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Introduction: Extirpation of multiple head and neck paragangliomas carries challenge due to close anatomic relationships with critical neurovascular bundles. Objectives: This study aims to assess whether the application of 3-D models can assist with surgical planning and treatment of these paragangliomas, decrease surgically related morbidity and mortality. Methods: Fourteen patients undergoing surgical resection of multiple head and neck paragangliomas were enrolled in this study. A preoperative 3-D model was created based on radiologic data, and relevant critical anatomic relationships were preoperatively assessed and intraoperatively validated. Results: All 14 patients presented with multiple head and neck paragangliomas, including bilateral carotid body tumors (CBT, n = 9), concurrent CBT with glomus jugulare tumors (GJT, n = 4), and multiple vagal paragangliomas (n = 1). Ten patients underwent genomic analysis and all harbored succinate dehydrogenase complex subunit D (SDHD) mutations. Under guidance of the 3-D model, the internal carotid artery (ICA) was circumferentially encased by tumor on 5 of the operated sides, in 4 (80%) of which the tumor was successfully dissected out from the ICA, whereas ICA reconstruction was required on one side (20%). Following removal of CBT, anterior rerouting of the facial nerve was avoided in 3 (75%) of 4 patients during the extirpation of GJT with assistance of a 3-D model. Two patients developed permanent postoperative vocal cord paralysis. There was no vessel rupture or mortality in this study cohort. Conclusion: The 3-D model is beneficial for establishment of a preoperative strategy, as well as planning and guiding the intraoperative procedure for resection of multiple head and neck paragangliomas. [ABSTRACT FROM AUTHOR]

Introduction: Resection of carotid body tumor (CBT) in patients of advanced ages has not been appreciated. Objectives: This study aims to assess the clinical characteristics and perioperative comorbidities for CBT resection in patients of advanced age and to validate the application of an "isolated island" technique for extirpation of CBT. Methods: Eight patients of advanced age (≥60 years) who underwent CBT resection were enrolled as the study group (SG). Another 29 patients of younger age (<45 years old) underwent CBT extirpation were assigned as the control group (CG). The perioperative issues were compared between these 2 groups. Results: The "isolated island" technique was successfully applied for resection of CBT in all 37 patients. The prevalence of Shamblin classification I, II, and III tumors in the SG was 12.5%, 62.5%, and 25%; whereas in the CG was 10.3%, 55.2%, and 34.5%, respectively. Bilateral CBT was observed in 7 patients of the CG and none in the SG. Vascular reconstruction was required for 1 (12.5%) patient in the SG, while it was required for 8 (27.6%) patients in the CG. Postoperative vocal cord palsy occurred in 37.5% of patients in SG, whereas the vocal cord palsy (34.5%) and dysphagia (6.9%) were commonly encountered in CG. In addition to postoperative length of stay (P =.004), no significant difference for operative time, intraoperative blood loss, or mortality were observed between these 2 groups (P >.05). Conclusion: Extirpation of CBT in patients of advanced age is rationale in appropriately selected patients. The "isolated island" technique is safe for CBT resection with seemingly low complication rates. [ABSTRACT FROM AUTHOR]

Keywords: air pollution; chronic disease; particulate matter EN air pollution chronic disease particulate matter 1200 1203 4 09/01/22 20220901 NES 220901 Sinonasal inverted papilloma (IP) is a benign tumor with a propensity for malignant transformation in 5% to 7% of cases.1 Although its pathogenesis remains uncertain, recent epidemiologic studies have implicated environmental and occupational exposures, such as organic solvents and welding fumes as potential contributors to IP.2-4 A meta-analysis has showed that occupational exposure would increase the risk of developing sinonasal cancer.5 Sham et al performed a case-control study on patients with IP and reported a higher incidence with outdoor occupations, such as construction.4 They concluded this higher incidence is likely due to outdoor air pollution, but this effect has not been directly studied. Air pollution, chronic disease, particulate matter Further research into the effects of air pollution, including particulate matter, ozone, and NO SB 2 sb , is warranted, especially in locations with a wider range of air pollution. [Extracted from the article]

