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Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706. [ABSTRACT FROM AUTHOR]

Background Many countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines. Methods In all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16INK4a biomarkers. Results The addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases. Conclusions Our estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites. [ABSTRACT FROM AUTHOR]

Elevated rates of human papillomavirus (HPV)-related anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) in populations like men who have sex with men (MSM) living with HIV underscore the need for effective screening. While high-resolution anoscopy-guided biopsy is the gold standard, limited provider availability poses a challenge. This has spurred interest in identifying biomarkers for improved AC prevention. Antibodies against HPV16 oncoprotein E6, known as markers for cervical and oropharyngeal cancers, are the focus of the current study. The systematic review and meta-analysis included six studies meeting inclusion criteria, assessing HPV16 E6 seroprevalence in individuals with anal HSIL or AC. A two-step meta-analysis estimated pooled odds ratios and 95% confidence intervals (CI) for HPV16 E6 seroprevalence and HSIL or AC. Pooled prevalence, sensitivity, specificity, and diagnostic odds ratios were also calculated. This meta-analysis revealed a 3.6-fold increased risk of HSIL for HPV16 E6 seropositive individuals, escalating to a 26.1-fold risk increase for AC. Pooled specificity and sensitivity indicated a high specificity (0.99; 95%CI: 0.99, 0.99) but lower sensitivity (0.19; 95%CI: 0.10, 0.34) for HPV16 E6 serostatus as an AC biomarker. In conclusion, while HPV16 E6 seroprevalence demonstrates specificity as a potential biomarker for HPV-related AC, its utility as a standalone screening tool may be limited. Instead, it could serve effectively as a confirmation test, particularly in high-risk populations, alongside other diagnostic methods. Further research is imperative to explore HPV16 E6 seroconversion dynamics and alternative screening algorithms. [ABSTRACT FROM AUTHOR]

BACKGROUND: Endometrial cancer is a hormone-dependent cancer, and estrogens play a relevant role in its etiology. However, little is known about the effects of environmental pollutants that act as xenoestrogens or that influence estrogenic activity through different pathways. OBJECTIVE: We aimed to assess the relationship between the combined estrogenic activity of mixtures of xenoestrogens present in serum samples and the risk of endometrial cancer in the Screenwide case–control study. METHODS: The total effective xenoestrogen burden (TEXB) attributable to organohalogenated compounds (TEXB-a) and to endogenous hormones and more polar xenoestrogens (TEXB-ß) was assessed in serum from 156 patients with endometrial cancer (cases) and 150 controls by combining chemical extraction and separation by high-performance liquid chromatography with the E-SCREEN bioassay for estrogenicity. RESULTS: Median TEXB-a and TEXB-ß levels for cases (0.30 and 1.25 Eeq pM/mL, respectively) and controls (0.42 and 1.28 Eeq pM/mL, respectively) did not significantly differ (??=0.653 and 0.933, respectively). An inverted-U risk trend across serum TEXB-a and TEXB-ß levels was observed in multivariate adjusted models: Positive associations were observed for the second category of exposure in comparison to the lowest category of exposure [odds ratio (OR) = 2.11 (95% CI: 1.13, 3.94) for TEXB-a, and OR=3.32 (95% CI: 1.62, 6.81) for TEXB-ß], whereas no significant associations were observed between the third category of exposure and the first [OR = 1.22 (95% CI: 0.64, 2.31) for TEXB-a, and OR=1.58 (95% CI: 0.75, 3.33) for TEXB-ß]. In mutually adjusted models for TEXB-a and TEXB-ß levels, the association of TEXB-a with endometrial cancer risk was attenuated [OR=1.45 (95% CI: 0.61, 3.47) for the second category of exposure], as well as estimates for TEXB-ß (OR=2.68; 95% CI: 1.03, 6.99). Most of the individual halogenated contaminants showed no associations with both TEXB and endometrial cancer. CONCLUSIONS: We evaluated serum total xenoestrogen burden in relation to endometrial cancer risk and found an inverted-U risk trend across increasing categories of exposure. The use of in vitro bioassays with human samples may lead to a paradigm shift in the way we understand the negative impact of chemical mixtures on human health effects. These results are relevant from a public health perspective and for decision-makers in charge of controlling the production and distribution of chemicals with xenoestrogenic activity. [ABSTRACT FROM AUTHOR]

Introduction: New approaches are being developed to early detect endometrial cancer using molecular biomarkers. These approaches offer high sensitivities and specificities, representing a promising horizon to develop early detection strategies. Objective: To evaluate the effectiveness and cost-effectiveness of introducing molecular testing to detect endometrial cancer in women with postmenopausal bleeding compared to the current strategy using the national healthcare service perspective. Methods: A Markov model was developed to assess the two early detection strategies. The model predicts the number of hysterectomies, lifetime expectancy, quality-adjusted life-years, endometrial cancer prevalence and incidence, mortality from endometrial cancer and the lifetime cost of screening, diagnosis, and treatment. Strategies were compared using the incremental cost-effectiveness ratio. Results: The molecular strategy reduces 1.9% of the overall number of hysterectomies and the number of undetected cancer cases by 65%. Assuming a molecular test cost of 310€, the molecular strategy has an incremental cost of -32,952€ per QALY gained, being more effective and less expensive than the current strategy. Conclusions: The introduction of molecular testing to diagnose endometrial cancer in women presenting postmenopausal bleeding provides more health benefit at a lower cost, and therefore has the potential to be cost-effective. [ABSTRACT FROM AUTHOR]

Squamous cell carcinomas with two or more coexisting clearly different histological subtypes of penile carcinomas are designated as mixed carcinomas in current classification models. They represent about 10% of all penile carcinomas. The aim of this study was to detect HPV genotypes in these unusual tumors. Tumors were selected from an international series of 1010 patients with penile carcinomas. Mixed carcinomas were grouped, according to WHO recommendations, as follows: 1. Carcinomas with warty/basaloid features mixed with HPV-independent carcinomas and 2. HPV-independent subtypes mixed with each other. HPV detection and p16INK4a immunostaining were performed. For HPV detection, whole tissue section-PCR analyses were performed by SPF10-DEIA-LiPA25 (version 1). As expected, HPV was detected more frequently in HPV-associated mixed carcinomas than in HPV-independent mixed carcinomas. Carcinomas with basaloid or warty features mixed with other SCC subtypes showed an HPV positivity rate of 46% (33 of 72 tumors) compared with 7% found in tumors with nonwarty/basaloid morphology (2 of 29 tumors). Eleven high-risk HPV genotypes were identified and the most common was HPV16 (65%) usually associated with basaloid morphology. p16INK4a immunostaining was positive in 76% of HPV-positive tumors. As in nonmixed carcinomas, although in lower proportion, a variable array of HPV genotypes was detected in mixed carcinomas. Apparently, the presence of a non-HPV component in an otherwise typical HPV-associated type tumor does adversely affect the prevalence of HPV positivity. Any amount of HPV-associated morphology superior to 20% in a mixed tumor is sufficient to classify them as HPV-associated, a WHO requirement. [ABSTRACT FROM AUTHOR]

BACKGROUND: We aimed to provide updated information about the global estimates of attributable fraction and type distribution of human papillomavirus (HPV) in head and neck squamous cell carcinomas by doing a systematic review and meta-analysis. METHODS: We did a literature search on PubMed to identify studies that used PCR for detection of HPV DNA in head and neck squamous cell carcinomas with information about HPV genotype distribution. We included studies that tested 20 or more biopsies per cancer site and were published between July 15, 1990, and Feb 29, 2012. We collected information about sex, risk factors, HPV detection methods, and biomarkers of potentially HPV-induced carcinogenesis (E6/E7 mRNA and p16(INK4a)). If it was not possible to abstract the required information directly from the paper, we contacted the authors. We did a meta-analysis to produce pooled prevalence estimates including a meta-regression to explore sources of heterogeneity. FINDINGS: 148 studies were included, contributing data for 12163 cases of head and neck squamous cell carcinoma from 44 countries. HPV DNA was detected in 3837 cases. HPV16 accounted for 82·2% (95% CI 77·7-86·4) of all HPV DNA positive cases. By cancer site, pooled HPV DNA prevalence estimates were 45·8% (95% CI 38·9-52·9) for oropharynx, 22·1% (16·4-28·3) for larynx (including hypopharynx), and 24·2% (18·7-30·2) for oral cavity. The percent positivity of p16(INK4a) positive cases in HPV-positive oropharyngeal cancer cases was 86·7% (95% CI 79·2-92·9) and of E6/E7 mRNA positive cases was 86·9% (73·2-96·8). The estimate of HPV attributable fraction in oropharyngeal cancer defined by expression of positive cases of E6/E7 mRNA was 39·8% and of p16(INK4a) was 39·7%. Of subsites, tonsils (53·9%, 95% CI 46·4-61·3) had the highest HPV DNA prevalence. HPV DNA prevalence varied significantly by anatomical site, geographic region, but not by sex or tobacco or alcohol consumption. INTERPRETATION: The contribution of HPV prevalence in head and neck squamous cell carcinoma and in particular that of HPV16 in the oropharynx shows the potential benefit of prophylactic vaccines. FUNDING: European Commission. [ABSTRACT FROM AUTHOR]

