Article

High-risk human papillomavirus and cervical lymph node metastasis in patients with oropharyngeal cancer

January 2012
Head & Neck 34(1):10-4

January 2012
34(1):10-4

DOI:10.1002/hed.21697

Source
PubMed

Authors:

Chan Kwon Jung

Catholic University of Korea

Jun-Ook Park

Catholic University of Korea

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The purpose of this study was to determine the role of high-risk human papillomavirus (HPV) in lymph node metastasis and the depth of invasion in oropharyngeal cancer. The study included patients with 90 oral carcinomas and 66 oropharyngeal carcinomas. High-risk HPV in situ hybridization was performed to detect HPV infection. The positive rate of high-risk HPV in situ hybridization was 15.4% (24 of 156). There was a significant difference in the fraction of positive high-risk HPV between oral (6.7%) and oropharyngeal (27.3%) cancers (p < .000). Significant correlations were found between positive high-risk HPV and cervical lymph node metastasis, tumor depth of invasion in patients with oropharyngeal cancer (p = .002, p = .016, respectively). There was a statistically significant association between high-risk HPV positivity and the disease-specific survival in patients with oropharyngeal cancer (p = .035). High-risk HPV infection was significantly related to cervical lymph node metastasis and depth of invasion in patients with oropharyngeal cancer. © 2011 Wiley Periodicals, Inc. Head Neck, 2012.

Role of human papillomavirus in oropharyngeal squamous cell carcinoma: A review

Article

Full-text available

Jun 2014

Human papillomavirus (HPV) has been implicated in the pathogenesis of a subset of oropharyngeal squamous cell carcinoma. As a result, traditional paradigms in relation to the management of head and neck squamous cell carcinoma have been changing. Research into HPV-related oropharyngeal squamous cell carcinoma is rapidly expanding, however many molecular pathological and clinical aspects of the role of HPV remain uncertain and are the subject of ongoing investigation. A detailed search of the literature pertaining to HPV-related oropharyngeal squamous cell carcinoma was performed and information on the topic was gathered. In this article, we present an extensive review of the current literature on the role of HPV in oropharyngeal squamous cell carcinoma, particularly in relation to epidemiology, risk factors, carcinogenesis, biomarkers and clinical implications. HPV has been established as a causative agent in oropharyngeal squamous cell carcinoma and biologically active HPV can act as a prognosticator with better overall survival than HPV-negative tumours. A distinct group of younger patients with limited tobacco and alcohol exposure have emerged as characteristic of this HPV-related subset of squamous cell carcinoma of the head and neck. However, the exact molecular mechanisms of carcinogenesis are not completely understood and further studies are needed to assist development of optimal prevention and treatment modalities.

Induction of heparanase by HPV E6 oncogene in head and neck squamous cell carcinoma

Article

Full-text available

Nov 2013
J CELL MOL MED

High-risk human papillomavirus (HPV)-positive head and neck squamous cell carcinomas (HNSCCs) are highly invasive; however the identity of downstream effectors responsible for their aggressive phenotype remains underinvestigated. Here, we report that HPV-mediated up-regulation of heparanase enzyme can provide mechanistic explanation for augmented invasiveness of HPV-positive HNSCCs. Heparanase is the sole mammalian enzyme (endo-β-d-glucuronidase) degrading heparan sulphate glycosaminoglycan, key polysaccharide of the extracellular matrix. Cleavage of heparan sulphate by heparanase leads to disassembly of extracellular barriers, enabling local invasion and metastatic spread of the tumour, and releases heparan sulphate-bound growth factors from the extracellular depots. Heparanase is tightly implicated in head and neck cancer progression; yet, molecular mechanisms underlying transcriptional activation of the heparanase gene in HNSCC are largely unknown. We found that HPV16 oncogene E6 is capable of inducing overexpression of heparanase in HNSCC. Notably, radiation treatment dose-dependently suppresses E6-induced heparanase expression in vitro. Our results provide the first evidence for a functional involvement of HPV in heparanase induction in head and neck tumourigenesis and, given ongoing clinical testing of several heparanase-inhibiting compounds, offer important avenue for future therapeutic exploration in HNSCC, as well as other HPV-associated malignancies (i.e. cervical carcinoma).

The Frequency of Human Papillomavirus Positivity in Iranian Patients with Head and Neck Squamous Cell Carcinoma

Article

Full-text available

Jan 2021

Background & objective: Human papillomavirus (HPV) has been associated with prognosis in patients with head and neck squamous cell carcinoma (HNSCC). Similar to the global studies, different prevalence rates of this viral infection have been reported in Iran. Therefore, we aimed to report the prevalence of this virus and its significance in HNSCC patients. Methods: Patients who were referred to the five hospitals of Tehran city from May 2018 to May 2019 were enrolled in this study. All patients were diagnosed with HNSCC based on pathologic study. The pathologic disease staging was defined, and DNAs were extracted from the fresh tissue samples via kits. After polymerase chain reaction (PCR), HPV positive samples were evaluated for determining genotypes and data analysis. Results: Of the 46 patients, three patients (6.5%) showed positive HPV results with the following subtypes: 18 (in two patients), 52 (in three patients), 61 (in two patients), 67, and 73.Comparison of variables between the groups with and without HPV showed a significant difference based on the tumor's lymphatic invasion (P=0.041), peripheral lymph node involvement (P=0.008), and histologic grade (P=0.011), but no statistically significant difference in terms of other variables such as age, primary tumor site, size, pathologic stage, vascular or perineural invasion, metastasis, smoking, and alcohol consumption was found.

Epithelial to mesenchymal transition and HPV infection in squamous cell oropharyngeal carcinomas: The papillophar study

Article

Full-text available

Jan 2017
BRIT J CANCER

Background: Human Papillomavirus (HPV) infection is recognised as aetiological factor of carcinogenesis in oropharyngeal squamous cell carcinomas (OPC). HPV-related OPC respond better to treatments and have a significantly favourable outcome. Epithelial to mesenchymal transition (EMT) implicated in tumour invasion, is a hallmark of a poor prognosis in carcinomas. Methods: We have studied the relationship of EMT markers (E-cadherin, β-catenin and vimentin) with HPV infection (DNA and E6/E7 mRNA detection), p16(INK4a) expression and survival outcomes in a cohort of 296 patients with OPC. Results: Among the 296 OPSSC, 26% were HPV positive, 20.3% had overt EMT (>25% of vimentin positive tumour cells). Lower E-cadherin expression was associated with a higher risk of distant metastasis in univariate (P=0.0110) and multivariate analyses (hazard ratios (HR)=6.86 (1.98; 23.84)). Vimentin expression tends towards worse metastasis-free survival (MFS; HR=2.53 (1.00; 6.41)) and was an independent prognostic factor of progression-free survival (HR=1.55 (1.03; 2.34)). Conclusions: There was a non significant association of EMT with HPV status. This may be explained by a mixed subpopulation of patients HPV positive with associated risk factors (HPV, tobacco and alcohol). Thus, the detection of EMT in OPC represents another reliable approach in the prognosis and the management of OPC whatever their HPV status.British Journal of Cancer advance online publication, 10 January 2017; doi:10.1038/bjc.2016.434 www.bjcancer.comPublished online 10 January 2017.

Human Papillomavirus Type 16 Infection and Local Lymph Node Metastasis in Patients with Squamous Cell Carcinoma

Article

Apr 2016

Human papillomavirus (HPV) infection is known to be an independent etiologic factor for oral squamous cell carcinoma (OSCC). Especially, HPV-16 is associated with a significant risk of developing OSCC. The most important prognostic factor in OSCC is local lymph node metastasis (LNM); therefore, knowledge of LNM status is crucial for selecting proper treatment plans. However, it is not clarify relationship between HPV-16 infection and LNM in OSCC. The purpose of this study was to determine the role of HPV-16 infection in LNM in OSCC. We analyzed 130 cases of OSCC (100 cases of OSCC without LNM; 30 cases of OSCC with LNM). HPV-16 infection was detected by PCR, immunohistochemical examination and in situ hybridization. HPV-16 positivity rates among primary tumor (PT) specimens without LNM were 43.0 % (43/100), and HPV-16 positivity rates among PT specimens with LNM were 26.7 % (8/30). In addition, HPV-16 positivity rates in both PT and LNM specimens in 30 OSCC patients with LNM were 10 % (3/30). OSCC with HPV-16 DNA detected by PCR showed positive staining on immunohistochemical examination and in situ hybridization. The HPV-16 infection rate in OSCC with LNM was significantly lower than that for OSCC without LNM. In the case of OSCC with LNM, HPV-16 infection rates for both in PT and LNM were low. This suggests that HPV-16 positive cases had a significantly lower risk of LNM when compared with patients having HPV-16 negative OSCC. The results of the present study suggest that HPV status in OSCC is able to act as a marker for risk of LNM.

Do 18F-FDG PET/CT parameters in oropharyngeal and oral cavity squamous cell carcinomas indicate HPV status?

Article

Full-text available

Jan 2015

The aim of this study was to explore the relationship of PET/CT parameters with human papillomavirus (HPV) status of oropharyngeal (OP) and oral cavity (OC) squamous cell carcinomas (SCCs). We retrospectively reviewed 39 patients with OC and OP-SCC who underwent staging F-FDG PET/CT. PET/CT parameters were measured for the primary tumor and the hottest involved node, including SUVmax, SUVmean, SUVpeak, metabolic tumor volume, total lesion glycolysis, standardized added metabolic activity (SAM), and normalized SAM. Patient characteristics were compared between HPV positive (HPV+) and negative (HPV-) groups. Receiver operating characteristic analysis was used to dichotomize PET/CT parameters into high and low. Logistic regression models predicting HPV status were fit for each PET/CT parameter. The HPV+ group was composed of 18 patients all with OP-SCC; the HPV- group consisted of 21 patients, 4 OP cancer patients and 17 OC cancer patients. The HPV+ group had a higher proportion of N2 stage (94% vs 43%; P < 0.001). Nodal PET/CT parameters were higher in the HPV+ group (P < 0.01); this difference was not present for the primary lesion. After adjusting for sex and age, the association of higher nodal SUVmax (odds ratio [OR], 9.67), SUVmean (OR, 10.48), SUVpeak (OR 9.67), metabolic tumor volume (OR, 14.52), total lesion glycolysis (OR, 11.84), and SAM, normalized SAM (OR, 16.21) with HPV+ status remained statistically significant (P < 0.05). Nodal PET/CT parameters predict HPV status. High nodal FDG uptake should raise suspicion for positive HPV status in the evaluation of the primary lesion.

Characteristics and Prognostic Implications of High-Risk HPV-Associated Hypopharyngeal Cancers

Article

Full-text available

Nov 2013
PLOS ONE

High-risk human papillomavirus (HPV) is an oncogenic virus that causes oropharyngeal cancers, and it has a favorable outcome after the treatment. Unlike in oropharyngeal cancer, the prevalence and role of high-risk HPV in the etiology of hypopharyngeal squamous cell carcinoma (HPSCC) is uncertain. The aim of the present study was to evaluate the effect and prognostic significance of high-risk HPV in patients with HPSCC. The study included 64 subjects with HPSCC who underwent radical surgery with or without radiation-based adjuvant therapy. Primary tumor sites were the pyriform sinus in 42 patients, posterior pharyngeal wall in 19 patients, and postcricoid area in 3 patients. High-risk HPV in situ hybridization was performed to detect HPV infection. The positive rate of high-risk HPV in situ hybridization was 10.9% (7/64). There was a significant difference in the fraction of positive high-risk HPV among pyriform sinus cancer (16.7%), posterior pharyngeal wall cancer (0%), and postcricoid area cancer (0%) (p = 0.042). The laryngoscopic examination revealed a granulomatous and exophytic appearance in 85.7% (6/7) of patients with high-risk HPV-positive pyriform sinus cancer, but in only 31.4% (11/35) of patients with high-risk HPV-negative pyriform sinus cancer (p = 0.012). Significant correlations were found between positive high-risk HPV and younger age (p = 0.050) and non-smoking status (p = 0.017). HPV-positive patients had a significantly better disease-free survival (p = 0.026) and disease-specific survival (p = 0.047) than HPV-negative patients. High-risk HPV infection is significantly related to pyriform sinus cancer in patients with HPSCC.

