Proton therapy re-irradiation outcomes and genomic landscape of patients with recurrent head and neck cancer.

INTRODUCTION: Re-irradiation (re-RT) for recurrent head and neck cancer (rHNC) is challenging. We describe clinical outcomes and toxicity of proton therapy (PT) for recurrent HNC, and report genomic alterations associated with patterns of failure. MATERIALS & METHODS: We performed a retrospective analysis of rHNC patients treated with PT. Outcomes were estimated using the Kaplan-Meier method. Univariate (UVA) and multivariate analyses (MVA) were performed to assess multiple patient factors. Next-generation sequencing and genomic analyses were performed on available samples. RESULTS: Eighty-nine patients treated with PBS-PT for rHNC with a median follow-up of 12 mo (0-71 mo) were included. The 1- and 2-y local control (LC) rates were 80.8 % (95 % CI: 70.8-90.8) and 66.2 % (95 % CI: 50.7-81.7), and 1- and 2-y distant metastasis-free survival (DMFS) were 41.0 % (95 % CI: 30.0-52.0) and 26.3 % (95 % CI: 15.7-36.9). The median overall survival (OS) was 13 mo (95 % CI: 9.3-16.7). On UVA and MVA, smaller gross tumor volume (GTV) was associated with improved OS (HR 1.002, P = 0.004), DMFS (HR 1.002, P = 0.004), and PFS (HR 1.002, P = 0.014). There were 35 late Gr3 + toxicity events (30.3 %). Patients with higher candidate gene-specific mutation burden (genes with [OR] > 2, P < 0.05) had inferior PFS. TP53, NOTCH4, and ARID1B mutations were associated with inferior DMFS (OR > 2, P < 0.05). CONCLUSIONS: PBS-PT is effective at achieving LC for rHNC with favorable toxicity. Distant metastases are common, and associated with TP53, NOTCH4, and ARID1B mutations. Inclusion of genomic alterations in the clinical decision process may be warranted.

Disease and toxicity outcomes for a modern cohort of patients with squamous cell carcinoma of cutaneous origin involving the parotid gland: Comparison of volumetric modulated arc therapy and pencil beam scanning proton therapy.

OBJECTIVES: We sought to describe outcomes for locally advanced cutaneous squamous cell carcinoma (SCC) involving the parotid treated with volumetric modulated arc therapy (VMAT) versus pencil beam scanning proton beam therapy (PBT). MATERIALS AND METHODS: Patients were gathered from 2016 to 2022 from 5 sites of a large academic RT department; included patients were treated with RT and had parotid involvement by: direct extension of a cutaneous primary, parotid regional spread from a previously or contemporaneously resected but geographically separate cutaneous primary, or else primary parotid SCC (with a cutaneous primary ostensibly occult). Acute toxicities were provider-reported (CTCAE v5.0) and graded at each on treatment visit. Statistical analyses were conducted. RESULTS: Median follow-up was 12.9 months (1.3 - 72.8); 67 patients were included. Positive margins/extranodal extension were present in 34 cases; gross disease in 17. RT types: 39 (58.2 %) VMAT and 28 (41.8 %) PBT. Concurrent systemic therapy was delivered in 10 (14.9 %) patients. There were 17 treatment failures (25.4 %), median time of 168 days. Pathologically positive neck nodes were associated with locoregional recurrence (p = 0.015). Oral cavity, pharyngeal constrictor, and contralateral parotid doses were all significantly lower for PBT. Median weight change was -3.8 kg (-14.1 - 5.1) for VMAT and -3 kg (-16.8 - 3) for PBT (p = 0.013). Lower rates of ≥ grade 1 xerostomia (p = 0.002) and ≥ grade 1 dysguesia (p < 0.001) were demonstrated with PBT. CONCLUSIONS: Cutaneous SCC involving the parotid can be an aggressive clinical entity despite modern multimodal therapy. PBT offers significantly lower dose to organs at risk compared to VMAT, which seemingly yields diminished acute toxicities.

Two Head and Neck Carcinomas With Squamous and Mucinous Components and Human Papillomavirus Associations: Maxillary Mucoepidermoid Carcinoma ex Sinonasal Schneiderian Papilloma and Tonsillar Invasive Stratified Mucin Producing Carcinoma (ISMC).

