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Hyperspectral imaging (HSI) is a noninvasive optical modality that holds promise for early detection of tongue lesions. Spectral signatures generated by HSI contain important diagnostic information that can be used to predict the disease status of the examined biological tissue. However, the underlying pathophysiology for the spectral difference between normal and neoplastic tissue is not well understood. Here, we propose to leverage digital pathology and predictive modeling to select the most discriminative features from digitized histological images to differentiate tongue neoplasia from normal tissue, and then correlate these discriminative pathological features with corresponding spectral signatures of the neoplasia. We demonstrated the association between the histological features quantifying the architectural features of neoplasia on a microscopic scale, with the spectral signature of the corresponding tissue measured by HSI on a macroscopic level. This study may provide insight into the pathophysiology underlying the hyperspectral dataset.

Hyperspectral imaging (HSI) holds the potential for the noninvasive detection of cancers. Oral cancers are often diagnosed at a late stage when treatment is less effective and the mortality and morbidity rates are high. Early detection of oral cancer is, therefore, crucial in order to improve the clinical outcomes. To investigate the potential of HSI as a noninvasive diagnostic tool, an animal study was designed to acquire hyperspectral images of in vivo and ex vivo mouse tongues from a chemically induced tongue carcinogenesis model. A variety of machine-learning algorithms, including discriminant analysis, ensemble learning, and support vector machines, were evaluated for tongue neoplasia detection using HSI and were validated by the reconstructed pathological gold-standard maps. The diagnostic performance of HSI, autofluorescence imaging, and fluorescence imaging were compared in this study. Color-coded prediction maps were generated to display the predicted location and distribution of premalignant and malignant lesions. This study suggests that hyperspectral imaging combined with machine-learning techniques can provide a noninvasive tool for the quantitative detection and delineation of squamous neoplasia., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Previous studies revealed diverging results regarding the role of survivin in squamous cell carcinoma of the head and neck (SCCHN). This study aimed to evaluate the clinical significance of survivin expression in SCCHN; the function of survivin in DNA-damage repair following ionizing radiation therapy (RT) in SCCHN cells; and the potential of honokiol to enhance RT through downregulation of survivin. Experimental Design: Expression of survivin in SCCHN patient primary tumor tissues ( n = 100) was analyzed and correlated with clinical parameters. SCCHN cell lines were used to evaluate the function of survivin and the effects of honokiol on survivin expression in vitro and in vivo Results: Overexpression of survivin was significantly associated with lymph nodes' metastatic status ( P = 0.025), worse overall survival (OS), and disease-free survival (DFS) in patients receiving RT ( n = 65, OS: P = 0.024, DFS: P = 0.006) and in all patients with SCCHN ( n = 100, OS: P = 0.002, DFS: P = 0.003). In SCCHN cells, depletion of survivin led to increased DNA damage and cell death following RT, whereas overexpression of survivin increased clonogenic survival. RT induced nuclear accumulation of survivin and its molecular interaction with γ-H2AX and DNA-PKCs. Survivin specifically bound to DNA DSB sites induced by I-SceI endonuclease. Honokiol (which downregulates survivin expression) in combination with RT significantly augmented cytotoxicity in SCCHN cells with acquired radioresistance and inhibited growth in SCCHN xenograft tumors. Conclusions: Survivin is a negative prognostic factor and is involved in DNA-damage repair induced by RT. Targeting survivin using honokiol in combination with RT may provide novel therapeutic opportunities. Clin Cancer Res; 24(4); 858-69. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: We examined the prognostic value of a panel of biomarkers in patients with squamous cell carcinoma of the head and neck (SCCHN) who were human immunodeficiency virus (HIV) positive (HIV-positive head and neck cancer) and HIV negative (HIV-negative head and neck cancer)., Methods: Tissue microarrays (TMAs) were constructed using tumors from 41 disease site-matched and age-matched HIV-positive head and neck cancer cases and 44 HIV-negative head and neck cancer controls. Expression of tumor biomarkers was assessed by immunohistochemistry (IHC) and correlations examined with clinical variables., Results: Expression levels of the studied oncogenic and inflammatory tumor biomarkers were not differentially regulated by HIV status. Among patients with HIV-positive head and neck cancer, laryngeal disease site (P = .003) and Clavien-Dindo classification IV (CD4) counts <200 cells/μL (P = .01) were associated with poor prognosis. Multivariate analysis showed that p16 positivity was associated with improved overall survival (OS; P < .001) whereas increased expression of transforming growth factor-beta (TGF-β) was associated with poor clinical outcome (P = .001)., Conclusion: Disease site has significant effect on the expression of biomarkers. Expression of tumor TGF-β could be a valuable addition to the conventional risk stratification equation for improving head and neck cancer disease management strategies., (© 2017 Wiley Periodicals, Inc.)