Human Papillomavirus Infection and Prognostic Predictors in Patients with Oropharyngeal Squamous Cell Carcinoma

Article

Mar 2012
ASIAN PAC J CANCER P

This study focused on infection rates and subtypes of human papillomavirus (HPV) in patients with oropharyngeal squamous cell carcinoma (OSCC), and the relationship between HPV status and prognosis of the disease. We evaluated sixty-six OSCC patients who met the enrollment criteria during the period from January 1999 to December 2009. The presence or absence of oncogenic HPV types in tumors was determined using the SPF10 LiPA25 assay. Overall survival (OS) and disease specific survival (DSS) for HPV positive and HPV negative patients were estimated using Kaplan-Meier analysis. The Cox regression model was applied for multivariate analysis. HPV-DNA was detected in 11(16.7%) of all specimens. Among them, 7 were type HPV-16, while other types were HPV-16/11, HPV-35, HPV-58/52, and HPV-33/52/54. Patients with HPV positive tumors were more likely to be female, non-smokers and non-drinkers (p=0.002, 0.001 and 0.001, respectively). After a median follow-up of 24.5 months, patients with HPV positive tumors had significantly better overall survival (HR=0.106[95%CI=0.014-0.787], p=0.016,) and disease specific survival (HR=0.121[95%CI=0.016-0.906], p=0.030). Patients with HPV positive OSCC have significantly better prognosis than patients with HPV negative tumors. HPV infection is an independent prognostic factor.

Multiparametric MRI Evaluation of Oropharyngeal Squamous Cell Carcinoma. A Mono-Institutional Study

Article

Full-text available

Aug 2021

The aim of this paper is to define the pre-treatment radiological characteristics of oropharyngeal squamous cell carcinoma (OPSCC) using morphological and non-morphological magnetic resonance imaging (MRI), based on HPV status, in a single-institution cohort. In total, 100 patients affected by OPSCC were prospectively enrolled in the present study. All patients underwent 1.5T MR with standard sequences, including diffusion-weighted imaging with and intravoxel incoherent motion (IVIM-DWI) technique and a dynamic contrast-enhanced (DCE) MRI. For all patients, human papillomavirus (HPV) status was available. No statistically significant differences in the volume of primary tumors (PTs) and lymph nodes (LNs) were observed based on HPV status. When comparing the two patient groups, no significant differences were found for the PT radiologic characteristics (presence of well-defined borders, exophytic growth, ulceration, and necrosis) and LN morphology (solid/cystic/necrotic). Tumor subsite, smoking status, and alcohol intake significantly differed based on HPV status, as well as ADC and Dt values of both PTs and LNs. We detected no significant difference in DCE-MRI parameters by HPV status. Based on a multivariate logistic regression model, the combination of clinical factors, such as tumor subsite and alcohol habits, with the perfusion-free diffusion coefficient Dt of LNs, may help to accurately discriminate OPSCC by HPV status.

Prevalence of high-risk human papillomavirus and its genotype distribution in head and neck squamous cell carcinomas

Article

Full-text available

Jul 2020

Background: High-risk (HR) human papillomavirus (HPV) is found in a subset of head and neck (HN) squamous cell carcinomas (SCCs). For oropharyngeal SCCs, HR HPV positivity is known to be associated with good prognosis, and a separate staging system for HPV-associated carcinomas using p16 immunohistochemistry (IHC) as a surrogate test has been adopted in the 8th American Joint Committee on Cancer staging system. We examined the HR HPV status and the genotype distribution in five HN subsites. Materials and methods: Formalin-fixed paraffin-embedded tissue sections were used for p16 IHC and DNA extraction. HPV DNA detection and genotyping were done employing either a DNA chip-based or real-time polymerase chain reaction-based method. Results: During 2011-2019, a total of 466 SCCs were tested for HPV DNA with 34.1% positivity for HR HPV. Among HN subsites, the oropharynx showed the highest HR HPV prevalence (149/205, 75.1%), followed by the sinonasal tract (3/14, 21.4%), larynx (5/43, 11.6%), hypopharynx (1/38, 2.6%), and oral cavity (1/166, 0.6%). The most common HPV genotype was HPV16 (84.3%) followed by HPV35 (6.9%) and HPV33 (4.4%). Compared with HR HPV status, the sensitivity and specificity of p16 IHC were 98.6% and 94.3% for the oropharynx, and 99.2% and 93.8% for the tonsil, respectively. Conclusion: Using a Korean dataset, we confirmed that HR HPV is most frequently detected in oropharyngeal SCCs. p16 positivity showed a good concordance with HR HPV DNA for oropharyngeal and especially tonsillar carcinomas. The use of p16 IHC may further be extended to predict HR HPV positivity in sinonasal tract SCCs.

Effect of Fucoxanthin on PI3K/Akt Signaling Pathway in Human Cervical Cancer HeLa Cells

Article

Full-text available

Oct 2018

GuoLiu YE

Reader performance in the ultrasonographic evaluation of oropharyngeal carcinoma

Article

Feb 2018

Objective: To examine reader performance in evaluating oropharyngeal anatomy on ultrasonography. Materials and methods: Ultrasound images of the oropharynx comprising normal and malignant anatomic variants were organized into slideshows. Slideshows were administered to 6 readers blinded to participant tumor status and with varying experience reading oropharyngeal sonograms. A training slideshow oriented readers to images of the oropharynx with and without malignant lesions. Readers then evaluated images in a test slideshow for tumor presence and marked orthogonal long and short dimensions of the tumor. Results were analyzed for accuracy, sensitivity, specificity, inter-reader agreement, and measurement error relative to prospectively-identified reference measurements. Results: Eighty-seven percent of base of tongue (BOT) sonograms were identified correctly by a majority of readers. In identifying BOT tumors, median accuracy, sensitivity, specificity, and Fleiss's kappa were 79%, 73%, 85%, and 0.51, respectively. Median measurement error in the long and short axes for BOT tumors was -2.6% (range: -40% to 29%) and -2.6% (range: -56% to 156%), respectively. Eighty-four percent of palatine tonsil sonograms were identified correctly by a majority of readers. In identifying tonsil tumors, median accuracy, sensitivity, specificity, and Fleiss's kappa were 77%, 74%, 78%, and 0.41, respectively. Median measurement error in the long and short axes for tonsil tumors was 3.8% (range: -45% to 32%) and -6.5% (range: -83% to 42%), respectively. Conclusions: Overall, US has clinically useful sensitivity for identification of oropharyngeal carcinoma among readers of diverse clinical backgrounds and experience. US may be useful for the evaluation of features such as tumor dimensions.

Biomarker quantification by multiplexed quantum dot technology for predicting lymph node metastasis and prognosis in head and neck cancer

Article

Full-text available

May 2016

Purpose: To predict lymph node metastasis and prognosis in head and neck squamous cell carcinoma (HNSCC). Results: The combination of membranous E-cadherin and membranous epidermal growth factor receptor (EGFR) quantified by QD technology with age, gender, and grade had greater predictive power than any of the single biomarkers or the two combined biomarkers quantified by conventional immunohistochemistry (IHC). The predictive power of this model was validated in another independent sample set; the predictive sensitivity of this model for LNM was 87.5%, with specificity up to 97.4%, and accuracy 92.9%. Furthermore, a higher membranous E-cadherin level was significantly correlated with better overall and disease-free survival (OS, DFS; P = 0.002, 0.033, respectively), while lower cytoplasmic vimentin and membranous EGFR levels were significantly correlated with better OS (P = 0.016 and 0.021, respectively). The combined biomarkers showed a stronger prognostic value for OS and DFS than any of the single biomarkers. Methods: Multiplexed quantum dots (QDs) were used to simultaneously label E-cadherin, vimentin, and EGFR with β-actin as an internal control. Primary tissue samples from 97 HNSCC patients, 49 with and 48 without LNM were included in the training set. Levels of membranous E-cadherin, cytoplasmic vimentin, and membranous EGFR were quantified by InForm software and correlated with clinical characteristics. Conclusions: Multiplexed subcellular QD quantification of EGFR and E-cadherin is a potential strategy for the prediction of LNM, DFS, and OS of HNSCC patients.

Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma

Article

Full-text available

Jun 2015
JPN J CLIN ONCOL

Objective: In a previous study, we reported the value of p16 expression and alcohol consumption in oropharyngeal carcinoma in Japan. We now report the clinical significance of human papillomavirus status and p16 expression in oropharyngeal carcinoma in Japan. Methods: Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify tumor samples of oropharyngeal carcinoma. We performed immunohistochemistry for the p16 protein, in situ hybridization for human papillomavirus-deoxyribonucleic acid and polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 in oropharyngeal carcinoma in Japanese patients. We evaluated the human papillomavirus status in patients with oropharyngeal carcinoma to determine its prevalence and association with prognosis. We defined human papillomavirus(+) and human papillomavirus(-) oropharyngeal carcinoma cohorts as those with and without polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 or in situ hybridization-human papillomavirus. Results: In oropharyngeal carcinoma, the prevalences of p16(+)human papillomavirus(+), p16(+)human papillomavirus(-), p16(-)human papillomavirus(+) and p16(-)human papillomavirus(-) were 32% (48/150), 7% (10/150), 2% (3/150) and 59% (89/150), respectively. Low tobacco and alcohol consumption, tonsil or base of tongue localization, but not age, were associated with p16(+)human papillomavirus(+). Low alcohol consumption was associated with p16(+)human papillomavirus(-). There was a significant difference in overall survival between p16(+)human papillomavirus(-) and p16(-)human papillomavirus(-) (P = 0.03). In multivariate Cox regression models, p16 was the independent prognostic factor, regardless of human papillomavirus status. Conclusion: p16 expression was a reliable prognostic biomarker regardless of human papillomavirus status.

The role of histologic subtype, p16INK4a expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma

Article

Full-text available

Apr 2015
BMC CANCER

Background Up to 50% of penile squamous cell carcinomas (pSCC) develop in the context of high-risk human papillomavirus (HR-HPV) infection. Most of these tumours have been reported to show basaloid differentiation and overexpression of tumour suppressor protein p16INK4a. Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research. Methods In tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16INK4a immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters. Results 90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16INK4a staining patterns was observed in 58.6% of samples regardless of histologic subtype. Sensitivity of basaloid subtype to predict HR-HPV positivity was poor (11.8%). In contrast, sensitivity and specificity of p16INK4a staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16INK4a, specificity could be improved to 83%. Both expression of p16INK4a and presence of HR-HPV DNA, but not histologic grade, were inversely associated with pSCC tumour invasion (p = 0.01, p = 0.03, and p = 0.71). However, none of these correlated with nodal involvement or distant metastasis. In contrast to pathological tumour stage, the HR-HPV status, histologic grade, and p16INK4a positivity failed to predict cancer-specific survival. Conclusions Our results confirm intense nuclear positivity for p16INK4a, rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV / p16INK4a positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16INK4a/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC.

