and study quality/deficiencies.
Methods: PubMed, EMBASE, Ovid Medline, and Web of Science were searched between 1/1/1990 and 8/10/2021 for studies investigating HPV infections/cancers and type concordance between the oral cavity/oropharynx and cervix. Dual-site and concordant HPV infection rates were summarized as percentages; cancer diagnoses studies were summarized using standardized incidence ratios (SIR). The Quality Assessment Tool for Quantitative Studies (QATQS) evaluated study methodology.
Results: One hundred fourteen papers were identified. Most were cross-sectional (n=79, 69%), involved synchronous dual-site HPV testing (n=80, 70%), did not report HPV type concordance (n=62, 54%), and achieved moderate methodological QATQS ratings (n=81, 71%). The overall dual-site infection rate averaged 16%; the HPV type concordance rate averaged 41%, among those dually-infected women. Most HPV-related cancer diagnoses studies reported increased secondary cancer risk, with SIRs generally ranging from 1.4 to 29.4 for secondary cervical cancer after primary oral cancer and from 1.4 to 6.3 for secondary oral cancer after primary cervical cancer.
Conclusion/Impact: Oral-cervical HPV infections/cancers remain understudied. Future research should use stronger methodologies and HPV concordance analyses to better understand oral-cervical HPV epidemiology.
Introduction
Human papillomavirus (HPV) is the most prevalent sexually transmitted infection (1). The virus exists in 200+ types—some more high risk (i.e., potentially malignant) than others (1). Various HPV types can infect the cervix, vagina, vulva, penis, anus, and/or oropharyngeal region, increasing the risk for the development of warts and/or cancers (1). Globally, about 630,000 incident cancers are HPV-related with most occurring in the oropharynx and cervix (1, 2). Oral HPV infections and cancer biology remain less understood than cervical HPV (3–7). Cervical HPV infection is clearly acquired through vaginal intercourse, whereas acquisition of oral HPV, potentially during orogenital sex, remains uncertain, especially in women (3, 4, 8, 9). Therefore, women are disproportionately burdened with the disease, amassing 90% of all HPV-related cancers (1).
HPV can be attributed to more than 70% of oropharyngeal cancers in the United States (US) (8, 10). In 2020, there were 98,412 new oropharyngeal cancer cases worldwide (11). High-risk HPV types (e.g., HPV16) account for a substantial proportion of oral HPV cases (3). HPV tends to infect the back of the oral cavity from the base of the tongue through the esophagus, including the oropharynx and tonsils (3, 9). However, there is no routine screening for oral HPV infection and methods are less-refined for oral HPV cancer detection, resulting in later stage diagnoses and more aggressive cancer treatments (3).
Approximately 604,127 women were diagnosed with cervical cancer worldwide in 2020 (11). Essentially all cervical cancers are HPV-related (10). HPV types 16 and 31/18/33 are the first and second most common type groupings routinely identified in advanced cervical infections and cancers, respectively (5). Slow disease progression and effective screening methods, including Papanicolaou (Pap) tests, allow for opportunities to detect and treat cervical abnormalities to reduce the risk for cancer development (12).
Results from studies of dual-site oral-cervical HPV infections/cancers are inconsistent. Investigating HPV status in both oral and cervical sites in women can aid in determining how HPV is transmitted (e.g., orogenital interaction, autoinoculation, unrelated events) (4). For example, oral-cervical HPV type concordance (i.e., same HPV type(s) in both sites) would suggest a transfer of infection across sites. Whereas HPV type discordance would suggest the infections were separate. Clarity in the oral-cervical HPV+ association could improve prevention, screening, and/or treatment approaches for both diseases, ultimately reducing HPV-related cancer rates overall.
Current systematic reviews on the topic of oral HPV infections and cervical cancers have only studied the infections independently of one another. This prohibits a complete assessment of HPV type concordance between the anatomical sites. The one meta-analysis that investigated oral and cervical HPV infections estimated an HPV concordance rate of 27% (4). However, the study was limited in publication years, databases, search terms, and oral HPV data collection methodologies, including just 10 studies, and without any quality assessment.
To date, there is no published comprehensive systematic review incorporating a quality assessment of the literature that examines the potential for both oral and cervical HPV infections in women. This systematic review aims to fill significant gaps in the HPV literature regarding oral and cervical dual-site and concordance rates of HPV. In summary, there is no consensus on whether oral and cervical HPV-related infections and/or cancers are more likely to be related or unrelated events. This systematic review aims to critically assess studies with participants who have at least one HPV-related oral and/or cervical infection/cancer diagnosis, comparing any HPV types across the two biological sites, to determine if there is a higher probability that any HPV types at the two sites had concordance.
