Joint effect of human papillomavirus exposure, smoking and alcohol on risk of oral squamous cell carcinoma.

BACKGROUND: Smoking, alcohol consumption, and human papillomavirus (HPV) infection are known risk factors for oral squamous cell carcinoma (OSCC) including SCC of oropharynx (SCCOP) and SCC of oral cavity (SCCOC). Researchers have examined each of these risk factors independently, but few have observed the potential risk of their interaction. This study investigated the interactions among these risk factors and risk of OSCC. METHODS: Totally 377 patients with newly diagnosed SCCOP and SCCOC and 433 frequency-matched cancer-free controls by age and sex were included. Multivariable logistic regression was performed to calculate ORs and 95% CIs. RESULTS: We found that overall OSCC risk was independently associated with smoking (adjusted OR(aOR), 1.4; 95%CI, 1.0-2.0), alcohol consumption (aOR, 1.6; 95%CI, 1.1-2.2), and HPV16 seropositivity (aOR, 3.3; 95%CI, 2.2-4.9), respectively. Additionally, we found that HPV16 seropositivity increased the risk of overall OSCC in ever-smokers (aOR, 6.8; 95%CI, 3.4-13.4) and ever-drinkers (aOR, 4.8; 95%CI, 2.9-8.0), while HPV16-seronegative ever-smokers and ever-drinkers had less than a twofold increase in risk of overall OSCC (aORs, 1.2; 95%CI, 0.8-1.7 and 1.8; 95%CI, 1.2-2.7, respectively). Furthermore, the increased risk was particularly high for SCCOP in HPV16-seropositive ever-smokers (aOR, 13.0; 95%CI, 6.0-27.7) and in HPV16-seropositive ever-drinkers (aOR, 10.8; 95%CI, 5.8-20.1), while the similar increased risk was not found in SCCOC. CONCLUSION: These results suggest a strong combined effect of HPV16 exposure, smoking, and alcohol on overall OSCC, which may indicate a strong interaction between HPV16 infection and smoking and alcohol consumption, particularly for SCCOP.

A synthesis of evidence for cancer-specific screening interventions: A Preventive Medicine Golden Jubilee Review.

The goal of cancer screening guidelines is to inform health practitioners to practice evidence-based cancer prevention. Cancer screening aims to detect treatable precancerous lesions or early-stage disease to enable actions aimed at decreasing morbidity and mortality. Continuous assessment of the available evidence for or against screening interventions by various organizations often results in conflicting recommendations and create challenges for providers and policymakers. Here we have summarized the current cancer screening recommendations by five leading organizations in North America and Europe: the National Cancer Institute's Physician Data Query (PDQ), the U.S. Preventive Services Task Force (USPSTF), the Canadian Task Force on Preventive Health Care (CTFPHC), the Cochrane Database of Systematic Reviews (CDSR), and the UK National Screening Committee for the National Health Service (UK NSC). All organizations assess evidence based on strength, quality, and quantity, and recommendations are similar although with differences with respect to screening start and stop ages. Recommendations are consistent for colorectal cancer screening with fecal occult blood test or fecal immunochemical test, cervical cancer screening with Pap-test, HPV-test, or co-testing, and breast cancer screening with mammography. However, guidelines vary with respect to age to start and end screening and testing frequency. Tests that have proven to be inefficient or whose use is capable of causing harm are routinely recommended against. Continuous review of screening guidelines is necessary to evaluate the many promising screening tests currently under investigation.

Genetic variants in CYP2B6 and HSD17B12 associated with risk of squamous cell carcinoma of the head and neck.