Human papillomavirus in carcinomas of the tongue: Clinical and prognostic implications

Article

Jan 2013
INT J ORAL MAX SURG

It is not clear whether the presence of human papillomavirus (HPV) in squamous cell carcinomas of the tongue (SCCT) is of etiopathogenic and clinical significance. This study was designed to establish the incidence of HPV in SCCT and to determine the influence of HPV detection on clinical parameters and the prognosis. Clinical and histopathological data of 64 patients with SCCT were collected. Thirty benign lesions of the tongue were analyzed in parallel, in order to compare the HPV incidence and genotypes in these lesions with those of SCCT. Paraffin blocks of all cases were collected and PCR was carried out using SPF10 primers and the INNO-LiPA genotyping methodology. HPV was detected in 26.2% of the patients. Hybridization results showed that all patients except one had high-risk (HR)-HPV. HPV56 was the most common (42.1%), followed by HPV18 (26.3%), HPV16 (10.5%), HPV66 (10.5%), HPV39 (5.3%), and HPV51 (5.3%). The odds ratio of HR-HPV infection in cases vs. controls was statistically significant (9.45, 95% confidence interval 1.18–75.46). Among the results of the univariate analysis correlating the presence of HR-HPV with different clinical parameters, only mortality showed a statistically significant correlation, being higher in HR-HPV patients (odds ratio 3.97, 95% confidence interval 1.07–14.7).

[Human papillomavirus in squamous cell cancer of the head and neck : A study at the Ulm Military Hospital, Germany.]

Article

Jul 2013
HNO

There is increasing evidence worldwide that human papillomavirus is a major risk factor for head and neck cancer. Only few studies on this association have been performed in Germany to date. For the purposes of the present study, tumor specimens from 223 patients with squamous cell cancer of the oral cavity, oropharynx, hypopharynx and larynx were analyzed for HPV DNA and p16INK4a expression. The prevalence of HPV genotype 16 (HPV16) DNA in the study population was 17.5 %. Further high-risk HPV types were not detected. All HPV16-positive tumors showed intense p16INK4a expression. HPV16 prevalence was highest in tonsillar carcinoma (37.5 %) and lowest in laryngeal cancer (2.8 %). We observed a significantly higher incidence of cervical lymph node metastases in patients with HPV16-positive tonsillar carcinoma in comparison to HPV-negative tumors (p < 0.016). Tobacco and/or alcohol consumption was significantly lower in patients with HPV-positive tumors (p < 0.0001).

Prognostic factors and survival unique to surgically treated p16+ oropharyngeal cancer

Article

Sep 2012
LARYNGOSCOPE

Objectives/hypothesis: Current head and neck epidemiology demonstrates a steadily increasing incidence of p16+ human papillomavirus-related oropharynx squamous cell cancer (OPSCC). This distinct tumor subtype is associated with better survival outcomes. There is a growing recognition of the need to define management regimens that take into account the inherent patho-biological attributes of these cancers and provide optimum oncological control with minimum morbidity. This is facilitated by a clear understanding of the prognostic variables that predict disease outcome in patients with p16+ OPSCC. To provide prognostic estimates, pathological staging and histopathological parameters are usually superior to clinical staging. However, knowledge of pathological predictors is sparse, mainly because of commonly employed nonsurgical management policies utilizing chemoradiotherapy. Minimally invasive approaches to the oropharynx, particularly transoral laser microsurgery (TLM), are well-reported effective primary treatments for oropharynx cancers. From such series, it is feasible to conduct a detailed appraisal based on pathologic information from surgical specimens of both the primary and neck, to establish prognosticators unique to p16+ oropharynx cancer patients. Study design: A prospectively assembled database of oropharynx cancer patients treated with primary TLM ± neck dissection ± adjuvant therapy from 1996 to 2010, analyzed retrospectively for survival and recurrence. Methods: The fundamental inclusion criteria were: 1) previously untreated biopsy-proven OPSCC treated with primary TLM ± neck dissection, 2) diffuse p16 positivity in the surgical specimen, 3) availability for adjuvant therapy, if indicated, and 4), minimum follow-up of 12 months or to death. Cox proportional hazard regression analyses were used to identify variables that were prognostic for disease-free survival (DFS), the primary end point of the study, as well as disease-specific survival (DSS) and overall survival. Kaplan-Meier survival estimates and patterns of disease recurrence were also assessed. We also explored concordance for T and N staging, when assessed by clinical (cT, cN) and pathological (cT, pT) measures. Results: Of 211 patients in the TLM database, 171 met all the eligibility criteria. The median follow-up was 47 months. The 3- and 5-year Kaplan-Meier estimates for DFS were 91% and 88%, respectively, whereas for DSS they were 95.5% and 94.4%, respectively. A total of 12 (7%) recurrences occurred: two local, four regional, and six distant. Of all T-stage categories, pT4 tumors were strongest predictors of poorer DFS. cT4 tonsil primaries, ever smoking status, three or more metastatic nodes, pN2b+ stage, and radiation-based adjuvant therapy were other prognosticators for DFS. Angioinvasion and T3-T4 tumors were prognostic for reduced DSS, although smoking parameters were not. Extracapsular spread, N stage, and margins were nonprognosticators. Recursive partitioning analysis defined high- and low-risk groupings of prognosticators. Downstaging of clinical T stage was observed for 31% of tumors on application of pathological classification. Conclusions: We document a well-delineated set of prognostic variables that specifically and accurately identify individuals at risk of reduced outcomes in an otherwise good prognosis p16+ OPSCC cohort. Based on these prognosticators, appropriate patient counseling, adjuvant treatment recommendations, and stratification for trials can more accurately be made. We also observed an additional edge conferred by TLM toward more accurate clinical as well as pathological T staging.

Liquiritigenin Inhibits Tumor Growth and Vascularization in a Mouse Model of Hela Cells

Article

Full-text available

Dec 2012
MOLECULES

Angiogenesis is one of the crucial steps in the transition of a tumor from a small, harmless cluster of mutated cells to a large, malignant growth, capable of spreading to other organs throughout the body. Vascular endothelial growth factor (VEGF) that stimulates vasculogenesis and angiogenesis is thought to be as an anti-angiogenic target for cancer therapy. Liquiritigenin (LQ), a flavanone existing in Radix glycyrrhiza, shows extensive biological activities, such as anti-inflammatory and anti-cancer properties. In our studies, liquiritigenin effectively inhibited the growth of tumors xenografted in nude mice from human cervical cancer cell line HeLa cells, and microvascular density (MVD) of the tumor exposed to liquiritigenin was reduced in a dose dependent manner, especially in the high dose group. Moreover, the expression and secretion of VEGF were down-regulated by the drug in vivo and in vitro. Therefore, liquiritigenin can be further studied on cancer and other diseases associated with VEGF up-regulation.

Virology and molecular pathogenesis of HPV (human papillomavirus)-associated oropharyngeal squamous cell carcinoma

Article

Apr 2012
BIOCHEM J

The current literature fully supports HPV (human papillomavirus)-associated OPSCC (oropharyngeal squamous cell carcinoma) as a unique clinical entity. It affects an unambiguous patient population with defined risk factors, has a genetic expression pattern more similar to cervical squamous cell carcinoma than non-HPV-associated HNSCC (head and neck squamous cell carcinoma), and may warrant divergent clinical management compared with HNSCC associated with traditional risk factors. However, a detailed understanding of the molecular mechanisms driving these differences and the ability to exploit this knowledge to improve clinical management of OPSCC has not yet come to fruition. The present review summarizes the aetiology of HPV-positive (HPV+) OPSCC and provides a detailed overview of HPV virology and molecular pathogenesis relevant to infection of oropharyngeal tissues. Methods of detection and differential gene expression analyses are also summarized. Future research into mechanisms that mediate tropism of HPV to oropharyngeal tissues, improved detection strategies and the pathophysiological significance of altered gene and microRNA expression profiles is warranted.

Characteristics of Human Papillomavirus Infection among Oropharyngeal Cancer Patients: A Systematic Review and Meta-Analysis

Article

Oct 2023
ARCH ORAL BIOL

The Role of HPV in Determining Treatment, Survival, and Prognosis of Head and Neck Squamous Cell Carcinoma

Article

Full-text available

Sep 2022

Human papillomavirus (HPV) infection has been identified as a significant etiological agent in the development of head and neck squamous cell carcinoma (HNSCC). HPV’s involvement has alluded to better survival and prognosis in patients and suggests that different treatment strategies may be appropriate for them. Only some data on the epidemiology of HPV infection in the oropharyngeal, oral cavity, and laryngeal SCC exists in Europe. Thus, this study was carried out to investigate HPV’s impact on HNSCC patient outcomes in the Irish population, one of the largest studies of its kind using consistent HPV testing techniques. A total of 861 primary oropharyngeal, oral cavity, and laryngeal SCC (OPSCC, OSCC, LSCC) cases diagnosed between 1994 and 2013, identified through the National Cancer Registry of Ireland (NCRI), were obtained from hospitals across Ireland and tested for HPV DNA using Multiplex PCR Luminex technology based in and sanctioned by the International Agency for Research on Cancer (IARC). Both overall and cancer-specific survival were significantly improved amongst all HPV-positive patients together, though HPV status was only a significant predictor of survival in the oropharynx. Amongst HPV-positive patients in the oropharynx, surgery alone was associated with prolonged survival, alluding to the potential for de-escalation of treatment in HPV-related OPSCC in particular. Cumulatively, these findings highlight the need for continued investigation into treatment pathways for HPV-related OPSCC, the relevance of introducing boys into national HPV vaccination programs, and the relevance of the nona-valent Gardasil-9 vaccine to HNSCC prevention.

Prognostic Value of Nodal Involvement in Patients With Oropharyngeal Carcinoma According to the HPV Status

Article

Jul 2020

Background and objective Different studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection. Material and methods Retrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990–2016 for whom information on HPV status was available. Results 14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours. Conclusions Regional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas.

Valoración de la capacidad pronóstica de la afectación ganglionar de los pacientes con carcinoma de orofaringe en función del estatus HPV

Article

Jan 2020
Acta Otorrinolaringol Esp

Background and objective: Different studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection. Material and methods: Retrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990-2016 for whom information on HPV status was available. Results: 14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours. Conclusions: Regional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas.

Long non‑coding RNA plasmacytoma variant translocation 1 gene promotes the development of cervical cancer via the NF‑κB pathway

Article

Jul 2019

The long noncoding RNA plasmacytoma variant translocation 1 gene (LncRNA PVT1) has an important role in tumor occurrence and development, yet the role and underlying molecular mechanisms of this RNA in cervical cancer have not yet been elucidated. In the present study, three cervical cancer cell lines (HeLa, Ca Ski and SiHa) were used to verify how LncRNA PVT1 mediates cervical cancer development, and the H8 cell line was used as a control. A LncRNA PVT1 overexpression vector or small interfering RNAs targeting LncRNA PVT1 were transfected into cervical cancer cells to generate LncRNA PVT1 overexpression and silencing in these cells. LncRNA PVT1 overexpression accelerated the growth of cervical cancer cells by advancing the cell cycle and inhibiting cellular apoptosis; increases in Cyclin D1 (CCND1) mRNA and activated Bcl‑2 protein expression levels also supported this finding. Furthermore, NF‑κB activation and expression was increased by LncRNA PVT1 overexpression. In addition, NF‑κB activation or inhibition induced changes in cell viability, accompanied by changes in CCND1 and Bcl‑2 expression. Increases or decreases in microRNA‑16 (miR‑16) expression (using miR mimics and inhibitors) also corresponded to changes in LncRNA PVT1 expression, in vitro. miR‑16 mimics and inhibitor had opposite effects to those of NF‑κB activity, and miR‑16 was demonstrated to directly interact with the NF‑κB gene as measured using the dual‑luciferase assay. In summary, LncRNA PVT1 inhibits the effect of miR‑16, promoting the cell cycle and inhibiting cellular apoptosis of cervical cancer cells, potentially via the NF‑κB pathway. The data from the present study will contribute to the current knowledge surrounding the theoretical basis of cervical cancer and provide a new perspective for the treatment of cervical cancer.

