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Objectives: To assess airway, safety, and resource utilization outcomes between transoral base of tongue (BOT) surgery with staged versus concurrent bilateral neck dissections (BND)., Methods: A retrospective cohort study of patients with human papilloma virus (HPV)-related BOT cancer who underwent transoral surgery and BND from January 2015 through June 2022 was conducted. Free flap patients were excluded., Results: Of 126 patients (46 [37%] staged and 80 [63%] concurrent BND), there were no significant differences in rates of postoperative intubation, tracheostomy, intensive care admission, operative takebacks, gastrostomy, and 30-day readmission. Total operative time (median difference 1.4 [95% CI 0.9-1.8] hours), length of stay (1.0 [1.0-1.0] day), and time between primary surgery and adjuvant therapy initiation (4.0 [0.0-8.0] days) were lower in the concurrent BND cohort., Conclusion: Concurrent BND alongside transoral BOT resection is safe with similar airway outcomes and lower total operative time, length of stay, and time to adjuvant therapy initiation compared to staged BND., (© 2024 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Objective: To determine the association between poor dental health and risk of oral cavity squamous cell cancer (OCSCC) at individual tumor subsites., Study Design: Case-control and cross-sectional METHODS: A case-control study was performed using a population-based cohort in North Carolina (Carolina Head and Neck Cancer Epidemiology Study [CHANCE]). A secondary cross-sectional analysis was performed with an institutional cohort (WashU/Siteman). Cases were adults with primary OCSCC and an identifiable tumor subsite. In the CHANCE cohort, controls were adults without head and neck cancer. In the Washington University/Siteman cohort, patients with tongue cancer served as the comparator group. We used number of missing teeth (categorized 0-6, 7-24, 25-28) as a surrogate for poor dental health, which was self-reported in CHANCE and measured on a pretreatment computed tomography scan in the WashU/Siteman study. Adjusted odds ratios (aORs) for missing teeth were estimated for each tumor subsite using binomial logistic regression models., Results: Near complete tooth loss (25-28 teeth) was associated with a 3.5-fold increased risk of alveolar ridge malignancy (aOR: 3.51; 95% confidence interval [CI]: 1.14-11.01, P = .03) in the CHANCE study. This association was confirmed in our cross-sectional analysis (WashU/Siteman study) where missing 25-28 teeth was associated with an increased risk of alveolar ridge compared to tongue cancer (aOR: 4.60; 95% CI: 1.97-11.10, P = .001)., Conclusions: This study suggests an association between poor dental health and risk of alveolar ridge cancer independent of smoking, alcohol use, age, race, and sex. Future prospective and translational studies are needed to confirm this association and elucidate the mechanism of dental disease in alveolar ridge malignancies., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: We aim to more accurately characterize the current distribution and rates of squamous cell carcinoma (SCC) cases across various oral cavity subsites in the United States., Study Design: Retrospective cohort., Setting: Database study evaluating cancer incidence in the United States from 2001 to 2017., Methods: We utilized the US Cancer Statistics Public Use Database, which includes deidentified cancer data reported to the Centers for Disease Control and Prevention's National Program of Cancer Registries and the National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results), capturing 97% of newly diagnosed cancers. We restricted our analysis to SCC arising from oral cavity subsites from 2001 to 2017. We calculated trends in annual cancer incidence rates using SEER*Stat, as well as annual and average annual percentage change and joinpoints with the National Cancer Institute's Joinpoint program., Results: Most oral cavity SCC cases arise from the oral tongue (41.7%), followed equally by lip and floor of mouth (each 16.5%), gingival (10.6%), buccal (6.7%), retromolar trigone (5.6%), and hard palate (2.3%) involvement. The overall incidence of oral tongue SCC continues to rise with an average annual percentage change of 1.8% (95% CI, 1.6%-2.1%; P < .001), with a 2.3% increase among women. This increase is seen among males and females of all age groups. Cancers involving the gum, buccal mucosa, and hard palate were also found to be increasing in rate, albeit to a lesser degree and with substantially lower incidence., Conclusions: The tongue is the most frequently involved subsite of oral cavity SCC and is increasing in incidence among males and females of all ages., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: Chemoradiation for patients with laryngeal squamous cell carcinoma (SCC) may achieve organ preservation, but appropriate patient selection remains unknown. This study investigates pre-treatment risk factors associated with functional and survival outcomes after radiation-based therapy in patients with advanced laryngeal SCC., Methods: A retrospective cohort study was performed on 75 adult patients with stage III or IV laryngeal SCC receiving definitive radiation-based therapy from 1997 to 2016 at a tertiary care center. Tracheostomy and gastrostomy dependence were the primary functional outcomes. Multivariable logistic regressions were performed to evaluate relationships between pre-treatment factors and tracheostomy and gastrostomy dependence. Time-to-event analyses were performed to determine risk factors associated with overall survival., Results: Among 75 patients included in the analysis, 30 (40%) patients were tracheostomy dependent and 31 (41%) were gastrostomy tube dependent. The median length of follow-up was 31 months (range = 1 to 142 months). Pre-treatment tracheostomy was a significant predictor of post-treatment tracheostomy (aOR = 13.9, 95% CI = 3.35 to 57.5) and moderate-severe comorbidity was a significant predictor of post-treatment gastrostomy dependence (aOR = 2.96, 95% CI = 1.04 