BACKGROUND: Human papillomavirus (HPV) is responsible for a growing proportion of oropharyngeal squamous cell carcinomas (OPSCCs) among men and White individuals. Whether similar trends apply to women, non‐Whites, and non‐oropharyngeal squamous cell carcinomas (non‐OPSCCs) is unknown. METHODS: This is a cross‐sectional analysis combining 2 multi‐institutional case series of incident head and neck squamous cell carcinoma (HNSCC) cases. Incident HNSCCs from 1995 to 2012 were enrolled retrospectively using banked tumor samples and medical record abstraction. Incident HNSCCs from 2013 to 2019 were enrolled prospectively. The prevalence of tumor HPV biomarkers was tested over 3 time periods (1995‐2003, 2004‐2012, and 2013‐2019). Centralized testing was done for p16 immunohistochemistry (p16) and oncogenic HPV in situ hybridization (ISH). RESULTS: A total of 1209 incident cases of HNSCC were included. Prevalence of p16‐ and ISH‐positive tumors increased significantly for oropharynx cancers over time. The majority were positive after 2013 for White patients (p16, 92%; P <.001; ISH 94%; P <.001), Black patients (p16, 72%; P =.021; ISH 67%; P =.011), and Hispanic patients (p16, 100%; P =.04; ISH 100%; P =.013). For women with OPSCC, the prevalence of p16‐ and ISH‐positive tumors increased significantly to 82% (P <.001) and 78% (P =.004), respectively. For non‐OPSCCs, there was increased p16 and ISH positivity overall with 24% p16 and 16% ISH positivity in the most recent time period (P <.001 for both). CONCLUSIONS: The majority of OPSCCs in US tertiary care centers are now p16 and ISH positive for all sex and race groups. In some populations in the United States, 91% of OPSCCs are now caused by HPV. Few non‐OPSCCs are p16 and ISH positive. This study evaluates the prevalence of p16 and in situ hybridization positivity in head and neck cancers over time. This study shows an increase in prevalence over time among women and non‐Whites, 2 groups that are understudied in the epidemiology of human papillomavirus. [ABSTRACT FROM AUTHOR]

Background: Recursive partitioning analysis (RPA) from the Radiation Therapy Oncology Group (RTOG)‐0129 has identified a low‐risk group of patients with oropharynx cancer (OPC) who might benefit from therapeutic de‐intensification. These risk groups have not yet been reproduced in an independent cohort treated heterogeneously. Therefore, the objective of this analysis was to validate the RPA risk groups and examine the prognostic impact of novel factors. Methods: Patients with OPC were enrolled in a prospective study at 3 academic medical centers from 2013 to 2018. Medical record abstraction was used to ascertain clinical variables including staging and survival according to the 7th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual. Human papillomavirus–positive tumor status was determined by p16 immunohistochemistry and/or HPV RNA in situ hybridization. Kaplan‐Meier and log‐rank methods were used to compare survival. Cox proportional hazards were used to generate univariate and multivariable hazard ratios (HRs). Results: Median follow‐up time was 3.2 years. The low‐, intermediate‐, and high‐risk groups had significant differences in 2‐year overall survival (OS, 99.1%; 95% CI, 94.4%‐99.9% vs OS, 93.0%; 95% CI, 74.7%‐98.2% vs OS, 80.0%; 95% CI, 40.9%‐94.6%; Poverall =.0001) and 2‐year progression‐free survival (PFS, 97.5%; 95% CI, 92.4%‐99.2% vs PFS, 89.3%; 95% CI, 70.3%‐96.4% vs PFS, 80.0%; 95% CI, 40.9%‐94.6%; Poverall <.002). After adjustment for age, sex, and level of educational attainment, OS and PFS were significantly lower for the intermediate‐ (OS adjusted hazard ratio [aHR], 5.0; 95% CI, 1.0‐23.0; PFS aHR, 3.4; 95% CI, 1.0‐11.5), and high‐ (OS aHR, 7.3; 95% CI, 1.4‐39; PFS aHR, 5.0; 95% CI, 1.2‐21.6) risk groups compared with the low‐risk group. Lower education was also independently significantly associated with worse OS (aHR, 8.9; 95% CI, 1.8‐44.3) and PFS (aHR, 3.1; 95% CI, 1.0‐9.6). Conclusions: In patients with OPC, the RTOG‐0129 RPA model is associated with OS and PFS in a heterogeneously treated cohort. In patients with oropharyngeal squamous cell carcinoma (OPC), the Radiation Therapy Oncology Group (RTOG)‐0129 recursive partitioning analysis model is associated with overall survival and progression‐free survival in a heterogeneously treated cohort. It is the hope that this study will contribute to identifying favorable, low‐risk patients with therapeutic implications for treatment de‐intensification in future clinical trials for OPC. [ABSTRACT FROM AUTHOR]

Background: Case‐control studies from the early 2000s demonstrated that human papillomavirus–related oropharyngeal cancer (HPV‐OPC) is a distinct entity associated with number of oral sex partners. Using contemporary data, we investigated novel risk factors (sexual debut behaviors, exposure intensity, and relationship dynamics) and serological markers on odds of HPV‐OPC. Methods: HPV‐OPC patients and frequency‐matched controls were enrolled in a multicenter study from 2013 to 2018. Participants completed a behavioral survey. Characteristics were compared using a chi‐square test for categorical variables and a t test for continuous variables. Adjusted odds ratios (aOR) were calculated using logistic regression. Results: A total of 163 HPV‐OPC patients and 345 controls were included. Lifetime number of oral sex partners was associated with significantly increased odds of HPV‐OPC (>10 partners: odds ratio [OR], 4.3 [95% CI, 2.8‐6.7]). After adjustment for number of oral sex partners and smoking, younger age at first oral sex (<18 vs >20 years: aOR, 1.8 [95% CI, 1.1‐3.2]) and oral sex intensity (>5 sex‐years: aOR, 2.8 [95% CI, 1.1‐7.5]) remained associated with significantly increased odds of HPV‐OPC. Type of sexual partner such as older partners when a case was younger (OR, 1.7 [95% CI, 1.1‐2.6]) or having a partner who had extramarital sex (OR, 1.6 [95% CI, 1.1‐2.4]) was associated with HPV‐OPC. Seropositivity for antibodies to HPV16 E6 (OR, 286 [95% CI, 122‐670]) and any HPV16 E protein (E1, E2, E6, E7; OR, 163 [95% CI, 70‐378]) was associated with increased odds of HPV‐OPC. Conclusion: Number of oral sex partners remains a strong risk factor for HPV‐OPC; however, timing and intensity of oral sex are novel independent risk factors. These behaviors suggest additional nuances of how and why some individuals develop HPV‐OPC. This comprehensive behavioral case‐control study of human papillomavirus (HPV)‐related oropharyngeal cancer reveals that oral sex and number of partners remain strong risk factors for HPV‐related oropharyngeal cancer. Measures of oral sexual behavior—including early age and intensity of exposure—are independent risk factors, suggesting that these behaviors may explain additional nuances of how and why some individuals develop HPV‐related oropharyngeal cancer. [ABSTRACT FROM AUTHOR]