Detection of HPV infection in head and neck cancers: Promise and pitfalls in the last ten years: A meta-analysis

Article

Full-text available

Oct 2018

The current controversial discussion on the disease-specific survival of patients with human papillomavirus (HPV)-positive (+) and -negative (−) squamous cell carcinoma (SCC) of the head neck region was the motivation for the present meta-analysis. Different detection methods for HPV are available, though these often lack sensitivity. As a consequence, there may be false interpretation of HPV positivity. A bias concerning HPV status and therefore also survival rates is serving a non-durable relevance in the discussion of tailored therapies. A literature search was performed via the online database PubMed/NCBI, and data extraction and statistical analysis were conducted. A total of 139 studies published between 2004 and 2014 were evaluated in the present meta-analysis. The HPV detection methods, patient characteristics, tumor localizations and stages, as well as (neo-) adjuvant therapies and survival times were analyzed. The average incidence rates of HPV⁺ patients with oropharyngeal tumors were higher than those of patients with cancers of other regions of the head and neck. Upon evaluating the results of different detection methods no significant differences were identified. We have compared the HPV incidence rates of each detection method, when studies have used more than one. Regarding overall survival, the pooled adjusted hazard ratio (HR) for oropharyngeal SCC was 0.31 [95% confidence interval (CI)=0.27–0.36]. Unfortunately, only 3 equivalent studies were available on nonoropharyngeal tumors, for which the pooled adjusted HR was 1 (95% CI=0.73–1.36). Overall, the evaluation demonstrated that the survival rates reported in numerous studies were not evaluated multifactorially and important confounders were excluded from the statistics. The HPV detection methods used were often not sufficient in representing HPV positivity. In addition, oropharyngeal and oral SCCs were assessed together in the localization. The widely differing number of HPV⁺ patients in each of the various studies may be explained by insufficient detection methods and by a lack of localization distinction. The considerations of a tailored therapy according to HPV status should be rejected based on the present information. The previously published studies should be read critically and do not represent a basis for therapeutic decisions.

Radiographic muscle invasion not a recurrence predictor in HPV-associated oropharyngeal squamous cell carcinoma: Muscle Invasion in HPV + Oropharyngeal Cancer

Article

Oct 2018

Objective To determine whether muscle invasion evident on pretreatment imaging in p16 + oropharyngeal squamous cell carcinoma (OPSCC) correlates with recurrence. Study Design Retrospective review. Methods Two‐hundred and seventy‐six patients with p16 + OPSCC treated at a tertiary referral center from 2003 to 2015 were analyzed. All scans were reviewed by a dedicated neuroradiologist with subspecialty expertise in head and neck imaging. Radiographic evidence of muscle invasion to the genioglossus, hyoglossus, medial pterygoid, and prevertebral muscles was analyzed. Local and regional recurrence rates were compared between the muscle invasion and no muscle invasion groups. Results One hundred and ninety patients met inclusion criteria with adequate follow‐up data and pretreatment imaging. Patients were predominantly male (87.5% male) and smokers (65.6% smokers) with a mean age of 56.7 (standard deviation: 9.0 years). Most commonly invaded muscles in the muscle invasion group were hyoglossus (57.8%) and genioglossus (56.3%). There was no statistically significant difference in primary site or nodal recurrence between the combined group, including definite or possible muscle invasion and the group without muscle invasion (P = 0.205 and P = 0.569, respectively). Additionally, no statistically significant difference was present in recurrence‐free and disease‐specific survival between the two groups at 3‐ and 5‐year follow‐up (P > 0.05). Conclusion Radiographic evidence of muscle invasion does not appear to be a predictor of human papilloma virus (+) OPSCC recurrence. Additional studies are needed to validate our findings. Level of Evidence 4. Laryngoscope, 2018

Effect of time to simulation and treatment for patients with oropharyngeal cancer receiving definitive radiotherapy in the era of risk stratification using smoking and human papillomavirus status

Article

Jan 2018
HEAD NECK-J SCI SPEC

Background: The effect of increasing time to definitive radiotherapy (RT) for patients with oropharyngeal squamous cell carcinoma (SCC) is unknown. Methods: Nodal tumor volumes at staging and simulation were compared for patients with oropharyngeal SCC. Time from staging to initiation of RT was tabulated. The primary endpoint of interest was nodal progression at simulation. Results: Increasing time to simulation was associated with nodal progression in 144 patients (r = 0.474; P < .001). Patients with human papillomavirus (HPV)-associated oropharyngeal SCC were more likely to have nodal progression (50% vs 26%; P = .008). A threshold of 32 days was associated (sensitivity 77.9% and specificity 60.2%) with nodal progression (P < .001). Increasing time from staging to treatment initiation was associated with a greater risk of distant failure (hazard ratio [HR] 4.157; 95% confidence interval [CI] 1.170-14.764) but not progression-free survival (PFS; P = .179) or overall survival (OS; P = .474). Conclusion: Increasing time before RT for patients with oropharyngeal SCC is associated with nodal progression and increased hazard of distant failure, although not PFS or OS in our population.

Otorhinolaryngology Manifestations Secondary to Oral Sex

Article

Full-text available

May 2017

Introduction Over the last few years, oral and pharyngeal signs and symptoms due to oral sex have increased significantly. However, no review articles related to this subject have been found in the medical literature. The objective of our study was to identify otorhinolaryngological manifestations associated with orogenital/oroanal contact, both in adults and children, in the context of consensual sex or sexual abuse. Methods We performed a review of the medical literature on otorhinolaryngological pathology associated with oral sex published in the last 20 years in the PubMed database. Results Otorhinolaryngological manifestations secondary to oral sex practice in adults can be infectious, tumoral or secondary to trauma. The more common signs and symptoms found in the literature were human papillomavirus infection (above all, condyloma acuminata and papilloma/condyloma), oral or pharyngeal syphilis, gonococcal pharyngitis, herpes simplex virus infection and pharyngitis from Chlamydia trachomatis. The incidence of human papillomavirus-induced oropharyngeal carcinoma has dramatically increased. In children past the neonatal period, the presence of condyloma acuminatus, syphilis, gonorrhoea or palatal ecchymosis (the last one, unless justified by other causes) should make us suspect sexual abuse. Conclusions Sexual habits have changed in the last decades, resulting in the appearance of otorhinolaryngological pathology that was rarely seen previously. For this reason, it is important for primary care physicians to have knowledge about the subject to perform correct diagnosis and posterior treatment. Some sexual abuse cases in children may also be suspected based on the knowledge of the characteristic oropharyngeal manifestations secondary to them.

The Presence of HPV DNA in Neck Lymph Node Metastasis Correlates with Improved Overall Survival of Patients with Oropharyngeal Cancer Undergoing Surgical Treatment

Article

Dec 2016

Background: Few studies have addressed how human papilloma virus (HPV) infection in oropharyngeal squamous cell carcinoma (OPSCC) affects the outcome of surgical therapy; furthermore, the relationship between the presence of HPV DNA and neck lymph node (LN) metastasis has not been well established. Methods: A total of 65 patients who underwent surgery as a first-line therapy for OPSCC were enrolled in this study. In HPV-positive patients, the presence of HPV DNA in metastatic neck LN lesions was evaluated. Results: The HPV-positive patients had significantly better overall survival than the HPV-negative patients (log-rank test, p = 0.04), whereas HPV infection status did not significantly affect disease-free survival (log-rank test, p = 0.65). In all of the HPV-positive OPSCC patients who developed cervical LN metastasis, the same HPV DNA type was found in both the primary tumour and the metastases. Conclusions: The present results suggest that HPV infection is a determining factor for good prognosis in patients undergoing first-line surgical therapy for OPSCC.

Lesiones otorrinolaringológicas secundarias al sexo oral

Article

Oct 2016

Introduction: Over the last few years, oral and pharyngeal signs and symptoms due to oral sex have increased significantly. However, no review articles related to this subject have been found in the medical literature. The objective of our study was to identify otorhinolaryngological manifestations associated with orogenital/oroanal contact, both in adults and children, in the context of consensual sex or sexual abuse. Methods: We performed a review of the medical literature on otorhinolaryngological pathology associated with oral sex published in the last 20 years in the PubMed database. Results: Otorhinolaryngological manifestations secondary to oral sex practice in adults can be infectious, tumoral or secondary to trauma. The more common signs and symptoms found in the literature were human papillomavirus infection (above all, condyloma acuminata and papilloma/condyloma), oral or pharyngeal syphilis, gonococcal pharyngitis, herpes simplex virus infection and pharyngitis from Chlamydia trachomatis. The incidence of human papillomavirus -induced oropharyngeal carcinoma has dramatically increased. In children past the neonatal period, the presence of condyloma acuminatus, syphilis, gonorrhoea or palatal ecchymosis (the last one, unless justified by other causes) should make us suspect sexual abuse. Conclusions: Sexual habits have changed in the last decades, resulting in the appearance of otorhinolaryngological pathology that was rarely seen previously. For this reason, it is important for primary care physicians to have knowledge about the subject to perform correct diagnosis and posterior treatment. Some sexual abuse cases in children may also be suspected based on the knowledge of the characteristic oropharyngeal manifestations secondary to them.

HPV-Positive Oropharyngeal Carcinoma: A Systematic Review of Treatment and Prognosis

Article

Jun 2015
OTOLARYNG HEAD NECK

Human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma is increasing in incidence and appears to exhibit improved response to treatment and better survival than that of HPV- head and neck squamous cell carcinoma. The purpose of this systematic review was to examine the current literature regarding treatment and prognosis of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) and identify whether type of treatment (primarily surgery vs primarily radiation) significantly affects survival rates. PubMed and Cochrane Library databases. A computerized search of the PubMed and Cochrane Library databases was performed to identify English-language articles published between January 1, 2000, and October 21, 2014. Studies were included only if they were prospective or retrospective observational series of OPSCC patients that reported HPV status, treatment regimen, and survival outcomes. Outcomes were determined for HPV+ and HPV- OPSCC patients, with subanalyses according to the type of treatment received. Fifty-six articles were eligible for this review. In the HPV+ analysis, the unadjusted hazard rate ratio (HR) for surgery vs radiation treatment was 1.33 (P = .114). Nine confounders were considered, and HRs were adjusted for each covariate. While HRs were almost all >1 for all covariates, none of the HRs was statistically significant at P < .05. The HR for HPV- OPSCC was higher for radiation than surgery. HPV+ OPSCC has an improved prognosis and lower rates of adverse events when compared with HPV- OPSCC. HPV- OPSCC had significantly worse outcomes when treated with primary radiation as compared with primary surgery. There was no statistically significant difference in HRs for HPV+ OPSCC with primary radiation vs primary surgery treatment. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.