Cancer of the oropharynx has attracted considerable attention in recent years given: (1) an increasing incidence in selected populations over the past three decades; (2) the discovery of human papillomavirus (HPV) infection as the driver of the increase, as opposed to the traditional risk factors such as tobacco (smoking and chewing) and alcohol; and (3) the promise of new prevention and treatment strategies. As a result of such developments, the International Agency for Research on Cancer (IARC) and the US National Cancer Institute (NCI), convened the fourth Cancer Seminar meeting in November 2018 to focus on this topic. This report summarizes the proceedings: a review of recent science on the descriptive epidemiology, etiology, biology, genetics, early detection, pathology and treatment of HPV-positive oropharyngeal cancer, and the formulation of key research questions to be addressed. [ABSTRACT FROM AUTHOR]

Background: Differences in oral human papillomavirus (HPV) prevalence and contrasts in HPV-attributable fractions (AFs) in oropharyngeal cancer (OPC) have not been evaluated in depth.Methods: A systematic review was performed to identify studies in which at least 50 healthy individuals were tested for oral HPV infection. Information on sex, age, tobacco/alcohol consumption, sex practices, specimen collection, HPV detection, and population type was extracted. Prevalences were pooled using random-effects models for meta-analyses of binomial data. Correlations were assessed by the Spearman test.Results: Forty-eight reports comprising 28 544 individuals fulfilled inclusion criteria. Global oral HPV prevalence was 4.9%. Estimates were highest in Europe, although regional differences were not statistically significant. HPV16 prevalence was 1.0% globally, and regional differences became statistically significant. A lifetime history of >6 sex partners showed a higher risk of oral HPV infection. The age-specific HPV distribution revealed a prevalence of ≥5% over 40 years of age and a lower prevalence at younger ages. There was no association between oral HPV prevalence and HPV-AFs or age-standardized rates (ASRs) of OPC, genital HPV in healthy women, or tobacco use.Conclusions: Differences in HPV-AFs or ASRs of OPC cannot be explained by differences in the prevalence of oral HPV infection across healthy populations. Consistent research on determinants of oral HPV prevalence, acquisition, clearance, and persistence is warranted. [ABSTRACT FROM AUTHOR]

Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16 INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998–2004 to 23% during 2005–2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP. [ABSTRACT FROM AUTHOR]

Unlabelled: Aim To estimate relative contribution and time trends of HPV types in cervical cancer in Cali, Colombia over a 50 years' period.Methods: Paraffin blocks of 736 cervical cancer histological confirmed cases were retrieved from the pathology laboratory at Hospital Universitario del Valle (Cali, Colombia) and HPV genotyped using SPF10-PCR/DEIA/LiPA25 (version 1) assay. Marginal effect of age and year of diagnosis in secular trends of HPV type prevalence among HPV+ cases were assessed by robust Poisson regression analysis.Results: 64.7% (95%CI: 59.9-69.2) of squamous cell carcinomas (SCCs) were attributed to HPV 16 and 18, 78.2% (95%CI: 74-82) to HPV 16, 18, 31, 33 and 45 and 84.8% (95%CI: 81-88.1) to HPV 16, 18, 31, 33, 45, 52 and 58 while ninety-three percent of adenocarcinomas (ADCs) were attributed to HPV 16, 18 and 45 only. The prevalence of specific HPV types did not change over the 50-year period. A significant downward trend of prevalence ratios of HPV16 (​P=0.017) and α7 but HPV 18 (i.e., HPV 39, 45, 68, 70, ​P=0.024) with increasing age at diagnosis was observed. In contrast, the prevalence ratio to other HPV genotypes of α9 but HPV 16 genotypes (i.e., HPV 31, 33, 35, 52, 58, 67, ​P=0.002) increased with increasing age at diagnosis.Conclusion: No changes were observed in the relative contribution of HPV types in cervical cancer in Cali, Colombia during the 50 years. In this population, an HPV vaccine including the HPV 16, 18, 31, 33, 45, 52 and 58 genotypes may have the potential to prevent ∼85% and 93% of SCC and ADC cases respectively. [ABSTRACT FROM AUTHOR]

Objective Human papillomavirus (HPV) vaccines can potentially control cervical cancer and help to reduce other HPV-related cancers. We aimed to estimate the relative contribution (RC) of the nine types (HPVs 16/18/31/33/45/52/58/6/11) included in the recently approved 9-valent HPV vaccine in female anogenital cancers and precancerous lesions (cervix, vulva, vagina and anus). Methods Estimations were based on an international study designed and coordinated at the Catalan Institute of Oncology (Barcelona-Spain), including information on 10,575 invasive cervical cancer (ICC), 1709 vulvar, 408 vaginal and 329 female anal cancer cases and 587 Vulvar Intraepitelial Neoplasia grade 2/3 (VIN2/3), 189 Vaginal Intraepitelial Neoplasia grade 2/3 (VaIN2/3) and 29 Anal Intraepitelial Neoplasia grade 2/3 (AIN2/3) lesions. Consecutive histologically confirmed paraffin-embedded cases were obtained from hospital pathology archives from 48 countries worldwide. HPV DNA-detection and typing was performed by SPF 10 -DEIA-LiPA 25 system and RC was expressed as the proportion of type-specific cases among HPV positive samples. Multiple infections were added to single infections using a proportional weighting attribution. Results HPV DNA prevalence was 84.9%, 28.6%, 74.3% and 90.0% for ICC, vulvar, vaginal and anal cancers, respectively, and 86.7%, 95.8% and 100% for VIN2/3, VaIN2/3 and AIN2/3, respectively. RC of the combined nine HPV types was 89.5% (95% confidence interval (CI): 88.8–90.1)-ICC, 87.1% (83.8–89.9)-vulvar, 85.5% (81.0–89.2)-vaginal, 95.9% (93.0–97.9)-female anal cancer, 94.1% (91.7–96.0)-VIN2/3, 78.7% (71.7–84.2)-VaIN2/3 and 86.2% (68.3–96.1)-AIN2/3. HPV16 was the most frequent type in all lesions. Variations in the RC of HPVs 31/33/45/52/58 by cancer site were observed, ranging from 7.8% (5.0–11.4)-female anal cancer to 20.5% (16.1–25.4)-vaginal cancer. Conclusions The addition of HPVs 31/33/45/52/58 to HPV types included in current vaccines (HPV16/18) could prevent almost 90% of HPV positive female anogenital lesions worldwide. Taking into account that most HPV-related cancers are ICC ones, the 9-valent HPV vaccine could potentially avoid almost 88% of all female anogenital cancers. [ABSTRACT FROM AUTHOR]

Head and neck cancers are increasingly associated with human papillomavirus (HPV) infection. Previous studies of oral HPV indicate considerable heterogeneity across geographic regions and by sex, but studies differ in methodologies used and risk groups included. Understanding the natural history of oral HPV in the general population is important to assess HPV-related disease burden and plan effective prevention programs. In this study, we aim to assess the prevalence, incidence, and persistence of oral HPV among adult men and women. Factors independently associated with oral HPV will also be evaluated. The PROGRESS (PRevalence of Oral hpv infection, a Global aSSessment) study is a non-interventional study of 7877 healthy men and women aged 18–60 years, from France, Germany, Spain, the United Kingdom (UK) and the United States (US). Oral HPV prevalence will be measured using a commercially available PCR DNA test. In the US, participants will be followed prospectively every 6 months for 24 months to assess incidence, clearance, and persistence of oral HPV infection. Eligible individuals presenting for regular dental check-ups will be recruited from participating dental offices via systematic consecutive sampling. Participant dentists will collect clinical characteristics, and participants will complete self-reported study questionnaires and provide an oral rinse and gargle (ORG) specimen for HPV-DNA detection and genotyping at each study visit. HPV-DNA detection and genotyping will be performed in two reference laboratories, using the SPF10/DEIA/LiPA25 system. PROGRESS study aims to fill knowledge gaps concerning the natural history of oral HPV using a standardized methodology. PROGRESS will also assess factors associated with oral HPV prevalence and natural history in the general population. [ABSTRACT FROM AUTHOR]

