Oral cancer,HPV infection and evidence of sexual transmission

The incidence of oropharyngeal cancer and oral cancer is growing worldwide, both in young non-smokers and in young non-drinkers (smoking and drinking are considered the main risk factors). Epidemiologic studies suggest a strong association between the infection by human papillomavirus (HPV), especially types 16 and 18 (high oncological risk) which have already demonstrated their etiological role in anal tumours as well as in cervix cancer. There is clear epidemiologic evidence that both types of tumours relate to changes in sexual behaviour and that both are linked to sexual transmission of HPV. The number of oral and oropharyngeal cancer cases is rising nowadays, especially among young individuals with no typical toxic habits, such as tobacco and/or alcohol. In this review we set out to update the aspects related to the onset of oral cancer, its relationship with HPV infection and whether this association may be due to the sexual transmission of the virus. Key words:Human papillomavirus, oral sex, head and neck cancer, oral cancer, squamous cell carcinoma, oropharyngeal cancer.     

The prevalence of human papilloma virus (HPV) infections in oral squamous cell carcinomas: A retrospective analysis of 88 patients and literature overview

In addition to tobacco and alcohol consumption, the two main risk factors for oral squamous cell carcinoma (OSCC), recent studies have revealed infections with human papilloma virus (HPV) as an additional risk factor for OSCC development. In the field of head and neck malignancies, the prevalence of HPV infections in oropharyngeal cancer (OC) ranges in different studies up to 84%. While HPV infection is discussed as an independent risk factor in this region, its distinguished role in carcinogenesis of tumours localized to the oral cavity remains still uncertain.In this study, we analysed the HPV status in 88 consecutive patients with OSCCs localized anterior of the palatoglossal arch who were treated in the Department of Oral and Maxillofacial Surgery at the University Medical Center Mainz. The HPV status analysis was performed using DNA-PCR and immunostaining of p16 protein.The prevalence of HPV-positive OSCCs was about 6% (5 patients). In 3 patients the HPV subtypes 16/18 were found. No significant differences between the HPV positive and negative patients regarding age, gender, smoking and alcohol consumption, localization and TNM level could be detected. Contrary to other studies focussing on cancers of the lingual and palatine tonsil, the prevalence of HPV infections was much lower in the oral cavity. Therefore HPV infection might play a less important role in oral carcinogenesis.     

2019年NCCN口腔口咽癌诊疗指南更新解读

美国癌症联合委员会2017年第8版《AJCC肿瘤分期手册》出版,口腔及口咽癌TNM分期标准中新增侵袭深度（DOI）、淋巴结外扩展（ENE）、人乳头瘤病毒（HPV）等指标,并将口咽癌分为HPV阳性（p16+）与HPV阴性（p16-）,分别制定了不同的TNM分期标准。2018年,美国国立综合癌症网（NCCN）首次为HPV阳性（p16+）口咽癌制定了诊疗指南。2019年第1版NCCN头颈癌诊疗指南已经发布,其中对口腔口咽癌指南做了部分修订。为临床工作需要,本文结合2版变化进行部分解读。     

Overexpression of p53 and bcl-2 proteins and the presence of HPV infection are independent events in head and neck cancer

The expression of p53 and bcl-2 proteins by immunohistochemistry and the identification of human papillomavirus (HPV) infection by a non-isotopic polymerase chain reaction (PCR)based method were investigated in 30 patients with head and neck cancer. Ten cases were HPV-positive (33%), mostly as double or multiple infections by high- or intermediate-risk types. Twenty-one patients were p53-positive (70%), 9/10 with HPV-positive tumours and 12/20 with HPV-negative tumours; this difference was not statistically significant. Only four cases were bcl-2-positive, irrespective of the presence of either HPV or p53. No correlation was found between these biological factors and tumour stage, differentiation grade, and alcohol or tobacco use. Our findings indicate that p53 is involved in the majority of cases, bcl-2 is rare, and high-risk HPV could play a key role, especially in tumours of tongue and tonsil. In conclusion p53 and bcl-2 protein expression and the presence of HPV infection are independent events in these malignancies.     