Materials and Methods
Literature Search Strategy
A review of the literature was conducted in PubMed, EMBASE, Ovid Medline, and Web of Science databases using variations to the search terms oropharynx and cervix and human papillomavirus and infection or cancer. Searches were restricted to peer-reviewed papers published from January 1, 1990 to August 10, 2021. For example in PubMed, the following terms were used:
These search strategies were reproduced in each of the other three databases (Supplementary Table). Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines were used in this systematic review with respect to design and reporting.
Eligibility Criteria
Inclusion Criteria
Studies were eligible for inclusion if they: involved human subjects; investigated both person-specific anatomical sites of oral cavity/oropharynx and cervix for HPV synchronously (i.e., evaluated simultaneously) or asynchronously (i.e., evaluated at different times); and were full-text papers of original research written in English. Partner studies with both men and women were included if any HPV data pertaining to women could be independently differentiated from any HPV data presented on men. Studies including participants with a positive oral HPV test or any HPV-related oral cancer (i.e., non-tobacco/alcohol-related oral cancers) were included. Oral sites could range from the oral cavity to the esophagus (both potentially HPV-associated), including the oropharyngeal region with the base of the tongue and the tonsils (both HPV-related), as long as the original study authors had justified the sites to be at least possibly oral HPV-related (3, 9). All cervical abnormalities/cancers were assumed to be HPV-related since 95–99% of cervical cancer cases involve HPV (13).
Exclusion Criteria
Studies were excluded if they were not relevant to within-person HPV evaluation of both oral and cervical infections (e.g., both sites but in different people, wrong biological site or cancer or population), involved only HPV infections in the oral cavity/oropharynx or cervix, not original research (e.g., reviews, abstracts, letters, commentaries, meetings, protocols), or were case reports or series (i.e., N <10).
Data Collection, Categories, and Analyses
Data Extraction
Duplicate citations from the four databases were reviewed and removed. The remaining citations were divided equally, reviewed separately, and then summarized with data extraction by three study authors (KHJ, CBH, XZ). Any questions regarding inclusion were resolved by consensus among the three authors listed above.
Assessment of Risk of Bias and Quality of Studies
As described by Thomas et al., the Quality Assessment Tool for Quantitative Studies (QATQS) from the Effective Public Health Practice Project criteria was utilized to determine the quality of each included study (14). The assessment tool evaluates: 1) selection bias, 2) study design, 3) confounder adjustment, 4) blinding, 5) data collection methods, and 6) withdrawals and dropouts (14). All topics were evaluated for studies included in this systematic review, excluding blinding since all studies were observational in nature and no intervention or randomized control trial methods were considered for HPV evaluation in the oropharynx/oral cavity sites and/or cervix. Included papers were divided such that two authors (KHJ, CBH, or XZ) reviewed and scored the QATQS for each study independently. Each topic area evaluated received a rating of strong, moderate, or weak quality, dependent on topic-specific criteria. Studies attaining only moderate and/or strong quality topic ratings were classified as “strong”; studies with one weak quality topic rating were classified as “moderate” while studies with two or more weak quality topic ratings were classified as “weak” (14). The primary paper evaluator (KHJ, CBH, or XZ) compared the two-author ratings for inconsistencies. Discrepancies were discussed amongst authors and a consensus was reached.
Outcomes
Concurrent infections were defined as any HPV infection(s) occurring in both the oral cavity/oropharynx and cervix simultaneously due to synchronous site testing. If HPV infection was absent at either or both sites, then any infection was not considered concurrent. “Dual-site infections” were defined as any HPV infections occurring in both the oral cavity/oropharynx and cervix at different times due to asynchronous (i.e., non-simultaneous) testing of the two sites. Concordant infections were identified in women who shared at least one HPV type across oral and cervical sites at any time (synchronously or asynchronously) (Table 1).
Table 1 Definitions and summary statistics for a 1990-2021 systematic review of oral-cervical human papillomavirus (HPV) infection/cancer rates in women.
Studies investigating oral-cervical cancer diagnoses from registry data were also considered. We included studies that examined the occurrence of cervical cancer after a primary diagnosis of HPV-related oral cancer and occurrence of HPV-related oral cancer after a primary diagnosis of cervical cancer. Infections were also included here, if documented accordingly in the registries/databases.