Carcinomas of the head-and-neck region with squamous and glandular/mucinous features constitute a heterogeneous group, with a significant minority of tumors showing an human papillomavirus (HPV) association. The differential diagnosis is usually between mucoepidermoid carcinoma (MEC) and adenosquamous carcinoma. We present here two tumors that exemplify both the challenges of diagnostic classification, as well as the complex relationship to HPV: (a) a low risk HPV positive/p16 negative carcinoma that is most consistent with a relatively typical intermediate grade mucoepidermoid type carcinoma with complete MEC phenotype (three cell types), originating from intranasal sinonasal papillomas with exophytic and inverted patterns, and invading surrounding maxillary compartments, and (b) a p16 and keratin 7 (KRT7) positive carcinoma of the right tonsil, characterized by stratified squamous and mucinous cell (mucocyte) features. Whereas the first tumor represents a typical MEC ex-Schneiderian papilloma, the second is morphologically most consistent with the, novel for this anatomic location, diagnosis of "invasive stratified mucin producing carcinoma" (ISMC), pointing to an analogy to similar, high-risk HPV-driven malignancies recently described in the gynecologic (GYN) and genitourinary (GU) areas. Both tumors, despite their mucoepidermoid-like features had no connection to salivary glands and lacked the MAML2 translocation typical of salivary gland MEC, pointing to a mucosal/non-salivary gland origin. Using these two carcinomas as examples, we attempt to address questions related to: (a) the histological distinction between MEC, adenosquamous carcinoma, and ISMC, (b) similarities and differences between these histological entities in mucosal sites versus morphologically similar salivary gland tumors, and (c) the role of HPV in these tumors.

Regionalization of Head and Neck Oncology Tumor Boards: Perspectives of Collaborating Physicians.

Objectives: To survey academic and community physician preferences regarding the virtual multidisciplinary tumor board (MTB) for further improvement and expansion. Study Design: This anonymous 14-question survey was sent to individuals that participated in the head and neck virtual MTBs. The survey was sent via email beginning August 3, 2021, through October 5, 2021. Setting: The University of Maryland Medical Center and regional practices in the state of Maryland. Methods: Survey responses were recorded and presented as percentages. Subset analysis was performed to obtain frequency distributions by facility and provider type. Results: There were 50 survey responses obtained with a response rate of 56%. Survey participants included 11 surgeons (22%), 19 radiation oncologists (38%), and 8 medical oncologists (16%), amongst others. More than 96% of participants found the virtual MTB to be useful when discussing complex cases and impactful to future patient care. A majority of respondents perceived a reduction in time to adjuvant care (64%). Community and academic physician responses strongly agreed that the virtual MTB improved communication (82% vs 73%), provided patient-specific information for cancer care (82% vs 73%), and improved access to other specialties (66% vs 64%). Academic physicians, more so than community physicians, strongly agreed that the virtual MTB improves access to clinical trial enrollment (64% vs 29%) and can be useful in obtaining CME (64% vs 55%). Conclusion: Academic and community physicians view the virtual MTB favorably. This platform can be adapted regionally and further expanded to improve communication between physicians and improve multidisciplinary care for patients.

Gross tumor volume margin and local control in p16-positive oropharynx cancer patients treated with intensity modulated proton therapy.

BACKGROUND: To determine if the extent of high-dose gross tumor volume (GTV) to clinical target volume (CTV) expansion is associated with local control in patients with p16-positive oropharynx cancer (p16+ OPC) treated with definitive intensity modulated proton therapy (IMPT). METHODS: We performed a retrospective analysis of patients with p16+ OPC treated with IMPT at a single institution between 2016 and 2021. Patients with a pre-treatment PET-CT and restaging PET-CT within 4 months following completion of IMPT were analyzed. RESULTS: Sixty patients were included for analysis with a median follow-up of 17 months. The median GTV to CTV expansion was 5 mm (IQR: 2 mm). Thirty-three percent of patients (20 of 60) did not have a GTV to CTV expansion. There was one local failure within the expansion group (3%). CONCLUSION: Excellent local control was achieved using IMPT for p16+ OPC independent of GTV expansion. IMPT with minimal target expansions represent a potential harm-minimization technique for p16-positive oropharynx cancer.