Analysis of human papillomavirus DNA in oral squamous cell carcinomas

Evidence from several laboratories suggests that HPV plays a role in the etiology of squamous cell carcinomas of the oral cavity. A rnultifactorial risk factor profile for the development of oral cancer may include HPV in addition to well-established risk factors such as tobacco and alcohol use. The prevalence of oral carcinomas repotted to be associated with HPV has varied widely due to differences in the sensitivity of the assay used for HPV detection. The aims of this study were: (1) to ascertain the prevalence of HPV DNA in oral squamous cell carcinomas using the most sensitive technique available, the polymerase chain reaction; (2) to determine the type of HPV in the tumors; and 3) to correlate the virologic data with other risk factor data obtained from patients' records. Fourteen (78%) of 18 primary tumors, 6 (67%) of 9 normal epithelial tissues from the patients and 5 (100%) of 5 neck metastases were HPV DNA-positive. Of the 14 HPV DNA-positive primary tumors, specific typing revealed HPV 16 in 2, HPV 18 in 2, HPV 16 and IS in 5, HPV 6/11, 16 and 18 in 4, and HPV 6/11 in 1. HPV types in the normal or metaslatic tissue were usually the same as those in the respective primary tumor. There was no significant association between HPV presence and any of 12 factors or patient characteristics studied.     

National prevalence of oral HPV infection and related risk factors in the U.S. adult population

This article reviews the rapidly growing evidence that oral human papilloma viruses (HPV) infection contributes to the risk of oral squamous cell carcinoma. It also reports the first nationally representative estimates of oral HPV prevalence in the United States adult population. An estimated 7.3% (95% CI: 6.0, 8.9) of the U.S. population had one or more oral HPV types detected in oral rinse; 3.1% (95%CI: 2.4, 3.9) of the U.S. population had one or more oncogenic HPV types. A substantial excess risk of HPV infection in men is not explained by education, smoking, age of sexual debut, or number of lifetime sex partners. Based on the published finding from a case-control study, where there was an odds ratio of 2.6 (95% CI: 1.5, 4.2) for the association of head and neck cancer oncogenic oral HPV infection, the estimated population attributable risk for head and neck cancer in the U.S. population was 4.7%. In other words, there would be a 4.7% reduction in incidence rate of head and neck cancer in the United States if oncogenic HPV infection could be prevented. The results also provide population data that help evaluate the likely public health benefits of prophylactic vaccination against oral HPV acquisition.     

Human papillomavirus type 16 and 18 DNA in oral squamous cell carcinoma and normal mucosa

The aim of this study was to ascertain the prevalence of HPV 16/18 DNA in oral squamous cell carcinoma (OSCC) vs. normal oral mucosa, and to correlate the virologic data with other factors obtained from the patients' records. One hundred and thirteen paraffin embedded tissue samples (73 OSCC and 40 normal oral mucosa) were studied using HPV type specific primer-mediated polymerase chain reaction (PCR). Seventy-four per cent (54/73) of OSCC and 55% (22/44) of normal oral mucosa were positive for HPV 16/18 DNA. Statistical analysis indicated there was a significant difference between HPV16/18 positive OSCC vs. normal oral mucosa (P=0.040), and that age (<60 years) and gender (male) were correlated with the presence of HPV16/18 in the tumour. No significant association was found between the presence of HPV and other risk factors, including tobacco use, alcohol use, tumour location, histologic grade or TNM staging. We found a significant association of HPV16/18 with oral squamous cell carcinoma. Also, HPV16/18 is a co-factor in oral carcinogenesis, particularly in male patients and patients under the sixth decade. In addition, we found that HPV infection is a common event in the normal oral mucosa.     

The connection between human papillomavirus and oropharyngeal squamous cell carcinomas in the United States: implications for dentistry

BackgroundResults from studies conducted in the past several years suggest that some oropharyngeal cancers, those of the base of the tongue and the tonsils, are associated with high-risk types of human papillomavirus (HPV). In this article, the authors summarize the availabel evidence regarding the epidemiology of HPV-associated oropharyngeal cancers in the United States, the availabel HPV vaccines and the implications of these for dentistry. They also examine the differences in HPV prevalence between cancers of the oral cavity and those of the oropharynx.Types of Studies ReviewedThe authors searched PubMed, Web of Science, The Cochrane Library and the National Guideline Clearinghouse to identify English-language systematic reviews and meta-analyses focused on HPV-associated oropharyngeal squamous cell cancers published from January 2005 through May 2011.ResultsMolecular and epidemiologic evidence suggest a strong etiologic association of HPV with oropharyngeal cancers. The incidence of oropharyngeal cancers in the United States has increased between 1973 and 2007, whereas that of cancers at other head and neck sites has decreased steadily. Compared with HPV-negative cancers, HPV-positive oropharyngeal cancers are associated with certain sexual behaviors, occur more often among white men and people who do not use tobacco or alcohol, and may occur in a population younger by about four years (median ages, 52–56 years). Despite often having a later stage of diagnosis, people with HPV-positive oropharyngeal cancers have a lower risk of dying or recurrence than do those with HPV-negative cancers. The effectiveness of the HPV vaccine in preventing oropharyngeal cancers is unknown.Clinical ImplicationsDental health care personnel (DHCP) should be knowledgeable about the role of HPV in carcinogenesis, the association of HPV with oropharyngeal cancers and HPV vaccines, and they should be prompt in referring patients with suggestive symptoms for evaluation. DHCP can play an important role in increasing patients’ knowledge about HPV and oropharyngeal cancers.     