Categories
Eligible studies were divided into three categories based on the timing of HPV evaluation at both sites (i.e., synchronously, asynchronously, or cancer diagnoses). Synchronous HPV evaluation studies actively collected oral and cervical samples and tested them both for HPV DNA at the same visit (with one study testing oral samples within three weeks of cervical samples). Asynchronous HPV evaluation studies either HPV-tested the oral and cervical sites at separate visits or one anatomical site was previously diagnosed with a HPV-related cancer and the other anatomical site was actively tested for HPV infection during the study. Cancer diagnoses only studies relied on data from cancer registries or medical records to determine prior primary and secondary cancer diagnoses of the oral cavity/oropharyngeal region and cervix.
Statistical Analyses
When individual synchronous and asynchronous studies presented sufficient results, we summarized concurrent/dual-site infection data as percentages of women with any oral-cervical HPV infections at any time. HPV type concordance data was summarized as percentages of women with the same oral-cervical HPV type(s) at any time. Overall concurrent/dual-site and concordant oral-cervical HPV infection rates were determined by averaging respective individual study percentages (Table 1). For cancer diagnoses studies, we summarized the overall rates of secondary cervical and/or oral cancers (number of cases per 10,000 women) and reported the standardized incidence ratios (SIR) to indicate whether the age-adjusted observed cancer cases were higher than expected for individual study populations. Results were not pooled across studies but stated as ranges.
Results
A total of 8768 papers were identified through PubMed, EMBASE, Ovid Medline, and Web of Science databases after removing duplicates (Figure 1). Titles, abstracts, and full-text papers were screened, 8654 did not meet the eligibility criteria and subsequently were removed. Specifically, 1842 (21%) studies were not topic relevant, 3071 (35%) studies evaluated HPV only in the oropharynx/oral cavity [2289 (26%) studies] or cervix [782 (9%) studies], 5 (0.06%) studies did not relate oral cancers to HPV status, 3412 (39%) studies were not original research, and 324 (4%) studies were case reports or series. A total of 114 papers were included.
Figure 1 Flow diagram of study selection for a systematic review of oral-cervical HPV infection/cancer epidemiology literature.
Most studies (n=80, 70%) (4, 15–93) evaluated oral and cervical sites with synchronous HPV testing; the remaining studies were divided between asynchronous evaluations (n=12, 11%) (94–105) and cancer diagnoses only (n=22, 19%) (106–127). Combining synchronous (4, 15–93) and asynchronous (94–105) study data, the overall estimate of oral and cervical dual-site HPV infections was 16% and the overall estimate of oral-cervical HPV type concordance among dually-infected women was 41% (Table 1). Among cancer diagnoses only studies (106–127), the incidence of a secondary cervical cancer diagnosis ranged from as few as 4.5/10,000 to as many as 192.5/10,000 women; the incidence of a secondary oral HPV-related cancer ranged from 1.0 to 45.8 per 10,000 women.
Synchronous Oral-Cervical HPV Testing (n=80)
Eighty studies synchronously evaluated HPV-related infections at both the oral and cervical sites (4, 15–93) (Table 2A). Cervical samples were collected by a variety of measures with most studies using swabs or a combination of methods; oral samples were collected mainly by rinses or swabs. HPV DNA detection was most often determined through polymerase chain reaction (PCR) (n=60, 75%) (4, 16–20, 24–29, 33–35, 38, 39, 42–49, 52–56, 61–65, 67–76, 78–89, 91–93).
Table 2A Description of methodology used in synchronous oral-cervical HPV evaluation papers (n=80).
Table 2B Description of methodology used in asynchronous oral-cervical HPV evaluation papers (n=12).
Table 2C Description of methodology used in oral-cervical human papillomavirus (HPV)-related cancer diagnoses only papers (n=22).
Overall rates of cervical HPV+ and oral HPV+ cases varied by study (Table 3A). Almost all studies found higher rates of cervical HPV+ than oral HPV+ (n=76/80, 95%) (4, 15–19, 21–67, 69–79, 81–84, 86–93). On average, 53% of women were HPV+ in the cervix; an average of 15% of women were HPV+ in the oral cavity/oropharyngeal region. Most papers included high-risk HPV type results from DNA genotyping (n=74/80, 93%) (4, 15–29, 31–33, 35–37, 39–45, 47–66, 68–70, 72–93) with 82% (n=61/74) (4, 15–26, 29, 31, 33, 35–37, 40, 42, 44, 45, 47–52, 54–62, 65, 66, 69, 70, 72, 74–79, 81, 83–93) reporting exact HPV types observed.