Human Papillomavirus Impact on Temporal Treatment Trends in Oropharyngeal Carcinoma: 2010-2016.

INTRODUCTION: The study objective was to identify practice patterns in oropharyngeal cancer management from 2010 to 2016 among human papillomavirus (HPV)-associated and non-HPV-associated oropharyngeal squamous-cell carcinoma (OPSCC) patients. METHODS: The National Cancer Database was utilized to identify OPSCC patients from 2010 to 2016. Frequency distributions and multivariable analyses were generated to identify practice patterns and predictors of treatment modality. RESULTS: A total of 35,956 patients with nonmetastatic OPSCC were included. HPV status was not associated with a treatment modality preference. At academic centers, the proportion of HPV-associated OPSCC patients versus non-HPV-associated OPSCC patients undergoing surgical management was similar (35.7%; 35.9%). Community cancer programs treated patients less often surgically but with no significant treatment preference based on HPV status. Within each facility type, HPV status was not a predictor of surgical or nonsurgical management. CONCLUSION: HPV association does not appear to significantly influence treatment modality preference among OPSCC patients. The proportion of OPSCC patients undergoing surgical treatment declined from 2010 to 2016.

Advances in oral tongue reconstruction: a reconstructive paradigm and review of functional outcomes.

PURPOSE OF REVIEW: Glossectomy remains a common treatment of oral tongue malignancies, which has a range of functional impacts depending on the extent of resection. This review aims to categorize and provide context for the approach to reconstructing these defects using recent evidence. RECENT FINDINGS: The reconstruction method of choice should be tailored to the size and location of the glossectomy defect with special consideration to replace tongue volume and preserve mobility. There has been an increasing focus on patient-reported outcomes in oral tongue reconstruction. For defects beyond one-third of the tongue, free tissue reconstruction, and more recently, the submental artery island flap yield excellent results. Advances in reconstruction of larger defects have included preoperative soft tissue planning and assessment of outcomes in total glossectomy patients with laryngeal preservation. SUMMARY: Depending on the defect, the appropriate reconstruction may range from healing by secondary intention to large volume free tissue transfer. In general, functional outcomes diminish with increasing size and complexity of the defect regardless of the reconstructive technique.

Impact of the Novel Coronavirus 2019 (COVID-19) Pandemic on Head and Neck Cancer Care.

OBJECTIVE: The study aimed to assess the impact of the coronavirus disease 2019 (COVID-19) pandemic on head and neck oncologic care at a tertiary care facility. STUDY DESIGN: This was a cross-sectional study conducted between March 18, 2020, and May 20, 2020. The primary planned outcome was the rate of treatment modifications during the study period. Secondary outcome measures were tumor conference volume, operative volume, and outpatient patient procedure and clinic volumes. SETTING: This single-center study was conducted at a tertiary care academic hospital in a large metropolitan area. METHODS: The study included a consecutive sample of adult subjects who were presented at a head and neck interdepartmental tumor conference during the study period. Patients were compared to historical controls based on review of operative data, outpatient procedures, and clinic volumes. RESULTS: In total, 117 patients were presented during the review period in 2020, compared to 69 in 2019. There was an 8.4% treatment modification rate among cases presented at the tumor conference. There was a 61.3% (347 from 898) reduction in outpatient clinic visits and a 63.4% (84 from 230) reduction in procedural volume compared to the prior year. Similarly, the operative volume decreased by 27.0% (224 from 307) compared to the previous year. CONCLUSION: Restrictions related to the COVID-19 pandemic resulted in limited treatment modifications. Transition to virtual tumor board format observed an increase in case presentations. While there were reductions in operative volume, there was a larger proportion of surgical cases for malignancy, reflecting the prioritization of oncologic care during the pandemic.

Prospective Evaluation of Swallowing Symptoms in Human Papillomavirus-Associated Oropharynx Cancer.