to 8.43). The five-year overall survival was 51% (95% CI = 38 to 64%). Pre-treatment gastrostomy tube dependence was associated with an increased risk of death (aHR = 2.45, 95% CI = 1.09 to 5.53)., Conclusions: Baseline laryngeal functional status and overall health in advanced laryngeal SCC are associated with poor functional outcomes after radiation-based therapy, highlighting the importance of patient selection when deciding between surgical and non-surgical treatment plans. Laryngoscope, 133:594-600, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENE mi ) and role of adjuvant concurrent chemoradiation (CRT) for ENE mi remain unclear. This study evaluates (1) the prognostic significance of ENE mi in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients., Study Design: Retrospective cohort study., Setting: Commission on Cancer (CoC)-accredited facilities., Methods: This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENE mi or no ENE who had undergone margin-negative surgery. The association of ENE mi with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENE mi receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS., Results: We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENE mi . On multivariable analysis, ENE mi was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENE mi who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27)., Conclusion: For patients with HPV-negative HNSCC, pN+ with ENE mi is associated with worse OS than pN+ without ENE. However, for patients with ENE mi , concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENE mi requires additional investigation.

Background: The number of elderly patients with oral squamous cell carcinoma (OCSCC) is increasing as the elderly population increases. Unfortunately, evidence to guide the management of these patients is lacking., Methods: Patients with OCSCC identified from the National Cancer Database (NCDB) were stratified into age-based cohorts. Demographics, comorbidities, and treatment patterns were analyzed. Patients were stratified into early stage (Stage I/II) and advanced stage (Stage III/IV) disease. The likelihood of receiving multimodality therapy by age was calculated using multinomial logistic regression for each stratum while controlling for potential confounders. Cox proportional hazard regression was used to calculate 5-year mortality risk while controlling for potential confounders., Results: Surgery alone or palliative options were offered to older patients more frequently. After controlling for confounders, older patients were less likely to receive multimodality therapy for both early stage and advanced stage disease. Patients with advanced disease across all age cohorts had improved 5-year survival with surgery and adjuvant therapy., Conclusion: Our analyses suggest that elderly patients have unique demographic and pathologic features. They frequently receive less treatment than similarly staged younger patients, yet they benefit from multimodality therapy when feasible. These data suggest an urgent need to critically appraise the care of elderly OCSCC patients within the broader context of their individual comorbidity burden, functional status, and treatment goals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Guidelines for many head and neck cancers, especially laryngeal cancers, allow for multiple treatment options. Currently, inequitable provision of surgery may contribute to outcome disparities. However, the role of geospatial factors remains understudied., Objective: To assess the association between US geospatial factors and treatment selection for patients with laryngeal cancer., Design, Setting, and Participants: In this retrospective cohort study, patients diagnosed with laryngeal squamous cell carcinoma between January 1, 2004, and December 31, 2014, were identified from the Surveillance, Epidemiology, and End Results database. Adjusted odds ratios (aORs) for surgical treatment were generated from multivariable, hierarchical models to assess associations with oncologic, demographic, and county variables. Outlier US counties with the highest and lowest aORs were described. Data analysis was performed from April 29 to September 11, 2020., Exposures: County of residence., Main Outcomes and Measures: The aORs for surgical treatment were generated from multivariable, hierarchical models. Outlier counties with the highest and lowest aORs are described., Results: The cohort includes 21 289 patients (mean [SD] age, 63.6 [11.2] years; 17 214 [80.9%] male) in 598 counties. Most counties had no otolaryngologist (365 [61.0%]) or radiation oncologist (434 [72.6%]). Surgery rates varied from 7.1% to 85.7% among counties with at least 10 cases. After oncologic variables were controlled for, factors independently associated with surgical treatment included patient age (aOR [95% CI], 0.94; 0.91-0.98 per 10 years), marital status (single versus married: aOR [95% CI], 0.87 [0.79-0.97]), and county social deprivation index (aOR [95% CI], 0.98 [0.97-1.00 per 5 points]) but not physician number (≥2 otolaryngologists: aOR [95% CI], 0.91 [0.75-1.11] vs ≥1 radiation oncologist: aOR [95% CI], 0.91; 0.75-1.11). The 5% of counties most likely to provide surgery (aOR, >1.23) were nearly all large metropolitan areas (2593 patients [93.3%]) and treated a disproportionately large number of patients (2778 [13.1%]). The 5% of counties least likely to provide surgery (aOR, <0.79) were also mostly large metropolitan areas (1676 patients [91.2%]) and treated a disproportionately large number of patients (1838 [8.6%]). Patients in counties least likely to provide surgery had inferior survival compared with those most likely to provide surgery (adjusted hazard ratio, 1.16; 95% CI, 1.00-1.35)., Conclusions and Relevance: These findings suggest that sociodemographic factors contribute to the wide variety in surgical treatment practices by county. The largest metropolitan counties were often outliers regarding their adjusted odds of surgical treatment. This finding is concerning for the counties least likely to provide surgery where survival is inferior.