Table 3A Results of the synchronous oral-cervical HPV evaluation papers (n=80).
Table 3B Results of the asynchronous oral-cervical HPV evaluation papers (n=12).
Table 3C Results of the oral-cervical human papillomavirus (HPV)-related cancer diagnoses only papers (n=22).
Eighty-three percent of all synchronous testing studies (n=67/80, Table 3A) (4, 15–21, 23, 25–27, 29–44, 47, 49–52, 54–65, 67–78, 84–93) provided some form of data on concurrent oral-cervical HPV+ cases. Concurrent oral and cervical HPV infection rates could be calculated for most, but not all, of these studies (n=59/67, 88%) (4, 15–17, 20, 21, 23, 25–27, 29–39, 41–44, 47, 49–52, 54–65, 67–72, 76–78, 84–89, 91–93). The calculated concurrent rates ranged from 0% to 95%, depending on the study. On average, 15% of women had HPV infections occurring concurrently in both sites. Most rates of concurrent oral and cervical HPV infections were ≤10% (n=39/59, 66%) (15, 17, 20, 21, 23, 26, 27, 29–32, 34–37, 39, 41, 43, 44, 49, 51, 52, 55, 56, 59–65, 67, 69, 77, 78, 84–86, 92). Only four studies (7%) (54, 72, 89, 93) had concurrent oral and cervical HPV infection rates over 65%.
Among the 67 studies identifying concurrent oral and cervical HPV+ cases, 70% (n=47/67) (4, 15, 16, 18–20, 23, 25–27, 29, 32, 33, 36–40, 42, 43, 47, 50–52, 56–60, 62, 63, 65, 68, 70, 72–74, 84–93) determined concordance in oral-cervical HPV types (Table 3A). For studies reporting overall rates (n=40/47, 85%) (4, 15, 16, 20, 23, 25–27, 29, 32, 33, 36–39, 42, 43, 47, 50–52, 56–60, 62, 63, 65, 68, 70, 72, 84–86, 88, 89, 91–93), concordance in oral and cervical HPV infection types ranged from 0% to 100%, with an average of 41% of the women having infections of the same type in both sites. More than half of the studies had oral-cervical HPV type concordance rates of <50% (n=23/40, 58%) (4, 16, 25, 27, 32, 36, 37, 39, 43, 51, 52, 56, 58, 59, 62, 63, 65, 70, 72, 85, 89, 91, 93), yet seven studies reported concordance rates of >80% (15, 23, 47, 50, 60, 86, 88).
Asynchronous Oral-Cervical HPV Testing (n=12)
Twelve studies evaluated HPV-related infections of the oral cavity/oropharynx and cervix asynchronously (94–105) (Table 2B). Most studies sampled women with cervical infections for oral HPV (n=7/12, 58%) (95, 96, 98, 100, 101, 103, 105). Cervical HPV data collection usually relied on medical records (94–96, 98, 100–105) while at least some oral samples were actively evaluated for HPV during the study (94–105). Oral HPV sampling methodology used a buccal (brush) sample (95, 98, 101, 103), biopsied lesions (96, 97, 102, 104), or a gargle/rinse sample (94, 99, 100, 105). Cervical and oral HPV DNA was often detected by PCR (94–96, 100–105).
Half of the asynchronous studies (n=6/12, 50%) showed that more women were HPV+ in the cervix than in the oral cavity/oropharynx (98–101, 103, 105) while essentially the other half (n=5/12, 42%) found the opposite (94, 96, 97, 102, 104). Most asynchronous studies (n=9/12, 75%) provided some data regarding the high-risk HPV types (94–101, 105) (Table 3B), tending to only specify when high-risk oral HPV was found (n=5/9, 56%) (94, 95, 98, 99, 101). Due to HPV assessments occurring at different times, studies rarely (n=4/9, 44%) reported both the specific high-risk oral and cervical HPV types found at the person level (96, 97, 100, 105).
