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Introduction Human papillomavirus-related (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

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Abstract Introduction Human papillomavirus-related (HPV +) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

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Some studies have addressed the prevalence of human papillomavirus (HPV) in head and neck cancer in South America; however, no studies have systematically gathered prevalence and conducted a meta-analysis. This study aims to estimate the prevalence of HPV in oral and oropharyngeal squamous cell carcinomas in South America. We performed a systematic review and metaanalysis using the following databases: PubMed, Embase, Lilacs, Medline, Scopus, and Web of Science. Data were extracted and analyzed using random-effects models to estimate the pooled prevalence of HPV. We identified 209 nonduplicated studies, of which 38 were selected. The overall prevalence of HPV was 24.31% (95% CI 16.87-32.64; I2 = 96%, p heterogeneity <0.001). HPV prevalence in oropharyngeal cancer was 17.9% (95% CI 7.6-31.4; I2 = 96%, p heterogeneity <0.001) and that in oral cavity cancer was 23.19% (95% CI 14.94-32.63; I2 = 94%, p heterogeneity <0.001). We found an overall prevalence of HPV in 24.31% of oral and oropharyngeal squamous cell carcinomas in South American patients. The prevalence of HPV was 17.9% for oropharyngeal cancer and 23.19% for oral cavity cancer.

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HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. ZNF541 and CCNL1 higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.

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Abstract Introduction: Human papilloma virus (HPV) and oral bacteria capable of acetaldehyde production from ethanol, such as Streptococcus anginosus, Prevotella melaninogenica, and Fusobacterium naviforme are among oropharyngeal squamous cell carcinoma (OSCC) infectious risk factors. Objective: Determine associations with HPV and S. anginosus, P. melaninogenica, and F. naviforme in patients with and without OSCC. Methods: Presence of HPV and HPV-16 was determined in 26 patients with OSCC and 26 without OSCC by conventional PCR and simultaneous presence of S. anginosus, P. melaninogenica, and F. naviforme quantification through q-PCR. Statistical analysis was carried out using Pearson's X² and Student's-t test. Results: Patients with OSCC had HPV and HPV-16 frequencies of 84% and 61.5%, respectively, in contrast for patients without OSCC frequencies were 34.6 and 30.7%. P. melaninogenica, and F. naviforme microorganisms were not present in any participant in this study. S. anginosus frequency in patients with OSC was 38.4% and in patients without OSCC was 30.7%. Patients with OSCC had S. anginosus + HPV co-infection at a 38.4% frequency and S. anginosus + HPV-16 at a 23.1% frequency. For individuals without OSCC S. anginosus + HPV co-infection was 3.8% and S. anginosus + HPV-16 3.8%. A greater frequency of S. anginosus + HPV co-infection and S. anginosus + HPV-16 was observed in patients with OSCC in comparison with individuals without OSCC, suggesting the importance of detecting HPV/HPV-16 and S. anginosus simultaneously in individuals at risk of developing OSCC

Resumo O vírus do papiloma humano (VPH) e bactérias orais capacidade de produção acetaldeído a partir do etanol, tais como Streptococcus anginosus, Prevotella melaninogenica e Fusobacterium naviforme, estão entre os fatores de risco infecciosos do carcinoma de células escamosas de orofaringe (CCEO). Determinar associações o VPH e S. anginosus, P. melaninogenica, e F. naviforme em pacientes com e sem o CCEO. A presença de VPH e VPH-16 foi determinada em 26 pacientes com CCEO e 26 sem CCEO por PCR convencional e presença simultânea de quantificação de S. anginosus, P. melaninogenica e F. naviforme por meio de q-PCR. Uma análise estatística foi realizada por meio do t-Student e χ² de Pearson. Os pacientes com CCEO apresentaram frequências de VPH e VPH-16 de 84% e 61,5%, respectivamente, em contraste, para os pacientes sem CCEO frequências de 34,6 e 30,7%. Os microorganismos P. melaninogenica e F. naviforme não estavam presentes em nenhum dos participantes deste estudo. A freqüência de S. anginosus em pacientes com CCEO foi de 38,4% e em pacientes sem CCEO foi de 30,7%. Os pacientes com CECO apresentaram coinfecção com S. anginosus + VPH em uma freqüência de 38,4% e S. anginosus + VPH-16 com freqüência de 23,1%. Para os indivíduos sem CCEO, co-infecção com S. anginosus + VPH foi de 3,8% e S. anginosus + VPH-16 foi de 3,8%. A Maior frequência de co-infecção com S. anginosus + VPH e S. anginosus + VPH-16 foi observada em pacientes com CCEO em comparação com indivíduos sem CCEO, sugerindo a importância da detecção de VPH / VPH-16 e S. anginosus simultaneamente em indivíduos em risco de desenvolver CCEO.

