Prognostic significance of time trends in treatment of head and neck squamous cell carcinoma.

PURPOSE: To analyze the impact of demographic, clinical, and management variables on time to treatment initiation (TTI) and overall survival (OS). STUDY DESIGN: Retrospective chart review. MATERIALS AND METHODS: Medical records of patients diagnosed with head and neck cancer from 2018 to 2020 were reviewed. Univariate linear and Cox-regressions identified predictors of TTI and OS. Kaplan Meier (KM) curves assessed the difference in survival by diagnostic year and TTI. RESULTS: 381 patients met eligibility criteria. Median TTI was 35.0 days (IQR: 25.0-49.0). Only 10.8 % of all patients reported any treatment delay, with TTI exceeding 90 days found in 3.7 % of patients. TTI increased with African American race (p = 0.02), ED referrals (p = 0.02), and direct admission status (p = 0.01). When compared to treatment with surgery alone, TTI was shorter in patients undergoing surgery with adjuvant radiation (p = 0.02), adjuvant chemoradiation (p = 0.04), and salvage surgery (p = 0.04). Univariate Cox-regressions found smoking (p = 0.01), direct admission status (p = 0.02), increased duration of symptoms (p = 0.02), placement of PEG tubes (p < 0.01) and tracheostomies (p < 0.01), combination treatment (p < 0.01), and surgery with adjuvant chemoradiation treatment (p = 0.01) to increase mortality risk. Disease characteristics, including tumor size (p < 0.01), presence of nodal disease (p = 0.02), and late-stage disease (p < 0.01), increased mortality risk. TTI and diagnostic year did not impact survival. CONCLUSIONS: Our analysis determined several demographic, referral, and treatment factors impacted TTI. However, increased TTI did not impact survival. Characteristics consistent with advanced disease worsened OS. Despite the pandemic burden, patients diagnosed in 2020 showed no difference in short-term survival compared to prior years.

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

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

Loss to Follow-up in Head and Neck Cancer: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To evaluate the reporting and rates of loss to follow-up (LTFU) in head and neck cancer (HNC) randomized controlled trials based in the United States. DATA SOURCES: Pubmed/MEDLINE, Cochrane, Scopus databases. REVIEW METHODS: A systematic review of titles in Pubmed/MEDLINE, Scopus, and Cochrane Library was performed. Inclusion criteria were US-based randomized controlled trials focused on the diagnosis, treatment, or prevention of HNC. Retrospective analyses and pilot studies were excluded. The mean age, patients randomized, publication details, trial sites, funding, and LTFU data were recorded. Reporting of participants through each stage of the trial was documented. Binary logistic regression was performed to evaluate associations between study characteristics and reporting LTFU. RESULTS: A total of 3255 titles were reviewed. Of these, 128 studies met the inclusion criteria for analysis. A total of 22,016 patients were randomized. The mean age of participants was 58.6 years. Overall, 35 studies (27.3%) reported LTFU, and the mean LTFU rate was 4.37%. With the exception of 2 statistical outliers, study characteristics including publication year, number of trial sites, journal discipline, funding source, and intervention type did not predict the odds of reporting LTFU. Compared to 95% of trials reporting participants at eligibility and 100% reporting randomization, only 47% and 57% reported on withdrawal and details of the analysis, respectively. CONCLUSION: The majority of clinical trials in HNC in the United States do not report LTFU, which inhibits the evaluation of attrition bias that may impact the interpretation of significant findings. Standardized reporting is needed to evaluate the generalizability of trial results to clinical practice.

Incidence and medical complications of COVID-19 in the total laryngectomy population: A population-based study.