Most asynchronous studies (n=11/12, 92%) differentiated between women with and without dual-site oral and cervical HPV infections at any time (95–105) (Table 3B). One woman (2%) to as many as all (100%) women asynchronously tested positive for HPV in both the oral cavity/oropharynx and cervix. The overall dual-site oral and cervical HPV+ infection rate estimate was 26% (95–105). On average, when women had (pre)existing cervical infections (95, 98, 100, 101, 103, 105), almost twice as many were dually-infected with HPV in the oral cavity/oropharynx (avg.: 37%, range: 2-100%) as compared to women with (pre)existing oral HPV infections who were also cervical HPV+ (avg.: 21%, range: 4-46%) (97, 102, 104). Women without a known, prior oral or cervical HPV infection were not as likely to be dually HPV infected at both sites, with rates ranging from 1.1-5% (96, 99).
Among studies where women were known to be dually-infected with oral and cervical HPV, 27% (n=3/11) measured concordance in HPV types across both sites at any time (96, 97, 105). On average, 39% of asynchronous oral and cervical infections within women had an HPV type in common (96, 97, 105) (Table 3B). Women who had an HPV+ oral cancer and a cervical HPV infection present had the greatest concordance in oral-cervical HPV types (100%) (96, 97, 105). Rates of concordant oral-cervical HPV types were lower in studies where not all women had prior HPV-related infections (2-14%) (96, 97, 105).
Cancer Diagnoses Only (Primary Oral/Cervical, Secondary Cervical/Oral, n=22)
Twenty-two retrospective studies focused on the diagnosis of a secondary cervical or oral cancer after a primary cancer diagnosis of oral or cervical cancer (106–127) (Table 2C). Although we specifically included studies focused on HPV-related oral cancers, the sites of oral cancers varied across studies (e.g., some studies included oropharynx, oral cavity and pharynx, some only included oropharyngeal, and some vaguely defined HPV-related head and neck sites). Five studies examined the risk of a secondary cervical cancer after a primary diagnosis of oral cancer (113, 120–123). Half of the studies (n=11/22, 50%) examined the risk of a secondary oral cancer diagnosis after a primary diagnosis of a cervical cancer (n=6) (106–108, 111, 115, 116) or a cervical intraepithelial neoplasia (CIN) (n=5) (109, 110, 118, 124, 125). Six studies investigated the risk of a secondary cervical and/or oral cancer after a primary diagnosis of an oral and/or cervical cancer (112, 114, 117, 119, 126, 127). Most studies utilized data from country or state level cancer registries to monitor disease surveillance (n=15/22, 68%) (106–118, 124, 126); three studies conducted medical chart reviews (120, 121, 123); four studies collected at least some data from institutional or provincial tumor registries (119, 122, 125, 127).
Among women with a primary diagnosis of oral cancer, the number of secondary cervical cancers was lowest among medical record-based studies (122, 123), followed by provincial registries (121, 127), and highest among national studies (112, 113, 117, 120, 126). National studies reported that the incidence of a secondary cervical cancer ranged from 4.5-192.5 per 10,000 women (112, 113, 117, 120, 126) (Table 3C). The observed cases of a secondary cervical cancer were higher than expected in five studies with the SIR generally ranging from 1.4-29.4 (113, 117, 120, 121, 127). Interestingly, Gan et al. found that the SIR of a secondary cervical cancer was smaller among women diagnosed with HPV-related oral cancers (SIR range: 3.3-4.0) compared to women diagnosed with non-HPV-related oral cancers (SIR range: 8.3-12.8) (120). Two studies did not observe any differences between the numbers of observed and expected cases of a secondary cervical cancer among women who had a primary oral cancer (112, 126).
Among women with a primary cervical cancer, one provincial-level registry found very few cases of secondary oral cancers (125). Nationally, studies that reported the incidence of a secondary oral/head and neck cancer ranged from 1.0-45.8 per 10,000 women (106–108, 110–112, 114–117, 126); one study had an incidence of zero for secondary oropharyngeal cancers (124) (Table 3C). The incidence rates varied due to differences in included oral cancer sites across studies. The observed cases of a secondary oral cancer were higher than expected in almost all national studies, including primary CIN3 cases, with the SIR ranging from 1.4-6.3 (106–109, 111, 112, 114–118, 126).