Polycyclic aromatic hydrocarbons (PAH) and tobacco-specific nitrosamines (TSNA) metabolism-related genes play an important role in the development of cancers. We assessed the associations of genetic variants in genes involved in the metabolism of PAHs and TSNA with risk of squamous cell carcinoma of the head and neck (SCCHN) in European populations using two published genome-wide association study datasets. In the single-locus analysis, we identified two SNPs (rs145533669 and rs35246205) in CYP2B6 to be associated with risk of SCCHN (P = 1.57 × 10-4 and .004, respectively), two SNPs (EPHX1 rs117522494 and CYP2B6 rs145533669) to be associated with risk of oropharyngeal cancer (P = .001 and .004, respectively), and one SNP (rs4359199 in HSD17B12) to be associated with risk of oral cancer (P = .006). A significant interaction effect was found between rs4359199 and drinking status on risks of SCCHN and oropharyngeal cancer (P < .05). eQTL and sQTL analyzes revealed that two SNPs (CYP2B6 rs35246205 and HSD17B12 rs4359199) were correlated with alternative splicing or mRNA expression levels of the corresponding genes in liver cells (P < .05 for both). In silico functional annotation suggested that these two SNPs may regulate mRNA expression by affecting the binding of transcription factors. Results from phenome-wide association studies presented significant associations between these genes and risks of other cancers, smoking behavior and alcohol dependence (P < .05). Thus, our study provided some insight into the underlying genetic mechanism of head and neck cancer, which warrants future functional validation.

Conditional survival among patients with oropharyngeal cancer treated with radiation therapy and alive without recurrence 5 years after diagnosis.

BACKGROUND: Risk of recurrence among patients with oropharyngeal cancer (OPC) who survive 5 years is low. The goal of this study was to assess long-term survival of patients with OPC alive without recurrence 5 years after diagnosis. METHODS: This study included newly diagnosed patients with OPC, who had been treated with radiation and were alive without recurrence 5 years after diagnosis. Overall survival (OS) probabilities beyond 5 years were estimated using the Kaplan-Meier method. Factors associated with OS were determined using Bayesian piecewise exponential survival regression. Standardized mortality ratios for all-cause death were estimated controlling for study year, age, and sex in the US general population. RESULTS: Among 1699 patients, the additional 2-year, 5-year, and 10-year OS probabilities were 94%, 83%, and 63%, respectively, and were lower than those in the general population. Patients who were older, were current or former smokers, had other than tonsil or base of tongue tumors, or had T4 tumors had a higher risk of death. Patients who had base of tongue tumors and had received intensity-modulated radiation therapy (IMRT) or lower-radiation doses had a lower risk of death. Standardized mortality ratios were higher among current and heavy smokers and lower among recipients of IMRT and lower radiation doses. CONCLUSIONS: In this large cohort, long-term survival among patients with OPC was good but lower than predicted for the general population. Patients treated with IMRT and those with less tobacco exposure had better outcomes.

Blood-based biomarkers of human papillomavirus-associated cancers: A systematic review and meta-analysis.

BACKGROUND: Despite the significant societal burden of human papillomavirus (HPV)-associated cancers, clinical screening interventions for HPV-associated noncervical cancers are not available. Blood-based biomarkers may help close this gap in care. METHODS: Five databases were searched, 5687 articles were identified, and 3631 unique candidate titles and abstracts were independently reviewed by 2 authors; 702 articles underwent a full-text review. Eligibility criteria included the assessment of a blood-based biomarker within a cohort or case-control study. RESULTS: One hundred thirty-seven studies were included. Among all biomarkers assessed, HPV-16 E seropositivity and circulating HPV DNA were most significantly correlated with HPV-associated cancers in comparison with cancer-free controls. In most scenarios, HPV-16 E6 seropositivity varied nonsignificantly according to tumor type, specimen collection timing, and anatomic site (crude odds ratio [cOR] for p16+ or HPV+ oropharyngeal cancer [OPC], 133.10; 95% confidence interval [CI], 59.40-298.21; cOR for HPV-unspecified OPC, 25.41; 95% CI, 8.71-74.06; cOR for prediagnostic HPV-unspecified OPC, 59.00; 95% CI, 15.39-226.25; cOR for HPV-unspecified cervical cancer, 12.05; 95% CI, 3.23-44.97; cOR for HPV-unspecified anal cancer, 73.60; 95% CI, 19.68-275.33; cOR for HPV-unspecified penile cancer, 16.25; 95% CI, 2.83-93.48). Circulating HPV-16 DNA was a valid biomarker for cervical cancer (cOR, 15.72; 95% CI, 3.41-72.57). In 3 cervical cancer case-control studies, cases exhibited unique microRNA expression profiles in comparison with controls. Other assessed biomarker candidates were not valid. CONCLUSIONS: HPV-16 E6 antibodies and circulating HPV-16 DNA are the most robustly analyzed and most promising blood-based biomarkers for HPV-associated cancers to date. Comparative validity analyses are warranted. Variations in tumor type-specific, high-risk HPV DNA prevalence according to anatomic site and world region highlight the need for biomarkers targeting more high-risk HPV types. Further investigation of blood-based microRNA expression profiling appears indicated.

