Phase II Randomized Trial of Transoral Surgery and Low-Dose Intensity Modulated Radiation Therapy in Resectable p16+ Locally Advanced Oropharynx Cancer: An ECOG-ACRIN Cancer Research Group Trial (E3311).

PURPOSE: Definitive or postoperative chemoradiation (CRT) is curative for human papillomavirus-associated (HPV+) oropharynx cancer (OPC) but induces significant toxicity. As a deintensification strategy, we studied primary transoral surgery (TOS) and reduced postoperative radiation therapy (RT) in intermediate-risk HPV+ OPC. METHODS: E3311 is a phase II randomized trial of reduced- or standard-dose postoperative RT for resected stage III-IVa (American Joint Committee on Cancer-seventh edition) HPV+ OPC, determined by pathologic parameters. Primary goals were feasibility of prospective multi-institutional study of TOS for HPV+ OPC, and oncologic efficacy (2-year progression-free survival) of TOS and adjuvant therapy in intermediate-risk patients after resection. TOS plus 50 Gy was considered promising if the lower limit of the exact 90% binomial confidence intervals exceeded 85%. Quality of life and swallowing were measured by functional assessment of cancer therapy-head and neck and MD Anderson Dysphagia Index. RESULTS: Credentialed surgeons performed TOS for 495 patients. Eligible and treated patients were assigned as follows: arm A (low risk, n = 38) enrolled 11%, intermediate risk arms B (50 Gy, n = 100) or C (60 Gy, n = 108) randomly allocated 58%, and arm D (high risk, n = 113) enrolled 31%. With a median 35.2-month follow-up for 359 evaluable (eligible and treated) patients, 2-year progression-free survival Kaplan-Meier estimate is 96.9% (90% CI, 91.9 to 100) for arm A (observation), 94.9% (90% CI, 91.3 to 98.6]) for arm B (50 Gy), 96.0% (90% CI, 92.8 to 99.3) for arm C (60 Gy), and 90.7% (90% CI, 86.2 to 95.4) for arm D (66 Gy plus weekly cisplatin). Treatment arm distribution and oncologic outcome for ineligible or step 2 untreated patients (n = 136) mirrored the 359 evaluable patients. Exploratory comparison of functional assessment of cancer therapy-head and neck total scores between arms B and C is presented. CONCLUSION: Primary TOS and reduced postoperative RT result in outstanding oncologic outcome and favorable functional outcomes in intermediate-risk HPV+ OPC.

N95 vs Half-face Respirator Wear in Surgical Trainees: Physiologic and Psychological Effects of Prolonged Use.

OBJECTIVES: As specialists of the upper airway, otolaryngologists are at high risk for COVID-19 transmission. N95 and half-face respirator (HFR) masks are commonly worn, each with advantages in functionality and comfort. In this study, physiologic and psychological parameters of prolonged N95 vs HFR wear were compared. STUDY DESIGN: Prospective crossover cohort study. SETTING: Single academic tertiary care hospital. METHODS: A prospective crossover cohort study was performed. Healthy otolaryngology trainees and medical students (N = 23) participated and wore N95 and HFR masks continuously for 3 hours each on separate days. Various measures were analyzed: vitals, spirometry variables, scores on the State-Trait Anxiety Inventory and HIT-6 (Headache Impact Test-6), distress, and "difficulty being understood." RESULTS: The average age was 26.3 years (SD, 3.42). There were no significant differences in vital signs and spirometry variables between N95 and HFR wear. N95 wear was associated with decreases in oxygen saturation of approximately 1.09% more than with HFRs (95% CI, 0.105-2.077). State-Trait Anxiety Inventory scores increased more with HFR wear when compared with mean changes with N95 wear (95% CI, 1.350-8.741). There were no significant differences in HIT-6 scores or distress levels between masks. The proportions of participants reporting difficulty being understood was significantly higher with HFRs. CONCLUSIONS: Oxygen saturation decreases with prolonged N95 wear, but anxiety and difficulty being understood are greater with HFR wear. Although HFRs have less resistance to gas exchange, N95 respirators may produce less anxiety and distress in clinical situations. Further studies are warranted to evaluate the clinical significance of these differences. LEVEL OF EVIDENCE: 2.

Current salivary biomarkers for detection of human papilloma virus-induced oropharyngeal squamous cell carcinoma.

