Diverse tumorigenic consequences of human papillomavirus integration in primary oropharyngeal cancers.

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC) and immune evasion (i.e., CD274). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression.

Treatment decision and estimation of growth of head and neck paragangliomas.

PURPOSE: Head and neck paragangliomas are slow growing tumors where observation has become more widely accepted. Tumor growth rate as well as predictors of increased tumor growth were analyzed with the goal to identify factors to better predict disease progression and counsel patients. MATERIALS AND METHODS: Multi-institutional retrospective cohort study from 2011 to 2020. RESULTS: 130 head and neck paragangliomas in 125 patients were analyzed. 38 were observed (30.4%), 16 radiated (12.8%), and 71 underwent surgery (56.8%). Surgical patients were significantly younger (p = 0.038) and with more genetically mediated paragangliomas (p = 0.026). Significantly more patients were asymptomatic in the observation group (p = 0.005). Of the 39 observed tumors, 43.6% (n = 17) grew with a tumor doubling time of 5.67 years. More than half of the observed paragangliomas had no growth. When examining symptoms postoperatively and at follow-up, the surgical cohort had significantly more worsening symptoms (p = 0.007) and new cranial neuropathies (p = 0.031). CONCLUSIONS: Head and neck paragangliomas have slow growth rates if they grow at all. Patients in the surgical cohort had more clinical symptoms at presentation and worsening postoperative symptoms.

National treatment trends in human papillomavirus-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-mediated oropharyngeal cancer (OPC) is associated with dramatically improved survival in comparison with HPV-negative OPC and can be successfully treated with surgical and nonsurgical approaches. National treatment trends for OPC were investigated with the National Cancer Data Base (NCDB). METHODS: The NCDB was reviewed for primary HPV-mediated OPC in 2010-2014. Multivariable regression was used to identify predictors of both nonsurgical therapy and receipt of adjuvant chemoradiation (CRT). RESULTS: There were 13,363 patients identified with a median age at diagnosis of 58 years. The incidence of triple-modality treatment (surgery with adjuvant chemotherapy) decreased from 23.7% in 2010 to 16.9% in 2014 (R2  = 0.96), whereas the incidence of nonsurgical treatment increased from 63.9% to 68.7% (R2  = 0.89). Hospitals in the top treatment volume quartile (quartile 1 [Q1]; n = 29) had a lower rate of positive margins (16.3%) than bottom-quartile centers (n = 741; rate of positive margins, 36.4%; P < .001); Q1 hospitals used surgical therapy significantly more. Independent predictors of nonsurgical therapy included older age, advanced disease, lower hospital volume, and living closer to the hospital or outside the Pacific United States. In surgically treated patients, younger age, lower hospital volume, nodal disease, positive surgical margins, and extranodal extension (ENE) also predicted more adjuvant CRT use. CONCLUSIONS: The use of upfront surgical treatment decreased from 2010 to 2014. Hospital volume shows a strong, inverse correlation with the rate of positive surgical margins. The upfront treatment strategy is predicted not only by staging but also by patient-, geographic-, and hospital-specific factors. Lower hospital volume remains independently associated with increased triple-modality therapy after adjustments for positive margins, ENE, and pathologic staging.

The Role of Hyperbaric Oxygen in Head and Neck Reconstruction and Facial Cosmetic Surgery.

Hyperbaric oxygen (HBO) is a treatment modality with the primary mechanism of therapy being the delivery of oxygen to hypoxic tissues. A review of HBO applications in the field of head and neck reconstruction and facial cosmetic surgery is provided. HBO can be useful in the management of radiation sequelae and treatment of compromised flaps and grafts. It may also have application in tissue compromise following cosmetic surgery and dermal fillers. We provide evidence from the available literature as well as highlight our experience in using HBO in head and neck reconstruction.

Custom Presurgical Planning for Midfacial Reconstruction.