OBJECTIVES: Laryngeal and hypopharyngeal cancers treated with total laryngectomy (TL) may provide a unique avenue for COVID-19 to infect cancer patients. The objective of this investigation was to identify incidence of COVID-19 infection and potential complications in TL patients. MATERIALS AND METHODS: Data was extracted from TriNetX COVID-19 research network from from 2019 to 2021 and ICD-10 codes were utilized to query for laryngeal or hypopharyngeal cancer, and outcomes of interest. Cohorts were propensity score-matched based on demographics and co-morbidities. RESULTS: A query of active patients in TriNetX from January 1, 2019 to December 31, 2021 identified 36,414 patients with laryngeal or hypopharyngeal cancer out of the 50,474,648 active patients in the database. The overall COVID-19 incidence in the non-laryngeal or hypopharyngeal cancer population was 10.8% compared to 18.8% (p < 0.001) in the laryngeal and hypopharyngeal cancer group. Those who underwent TL had a statistically significant increased incidence of acquiring COVID-19 (24.0%) when compared to those without TL (17.7%) (p < 0.001). TL patients with COVID-19 had a higher risk of developing pneumonia RR (risk ratio) 1.80 (1.43, 2.26), death 1.74 (1.41, 2.14), ARDS 2.42 (1.16, 5.05), sepsis 1.77 (1.37, 2.29), shock 2.81 (1.88, 4.18), respiratory failure 2.34 (1.90, 2.88), and malnutrition 2.46 (2.01, 3.01) when matched with those COVID-19 positive cancer patients without TL. CONCLUSIONS: Laryngeal and hypopharyngeal cancer patients had a higher rate of acquiring COVID-19 than patients without these cancers. TL patients have a higher rate of COVID-19 compared to those without TL and may be at a higher risk for sequalae of COVID-19.

Patient-derived three-dimensional culture techniques model tumor heterogeneity in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) outcomes remain stagnant, in part due to a poor understanding of HNSCC biology. The importance of tumor heterogeneity as an independent predictor of outcomes and treatment failure in HNSCC has recently come to light. With this understanding, 3D culture systems, including patient derived organoids (PDO) and organotypic culture (OTC), that capture this heterogeneity may allow for modeling and manipulation of critical subpopulations, such as p-EMT, as well as interactions between cancer cells and immune and stromal cells in the microenvironment. Here, we review work that has been done using PDO and OTC models of HNSCC, which demonstrates that these 3D culture models capture in vivo tumor heterogeneity and can be used to model tumor biology and treatment response in a way that faithfully recapitulates in vivo characteristics. As such, in vitro 3D culture models represent an important bridge between 2D monolayer culture and in vivo models such as patient derived xenografts.

High surgical volume is associated with improved survival in head and neck cancer.

OBJECTIVES: Examine the relationship between hospital volume and overall mortality in a surgical cohort of head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS & METHODS: A retrospective review of the NCDB was completed for adults with previously untreated HNSCC diagnosed between 2004 and 2016. Mean annual hospital volume was calculated using the number of head and neck cancer cases treated at a given facility divided by the number of years the facility reported to the NCDB. Facilities were separated into three categories based on their volume percentile, informed by inflection points from a natural cubic spline: Hospital Group 1 (<50%); Hospital Group 2 (50-90%); Hospital Group 3 (90%+). Cox proportional hazard models were used to examine the association between volume percentiles (continuous or categorical) with patient overall survival, adjusting for important patient and facility variables known to impact survival. RESULTS: Risk of death decreased by 2.97% for every 10% increase in facility percentile after adjusting for other risk factors. Patients treated at facilities in Hospital Group 1 had a 23.1% increase in risk of mortality (HR 1.231 [95% CI 1.12-1.35]) relative those at facilities in Hospital Group 3. No significant difference in mortality risk was found between Hospital Group 2 versus Hospital Group 3 (HR 1.031 [95% CI 0.97-1.10]). CONCLUSIONS: Survival of HNSCC patients is significantly improved when treated at facilities >50th percentile in annual hospital volume. This may support the regionalization of care to high volume head and neck centers with comprehensive facilities and supportive services to maximize patient outcomes.

Advantages of the scapular system in mandibular reconstruction.

BACKGROUND: Fibula free flaps (FFF) are often considered the first choice for mandibular reconstruction, but scapular system free flaps (SFF) have increased in popularity due to versatility, donor site advantages, and patient factors. METHODS: Retrospective chart review of patients undergoing mandibulectomy with FFF or SFF reconstruction from 2016 to 2021. RESULTS: Hundred and seventy-six patients (FFF n = 145, SFF n = 31) underwent the aforementioned procedures. Mean FFF operative time was 9.47 h versus 9.88 for SFF (p = 0.40). Two-flap reconstructions required 12.65 h versus 10.09 for SFF with soft tissue (p = 0.002). Donor site complications were identified in 65.6% of FFF with skin grafting. CONCLUSIONS: These findings suggest that SFF requires similar operative time and results in reduced donor site morbidity as compared to FFF. Supine, concurrent harvesting of SFF allows for single-flap harvest with significantly shorter operative time. SFF could be considered a primary option for mandible reconstruction for complex defects and in select patients.