Human papilloma virus (HPV) infection is a key risk factor and etiology for oropharyngeal squamous cell carcinoma (OPSCC). HPV-induced OPSCC is rapidly increasing in incidence, with men experiencing increased mortality. When identified at an early stage, HPV-induced OPSCC can be successfully treated. Diagnosis of HPV-related OPSCC relies on an expert physical examination and invasive biopsy. Since saliva bathes the oropharyngeal mucosa and can be collected noninvasively, saliva obtained via salivary risings is an attractive body fluid for early detection of HPV-induced OPSCC. A plethora of DNA, RNA, and protein salivary biomarkers have been explored. This review discusses these markers and their robustness for detecting oncogenic HPV in OPSCC saliva samples. Methods detecting HPV DNA were more reliable than those detecting RNA, albeit both require time-consuming analyses. Salivary HPV proteomics are a new, promising focus of HPV detection research, and while more practical, lag behind nucleic acid detection methods in their development.

Benign and Malignant Granular Cell Tumor of the Hypopharynx: Two Faces of a Rare Entity.

Granular cell tumors (GCT) are rare soft tissue tumors that involve the head and neck in 50% of patients. Two distinct variants of GCT, one benign (bGCT) and the other malignant (mGCT), involving the hypopharynx, a subsite of the larynx, are presented here. The clinical presentations, radiographic features, pathologic diagnosis in these two variants of GCT are discussed. The mGCT was diagnosed only after complete tumor excision. This report highlights the importance of complete excision of the tumor mass, as diagnosis of mGCT can be exceedingly difficult to make on a small biopsy specimen. Therefore, complete excision is recommended for definitive diagnosis and treatment of GCTs.

A novel surgeon credentialing and quality assurance process using transoral surgery for oropharyngeal cancer in ECOG-ACRIN Cancer Research Group Trial E3311.

PURPOSE: Understanding the role of transoral surgery in oropharyngeal cancer (OPC) requires prospective, randomized multi-institutional data. Meticulous evaluation of surgeon expertise and surgical quality assurance (QA) will be critical to the validity of such trials. We describe a novel surgeon credentialing and QA process developed to support the ECOG-ACRIN Cancer Research Group E3311 (E3311) and report outcomes related to QA. PATIENTS AND METHODS: E3311 was a phase II randomized clinical trial of transoral surgery followed by low- or standard-dose, risk-adjusted post-operative therapy with stage III-IVa (AJCC 7th edition) HPV-associated OPC. In order to be credentialed to accrue to this trial, surgeons were required to demonstrate active hospital credentials and technique-specific surgical expertise with ≥20 cases of transoral resection for OPC. In addition, 10 paired operative and surgical pathology reports from the preceding 24 months were reviewed by an expert panel. Ongoing QA required <10% rate of positive margins, low oropharyngeal bleeding rates, and accrual of at least one patient per 12 months. Otherwise surgeons were placed on hold and not permitted to accrue until re-credentialed using a new series of transoral resections. RESULTS: 120 surgeons trained in transoral minimally invasive surgery applied for credentialing for E3311 and after peer-review, 87 (73%) were approved from 59 centers. During QA on E3311, positive final pathologic margins were reported in 19 (3.8%) patients. Grade III/IV and grade V oropharyngeal bleeding was reported in 29 (5.9%) and 1 (0.2%) of patients. CONCLUSIONS: We provide proof of concept that a comprehensive credentialing process can support multicenter transoral head and neck surgical oncology trials, with low incidence of positive margins and *grade III/V oropharyngeal bleeding.

False-positive reverse transcriptase polymerase chain reaction screening for SARS-CoV-2 in the setting of urgent head and neck surgery and otolaryngologic emergencies during the pandemic: Clinical implications.

BACKGROUND: No reports describe falsepositive reverse transcriptase polymerase chain reaction (RT-PCR) for novel coronavirus in preoperative screening. METHODS: Preoperative patients had one or two nasopharyngeal swabs, depending on low or high risk of viral transmission. Positive tests were repeated. RESULTS: Forty-three of 52 patients required two or more preoperative tests. Four (9.3%) had discrepant results (positive/negative). One of these left the coronavirus disease (COVID) unit against medical advice despite an orbital abscess, with unknown true disease status. The remaining 3 of 42 (7.1%) had negative repeat RT-PCR. Although ultimately considered falsepositives, one was sent to a COVID unit postoperatively and two had urgent surgery delayed. Assuming negative repeat RT-PCR, clear chest imaging, and lack of subsequent symptoms represent the "gold standard," RT-PCR specificity was 0.97. CONCLUSIONS: If false positives are suspected, we recommend computed tomography (CT) of the chest and repeat RT-PCR. Validated serum immunoglobulin testing may ultimately prove useful.

Ethical surgical triage of patients with head and neck cancer during the COVID-19 pandemic.