To demonstrate that the lack of significant swallowing-related symptoms in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma is attributable to smaller mucosal primaries. A validated dysphagia symptom questionnaire and eating assessment tool was prospectively provided to patients presenting with untreated human papillomavirus-associated oropharyngeal cancer at the University of Maryland from July 2017 to December 2018. A 10-item Eating Assessment Tool (EAT-10) was completed by each patient prior to intervention. All EAT-10 data were collected prospectively. Patient demographic and oncologic characteristics were also obtained. Seventy consecutive patients were enrolled and included in the study. This study cohort included 66 (94%) male patients. Sixty (86%) of patients were Caucasian. The mean EAT-10 score was 3.77 (95% CI 2.04, 5.50). Fifty-two (74.3%) patients presented with normal swallowing (EAT-10 scores less than 3). Spearman correlation indicated there was a significant positive association between tumor size and EAT-10 score (r(68) = 0.429, p < 0.005), with larger tumors associated with increased swallowing-related symptoms. The majority of patients presenting with HPV-associated oropharyngeal squamous cell carcinoma do not report any swallowing difficulties. Dysphagia-related symptoms are associated with large size tumors when they do occur.

Parotid Salivary Duct Carcinoma With a Prominent Squamous Component: Immunohistochemical Profile, Diagnostic Pitfalls, and Therapeutic Implications.

Salivary duct carcinoma of the parotid gland is a highly aggressive epithelial malignancy morphologically resembling high-grade, invasive, and in situ breast carcinoma. It can occasionally present with variable morphology making it diagnostically challenging in cases with unusual morphological components. Ancillary testing, particularly androgen receptor (AR) positivity on immunohistochemistry, can be very helpful in cases that demonstrate extensive squamous morphology, since AR positivity is uncommon in both the primary salivary gland and metastatic squamous cell carcinomas to the parotid. In this report, we describe a case of salivary duct carcinoma that showed only a squamous cell carcinoma component on the initial primary tumor site biopsy, as well as in subsequent contralateral neck lymph node and skin metastases. Apart from the variable morphology, the typical salivary duct and squamous cell carcinoma tumor components also showed significant immunohistochemical differences, including differential staining of human epidermal growth factor receptor 2/neu. The associated diagnostic pitfalls, distinct immunoprofiles of the tumor components, helpful adjuncts for making the correct diagnosis, and associated therapeutic implications are discussed.

The lateral arm free flap for head and neck reconstruction.

PURPOSE OF REVIEW: The aim of this study was to review the recent literature on the utilization of the lateral arm free flap use in head and neck reconstruction. RECENT FINDINGS: The lateral arm free flap provides a reliable fasciocutaneous free tissue transfer option ideally suited for reconstruction of the oral cavity, pharynx and parotid. Primary donor site closure, compartmentalized fat and excellent colour match make it an excellent option for head and neck reconstruction. Donor site morbidity is low, and the primary limitation is the short and narrow vascular pedicle. SUMMARY: The lateral arm free flap should be considered in cases of oral cavity and skin reconstruction, particularly in cases wherein pedicle length is not restrictive.

Machine Learning Prediction of Extracapsular Extension in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

OBJECTIVE: To determine whether machine learning (ML) can predict the presence of extracapsular extension (ECE) prior to treatment, using common oncologic variables, in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). STUDY DESIGN: Retrospective database review. SETTING: National Cancer Database study. METHODS: All patients with HPV-associated OPSCC treated surgically between January 1, 2010, and December 31, 2015, were selected from the National Cancer Database. Patients were excluded if surgical pathology reports did not include information regarding primary tumor stage, number of metastatic regional lymph nodes, size of largest metastatic regional lymph node, and tumor grade. The data were split into a random distribution of 80% for training and 20% for testing with ML methods. RESULTS: A total of 3753 adults with surgically treated HPV-associated OPSCC met criteria for inclusion in the study. Approximately 38% of these patients treated with surgical management demonstrated ECE. ML models demonstrated modest accuracy in predicting ECE, with the areas under the receiver operating characteristic curves ranging from 0.58 to 0.68. The conditional inference tree model (0.66) predicted the metastatic lymph node number to be the most important predictor of ECE. CONCLUSION: Despite a large cohort and the use of ML algorithms, the power of clinical and oncologic variables to predict ECE in HPV-associated OPSCC remains limited.