Persistent human papillomavirus (HPV) infection is an important risk factor for a subset of head and neck cancers (HNCs). However, estimates of the HPV-attributable fraction of oropharyngeal cancers vary greatly, and the proportion is increasing. Growing evidence indicates smaller proportions of oral cavity and laryngeal cancers are also HPV-attributable, but this requires further investigation. The primary objective of the BROADEN study is to estimate the fraction of HNCs attributable to HPV in selected European and Asian countries by anatomic site. Secondary objectives are to determine HPV genotypes involved and to describe primary tumor and patient characteristics by HPV status. BROADEN is a non-interventional, cross-sectional study of patients with HNC in China, France, Germany, Italy, Japan, Portugal, and Spain. The HPV-attributable HNC fraction will be determined within pre-defined time-periods (2008–2009, 2013–2014 [China only], 2018–2019). Approximately 9000 patients from an estimated 90 hospitals with reference HNC diagnostic units and local reference pathology laboratories will participate. Sample size estimates were generated by grouped anatomic site (oropharynx, oral cavity, nasopharynx, hypopharynx, and larynx) and country. HPV testing (HPV-DNA and p16 immunohistochemistry [IHC]) will be performed at a central laboratory on formalin-fixed paraffin-embedded tissue samples. All HPV-DNA-positive samples and HPV-DNA-negative/p16 IHC-positive samples, plus 10% of remaining HPV DNA-negative (control) samples will be tested for HPV mRNA. BROADEN is a large global epidemiologic study to estimate current and recent past HPV burden in oropharyngeal and non-oropharyngeal HNCs. BROADEN is expected to provide robust estimates of HPV attributability by anatomic site in participating countries. [ABSTRACT FROM AUTHOR]

WHO/UNICEF estimates for HPV vaccination coverage from 2010 to 2019 are analyzed against the backdrop of the 90% coverage target for HPV vaccination by 2030 set in the recently approved global strategy for cervical cancer elimination as a public health problem. As of June 2020, 107 (55%) of the 194 WHO Member States have introduced HPV vaccination. The Americas and Europe are by far the WHO regions with the most introductions, 85% and 77% of their countries having already introduced respectively. A record number of introductions was observed in 2019, most of which in low- and middle- income countries (LMIC) where access has been limited. Programs had an average performance coverage of around 67% for the first dose and 53% for the final dose of HPV. LMICs performed on average better than high- income countries for the first dose, but worse for the last dose due to higher dropout. Only 5 (6%) countries achieved coverages with the final dose of more than 90%, 22 countries (21%) achieved coverages of 75% or higher while 35 (40%) had a final dose coverage of 50% or less. When expressed as world population coverage (i.e., weighted by population size), global coverage of the final HPV dose for 2019 is estimated at 15%. There is a long way to go to meet the 2030 elimination target of 90%. In the post-COVID era attention should be paid to maintain the pace of introductions, specially ensuring the most populous countries introduce, and further improving program performance globally. [ABSTRACT FROM AUTHOR]

Objectives: To test the performance of an oral cancer prognostic 13-gene signature for the prediction of survival of patients diagnosed with HPV-negative and p16-negative oral cavity cancer.Materials and Methods: Diagnostic formalin-fixed paraffin-embedded oral cavity cancer tumor samples were obtained from the Fred Hutchinson Cancer Research Center/University of Washington, University of Calgary, University of Michigan, University of Utah, and seven ARCAGE study centers coordinated by the International Agency of Research on Cancer. RNA from 638 Human Papillomavirus (HPV)-negative and p16-negative samples was analyzed for the 13 genes using a NanoString assay. Ridge-penalized Cox regressions were applied to samples randomly split into discovery and validation sets to build models and evaluate the performance of the 13-gene signature in predicting 2-year oral cavity cancer-specific survival overall and separately for patients with early and late stage disease.Results: Among AJCC stage I/II patients, including the 13-gene signature in the model resulted in substantial improvement in the prediction of 2-year oral cavity cancer-specific survival. For models containing age and sex with and without the 13-gene signature score, the areas under the Receiver Operating Characteristic Curve (AUC) and partial AUC were 0.700 vs. 0.537 (p < 0.001), and 0.046 vs. 0.018 (p < 0.001), respectively. Improvement in predicting prognosis for AJCC stage III/IV disease also was observed, but to a lesser extent.Conclusions: If confirmed using tumor samples from a larger number of early stage oral cavity cancer patients, the 13-gene signature may inform personalized treatment of early stage HPV-negative and p16-negative oral cavity cancer patients. [ABSTRACT FROM AUTHOR]

Purpose: The assessment of p16INK4a (p16) in oropharyngeal squamous cell carcinoma (OPSCC) has been incorporated into tumor classification, as p16 has been shown to impact survival probability. However, a recent study demonstrated that human papillomavirus (HPV) status in addition to p16 may have a better discriminatory effect on survival probability. This study aims to determine the impact of combined evaluation of p16 and HPV on prognosis., Methods: This was a multicenter, multinational analysis including retrospective and prospective cohorts of patients treated for primary OPSCC with curative intent, based on the data of the HNCIG-EPIC study. The primary outcome was to determine how the combined assessment of HPV and p16 status predicts prognosis of patients with OPSCC compared to p16 assessment alone. We employed multivariable analyses models to compute hazard ratios regarding survival. Analyses were stratified by stage, smoking status, and sub-anatomical region., Results: The study included 7654 patients, with approximately half of the tumors being p16-negative (50.3 %, n = 3849). A total of 9.2 % of patients had discordant p16 and HPV status (n = 704). HPV status significantly impacted overall survival and disease-free survival regardless of p16 status and across both UICC 8th stage I-II and III-IVb cancers. p16-positive/HPV-positive OPSCC patients exhibited the best survival probability., Conclusion: The detection of HPV had a significant impact on survival probability for OPSCC patients with both p16-positive and p16-negative tumors. HPV testing should be integrated in cancer staging, especially in regions of low attributable fraction, alongside p16 evaluation to ensure a comprehensive assessment of prognosis., Competing Interests: Declaration of Competing Interest JPK receiving honoraria from MSD, Merck and BMS; research funding from MSD. No other authors have any conflict of interests to declare., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes., (© 2024. The Author(s).)

Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection., Methods: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics., Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64)., Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

There is limited understanding of epidemiology and time trends of human papilloma virus (HPV)-driven head and neck cancers (HNC) in Japan, especially outside of the oropharynx. To assess HPV-driven HNC, a non-interventional study (BROADEN) of HNC patients diagnosed in 2008-2009 and 2018-2019 was conducted in Japan. Adult patients with oropharyngeal, nasopharyngeal, laryngeal, hypopharyngeal or oral cavity cancers were included in this study. HPV was centrally tested using p16INK4a immunohistochemistry, HPV-DNA PCR and HPV E6*I mRNA. HPV attributability required positivity in at least two tests (p16INK4a immunohistochemistry, HPV-DNA PCR, HPV E6*I mRNA) in the oropharynx, and HPV-DNA and HPV E6*I mRNA positivity for non-oropharynx sites. Nineteen hospitals included a total of 1108 patients, of whom 981 had valid samples. Men accounted for 82% of HNC diagnoses. Patients in the earlier cohort were younger and included a higher percentage of smokers. There was an increasing trend of HPV-driven oropharyngeal cancer over the last decade, from 44.2% to 51.7%. HPV attribution in nasopharyngeal cancers was 3.2% in 2008-2009 and 7.5% in 2018-2019; and 4.4% and 0% for larynx respectively. In total, 95.2% of HPV-driven HNC were attributed to HPV genotypes included in the 9-valent HPV vaccine being HPV16 the most prominent genotype. These results suggest that an epidemiologic shift is happening in Japan, with a decrease in smoking and alcohol use and an increase in HPV-driven HNC. The increasing trend of HPV-driven HNC in Japan highlights the need for preventive strategies to mitigate the rise of HPV-driven HNC., (© 2024 Merck Sharp and Dohme LLC and The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Purpose of Review: New evidence has recently emerged regarding the utility and benefits of dual p16 INKa (p16) and Human papillomavirus (HPV) status testing when determining the diagnosis and prognosis of patients with oropharyngeal cancer., Recent Findings: HPV RNA polymerase chain reaction (PCR) is the most accurate diagnostic test. The other assays (HPV DNA PCR, HPV DNA/RNA in-situ hybridization (ISH) and p16) applied to formalin fixed tumour tissue have varying but high sensitivities and specificities. Dual p16 and HPV testing identifies discordant (p16+/HPV- or p16-/HPV+) results in 9.2% of cases, who have significantly poorer prognoses than p16+/HPV+, particularly in smokers. The proportion of discordant cases varies by region, and appears to be highest in regions with lowest attributable (p16+/HPV+) fractions. Dual testing improves prognostication for oropharyngeal cancer cases by identifying discordant cases and improving the prognostic power of the Tumour Node Metastasis (TNM) classification, especially in regions with high discordant rates., Summary: Dual testing is essential when considering patients for clinical trials of treatment de-escalation, and may be important when counselling patients on prognosis, especially in regions with high discordant rates and in smokers., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