A survey of head and neck surgical oncologists regarding the inclusion of level IIb in a neck dissection of the node negative neck

There is controversy as to whether IIb should be dissected in the node negative neck. The aim of this survey was to ascertain how often head and neck surgical oncologists performed a level IIb neck dissection for node negative T2 and T4 tumours of the oral cavity, oropharynx and larynx, and to gauge how many might be willing to take part in a RCT of sparing IIb. A convenience sample of 110 MFU colleagues and 125 members of the ENTUK head and neck group were questioned. Response rate for the MFU was 62% and ENT 30%. A clear majority from MFU had a strong preference for including IIb in all clinical scenarios apart from laryngeal T2 tumours whilst ENT included IIb with oral cavity T4, oropharyngeal T2 and oropharyngeal T4 tumours. This survey would support the need for a multicentre study with 53 responders interested in taking part.     

口腔鳞状细胞癌高危型人乳头状瘤病毒感染的检测

目的 观察口腔鳞癌及口腔粘膜高危型人乳头状瘤病毒（HPV）感染情况,探讨HPV感染与临床及病理资料的关系。方法 用多聚酶链反应（PCR）检测73例口腔鳞癌及40例正常口腔粘膜石蜡包埋组织中HPV16、HPV18的DNA。统计分析其与临床及病理资料的关系。结果 口腔鳞癌HPV16／HPV18 DNA阳性率为74％（54／73）,正常口腔粘膜为55％（22／40）。口腔鳞癌与正常口腔粘膜HPV阳性率存在显著性差异（P＝0．040）。统计分析显示：HPV感染与患者的性别、年龄有关,与其它因素（肋瘤发生部位、嗜烟酒情况、肿瘤病理分级、临床分期）无关。结论 高危型HPV感染与口腔鳞癌的发生有关。口腔粘膜中HPV感染普遍存在,提示HPV在口腔肿瘤的发生中并非独立发挥作用。     

Human papilloma virus: An etiological and prognostic factor for oral cancer?

The increasing prevalence of human papilloma virus (HPV)‐positive oral tumors can be considered an epidemic. Although the incidence of HPV cervical cancer is decreasing, the incidence of oral cavity and oropharyngeal cancers associated with HPV is increasing. The presence of certain HPV genotypes could be a predictor of future oral cancer lesions, although lesions associated with HPV could be less aggressive and exhibit a higher survival rate. In the present study, we review the most important biologic, clinic, epidemiologic, and prognostic factors associated with HPV infection and oral cancer.     

Low prevalence of human papillomavirus infection in the healthy oral mucosa of a Northern Italian population

J Oral Pathol Med (2012) 41 : 16–20 Background: Oral cancer is the sixth most common malignancy in developed countries, representing almost 3% of malignant tumors. Tobacco use and alcohol consumption are well‐established risk factors. However, the observation that most patients with oral cancer have not been exposed to these risk factors suggests that additional causes may promote oral carcinogenesis. A link has been suggested between human papillomavirus (HPV) and oral cavity cancer but the significance of HPV contribution to oral carcinogenesis as well as the prevalence of HPV infection in normal oral cavity mucosa remains debated. Methods: In this study, the prevalence of oral HPV infection was evaluated in 81 randomly selected Northern Italian subjects with clinically normal oral mucosa using a nested PCR on DNA extracted by oral smears. Results and conclusions: No HPV‐related lesions were detectable in any of the smears analyzed by cytological approach. nPCR identified HPV DNA in only one (1.2%) of the specimens obtained from clinically healthy oral mucosa and subsequent characterization assigned the positive case to HPV type 90. These data suggest that the incidence of HPV infection in the healthy population might be very low and that other risk factors are likely responsible to promote oral carcinogenesis.     

Detection of HPV in mouth floor squamous cell carcinoma and its correlation with clinicopathologic variables,risk factors and survival

The human papillomavirus (HPV) has been historically associated with head and neck cancers, although its role in oral carcinogenesis remains poorly defined. The purpose of this study was to investigate the prevalence of HPV in mouth floor squamous cell carcinoma and correlate it with clinicopathologic variables, risk factors and survival. HPV presence was evaluated by nested polymerase chain reaction (nPCR) in 29 paraffin‐embedded specimens of mouth floor squamous cell carcinoma. HPV DNA was detected in 17.2% (5 of 29) of the specimens; the highest prevalence was observed in non‐smoking patients over the age of 60 years. All HPV DNA positive specimens were detected in men with clinical stage III and IV lesions, being most of which were moderately differentiated. Despite this correlation there were no statistically significant differences observed among the analyzed variables, including patients’ survival. The relatively low incidence of HPV DNA present in these tumors suggests that this virus does not, by itself, have a significant role in the development of mouth floor squamous cell carcinoma.     