Association between the standardized uptake value and high-risk HPV in hypopharyngeal squamous cell carcinoma

Article

Sep 2014

Conclusion: Median (18)F-FDG PET/CT maximum standardized uptake values (SUV max) cut-off values of 7.9 or greater were associated with high-risk human papillomavirus (HPV) negativity in patients with hypopharyngeal squamous cell carcinoma (HPSCC). Furthermore, median (18)F-FDG PET/CT SUV max cut-off values of 7.9 or greater and high-risk HPV negativity were associated with adverse outcomes. Objectives: We studied the association and the potential prognostic significance of (18)F-FDG PET/CT and high-risk HPV status in HPSCC. Methods: The medical records of 45 patients who underwent (18)F-FDG PET/CT for HPSCC before surgery were reviewed. High-risk HPV in situ hybridization was performed to detect HPV infection. Results: The median SUV max was 9.91 ± 4.91 (range 1.9-22.1) and the positive rate of high-risk HPV in situ hybridization was 11% (5 of 45). The SUV max values of negativity for the high-risk HPV subtypes (10.47 ± 4.87) and positivity (5.48 ± 2.45) were found to be significantly different (p = 0.030). The SUV max cut-off value for differentiating negativity for the high-risk HPV subtypes from positivity was 7.9, with a sensitivity of 65% and a specificity of 80%. The 5-year disease-specific survival rate (DSSR) in our cohort was 57%. Patients with an SUV max value higher than 7.9 (p = 0.005) and high-risk HPV negativity (p = 0.047) had decreased 5-year DSSR.

Fucoxanthin induces apoptosis in human cervical cancer cell line HeLa via PI3K/Akt pathway

Article

Aug 2014

Cervical cancer (CC) is a malignant neoplasm arising from cells originating in the cervix uteri, among the top causes of death from cancer in women. In a gene expression profiling study of metabolic response to treatment, PI3K/Akt signaling pathway are associated with the development of CC. A common mechanism of Akt activation seen in cancer types is alterations in the upstream regulators of Akt such as phosphatidylinositol 3-kinase (PI3K), which is overexpressed in cervical cancer tissues, and leads to phosphorylation of Akt. Both PI3K and Akt inhibitors exist and may be therapeutically valuable. In the present study, we use MTT assay and western blot for the high-throughput screening to select specific inhibitors of PI3K/Akt signaling pathway, and then obtain fucoxanthin. Fucoxanthin is a water-soluble dietary fiber, taken from the unique slimy component of alginic cells. Various studies have pointed out that fucoxanthin is very effective for the treatment of cancer. Our results have shown that fucoxanthin induced a significant apoptosis of HeLa cells, compared with other candidates. After treatment with fucoxanthin for 24 h, the level of phosphorylation was inhibited in a dose-dependent manner, and the proteins of apoptotic markers were changed in HeLa cells. And fucoxanthin could suppress tumor growth in vivo. In addition, the mitochondrial signal transduction pathway maybe was involved in its mechanism and NF-κB activation was decreased after treatment with fucoxanthin. Therefore, fucoxanthin may be used as anti-cervical cancer drugs in the future.

Prevalence of Human Papillomavirus Infection in the Korean Oral Cancer Patients

Article

Full-text available

Jul 2013

Purpose: High risk human papillomavirus (HPV) is the main source of cervical cancer, nearly up to 100%. Because there are no affordable data regarding the incidence of HPV in different sites of oral cavity, the purpose of this study is to review the previous article and to find out about the incidence and types of HPV in specific areas of oral cavity. Methods: We examined a total of 106 patients with oral cavity cancer for HPV detection. Available DNA chip (MY-HPV chip kit, Mygene Co., Korea) was used for the detection of low risk HPV types (6, 11, 34, 40, 42, 43, 44) and high risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58). Patients were previously diagnosed as invasive cancer of oral cavity. Specimen used for HPV detection was extracted from the main mass during resection and were tested for HPV type, performed by a DNA chip method. Results: Histologic results showed that there were squamous cell carcinomas, mucoepidermoid carcinomas, cystadenocarcinomas, leiomyosarcoma and etc. Among HPV positive cancer, 2 patients showed positive for high risk HPV type 16, 3 patients showed positive for low risk HPV type 6 and the other 2 patients were positive for other types of HPV. Of the 7 patients with HPV positive, 4 patients were on the tongue, 3 on the lower gingiva. Conclusion: Most of the HPV positive cancers were on the tongue in our study. Cervical cancer of HPV infection is reported to be increasing in our society and because HPV infection largely spreads by sexual contact, the incidence of oral cancer with HPV infection is greatly assumed to be on the increase, simultaneously. Because the incidence of HPV on specific areas of oral cavity among oral cancer patients is not identified, more studies are ongoing.

Induction of epithelial-mesenchymal transition and loss of podoplanin expression are associated with progression of lymph node metastases in human papillomavirus-related oropharyngeal carcinoma

Article

Jul 2014
HISTOPATHOLOGY

Aims: To examine human papillomavirus (HPV) status, the expression of podoplanin and epithelial-mesenchymal transition (EMT) markers and lymphatic vessel counts (LVC) in oropharyngeal squamous cell carcinoma (OPSCC) tissues, and to evaluate whether these factors were associated with survival and nodal status. Methods and results: A total of 53 OPSCC specimens were evaluated for HPV status and expression of proteins such as podoplanin and EMT markers by immunohistochemistry. E-cadherin-negative and vimentin-positive specimens were defined as EMT-positive. Twenty-two OPSCCs were HPV-positive. There was significant progression of nodal status in patients with HPV-positive tumours (P = 0.0475). HPV-positive cases had significantly lower expression of podoplanin (P = 0.0016) and were more frequently EMT-positive (P = 0.0172). Podoplanin-negative cases and EMT-positive cases showed significantly more advanced nodal status than their respective counterparts (P = 0.0082 and P = 0.0186, respectively). LVC correlated with neither HPV nor nodal status. Multivariate analyses revealed that HPV infection was an independent marker of longer disease-specific survival (P = 0.014). Conclusions: HPV-positivity in OPSCC was associated with loss of podoplanin expression and with EMT induction, which resulted in progression of nodal status. The mechanisms leading to an improved prognosis in HPV-positive OPSCC patients requires elucidation, as this is inconsistent with the aggressive phenotype with lymph node metastases.

Humane Papillomavirusinfektionen bei Plattenepithelkarzinomen des Kopf- und Halsbereichs: Eine Untersuchung am Krankengut des Bundeswehrkrankenhauses Ulm

Article

Jul 2013

High-risk human papillomavirus and lymph node size in patients with single node metastasis of oral and oropharyngeal cancer

Article

Apr 2014
ACTA OTO-LARYNGOL

Conclusion: High-risk human papillomavirus (HPV) infection was significantly related to lymph node size in patients with single node metastasis of oral and oropharyngeal cancer. Objective: The purpose of this study was to examine the relationship between high-risk HPV infection and lymph node size in patients with single node metastasis of oral and oropharyngeal carcinoma. Methods: This study included 48 patients with oral and oropharyngeal carcinoma. Pathologic lymph node stages comprised 36 N1 and 12 N2a. Results: High-risk HPV in situ hybridization was positive in 29% of patients (14/48). Of those patients with high-risk HPV, there was a significant difference (p = 0.008) between oral (9.5%) and oropharyngeal (44.4%) cancers. Average lymph node diameter was 20.7 ± 12.6 mm (range 5-54 mm). We found a positive correlation between high-risk HPV status and lymph node size (p = 0.018). Mean lymph node diameter in high-risk HPV-positive cases was 27.3 ± 13.1 mm and 18.0 ± 11.5 mm in high-risk HPV-negative cases. Extracapsular spread (p = 0.030) and cystic nodal metastases (p = 0.019) were also significantly related to lymph node size. High-risk HPV negative status (p = 0.043), advanced tumor stage (p = 0.009), and extracapsular spread (p = 0.038) all had significant adverse effects on 5-year disease-specific survival.

Cervical metastases from squamous cell carcinoma of hard palate and maxillary alveolus: A retrospective study of 10 years

Article

Jul 2014
HEAD NECK-J SCI SPEC

Background: The purpose of this study was to investigate the incidence of cervical metastasis in squamous cell carcinoma (SCC) of hard palate and maxillary alveolus and to define its impact factors. Methods: We conducted a retrospective study of patients surgically treated for SCC of hard palate and maxillary alveolus from 2002 to 2011. In situ hybridization was performed to detect high-risk human papillomavirus (HPV) infection. Results: The incidences of cervical metastasis and occult metastasis were 17.2% (11/64) and 9.8% (5/51), respectively. The pT classification and vascular invasion were correlated with cervical metastasis. Occult metastatic risk was significantly higher among patients with pT4. Presence of positive nodes impaired prognosis significantly. Conclusion: SCC of hard palate and maxillary alveolus has nonnegligible incidences of both overall and occult metastasis, which were highly associated with pT classification. We recommend routine, synchronous elective neck dissection for T4 lesions, whereas observation is an alternative for T1 to T3 lesions.

An Analysis of the Epidemiological and Etiological Factors of Oral Tumors of Young Adults in a Central-Eastern European Population

Article

Full-text available

May 2013
PATHOL ONCOL RES

The etiology of tumors in young age is not precisely known yet, but studies on the topic generally agree that in this group of patients the traditionally known behavioural risk factors (tobacco and alcohol abuse) play no or a significantly less important role. Oral squamous cell carcinoma occurring at a young age is a topic of utmost importance that is extensively and intensively researched as, while the overall incidence of oral cancer is decreasing worldwide, that of squamous cell carcinoma diagnosed in young adults is steadily increasing. The present article aims at presenting the main questions and characteristics of tumors in young adults in Central-Eastern Europe and in developed West European countries as contrasted to tumors found in middle aged and elderly patients. Factors influencing the development of oral cancer include regulatory factors of the cell cycle, the inherited vulnerability of the genetic code of certain proteins and the presence of HPV infection with an oncogenic genotype. The connections of HPV infection and genetic damages are studied intensively. It is known that the prevalence of oral HPV infections is growing with a background of potentially changing sexual habits. It is debated, however, whether smoking and alcohol consumption could have a connection to HPV associated oral cancer and whether the spread of HPV in itself could be an explanation for the growing occurrence of young-age tumors. There is no consensus in the literature as to the prognostic significance of age. Some research groups have found a better life expectancy for young patients, while other authors found a worse prognosis for these patients. It is known that the prognosis of head and neck tumors, the prevalence of HPV infections as well as genetic mutations show regional and ethnic variations. This might be explained by differences in the degree of development of a preventive system, in the quality of care and in the attitudes of young patients towards visiting a doctor. The study is made difficult by incomparable patient selection criteria as well as by the question of the intraoral localisation of tumors as an independent risk factor.

Human Papillomavirus-16 Infection in Advanced Oral Cavity Cancer Patients Is Related to an Increased Risk of Distant Metastases and Poor Survival

Article

Full-text available

Jul 2012
PLOS ONE

Human papillomavirus (HPV) is an oncogenic virus causing oropharyngeal cancers and resulting in a favorable outcome after the treatment. The role of HPV in oral cavity squamous cell carcinoma (OSCC) remains ambiguous. This study aimed to examine the effect of HPV infection on disease control among patients with OSCC following radical surgery with radiation-based adjuvant therapy. We prospectively followed 173 patients with advanced OSCC (96% were stage III/IV) who had undergone radical surgery and adjuvant therapy between 2004 and 2006. They were followed between surgery and death or up to 60 months. Surgical specimens were examined using a PCR-based HPV blot test. The primary endpoints were the risk of relapse and the time to relapse; the secondary endpoints were disease-free survival, disease-specific survival, and overall survival. The prevalence of HPV-positive OSCC was 22%; HPV-16 (9%) and HPV-18 (7%) were the genotypes most commonly encountered. Solitary HPV-16 infection was a poor predictor of 5-year distant metastases (hazard ratio, 3.4; 95% confidence interval, 1.4-8.0; P = 0.005), disease-free survival (P = 0.037), disease-specific survival (P = 0.006), and overall survival (P = 0.010), whereas HPV-18 infection had no impact on 5-year outcomes. The rate of 5-year distant metastases was significantly higher in the HPV-16 or level IV/V metastasis group compared with both the extracapsular spread or tumor depth ≥ 11-mm group and patients without risk factors (P<0.001). HPV infections in advanced OSCC patients are not uncommon and clinically relevant. Compared with HPV-16-negative advanced OSCC patients, those with a single HPV-16 infection are at higher risk of distant metastases and poor survival despite undergoing radiation-based adjuvant therapy and require a more aggressive adjuvant treatment and a more thorough follow-up.