We communicate here two complete Human papillomavirus 11 (HPV11) genomes recovered from one transitional and from one squamous inverted sinonasal papilloma, a rare proliferative disease in humans. Both genomes belong to the HPV11&#95;A2 sublineage., Competing Interests: The authors declare no conflict of interest.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16 INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Data on the role of circadian related factors in the etiology of endometrial cancer are scarce. We collected individual data on night shift work or daily sleep duration from 7,207 cases and 22,027 controls participating in 11 studies from the Epidemiology of Endometrial Cancer Consortium (E2C2). Main analyses were performed among postmenopausal women: 6,335 endometrial cancer cases and 18,453 controls. Using individual data, study-specific odd ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated with logistic regression and pooled analyses were conducted using random-effects meta-analyses. A non-significant inverse association was observed between endometrial cancer and night shift work (OR=0.89, 95%CI=0.72-1.09; I 2 =0.0%, P heterogeneity= 0.676). Associations did not vary by shift type (permanent or rotating), or duration of night work. Categorizations of short (<7h) or long (≥9h) sleep duration were not associated with endometrial cancer risk (OR short =1.02, 95%CI=0.95-1.10; I 2 =55.3%, P heterogeneity =0.022; OR long =0.93, 95%CI=0.81-1.06; I 2 =11.5%, P heterogeneity =0.339). No associations were observed per 1-h increment of sleep (OR=0.98, 95%CI=0.95-1.01; I 2 =46.1%, P heterogeneity =0.063), but an inverse association was identified among obese women (OR=0.93, 95%CI=0.89-0.98 per 1-h increment; I 2 =12.7%, P heterogeneity =0.329). Overall, these pooled analyses provide evidence that night shift work and sleep duration are not strong risk factors for endometrial cancer in postmenopausal women., Competing Interests: Declaration of competing interest The authors of this paper have no conflicts of interest to disclose relevant to the present work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Endometrial cancer is the most common gynaecological tumour in developed countries and disease burden is expected to increase over the years. Identifying modifiable risk factors may help developing strategies to reduce the expected increasing incidence of these neoplasms., Objective: This study evaluates the association between occupational exposure to pesticides and endometrial cancer using data from a recent case-control study in Spain., Methods: The analyses included data from 174 consecutive incident endometrial cancer cases and 216 hospital controls frequency-matched by age. Data were collected through structured epidemiological questionnaires and exposure to pesticides was assessed using a Spanish job-exposure matrix (MatEmESp)., Results: Overall, 12% of controls and 18% of cases were occupationally exposed to pesticides. We observed a positive association between occupational exposure to pesticides and endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88 compared to non-exposed). In general, exposures that occurred farther in the past were significantly associated with endometrial cancer. Exposure to insecticides, fungicides and herbicides were positively associated with endometrial cancer (OR = 2.08; 95% CI = 1.13-3.88, OR = 4.40; 95% CI = 1.65-13.33, and OR = 5.25; 95% CI = 1.84-17.67, respectively). The agricultural, poultry and livestock activities scenario was associated with endometrial cancer (OR = 4.16; 95% CI = 1.59-12.32), while the cleaning exposure scenario was not (OR = 1.22; 95% CI = 0.55-2.67)., Conclusions: Assessment of occupational exposure to pesticides assessed using a Spanish job-exposure matrix revealed a positive association with endometrial cancer. The elucidation of the role of pesticide compounds on endometrial cancer should shed a light on the aetiology of this tumour., (© 2023. The Author(s).)

Purpose: Current diagnostic methods for endometrial cancer lack specificity, leading to many women undergoing invasive procedures. The aim of this study was to evaluate somatic mutations in urine to accurately discriminate patients with endometrial cancer from controls., Experimental Design: Overall, 72 samples were analyzed using next-generation sequencing (NGS) with molecular identifiers targeting 47 genes. We evaluated urine supernatant samples from women with endometrial cancer (n = 19) and age-matched controls (n = 20). Cell pellets from urine and plasma samples from seven cases were sequenced; further, we also evaluated paired tumor samples from all cases. Finally, immunohistochemical markers for molecular profiling were evaluated in all tumor samples., Results: Overall, we were able to identify mutations in DNA from urine supernatant samples in 100% of endometrial cancers. In contrast, only one control (5%) showed variants at a variant allele frequency (VAF) ≥ 2% in the urine supernatant samples. The molecular classification obtained by using tumor samples and urine samples showed good agreement. Analyses in paired samples revealed a higher number of mutations and VAF in urine supernatants than in urine cell pellets and blood samples., Conclusions: Evaluation of somatic mutations using urine samples may offer a user-friendly and reliable tool for endometrial cancer detection and molecular classification. The diagnostic performance for endometrial cancer detection was very high, and cases could be molecularly classified using these noninvasive and self-collected samples. Additional multicenter evaluations using larger sample sizes are needed to validate the results and understand the potential of urine samples for the early detection and prognosis of endometrial cancer., (©2023 American Association for Cancer Research.)