Resection and reconstruction of midface involve complex ablative and reconstructive tools in head and oncology and maxillofacial prosthodontics. This region is extraordinarily important for long-term aesthetic and functional performance. From a reconstructive standpoint, this region has always been known to present challenges to a reconstructive surgeon due to the complex three-dimensional anatomy, the variable defects created, combination of the medical and dental functionalities, and the distance from reliable donor vessels for free tissue transfer. Another challenge one faces is the unique features of each individual resection defect as well as individual patient factors making each preoperative planning session and reconstruction unique. Understanding the long-term effects on speech, swallowing, and vision, one should routinely utilize a multidisciplinary approach to resection and reconstruction, including head and neck reconstructive surgeons, prosthodontists, speech language pathologists, oculoplastic surgeons, dentists, and/or craniofacial teams as indicated and with each practice pattern. With this in mind, we present our planning and reconstructive algorithm in midface reconstruction, including a dedicated focus on dental rehabilitation via custom presurgical planning.

Management of complications and compromised free flaps following major head and neck surgery.

Microvascular free flaps are preferred for most major head and neck reconstruction surgeries because of better functional outcomes, improved esthetics, and generally higher success rates. Numerous studies have investigated measures to prevent flap loss, but few have evaluated the optimal treatment for free flap complications. This study aimed to determine the complication rate after free flap reconstructions and discusses our management strategies. Medical records of 260 consecutive patients who underwent free flap reconstructions for head and neck defects between July 2006 and June 2010 were retrospectively reviewed for patient and surgical characteristics and postoperative complications. The results revealed that microvascular free flaps were extremely reliable, with a 3.5 % incidence of flap failure. There were 78 surgical site complications. The most common complication was neck wound infection, followed by dehiscence, vascular congestion, abscess, flap necrosis, hematoma, osteoradionecrosis, and brisk bleeding. Twenty patients with poor wound healing received hyperbaric oxygen therapy, which was ineffective in three patients who eventually experienced complete flap loss. Eleven patients with vascular congestion underwent medicinal leech therapy, which was effective. Among the 78 patients with complications, 44 required repeat surgery, which was performed for postoperative brisk bleeding in three. Eventually, ten patients experienced partial flap loss and nine experienced complete flap loss, with the latter requiring subsequent pectoralis major flap reconstruction. Microvascular free flap reconstruction represents an essential and reliable technique for head and neck defects and allows surgeons to perform radical resection with satisfactory functional results and acceptable complication rates.

Surgical anatomy of oropharynx and supraglottic larynx for transoral robotic surgery.

Traditional external surgical approaches have been used for the surgical management of the oropharyngeal and laryngeal tumors. Trans-oral robotic surgery allows surgeon to operate oropharyngeal and supraglottic tumors through the mouth with preservation of functions. The surgeons must be knowledgeable about the anatomy of the oral cavity and oropharynx medial to lateral perspective. In this article, we will describe the relevant inside out surgical anatomy and its clinical implications for trans-oral robotic surgery.

Transoral robotic surgery (TORS) for laryngeal and hypopharyngeal cancers.

Transoral robotic surgery (TORS) is increasingly used in laryngeal/hypopharyngeal cancer surgery. Ablative procedures described in these anatomical sites include: (i) supraglottic laryngectomy, (ii) total laryngectomy, (iii) glottic cordectomy, and (iv) partial pharyngectomy. TORS supraglottic laryngectomy remains the most commonly performed of these procedures. Initial oncologic and functional outcomes with these procedures are promising and comparable to other treatment options. As robotic instrumentation technology advances a rise in TORS laryngeal/hypopharyngeal surgery is anticipated.

Transoral robotic surgery for carcinoma of unknown primary in the head and neck.

Multiple diagnostic and treatment paradigms exist for the management of carcinoma of unknown primary (CUP) metastatic to cervical lymph nodes. Transoral robotic surgery (TORS) has emerged as a modality for diagnosis and treatment of CUP, optimizing identification and resection of the primary tumor, although also preventing chemotherapy in a subset of patients. This article presents the authors' treatment paradigm and reviews the literature supporting the use of TORS in the management of CUP.