Epidemiology of Human Papillomavirus-Related Head and Neck Cancer

Article

Aug 2012

Human papillomavirus (HPV) is now recognized to cause a subset of head and neck squamous cell carcinomas (HNSCC). Although excessive tobacco and alcohol use continue to be important risk factors for HNSCC, epidemiologic studies suggest that more than 25% of HNSCC are now caused by HPV. The incidence of HPV-related HNSCC is increasing, highlighting the need to understand the oral HPV infections causing these cancers. This article reviews the evidence for a causal association between HPV and HNSCC, examines the changing epidemiologic trends of HNSCC, and discusses what is currently known about oral HPV infection, natural history, and transmission.

Current advances in diagnosis and surgical treatment of lymph node metastasis in head and neck cancer

Article

Full-text available

Mar 2012

Still today, the status of the cervical lymph nodes is the most important prognostic factor for head and neck cancer. So the individual treatment concept of the lymphatic drainage depends on the treatment of the primary tumor as well as on the presence or absence of suspect lymph nodes in the imaging diagnosis. Neck dissection may have either a therapeutic objective or a diagnostic one. The selective neck dissection is currently the method of choice for the treatment of patients with advanced head and neck cancers and clinical N0 neck. For oncologic reasons, this procedure is generally recommended with acceptable functional and aesthetic results, especially under the aspect of the mentioned staging procedure. In this review article, current aspects on pre- and posttherapeutic staging of the cervical lymph nodes are described and the indication and the necessary extent of neck dissection for head and neck cancer is discussed. Additionally the critical question is discussed if the lymph node metastasis bears an intrinsic risk of metastatic development and thus its removal in a most possible early stage plays an important role.

Article

Full-text available

Apr 1996

Matrix metalloproteinases (MMPs) have been implicated in invasion and metastasis of tumor cells. Transcription regulatory regions of MMP genes often contain binding sites for ets transcription factors. We recently isolated a cDNA encoding human E1A-F, a member of the ets oncogene family, and showed that E1A-F can upregulate MMP genes by CAT assay. We attempted to investigate the relationship between E1A-F mRNA expression and MMP protein expression in four different types of oral squamous-cell-carcinoma-derived cell lines (HSC 3, SAS, KB, and Ca 9.22). HSC 3 and SAS are highly invasive cell lines when they are injected in the tongue of nude mice. Raft culture of HSC 3 and SAS revealed the same characteristics as seen in tumors implanted in vivo. Both type I collagenase (MMP-1) and 92-kd type IV collagenase (MMP-9) were detected in cultured HSC 3 and SAS cells. E1A-F mRNA was demonstrated to be highly expressed in HSC 3 and SAS by Northern blotting, and in situ hybridization confirmed E1A-F mRNA expression at the invasion front of tumor cells seeded on collagen gel. On the other hand, KB and Ca 9.22 have little potential for invasion, and MMP-1 and MMP-9 protein and E1A-F mRNA could not be detected. These results suggest that the ets-related E1A-F participates in the regulation of invasion-associated MMP genes and is involved in presenting invasive activity in tumor cells of oral squamous cell carcinoma.

Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers

Article

Full-text available

Feb 2004

There are few well-established patient risk factors associated with human papillomavirus (HPV) infection in cancers of the oral cavity and oropharynx. The purpose of this study was to determine if there were significant different risk factors and tumor characteristics between HPV-positive and HPV-negative cancer cases. HPV was evaluated in cancer tissue and exfoliated oral cells of 193 oral cavity/oropharynx cancer patients using PCR and direct DNA sequencing. A patient questionnaire collected information about risk factors, sexual practices and medical history. The prevalence of HPV high-risk (HR) types was 20% in cancer cases. Three types were identified: HPV-16 (87%), HPV-18 (3%) and HPV-33 (11%). Risk factors for HPV-HR included younger age (< or = 55 years vs. > 55 years; adjusted OR = 3.4; 95% CI = 1.6-7.3) and younger-age cases who had more lifetime sex partners (adjusted OR = 3.8; 95% CI = 1.4-10.1), practiced oral-genital sex (adjusted OR = 4.3; 95% CI = 1.8-10.4) or oral-anal sex (adjusted OR = 19.5; 95% CI = 3.4-113). Compared to HPV-negative cancers, HPV-HR cancers were more likely to have a positive HPV-HR exfoliated oral cytology test (adjusted OR = 7.8; 95% CI = 3.4-18.4), later stage (adjusted OR = 3.0), nodal involvement (adjusted OR = 4.1) and advanced grade (adjusted OR = 3.0). This study shows new evidence that the prevalence of oncogenic mucosal HPV is higher in younger-age oral cavity/oropharynx cancer cases whose sexual practices are typically associated with sexual transmission of the virus. HPV detection also appears to be an indicator of advanced disease characteristics that may require different clinical treatment for this subset of patients. An exfoliated oral cytology test for HPV was a significant predictor of HR types in the cancers, suggesting that an oral rinse may provide an early biomarker of infected tumors.

Kreimer AR, Clifford GM, Boyle P, Franceschi SHuman papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14(2): 467-475

Article

Full-text available

Mar 2005

Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear. We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site. Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx.

Molecular Classification Identifies a Subset of Human Papillomavirus-Associated Oropharyngeal Cancers With Favorable Prognosis

Article

Full-text available

Mar 2006
J CLIN ONCOL

We sought to determine the prevalence of biologically relevant human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC). Retinoblastoma (Rb) downregulation by HPV E7 results in p16 upregulation. We hypothesized that p16 overexpression in OSCC defines HPV-induced tumors with favorable prognosis. Using real-time polymerase chain reaction for HPV16, we determined HPV16 viral load in a cohort of 79 OSCCs annotated with long-term patient follow-up. A tissue microarray including these cases was also analyzed for p53, p16, and Rb utilizing in situ quantitative protein expression analysis. Seventy-seven tumors were classified into a three-class model on the basis of p16 expression and HPV-DNA presence: class I, HPV-, p16 low; class II, HPV+, p16 low; and class III, HPV+, p16 high. Sixty-one percent of OSCCs were HPV16+; HPV status alone was of no prognostic value for local recurrence and was barely significant for survival times. Overall survival was improved in class III (79%) compared with the other two classes (20% and 18%; P = .0095). Disease-free survival for the same class was 75% versus 15% and 13% (P = .0025). The 5-year local recurrence was 14% in class III versus 45% and 74% (P = .03). Only patients in class III had significantly lower p53 and Rb expression (P = .017 and .001, respectively). Multivariable survival analysis confirmed the prognostic value of the three-class model. Using this system for classification, we define the molecular profile of HPV+ OSCC with favorable prognosis, namely HPV+/p16 high (class III). This study defines a novel classification scheme that may have value for patient stratification for clinical trials testing HPV-targeted therapies.

Estimates of the worldwide mortality from 25 cancers in 1990

Article

Sep 1999

We present here worldwide estimates of annual mortality from all cancers and for 25 specific cancer sites around 1990, Crude and age-standardised mortality rates and numbers of deaths were computed for 23 geographical areas. Of the estimated 5.2 million deaths from cancer (excluding nonmelanoma skin cancer), 55% (2.8 million) occurred in developing countries. The sex ratio is 1.33 (M:F), greater than that of incidence (1.13) due to the more favourable prognosis of cancer in women. Lung cancer is still the most common cause of death from cancer worldwide with over 900,000 deaths per year, followed by gastric cancer with over 600,000 deaths and colorectal and liver cancers accounting for at least 400,000 deaths each. In men, deaths from liver cancer exceed those due to cole-rectal cancer by 38%. Over 300,000 deaths of women are attributed to breast cancer, which remains the leading cause of death from cancer in women, followed by cancers of the stomach and lung with 230,000 annual deaths each. In men, the risk of dying from cancer is highest in eastern Europe, with an age-standardised rate for all sites of 205 deaths per 100,000 population. Mortality rates in all other developed regions are around 180. The only developing area with an overall rate of the same magnitude as that in developed countries is southern Africa. All of eastern Asia, including China, has mortality rates above the world average, as do all developed countries. The region of highest risk among women is northern Europe (age-standardised rate = 125.4), followed by North America, southern Africa and tropical South America. Only south central and western Asia (Indian subcontinent, central Asia and the middle-eastern countries) and Northern Africa are well below the world average of 90 deaths per 100,000 population annually. Our results indicate the potential impact of preventive practices. It is estimated that 20% of all cancer deaths (I million) could be prevented by eliminating tobacco smoking. Infectious agents account for a further 16% of deaths. (C) 1999 Wiley-Liss, Inc.

Erratum: Estimates of the worldwide mortality from 25 cancers in 1990 (International Journal of Cancer (1999) 83 (18-29))

Article

Dec 1999

Pisani, P., Parkin, D.M., Bray, F. and Ferlay, J. Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer,83, 18–29 (1999). Due to a printer's error, incorrect table headings were entered in Tables II–IV after the proofs of the article had been approved by the author. The correct tables are reprinted on the following pages. The publisher regrets this error.

Estimates of the worldwide mortality from 25 cancers in 1990

Article

Dec 1999

Head and Neck Surgery and Oncology, 3rd Ed

Article

Apr 2004
PLAST RECONSTR SURG

David L. Larson

O86 Cystic lymph node metastasis in patients with head and neck cancer: an HPV-related phenomenon

Article

May 2007
Oral Oncol Suppl

Cystic lymph node metastasis in patients with head and neck cancer: An HPV‐associated phenomenon

Article

Jul 2008
HEAD NECK-J SCI SPEC

Cystic lymph node metastases have been associated with tonsil cancer. A subset of oropharyngeal cancers contain human papillomavirus (HPV) DNA. The clinical and virologic associations of cystic nodal metastasis in head and neck cancer (HNSCC) were investigated. A retrospective review of patients undergoing neck dissection between 2002 and 2004 identified patients with cystic lymph node metastases. Clinical and pathologic information was recorded. The presence of HPV DNA was analyzed using in situ hybridization in a subset of patients. One hundred neck dissections were reviewed and 20 had cystic nodes. Seventeen of these patients had primary tumors arising in the palatine or lingual tonsil. Three were “unknown primary.” HPV DNA was present in 11 of 13 patients with cystic metastases with tissue available for analysis (87%). No HPV DNA was identified in tumor from 21 patients with solid nodal metastasis (p <.0001). Cystic cervical lymph node metastasis is strongly associated with HPV-related tonsillar HNSCC. © 2008 Wiley Periodicals, Inc. Head Neck 2008

The expression of key cell cycle markers and presence of human papillomavirus in squamous cell carcinoma of the tonsil