Radical Tonsillectomy and Superior Pharyngeal Constrictor Anatomy: A Cadaveric and Oncologic Specimen Assessment.

INTRODUCTION: The rise in primary surgical management of oropharyngeal squamous cell carcinoma has led to varying interpretations of the histopathologic evaluation following a radical tonsillectomy. The oncologic margin may be significantly influenced by the morphologic relations and anatomic dimensions of the palatine tonsil and superior pharyngeal constrictor (SPC) muscle. OBJECTIVE: The aim of this study was to characterize the gross and histologic anatomic features of the palatine tonsil and SPC muscle following an en bloc radical tonsillectomy. METHODS: Radical tonsillectomy specimens were collected from cadaveric and oncologic subjects. Specimens were processed using standard histopathologic techniques and were analyzed by a board-certified head and neck pathologist. The thickness of the SPC muscle and relationship to the tonsillar carcinoma were assessed. RESULTS: Six cadaveric and 10 oncologic specimens were analyzed. The mean minimum SPC width for all cadaveric specimens was 1.02 ± 0.50 mm. The mean minimum width for oncologic specimens was 0.76 ± 0.46 mm. The mean distance from tonsil carcinoma to the lateral specimen margin was 1.79 ± 1.39 mm. CONCLUSION: Due to the limited width of the SPC muscle, a margin in excess of 2 mm may not be attainable in a transoral radical tonsillectomy. Margin status may be ideally determined by the integrity of the SPC muscle in future oncologic studies, rather than an adequate distance measurement.

Defining the Role of Free Flaps for Transoral Robotic Surgery.

BACKGROUND: Transoral surgical techniques for oropharyngeal tumors have been widely accepted, yet often results in a significant functional deficit. Current reports on the safety, feasibility, and swallowing performance after microvascular reconstruction are limited to small volume case series. MATERIALS AND METHODS: Retrospective review of 42 consecutive patients, between December 2013 and May 2016, who underwent transoral robotic surgery oropharyngectomy followed by microvascular reconstruction. RESULTS: Swallowing outcomes postoperatively resulted in 39 (93%) of patients tolerating oral intake postoperatively, with 13 (87%) of 15 patients at 1-year follow-up consuming an entirely oral diet. Thirty-eight (95%) of 40 patients who underwent a tracheostomy at the time of surgery were ultimately decannulated. No patients experienced complete flap failure in the current study. CONCLUSIONS: Minimally invasive transoral surgical techniques have offered the opportunity to minimize surgical morbidity and potentially deintensify adjuvant therapies. Reconstructive options have evolved to match surgical advances seen with robotic surgeries of oropharyngeal cancers. Microvascular reconstruction has been indicated in select patients including those with extensive soft palate resection, primary tumor abutment of the medial pterygoid musculature, exposure of internal carotid artery vasculature, prior radiation therapy, or a significant defect of the oropharyngeal sphincter. Select patients, based on previously identified criteria, were preoperatively identified as suitable candidates for microvascular reconstruction of oropharyngeal defects. This study demonstrates that complex transoral robotic surgical defects are amenable to microvascular reconstructive in carefully selected patients.

Denatonium-induced sinonasal bacterial killing may play a role in chronic rhinosinusitis outcomes.

BACKGROUND: Sinonasal bitter taste receptors (T2Rs) contribute to upper airway innate immunity and correlate with chronic rhinosinusitis (CRS) clinical outcomes. A subset of T2Rs expressed on sinonasal solitary chemosensory cells (SCCs) are activated by denatonium, resulting in a calcium-mediated secretion of bactericidal antimicrobial peptides (AMPs) in neighboring ciliated epithelial cells. We hypothesized that there is patient variability in the amount of bacterial killing induced by different concentrations of denatonium and that the differences correlate with CRS clinical outcomes. METHODS: Bacterial growth inhibition was quantified after mixing bacteria with airway surface liquid (ASL) collected from denatonium-stimulated sinonasal air-liquid interface (ALI) cultures. Patient ASL bacterial killing at 0.1 mM denatonium and baseline characteristics and sinus surgery outcomes were compared between these populations. RESULTS: There is variability in the degree of denatonium-induced bacterial killing between patients. In CRS with nasal polyps (CRSwNP), patients with increased bacterial killing after stimulation with low levels of denatonium undergo significantly more functional endoscopic sinus surgeries (FESSs) (p = 0.037) and have worse 6-month post-FESS 22-item Sino-Nasal Outcome Test (SNOT-22) scores (p = 0.012). CONCLUSION: Bacterial killing after stimulation with low levels of denatonium correlates with number of prior FESS and postoperative SNOT-22 scores in CRSwNP. Some symptoms of CRS in patients with hyperresponsiveness to low levels of denatonium may be due to increased airway immune activity or inherent disease severity.