Quality Assessment
For the quality assessment of the 114 included papers based on the QATQS tool, 26 studies (23%) were classified as strong (73, 76, 77, 79–81, 104–111, 113–116, 118, 121–127), 81 studies (71%) were moderate (4, 15–26, 28, 29, 31–49, 52–58, 60, 62–72, 74, 75, 78, 82–91, 93–103, 112, 117, 119, 120), and 7 (6%) were weak (27, 30, 50, 51, 59, 61, 92) (Tables 3A–C). The most common component rated as weak was study design (n=79, 69%) (4, 15–72, 84–103); only a few studies used a case-control design (n=2, 2%) (76, 104) or cohort design (n=33, 29%) (73–75, 77–83, 105–127) with the majority being cross-sectional designs (n=79, 69%) (4, 15–72, 84–103). In addition, few studies randomly selected participants for inclusion from a comprehensive list of the target population (n=26, 23%) (18, 21, 24, 32, 34, 36, 37, 44, 45, 83, 92, 104, 108, 109, 111–113, 115–119, 121, 124, 126, 127). This contributed to most studies being classified as ‘moderate’ for selection bias (n=99, 87%) (4, 15–26, 28–33, 35–43, 46–49, 51–58, 60–77, 79–82, 84–91, 93–103, 105–107, 109–116, 118–123, 125). For data collection within synchronous and asynchronous HPV testing studies, some studies did not specify an HPV infection sample collection method, so the validity and reliability were unknown or they relied on self-reported HPV infections (n=10/92, 11%) (4, 33, 40, 55, 63, 64, 73, 94, 99, 101). For the last criteria, withdrawals and dropouts, few cohort studies described the number of and/or reasons for participants being lost-to-follow-up (n=8/33, 24%) (73, 74, 78–81, 83, 108).
Discussion
After an expansive search of four databases for studies of dual-site oral and cervical HPV infections/cancers, we included 114 papers that evaluated the sites synchronously (n=80) (4, 15–93), asynchronously (n=12) (94–105), or by cancer diagnoses only (n=22) (106–127). This systematic review enhances the previous meta-analysis (4) by including more publication years, comprehensive search terms, databases, general oral HPV testing approaches, and formal study quality assessments of included studies using QATQS. We found that studies evaluating both oral and cervical HPV infections had cervical HPV+ rates that were higher than oral HPV+ rates.
The reporting of dual-site oral and cervical HPV infection rates was wide-ranging. On average, 15% of infections occurred concurrently in the oral cavity/oropharynx and cervix. Among concurrent oral-cervical HPV+ cases, HPV types were concordant across the two sites in an average of 41% of women. Asynchronous dual-site (oral-cervical) HPV infection rates also varied, spanning from 1.1% to 100%, with an average of 26% of study populations testing positive for both oral and cervical HPV at different times. Oral-cervical HPV type concordance was either very low (2%) or high (100%) for these asynchronously tested and dually-infected women, producing an average concordance rate of 39%. Combining synchronous and asynchronous oral-cervical HPV testing data, it was estimated that 16% of women were dually infected and 41% of the dually infected women had at least one concordant HPV type across sites. Most cancer diagnoses only studies reported an increased risk for a secondary cervical and/or oral cancer, resulting in incidence spanning 1.0-192.5/10,000 women. Regardless of timing, most studies were cross-sectional (n=79, 69%) (4, 15–72, 84–103) and therefore achieved an overall moderate rating with QATQS scoring criteria (n=81, 71%) (4, 15–26, 28, 29, 31–49, 52–58, 60, 62–72, 74, 75, 78, 82–91, 93–103, 112, 117, 119, 120).
Oral HPV infection can be especially difficult to detect which may explain the lower oral-cervical HPV type concordance rates or lack of significant findings in the reviewed studies. Saliva continuously rinses the mouth so it may aid in regional virus clearance, making oral HPV more transient than HPV infections at other sites. Most people clear oral HPV infections, often in as little as a few months, which means it can easily be missed (3). HPV detection in the oral cavity is not indicative of oropharyngeal cancer either. The virus tends to inhabit the oropharynx (e.g., tonsils), so if only buccal samples are being tested, HPV may go undetected. Rinsing or gargling within the oral cavity may only partially capture any HPV inhabiting the oropharyngeal region (3, 9, 99, 128). HPV testing materials were originally designed for cervical HPV; although repeatedly shown to be capable of HPV detection at other sites, materials might not be as effective at identifying oral HPV (94, 129). Many existing oral cancer diagnostic tests are questionable, lacking standard diagnostic protocols. New diagnostic approaches are evolving but are not yet validated (3). With the increase in oral HPV cancers, oral HPV sampling and testing methodology should improve over time.