Human papillomavirus (HPV) is detected in 30-50% of invasive penile carcinomas, and it is frequently associated with basaloid and warty morphological features. Based on this heterogeneity and different clinical behaviors, we hypothesized a variation in their HPV genotypic composition. To test this, we evaluated 177 HPV-positive cases: basaloid (114), warty-basaloid (28), and warty (condylomatous) (35) invasive carcinomas. HPV DNA detection and genotyping was performed using the SPF-10/DEIA/LiPA 25 system. Nineteen HPV genotypes were detected. High-risk HPVs predominated (96%), and low-risk HPVs were rarely present. Most common genotype was HPV16 followed by HPVs 33 and 35. According to the genotypes identified, 93% of the cases would be covered with current vaccination programs. There was a significant variation in the distribution of HPV16 and non-HPV16 genotypes according to histological subtype. HPV16 was significantly frequent in basaloid (87%) and was less frequent in warty carcinomas (61%). This molecular difference, along with their distinctive macro-microscopic and prognostic features, makes basaloid and warty carcinomas unique. The gradual decreasing frequency of HPV16 demonstrated in basaloid, warty-basaloid, and warty carcinomas suggest that the basaloid cell, present in those types in decreasing proportions, may be responsible for the differences., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The epidemiology of human papillomavirus (HPV) in women has been well documented. Less is known about the epidemiology of HPV in men. We aim to provide updated global and regional pooled overall, type-specific, and age-specific prevalence estimates of genital HPV infection in men., Methods: We conducted a systematic review and meta-analysis to assess the prevalence of genital HPV infection in the general male population. We searched Embase, Ovid MEDLINE, and the Global Index Medicus for studies published between Jan 1, 1995, and June 1, 2022. Inclusion criteria were population-based surveys in men aged 15 years or older or HPV prevalence studies with a sample size of at least 50 men with no HPV-related pathology or known risk factors for HPV infection that collected samples from anogenital sites and used PCR or hybrid capture 2 techniques for HPV DNA detection. Exclusion criteria were studies conducted among populations at increased risk of HPV infection, exclusively conducted among circumcised men, and based on urine or semen samples. We screened identified reports and extracted summary-level data from those that were eligible. Data were extracted by two researchers independently and reviewed by a third, and discrepancies were resolved by consensus. We extracted only data on mucosal α-genus HPVs. Global and regional age-specific prevalences for any HPV, high-risk (HR)-HPV, and individual HPV types were estimated using random-effects models for meta-analysis and grouped by UN Sustainable Development Goals geographical classification., Findings: We identified 5685 publications from database searches, of which 65 studies (comprising 44 769 men) were included from 35 countries. The global pooled prevalence was 31% (95% CI 27-35) for any HPV and 21% (18-24) for HR-HPV. HPV-16 was the most prevalent HPV genotype (5%, 95% CI 4-7) followed by HPV-6 (4%, 3-5). HPV prevalence was high in young adults, reaching a maximum between the ages of 25 years and 29 years, and stabilised or slightly decreased thereafter. Pooled prevalence estimates were similar for the UN Sustainable Development Goal geographical regions of Europe and Northern America, Sub-Saharan Africa, Latin America and the Caribbean, and Australia and New Zealand (Oceania). The estimates for Eastern and South-Eastern Asia were half that of the other regions., Interpretation: Almost one in three men worldwide are infected with at least one genital HPV type and around one in five men are infected with one or more HR-HPV types. Our findings show that HPV prevalence is high in men over the age of 15 years and support that sexually active men, regardless of age, are an important reservoir of HPV genital infection. These estimates emphasise the importance of incorporating men in comprehensive HPV prevention strategies to reduce HPV-related morbidity and mortality in men and ultimately achieve elimination of cervical cancer and other HPV-related diseases., Funding: Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020., Translations: For the Spanish and French translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests The Cancer Epidemiology Research Program (with which LB, LA, and GA are affiliated) has received sponsorship for grants from Merck and HPV test kits at no cost from Roche for research purposes. ARG reports payments from Merck to her institution, and as consulting fees to herself, and payments from Merck for participation on an advisory board. All other authors declare no competing interests., (© 2023 World Health Organization. Published by Elsevier Ltd. All rights reserved. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Importance: In the US, oropharyngeal cancer, predominantly caused by high-risk (HR) human papillomavirus (HPV) infection, is the most frequent HPV-associated cancer, surpassing cervical cancer. However, little is known about oral HPV prevalence and genotype distribution in the general population., Objective: To assess oral HPV prevalence and factors associated with HR and low-risk infection in a general US population., Design, Setting, and Participants: PROGRESS (Prevalence of Oral HPV Infection, a Global Assessment) was a cross-sectional observational study conducted between November 2021 and March 2022 in 43 dental offices in the US (24 urban, 13 urban cluster, and 6 rural sites), spanning 21 states. Eligible participants were aged 18 to 60 years, visiting dental clinics for routine dental examination. Dental clinics used targeted sampling to recruit equal distributions of men and women and across age groups., Exposure: Participants provided an oral gargle specimen for HPV DNA and genotyping and completed behavioral questionnaires, and dentists reported oral health status. Detection of HPV DNA and genotyping was performed using the SPF10/DEIA/LiPA25 system at a central laboratory., Main Outcome: Oral HPV prevalence., Results: Of the 3196 participants enrolled, mean (SD) age was 39.6 (12.1) years, and 55.5% were women. Oral HPV prevalence was 6.6% (95% CI, 5.7%-7.4%) for any HPV genotype, and 2.0% (95% CI, 1.5%-2.5%), 0.7% (95% CI, 0.4%-1.0%), and 1.5% (95% CI, 1.1%-1.9%) for HR, HPV-16, and 9-valent-HPV vaccine types, respectively. Among HPV-positive participants, HPV-16 was the most prevalent genotype (12.4% among men and 8.6% among women). Prevalence of HPV was higher in men than women and highest among men aged 51 to 60 years (16.8%, 6.8%, and 2.1% for any HPV, HR HPV, and HPV-16, respectively). Factors associated with HR oral infection included being male (adjusted odds ratio [AOR], 3.1; 95% CI, 1.2-8.5), being aged 51 to 60 years (AOR, 3.3; 95% CI, 1.5-7.3), having 26 or more lifetime male sex partners (AOR, 6.5; 95% CI, 2.3-18.7), and having 6 to 25 lifetime female oral sex partners (AOR, 3.4; 95% CI, 1.3-8.7)., Conclusions and Relevance: In this cross-sectional study, oral HPV burden was highest among older men who may be at higher risk of developing oropharyngeal cancer. In addition to male sex and older age, HR oral HPV infection was also associated with sexual behaviors, including increasing number of male sex partners and female oral sex partners.

Twelve high-risk alpha human papillomavirus (HPV) genotypes cause approximately 690,000 cancer cases annually, with cervical and oropharyngeal cancer being the two most prominent types. HPV testing is performed in laboratory settings for various applications of a clinical, epidemiological, and research nature using a range of clinical specimens collected by clinicians or by individuals (self-collected specimens). Here, we reflect on the importance and justification of using the right test for the right application and provide practical updates for laboratories either participating in or anticipating involvement in HPV testing in three specimen types, namely, urine, blood, and oral specimens, which are considered "alternative" specimens by many. In addition to clinician-collected cervical samples and self-collected cervicovaginal samples, first-void urine is emerging as a credible specimen for HPV-based cervical cancer screening, triage of HPV screen-positive women, monitoring HPV vaccine impact, and HPV testing in groups for which a less invasive sample is preferred. Detection of cell-free DNA (including HPV DNA) in blood has great promise for the early detection of HPV-attributable oropharyngeal cancer (HPV-AOC) and potentially other HPV-driven cancers and as an adjunct prognostic marker in long-term tumor surveillance, including treatment response. The moderate sensitivity of HPV testing in oral rinses or swabs at HPV-AOC diagnosis prevents its use in HPV-AOC secondary prevention but represents a promising prognostic tool in HPV-AOC tertiary prevention, where the HPV persistence in oral rinses throughout treatment may predict early HPV-AOC recurrences and/or the development of secondary HPV-AOC. The increasing sophistication of specific collection devices designed for alternative samples and the enhanced precision of novel molecular technologies are likely to support the evolution of this field and catalyze potential translation into routine practice., Competing Interests: The authors declare a conflict of interest. M.P. institution received research funding, free-of-charge reagents, and consumables to support research in the last 3 years from Qiagen, Seegene, Abbott, and Roche, all paid to his employer. K.C. institution received research funding, reagents, and consumables to support research in the last 3 years from Cepheid, Euroimmun, GeneFirst, Self-screen, Hiantis, Seegene, Roche, Abbott, Hologic, and Vaccitech, all paid to her employer. K.C. also attended an advisory board meeting of Hologic where UK-based travel expenses were supported and is currently on the advisory board of Vaccitech (with any associated reimbursement paid to employer). L.A. institution received funding to support research in the last 3 years from Merck Sharp & Dohme, Roche, GSK, Vitro, Hologic, and Seegene, all paid to her employer. A.V. institution received funding to support research and setting up professional meetings in the last 3 years from Merck, Roche, GSK, Hologic, Abbott, Novosanis and Becton, Dickinson and Company, all paid to his employer. A.V. is the co-founder of Novosanis, a spin-off company of the University of Antwerp, Belgium, and a subsidiary of OraSure Technologies, Inc. since 2019, and he was a board member and minority shareholder until January 2019.