BACKGROUND: Coronavirus has serially overtaken our metropolitan hospitals. At peak, patients with acute respiratory distress syndrome may outnumber mechanical ventilators. In our Miami Hospital System, COVID-19 cases have multiplied for 4 weeks and elective surgery has been suspended. METHODS: An Otolaryngologic Triage Committee was created to appropriately allocate resources to patients. Hospital ethicists provided support. Our tumor conference screened patients for nonsurgical options. Patients were tested twice for coronavirus before performing urgent contaminated operations. N95 masks and protective equipment were conserved when possible. Patients with low-grade cancers were advised to delay surgery, and other difficult decisions were made. RESULTS: Hundreds of surgeries were canceled. Sixty-five cases screened over 3 weeks are tabulated. Physicians and patients expressed discomfort regarding perceived deviations from standards, but risk of COVID-19 exposure tempered these discussions. CONCLUSIONS: We describe the use of actively managed surgical triage to fairly balance our patient's health with public health concerns.

CD44 and associated markers in oral rinses and tissues from oral and oropharyngeal cancer patients.

OBJECTIVES: Oral and oropharyngeal squamous cell carcinoma (OOPSCC) is a debilitating disease. Salivary rinses contain soluble tumor markers including CD44 (solCD44) and total protein (TP) that may aid detection and prognosis of these aggressive tumors. Here we aim to examine the relationship between these salivary biomarkers and tissue markers p16 and CD44 and determine whether these markers can predict progression-free survival (PFS) and overall survival (OS). MATERIALS AND METHODS: Prospective study to update biomarkers using oral rinses and tissues from OOPSC patients enrolled between 2007 and 2012 at an academic tertiary referral center. 64 cases from a 300-subject case-control study with archived tissue for immunohistochemistry were included. RESULTS: 82.8% were male, 84.4% were ever smokers, 70.3% had disease stage T3-T4, and 57.8% presented with nodal disease. Nineteen patients (25%) were p16 positive. The group with strong tissue CD44 expression in membrane and cytoplasm had higher levels of solCD44 (mean 10.73 ng/ml) than other groups (5.47 ng/ml) (p = 0.033). TP levels were significantly reduced in oral rinses from subjects with p16 universal gross tumor tissue staining (mean 0.80 vs. 1.08 mg/ml; p = 0.039). On multivariate analysis, universal CD44 gross tissue staining and TP levels ≥ 1 mg/ml demonstrated poorer PFS, with the latter also affecting OS. Poorer survival was associated with soluble CD44 ≥ 5.33 ng/ml and TP ≥ 1 mg/ml. CONCLUSIONS: Direct associations were found between high solCD44 levels and strong membrane and cytoplasmic CD44 expression, and between high TP levels and peripheral/mixed p16 gross staining. Poorer PFS and OS are significantly associated with higher levels of solCD44 and protein in oral rinses.

Meta-analysis comparing outcomes of different transoral surgical modalities in management of oropharyngeal carcinoma.

BACKGROUND: Optimal transoral surgical modality for oropharyneal carcinoma is currently unclear. Transoral laser surgery (TLS), transoral robotic surgery (TORS), and conventional direct transoral (DT) oropharyngectomy are the main current transoral surgical modalities for oropharyngeal carcinoma. METHODS: MEDLINE was systematically searched through PubMed. Reference lists were reviewed. Random-effects models were used to combine studies within each group. Tests for heterogeneity were used to explore difference in effect size between groups in subgroup analysis. RESULTS: Nine studies (404 patients) in TORS arm, five studies (498 patients) in TLS arm, and three studies (335 patients) in DT arm were included. Early T classification (T1-T2) for TORS and DT were higher compared to TLS group (P < .001). There was no significant difference between groups in the rate of invaded margin, post-operative oropharyngeal bleeding, temporary tracheotomy, and gastrostomy dependence. CONCLUSION: The available data do not yet provide clear evidence of superiority of any one modality.

Human papillomavirus-induced oropharyngeal cancer in Hispanics in the United States.