Prevalence of high-grade anal dysplasia among women with high-grade lower genital tract dysplasia or cancer: Results of a pilot study.

OBJECTIVE: To estimate the prevalence of high-grade anal dysplasia in women with high-grade dysplasia or carcinoma of the cervix, vagina or vulva. METHODS: In this cross-sectional study, participants underwent anal cytology, anal HPV testing with Cervista HPV16/18 and high-resolution anoscopy (HRA). Patients with HSIL (high-grade squamous cell intraepithelial lesion) or greater on anal cytology or anal biopsy were referred to a colorectal surgery specialist for further evaluation. RESULTS: Seventy-five women were enrolled in the study, including 47 with cervical (cervix group), 10 with vaginal (vagina group), 15 with vulvar (vulva group), 1 with cervical and vaginal, and 2 with vulvar and vaginal disease. The median age in the cervix group (40 years (range 26-69)) was substantially younger than in the vagina (60 years (38-69)) and the vulva (59 years (36-75)) groups. Anal HSIL based on composite endpoints of the most severe cytology or histology result was diagnosed in 6 patients (8.0%). Anal cytology revealed HSIL in 2 (2.7%), atypical squamous cells of undetermined significance (ASCUS) in 12 (16.0%), low-grade squamous cell intraepithelial lesion (LSIL) in 2 (2.7%), and was normal in 59 (78.7%) patients. Anal HPV16/18 test was positive in 15 (20.0%), negative in 48 (64.0%) and insufficient in 12 (16.0%) patients. Of the 6 women with high-grade anal dysplasia, three (50%) had a positive anal HPV16/18 test. No case of anal cancer was observed. CONCLUSION: Our results suggest that the prevalence of anal HSIL is elevated among women with HPV-related lower genital tract dysplasia or cancer. To further support the inclusion of this high-risk group into screening guidelines for anal dysplasia, further studies are necessary to determine what screening strategy is suited to this population.

A TGF-ß1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16-associated oropharyngeal cancer.

TGF-ß1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-ß1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility. HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC). Thus, we hypothesized that TGF-ß1rs1982073 polymorphism at the miRNA-187 binding site combined with HPV16 L1 seropositivity may have a joint effect on OSCC susceptibility. We determined the genotypes of TGF-ß1rs1982073 and HPV16 status in 325 OSCC subjects and 335 cancer-free controls in the non-Hispanic white population, and used logistic regression models to evaluate the joint effects on OSCC susceptibility. TGF-ß1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6-960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2-1,000.0), respectively. Younger subjects had a higher risk of OPSCC than older subjects (OR, 23.5; 95% CI, 6.3-87.0 vs. OR, 6.0; 95% CI, 1.7-17.9, respectively). The significant associations between this polymorphism and HPV16-associated OSCC and OPSCC were also observed. However, OCSCC subjects did not have similar results. Our findings suggest that the joint effects of TGF-ß1rs1982073 and HPV16 L1 seropositivity can increase risk of HPV16-associated oral cancer, particularly in OPSCC subjects who are never-smokers, never-drinkers and young. This result may help us understand the tumorigenesis process and improve early detection, which are critical for prevention and intervention strategies. However, larger studies are needed to validate our findings.

Diagnostic accuracy of serum antibodies to human papillomavirus type 16 early antigens in the detection of human papillomavirus-related oropharyngeal cancer.