Background: For human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), management recommendations for patients with a single metastatic lymph node <6 cm in diameter remain nebulous, leading to treatment heterogeneity in this common subgroup of patients., Methods: We utilized the National Cancer Database to perform survival and multivariable analyses of patients with HPV+ OPSCC with one positive lymph node <6 cm and negative surgical margins., Results: We found that 5-year survival is comparable between patients who receive surgery and adjuvant radiation versus surgery alone. In multivariable analyses, we found no significant difference in the hazard ratio of overall survival after adjusting for various potential confounders., Conclusions: These data suggest that patients with margin-negative HPV+ OPSCC with a single positive lymph node <6 cm have comparable survival with or without adjuvant radiation. Future studies exploring outcomes for this specific group in randomized-controlled trials will be critical for further evaluating these initial observations., (© 2021 Wiley Periodicals LLC.)

Objective/hypothesis: To assess whether young patients with oral cavity squamous cell carcinoma (OCSCC) demonstrate worse oncologic outcomes than older patients after definitive therapy., Study Design: Systematic review and meta-analysis., Methods: A medical librarian composed a search strategy to identify relevant studies in Medline, Embase, Scopus, and other major databases (Prospero registration number CRD42019127974). Inclusion criteria were adults with histologically diagnosed OCSCC that underwent treatment, comparator groups with an age cutoff of 40 years old, and reported survival outcomes. Articles were excluded if they contained patients with oropharyngeal squamous cell carcinoma or patients treated for palliative intent. Overall survival hazard ratios were analyzed with a meta-analysis., Results: There were 23,382 patients with OCSCC that were treated with definitive therapy from 22 included studies. The pooled cohort contained 2,238 (10%) patients ≤40 years of age. Oral tongue was the most common subsite in both the younger (n = 1,961, 91%) and older (n = 18,047, 88%) cohorts. The majority of OCSCCs were either T1 or T2, representing 859 (80%) malignancies in younger patients and 8,126 (77%) malignancies in older patients. A meta-analysis of nine studies demonstrated that younger patients did not experience worse survival outcomes than older patients (hazard ratio = 0.97, 95% confidence interval = 0.66-1.41)., Conclusions: Young adults with OCSCC experienced similar oncologic outcomes as older patients with OCSCC after definitive treatment. Until compelling evidence demonstrates clinically relevant differences between these two cohorts, their approach to management should be similar. Future studies should consider comorbidities and using age 40 as a standard age cutoff to provide more uniform data moving forward. Laryngoscope, 131:1310-1319, 2021., (© 2020 American Laryngological, Rhinological and Otological Society Inc, "The Triological Society" and American Laryngological Association (ALA).)