Background: The incidence of endometrial cancer is increasing worldwide. While delays in diagnosis reduce survival, case molecular misclassification might be associated with under- and over-treatment. The objective of this study was to evaluate genetic alterations to detect and molecularly classify cases of endometrial cancer using non-invasive samples., Methods: Consecutive patients with incident endometrial cancer (N = 139) and controls (N = 107) from a recent Spanish case-control study were included in this analysis. Overall, 339 cervicovaginal samples (out of which 228 were clinician-collected and 111 were self-collected) were analysed using a test based on next-generation sequencing (NGS), which targets 47 genes. Immunohistochemical markers were evaluated in 133 tumour samples. A total of 159 samples were used to train the detection algorithm and 180 samples were used for validation., Findings: Overall, 73% (N = 94 out of 129 clinician-collected samples, and N = 66 out of 90 self-collected samples) of endometrial cancer cases had detectable mutations in clinician-collected and self-collected samples, while the specificity was 80% (79/99) for clinician-collected samples and 90% (19/21) for self-collected samples. The molecular classifications obtained using tumour samples and non-invasive gynaecologic samples in our study showed moderate-to-good agreement. The molecular classification of cases of endometrial cancer into four groups using NGS of both clinician-collected and self-collected cervicovaginal samples yielded significant differences in disease-free survival. The cases with mutations in POLE had an excellent prognosis, whereas the cases with TP53 mutations had the poorest clinical outcome, which is consistent with the data on tumour samples., Interpretation: This study classified endometrial cancer cases into four molecular groups based on the analysis of cervicovaginal samples that showed significant differences in disease-free survival. The molecular classification of endometrial cancer in non-invasive samples may improve patient care and survival by indicating the early need for aggressive surgery, as well as reducing referrals to highly specialized hospitals in cancers with good prognosis. Validation in independent sets will confirm the potential for molecular classification in non-invasive samples., Funding: This study was funded by a competitive grant from Instituto de Salud Carlos III through the projects PI19/01835, PI23/00790, and FI20/00031, CIBERESP CB06/02/0073 and CIBERONC CB16/12/00231, CB16/12/00234 (Co-funded by European Regional Development Fund. ERDF: A way to build Europe). Samples and data were provided by Biobank HUB-ICO-IDIBELL, integrated into the Spanish Biobank Network, and funded by the Instituto de Salud Carlos III (PT20/00171) and by Xarxa de Bancs de Tumors de Catalunya (XBTC) sponsored by Pla Director d'Oncologia de Catalunya. This work was supported in part by the AECC, Grupos estables (GCTRA18014MATI). It also counts with the support of the Secretariat for Universities and Research of the Department of Business and Knowledge of the Generalitat de Catalunya, and grants to support the activities of research groups 2021SGR01354 and 2021SGR1112., Competing Interests: Declaration of interests L.C. received supplies from Integrated DNA Technologies (IDT) and Roche Diagnostics at a 50% discount for the pilot study of this project and received a speaker's honoraria from Roche. Idibell and Roche signed a contract to collaborate in the development of the bioinformatics pipeline. L.C. has received Colli-Pee® devices (Novosanis) for a research project free of charge. X.B. and L.A. received funds from Merck & Co, Elsevier, Hologic, GlaxoSmithKline (GSK) and SP received funds to attend a meeting from Seegene. P.P.T received funds from Merck & Co and Werfen. JHcispoly and IDIBELL signed a service agreement for another project on endometrial cancer., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Women with Lynch syndrome (LS) are at increased risk of endometrial cancer (EC), among other tumors, and are characterized by mismatch repair (MMR) deficiency and microsatellite instability (MSI). While risk-reducing gynecologic surgeries effectively decrease EC incidence, doubts arise regarding the appropriate timing of the surgery. We explored the usefulness of highly sensitive MSI (hs-MSI) assessment in endometrial aspirates for individualizing gynecologic surveillance in LS carriers. Ninety-three women with LS, 25 sporadic EC patients (9 MMR-proficient and 16 MMR-deficient), and 30 women with benign gynecologic disease were included in this study. hs-MSI was assessed in prospectively collected endometrial aspirates in 67 LS carriers, EC cases, and controls. MMR, PTEN, ARID1A, and PAX2 protein expression patterns were evaluated in the LS samples. Follow-up aspirates from 8 LS carriers were also analyzed. Elevated hs-MSI scores were detected in all aspirates from MMR-deficient EC cases (3 LS and 16 sporadic) and negative in aspirates from controls and MMR-proficient EC cases. Positive hs-MSI scores were also detected in all 4 LS aspirates reported as complex hyperplasia. High hs-MSI was also present in 10 of 49 aspirates (20%) from LS carriers presenting a morphologically normal endometrium, where MMR protein expression loss was detected in 69% of the samples. Interestingly, the hs-MSI score was positively correlated with MMR-deficient gland density and the presence of MMR-deficient clusters, colocalizing PTEN and ARID1A expression loss. High hs-MSI scores and clonality were evidenced in 2 samples collected up to 4 months before EC diagnosis; hs-MSI scores increased over time in 5 LS carriers, whereas they decreased in a patient with endometrial hyperplasia after progestin therapy. In LS carriers, elevated hs-MSI scores were detected in aspirates from premalignant and malignant lesions and normal endometrium, correlating with MMR protein loss. hs-MSI assessment and MMR immunohistochemistry may help individualize EC risk assessment in women with LS., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer., (© 2023 UICC.)