Treatment failure patterns are similar between p16- and p16+ oropharyngeal squamous cell carcinomas.

Background: The incidence of p16+ oropharyngeal squamous cell carcinoma (OPSCC) has been increasing. The notion that p16+ OPSCC has a propensity for atypical and disseminating metastasis has gained traction. We compared treatment failure patterns in p16+ and p16- OPSCC and evaluated survival impact. Methods: Retrospective analysis of patients with recurrent/metastatic OPSCC disease between 1/2009 and 12/2019. Results: Thirty-eight p16+ and 36 p16- patients were identified. Three distinct failure patterns (distant vs. locoregional, atypical vs. typical, and disseminating vs. non-disseminating) were studied. No significant differences were found between p16+ and p16- patients. Multivariate analysis showed p16 status was an independent prognostic biomarker; p16+ patients have a favorable overall survival compared to p16- patients (HR 0.34, 95% CI 0.16-0.77; P = .005). Conclusions: We challenge the view that p16+ OPSCC exhibits a distinctive treatment failure pattern and showed that p16 status impacts patient survival independent of disease progression.

Job market in head and neck surgery: A survey and analysis of recent fellowship graduates.

OBJECTIVE: Recent years have seen increase in individuals pursuing postgraduate fellowships in head and neck (HN) surgery. This has presented concerns about insufficient jobs where graduates can apply their scope of specialized training. METHODS: Data was collected in two manners- a survey and a manual online search of American Head and Neck Society (AHNS) fellowship graduates. A 25-question survey was sent in 2021 to approximately 400 HN fellows who graduated between 2010 and 2020. The AHNS list of graduates from the same years were searched online to collect information including gender, graduation year, fellowship training, and current job practice. RESULTS: Of the 78 survey responses, 64.1 % were male and 34.6 % female. 96.2 % reported ablative, 84.6 % microvascular, and 82.1 % TORS training. Mean number of interviews was 4 with most interviewing during the 3rd quarter (January to March). Majority reported being in academic and university-based practices (79.6 %). Online search was done on 393 graduates. Since 2010 the number of graduates almost doubled. There was a statistically significant increase in females by year (p = 0.022). There was a significant decrease (p = 0.022) in graduates with additional fellowship training from that of their AHNS fellowship. There was also a statistically significant increase in graduates being in academic practices (p = 0.022). CONCLUSION: Despite growing numbers, there appears to be more graduates entering an academic practice, although the definition of an academic HN practice may be evolving. These results provide guidance on how to approach the job search in a select market. LEVEL OF EVIDENCE: II.

A machine learning model for separating epithelial and stromal regions in oral cavity squamous cell carcinomas using H&E-stained histology images: A multi-center, retrospective study.

OBJECTIVE: Tissue slides from Oral cavity squamous cell carcinoma (OC-SCC), particularly the epithelial regions, hold morphologic features that are both diagnostic and prognostic. Yet, previously developed approaches for automated epithelium segmentation in OC-SCC have not been independently tested in a multi-center setting. In this study, we aimed to investigate the effectiveness and applicability of a convolutional neural network (CNN) model to perform epithelial segmentation using digitized H&E-stained diagnostic slides from OC-SCC patients in a multi-center setting. METHODS: A CNN model was developed to segment the epithelial regions of digitized slides (n = 810), retrospectively collected from five different centers. Deep learning models were trained and validated using well-annotated tissue microarray (TMA) images (n = 212) at various magnifications. The best performing model was locked down and used for independent testing with a total of 478 whole-slide images (WSIs). Manually annotated epithelial regions were used as the reference standard for evaluation. We also compared the model generated results with IHC-stained epithelium (n = 120) as the reference. RESULTS: The locked-down CNN model trained on the TMA image training cohorts with 10x magnification achieved the best segmentation performance. The locked-down model performed consistently and yielded Pixel Accuracy, Recall Rate, Precision Rate, and Dice Coefficient that ranged from 95.8% to 96.6%, 79.1% to 93.8%, 85.7% to 89.3%, and 82.3% to 89.0%, respectively for the three independent testing WSI cohorts. CONCLUSION: The automated model achieved a consistently accurate performance for automated epithelial region segmentation compared to manual annotations. This model could be integrated into a computer-aided diagnosis or prognosis system.