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BACKGROUND: This study investigated the influence of single nucleotide polymorphisms (SNP) in RAD51 and XRCC3 on susceptibility to oral and oropharyngeal squamous cell carcinomas (SCC) and determined their clinicopathological significance. SUBJECTS AND METHODS: SNPs rs1801320 and rs1801321 in RAD51 and rs861539 in XRCC3 were genotyped in 81 patients presenting oral SCC, 45 presenting oropharyngeal SCC, and 130 healthy controls, using TaqMan allelic discrimination assays. Multiple logistic regression models were used to explore the association between SNPs and cancer development, as well as gene-gene (GxG) interaction and gene-environmental factor (GxE) interaction. Clinicopathological associations were verified through the chi-square test, and univariate and multivariate methods were applied for survival analyses. RESULTS: Although allelic and genotypic models and the GxG interaction analysis were nonsignificant, the GxE analysis revealed synergistic effects of the risk alleles of rs1801320, rs1801321, and rs861539 with smoking and alcohol consumption on susceptibility to oral and oropharyngeal SCC. Furthermore, oropharyngeal SCC patients carrying the XRCC3 rs861539 GT/TT genotype (T risk allele) presented a shorter overall survival than GG genotype carriers. CONCLUSION: Combined effects of RAD51 (rs1801320 and rs1801321) and XRCC3 (rs861539) SNPs with environmental carcinogens (tobacco and alcohol) are associated with oral and oropharyngeal SCC development.

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Although the mortality rate of oropharyngeal squamous cell carcinoma (OPSCC) has been decreasing over the last 30 years, there has been a significant increase in the frequency of diagnosis of this type of cancer in several countries. Beyond the classic prognostic factors, such as TNM stage, there is a lack of predictive factors for recurrence and treatment response. A retrospective analysis of patients with OPSCC treated at the Oncology Department of the Santa Terezinha University Hospital between 2007 and 2012 was performed, with the aim of identifying new prognostic factors. In addition to the significance of clinical stage as a prognostic factor for recurrence, OPSCC patients with advanced TNM stage and those treated with radiotherapy, chemoradiation or palliative measures, had a worse prognosis. Patients with moderate or severe weight loss (>5%) at diagnosis had a higher tumor recurrence rate compared with those with mild or no weight loss (P=0.007). Furthermore, 76.9% of patients with moderate or severe weight loss, as opposed to 13.3% of patients with mild or no weight loss, eventually succumbed to the disease (P=0.0001). These data suggest that moderate and severe weight loss at diagnosis is a prognostic factor for OPSCC and it is associated with disease recurrence.

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Toll-like receptors (TLRs) have been widely investigated due to their importance in the inflammatory response and possible links to tumor promotion/regression and prognosis. In cancers with an infective etiology, such as human papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC), TLR responses may be activated and play a role in tumorigenesis. Our aim was to assess the expression of all TLRs in OPSCC cell lines (both HPV+ and HPV-) by qPCR, Western Blot and flow cytometry and assess their response to TLR ligands lipopolysaccharide (LPS), LPS ultra-pure (LPS-UP) and peptidoglycan (PGN) by analyzing IL-8 and IL-6 production. We also immunostained 61 OPSCC tissue samples with anti-TLR4. Results showed lower TLR1 and TLR6 mRNA expression and higher TLR9 protein expression in HPV+ when compared to HPV-OPSCC cells. TLR4 expression did not vary by HPV status in OPSCC cells, but TLR4 expression was significantly lower in HPV+OPSCC tissues. After stimulation with PGN, only one cell line (HPV+) did not secrete IL-6 or IL-8. Furthermore, HPV+OPSCC lines showed no IL-6 or IL-8 production on treatment with LPS/LPS-UP. The data suggest changes in TLR4 signaling in HPV+OPSCC, since we have shown lower tissue expression of TLR4 and no pro-inflammatory response after stimulation with LPS and LPS-UP. Also, it suggests that OPSCC may respond to HPV infection by increased expression of TLR9. This study demonstrates differences in expression and function of TLRs in OPSCC, which are dependent on HPV status, and may indicate subversion of the innate immune response by HPV infection.