Background: Central neck scars following thyroidectomy can negatively impact patient quality of life. Transoral endoscopic thyroidectomy can reduce postoperative cosmetic burden. Methods: Prospective cohort study of patients seen between June 2018 and January 2019. Scar cosmesis was determined using the validated Scar Cosmesis Assessment and Rating (SCAR) scale and a Visual Analog Scale (VAS) measuring color, contour, and irregularity. Results: Eighty‐one patients (80% female, mean age 43.7 years) were analyzed, with 60% and 40% receiving transcervical and transoral thyroidectomy. Median time from surgery was 3.4 (range: 1‐37.1) weeks. Mean SCAR score was greater for transcervical recipients (4.69 vs transoral 0.99, P <.001), indicating worse cosmesis. Mean surgeon‐rated total VAS score was similarly increased for transcervical recipients (72.84 vs transoral 16.73, P <.001). Interrater reliability for both SCAR and total VAS scores was excellent (intraclass correlation 0.93; 95% CI: 0.90‐0.95 for both). Conclusion: Transoral thyroidectomy provides significantly enhanced early cosmesis over the transcervical approach. [ABSTRACT FROM AUTHOR]

Background: Human papillomavirus (HPV)‐positive oropharyngeal cancer (HPV‐OPC) is distinct from HPV‐unassociated head and neck cancer. However, whether risk factors for HPV‐positive oropharyngeal and nonoropharyngeal squamous cell cancer are the same is unclear. Methods: Incident cases of HPV‐positive head and neck cell cancer and matched non‐cancer controls were enrolled in a multi‐institutional, prospective study examining risk factors, biomarkers, and survival. Results: HPV‐nonOPC (n = 20) were more likely to be ever smokers than controls (n = 80, OR 3.49, 95%CI 1.11‐10.9) and HPV‐OPC (n = 185, OR 3.28, 95%CI 1.10‐10.2). Compared with HPV‐OPC, HPV‐nonOPC were less likely to have had over 3 oral sexual partners (OR 0.29, 95%CI 0.06‐0.9), more likely to have multimorbidity (OR 3.30, 95%CI 1.04‐10.5), and less likely to have antibodies to HPV16 E6 (90% vs 28%, OR 0.05, 95%CI 0.02‐0.2). HPV‐nonOPC had worse 4‐year OS (77% vs 96%, P =.001) and RFS (69% vs 94%, P <.001) than HPV‐OPC. Conclusions: HPV‐positive nonoropharyngeal are distinct from HPV‐positive oropharyngeal cancers. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: To examine the cumulative effect of diagnostic steps for primary tumor identification in patients with head and neck squamous cell carcinoma of unknown primary (HNSCCUP), including lingual tonsillectomy, and the impact of primary tumor identification on subsequent treatment.Study Design: Retrospective analysis.Methods: We reviewed the records of 110 patients diagnosed with HNSCCUP between 2003 and 2015. Results of diagnostic imaging (fluorodeoxyglucose-positron emission tomography/computed tomography [FDG-PET/CT]), tumor detection with direct laryngoscopy with biopsies, palatine tonsillectomy, and transoral robotic surgery (TORS) lingual tonsillectomy were recorded. Associations between demographic and treatment variables with overall survival (OS) and progression-free survival (PFS) were modeled with Cox proportional hazards models.Results: FDG-PET/CT was suspicious for a primary site in 23/77 (30%) patients. Direct laryngoscopy identified a primary tumor in 34/110 patients (31%). Forty-seven patients underwent palatine tonsillectomy, which identified 17 primaries (36%), yielding a cumulative primary tumor identification of 51/110 (46%). Fourteen patients underwent TORS lingual tonsillectomy, which identified eight primaries (57%), resulting in a cumulative identification of 59/110 (53%). The detection rate increased from 28/63 (44%) to 31/47 (66%) after the addition of TORS lingual tonsillectomy to our institutional approach. Detection rates varied by HPV status. Primary tumor identification altered subsequent radiation planning, as patients with an identified primary tumor received radiation to a smaller volume of tissue than did those without an identified primary tumor. However, there was no significant association between primary tumor identification and OS or PFS.Conclusions: A stepwise approach to primary tumor identification identifies a primary tumor in a majority of patients.Level Of Evidence: 4 Laryngoscope, 129:1610-1616, 2019. [ABSTRACT FROM AUTHOR]