Impact of AJCC 8th edition staging system and definitive treatment choice on the prognosis of complete responders with p16+ and p16- oropharyngeal squamous cell carcinomas.

OBJECTIVES: To identify predictors of overall survival (OS) in oropharyngeal squamous cell carcinoma (OPSCC) patients who achieved complete response (CR). METHODS: We performed a retrospective study of OPSCC patients who achieved CR from a single academic medical center. Associations between OS, AJCC 8th edition staging system, definitive treatment choice, smoking history, and p16 status were assessed. RESULTS: p16+ status was associated with favorable prognosis for CR (p < 0.001) but not non-CR (p = 0.67) patients. For early stage, p16+ OPSCC patients who achieved CR, surgery + adjuvant radiation (RT) treatment was more durable compared to concurrent chemoradiation (CRT), particularly in smokers. CONCLUSIONS: Curative intent treatment choice and smoking history has an impact on the long-term OS of the CR p16+ OPSCC cohort. Prospective studies to define the optimal multi-modality treatment option to manage p16+ OPSCC patients is needed.

Impact of intraoperative ischemia time on acute complications of head and neck microvascular free tissue transfer: A systematic review and meta-analysis.

BACKGROUND: To evaluate the relationship between intraoperative ischemia time with acute microvascular free tissue transfer (MFTT) complications in head and neck reconstruction. METHODS: A systematic review using PRISMA guidelines was performed. Inclusion encompassed all available studies published and indexed using PubMed, Medline, and Embase. Meta-analyses were performed using the Cochrane Review Manager tool. Methodological Index for Non-Randomized Studies (MINORS), the Revised Cochrane risk-of-bias tool for randomized trials, and the NIH Study Quality Assessment Tool for non-randomized prospective studies. RESULTS: A total of 430 citations were reviewed. 25 were included in our overall qualitative analysis, and 14 for meta-analysis. When comparing ischemia times for flaps with and without complications, no significant difference was observed (p = 0.98). Additionally, in a separate cohort, no significant effect was realized when correlating ischemia time to overall rates and total complications. CONCLUSION: Ischemia time was not significantly different between those with and without acute flap complications.

Occult nodal metastasis in major salivary gland malignancy: An update from the National Cancer Database.

OBJECTIVES: Malignant salivary gland tumors are rare neoplasms that are vastly heterogenous in their histological patterns and clinical behaviors. As a consequence, studies have lacked the robust sample sizes needed to define treatment strategies. In this study, we used the National Cancer Database to identify the incidence of occult nodal metastasis and effect on overall survival for the most common malignant salivary gland subtypes. A retrospective review of patients in the National Cancer Database with primary site malignancies of major salivary glands between 2004 and 2016 was performed. Subjects included in the study underwent surgical treatment with and without adjuvant radiation and had complete information on TNM pathological stage. MATERIALS AND METHODS: 8,689 patients with primary malignant salivary gland cancer were analyzed. The sample was stratified by histologic subtype. Univariate analysis of lymph node metastasis of the whole cohort showed a higher risk of death (p < 0.001), when compared to those without. Also when comparing occult vs evident metastasis, the risk of death was higher for the latter (p < 0.001). RESULTS AND CONCLUSION: Occult cervical lymph node metastasis ranged from 14.9% to 35.8% in malignant salivary gland cancers, depending on histological subtype. Occult nodal metastasis was a poor prognostic factor with significantly worse overall survival.

Repositioning Fenofibrate to Reactivate p53 and Reprogram the Tumor-Immune Microenvironment in HPV+ Head and Neck Squamous Cell Carcinoma.

Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV- HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

Impact of p16 Status and Anatomical Site in Anti-PD-1 Immunotherapy-Treated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Patients.