How often parapharyngeal space is encountered in TORS oropharynx cancer resection.

Early stage oropharyngeal squamous cell carcinoma (OPSCC) may occasionally invade parapharyngeal space (PPS). Tumor invasion of PPS structures such as the carotid artery, internal jugular vein and cranial nerves IX-XII may add significant morbidity. We analyzed 73 patients who underwent transoral robotic surgery (TORS) for OPSCC between 2008 and 2012. Patients were selected based on preoperative evaluation including detailed physical and endoscopic examination, neck CT and/or PET-CT scan. T1, T2 and selected T3 cases were included in this study. None of the patients had obvious PPS extension on preoperative evaluation. All patients had OPSCC in palatine tonsil (60; 82.2 %) and base of tongue (13; 17.8 %). Twenty-seven patients had cT1 (37 %), 39 had cT2 (53.4 %), and 7 had cT3 (9.6 %) disease in clinical and radiologic evaluation. None of the oropharyngeal lesions had obvious radiologic PPS extension prior to operation. During TORS procedure, we encountered PPS in 18 (24.6 %) patients while resecting the deep margin. These parapharynx resections involved external carotid artery in 1, medial pterygoid muscle in 2, and parapharyngeal fat with or without styloid musculature in the remaining 15 patients. Except three cases, we were able to remove the lesions en bloc with negative surgical margins. TORS resection of oropharyngeal cancer extending to PPS appears to be a safe and feasible technique with minimal complications. Significant experience with TORS and further understanding of the endoscopic anatomy of PPS could obviate the morbidity associated with tumor resection in this dense neurovascular region.

Feasibility and clinical outcomes of transoral robotic surgery and transoral robot-assisted carbon dioxide laser for hypopharyngeal carcinoma.

Transoral robotic surgery (TORS) has been used as a novel procedure for squamous cell carcinoma of the laryngopharyngeal cancers with encouraging outcomes. The safety, feasibility, and efficacy regarding this approach have previously been demonstrated. There are several studies proposing the benefit of combining TORS with carbon dioxide (CO2) laser in resecting upper aerodigestive tract tumors. We report a series of patients with hypopharyngeal carcinoma treated with primary TORS with or without the flexible carbon dioxide (CO2) laser. All TORS resections were completed without any intraoperative complication. None required conversion to an open procedure. Clinical outcomes in this preliminary analysis indicate that magnified view, 3D visualization with the wristed instruments and tremor reduction technology of robotic experience, allow en bloc resection of early stage hypopharyngeal cancers. TORS with CO2 laser is a promising, minimally invasive surgical alternative for the treatment of hypopharyngeal tumors with comparable oncologic outcomes.

Elevated intrinsic cancer stem cell population in human papillomavirus-associated head and neck squamous cell carcinoma.

BACKGROUND: Human papillomavirus 16 (HPV16) is a major risk factor for the development of head and neck squamous cell carcinoma (HNSCC), particularly the development of oropharyngeal squamous cell carcinoma (OPSCC). Cancer stem cells (CSCs) are resistant to conventional therapies, and it is postulated that they are responsible for disease recurrence and/or progression. Because the prognoses of patients with HPV16-positive and HPV-negative HNSCC are distinct, the authors sought to determine whether differences in the number of CSCs could account for this clinical observation. METHODS: CSC populations in HPV16-positive and HPV-negative HNSCC were assessed using a proprietary assay based on expression of the enzyme aldehyde dehydrogenase (ALDH), an in vitro tumorsphere formation assay, and an in vivo limiting cell dilution in nonobese diabetic/severe combined immunodeficiency mice. A high-density tissue microarray was stained with ALDH1, a CSC marker, to determine the association between CSCs and HPV16-positive/HPV-negative OPSCC. RESULTS: HPV16-positive HNSCC had a greater intrinsic CSC pool than HPV-negative HNSCC. Inactivation of p53 has been identified as a major mechanism for the elevated CSC population in HPV16-positive HNSCC. In vivo limiting cell dilution experiments using tumors from patients with HPV16-positive and HPV-negative OPSCC indicated that the CSC frequency was 62.5-fold greater in an HPV16-positive OPSCC tumor than in an HPV-negative OPSCC tumor. Primary tumors from patients with HPV16-positive OPSCC were associated with elevated tumor ALDH1 staining, further extending the association between HPV16 and CSCs. CONCLUSIONS: The current data and the clinical observation that patients with HPV16-positive HNSCC respond more favorably to current treatment paradigms than patients with HPV-negative HNSCC support the suggestion that CSC phenotype is not homogeneous. Therefore, the reliance on the CSC number may be insufficient to accurately assess the potential of a particular tumor for disease recurrence and/or progression.