Introduction: Radiation-associated soft tissue sarcomas of the neck (RASN) constitute a rare and aggressive tumor type. Methods: A retrospective chart review at the authors' institution revealed 3 patients with RASN. A systematic review of the literature was also conducted using MEDLINE, Ovid, the Cochrane Library, and Embase. Results: Patients within the authors' institutional chart review presented from 6 to 26 years after neck radiation with neck masses. All patients underwent surgical resection with clear margins, and adjuvant radiation was offered when feasible. Patients had no evidence of disease at most recent follow-up. A total of 867 articles were screened for systematic review, revealing 9 articles detailing outcomes of RASN. Studies were small and heterogeneous, precluding pooled data. The importance of complete surgical extirpation was noted. Conclusions: Complete surgical resection appears to be the mainstay of therapy, but there are limited data on management and outcomes of patients with RASN. [ABSTRACT FROM AUTHOR]

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients.Methods: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models.Results: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status.Conclusions: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Patients undergoing free tissue reconstruction are at risk for development of an anastomotic pseudoaneurysm, which may present as delayed neck hemorrhage or a pulsatile neck mass. Diagnosis may be achieved by noninvasive imaging, angiography, and exploration. Management strategies for head and neck pseudoaneurysms have included open vessel ligation, open direct vessel repair, endovascular parent vessel embolization, and, most recently, endovascular pseudoaneurysm embolization. In patients with anastomotic pseudoaneurysms where adequate flap inosculation is doubted, endovascular pseudoaneurysm embolization with pedicle preservation may be an appropriate primary treatment approach. We discuss the successful endovascular coiling of an external carotid artery branch anastomotic pseudoaneurysm in a patient one month after free tissue reconstruction of a total laryngopharyngectomy and partial glossectomy defect. [ABSTRACT FROM AUTHOR]

To evaluate the incidence of a subsequent primary thyroid malignancy in patients with an index head and neck squamous cell carcinoma (HNSCC), we analyzed the National Cancer Institute’s Surveillance, Epidemiology, and End Results database to identify a cohort of patients who had been diagnosed with a primary HNSCC from 1973 through 2004. The study population was made up of 60,323 patients of all ages, roughly three-quarters of whom were male. A total of 60 patients (0.1%) developed a subsequent thyroid malignancy—not a statistically significant finding. The overall standard incidence ratio (SIR) for a subsequent thyroid malignancy was 1.58 (p < 0.05). The highest SIRs were seen during in the first 5 years after diagnosis of the original primary (SIR: 3.05; p < 0.05), more specifically in 2 to 11 months after diagnosis (SIR: 7.11; p < 0.05). Further analyses demonstrated that SIRs were significantly higher in males (SIR: 1.71), in patients aged 60 through 79 years (SIR: 1.71), in whites (SIR: 1.55), in patients who had undergone external-beam radiotherapy for their index primary (SIR: 1.84), in those whose tumor was initially staged as regional (SIR: 1.96), and in patients whose index primary was in the oral cavity (SIR: 1.71) or larynx (SIR: 1.88) (p < 0.05 for all). We conclude that the incidence of a subsequent primary thyroid malignancy in patients with an HNSCC is highest during the first 5 years after diagnosis of the index primary, reflecting the benefit of continued surveillance. [ABSTRACT FROM AUTHOR]

Objectives/hypothesis: The purpose of this study was to retrospectively review patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) for the presence of retropharyngeal lymph nodes (RPLNs) prior to treatment using positron emission tomography/computed tomography (PET/CT), and to determine if the presence of RPLNs is of utility in predicting outcomes.Study Design: Retrospective review of patient data from a single institution.Methods: Two hundred thirty patients with a diagnosis of HPV-associated OPSCC were identified from 2002 to 2013. The presence of RPLNs was determined primarily from findings on PET/CT as reviewed in a standardized fashion by two neuroradiologists.Results: Of the 230 patients, 165 had pretreatment PET/CT imaging available for review. There were a total of 16 patients (9.70%) with evidence of RPLNs. Among patients positive for RPLNs pretreatment, with an average follow-up of 2 years, there was a 5.2-times greater odds of having recurrence or death (31.3% vs. 8.1%, P=.004). When T and N stage were adjusted for with multiple regression, there was no significant association between RPLN status and recurrence free survival.Conclusions: This is a unique investigation utilizing PET/CT to classify RPLN status in HPV-associated OPSCC. RPLNs were relatively common in our HPV-associated OPSCC cohort at 9.70%, at the low end of the quoted positivity of 10% to 27% in all OPSCC. A combination of PET/CT is useful in identifying RPLNs. Prospective investigation will be needed to determine the sensitivity and specificity of PET/CT in identifying RPLNs, and the precise impact of RPLNs on HPV-associated OPSCC treatment and outcomes.Level Of Evidence: 4. [ABSTRACT FROM AUTHOR]