Purpose of Review: Human papillomavirus (HPV) is responsible of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in high-income countries. This significant epidemiological change requires several and diverse prevention strategies., Recent Findings: The cervical cancer prevention model is the paradigm of HPV-related cancer, and its success provides encouragement for the development of similar methods to prevent HPV-related OPSCC. However, there are some limitations that hinder its application in this disease. Here, we review the primary, secondary and tertiary prevention of HPV-related OPSCC and discuss some directions for future research., Summary: The development of new and targeted strategies to prevent HPV-related OPSCC is needed since they could definitely have a direct impact on the reduction of morbidity and mortality of this disease., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: p16 INK4a (p16) immunohistochemistry is the most widely used biomarker assay for inferring HPV causation in oropharyngeal cancer in clinical and trial settings. However, discordance exists between p16 and HPV DNA or RNA status in some patients with oropharyngeal cancer. We aimed to clearly quantify the extent of discordance, and its prognostic implications., Methods: In this multicentre, multinational individual patient data analysis, we did a literature search in PubMed and Cochrane database for systematic reviews and original studies published in English between Jan 1, 1970, and Sept 30, 2022. We included retrospective series and prospective cohorts of consecutively recruited patients previously analysed in individual studies with minimum cohort size of 100 patients with primary squamous cell carcinoma of the oropharynx. Patient inclusion criteria were diagnosis with a primary squamous cell carcinoma of oropharyngeal cancer; data on p16 immunohistochemistry and on HPV testing; information on age, sex, tobacco, and alcohol use; staging by TNM 7th edition; information on treatments received; and data on clinical outcomes and follow-up (date of last follow-up if alive, date of recurrence or metastasis, and date and cause of death). There were no limits on age or performance status. The primary outcomes were the proportion of patients of the overall cohort who showed the different p16 and HPV result combinations, as well as 5-year overall survival and 5-year disease-free survival. Patients with recurrent or metastatic disease or who were treated palliatively were excluded from overall survival and disease-free survival analyses. Multivariable analysis models were used to calculate adjusted hazard ratios (aHR) for different p16 and HPV testing methods for overall survival, adjusted for prespecified confounding factors., Findings: Our search returned 13 eligible studies that provided individual data for 13 cohorts of patients with oropharyngeal cancer from the UK, Canada, Denmark, Sweden, France, Germany, the Netherlands, Switzerland, and Spain. 7895 patients with oropharyngeal cancer were assessed for eligibility. 241 were excluded before analysis, and 7654 were eligible for p16 and HPV analysis. 5714 (74·7%) of 7654 patients were male and 1940 (25·3%) were female. Ethnicity data were not reported. 3805 patients were p16-positive, 415 (10·9%) of whom were HPV-negative. This proportion differed significantly by geographical region and was highest in the areas with lowest HPV-attributable fractions (r=-0·744, p=0·0035). The proportion of patients with p16+/HPV- oropharyngeal cancer was highest in subsites outside the tonsil and base of tongue (29·7% vs 9·0%, p<0·0001). 5-year overall survival was 81·1% (95% CI 79·5-82·7) for p16+/HPV+, 40·4% (38·6-42·4) for p16-/HPV-, 53·2% (46·6-60·8) for p16-/HPV+, and 54·7% (49·2-60·9) for p16+/HPV-. 5-year disease-free survival was 84·3% (95% CI 82·9-85·7) for p16+/HPV+, 60·8% (58·8-62·9) for p16-/HPV-; 71·1% (64·7-78·2) for p16-/HPV+, and 67·9% (62·5-73·7) for p16+/HPV-. Results were similar across all European sub-regions, but there were insufficient numbers of discordant patients from North America to draw conclusions in this cohort., Interpretation: Patients with discordant oropharyngeal cancer (p16-/HPV+ or p16+/HPV-) had a significantly worse prognosis than patients with p16+/HPV+ oropharyngeal cancer, and a significantly better prognosis than patients with p16-/HPV- oropharyngeal cancer. Along with routine p16 immunohistochemistry, HPV testing should be mandated for clinical trials for all patients (or at least following a positive p16 test), and is recommended where HPV status might influence patient care, especially in areas with low HPV-attributable fractions., Funding: European Regional Development Fund, Generalitat de Catalunya, National Institute for Health Research (NIHR) UK, Cancer Research UK, Medical Research Council UK, and The Swedish Cancer Foundation and the Stockholm Cancer Society., Competing Interests: Declaration of interests HMe reports grants from UK National Institute of Health research, Cancer Research UK, the UK Medical Research Council, and AstraZeneca; advisory board fees from AstraZeneca, MSD, Merck, Nanobiotix, and Seagen; and is Director of Warwickshire head neck clinic and Docpsert Health. CRL reports a grant from the Dutch Cancer society, consulting fees from Merck & Co, and expenses from the European Head and Neck Society. JPK reports grant funding from MSD (funding for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. JPK also declares research grant funding from the European fund for regional development (EFRE) for ImmunPredict (FKZ EFRE EFRE-0801308). LM reports payment to institution from 20200059/Stockholms Läns Landsting. NW reports a grant from Merk, Sharpe, & Dohme (MSD; for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. LM is also supported by the Cologne Clinician Scientist Programme, funded by the German Research Council (FI 773/15-1; 50% salary funding for the project Monitoring disease status in patients with oropharyngeal squamous cell carcinoma by detection of cell-free human papillomavirus DNA in liquid biopsies); funding from EFRE (salary funding for the project ImmunPredict FKZ EFRE EFRE-0801308); honoraria for lectures from MSD, and has a patent for CRISPR-based HPV-diagnostics (EP 22197523.8). RHB declares grants from the Dutch Cancer Society to institution; from ZonMW Government to institution; GenMab BV to institution; consulting fees from Nanobiotix; and payment from the Italian Association for Cancer Research as an unpaid board member. SW declares a grant from MSD under the administration of the University of Cologne (for the project Implementation of a German Oropharyngeal Cancer Registry Providing State-of-the-Art-HPV-Diagnostics). Data derived from this project were used in the present study. The funders had no influence on the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to publish the results. TD reports a research grant from the Swedish Cancer Foundation. ST reports grants from Merck, Roche, GlaxoSmithKline, Vitro, Hologic, and Seagene and consulting fees from Merck. All other authors declare no other competing interests. HMe is a National Institute for Health Research (NIHR) Senior Investigator. The views expressed in this article are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16 INK4a immunostaining as a possible HPV surrogate for high-risk HPV infection in penile precancerous lesions. Samples consisted of 84 PeIN cases, part of a retrospective cross-sectional analysis of 1095 penile carcinomas designed to estimate the HPV DNA prevalence in penile cancers using PCR and p16 INK4a immunostaining. Penile Intraepithelial Neoplasia (PeIN) was classified in HPV-related (basaloid, warty-basaloid, warty, hybrid, and mixed subtypes) and non-HPV-related (differentiated), the former being the most frequent. PeIN subtypes were differentiated (non-HPV-related) and basaloid, warty-basaloid, warty, hybrid and mixed (HPV-related). Basaloid PeIN was the most commonly diagnosed subtype, and HPV16 was the most frequent HPV genotype detected. Warty-basaloid and warty PeIN showed a more heterogeneous genotypic composition. Most HPV genotypes were high-risk but low-risk HPV genotypes were also present in a few cases (4%). A single HPV genotype was detected in 82% of HPV positive cases. In contrast, multiple genotypes were detected in the remaining 18% of cases. The findings in this study support the paradigm that penile in situ neoplasia, like its invasive counterparts, is HPV dependent or independent and has distinctive morphological subtypes readily identified in routine practice. Considering that HPV16 is clearly the predominant type, and that the three available vaccines have HPV16, all of them will be suitable for vaccination programs; the price of the vaccines will be probably the main determinant to choose the vaccine., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Endometrial cancer (EC) incidence has been rising over the past 10 years. Delays in diagnosis reduce survival and necessitate more aggressive treatment. We aimed to develop and validate a simple, noninvasive, and reliable triage test for EC to reduce the number of invasive diagnostic procedures and improve patient survival., Methods: We developed a test to screen and triage women with suspected EC using 726 cervical smear samples from women with and without EC, and validated the test in 562 cervicovaginal samples using three different collection methods (cervical smear: n = 248; vaginal swab: n = 63; and self-collection: n = 251) and four different settings (case/control: n = 388; cohort of women presenting with postmenopausal bleeding: n = 63; a cohort of high-risk women with Lynch syndrome: n = 25; and a nested case/control setting from a screening cohort and samples taken up to 3 years before EC diagnosis: n = 86)., Results: We describe the W omen's cancer risk ID entification - q uantitative polymerase chain reaction test for E ndometrial C ancer (WID-qEC), a three-marker test that evaluates DNA methylation in gene regions of GYPC and ZSCAN12 . In cervical, self-collected, and vaginal swab samples derived from symptomatic patients, it detected EC with sensitivities of 97.2% (95% CI, 90.2 to 99.7), 90.1% (83.6 to 94.6), and 100% (63.1 to 100), respectively, and specificities of 75.8% (63.6 to 85.5), 86.7% (79.3 to 92.2), and 89.1% (77.8 to 95.9), respectively. The WID-qEC identified 90.9% (95% CI, 70.8 to 98.9) of EC cases in samples predating diagnosis up to 1 year. Test performance was similar across menopausal status, age, stage, grade, ethnicity, and histology., Conclusion: The WID-qEC is a noninvasive reliable test for triage of women with symptoms suggestive of ECs. Because of the potential for self-collection, it could improve early diagnosis and reduce the reliance for in-person visits., Competing Interests: Chiara HerzogStock and Other Ownership Interests: Sola Diagnostics GmbHPatents, Royalties, Other Intellectual Property: Named inventor on a patent combining epigenetic signatures for detection and risk stratification for breast cancer (WID-qtBC, Women's cancer risk identification—quantitative trait Breast Cancer) Paula Peremiquel-TrillasHonoraria: WerfenTravel, Accommodations, Expenses: Werfen Joan BrunetConsulting or Advisory Role: MSD Oncology, AstraZeneca SpainTravel, Accommodations, Expenses: GlaxoSmithKline Jordi PonceConsulting or Advisory Role: Medtronic, Abex, KCI Xavier Matias-GuiuConsulting or Advisory Role: AstraZeneca, Lilly, Amgen, Janssen, GlaxoSmithKlineTravel, Accommodations, Expenses: GlaxoSmithKline, Roche Laia AlemanyOther Relationship: Integrated DNA Technologies (Inst), Roche (Inst)Uncompensated Relationships: Roche (Inst) Adam RosenthalConsulting or Advisory Role: AbcodiaResearch Funding: Abcodia (Inst) David CibulaConsulting or Advisory Role: AstraZeneca, Sotio, Roche, GlaxoSmithKline, Novocure, Akeso Biopharma, MSD, Mersana Karin SundströmConsulting or Advisory Role: Merck (Inst)Research Funding: Merck (Inst) Laura CostasHonoraria: Roche Sequencing SolutionsOther Relationship: Integrated DNA Technologies (Inst), Roche (Inst)Uncompensated Relationships: Roche (Inst) Martin WidschwendterPatents, Royalties, Other Intellectual Property: I am a shareholder of Sola Diagnostics GmbH, which holds an exclusive license to the intellectual property that protects the commercialization of the WID tests. I am an inventor on pending patents describing the various WID tests. I am a shareholder of BreOva, which aims to license IP for developing and applying cell-free DNA methylation tests. I am an inventor on two pending patents on cell-free DNA methylation analysis for breast and ovarian cancerNo other potential conflicts of interest were reported.

Background: Cervical cancer screening coverage is a key monitoring indicator of the WHO cervical cancer elimination plan. We present global, regional, and national cervical screening coverage estimates against the backdrop of the 70% coverage target set by WHO., Methods: In this review and synthetic analysis, we searched scientific literature, government websites, and official documentation to identify official national recommendations and coverage data for cervical cancer screening for the 194 WHO member states and eight associated countries and territories published from database inception until Oct 30, 2020, supplemented with a formal WHO country consultation from Nov 27, 2020, to Feb 12, 2021. We extracted data on the year of introduction of recommendations, the existence of individual invitation to participate, financing of screening tests, primary screening and triage tests used, recommended ages and screening intervals, use of self-sampling, and use of screen-and-treat approaches. We also collected coverage data, either administrative or survey-based, as disaggregated as possible by age and for any available screening interval. According to data completeness and representativeness, different statistical models were developed to produce national age-specific coverages by screening interval, which were transformed into single-age datapoints. Missing data were imputed. Estimates were applied to the 2019 population and aggregated by region and income level., Findings: We identified recommendations for cervical screening in 139 (69%) of 202 countries and territories. Cytology was the primary screening test in 109 (78%) of 139 countries. 48 (35%) of 139 countries recommended primary HPV-based screening. Visual inspection with acetic acid was the most recommended test in resource-limited settings. Estimated worldwide coverage in women aged 30-49 years in 2019 was 15% in the previous year, 28% in the previous 3 years, and 32% in the previous 5 years, and 36% ever in lifetime. An estimated 1·6 billion (67%) of 2·3 billion women aged 20-70 years, including 662 million (64%) of 1·0 billion women aged 30-49 years, had never been screened for cervical cancer. 133 million (84%) of 158 million women aged 30-49 years living in high-income countries had been screened ever in lifetime, compared with 194 million (48%) of 404 million women in upper-middle-income countries, 34 million (9%) of 397 million women in lower-middle-income countries, and 8 million (11%) of 74 million in low-income countries., Interpretation: Two in three women aged 30-49 years have never been screened for cervical cancer. Roll-out of screening is very low in low-income and middle-income countries, where the burden of disease is highest. The priority of the WHO elimination campaign should be to increase both screening coverage and treatment of detected lesions; however, expanding the efforts of surveillance systems in both coverage and quality control are major challenges to achieving the WHO elimination target., Funding: Instituto de Salud Carlos III, European Regional Development Fund, Secretariat for Universities and Research of the Department of Business and Knowledge of the Government of Catalonia, and Horizon 2020., Translations: For the French, Spanish translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests The Cancer Epidemiology Research Programme (with which LB, BS, ER, and LA are affiliated) has received sponsorship for grants from Merck Sharp & Dohme and HPV test kits at no cost from Roche for research purposes. All other authors report no competing interests. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of WHO. Authors who are identified as personnel of the International Agency for Research on Cancer, WHO, are responsible alone for the views expressed in this article, and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer, WHO., (Copyright © 2022 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) represent a distinct clinical entity compared with HPV-negative tumors with particular regard to treatment response and survival outcome. The aim of this study was to assess the AmpFire Multiplex HR-HPV tests, for the detection and genotyping of 15 high-risk (HR) HPV types in formalin-fixed, paraffin-embedded (FFPE) samples and identify HPV-driven OPSCC. DNA from 160 OPSCC FFPE specimens plus 23 samples from other head and neck primary sites was tested. Results were compared with those obtained using Linear Array HPV-DNA Genotyping Test. Linear Array and AmpFire Multiplex HR-HPV tests showed, for all samples and specifically for OPSCCs, an overall concordance agreement of 98.9% and 99.4% and a Cohen κ coefficient of 0.972 and 0.984, respectively. A concordance of 100% for HPV16 and HPV18 was observed. The overall agreement between p16 INK4a overexpression and HPV detection by the AmpFire Multiplex HR-HPV assay in 145 OPSCC samples was 93.8%, with a Cohen κ coefficient of 0.848. The AmpFire HPV Tests are simple assays for detection and genotyping of HPV-DNA in OPSCC FFPE samples and can be easily implemented in the clinical practice setting for HPV-DNA detection., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC., (© 2021. The Author(s).)