Does body mass index matter while selecting the flap type for pharyngeal reconstructions?

The aim of our study was to investigate the effect of patient-related factors, such as the body mass index (BMI) and tumor size, in selecting the flap type for the reconstruction of pharyngeal defects. This retrospective review included 182 patients with pharyngeal defect reconstructions with free and pedicled flaps at the Ohio State University from January 2005 to December 2008. We conducted a retrospective comparison of variety of different flap reconstruction techniques. We compared different flap reconstruction with BMI and tumor size without functional outcome such as swallowing and speech data. Although there was no statistically significant correlation (P > 0.05) when comparing the free flaps with pedicled flaps according to the BMI and tumor size, there was an obvious tendency to prefer radial forearm free flap over anterolateral thigh free flap in patients who are overweight and those with obesity with a ratio of 32:3. In the same group of patients, a similar tendency was observed to prefer fibular free flap over iliac crest free flap with a ratio of 14:5, whereas the ratio was becoming 3:5 in favor of iliac crest free flap over fibular free flap in patients with BMI of 24 or lower. Despite the fact that surgeons' experience with a certain flap type is one of the most important factors while determining which flap to reconstruct, BMI might have a significant impact while selecting the free flap types for the reconstruction of pharyngeal defects.

Pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest for salvage mandibular reconstruction: Case and technique.

In the era of free flap reconstruction, mandibular defects are routinely reconstructed with osseous free flaps, and non-free flap bony reconstruction options are limited. A patient with T4N0 mandibular squamous cell carcinoma underwent resection with fibula free flap reconstruction of a parasymphyseal to angle defect. After free flap failure due to venous congestion, the flap was explanted. He declined additional free flap reconstruction and elected to proceed with pedicled osteomyocutaneous pectoralis major with rib. In this case presentation, we discuss the technical details of harvest of this flap using the 6th rib. The pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest, which is infrequently described in the literature, remains a viable option for bony reconstruction, particularly in the salvage setting.

National Trends in 30-Day Readmission Following Transoral Robotic Surgery for Oropharyngeal Squamous Cell Carcinoma.