Use of free tissue transfer in head and neck cancer surgery and risk of overall and serious complication(s): An American College of Surgeons-National Surgical Quality Improvement Project analysis of free tissue transfer to the head and neck.

BACKGROUND: The purpose of this article was to assess the rates of head and neck free tissue transfer and variables available in the American College of Surgeons - National Surgical Quality Improvement Project (ACS-NSQIP) dataset to predict overall and serious complications. METHODS: We conducted a data analysis from 2005 to 2014 on free tissue cases in the head and neck with descriptive and cross-sectional analysis to examine correlation of NSQIP variables with complications (p < .05). RESULTS: Of 1643 flaps, 906 complications occurred, such as blood transfusion, return to the operating room, extended ventilator support, pneumonia, and superficial surgical site infection. Insulin-dependent diabetes, operative time, age, white blood cell (WBC) count, and smoking correlated with overall complications. Five hundred one patients experienced 859 serious complications: return to the operating room, pneumonia, deep surgical site infection, sepsis, and unplanned intubation. Operative time, clean contaminated wound status, dirty wound classification, and history of congestive heart failure were predictive. CONCLUSION: Identification of risks for complications is an opportunity for improvement. Extended operative time consistently predicts for both overall and serious complications, suggesting long surgery within contaminated sites risks complication. © 2016 Wiley Periodicals, Inc. Head Neck 39: 702-707, 2017.

Transoral Robotic Surgery-Assisted Endoscopy With Primary Site Detection and Treatment in Occult Mucosal Primaries.

Importance: Management of cervical lymph node metastasis without a known primary tumor is a diagnostic and treatment challenge for head and neck oncologists. Identification of the occult mucosal primary tumor minimizes the morbidity of treatment. Objective: To analyze the role of transoral robotic surgery (TORS) in facilitating the identification of a primary tumor site for patients presenting with squamous cell carcinoma of unknown primary (CUP). In addition, we assessed treatment deintensification by determining the number of patients who did not undergo definitive radiation therapy and chemotherapy. Design, Setting, and Participants: In this retrospective case series from January 2011 to September 2015, 60 consecutive patients with squamous cell CUP who underwent TORS-assisted endoscopy and ipsilateral neck dissection were included from an academic medical center and studied to study the rate success rate of TORS identifying occult mucosal malignancy. Main Outcomes and Measures: Success rate of identifying occult mucosal malignancy; usage of radiation therapy and chemotherapy. Results: Overall, 60 patients (mean [SD] age, 55.5 [8.9] years) were identified; 48 of the 60 patients (80.0%) had a mucosal primary identified during their TORS-assisted endoscopic procedure. The mean (SD) size of the identified mucosal primary lesions was 1.3 (0.1) cm. All mucosal primaries, when found, originated in the oropharynx including the base of tongue in 28 patients (58%), palatine tonsil in 18 patients (38%), and glossotonsillar sulcus in 2 patients (4%). Among patients in this study, 40 (67%) did not receive chemotherapy, and 15 (25%) did not receive radiation therapy. Conclusions and Relevance: Advances in transoral surgical techniques have helped identify occult oropharyngeal malignancies that traditionally have been treated with comprehensive radiation to the entire pharyngeal axis. We demonstrate the efficacy of a TORS-assisted approach to identify and surgically treat the primary tumor in patients presenting with CUP. In addition, patients managed with the TORS-assisted endoscopic approach benefit from surgical and pathological triage, which in turn results in deintensification of treatment by eliminating the need for chemotherapy in the majority of patients, as well as avoiding radiation therapy in select patients.