OBJECTIVES/HYPOTHESIS: Determine disparities in survival outcome and clinical presentation between Hispanic and non-Hispanic white patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma. STUDY DESIGN: Retrospective clinical research. METHODS: Clinical data on Hispanics and non-Hispanic white patients with diagnosis of human papillomavirus/p16-positive oropharyngeal squamous cell carcinoma were drawn from a tumor registry from the University of Miami Hospitals and Clinics from 2008 to 2014. Of 436 patients with oropharyngeal squamous cell carcinoma, 237 patents met inclusion criteria. Patient's age, gender, smoking history, alcohol history, race/ethnicity, tumor T stage, nodal N stage, and composite TNM stage were included in the analysis. Associations between race and other categorical variables were explored with χ2 test or Fisher exact test where appropriate. Survival curves were generated using the Kaplan-Meier method. RESULTS: Significant differences in clinical presentation was detected between Hispanic (N = 70) and non-Hispanic white (N = 167) patients. Hispanic human papillomavirus-positive oropharyngeal squamous cell carcinoma patients showed a higher proportion of women with disease, a higher proportion of patients presenting with tonsil rather than tongue base primary subsite cancer, and a higher proportion of patients who do not consume alcohol compared to non-Hispanic white human papillomavirus-positive oropharyngeal squamous cell carcinoma patients. A statistically significant survival difference between these two ethnic groups was not detected in the current dataset. CONCLUSIONS: Unique differences in clinical presentations between Hispanic patients and non-Hispanic whites with human papillomavirus-positive oropharyngeal squamous cell carcinoma were detected. This may be the first study to report novel clinical presentation in Hispanic human papillomavirus-positive patients with oropharyngeal squamous cell carcinoma living in the United States. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1097-1101, 2017.

Lipoma and liposarcoma of the larynx: case reports and literature review.

OBJECTIVE: Two cases of laryngeal lipomatous tumors are presented. Their diagnoses and management are discussed and contrasted. METHODS: Case report and literature review. RESULTS: Patient 1 is a 58 year old male presenting with five years of progressive shortness of breath, dysphagia, and globus sensation. Clinical exam and imaging study showed a 3.5 cm hypodense laryngeal mass, and he underwent transoral robotic-assisted surgery for complete excision. Final pathology revealed a well-differentiated liposarcoma. Patient 2 is a 79 year old female presenting with one year of non-progressive hoarseness and globus sensation. Clinical examination and imaging study revealed a 1.8 cm hypodense laryngeal mass. Transoral endoscopic complete excision of the submucosal mass was performed. Final pathology revealed benign spindle-cell lipoma. CONCLUSION: Liposarcoma and lipoma may present with similar symptomatology, clinical, and imaging findings. Pathology evaluation is of utmost importance for definitive diagnosis. Therefore, diagnosis and treatment of laryngeal lipomatous lesions are best accomplished with complete excision of the mass.

Pleomorphic adenoma of the trachea.

Primary pleomorphic adenoma of the trachea is rare, as only 33 cases have been previously reported worldwide since 1922. We describe a new case of primary tracheal pleomorphic adenoma that was discovered incidentally in a 78-year-old man. The tumor was excised, and the patient recovered without complication. Salivary gland tumors of the trachea should be considered in the differential diagnosis of tracheal lesions; the diagnosis is confirmed by pathologic evaluation. Patients are adequately treated with sleeve resection and primary anastomosis whenever possible.

Unequal burden of head and neck cancer in the United States.

BACKGROUND: Black Americans are adversely affected by many types of malignancies. METHODS: We reviewed data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program to evaluate racial disparities in head and neck cancer incidence, mortality, and survival. RESULTS: Head and neck cancer incidence is greater in the black population and peaks at a younger age. The incidence disparity is decreasing over time and is less for cancers of the oral cavity/pharynx (OCP) than for cancers of the larynx. The disparity in survival after diagnosis is substantial for both sites and is increasing over time because of improvement in survival for the white population, but not for the black population. Some, but not all, of the survival disparity is due to more advanced stage at the time of diagnosis within the black population. The age-adjusted mortality rate for black men is approximately twice the rate for white men. CONCLUSION: Black Americans clearly bear a greater burden from head and neck cancer. The underlying causes are largely unknown, but are most likely due to a complex interplay of differences in access to health care, quality of medical care, biologic/genetic factors, incidence of comorbid conditions, exposure to carcinogens, diet, and cultural beliefs. Prospective studies are needed to define the relative importance of these factors and to inform intervention strategies.

Complete esophageal stenosis secondary to peptic stricture in the cervical esophagus: case report.

Complete esophageal stenosis secondary to peptic stricture in the upper esophagus is rare. It is, however a serious medical problem that may require otolaryngologic intervention because of life-threatening dysphagia and weight loss. We report the case of an elderly patient who presented with an upper esophageal stricture, without the typical symptoms of gastroesophageal reflux disease, that progressed to complete esophageal obstruction despite use of proton pump inhibitors and esophageal dilatation. Definitive management of this difficult problem required esophagectomy and gastric pull-up. We discuss the pathophysiology, clinical presentation, differential diagnosis, and multidisciplinary management of peptic esophageal strictures. This case illustrates the difficulty in managing high peptic strictures.

Endogenous expression of CD80 co-stimulatory molecule facilitates in vivo tumor regression of oral squamous carcinoma.