Other reasons for non-significant findings within studies might be site-independent or biological in nature. Virus detection methods (e.g., assay, technique) vary in sensitivity levels and are often HPV type specific, so the chosen HPV test may not be able to detect the HPV type present, suggesting no infection (98–100, 103, 129–131). Poor or inappropriate sample collections at either site might also hinder a positive HPV result (98). HPV-infected, but otherwise healthy people can test negative for the virus and/or may develop HPV type-specific immunity at other uninfected mucosal sites (96, 98, 132). It is also biologically plausible for a cervical HPV+ woman to not be oral HPV+ given that cervical-oral HPV transmission between heterogeneous partners is common, but oral-oral HPV transmission is infrequent (94).
The current systematic review expands upon the narrowly-focused topic-related meta-analysis of 2010 (4) with the inclusion of additional oral-cervical HPV studies and their quality assessments. We identified a significant gap in the oral-cervical HPV literature with HPV type concordance between sites being understudied, highlighting the need for better HPV data collection and reporting efforts. HPV type was frequently missing. Synchronous studies usually provided HPV type data for one site and only HPV+/- status for the other site, despite data for both sites being collected concurrently. Asynchronous studies recruiting women with (pre)existing HPV conditions tended to only report basic HPV status for the secondary anatomical site. Cancer diagnoses only or registry-based studies did not collect any HPV type information. When HPV types were reported, data tended to be presented at aggregate levels with either totals or broad categories by anatomical site and/or HPV type (e.g., HPV+/- status only, HPV16/not HPV16, oncogenic/not oncogenic, groups of multiple HPV types).
Additional problems with vague data reporting were observed, irrespective of whether or not studies involved synchronous or asynchronous oral and cervical HPV testing or cancer diagnoses only. Many studies provided a general summary statement regarding the oral-cervical HPV relationship across sites with the corresponding statistics (e.g., odds ratios, (Cohen) kappa statistics, p-values). Enumeration of sub-sites of oral cancers made it difficult to calculate incidence consistently among cancer diagnoses only papers. Information on HPV type was represented as ranges or in bar graphs, which made it difficult to extract specific values and interpret results. Still others did not stratify oral HPV results by sex so cervical HPV data could not be cross-compared with respective oral samples in females.
Without specific HPV type information presented at the person-level for both the oral cavity/oropharynx and cervix, concurrent/dual-site versus concordant infections could not be elucidated. Additionally, not all dual-site HPV+ studies, especially asynchronous and cancer diagnoses only papers, discussed the potential for concurrent infections which made it difficult to determine if the identified oral and cervical HPV infections could be related. Few studies listed participant data individually, making it unclear if a participant had the same infection in both sites. In turn, oral-cervical HPV type concordance data was missing or could not be deduced for more than half of the papers (n=62/114, 54%) (17–19, 22, 24, 28, 30, 34, 35, 40, 41, 44–46, 48, 49, 53–55, 64, 66, 71, 75, 76, 79–83, 87, 90, 94, 95, 98–104, 106–127).
Lack of HPV type details also made it difficult to describe the oral-cervical HPV infection epidemiology more generally. About 10% of synchronous and asynchronous studies quantified the number of HPV infections (vs. HPV+ women) to account for multiple infections in women, which is an important detail to note, but complicated the estimation of the disease burden. More than 10% of synchronous and asynchronous studies did not discuss if any detected HPV types were high-risk. The interpretation of cancer diagnoses only papers could not be compared collectively with synchronous and asynchronous papers due to different effect estimates being used (i.e., SIR). Additionally, almost one-third of cancer diagnoses only papers (n=7/22, 32%) were missing SIR values (118–120, 122–125).
The current systematic review also had its limitations. Unpublished works and conference abstracts were excluded, potentially missing some information, however, we evaluated many peer-reviewed publications with broad search terms. Only papers written and published in English were included so there could be a lack of generalizability to international research. However, 94 international studies were captured with our search criteria (or 82.5% of all papers included in this systematic review were conducted outside the US). The inability to decipher the vagueness in oral cancer types (i.e., HPV vs. tobacco/alcohol related) and/or a lack of differentiation between HPV infection sites (e.g., oral-cervical data combined within multi-site results) potentially prevented some topic-relevant papers from being included in the current review. Regardless, studies had to justify oral cancers as potentially HPV-related to be included. Using strict review criteria, the current review included studies focused on HPV-related oral and cervical infections/cancers only, minimizing misclassification bias concerns. The systematic review also relied on literature-reported “oral HPV-related cancer” terminology to portray results. Inconsistent use of varying terms across publications impeded the summarization of results across studies. The standardized QATQS tool could not be fully utilized due to the topic-related nature of this systematic review relying only on observational studies.