Background: Methylation profiling of tumor suppressor gene (TSGs) promoters is quickly becoming a powerful diagnostic tool for the early detection, prognosis, and even prediction of clinical response to treatment. Few studies address this in salivary gland tumors (SGTs); hence the promoter methylation profile of various TSGs was quantitatively assessed in primary SGT tissue to determine if tumor-specific alterations could be detected. Methodology: DNA isolated from 78 tumor and 17 normal parotid gland specimens was assayed for promoter methylation status of 19 TSGs by fluorescence-based, quantitative methylation-specific PCR (qMSP). The data were utilized in a binary fashion as well as quantitatively (using a methylation quotient) allowing for better profiling and interpretation of results. Principal Findings: The average number of methylation events across the studied genes was highest in salivary duct carcinoma (SDC), with a methylation value of 9.6, compared to the normal 4.5 (p<0.0003). There was a variable frequency and individual methylation quotient detected, depending on the TSG and the tumor type. When comparing normal, benign, and malignant SGTs, there was a statistically significant trend for increasing methylation in APC, Mint 1, PGP9.5, RAR-β, and Timp3. Conclusions/Significance: Screening promoter methylation profiles in SGTs showed considerable heterogeneity. The methylation status of certain markers was surprisingly high in even normal salivary tissue, confirming the need for such controls. Several TSGs were found to be associated with malignant SGTs, especially SDC. Further study is needed to evaluate the potential use of these associations in the detection, prognosis, and therapeutic outcome of these rare tumors. [ABSTRACT FROM AUTHOR]

AbstractFanconi anemia (FA) and dyskeratosis congenita (DC) are rare inherited syndromes that cause head and neck squamous cell cancer (HNSCC). Prior studies of inherited forms of cancer have been extremely important in elucidating tumor suppressor genes inactivated in sporadic tumors. Here, we studied whether sporadic tumors have epigenetic silencing of the genes causing the inherited forms of HNSCC. Using bisulfite sequencing, we investigated the incidence of promoter hypermethylation of the 17 Fanconi- and DC-associated genes in sporadic HNSCC. Genes that only showed methylation in the tumor patients were chosen for quantitative methylation-specific PCR (qMSP) in a set of 45 tumor and 16 normal patients. Three gene promoters showed differences in methylation: FancB (FAAP95, FA core complex), FancJ (BRIP1, DNA Helicase/ATPase), and DKC1 (dyskeratin). Bisulfite sequencing revealed that only FancB and DKC1 showed no methylation in normal patients, yet the presence of promoter hypermethylation in tumor patients. On qMSP, 1/16 (6.25) of the normal mucosal samples from non-cancer patients and 14/45 (31.1) of the tumor patients demonstrated hypermethylation of the FancB locus (p < 0.05). These results suggest that inactivation of FancB may play a role in the pathogenesis of sporadic HNSCC.Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Epigenetic changes have been implicated in the pathogenesis of solid tumors, including head and neck squamous cell carcinoma (HNSCC). Prior efforts have primarily examined regional promoter hypermethylation as a silencer of tumor suppressor gene expression. To analyze the global state of methylation in the HNSCC genome, we utilize pyrosequencing of repetitive elements (LINEs) to compare the state of global methylation in HNSCC to normal aerodigestive mucosa. 137 samples (119 HNSCC tumors and 18 normal mucosal tissues) were digested to extract DNA and subjected to bisulfite treatment. Treated DNA was amplified using PCR primers for the repetitive LINEs sequence and produced a heterogeneous sample of products, from many genomic loci. These products were pyrosequenced to quantitatively evaluate their global genomic methylation status. HNSCC specimens showed global hypomethylation, with a mean level of genomic methylation of 46.8% methylated with a standard deviation of 9.0. Conversely, the normal upper airway mucosa had a global methylation level of 54.0 and a standard deviation of 4.6 (Mann-Whitney p value < 0.001). The tumor specimens also showed an increasing degree of hypomethylation associated with advanced tumor stage (ANOVA p-value of 0.003). About 67% of HNSCC's are globally hypomethylated when evaluated against the minimum level of methylation in the normal mucosal specimens. Degree of global hypomethylation was associated with smoking history, alcohol use and stage in univariate analysis ( p-value 0.02), however, only HNSCC diagnosis remained significant on multivariate analysis. Despite the presence of regional promoter hypermethylation, HNSCC demonstrates global genomic hypomethylation. The effects of stage, alcohol use and smoking on global hypomethylation were not independently significant. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis Salivary gland stones (sialoliths) are a common cause of salivary gland enlargement, but such stones are uncommon in children. Low-flow vascular malformations of the head and neck region may develop phleboliths. Phleboliths within a venous malformation may be mistaken for a salivary stone given the similar calcified nature and location. We present two children who were referred to us for evaluation of submandibular gland sialoliths but were found to have venous malformations containing phleboliths. Multiple calcifications, calcifications > 1 cm, within a soft tissue mass separate from the substance of the submandibular gland suggest a diagnosis, of phleboliths within a venous malformation as opposed to a sialolith. Laryngoscope, 124:2826-2828, 2014 [ABSTRACT FROM AUTHOR]