Importance: Overall, the prognosis of sinonasal squamous cell carcinoma (SCC) is poor. This malignancy can arise de novo or from inverted papillomas, but it is unclear whether survival differences between the 2 pathologies exist., Objective: To assess for survival differences between patients with sinonasal de novo SCC (dnSCC) and those with inverted papilloma-associated SCC (IPSCC)., Data Sources: A search of Ovid MEDLINE, Embase, Scopus, and the Cochrane Library from inception to January 23, 2020, with cross-referencing of retrieved studies, was performed. Additional data were requested from authors., Study Selection: Inclusion and exclusion criteria were designed to capture studies with survival outcomes of adults with sinonasal SCC who underwent regular treatment. Clinical trials, cohort studies, case-control studies, and case series with more than 10 adults aged 18 years or older with sinonasal SCC were included. Exclusion criteria were studies on non-SCC sinonasal neoplasms, studies without histopathologic diagnoses, non-English language articles, nonhuman animal studies, and abstract-only articles. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) screened each abstract and full text, and a third investigator (J.J.L. or P.P.) adjudicated discrepancies. Of 729 unique citations, 26 studies of 1194 total patients were included., Data Extraction and Synthesis: Meta-Analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. The Methodological Index for Nonrandomized Studies (MINORS) criteria were used to assess study quality. Two blinded investigators (J.J.L., A.M.P., T.W.E., or N.S.W.) independently extracted data from each study. Data were pooled using a random-effects model., Main Outcomes and Measures: The primary outcome was overall survival, and secondary outcomes were disease-free and disease-specific survival. Before data collection, it was hypothesized that the dnSCC cohort would have worse survival outcomes than the IPSCC cohort., Results: One study of patients with dnSCC, 12 studies of patients with IPSCC, and 5 studies with both cohorts were included in the meta-analysis of overall survival. The pooled 5-year overall survival rate for 255 patients with dnSCC was 56% (95% CI, 41%-71%; I2 = 83.8%) and for 475 patients with IPSCC was 65% (95% CI, 56%-73%; I2 = 75.7%). Five comparative studies of both cohorts totaling 240 patients with dnSCC and 155 patients with IPSCC were included in another meta-analysis. The pooled overall survival hazard ratio was 1.87 (95% CI, 1.24-2.84; I2 = 0%)., Conclusions and Relevance: This systematic review and meta-analysis found that patients with dnSCC had almost a 2-fold increased risk of mortality compared with those with IPSCC. Large, multicenter studies are necessary to validate these findings before considering treatment alterations such as de-escalation based on histopathology.

Importance: Regional lymph node metastasis remains an important prognostic factor in patients with oropharyngeal squamous cell carcinoma (OPSCC). Although survival among patients with regional metastasis in human papillomavirus (HPV)-related OPSCC is more favorable compared with patients who are HPV negative, prognostic variables associated with failure in patients with single-node metastasis are not known., Objective: To evaluate recurrence and survival in patients with HPV-related OPSCC with single-lymph node metastasis treated with transoral surgery., Design, Setting, and Participants: A retrospective cohort study was conducted of 207 adults with newly diagnosed p16-positive OPSCC and pathology-confirmed single-node disease who underwent surgical resection with or without adjuvant therapy at 2 tertiary academic medical centers from January 1, 2007, to December 31, 2016. Statistical analysis was performed from September 1, 2018, to September 1, 2020., Interventions: Surgery alone (n = 59), surgery with adjuvant radiation (n = 75), or surgery with adjuvant chemoradiation (n = 73)., Main Outcomes and Measures: The primary outcome was regional recurrence. Secondary outcomes included overall survival, any recurrence, and identification of factors associated with regional recurrence and overall survival., Results: Among 207 patients, 178 (86%) were men, with a median age of 57 years (range, 35-82 years) at the time of surgery. Median follow-up was 36.2 months (range, 7-127 months). Regional recurrence occurred in 11 patients (5%). Of these, 1 patient (9%) was lost to follow-up after diagnosis, 1 (9%) was treated with palliative chemotherapy, and 9 (82%) were treated with curative intent. Ultimately, 7 patients received successful salvage treatment, and 3 died with disease. Overall, there were 21 patients (10%) with any recurrence, with 4 patients (19%) experiencing local recurrence, 11 (52%) experiencing regional recurrence, and 6 (29%) experiencing distant metastasis. The 5-year overall survival was 95% (95% CI, 89%-98%) for all patients. Older age (odds ratio [OR], 1.2; 95% CI, 1.1-1.2), advanced T stage (OR, 3.5; 95% CI, 0.9-14.0), and positive margins (OR, 10.9; 95% CI, 1.8-67.5) were associated with increased regional recurrence. Extranodal extension (OR, 0.2; 95% CI, 0.04-0.8), lymph node size greater than 3 cm (OR, 0.2; 95% CI, 0.1-0.7), and adjuvant therapy (OR, 0.08; 95% CI, 0.02-0.4) were associated with decreased regional recurrence. Advanced comorbidities (hazard ratio, 6.20; 95% CI, 1.4-27.7), lymphovascular invasion (hazard ratio, 4.7; 95% CI, 1.0-21.2), and regional recurrence (hazard ratio, 16.0; 95% CI, 3.1-82.0) were associated with worse overall survival., Conclusions and Relevance: The findings of this cohort study suggest that patients with HPV-related OPSCC and single-node disease undergoing surgical resection with or without adjuvant treatment have excellent survival. Adjuvant therapy appears to improve regional control. Among patients with regional recurrence of OPSCC, there is a high rate of successful salvage treatment.