Article

Jan 2004
HEAD NECK-J SCI SPEC

Chemical carcinogens induce squamous cell carcinoma (SCC) of the head and neck by targeting the p53 and the retinoblastoma (pRb) pathways. Human papillomavirus (HPV) might have an etiologic role in these cancers at particular sites. Few studies have compared cell cycle protein expression in HPV-positive and HPV-negative tumors in this region. Fifty tonsil SCCs were analyzed for HPV by PCR and for expression of cell cycle proteins (p53, pRb, p16INK4A, p21CIP1/WAF1, p27KIP1, and cyclinD1) by immunohistochemistry. HPV was present in 42%; almost all were type 16. There were statistical associations between HPV positivity and reduced expression of pRb and cyclinD1, overexpression of p16, and younger patient age. Tumor with down-regulated p27 tended to have down-regulated pRb and p21. HPV-positive tonsil SCCs have distinct molecular pathways. Their association with younger patient age suggests that they are biologically distinct from HPV-negative tumors. © 2004 Wiley Periodicals, Inc. Head and Neck 26: 1–9, 2004

Human papillomavirus positive squamous cell carcinoma of the oropharynx

Article

Aug 2001
CANCER-AM CANCER SOC

BACKGROUND Epidemiologic evidence points to a connection between viral infection by the human papillomavirus (HPV) and a subgroup of squamous cell carcinoma of the oropharynx. To assess the impact of HPV infection on the response of these tumors toward radiotherapy, the authors retrospectively determined the presence of the virus and the integrity of the viral E2 gene in tumors of patients who have undergone curative irradiation.METHODS Paraffin embedded biopsies from 99 patients were analyzed for HPV infection and E2 gene integrity by multiplex PCR. The experimental findings were correlated with clinical characteristics, known risk factors, and treatment outcome.RESULTSFourteen of 99 tumors were HPV positive (11 HPV16, 1 HPV33, 1 HPV35, and 1 HPV45). Human papillomavirus positivity was closely linked to female gender (odds ratio [OR], 5.75; P = 0.004), age older than 56 years (OR, 7.42; P = 0.012), nonsmokers (OR, 21.33; P = 0.00001), and alcohol abstainers (OR, 5.35; P = 0.012). There was an inverse association with p53 nuclear immunoreactivity (OR, 0.06; P = 0.008). The Kaplan–Meier survival estimates showed a better local control (P = 0.050, log-rank) and a better overall survival (P = 0.046, log-rank) for patients with HPV positive tumors. In the multivariate analysis, HPV positivity remained to be associated with a lower risk of local failure (risk ratio [RR], 0.31; P = 0.048). Four of 11 HPV16 positive tumors had a disrupted E2 gene. Only tumors with a disrupted E2 gene manifested local treatment failure.CONCLUSIONS Human papillomavirus positivity designates a specific subgroup of oropharyngeal squamous cell carcinomas of the oropharynx that arise preferentially among individuals with no consumption of tobacco and alcohol and that have a favorable outcome attributable to an increased sensitivity toward radiotherapy. Cancer 2001;92:805–13. © 2001 American Cancer Society.

Burden of Potentially Human Papillomavirus-associated Cancers of the Oropharynx and Oral Cavity in the US, 1998-2003

Article

Nov 2008

As human papillomavirus (HPV) vaccination becomes widely available in the US for cervical cancer prevention, it may also affect the rates of other cancers potentially associated with HPV. The objective of the current study was to describe the incidence rates of oropharyngeal and oral cavity cancers in the US with a focus on anatomic sites potentially associated with HPV infection. Incident cases diagnosed between 1998 and 2003 identified through 39 population-based registries that participate in the National Program of Cancer Registries and/or the Surveillance, Epidemiology, and End Results Program were examined. The incidence rates of potentially HPV-associated oropharyngeal and oral cavity cancers by various characteristics were estimated. The 1998 through 2003 trends in these rates were also compared with rates for sites not previously shown to be associated with HPV (comparison sites). In all, 44,160 cases of potentially HPV-associated cancers of the oropharynx and oral cavity were identified, including 19,239 (43.6%) tonsillar, 16,964 (38.4%) base of tongue, and 7957 (18.0%) other oropharyngeal cancers. The incidence rates for these sites were highest among blacks, and higher among non-Hispanics and men than among Hispanics and women. The annual incidence rates of potentially HPV-associated cancers of the tonsil and base of tongue both increased significantly from 1998 through 2003 (annual percentage change [APC], 3.0; P < .05 for both sites), whereas the incidence rates of cancer at the comparison sites generally decreased. The results of the current study provide baseline incidence rates of potentially HPV-associated cancers of the oropharynx and oral cavity that can be compared with rates after the widespread implementation of the HPV vaccination.

HPV status and regional metastasis in the prognosis of oral and oropharyngeal cancer

Article

Jul 2008

Prognostic factors are important for treatment decisions as they help adapt the therapy on a case-to-case basis. Nodal status, number of positive nodes, and presence of extracapsular spread are considered to be the important prognostic factors in head and neck cancer. Some studies suggest that human papillomavirus (HPV) status also influences the outcome of the treatment. This influence can be explained by the variation in tendency to develop regional metastases and by variation in the type of neck node involvement. The study objectives were to compare patients with HPV positive and HPV-negative tumors for survival and prevalence and type of regional metastasis, to identify prognostic factors and to test whether HPV presence is an independent factor of survival. The study included 81 patients treated by surgery including neck dissection for oral or oropharyngeal squamous cell cancer. A computerized medical report was completed for each patient. Analysis of the tumor specimen for the HPV DNA presence was done on paraffin-fixed tissue. HPV DNA detection and typing were performed by PCR with GP5+/GP6+BIO primers and reverse line blot hybridization. Overall, 64% (52/81) of tumors were HPV positive with 80% in the tonsillar site. HPV-positive patients had significantly better both overall (73 vs. 35%) (P=0.0112) and disease-specific (79 vs. 45%) (P=0.0015) survival rates than HPV-negative patients. No significant differences were found in the pN classification, in the number of positive nodes and the presence of extracapsular spread in the involved nodes between HPV positive and HPV-negative tumors. Multivariate analysis showed that significant prognostic factors of survival were the presence of HPV in the tumor, extracapsular spread and tumor size. HPV was the most significant prognostic factor in the studied group of patients with oropharyngeal tumors (HR=0.27, 95%CI 0.12-0.61) and possibly should be considered in treatment decisions.

Relationship between vascular endothelial growth factor and Notch1 expression and lymphatic metastasis in tongue cancer

Article

May 2009

To determine the role of angiogenesis in lymph node metastasis and the depth of invasion in early tongue cancer. Retrospective analysis. The study included 51 subjects with tongue cancer. Immunohistochemical staining for vascular endothelial growth factor, Notch1, and Notch3 was performed. Microvessel density was evaluated by counting the number of CD34-stained microvessels in each pathologic specimen. Significant correlations were found between vascular endothelial growth factor and Notch1 expression and cervical lymph node metastasis (P = 0.020 and P < 0.009, respectively), tumor depth of invasion (P = 0.001 and P < 0.001, respectively), and microvessel density indicated by CD34 staining (P = 0.001 and P < 0.001, respectively). Nodal metastasis (P = 0.022), T stage (P = 0.002), and positive VEGF expression (P = 0.044) were statistically significant prognostic factors for disease-specific survival. Vascular endothelial growth factor and Notch1 expression are significantly related to cervical lymph node metastasis and depth of invasion in tongue cancer patients.

HPV infections and their associations with oral disease

Article

Sep 1991

More than 65 distinct types of human papillomavirus (HPV) have been identified to date. Several of the HPV types have been proposed as etiologic agents of squamous cell carcinoma. In the oral cavity, HPVs have been found associated with several benign squamous cell proliferations. Evidence from histology and DNA hybridization studies suggests that HPV is also involved in oral carcinogenesis. It is apparent, however, that substantial amount of confusion exists in the diagnosis of oral HPV infections. The keratotic, papillary lesions in the oral cavity are usually small and easily overlooked. The gross appearance of these viral lesions is not distinct enough to be readily diagnosed by the clinicians. Degenerative changes found on oral mucosa frequently simulate koilocytosis. Thus, caution should be exercised to avoid overdiagnosis of HPV infection in the oral cavity. The present review summarizes the current evidence available on HPV infections in general and on oral HPV infections in particular. The diagnostic techniques available as well as the problems encountered in the distinction of these lesions are also discussed in short.

Predictive Value of Tumor Thickness in Squamous Carcinoma Confined to the Tongue and Floor of Mouth

Article

Nov 1986
AM J SURG

In this review of 105 consecutive patients who underwent operation for previously untreated, N0 squamous carcinomas arising in the oral tongue or the floor of the mouth, 86 percent of the determinate patients remained alive and well 2 years after treatment. Included were 48 patients, 49 patients, and 8 patients who had T1, T2, and T3 tumors respectively. Elective cervical lymphadenectomy was performed in about a third, but tumor staging did not facilitate selection of those who were most likely to have occult metastases. For this reason, we retrospectively assessed the impact of tumor thickness using an optical micrometer to measure the thickness in millimeters of the excised tumors in routinely prepared paraffin sections. Disease-related death appears to be unusual when oral tumors are thin (2 mm or less), regardless of the tumor stage. Multivariate analysis confirms that increasing tumor thickness, rather than tumor stage, had the best correlation with treatment failure and survival. These findings need to be verified in prospective studies involving a larger patient population and other head and neck sites, but they strongly suggest that measurement of tumor thickness may be a better way to select those oral cancer patients who are most likely to benefit from elective treatment of the N0 neck.

Head and neck surgery for the surgical oncologist

Article

Oct 1995

Jatin P. Shah

Without Abstract

Tumor angiogenesis as a predictor of tumor aggressiveness and metastatic potential in squamous cell carcinoma of the head and neck

Article

Feb 1995

Squamous cell carcinoma of the head and neck induces neovascularization to support tumor growth and facilitate the metastatic spread. Others have suggested that the density of microvessels within the tumor correlates with the neovascularization process and therefore with clinical behavior and outcome. To ascertain the value of the microvessel count as an independent prognostic indicator for squamous cel carcinoma of the head and neck, we studied the primary tumors of 44 patients. Histological slides were stained for factor VIII and the individual microvessels were counted on a 200 x field (0.49 mm). No statistically significant difference was found between the microvessel counts of tumors that metastasize or recur locally, as compared with tumors that did not. The possibility of a beta-error due to the small number of cases mandates a larger possibly multi-institutional, study to better ascertain the significance of a microvessel count as an independent prognostic indicator.

Pisani P, Parkin DM, Bray F, Ferlay J (1999a) Erratum: estimates of the worldwide mortality from 25 cancers in 1990. Int J Cancer, 83, 18-29. Int J Cancer 83: 870-873

Article

Oct 1999

We present here worldwide estimates of annual mortality from all cancers and for 25 specific cancer sites around 1990. Crude and age-standardised mortality rates and numbers of deaths were computed for 23 geographical areas. Of the estimated 5.2 million deaths from cancer (excluding non-melanoma skin cancer), 55% (2.8 million) occurred in developing countries. The sex ratio is 1.33 (M:F), greater than that of incidence (1.13) due to the more favourable prognosis of cancer in women. Lung cancer is still the most common cause of death from cancer worldwide with over 900,000 deaths per year, followed by gastric cancer with over 600,000 deaths and colorectal and liver cancers accounting for at least 400,000 deaths each. In men, deaths from liver cancer exceed those due to colo-rectal cancer by 38%. Over 300,000 deaths of women are attributed to breast cancer, which remains the leading cause of death from cancer in women, followed by cancers of the stomach and lung with 230,000 annual deaths each. In men, the risk of dying from cancer is highest in eastern Europe, with an age-standardised rate for all sites of 205 deaths per 100,000 population. Mortality rates in all other developed regions are around 180. The only developing area with an overall rate of the same magnitude as that in developed countries is southern Africa. All of eastern Asia, including China, has mortality rates above the world average, as do all developed countries. The region of highest risk among women is northern Europe (age-standardised rate = 125.4), followed by North America, southern Africa and tropical South America. Only south-central and western Asia (Indian subcontinent, central Asia and the middle-eastern countries) and Northern Africa are well below the world average of 90 deaths per 100,000 population annually. Our results indicate the potential impact of preventive practices. It is estimated that 20% of all cancer deaths (1 million) could be prevented by eliminating tobacco smoking. Infectious agents account for a further 16% of deaths.