Background: The rate of primary surgery for human papillomavirus-related oropharynx cancer (HPVOPC) has recently declined, while utilization of transoral robotic surgery (TORS) has lagged at community cancer centers (CCs). We hypothesize that differences in overall survival (OS) exist between patients undergoing surgery for HPVOPC at CCs and low (<15 TORS/year; LVACs) and high (≥15 TORS/year; HVACS) TORS volume academic centers., Methods: Cases from the US National Cancer Database with a diagnosis of HPVOPC from 2010-2019 that underwent primary surgical treatment were included. Trends in TORS utilization, rates of positive surgical margins (PMs), quality of adjuvant treatment and 5-year OS were compared between CCs, LVACs and HVACs., Results: 5,406 cases met study criteria. A significantly lower proportion of cases at CCs utilized TORS than at LVACs or HVACs (26.2% vs 44.0% vs 73.9%, respectively, p < .001). The rate of PMs was significantly higher at CCs than at LVACs or HVACs (25.7% vs 15.3% vs 9.2%, p < .001). A greater proportion of cases undergoing adjuvant radiotherapy (RT) received prolonged courses (23.6% vs 13.1% vs 8.8%, p < .001) or excessive doses (16.5% vs 11.5% vs 8.7%, p < .001) of RT at CCs than at LVACs or HVACs, respectively. 5-year OS was lowest at CCs (85.2%, 95%CI: 81.7-88.2%), intermediate at LVACs (88.9%, 95%CI: 87.2-90.4%), and highest at HVACs (91.4%, 95%CI: 89.5-92.9%; pLR<0.01)., Conclusions: Significant differences in the type and quality of surgical and adjuvant treatment for HPVOPC exist between facility types based on TORS volume. Overall survival was lowest at CCs, intermediate at LVACs and highest at HVACs., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Extirpation of multiple head and neck paragangliomas carries challenge due to close anatomic relationships with critical neurovascular bundles., Objectives: This study aims to assess whether the application of 3-D models can assist with surgical planning and treatment of these paragangliomas, decrease surgically related morbidity and mortality., Methods: Fourteen patients undergoing surgical resection of multiple head and neck paragangliomas were enrolled in this study. A preoperative 3-D model was created based on radiologic data, and relevant critical anatomic relationships were preoperatively assessed and intraoperatively validated., Results: All 14 patients presented with multiple head and neck paragangliomas, including bilateral carotid body tumors (CBT, n = 9), concurrent CBT with glomus jugulare tumors (GJT, n = 4), and multiple vagal paragangliomas (n = 1). Ten patients underwent genomic analysis and all harbored succinate dehydrogenase complex subunit D (SDHD) mutations. Under guidance of the 3-D model, the internal carotid artery (ICA) was circumferentially encased by tumor on 5 of the operated sides, in 4 (80%) of which the tumor was successfully dissected out from the ICA, whereas ICA reconstruction was required on one side (20%). Following removal of CBT, anterior rerouting of the facial nerve was avoided in 3 (75%) of 4 patients during the extirpation of GJT with assistance of a 3-D model. Two patients developed permanent postoperative vocal cord paralysis. There was no vessel rupture or mortality in this study cohort., Conclusion: The 3-D model is beneficial for establishment of a preoperative strategy, as well as planning and guiding the intraoperative procedure for resection of multiple head and neck paragangliomas.

Introduction: Resection of carotid body tumor (CBT) in patients of advanced ages has not been appreciated., Objectives: This study aims to assess the clinical characteristics and perioperative comorbidities for CBT resection in patients of advanced age and to validate the application of an "isolated island" technique for extirpation of CBT., Methods: Eight patients of advanced age (≥60 years) who underwent CBT resection were enrolled as the study group (SG). Another 29 patients of younger age (<45 years old) underwent CBT extirpation were assigned as the control group (CG). The perioperative issues were compared between these 2 groups., Results: The "isolated island" technique was successfully applied for resection of CBT in all 37 patients. The prevalence of Shamblin classification I, II, and III tumors in the SG was 12.5%, 62.5%, and 25%; whereas in the CG was 10.3%, 55.2%, and 34.5%, respectively. Bilateral CBT was observed in 7 patients of the CG and none in the SG. Vascular reconstruction was required for 1 (12.5%) patient in the SG, while it was required for 8 (27.6%) patients in the CG. Postoperative vocal cord palsy occurred in 37.5% of patients in SG, whereas the vocal cord palsy (34.5%) and dysphagia (6.9%) were commonly encountered in CG. In addition to postoperative length of stay ( P = .004), no significant difference for operative time, intraoperative blood loss, or mortality were observed between these 2 groups ( P > .05)., Conclusion: Extirpation of CBT in patients of advanced age is rationale in appropriately selected patients. The "isolated island" technique is safe for CBT resection with seemingly low complication rates.