BACKGROUND: Most tumor tissues, especially those of non-hematopoietic origin, do not express CD80 co-stimulatory molecules, possibly as a mechanism to evade immune surveillance. The objective of this study was to determine whether abundant endogenous CD80 expression on oral squamous cell carcinoma (SCC) early during tumor progression can facilitate immune elimination and reverse immune tolerance. MATERIALS AND METHODS: The growth of regressor and progressor oral SCC lines with differing endogenous CD80 expression were examined in immune-competent and -deficient mice. Immune effectors were determined by T-cell depletion experiments and immunohistochemistry. RESULTS: Our studies show regression of early tumor growth when immunocompetent animals are inoculated with oral SCC progressor cell lines expressing abundant endogenous CD80. The CD80-induced antitumor response was due largely to induced T-cell responses. CONCLUSION: Our findings suggest that inadequate CD80 expression during early oral SCC formation may contribute to the escape of tumors from immune elimination. This information can be useful in the design of new approaches to generate more effective immunotherapy against this disease.

Animal models for the study of squamous cell carcinoma of the upper aerodigestive tract: a historical perspective with review of their utility and limitations. Part A. Chemically-induced de novo cancer, syngeneic animal models of HNSCC, animal models of transplanted xenogeneic human tumors.

Understanding the complex histological, genetic and molecular changes that lead to malignant transformation of squamous epithelia of the head and neck will likely guide the development of methods for improved diagnosis, monitoring and treatment of head and neck squamous cell carcinoma (HNSCC). The development and use of animal models that closely mimic the histopathology and molecular pathogenesis of HNSCC in humans would greatly expand the research possibilities and provide a means of testing potential therapeutic agents. However, many available animal models of HNSCC fall short of this objective. In order for investigators to select the appropriate model to answer scientific questions, it is important to understand the benefits and limitations of available animal models for the study of HNSCC. The purpose of this work is to give an overview of the most pertinent animal models of HNSCC, and to discuss future directions of research in this field.

Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) involves the upper aerodigestive tract and can destroy the structure and function of organs involved in voice, speech, taste, smell and hearing, as well as vital structures necessary for survival. HNSCC has long been a treatment challenge because of the high rate of recurrences and of advanced disease at the time of diagnosis. Molecular identification of tissue biomarkers in diagnostic biopsy specimens may not only identify patients at risk for developing HNSCC but may also select patients that may benefit from more aggressive treatment modalities. Several biomarkers studied to date such as the proteins p53, cyclin D1, p16, Cox-2 enzyme, epidermal growth factor and vascular endothelial growth factor receptors, matrix metalloproteinases and the Fhit marker for genomic instability could be manipulated for the therapeutic benefit of these patients. This review presents the most updated information on molecular biomarkers with the greatest prognostic potential in HNSCC and discusses some factors that contribute to the controversy concerning their prognostic importance.

A pilot study of longitudinal serum cytokine and angiogenesis factor levels as markers of therapeutic response and survival in patients with head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) were previously shown to express a repertoire of cytokines and angiogenesis factors that contribute to malignant pathogenesis and are detectable in serum. Pretreatment and posttreatment serum levels of cytokines and angiogenesis factors were evaluated as markers for outcome in patients with HNSCC. METHODS: Baseline cytokine and factor levels of 29 patients with HNSCC were compared with those of 15 age-matched and sex-matched controls, and pretreatment and posttreatment levels of 22 of the patients eligible for treatment and followed for a median of 37 months were compared. RESULTS: Mean serum concentrations of interleukin (IL)-6, IL-8, hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), and growth regulated oncogene 1 (GRO-1) were increased in patients with HNSCC, but elevation of these factors was not associated with clinical outcome. However, changes in first posttreatment serum cytokine levels were observed for many of the patients consistent with response, progression, and survival. Later increases in IL-6 or HGF were observed in patients who had a relapse and inflammatory or infectious complications. A relationship between the change in the pretreatment and first posttreatment cytokine measurement with survival was detected for HGF, IL-8, IL-6, and VEGF using a Cox-proportional hazards model (p = .004, p = .06, p = .10, and p = .11). The association between longitudinal decreases in IL-6, IL-8, VEGF, and HGF throughout the follow-up with survival was detected with a time-dependent Cox model (p = .01, .07, .08, and .05, respectively). CONCLUSIONS: Longitudinal changes in serum HGF, IL-6, IL-8, and VEGF were detected with treatment response, relapse, or complications in individual patients and were associated with survival, with HGF showing the strongest relationship with survival. HGF, IL-6, IL-8, and VEGF merit investigation as markers of response, survival, and recurrence in larger prospective studies.