Importance: As the incidence of oropharyngeal squamous cell carcinoma (OPSCC) continues to rise in the US, an increasing number of patients are being treated with transoral robotic surgery (TORS). Readmission following surgery can potentially delay initiation of adjuvant treatment and affect survival outcomes. Objective: To identify risk factors for 30-day postoperative readmission in patients undergoing TORS for OPSCC. Design, Setting, and Participants: This retrospective, population-based cohort study used data from the Nationwide Readmissions Database from 2010 to 2017. All patients undergoing TORS for OPSCC were identified using International Classification of Diseases codes and included. Exclusion criteria were age younger than 18 years or incomplete information regarding index admission or readmission. The analysis was performed from April to October 2023. Exposure: TORS for OPSCC. Main Outcomes and Measures: Univariate and multivariate analyses were performed to determine factors associated with 30-day readmission. Covariates included demographics and medical comorbidities, socioeconomic factors, hospital characteristics, and surgical details. Trends in readmission over time, reasons for readmission, and characteristics of the readmission were also examined. Results: A weighted total of 5544 patients (mean [SD] age, 60.7 [0.25] years; 4475 [80.7%] male) underwent TORS for OPSCC. The overall readmission rate was 17.5% (n = 971), and these rates decreased over the study period (50 of 211 patients [23.7%] in 2010 vs 58 of 633 patients [9.1%] in 2017). Risk factors associated with readmission included male sex (adjusted odds ratio [AOR], 1.54; 95% CI, 1.07-2.20) and a diagnosis of congestive heart failure (AOR, 2.42; 95% CI, 1.28-4.58). Factors associated with decreased rate of readmission included undergoing concurrent selective neck dissection (AOR, 0.30; 95% CI, 0.22-0.41). Among the 971 readmissions, the most common readmission diagnoses were bleeding (151 [15.6%]), electrolyte and digestive problems (44 [4.5%]), pneumonia (44 [4.5%]), and sepsis (26 [2.7%]). Conclusions and Relevance: In this cohort study, readmission rates following TORS for oropharynx cancer decreased over time; however, a subset of patients required readmission most commonly related to bleeding, infection, and electrolyte imbalance. Concurrent neck dissection may be protective against readmission. Elucidation of risk factors for readmission after TORS for OPSCC offers opportunities for evidence-based shared decision-making, quality improvement initiatives, and improved patient counseling.

Transoral robotic resection of selected parapharyngeal space tumors.

Currently, transoral robotic surgery (TORS) with the daVinci robot is mainly used for squamous cell carcinoma of the oropharynx and supraglottic larynx. The safety, efficacy, and functional outcomes regarding this approach have previously been described. In addition to transoral resection of squamous cell carcinoma, we have found use for this technique in removing selected tumors of the parapharyngeal space. Three patients with benign or malignant tumors of the parapharyngeal space who underwent successful transoral resection using the daVinci robot were included in the study. In all three cases, complete tumor excision was achieved without any complication. None required conversion to an open procedure. Mean TORS operative time and intraoperative blood loss were 16.3 min and 4.7 mL, respectively. Inadequate oral exposure, involvement of the internal carotid artery, limited cervical spine mobility and large tumor size are the main limitations of this approach. Result indicates that magnified view, 3D visualization with the combination of the transoral robotic experience, allow en bloc resection of selected parapharyngeal space tumors located medial to the carotid sheath.

Solitary fibrous tumor of the accessory parotid gland: a unique case.

Solitary fibrous tumors are benign spindle-cell neoplasms, mostly originating from the visceral pleura. They are common in individuals aged 20-70 with no sex predilection. To our knowledge, this is the unique case of the solitary fibrous tumor originating from the accessory parotid gland in the literature.

Body Mass Index (BMI) Related Morbidity with Thyroid Surgery.

OBJECTIVES: The increase in incidence of thyroid cancer correlates with strict increases in body mass index (BMI) and obesity in the United States. Thyroid hormone dysregulation has been shown to precipitate circulatory volume, peripheral resistance, cardiac rhythm, and even cardiac muscle health. Theoretically, thyroid surgery could precipitate injury to the cardiopulmonary system. METHODS: The American College of Surgery National Quality Improvement Program database was queried for thyroidectomy cases in the 2007-2020 Participant User files. Continuous and categorical associations between BMI and cardiopulmonary complications were investigated as reported in the database. RESULTS: The query resulted 186,095 cases of thyroidectomy procedures in which the mean age was 51.3 years and sample was 79.3% female. No correlation was evident in univariate and multivariate analyses between BMI and the incidence of postoperative stroke or myocardial infarction. The incidence of complications was extremely low. However, risk of deep venous thrombosis correlated with BMI in the categorical, univariate, and multivariate (OR 1.036, CI 1.014-1.057, p < 0.01) regression analysis. Additionally, increased BMI was associated with increased risk of pulmonary embolism (PE) (OR 1.050 (1.030, 1.069), p < 0.01), re-intubation (OR 1.012 (1.002, 1.023), p = 0.02), and prolonged intubation (OR 1.031 (1.017, 1.045), p < 0.01). CONCLUSION: Despite the rarity of cardiopulmonary complications during thyroid surgery, patients with very high BMI carry a significant risk of deep venous thrombosis, PE, and prolonged intubation. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2823-2830, 2023.