Objective: To determine the prognostic significance of smoking in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) when considering American Joint Committee on Cancer eighth edition (AJCC-8) stage., Study Design: Retrospective cohort study., Methods: Three hundred seventeen HPV-positive OPSCC patients with known AJCC-8 stage and smoking status (<10 or ≥10 pack-years) seen at a tertiary center from 1997 to 2017 were studied. We used the Kaplan-Meier method to compare 5-year overall survival (OS) by smoking status and by clinical AJCC-8 stage and smoking status combined. Hazard ratios (HRs) were estimated with Cox proportional hazard regression for the independent effects of smoking and AJCC-8 stage. We also studied pathologic stage and estimated the combined effects of smoking and clinical stage., Results: The ≥10 pack-years smokers had worse 5-year OS than <10 pack-years smokers (93.6%; 95% confidence interval (CI): 89.7-97.8 vs. 82.3%; 95% CI: 76.0%-89.1%). When stratified by AJCC-8 clinical stage, only stage I <10 pack-years smokers (98.7%; 95% CI: 96.3%-100.0%) had significantly better 5-year OS than their ≥10 pack-years (84.8%; 95% CI: 76.4%-94.1%) counterparts. In a multivariable analysis, ≥10 pack-years smoking was associated with increased hazard of death when adjusting for AJCC-8 clinical (HR: 2.52; 95% CI: 1.16-5.46) and pathologic (HR: 5.21; 95% CI: 1.47-18.5) stage. In both analyses, stage III patients demonstrated worse survival than stage I, and smoking had greater impact at lower stages., Conclusions: Smoking is a negative prognosticator in HPV-positive OPSCC and interacts with AJCC-8 clinical stage. It is important to understand the impact of smoking in HPV-positive disease when considering treatment plans and deintensification trials., Level of Evidence: 2b Laryngoscope, 130: 1961-1966, 2020., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To comprehensively examine the prognostic significance of extranodal extension (ENE) in human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-positive OPSCC)., Methods: Retrospective cohort of cases diagnosed with HPV-positive OPSCC from 2010 to 2015 in the National Cancer Database. Inclusion of all OPSCC HPV-positive cases with appropriate International Classification of Diseases-0-3 codes that received surgery with a neck dissection. Univariate and multivariable analyses were conducted. Hazard ratios (HR) for the independent effects of ENE and N stage on overall survival were estimated by Cox proportional hazards regression., Results: Cases that were ENE-negative had the highest 5-year survival (92.6%; 95% confidence interval [CI]: 90.5%-94.7%). ENE-positive cases had the lowest 5-year survival (84.0%; 95% CI: 80.7%-87.4%). After adjusting for confounding variables, ENE-positivity was associated with almost twice the hazard of death (HR = 1.90; 95% CI: 1.35-2.67) compared to ENE-negative cases. Nodal (N) category 1, ENE-positive status was associated with an increased risk of death (HR = 1.88; 95% CI: 1.26-2.80) compared with N1, ENE-negative status. Compared to N1/ENE-negative cases, N2/ENE-positive cases had the poorest survival (HR: 2.93; 95% CI: 1.94-4.43). Both microscopic and macroscopic ENE were associated with worse outcomes compared to node-positive/ENE-negative status., Conclusion: The implementation of the American Joint Committee on Cancer 8th edition staging system provides a much-improved framework to develop and discuss treatment plans for HPV-positive OPSCC. We feel that careful consideration should be given to the importance of ENE in patients with HPV-positive OPSCC., Level of Evidence: 4 Laryngoscope, 130:939-945, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To determine the influence of nodal yield during neck dissection on survival in surgically managed human papillomavirus (HPV)-associated oropharyngeal cancer., Methods: The National Cancer Database was used to identify patients with HPV-associated tumor T1 to T2 oropharyngeal squamous cell carcinoma who underwent upfront surgery with or without adjuvant therapy. Patients were stratified by lymph node yield (<26 vs. ≥26 nodes). Multivariable Cox proportional hazards regression analysis was used to identify factors associated with overall survival. Models were stratified by pathologically positive node number., Results: There were 2,554 patients identified with previously untreated T1 to T2 oropharyngeal squamous cell carcinoma who underwent resection of the primary tumor and neck dissection between 2010 and 2015. Fifty-two percent had zero to one pathologically involved lymph node. Among all study patients, lymph node harvest of ≥26 was not associated with survival when adjusted for relevant covariates (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-1.00). However, in patients with zero to one pathologically involved node, lymph node harvest of ≥26 was significantly associated with improved overall survival (HR 0.29, 95% CI 0.20-0.78). This survival