BACKGROUND: Because of the current epidemic of human papillomavirus (HPV)-related oropharyngeal cancer (OPC), a screening strategy is urgently needed. The presence of serum antibodies to HPV-16 early (E) antigens is associated with an increased risk for OPC. The purpose of this study was to evaluate the diagnostic accuracy of antibodies to a panel of HPV-16 E antigens in screening for OPC. METHODS: This case-control study included 378 patients with OPC, 153 patients with nonoropharyngeal head and neck cancer (non-OPC), and 782 healthy control subjects. The tumor HPV status was determined with p16 immunohistochemistry and HPV in situ hybridization. HPV-16 E antibody levels in serum were identified with an enzyme-linked immunosorbent assay. A trained binary logistic regression model based on the combination of all E antigens was predefined and applied to the data set. The sensitivity and specificity of the assay for distinguishing HPV-related OPC from controls were calculated. Logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for the association of head and neck cancer with the antibody status. RESULTS: Of the 378 patients with OPC, 348 had p16-positive OPC. HPV-16 E antibody levels were significantly higher among patients with p16-positive OPC but not among patients with non-OPC or among controls. Serology showed high sensitivity and specificity for HPV-related OPC (binary classifier: 83% sensitivity and 99% specificity for p16-positive OPC). CONCLUSIONS: A trained binary classification algorithm that incorporates information about multiple E antibodies has high sensitivity and specificity and may be advantageous for risk stratification in future screening trials. Cancer 2017;123:4886-94. © 2017 American Cancer Society.

A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck.

DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02-1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3'-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.

Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer.

BACKGROUND: Circulating Epstein-Barr virus DNA is a predictor of disease recurrence in patients with nasopharyngeal carcinoma. Circulating human papillomavirus (HPV) DNA has been detected in the sera of some patients with HPV-positive squamous cell carcinoma of the oropharynx (OPC). The goal of the current study was to determine whether pretreatment serum HPV DNA is a useful biomarker for disease recurrence in patients with HPV-positive OPC. METHODS: The study included patients with newly diagnosed, previously untreated OPC. Tumor HPV status was determined by polymerase chain reaction; serum HPV DNA was detected using real-time polymerase chain reaction. Differences in clinical characteristics between patients who were positive and negative for pretreatment serum HPV DNA were described using standard descriptive statistical methods. Kaplan-Meier curves were generated and log-rank tests were used to detect statistically significant differences in progression-free survival (PFS). RESULTS: A total of 262 patients were included. Patients with high N category and those with TNM stage IV disease were found to have higher rates of detectable pretreatment serum HPV DNA. Patients with HPV-positive tumors had better PFS than patients with HPV-negative tumors. Among patients with HPV-positive tumors, those who were negative for pretreatment serum HPV DNA had better PFS than those who were positive for pretreatment serum HPV DNA, but this result was not statistically significant. CONCLUSIONS: Pretreatment serum HPV DNA was associated with higher N category and overall disease stage. However, pretreatment serum HPV DNA does not appear to have clinical usefulness as a marker for disease recurrence among patients with OPC.

Metabolic activity measured on PET/CT correlates with clinical outcomes in patients with limb and girdle sarcomas.

OBJECTIVE: To explore the relationship between metabolic activity and outcome in patients with extremity sarcomas. METHODS: Between June 2004 and December 2011, 120 patients with newly diagnosed limb and girdle sarcomas underwent FDG-PET/CT for disease staging prior to curative intent treatment. The maximum standardized uptake value (SUV(max)) was measured for each primary tumor and correlated with outcome. Progression-free survival and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Soft-tissue sarcomas were more frequent (68%) than bone (27%) or cartilage (5%) tumors. Median follow-up was 33.2 months. 51% of patients progressed during the follow-up interval and 38% died. SUV(max) was dichotomized with a cut-point of 10.3. Patients with SUV(max) < 10.3 had better DFS and OS compared with patients with SUV(max) ≥ 10.3 (P < 0.001 and P < 0.001, respectively [log-rank test]). Multivariate analysis confirmed that even after adjusting for age, sex, site, tumor type (bone vs. soft-tissue), grade, and stage; an SUV(max) ≥ 10.3 correlated with a twofold risk of progression and 2.4 times greater risk of death (hazard ratio [HR] 2.0, 95% CI, 1.1-3.7, and HR, 2.4, 95% CI, 1.1-4.9). CONCLUSION: SUV(max) is an independent adverse prognostic factor for both progression and OS in patients with extremity sarcomas.

Impact of pretreatment body mass index on the survival of head and neck cancer patients.