What patients consider important: Temporal variations by early and late stage oral,oropharyngeal and laryngeal subsites

Functional outcomes are of high priority to cancer patients and are relevant when considering treatment strategies. This study aimed to collate and analyse importance rankings of UW-QOL over time for patients treated with curative intent for primary head and neck squamous cell carcinoma between 2000 and 2010, and to compare early and late stage oral, oropharyngeal and laryngeal subsites. There were 1614 patients comprising oral cavity 47% (751), oropharyngeal 24% (382), laryngeal 20% (320) and other HNC locations 10% (161). Items of importance remained relatively stable within clinical groups but there were notable differences between groups. For patients with early oral tumours no domain was especially dominant, whereas for late oral tumours swallowing, chewing, speech and saliva were selected more often. Swallowing and saliva were more important in oropharyngeal tumours, as was taste with more advanced oropharyngeal tumours. Speech and activity were important for those with early laryngeal tumours, as were swallowing and speech for more advanced laryngeal tumours. Swallowing and saliva were more important in advanced tumours for all sites. This data confirms the priority patients place on swallowing, chewing, speech, and saliva, therefore curative treatments should optimise these functions wherever possible and provide access to post-treatment interventions as required.     

Identification and characterization of novel human papillomaviruses in oral rinse samples from oral cavity and oropharyngeal cancer patients

ObjectivesThe objectives of this study were to: I) discover novel human papillomaviruses (HPVs) using next generation sequencing (NGS) technology in oral rinse samples collected from oral cavity cancer (OCC) and oropharyngeal cancer (OPC) patients; II) determine the prevalence of novel HPVs in archived OCC and OPC tissue samples; and III) examine the frequency of novel oncogenic HPVs in cancer and non-cancer oral rinse samples using real-time PCR.MethodsOral rinse samples were collected from 100 head and neck cancer patients, and 110 healthy individuals. NGS techniques were used to detect novel HPVs.ResultsThree potentially new types of HPV were discovered. Novel virus (NV) 14.4 was closely related to HPV76 with an 89% homology and is a member of the genus Beta-papillomavirus (β-PV); NV69.1 was distantly related to the genus Alpha-papillomavirus (α-PV), and NV95 was closely related to HPV147 with a 65–77% homology and is part of the genus Gamma-papillomavirus (γ-PV). In archived oral tissue samples, NV14.4 was detected in a single patient with OCC. Of the oral rinse samples, NV69.1 was more prevalent than the other two NVs.ConclusionsOur results demonstrated that there are novel HPVs present in oral rinse samples that may be associated with OCC and OPC. These novel HPVs can be identified and characterized using NGS techniques.     

Biopsy vs. superficial scraping: detection of human papillomavirus 6, 11, 16, and 18 in potentially malignant and malignant oral lesions

BACKGROUND: Several epidemiologic studies have shown a broad variation in the prevalence of human papillomavirus (HPV) in oral precancerous tissues and oral carcinomas. METHODS: Biopsies and superficial scrapes of lesions, clinically suspected of HPV infection, were taken from patients with potentially malignant and malignant oral lesions, and subject to HPV DNA detection by PCR-Southern blot analysis. RESULTS: From 22 patients with potentially malignant and malignant lesions analyzed, 41% of the biopsies were HPV DNA positive, whereas 95-100% of the superficial scrapes were positive (McNemar, P < 0.0001). Clinical presumption of HPV infection detected 67% (P < 0.0001) of the HPV DNA positive cases compared with 48% (P < 0.0001) determined by cytology and histopathology. The prevalence of HPV 6, 11, 16 and 18 in the oral mucosa was studied in 59 individuals. While 9% of normal controls were HPV DNA positive, 100% of the patients with potentially malignant and malignant lesions were HPV DNA positive, and the prevailing genotype was HPV 16 followed by HPV 18. CONCLUSIONS: The higher HPV DNA detection rate in superficial oral scrapes than in biopsies suggests that accurate epidemiological information on oral HPV infection/oral carcinogenesis depends not only on the DNA detection technique, but also on the tissue/cell sampling procedure.     