benefit was lost in patients with two or more positive nodes (2-4 positive nodes: HR 0.89, 95% CI 0.52-1.51; 5 or more positive nodes: HR 1.01, 95% CI 0.47-2.20)., Conclusion: For patients with surgically managed early T-stage HPV-associated oropharyngeal squamous cell carcinoma, lymph node yield was not associated with survival outcomes for patients with multiple positive lymph nodes. Those with a more limited burden of regional metastatic disease, however, may benefit harvest of at least 26 nodes during neck dissection., Level of Evidence: 4 Laryngoscope, 130:666-671, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: The optimal treatment strategy for patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) of the base of the tongue (BOT) has not been sufficiently studied., Objective: To investigate the rate of and risk factors for occult contralateral nodal disease in patients with HPV-related BOT OPSCC undergoing transoral surgery and bilateral neck dissections., Design, Setting, and Participants: This retrospective case series reviewed the medical records of patients with HPV-related BOT OPSCC who underwent transoral surgery and bilateral neck dissections from January 1, 2002, through December 31, 2018, at the tertiary care center of Washington University School of Medicine in St Louis. Patients had a median follow-up of 30.0 months (interquartile range, 11.0-60.4 months). Patients with recurrent disease or multiple synchronous OPSCC primary tumors were excluded for a total of 89 patients. Data were analyzed from January 1 through June 1, 2019., Main Outcomes and Measures: The primary outcome was the rate of contralateral occult nodal disease. Secondary outcomes were potential risk factors for contralateral occult nodal disease and regional recurrence rates., Results: Eighty-nine patients were included in the series, of whom 81 (91.0%) were men. The mean (SD) age was 60 (9) years. Overall, 34 patients (38.2%) had pathologic contralateral nodal metastases. Seventy patients had no clinical evidence of contralateral nodal disease. Of these 70, occult nodes were identified in 15 (21.4%). Risk of contralateral disease was higher when the primary tumor crossed midline (odds ratio, 6.23; 95% CI, 1.71-22.77). Of the 55 patients with no occult disease identified, only 2 (3.6%) received radiotherapy to the contralateral neck, and no regional recurrence of disease was noted., Conclusions and Relevance: Given the rate of occult contralateral nodal disease of 21.4%, it appears that contralateral elective neck dissection or radiotherapy should be recommended in patients with HPV-related BOT OPSCC. Patients with a pathologically negative result of contralateral neck dissection may not benefit from radiotherapy to that nodal basin. Future prospective investigations should evaluate functional and oncologic outcomes of contralateral elective neck dissection compared with elective radiotherapy in the contralateral neck for HPV-related BOT OPSCC.

Background: The incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) is rising, even in elderly patients. The outcomes of transoral surgery (TOS) in this population are not entirely known., Methods: A retrospective review was performed at two institutions from October 2003 to September 2016 on patients 70 years or older with HPV-related OPSCC treated with TOS., Results: A total of 75 patients were included with a mean age of 74 years (70-87 years). At a median follow-up of 35.7 months, 3-year overall survival was 81.5% and disease-specific survival was 94.3%. Advanced cT stage (odds ratio, 2.74; 95% confidence interval, 1.13-6.64) negatively impacted OS. Conjunctive consolidation was performed to create a staging system with patients older than 80 years, severe comorbidity, and cT3-4 having worse survival., Conclusions: Elderly patients with HPV-related OPSCC treated with TOS have excellent survival and therefore should not be excluded from such therapy based on age alone., (© 2019 Wiley Periodicals, Inc.)

Soft palate (SP) reconstruction remains a challenge for the head and neck reconstructive surgeon. One favorable local flap option is the longus capitis muscle (LCM), a deep neck flexor with redundant muscle function, appropriate bulk, and a relatively straightforward surgical harvest. A retrospective review of 3 patients with T2 to T4 tonsil squamous cell carcinoma requiring SP resection and LCM reconstruction at a single institution was performed. Three patients underwent primary transoral resection, all resulting in at least 50% full-thickness SP defects. Reconstruction comprised a superiorly based LCM local flap. Patients underwent adjuvant (chemo)radiation therapy as indicated. Within 3 to 8 months, each patient was tolerating a full oral diet with no dysphagia, nasal regurgitation, or velopharyngeal insufficiency. For select patients with SP defects, a superiorly based LCM flap may provide a functionally acceptable reconstruction with minimal donor site morbidity.