BACKGROUND: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite. METHODS: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival. RESULTS: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m2 was associated with improved survival, while BMI <18.5 kg/m2 was associated with reduced survival, particularly in patients with HPV-positive oropharyngeal cancer tumors. CONCLUSIONS: This exploratory analysis suggests that pretreatment BMI could be an independent prognostic factor of survival outcomes in SCCHN patients, particularly in patients with HPV-positive oropharyngeal cancer tumors. Further prospective investigations are warranted.

Incidence and pattern of second primary malignancies in patients with index oropharyngeal cancers versus index nonoropharyngeal head and neck cancers.

BACKGROUND: A recent review of the Surveillance, Epidemiology, and End Results registry suggested that patients with index squamous cell carcinoma (SCC) of the oropharynx (SCCOP) are less likely to develop second primary malignancies (SPM) than patients with index SCC of nonoropharyngeal sites (oral cavity, larynx, hypopharynx). The objectives of this study were to determine the impact of index primary tumor site on SPM risk and to explore factors that potentially affect this risk within a large, prospectively accrued cohort of patients with index SCC of the head and neck (SCCHN). METHODS: A cohort of 2230 patients with incident SCCHN was reviewed for development of SPM. Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards models were used to detect the impact of various factors, including index tumor site, on SPM risk. RESULTS: The SPM rate was lower for patients with index SCCOP than for patients with index nonoropharyngeal cancer (P < .001). Among patients with SCCOP, former smokers had a 50% greater risk of SPM, and current smokers had a 100% greater risk of SPM than never-smokers (Ptrend = .008). Also among patients with SCCOP, those with the classic SCCHN phenotype had an SPM risk similar to that of patients with index nonoropharyngeal cancers; those with a typical human papillomavirus phenotype had a very low SPM risk. SPM most commonly occurred at nontobacco-related sites in patients with index SCCOP and at tobacco-related sites in patients with index nonoropharyngeal cancers. CONCLUSIONS: In patients with SCCHN, index cancer site and smoking status affect the risk and distribution of SPM.

An evolution in demographics, treatment, and outcomes of oropharyngeal cancer at a major cancer center: a staging system in need of repair.

BACKGROUND: In this retrospective review, the authors examined demographic/clinical characteristics and overall survival in patients with squamous cell carcinoma of the oropharynx at a tertiary cancer center, and they report the characteristics that influenced any observed survival trends over time. METHODS: The study included 3891 newly diagnosed, previously untreated patients who presented at the authors' institution between 1955 and 2004. RESULTS: Over time, patients presented at younger ages and were more likely to have base of tongue or tonsil tumors and to be never-smokers or former smokers. Patients who were diagnosed between 1995 and 2004 were almost half as likely to die as those who were diagnosed before 1995 (hazard ratio, 0.6; 95% confidence interval, 0.6-0.8). In both multivariable and recursive partitioning survival analyses, the TNM staging system predicted the survival of patients who received treatment before 1995 but did not predict the survival patients treated during the period from 1995 to 2004. CONCLUSIONS: Survival among patients with squamous cell carcinoma of the oropharynx improved substantially over the past 50 years. The main contributing factors were changes in clinical characteristics, in particular surrogates for positive human papillomavirus status. The current TNM staging system for squamous cell carcinoma of the oropharynx is inadequate. The incorporation of human papillomavirus status and perhaps smoking status into the TNM system is encouraged.

Characterization of the oral microbiota among middle-aged men with and without human papillomavirus infection.

OBJECTIVES: To characterize the oral microbiota among middle-aged men and identify differences between men with a prevalent oral high-risk (oncogenic) HPV infection and those without. MATERIALS AND METHODS: This was a case-control study nested within a prospective screening study for HPV-related cancers among middle-aged men. 16S rRNA sequencing was used to characterize the oral microbiota and the cobas HPV Test was used to detect presence of oral high-risk HPV types. We determined the overall composition of the oral microbiota and assessed differences in relative abundance of bacterial taxa as well as alpha and beta diversity among men with a prevalent oral high-risk HPV infection compared to men who were HPV-negative. RESULTS: Among 13 high-risk HPV-positive and 30 HPV-negative men, we found significant differences in beta diversity but not alpha diversity. Fretibacterium, F0058, Kingella, Treponema, and Prevotella were more abundant among the high-risk HPV-positive men while Neisseria and Lactobacillus were more abundant among the HPV-negative men. CONCLUSION: This study adds to the evidence that the oral microbiota varies according to oral HPV infection status and may be associated with the natural history of oral HPV infection.