Detection and genotyping of human papillomavirus DNA in samples from healthy Sardinian patients: a preliminary study

The human papillomavirus (HPV) is involved in the development of different benign and malignant lesions that include in particular squamous tumours of the cervix, skin and the respiratory tracts. In particular, the 'high risk' HPV type 16 (HPV 16) causes genito-rectal epithelial cancers and is suspected of causing epithelial cancers of the head and neck. To determine the presence and genotypes of HPV was determined in saliva samples from 164 subjects recruited from the Department of Surgery and Odontostomatological Sciences (University of Cagliari). For this study a sensitive seminested polymerase chain reaction (PCR) method was used to detect HPV-DNA; moreover in all positive samples, HPV genotyping was based on sequencing of the HPV genome L1 region. The results obtained with these patients (who were ethnically homogeneous), showed an interesting percentage of positive samples for HPV-DNA (30 samples out of 164-18.3%). Only two HPV genotypes have been identified in these patients, HPV 16 and HPV 31 with 76.7% and 23.3% of the positive specimens, respectively, both correlating with high carcinogenic risk. This preliminary result leads us to reflect on the presence of HPV in saliva, in particular in young asymptomatic subjects (15.38%), and its prognostic value for the possible incidence in Sardinia of oral carcinoma.     

Raman spectroscopy in oral cavity and oropharyngeal cancer: a systematic review

Due to the high incidence of head and neck cancer and under-diagnosis in the early stages, non-invasive and highly accurate diagnostic tests are required for cancer detection. Recent advances in Raman spectroscopy techniques have yielded promising sensitivity and specificity results in the evaluation of cancer. The aim of this study was to investigate the potential value of Raman spectroscopy in oral cavity and oropharyngeal cancer diagnosis based on currently available scientific papers. A search of the PubMed database was performed using a specific strategy and according to the PRISMA guidelines. Raman spectroscopy achieved a maximum accuracy of 98% in cancer detection, while accuracy was 97.24% for tumour grading evaluation, 95% for cancer treatment assessment, and 77% for the detection of cancer recurrence. Moreover, early-stage cancer can be identified by Raman spectroscopy investigation of liquid biopsy samples. An in vivo technique with direct mucosa examination by fibre-optic Raman spectroscopy obtained a maximum accuracy of 94% in cancer diagnosis. The most prominent markers of the presence of malignancy were an increase in Raman signal intensity for proteins, nucleic acids, and water and a decrease for lipids. These cancer discriminants were detected in both fingerprint and high wavenumber regions. In conclusion, Raman spectroscopy is a promising tool for oral cavity and oropharyngeal cancer screening.     

Confronting Human Papilloma Virus/Oropharyngeal Cancer: A Model for Interprofessional Collaboration

A collaborative practice model related to Human Papilloma Virus (HPV) associated oropharyngeal cancer highlights the role of the dental hygienist in addressing this condition.BackgroundThe incidence of HPV associated head and neck cancer is rising. Multiple professionals including the dental hygienist can work collaboratively to confront this growing public health concern.MethodsA critical review applies the growth and utilization of interprofessional education (IPE) and interprofessional collaboration (IPC) to multi-disciplinary models addressing the human papilloma virus and oropharyngeal cancers.ConclusionsA model related to HPV associated oropharyngeal cancer addresses an oral systemic condition that supports the inclusion of a dental hygienist on collaborative teams addressing prevention, detection, treatment and cure of OPC.     

Staging and treatment outcomes in oropharyngeal squamous cell carcinoma: a single-centre UK cohort

The 8^th edition of the UICC TNM (UICC 8) staging rules for oropharyngeal squamous cell carcinoma (OPSCC) acknowledges dichotomous disease biology based on the human papillomavirus (HPV) tumour status. This retrospective study was undertaken to validate those staging rules in a single UK treatment centre. Given a recent resurgence of interest in primary surgery for OPSCC, a secondary objective was to identify subsets of patients who might benefit. Patients presenting with OPSCC between 2010 and 2017 to the South Glasgow head and neck multidisciplinary team were identified from a prospective database. Only patients managed with curative intent were included (n = 272). Stage group allocation according to the UICC 8 resulted in appropriate hazard discrimination, in contradistinction to the UICC 7 staging rules. Locally advanced (cT3-4) disease had a relatively poor prognosis irrespective of HPV status. No clear benefit for primary surgery in any subgroup was demonstrated. A dichotomous disease biology based on the HPV status of tumour is confirmed in this cohort. Patients with HPV-positive T1 and T2 primary tumours have an excellent prognosis when treated with non-surgical treatment regimens. The use of surgery as the primary management for categories of patients presenting with OPSCC should be in the context of clinical trials.