Objectives: To determine the oncologic outcomes of patients undergoing salvage surgery for recurrent oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) after initial treatment with surgery and adjuvant therapy., Study Design: Retrospective case series with chart review., Setting: Five academic tertiary care centers., Subjects and Methods: Patients included those with OCSCC and OPSCC who were initially treated with surgery and adjuvant therapy between 2000 and 2015 and underwent salvage surgery for local and/or regional recurrence., Results: A total of 102 patients were included (76% OCSCC, 24% OPSCC). Five-year overall survival was 31% (95% CI, 21%-41%) and was significantly improved among patients with human papillomavirus-associated oropharyngeal tumors (hazard ratio [HR], 0.34; 95% CI, 0.11-0.98) and significantly worse for those with postoperative positive margins (HR, 2.65; 95% CI, 1.43-4.93). Adjuvant (chemo)reirradiation was not associated with disease control or survival regardless of margin status. Combined locoregional recurrence was significantly correlated with a positive margin resection (HR, 5.75; 95% CI, 1.94-17.01). Twenty-five patients (25%) underwent a second salvage surgical procedure, of whom 8 achieved long-term disease control., Conclusion: Patients presenting with resectable recurrence after initial therapy with surgery and adjuvant therapy have a reasonable salvage rate when a negative margin resection can be attained. Patients with postoperative positive margins have poor survival outcomes that are not significantly improved with adjuvant (chemo)reirradiation. Those with combined locoregional recurrence are at particularly high risk for postoperative positive margins. The functional consequences of salvage surgery and its effect on quality of life are critical in decision making and require further investigation.

Importance: Cutaneous squamous cell carcinoma (CSCC) is one of the most common malignant tumors worldwide. There is conflicting evidence regarding the indications for and benefits of adjuvant radiation therapy for advanced CSCC tumors of the head and neck., Objective: To assess indications for adjuvant radiation therapy in patients with CSCC., Design, Setting, and Participants: Retrospective analysis of 349 patients with head and neck CSCC treated with primary resection with or without adjuvant radiation therapy at 2 tertiary referral centers from January 1, 2008, to June 30, 2016., Main Outcomes and Measures: Data were compared between treatment groups with a χ2 analysis. Disease-free survival (DFS) and overall survival (OS) were analyzed using a Kaplan-Meier survival analysis with log-rank test and a Cox proportional hazards multivariate regression., Results: A total of 349 patients had tumors that met the inclusion criteria (mean [SD] age, 70 [12] years; age range, 32-94 years; 302 [86.5%] male), and 191 (54.7%) received adjuvant radiation therapy. The 5-year Kaplan-Meier estimates were 59.4% for DFS and 47.4% for OS. Patients with larger, regionally metastatic, poorly differentiated tumors with perineural invasion (PNI) and younger immunosuppressed patients were more likely to receive adjuvant radiation therapy. On Cox proportional hazards multivariate regression, patients with periorbital tumors (hazard ratio [HR], 2.48; 95% CI, 1.00-6.16), PNI (HR, 1.90; 95% CI, 1.12-3.19), or N2 or greater nodal disease (HR, 2.16; 95% CI, 1.13-4.16) had lower DFS. Immunosuppressed patients (HR, 2.17; 95% CI, 1.12-4.17) and those with N2 or greater nodal disease (HR, 2.43; 95% CI, 1.42-4.17) had lower OS. Adjuvant radiation therapy was associated with improved OS for the entire cohort (HR, 0.59; 95% CI, 0.38-0.90). In a subset analysis of tumors with PNI, adjuvant radiation therapy was associated with improved DFS (HR, 0.47; 95% CI, 0.23-0.93) and OS (HR, 0.44; 95% CI, 0.24-0.86). Adjuvant radiation therapy was also associated with improved DFS (HR, 0.36; 95% CI, 0.15-0.84) and OS (HR, 0.30; 95% CI, 0.15-0.61) in patients with regional disease., Conclusions and Relevance: Among patients with advanced CSCC, receipt of adjuvant radiation therapy was associated with improved survival in those with PNI and regional disease.

Background: Oncologic outcomes of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) requiring resection of major muscular or neurovascular tissue during neck dissection for invasive nodal disease remain uncertain., Methods: Patients with HPV-related oropharyngeal SCC requiring resection of major muscular or neurovascular tissue during their neck dissections were retrospectively identified., Results: Seventy-two patients were included. Regional and distant recurrences occurred in 6% and 17% of patients. Advanced T classification, pathological node number of 5 or more, and omission of adjuvant therapy were associated with decreased disease-free survival (DFS). The addition of adjuvant chemotherapy was not associated with improved survival., Conclusion: Patients with invasive nodal disease from HPV-related oropharyngeal SCC can be managed with up-front surgery and adjuvant therapy, as indicated with good regional control. Although distant recurrence was the primary site of failure, adjuvant chemotherapy was not associated with improved outcomes. The T classification, node number, and adjuvant radiotherapy are independent prognostic factors in this patient population., (© 2018 Wiley Periodicals, Inc.)