Demographic and Academic Productivity Trends Among American Head & Neck Society Fellows Over a 20-Year Period.

Importance: Historical data reveal that, compared with women, men are more likely to pursue a head and neck surgical oncology fellowship, but little is known about possible gender differences in academic productivity. Objective: To assess demographic trends and academic productivity among American Head & Neck Society (AHNS) fellowship graduates. Design, Setting, and Participants: This cross-sectional study used electronically published data from the AHNS on fellowship graduates in the US and Canada from July 1, 1997, to June 30, 2022. Scopus was used to extract h-indices for each graduate. Exposure: Scholarly activity. Main Outcomes and Measures: Main outcomes were changes in demographic characteristics and academic productivity among AHNS graduates over time. Data analysis included effect size, η2, and 95% CIs. Results: A total of 691 AHNS fellowship graduates (525 men [76%] and 166 women [24%]) were included. Over the study period, there was an increase in the number of programs offering a fellowship (η2, 0.84; 95% CI, 0.68-0.89) and an increase in the absolute number of women who completed training (η2, 0.66; 95% CI, 0.38-0.78). Among early-career graduates pursuing an academic career, there was a small difference in the median h-index scores between men and women (median difference, 1.0; 95% CI, -1.1 to 3.1); however, among midcareer and late-career graduates, there was a large difference in the median h-index scores (midcareer graduates: median difference, 4.0; 95% CI, 1.2-6.8; late-career graduates: median difference, 6.0; 95% CI, 1.0-10.9). A higher percentage of women pursued academic positions compared with men (106 of 162 [65.4%] vs 293 of 525 [55.8%]; difference, 9.6%; 95% CI, -5.3% to 12.3%). Conclusions and Relevance: This cross-sectional study suggests that women in head and neck surgery begin their careers with high levels of academic productivity. However, over time, a divergence in academic productivity between men and women begins to develop. These data argue for research to identify possible reasons for this observed divergence in academic productivity and, where possible, develop enhanced early faculty development opportunities for women to promote their academic productivity, promotion, and advancement into leadership positions.

Immediate resection of positive margins improves local control in oral tongue cancer.

OBJECTIVES: This study investigates the impact of immediate resection of positive margins on local control of oral tongue cancer. MATERIALS AND METHODS: We analyzed 273 consecutive oral tongue cancers resected from 2013 to 2018. Additional resection was performed in cases during the initial operation based on surgeon inspection of the specimen and/or frozen margins. Positive margins were defined as invasive carcinoma/high-grade dysplasia < 1 mm from the inked edge. Patients were grouped as follows: negative margin (Group 1); positive margin with immediate additional tissue resection (Group 2); and positive margin without additional tissue resection (Group 3). RESULTS: Overall, the rate of local recurrence was 7.7 % (21/273), and the rate of positive main specimen margin was 17.9 %. Of these patients, 38.8 % (19/49) underwent immediate additional resection of the presumed positive margin. Group 3 had higher local recurrence rates than Group 1 after adjustment for T-stage (aHR 2.8 [95 % CI 1.0-7.7], p = 0.04). Group 2 had similar rates of local recurrence (aHR 0.45 [95 % CI 0.06-3.6], p = 0.45). Three year local recurrence free survival for Groups 1, 2, and 3 were 91 %, 92 % and 73 %, respectively. Compared to the main specimen margin, sensitivity of intraoperative frozen tumor bed margins was 17.4 %, and specificity was 95 %. CONCLUSION: In patients with positive main specimen margins, anticipation and detection in real-time with immediate additional tissue resection reduced local recurrence to rates similar to those with negative main specimen margins. These findings support the use of technology to provide real-time intraoperative margin data and guide additional resection for improved local control.