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PURPOSE: We examined the influence of OGG1 c.977C>G (rs1052133), APEX1 c.444T>G (rs1130409), XRCC1 c.-77T>C (rs3213245), c.580C>T (rs1799782), c.839G>A (rs25489) and c.1196G>A (rs25487) single-nucleotide polymorphisms (SNPs), involved in base-excision repair (BER) pathway, on oropharyngeal squamous cell carcinoma (OPSCC) risk and prognosis. METHODS: Aiming to identify the genotypes, DNA from 200 consecutive OPSCC patients and 200 controls was analyzed by PCR-RFLP. The prognostic impact of genotypes of SNPs on progression-free survival (PFS) and overall survival of OPSCC patients was examined using the Kaplan-Meier estimates and Cox regression analyses. RESULTS: XRCC1 c.580CT or TT genotypes (19.5 vs. 11.0 %, P = 0.04) and XRCC1 TTGG haplotype from c.-77T>C, c.580C>T, c.839G>A and c.1196G>A SNPs (17.5 vs. 10.0 %, P = 0.04) were more common in patients with OPSCC than in controls. Carriers of combined genotypes of c.580C>T and TTGG haplotype of XRCC1 gene were under 3.35- and 3.22-fold increased risk of OPSCC than others. For survival analysis, we selected only patients with tumor at stage IV. The median follow-up time was 24.5 months. At 24 months of follow-up, PFS was shorter in patients with OGG1 c.977CC genotype when compared with others genotypes (35.5 vs. 52.1 %, log-rank test, P = 0.03). After multivariate Cox analysis, patients with OGG1 c.977CC genotype had more chance to present tumor progression when compared with others (HR 1.68, P = 0.02). CONCLUSIONS: Our data present, for the first time, evidence that inherited OGG1 c.977C>G; XRCC1 c.-77T>C, c.580C>T, c.839G>A and c.1196G>A abnormalities of DNA BER pathway are important determinants of OPSCC and predictors of patient outcomes.

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Estudios recientes demuestran una realidad prácticamente ineludible que manifiesta que el Virus Papiloma Humano (VPH) puede estar asociado al desarrollo del Carcinoma de Células Escamosas en cavidad oral y orofarínge. Desde el descubrimiento en 1974 por parte de zur Hausen et al., quienes ayudaron a definir el mecanismo por medio del cual el VPH provoca la transformación del queratinocito normal a un estado maligno, han sido numerosos los estudios que han descrito la presencia del VPH en carcinomas de cabeza y cuello, específicamente en cavidad oral y orofarínge. La detección del virus en estos carcinomas podría tener implicaciones clínicas importantes en el pronóstico y tratamiento de estos tumores, con resultados más favorables para el paciente; así mismo, justificar planes de prevención orientados al diagnóstico temprano y a la protección específica contra el VPH. Actualmente están en desarrollo terapias experimentales mínimamente invasivas que potencian el sistema inmunitario para atacar estos tumores, sin embargo, aún no están aprobadas para su uso general. En Chile todavía no existen estudios que describan la situación actual del VPH con respecto al Carcinoma de Células Escamosas en cavidad oral y orofarínge que pudieran orientar al sistema de salud con respecto a la prevención y tratamiento de este tipo de cáncer. En esta revisión presentamos los principales aspectos que relacionan al virus con este tipo de carcinoma. Se revisaron artículos indexados en inglés (Pubmed, Scopus, Cochrane Library, Google Scholar) y español (SciELO, Google Scholar), con el objetivo de brindar al Odontólogo general y especialistas una información actualizada sobre este tema, tanto desde su epidemiología como desde los mecanismos de acción carcinogénica del virus, técnicas de diagnóstico avanzadas, además, formas de prevención y estado del arte en materia de tratamiento.

Recent studies indicate what has become a nearly inescapable reality in that Human Papilloma Virus can be associated to the development of Oral and Oropharyngeal Squamous Cell Carcinoma. Since the discovery of zur Hausen et al. that helped define the mechanism by which HPV causes normal keratinocyte transformation to a malignant state, there have been numerous studies that have described the presence of HPV in head and neck carcinomas, specifically in oral cavity and oropharynx. The detection of the virus in these carcinomas may have important clinical implications in the prognosis and treatment of these tumors with more favorable patient outcomes; likewise, justify prevention plans aimed at early diagnosis and specific protection against HPV. Currently minimally invasive experimental therapies that boost the immune system to attack these tumors are in development, however, they are not yet approved for general use. In Chile there are no studies that describe the current situation with regard to HPV Squamous Cell Carcinoma in oral cavity and oropharynx that may guide the health system regarding the prevention and treatment of this cancer. In this review we present the principal aspects that associate the virus with this type of oral and oropharyngeal carcinoma. We reviewed indexed articles in English (Pubmed, Scopus, Cochrane Library, Google Scholar) and Spanish (SciELO, Google Scholar), with the objective to provide Dental Surgeons and specialists the most updated information about this subject. The review was developed considering the epidemiology as well as the carcinogenic mechanisms of the virus, advanced diagnostic techniques, ways of prevention and state of the art in treatment matters.

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