Objectives: To explore the effect of incorporating cetuximab into induction chemotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC)., Materials and Methods: Retrospective comparative analysis of two consecutive prospective phase II trials was performed: trial 1 with nab-paclitaxel/cisplatin/5-FU and cetuximab (APF-C; n=30) and trial 2 with APF (n=30). Patients were scheduled to receive chemoradiation therapy (CRT) with cisplatin. T 2-4 classification oropharynx (OP)/larynx/hypopharynx SCC were included. Cumulative incidence of death of disease (CIDD), overall survival (OS), and cumulative incidence of relapse were compared between APF-C and APF., Results: No significant differences in patient or tumor characteristics were noted between the groups. Median follow-up of surviving patients was 52 (25-95) months. Relapse occurred in 5 (17%) patients treated with APF-C and in 2 (7%) treated with APF (p=0.37). In human papillomavirus (HPV)-related OPSCC (n=34), the CIDD at 52months was 3.4% with APF-C and 2.6% with APF and the two-year OSs were 94%. In HPV-unrelated HNSCC (n=25), the CIDD at 52months was 4.4% with APF-C and 3.3% with APF and two-year OSs were 83% and 92%, respectively. CIDD or OS did not differ when stratified by treatment group and HPV status (CIDD: p=0.80; OS: p=0.30)., Conclusion: This exploratory retrospective comparative analysis demonstrated no significant difference in CIDD, OS, or cumulative incidence of relapse between patients treated with APF-C or APF., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The indications, techniques, and outcomes for a minimally invasive surgical approach in oropharyngeal squamous cell carcinoma (OPSCC) unsuitable for transoral resection are not well-described., Methods: A retrospective case series was performed using a prospectively assembled database of transoral surgery-treated OPSCC patients who also underwent a "hybrid" approach of combined transoral and limited pharyngotomy for tumor resection. Disease and functional outcomes were evaluated., Results: Twenty patients underwent complete tumor resection using the hybrid approach. Median follow-up was 48 months. No postoperative pharyngocutaneous fistula occurred. One patient (5%) had a local recurrence. Kaplan-Meier estimates for disease-specific survival at 2 and 5 years were 94.4% (95% CI, 84%-100%) and 87% (95% CI, 70%-100%). All but 1 patient (due to chemoradiotherapy-related chondroradionecrosis) were decannulated, and 2 required long-term gastrostomy., Conclusion: In the absence of a favorable transoral access, the "hybrid" approach of combined transoral and limited pharyngotomy can accomplish margin-negative primary tumor resection, with a high degree of disease control and functional recovery in selected OPSCC patients.

Objective: The purpose of our study is to compare oncologic and functional outcomes of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) patients, in the presence and absence of planned radiation to the primary bed following transoral surgery (TOS), stratified by T-classification., Methods: Retrospective cohort study of 261, T1-T4, consecutively TOS-treated OPSCC patients., Results: At a median follow-up of 61months, local recurrence (LR) occurred in 6 (2.3%)patients (3 each in T1-T2 and T3-T4 groups), of which 5 had tumors in the tongue base and one in the tonsil. Of patients not receiving planned primary bed radiation, LR occurred in 3% of T1-T2s versus 17% of T3-T4s. In patients with T1-T2 tumors, Absolute Risk Reduction of LR with primary bed radiation was 3.26% (95% CI: -0.37%, 7%); Number Needed to Treat to prevent one LR was 31 (95% CI: 14.5, 271). Absolute Risk Increase for gastrostomy-tube with primary bed radiation was 34.4% (95% CI: 24%, 45%); Number Needed to Harm was 3 (95% CI: 2.2, 4.2), i.e., for every three patients with T1-T2 tumors receiving primary bed radiation, one had a gastrostomy-tube., Conclusions: Elimination of primary bed radiation in margin-negative resected, T1-T2 p16-positive OPSCC was not associated with significant compromise of local control, and correlated with superior swallowing preservation, assessed using gastrostomy rate as a surrogate. Lack of primary bed radiation in T3-T4 tumors associated with significantly increased LR rates., (Copyright © 2016 Elsevier Ltd. All rights reserved.)