Two etiopathogenic types of vulvar squamous cell carcinoma (VSCC) have been described: human papillomavirus (HPV)-associated and HPV-independent. Precursor lesions, frequently identified in the adjacent skin, are also distinct in the 2 types of VSCC: high-grade squamous intraepithelial lesions (HSILs) in HPV-associated VSCC and differentiated vulvar intraepithelial neoplasia (dVIN) or vulvar acanthosis with altered differentiation in HPV-independent VSCC. Although HPV-independent precursors mimicking HSIL have been described in the vulva, their frequency and morphologic spectrum have not been completely characterized. We explored, in a large series of HPV-independent VSSC, the frequency and the histologic features of precursors mimicking HSIL. We included 779 DNA HPV-negative/p16-negative VSCC with at least 1 cm of adjacent skin. We evaluated the histologic and immunohistochemical (p16 and p53) characteristics of the intraepithelial lesions, focusing on precursors mimicking HPV-associated vulvar HSIL. A total of 254 tumors (33%) had adjacent premalignant lesions. Of them, 186 (73%) had dVIN, 22 (9%) had vulvar acanthosis with altered differentiation, and 46 (18%) had lesions that mimicked HSIL. The mean age of the patients with these HSIL-like lesions was 72±15 years. Twenty-six of these HSIL-like lesions had basaloid morphology, 13 warty, and 7 mixed basaloid/warty features. All the HSIL-like precursors were DNA HPV-negative/p16-negative; 74% of them showed p53 abnormal staining and 35% of them had areas of conventional dVIN. In conclusion, about one fifth of the HPV-independent precursors mimic HSIL, showing either basaloid or warty features. Older age and the presence of areas of typical HPV-independent intraepithelial lesions, together with p16 negativity, should raise suspicion of an HPV-independent etiology.

Due to the anatomical continuity of the uterine cavity with the cervix, genomic exploitation of material from routine Pap smears and other noninvasive sampling methods represent a unique opportunity to detect signs of disease using biological material shed from the upper genital tract. Recent research findings offer a promising perspective in the detection of endometrial cancer, but certain questions need to be addressed in order to accelerate the implementation of novel technologies in a routine screening or clinical setting. We discuss here new perspectives on detection of endometrial cancer using genomic and other biomarkers in minimally invasive sampling methods with a special focus on public health classic screening criteria, highlighting current gaps in knowledge., (© 2019 UICC.)

Background: Human papillomavirus (HPV)16 can be separated into genetic sub-lineages (A1-4, B1-4, C1-4, D1-4) which may have differential cervical cancer risk., Methods: A next-generation sequencing assay was used to whole-genome sequence 7116 HPV16-positive cervical samples from well-characterised international epidemiological studies, including 2076 controls, 1878 squamous cell carcinoma (SCC) and 186 adenocarcinoma/adenosquamous cell carcinoma (ADC), and to assign HPV16 sub-lineage. Logistic regression was used to estimate region-stratified country-adjusted odds ratios (OR) and 95%CI., Results: A1 was the most globally widespread sub-lineage, with others showing stronger regional specificity (A3 and A4 for East Asia, B1-4 and C1-4 for Africa, D2 for the Americas, B4, C4 and D4 for North Africa). Increased cancer risks versus A1 were seen for A3, A4 and D (sub)lineages in regions where they were common: A3 in East Asia (OR=2.2, 95%CI:1.0-4.7); A4 in East Asia (6.6, 3.1-14.1) and North America (3.8, 1.7-8.3); and D in North (6.2, 4.1-9.3) and South/Central America (2.2, 0.8-5.7), where D lineages were also more frequent in ADC than SCC (3.2, 1.5-6.5; 12.1, 5.7-25.6, respectively)., Conclusions: HPV16 genetic variation can strongly influence cervical cancer risk. However, burden of cervical cancer attributable to different sub-lineages worldwide is largely driven by historical HPV16 sub-lineage dispersal., (Copyright © 2019 International Agency for Research on Cancer. Published by Elsevier B.V. All rights reserved.)

Background: We aimed to review the burden and the potential impact of human papillomavirus (HPV) vaccines on HPV-related diseases in the Republic of Korea and to discuss cervical cancer prevention practices in this country., Methods: Cancer burden statistics were retrieved from GLOBOCAN-2018 and Statistics Korea. HPV disease burden was assessed via systematic review. Vaccine types relative contribution (RC) was estimated using data from an international project using formalin-fixed paraffin-embedded specimens., Results: Despite a downtrend in cervical cancer in recent years, Korean rates remain high. In contrast, oropharyngeal cancer incidence has gradually increased and other anogenital cancers remain rare. In Korea, HPV prevalence in general population is around 20%. In cervical cancer, RC of HPVs 16/18 (74.0%) increased to 92.0% when including HPVs 31/33/45/52/58. Limited information was available for other HPV-related cancer sites. Regarding prevention, since the inclusion of the HPV vaccine into the National Immunization Program, almost half (49%) of the target cohort in 2016 had received the first dose of vaccine. Further, percentage of women screened with pap has increased from 41.1%-2009 to 53.0%-2016., Conclusions: HPV-related disease burden in Korea is significant. Results suggest that the combination of effective and high coverage HPV vaccination and screening programmes could substantially impact on HPV-related disease in Korea., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Many countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines., Methods: In all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16 INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16 INK4a biomarkers., Results: The addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases., Conclusions: Our estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites.

Aims: Neuroendocrine tumors (NET) of the cervix are rare tumors with a very aggressive course. The human papillomavirus (HPV) has been linked to its etiology. The objective of this study is to describe HPV prevalence and genotype distribution of NET., Methods and Results: Forty-nine tumors with histological neuroendocrine features were identified among 10,575 invasive cervical cancer (ICC) cases from an international study. HPV DNA detection was done using SPF10/DEIA /LiPA 25 system. Immunohistochemical (IHC) staining for neuroendocrine markers (chromogranin A, synaptophysin, CD56) and for p16 INK4a as a surrogate for HPV transforming infection was performed. In 13 samples with negative IHC for all 3 neuroendocrine markers studied, it was possible to conduct electron microscopy (EM). NET represented 0.5% of the total ICC series and HPV was detected in 42 out of 49 samples (85.7%, 95%CI:72.8%,94.1%). HPV16 was the predominant type (54.8%), followed by HPV18 (40.5%). p16 INK4a overexpression was observed in 38/44 cases (86.4%). Neuroendocrine IHC markers could be demonstrated in 24/37 (64.9%) cases. EM identified neuroendocrine granules in 8 samples with negative IHC markers., Conclusions: Our data confirms the association of cervical NET with HPV and p16 INK4a overexpression. Specifically, HPV16 and 18 accounted together for over 95% of the HPV positive cases. Current HPV vaccines could largely prevent these aggressive tumors., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value., Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16 INK4a /pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC., Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16 INK4a , HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16 INK4a , respectively. Being non-smoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16 INK4a showed strongest diagnostic accuracy and prognostic value., Conclusions: Double positivity for HPV-DNA/p16 INK4a , a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly., (Copyright © 2018 Elsevier Ltd. All rights reserved.)