Erratum: Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer, 83, 18–29 (1999)

Article

Jan 2000
INT J CANCER

Pisani, P., Parkin, D.M., Bray, F. and Ferlay, J. Estimates of the worldwide mortality from 25 cancers in 1990. Int. J. Cancer, 83, 18-29 (1999). Due to a printer's error, incorrect table headings were entered in Tables II-IV after the proofs of the article had been approved by the author. The correct tables are reprinted on the following pages. The publisher regrets this error.

Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck-Wikland EHuman papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 89: 300-304

Article

Jun 2000

Human papillomavirus (HPV) is more commonly found in tonsillar cancer than in other head and neck cancers. The importance of HPV status in tonsillar cancer for prognosis remains unclear. The aim of the present study was to investigate the frequency of HPV in tonsillar cancer and to correlate the presence of HPV with tumor stage, nodal status, grade of differentiation, risk of relapse, and survival. HPV DNA and HPV type were determined, using PCR, in pre-treatment biopsies from 60 cases of primary tonsillar cancer. All patients had undergone full-dose radiotherapy, 45% as the only treatment modality, and 55% in combination with surgery. HPV 16 was detected in 43% (26/60) of the cancers including 1 double infection of both HPV 16 and HPV 33. Patients with HPV(+) tonsillar cancer showed less risk of relapse within 3 years after diagnosis, with a better odds ratio of 4.18 as compared with HPV(-) patients (p = 0. 025). Furthermore, cause specific survival was significantly (p = 0. 047) better in patients with HPV(+) tonsillar carcinomas. At 3 years after diagnosis the survival rate was 65.3% in the HPV(+) group and 31.5% in the HPV(-) group, and at 5 years the survival rate was 53. 5% and 31.5%, respectively. The better outcome for patients with HPV(+) tonsillar cancer was independent of TNM stage, nodal status, gender and age. These results indicate that HPV status is a significantly favorable prognostic factor in tonsillar cancer and may be used as a marker in order to optimize the treatment of patients with this type of cancer.

Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma

Article

Sep 2001

Epidemiologic evidence points to a connection between viral infection by the human papillomavirus (HPV) and a subgroup of squamous cell carcinoma of the oropharynx. To assess the impact of HPV infection on the response of these tumors toward radiotherapy, the authors retrospectively determined the presence of the virus and the integrity of the viral E2 gene in tumors of patients who have undergone curative irradiation. Paraffin embedded biopsies from 99 patients were analyzed for HPV infection and E2 gene integrity by multiplex PCR. The experimental findings were correlated with clinical characteristics, known risk factors, and treatment outcome. Fourteen of 99 tumors were HPV positive (11 HPV16, 1 HPV33, 1 HPV35, and 1 HPV45). Human papillomavirus positivity was closely linked to female gender (odds ratio [OR], 5.75; P = 0.004), age older than 56 years (OR, 7.42; P = 0.012), nonsmokers (OR, 21.33; P = 0.00001), and alcohol abstainers (OR, 5.35; P = 0.012). There was an inverse association with p53 nuclear immunoreactivity (OR, 0.06; P = 0.008). The Kaplan-Meier survival estimates showed a better local control (P = 0.050, log-rank) and a better overall survival (P = 0.046, log-rank) for patients with HPV positive tumors. In the multivariate analysis, HPV positivity remained to be associated with a lower risk of local failure (risk ratio [RR], 0.31; P = 0.048). Four of 11 HPV16 positive tumors had a disrupted E2 gene. Only tumors with a disrupted E2 gene manifested local treatment failure. Human papillomavirus positivity designates a specific subgroup of oropharyngeal squamous cell carcinomas of the oropharynx that arise preferentially among individuals with no consumption of tobacco and alcohol and that have a favorable outcome attributable to an increased sensitivity toward radiotherapy.

Early Stage Cervical Cancers Containing Human Papillomavirus Type 18 DNA Have More Nodal Metastasis and Deeper Stromal Invasion

Article

Oct 2003

To investigate the clinical and pathological factors which might explain the poor prognosis associated with early stage cervical cancers containing human papillomavirus (HPV) type 18 DNA. A clinical and pathological review of 144 patients with stage IB cervical cancer treated with radical hysterectomy and bilateral pelvic lymph node dissection was done. HPV genotyping was determined from fresh tumor specimens through PCR. Clinical-pathological information, sites of recurrence, use of adjuvant radiation, and survival data were analyzed. Thirty-three (23%) tumors contained HPV 18 DNA. These tumors did not differ from those which contained non-HPV 18 DNA with respect to tumor grade or size. However, HPV 18-containing cancers were more likely to be adenocarcinomas. A higher incidence of pelvic lymph node metastasis was noted among the HPV 18 group (48%) as compared with the non-HPV 18 group (28%), and deeper stromal invasion was more common in HPV 18-associated tumors. Although a slightly higher proportion of patients with HPV 18-containing tumors received adjuvant radiation (67%) than those with non-HPV 18 cancers (49%), recurrences were more common among HPV 18 patients. Eleven (33%) of HPV 18-containing cancers relapsed compared with 18 (16%) of non-HPV18-containing tumors. The explanation for the worse prognosis associated with stage IB cervical cancers containing HPV 18 DNA treated with radical hysterectomy and bilateral pelvic lymph node dissection appears to be related to deeper cervical stromal invasion and more nodal metastases. Despite an increased use of adjuvant radiation therapy, these cancers are still more likely to relapse.

Human papillomaviruses in head and neck cancer: 8 year-survival-analysis of 73 patients

Article

Mar 2005

Depending on the primary tumour's anatomical location, squamous cell carcinoma of the head and neck (HNSCC) shows HPV prevalences between 20 and 30% for oro-, hypopharyngeal as well as laryngeal SCC and up to over 50% for SCC of the Waldeyer's tonsillar ring. There is persistent controversy on the role of HPV infection in HNSCC-progression, and on the influence of these infections on the final clinical outcome. To evaluate the possible relevance of HPV infection on survival and prognosis, 73 patients with HNSCC were investigated statistically with a median follow-up time of 28 (0.3-94) months. The statistical analysis revealed no differences in the overall survival of HPV-positive and HPV-negative cancer patients. A correlation between decreased survival and increased lymph node status was expected. Patients with carcinomas of the Waldeyer's tonsillar ring with a high HPV prevalence rate as compared to tumours of other anatomical locations revealed a better survival. Moreover, an association between HPV positivity and higher lymph node status at time of first diagnosis, and a better survival of HPV-positive patients compared to HPV-negative patients given the same initial nodal status (N0 vs. N1-N2b vs. N2c-N3) could be demonstrated. The influence of HPV on the patient's survival can only be observed statistically in combination with other prognostic factors, as the lymph nodal status of the patients. The better prognosis of survival of HPV-positive vs. the HPV-negative patients with lymph node neck metastasis is attributable to a better response of the HPV-positive group to therapy, especially radiotherapy.

Presence and Influence of Human Papillomaviruses (HPV) in Tonsillar Cancer

Article

Feb 2005
ADV CANCER RES

Tonsillar cancer is the most common of the oropharyngeal carcinomas and human papillomavirus (HPV) has been found to be present in approximately half of all cases. Patients with HPV-positive tonsillar cancer have been observed to have a better clinical outcome than patients with HPV-negative tonsillar cancer. Moreover, patients with tonsillar cancer and a high viral load have been shown to have a better clinical outcome, including increased survival, compared to patients with a lower HPV load in their tumors. Recent findings show that HPV-positive tumors are not more radiosensitive and do not have fewer chromosomal aberrations than HPV-negative tumors, although some chromosomal differences may exist between HPV-positive and -negative tonsillar tumors. Current experimental and clinical data indicate that an active antiviral cellular immune response may contribute to this better clinical outcome. These data are also in line with the findings that the frequency of tonsillar cancer is increased in patients with an impaired cellular immune system. Thus, therapeutic and preventive HPV-16 antiviral immune vaccination trials may be worthwhile, not only in cervical cancer, but also in tonsillar cancer.

Correlations of oral tongue cancer invasion with matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF) expression

Article

Mar 2006

In oral tongue cancer, the degree of tumor invasion has a significant effect on the prognosis. We hypothesized that the destruction of extracellular matrix and neovascularization are related to tumor infiltration mechanism. By studying the tissues of early stage oral tongue cancer patients, we are intending to clarify the invasion-related factors. To demonstrate the invasion process in early T-stage oral tongue cancer, the expressions of extracellular matrix destruction-related molecules (MMP-2, MMP-9) and neovascularization-related molecule (VEGF) were observed by immunohistochemical study. Also, staining of CD31 was done for quantification of neovascularization. We analyzed relationship between expression of each substances and tumor invasion depth, tumor free survival rates, and cervical lymph node metastasis rate. The expression rates of MMP-2, MMP-9, VEGF in 38 early oral cancer patients were 52.6%, 78.9%, and 52.6%, respectively. Significant correlation was found between the VEGF expression and microvessel density showed by CD31 immunohistochemical staining (P < 0.001). VEGF expressions were significantly related with tumor invasion depth (P = 0.002). The tumor-free survival rate of those patients with VEGF-positive tumors was significantly poorer than in those with VEGF-negative tumors (P = 0.019). These results indicate that VEGF is a useful marker for predicting the tumor invasion in patients with early tongue cancer.

Cystic lymph node metastasis in patients with head and neck cancer: An HPV-associated phenomenon

Article

Aug 2008
HEAD NECK-J SCI SPEC

: Cystic lymph node metastases have been associated with tonsil cancer. A subset of oropharyngeal cancers contain human papillomavirus (HPV) DNA. The clinical and virologic associations of cystic nodal metastasis in head and neck cancer (HNSCC) were investigated. : A retrospective review of patients undergoing neck dissection between 2002 and 2004 identified patients with cystic lymph node metastases. Clinical and pathologic information was recorded. The presence of HPV DNA was analyzed using in situ hybridization in a subset of patients. : One hundred neck dissections were reviewed and 20 had cystic nodes. Seventeen of these patients had primary tumors arising in the palatine or lingual tonsil. Three were "unknown primary." HPV DNA was present in 11 of 13 patients with cystic metastases with tissue available for analysis (87%). No HPV DNA was identified in tumor from 21 patients with solid nodal metastasis (p <.0001). : Cystic cervical lymph node metastasis is strongly associated with HPV-related tonsillar HNSCC: (c) 2008 Wiley Periodicals, Inc. Head Neck 2008.

Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers

Jan 2004
766-772

Ritchie Em Jm Smith
Summersgill
Kf

Smith EM, Ritchie JM, Summersgill KF, et al. Age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004;108:766–772.

Molecular classification identifies a subset of human papillomavirus–associated oropha-ryngeal cancers with favorable prognosis

Jan 2006
736-747

Weinberger
Yu Z Pm
Haffty
Bg

Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus–associated oropha-ryngeal cancers with favorable prognosis. J Clin Oncol 2006; 24:736–747.

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Abstract

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