To better understand the epidemiology of oral HPV transmission moving forward, data collection efforts need to be improved to include standardized reporting of HPV type data. Individual-level, site-specific HPV type data should be reported for every sample evaluated, especially when investigators are already using HPV DNA tests that provide such detailed information. Cancer diagnoses studies/registries should include a repository of HPV-evaluated bio-specimens such that site-specific HPV types can be identified. Broad categories, aggregated data, summary statistics, and analyses without stratum-specific results only provide an overview of a potential association of HPV infections/cancers across sites without being able to hone in on possible transmission routes which can only be divulged if HPV types are compared.
Detailed documentation of the timing of HPV site-specific sampling and evaluations are also needed to aid in determining concurrent HPV infections or the likelihood of an association between dual/multi-site HPV infections. Generation of a special access database to pool this person-level, site-specific HPV infection/cancer data would facilitate the additional analyses needed to understand the epidemiology of HPV transmission between sites. Better understanding site-specific HPV infection/cancer biology, including transmission routes, can further aid in preventing and minimizing future disease burdens.
In conclusion, few reviewed studies utilized strong epidemiological methodologies to determine HPV type concordance in dual-site oral and cervical infections. The results from this systematic review are inconclusive given the heterogeneity of included studies with wide-ranging oral-cervical HPV infection/cancer rates. Cervical HPV+ infection/cancer diagnoses tended to be more prevalent in women than oral HPV+ infections/cancers were. Given that these dual-site infection rates can vary significantly by female population and no oral HPV+ cancer screening approach exists, oral HPV+ cancer incidence may continue to increase unchecked. Additional studies identifying specific HPV infection types, both concurrently and over time, at multiple biological sites (especially oral and cervical, but also vaginal, vulval, penial, and anal) within women and men are needed to better understand how HPV is transmitted and determine any relationships between potentially HPV-related cancer sites. Pooling of these individual-level study results into a special access HPV database could facilitate future research investigations. From there, risk factors and populations with potentially increased oral and/or cervical HPV cancer risks could more easily be identified and incorporated into future public health prevention and control efforts, locally and globally, to reduce the HPV-related cancer burden in men and women.
Data Availability Statement
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
Author Contributions
All authors agree to be accountable for the content of the work. KJ: validation, formal analysis, investigation, data curation, writing-original draft, writing-review and editing, and project administration. CB: validation, formal analysis, investigation, data curation, writing-original draft, writing-review and editing, and visualization. XZ: validation, formal analysis, investigation, data curation, writing-original draft, and writing-review and editing. EP: conceptualization, methodology, resources, writing-review and editing, and supervision. All authors contributed to the article and approved the submitted version.
Funding
KJ (P01 CA229143-S1) and XZ (F99CA253745-01) both have National Cancer Institute (NCI) funding through the National Institutes of Health (NIH). CB is funded through The Ohio State University Comprehensive Cancer Center.
Conflict of Interest
EP receives grant funding through the university from Pfizer and Merck Foundation.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2022.848628/full#supplementary-material
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Keywords: female, (human) papillomavirus (HPV) infection, oropharynx, cervix (uteri), cancer, epidemiology, systematic review
Citation: Jordan KH, Beverly Hery CM, Zhang X and Paskett ED (2022) Low Rates of Dual-Site and Concordant Oral-Cervical Human Papillomavirus Infections and Cancers: A Systematic Review. Front. Oncol. 12:848628. doi: 10.3389/fonc.2022.848628
Received: 04 January 2022; Accepted: 18 February 2022;
Published: 29 March 2022.
Edited by:
Dana Kristjansson, Norwegian Institute of Public Health (NIPH), NorwayReviewed by:
Alfredo Cruz-Gregorio, National Autonomous University of Mexico, MexicoShowket Hussain, ICMR-National Institute of Cancer Prevention and Research, India
Copyright © 2022 Jordan, Beverly Hery, Zhang and Paskett. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Kelsey H. Jordan, S2Vsc2V5LkpvcmRhbkBvc3VtYy5lZHU=; Electra D. Paskett, ZWxlY3RyYS5wYXNrZXR0QG9zdW1jLmVkdQ==
†These authors have contributed equally to this work