In head and neck squamous cell carcinoma (HNSCC), anti-PD-1 inhibitors are approved for recurrent/metastatic (R/M) disease and anticipated to expand to other indications. The impact of p16 status and anatomical site on overall survival (OS) in immunotherapy-treated HNSCC patients remains unresolved. We performed a retrospective analysis of R/M HNSCC patients receiving anti-PD-1 immunotherapy at our academic medical center with an extensive community satellite network. Fifty-three R/M HNSCC patients were treated with anti-PD-1 immunotherapy and had a median OS of 6 months. Anatomical site was associated with distinct OS; oropharynx and larynx patients have superior OS compared to oral cavity patients. Analysis of the OPSCC subset showed p16+ status as a favorable, independent prognostic biomarker (HR 7.67 (1.23-47.8); p = 0.029). Further studies to assess the link between anatomical site, p16 status, and anti-PD-1 treatment outcomes in large cohorts of R/M HNSCC patients managed in real-world clinical practices and clinical trials should be prioritized.

Stage Migration and Survival Trends in Laryngeal Cancer.

BACKGROUND: During the last two decades, significant advancements in the treatment of laryngeal cancer have occurred. Although survival of head and neck cancer patients has improved over time, the temporal trend of laryngeal cancer survival is an area of controversy. METHODS: From 2004 to 2016, 77,527 patients who had laryngeal cancer treated with curative intent in the United States were identified in the National Cancer Database. Relative and observed survival rates were assessed for temporal trends. Multinomial logistic regression investigated the relationship between American Joint Committee on Cancer (AJCC) stage and increasing calendar year. RESULTS: No significant improvement in 2- or 5-year observed survival (OS) or relative survival (RS) was observed. The 5-year RS ranged from 61.72 to 63.97%, and the 5-year OS ranged from 54.26 to 56.52%. With each increasing year, the proportion of stage 4 disease increased, with risk for stage 4 disease at the time of diagnosis increasing 2.2% annually (adjusted odds ratio [aOR], 1.022; 95% confidence interval [CI], 1.017-1.028; p < 0.001). This increase was driven by a 4.7% yearly increase in N2 disease (aOR, 1.047; 95% CI, 1.041-1.053; p < 0.001), with an annual 1.2% increase in T3 disease (aOR, 1.012; 95% CI, 1.007-1.018; p < 0.001) and a 1.2% increase in T4 disease (aOR, 1.012; 95% CI, 1.005-1.018; p < 0.001). CONCLUSION: Despite advances in the field, laryngeal cancer survival in the United States is not improving over time. This may be due to an increase in the proportion of stage 4 disease, driven primarily by increasing nodal disease. To achieve survival improvement commensurate with scientific and technologic advances, efforts should be made to diagnose and treat laryngeal cancer at earlier stages to prevent further stage migration.

Outpatient Parotidectomy, a Safety and Financial Review.

OBJECTIVE: The objective of this study is to investigate the safety, efficacy, and potential cost-savings of the outpatient parotidectomy procedure. METHODS: This is a retrospective chart review of all patients who underwent a parotidectomy at a large academic center from 2015 through 2019 including demographic data, postoperative complications, drain placement, readmission, and financial cost. A comparison was performed between patients who underwent an outpatient vs inpatient parotidectomy. RESULTS: A total of 335 patients underwent parotidectomy (136 outpatient; 199 inpatient). Comparison of patient demographics, common comorbidities, tumor size, tumor type, postoperative complications, and readmission rate was similar between the inpatient and outpatient cohorts. The overall mean cost difference between inpatient parotidectomy and outpatient parotidectomy for all years was $1528.58 (95%CI: $1139-$1916). CONCLUSION: The outpatient parotidectomy procedure has a comparable safety profile to the inpatient procedure while providing a significant cost-savings benefit.

African Americans With p16+ and p16- Oropharyngeal Squamous Cell Carcinomas Have Distinctly Poor Treatment Outcomes Independent of Medical Care Access.