Stepped Behavioral and Biological Screening for Oral Oncogenic HPV DNA in Middle-aged and Elderly Adults: A Feasibility Study.

Novel preventive interventions are needed to address the rising incidence of human papillomavirus (HPV)-mediated oropharyngeal cancer (HPV+ OPC). This pilot study evaluated the feasibility of a stepped, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate HPV+ OPC outcome.This was a cross-sectional, feasibility study. Eligible 45-74 years old adults identified from three clinical research registries were administered a behavioral risk survey (step 1). Participant tobacco use and sexual behavior history were translated into a quantifiable risk of oral oncogenic HPV DNA, according to prior National Health and Nutrition Examination Survey analyses. Females with >2% risk and males with >7% risk were offered biological screening for oral oncogenic HPV DNA (step 2) via an oral rinse and gargle specimen.A total of 292 individuals were contacted, but only 144 (49%) were reached. Among these, 56 individuals (19%) were uninterested and 18 (13%) were ineligible. Seventy individuals began the survey and 66 completed it (step 1), among whom 46 were classified as low-risk. Among the remaining 20 participants classified as high-risk for an oral oncogenic HPV infection, 5% were current smokers and the median participant had performed oral sex on 10 unique partners. During step 2 (biological screening), 45% (9/20) completed testing, all of whom tested negative for oral oncogenic HPV DNA.In this pilot of a stepped, oral oncogenic HPV screening program, enrollment and study completion were suboptimal. These barriers to screening should be characterized and addressed before reevaluating the feasibility of this program. PREVENTION RELEVANCE: Novel preventive interventions are needed to address the rising incidence of HPV+ OPC. In this feasibility study, we characterized barriers to a two-step, behavioral and biological screening program for oral oncogenic HPV infection, an intermediate outcome for HPV+ OPC.

Is 2045 the best we can do? Mitigating the HPV-related oropharyngeal cancer epidemic.

INTRODUCTION: Oropharyngeal cancer (OPC) will be among the most common cancers in men by 2045 due to a rapid rise in human papillomavirus (HPV)-related OPC. Those who survive their cancer often suffer life-long treatment effects and early death. HPV vaccination could prevent virtually all HPV-related cancers but is not an effective preventive strategy for those already exposed. Without a dramatic increase in vaccine uptake in the U.S., HPV vaccination will have a negligible effect on OPC incidence through 2045 and no substantial impact until 2060. Additionally, targeted screening for earlier diagnosis may soon be feasible for those inadequately protected by vaccination. AREAS COVERED: PubMed search for English-language articles related to incidence, screening, and prevention of HPV-related malignancies, focused on OPC in the U.S. EXPERT OPINION: HPV-related OPC incidence will continue to increase for the foreseeable future with prophylactic vaccination offering no substantial public health impact for decades. Consequently, we must rapidly increase vaccination rates and develop screening methods to identify high-risk individuals. Such individuals would be eligible for potential preventive treatments and screening to diagnose early-stage HPV-related OPC allowing less morbid treatments. These methods will bridge the population into an era of decreasing incidence after vaccination takes effect.

Detection accuracy of the Cobas HPV assay for high-risk HPV in head and neck FNA biopsy specimens.