Due to the heterogenicity and morphological overlap among the broad spectrum of benign and malignant salivary gland lesions, cytopathology result interpretations can be challenging and variable even among the most experienced head and neck pathologist. There was no standardization of cytopathology result reporting until the recently proposed "Milan system for reporting salivary gland cytopathology" (MSRSGC). MSRSGC may offer more clarity and help minimize ambiguity, but surgeons, as part of multidisciplinary teams, do not only rely on the tiered stratification and risk of malignancy assessment. With only the MSRSGC reported, there may be critical information missing from the overall diagnostic evaluation of salivary gland masses. Cytopathologist evaluation, description of findings, and expert interpretation of the fine-needle aspiration cytology along with differential diagnosis can be critical pieces of information, that is, utilized in management discussions with patients and their families. This information needs to be included in every cytopathology interpretation in addition to the MSRSGC classification. In clinical practice, decisions concerning salivary gland tumor management are not based on single examinations but incorporate information from multiple sources including patient histories, clinical symptoms and signs, physical examinations, imaging studies, and when available, cytopathology. Additional cytopathology information will likely help to improve the utility and predictive power of MSRSGC, similar to Bethesda Classification and the predictive importance of nuclear atypia in indeterminate thyroid biopsy material for thyroid neoplasms., (© 2021 Wiley Periodicals LLC.)

Therapeutic IL-12 has demonstrated the ability to reduce local immune suppression in preclinical models, but clinical development has been limited by severe inflammation-related adverse events with systemic administration. Here, we show that potent immunologic tumor control of established syngeneic carcinomas can be achieved by i.t. administration of a tumor-targeted IL-12 antibody fusion protein (NHS-rmIL-12) using sufficiently low doses to avoid systemic toxicity. Single-cell transcriptomic analysis and ex vivo functional assays of NHS-rmIL-12-treated tumors revealed reinvigoration and enhanced proliferation of exhausted CD8+ T lymphocytes, induction of Th1 immunity, and a decrease in Treg number and suppressive capacity. Similarly, myeloid cells transitioned toward inflammatory phenotypes and displayed reduced suppressive capacity. Cell type-specific IL-12 receptor-KO BM chimera studies revealed that therapeutic modulation of both lymphoid and myeloid cells is required for maximum treatment effect and tumor cure. Study of single-cell data sets from human head and neck carcinomas revealed IL-12 receptor expression patterns similar to those observed in murine tumors. These results describing the diverse mechanisms underlying tumor-directed IL-12-induced antitumor immunity provide the preclinical rationale for the clinical study of i.t. NHS-IL-12.

Purpose: Natural killer (NK)-cell-based immunotherapy may overcome obstacles to effective T-cell-based immunotherapy such as the presence of genomic alterations in IFN response genes and antigen presentation machinery. All immunotherapy approaches may be abrogated by the presence of an immunosuppressive tumor microenvironment present in many solid tumor types, including head and neck squamous cell carcinoma (HNSCC). Here, we studied the role of myeloid-derived suppressor cells (MDSC) in suppressing NK-cell function in HNSCC., Experimental Design: The ability of peripheral and tumor-infiltrating MDSC from mice bearing murine oral cancer 2 (MOC2) non-T-cell-inflamed tumors and from patients with HNSCC to suppress NK-cell function was studied with real-time impedance and ELISpot assays. The therapeutic efficacy of SX-682, a small-molecule inhibitor of CXCR1 and CXCR2, was assessed in combination with adoptively transferred NK cells., Results: Mice bearing MOC2 tumors pathologically accumulate peripheral CXCR2 + neutrophilic-MDSC (PMN-MDSC) that traffic into tumors and suppress NK-cell function through TGFβ and production of H 2 O 2 . Inhibition of MDSC trafficking with orally bioavailable SX-682 significantly abrogated tumor MDSC accumulation and enhanced the tumor infiltration, activation, and therapeutic efficacy of adoptively transferred murine NK cells. Patients with HNSCC harbor significant levels of circulating and tumor-infiltrating CXCR1/2 + CD15 + PMN-MDSC and CD14 + monocytic-MDSC. Tumor MDSC exhibited greater immunosuppression than those in circulation. HNSCC tumor MDSC immunosuppression was mediated by multiple, independent, cell-specific mechanisms including TGFβ and nitric oxide., Conclusions: The clinical study of CXCR1/2 inhibitors in combination with adoptively transferred NK cells is warranted., (©2019 American Association for Cancer Research.)

Purpose: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse., Experimental Design: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays., Results: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen., Conclusions: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas., (©2019 American Association for Cancer Research.)