PURPOSE: Human papilloma virus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), diagnosed with p16 immunohistochemistry, is associated with favorable prognosis; however, this connection was established using European American (EA)-skewed populations. The impact of p16/human papillomavirus status on outcomes in African American (AA) OPSCC patients remains to be settled. In this study, we determine the association between cancer disparity and p16 status in an OPSCC cohort controlling for time to treatment initiation (TTI), a surrogate for medical care access. MATERIALS AND METHODS: We analyzed data from all patients diagnosed with OPSCC (N = 440) between 2010 and 2017, who received treatment at our academic medical center. Associations between age, disease stage, sex, p16 status, race, TTI, and overall survival (OS) were investigated. RESULTS: TTI was similar between AA and EA OPSCC patients in our p16+ (P = .291) or p16- (P = .715) cohorts. Among p16+ OPSCC patients, the median OS was > 8.65 years for EA patients compared with 5.038 years (95% CI, 2.019 to 5.30; P = .003, log-rank) for AA patients. For p16- patients, the median OS was 5.74 years (95% CI, 3.32 to 6.99) for EA patients and 1.85 years (95% CI, 0.978 to 4.50; P = .03, log-rank) for AA patients. Multivariate Cox regression analysis showed that race was an independent prognostic biomarker and the most impactful co-variate for OS (hazard ratio, 0.40; 95% CI, 0.00 to 0.69; P = .001). CONCLUSION: Our work showed that AAs with p16+ OPSCC have surprisingly poor clinical outcomes and are thus poor candidates for treatment de-escalation regimens. Caution should be exercised when extending clinical guidelines based on EA-majority studies to non-EA populations.

Plasma cell marker, immunoglobulin J polypeptide, predicts early disease-specific mortality in HPV+ HNSCC.

BACKGROUND: Patients with human papillomavirus (HPV+) head and neck squamous cell carcinoma (HNSCC) have superior prognoses compared with patients with HPV- HNSCC and strategies for treatment de-escalation are under investigation for the HPV+ setting. However, the survival advantage associated with HPV is not universal, and a subset of patients with HPV+ HNSCC fail definitive treatment and progress with metastatic/recurrent disease. Currently, no biomarker is available to distinguish aggressive from indolent HPV+ HNSCC. Immune dysfunction facilitates tumorigenesis and is associated with poor treatment response; therefore, we hypothesized that diminished intratumoral immune cell functionality may be attractive biomarkers to identify patients with HPV+ HNSCC at risk for early disease-specific mortality. METHODS: This is a retrospective analysis of The Cancer Genome Atlas (TCGA) HPV+ HNSCC cohort. RESULTS: Immunoglobulin J polypeptide (IGJ), uniquely expressed in plasma cells, showed a broad expression range in HPV+ HNSCC. Cox regression model, adjusting for clinical covariates, indicated that IGJ is an independent prognostic biomarker for disease-specific survival (DSS) and overall survival (OS). Patients with low IGJ had a 7.2-fold (p<0.001) increase in risk of disease-specific death with a median DSS of 13 months. Low IGJ showed an area under curve (AUC) of 0.89 with 91.0% sensitivity and 87.6% specificity to identify early disease-specific mortality (defined as DSS ≤12 months). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed a global dampening of immune pathways in low IGJ tumors. CONCLUSIONS: Our work showed that IGJ is a robust and independent prognostic biomarker for disease-specific mortality in HPV+ HNSCC. Patient with HPV+ HNSCC with limited adaptive immune functionality should not be candidates for treatment de-escalation modalities.

Impact of age and comorbidity on survival among patients with oral cavity squamous cell carcinoma.

OBJECTIVE: To identify predictors of overall survival (OS) and to stratify patients according to significant prognostic variables. METHODS: A retrospective study of 274 consecutive patients with primary Oral Cavity Squamous Cell Carcinoma. Kaplan-Meier, Cox proportional hazard models, and recursive partitioning analysis (RPA) were used for analysis of OS. These results were further validated using National Cancer Database cohort of 21 895 patients. RESULTS: Median OS was 3.65 years. T-classification and N-classification, alcoholic beverages/week, age, and adjuvant treatment were significant predictors of OS. RPA identified high-risk subpopulations: N0-1 patients with CCI ≥ 4.5 and N2-3 patients ordered by those not receiving adjuvant treatment, those with T3-4 disease despite adjuvant therapy, and those having T1-2 disease with adjuvant therapy. CONCLUSIONS: This study utilized significant prognostic indicators and RPA to highlight the importance of age, N-classification, T-classification, comorbidity, and adjuvant therapy in conjunction with American Joint Committee on Cancer staging to improve preoperative counseling.