BACKGROUND: This study evaluated the detection accuracy of the Cobas human papillomavirus (HPV) assay for high-risk human papillomavirus (hrHPV) and HPV-16 in head and neck fine-needle aspiration (FNA) specimens with squamous cell carcinoma. METHODS: Head and neck FNA biopsy specimens from 2012 to 2020 were retrospectively collected. Cobas HPV testing was performed on 90 FNA specimens with valid Cervista HPV testing results. Results of Cobas HPV and Cervista HPV assays were compared. A Linear Array or SPF10-LiPA25 HPV genotyping assay resolved cases with discrepant results. The κ value and accuracy of Cobas HPV testing were calculated. The accuracy of the Cobas HPV assay was also determined in 42 FNA needle-rinse specimens. RESULTS: Cobas HPV was positive in 82% of the FNA specimens (74 of 90). The concordance between Cobas HPV and Cervista HPV test results was 88.9% (80 of 90) with substantial agreement (κ = 0.669; 95% CI, 0.481-0.856). With HPV genotyping confirmation in cases with discrepant results between the 2 HPV assays, Cobas HPV showed 100% sensitivity and specificity for hrHPV. HPV-16 was detected in 88% of HPV-positive cases (65 of 74). HPV genotyping confirmed 1 false-negative HPV-16 result and 1 false-positive HPV-16 result. Overall, the accuracy of Cobas HPV for HPV-16 was 97.8%. The accuracy of Cobas HPV in FNA needle-rinse specimens was 100%. CONCLUSIONS: The Cobas HPV assay is highly accurate for determining the HPV status in head and neck FNA specimens. FNA needle rinse is valid for Cobas HPV testing in patients with squamous cell carcinoma.

A Cross-Sectional Study of the Prevalence of Anal Dysplasia among Women with High-Grade Cervical, Vaginal, and Vulvar Dysplasia or Cancer: The PANDA Study.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection is a risk factor for anal cancer, yet no anal cancer screening guidelines exist for women with lower genital tract HPV-related disease. We sought to describe the prevalence of anal HR-HPV or cytologic abnormalities in such women. METHODS: This cross-sectional study was performed between October 2018 and December 2021. Inclusion criteria were ≥21 years of age and a prior diagnosis of high-grade dysplasia/cancer of the cervix, vagina, or vulva. Participants underwent anal cytology and anal/cervicovaginal HR-HPV testing. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). RESULTS: 324 evaluable women were enrolled. Primary diagnosis was high-grade dysplasia/cancer of the cervix (77%), vagina (9%), and vulva (14%). Anal HR-HPV was detected in 92 patients (28%) and included HPV-16 in 24 (26%), HPV-18 in 6 (7%), and other HR-HPV types in 72 (78%) patients. Anal cytology was abnormal in 70 patients (23%) and included atypical squamous cells of undetermined significance (80%), low-grade squamous intraepithelial lesion (9%), high-grade intraepithelial lesion (HSIL; 1%), and atypical squamous cells-cannot rule out HSIL (10%). Of these patients, 55 (79%) underwent HRA. Anal biopsies were performed in 14 patients: 2 patients had anal intraepithelial neoplasia (AIN) 2/3, 1 patient had AIN 1, and 11 patients had negative biopsies. Both patients with AIN 2/3 had a history of cervical dysplasia. CONCLUSIONS: Our results suggest an elevated risk of anal HR-HPV infection and cytologic abnormalities in women with lower genital tract dysplasia/cancer. IMPACT: These results add to the growing body of evidence suggesting the need for evaluation of screening methods for anal dysplasia/cancer in this patient population to inform evidence-based screening recommendations.

Prevention and Screening of HPV Malignancies.

It is estimated that 5% of the global cancer burden, or approximately 690,000 cancer cases annually, is attributable to human papillomavirus (HPV). Primary prevention through prophylactic vaccination is the best option for reducing the burden of HPV-related cancers. Most high-income countries (HICs) have introduced the HPV vaccine and are routinely vaccinating adolescent boys and girls. Unfortunately, although they suffer the greatest morbidity and mortality due to HPV-related cancers, many lower- and middle-income countries (LMICs) have been unable to initiate and sustain vaccination programs. Secondary prevention in the form of screening has led to substantial declines in cervical cancer incidence in areas with established screening programs, but LMICs with absent or inadequate screening programs have high incidence rates. Meanwhile, HICs have seen incidence rates of anal and oropharyngeal cancers rise owing to the limited availability of organized screening for anal cancer and no validated screening options for oropharyngeal cancer. The implementation of screening programs for individuals at high risk of these cancers has the potential to reduce the burden of cervical cancer in LMICs, of anal and oropharyngeal cancers in HICs, and of anal cancer for highly selected HIV+ populations in LMICs. This review will discuss primary prevention of HPV-related cancers through vaccination and secondary prevention through screening of cervical, anal, and oropharyngeal cancers. Areas of concern and highlights of successes already achieved are included.