To evaluate the incidence of a subsequent primary thyroid malignancy in patients with an index head and neck squamous cell carcinoma (HNSCC), we analyzed the National Cancer Institute's Surveillance, Epidemiology, and End Results database to identify a cohort of patients who had been diagnosed with a primary HNSCC from 1973 through 2004. The study population was made up of 60,323 patients of all ages, roughly three-quarters of whom were male. A total of 60 patients (0.1%) developed a subsequent thyroid malignancy-not a statistically significant finding. The overall standard incidence ratio (SIR) for a subsequent thyroid malignancy was 1.58 (p < 0.05). The highest SIRs were seen during in the first 5 years after diagnosis of the original primary (SIR: 3.05; p < 0.05), more specifically in 2 to 11 months after diagnosis (SIR: 7.11; p < 0.05). Further analyses demonstrated that SIRs were significantly higher in males (SIR: 1.71), in patients aged 60 through 79 years (SIR: 1.71), in whites (SIR: 1.55), in patients who had undergone external-beam radiotherapy for their index primary (SIR: 1.84), in those whose tumor was initially staged as regional (SIR: 1.96), and in patients whose index primary was in the oral cavity (SIR: 1.71) or larynx (SIR: 1.88) (p < 0.05 for all). We conclude that the incidence of a subsequent primary thyroid malignancy in patients with an HNSCC is highest during the first 5 years after diagnosis of the index primary, reflecting the benefit of continued surveillance.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating and lethal disease. Despite significant advances in radiotherapy and surgical management, the 5-year survival rate for head and neck cancer has remained a dismal 50%. Advances in early detection have been made, but to improve patient outcomes better biomarkers and targeted therapeutic agents are needed. Novel biomarkers can improve early detection and provide data to optimize therapeutic strategy and patient survival, and could lead to potentially effective targeted therapies. OBJECTIVE: Report the advances in the discovery of novel biomarkers for HNSCC, and review the potential utility of biomarkers in the molecular diagnosis of HNSCC. METHODS: A review of the English literature (PubMed) from 1980 to 2009. RESULTS/CONCLUSION: Currently the most widely accepted biomarker for HNSCC is high risk HPV status. EGFR is another promising biomarker, however, further research is necessary to determine its prognostic benefit. A large number of promising biomarker candidates are currently being evaluated including epigenetic, expression, and genomic based markers. Studies to validate the sensitivity and specificity of these biomarkers in clinical samples from adequately powered prospective cohorts are needed for successful translation of these findings into potential molecular diagnostic, prognostic, and therapeutic biomarkers for HNSCC.

Purpose: Mitochondrial dysfunction has been linked to defects in the apoptotic pathway, and solid tumors, including head and neck squamous cell carcinoma (HNSCC), exhibit defects in apoptosis. Loss of mitochondrial membrane potential (DeltaPsim) is an early initiating event in the mitochondrial apoptotic pathway. We investigated the apoptotic response of 3 head and neck cancer cell lines treated with a mitochondrial-membrane-depolarizing agent, valinomycin, and studied the ability of depolarization to induce release of cytochrome c in these cell lines., Experimental Design: HNSCC cell lines JHU-011, -012 and -019, and a leukemia control cell line HL-60 were assayed for DeltaPsim after valinomycin treatment by staining with mitochondrial-membrane-potential-specific probe JC-1 and stained with apoptosis-specific probe annexin-V to measure their rate of apoptosis by FACS. Western blotting was also applied to detect cytoplasmic cytochrome c release., Results: DeltaPsim in head and neck cell lines started to show slight loss of DeltaPsim, while HL-60 showed significant loss of DeltaPsim after 30 min of treatment. All cell lines demonstrated complete mitochondrial depolarization within 24 h, however, only the control cell line HL-60 underwent apoptosis. In addition, HNSCC cell lines did not demonstrate cytoplasmic cytochrome c release despite significant mitochondrial membrane depolarization, while HL-60 cell initiated apoptosis and cytochcrome c release after 24 h of treatment., Conclusions: Head and neck cancer cell lines exhibit defects in mitochondrial-membrane-depolarization-induced apoptosis as well as impaired release of cytochrome c despite significant mitochondrial membrane depolarization. Proximal defects in the mitochondrial apoptosis pathway are a feature of HNSCC., (Copyright 2008 S. Karger AG, Basel.)

Objectives/hypothesis: To characterize the salient features of skull base metastasis from differentiated thyroid carcinoma, discuss the diagnostic and treatment strategies, and propose rational management guidelines for such tumors., Study Design: Case report., Methods: Review of English literature from MEDLINE with the addition of our case., Results: Skull base metastasis from differentiated thyroid carcinoma is rare, with only 20 cases reported to date, including our case report. On the basis of a review of all reported cases, both follicular and papillary thyroid cancers can metastasize to the skull base. Our case is unique because the lesion extends locally into the cavernous sinus and beyond. Histopathologic diagnosis is limited by the remote location of lesions. Most tumors are highly vascular, and there is potential for significant morbidity and mortality associated with surgical resection. The overall survival ranges from less than one year to 10+ years from the discovery of the metastasis and is similar in both tumor subtypes. There is no clear consensus on the management strategy for skull base metastasis from differentiated thyroid carcinoma. Interestingly, surgical resection of both the primary and metastatic lesions yields similar survival when compared with resection of the primary tumor alone., Conclusions: Distant metastasis from differentiated thyroid carcinoma needs to be considered in the differential diagnosis of destructive skull base lesions, regardless of the patient's age. Histopathologic tissue diagnosis should always be attempted, followed by total thyroidectomy, radioiodine, or external beam radiation, and chronic thyroid-stimulating hormone suppression. Surgical resection of the metastatic lesion should only be performed in carefully selected cases because it is associated with significant morbidity.