An estimated 200,000 deaths each year worldwide are due to cancer of the head and neck, mostly mucosal squamous cell carcinoma and nonmelanoma skin cancer. The status of surgical margins is important for prognosis and need for adjuvant therapy. We will discuss how margin status impacts outcomes and therapy, and the conundrum of determining margin status., (© 2015 Wiley Periodicals, Inc.)

Background: Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN., Methods: Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m(2) and then 250 mg/m(2) weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2., Results: The study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival., Conclusions: The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck., (© 2014 American Cancer Society.)

Head and neck cancer is a heterogenous group of cancers involving the upper aerodigestive tract. In this review article, the most common sites will be discussed, including the oral cavity, oropharynx, hypopharynx, and larynx. Etiology and epidemiology will be discussed followed by staging, treatment, and survival., (© 2014 Wiley Periodicals, Inc.)

Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.

Acetylated tubulin (AT) expression has been proposed as a marker for sensitivity to taxane chemotherapy. We wanted to explore AT as a prognostic marker in squamous cell carcinoma of the head and neck (SCCHN). We assessed AT expression in archival tissue from our institutional tissue bank of primary SCCHN specimens. We also examined AT expression on pre-therapy tissues of patients with SCCHN receiving induction chemotherapy with docetaxel, cisplatin and 5FU (TPF IC). AT expression was assessed on archival cases of SCCHN with (N = 63) and without (N = 82) locoregional lymph node metastases (LNM). The predominant tumor site was oral cavity (52 %). Immunohistochemistry staining was based on staining intensity and percentage of tumor cells stained to create a weighted index (WI). A total of nine patients who received TPF IC were evaluable for response by RECIST and also had pre-therapy tissues available. A significant independent correlation between AT and tumor grade (p = 0.001) and primary location (p = 0.008) was noted. There was a trend of higher AT in patients with presence of LNM (p = 0.052) and a trend in improved OS for patients with an AT WI below the median compared to those above the median for patients with no LNM (p = 0.054). For patients treated with induction TPF, we observed an inverse correlation between AT expression and response to TPF IC (p = 0.0071). AT expression is correlated with tumor grade and primary site. There was an observed trend correlating AT with presence nodal metastases. The observed inverse correlation with response to taxane based chemotherapy needs validation in a larger sample size.

Background: Paranasal sinus squamous cell carcinomas (PNSSCC) account for 3% of all head and neck malignancies. There has been little information on the trends in incidence and survival, and no randomized trials have been conducted to guide therapy., Methods: Patients with PNSSCC reported to the Surveillance, Epidemiology, and End Results (SEER) Program from 1973 through 2009 were categorized by sex, age, year of diagnosis, primary site, stage, and treatment. The incidence and survival were then compared across different demographic and disease-related categories by calculating rate ratios (RRs) and mortality hazard ratios along with the corresponding 95% confidence intervals (CIs)., Results: In total, 2553 patients with PNSSCC were identified. While incidence of PNSSCC showed a gradual decline, survival remained largely unchanged. The proportion of patients with advanced disease decreased from 14.7% during the period from 1983 to 1992 to 12.4% during 1993-2002 and to 9.5% during 2003-2009. Compared with whites, incidence was higher among African Americans (RR 1.63; 95% CI, 1.39, 1.90) and among all other racial groups (RR, 1.78; 95% CI: 1.53-2.07). After adjusting for age, sex, disease stage, tumor site, and treatment, mortality among African American patients also was increased (hazard ratio, 1.22; 95% CI, 1.04-1.43). Among patients with localized disease, the relation between race and mortality was no longer evident once the results were controlled for tumor classification., Conclusions: The current findings point to racial disparities in the incidence of PNSSCC and, to a lesser extent, in the outcome of patients with PNSSCC. Although there has been a decline in the proportion of patients presenting with advanced PNSSCC, the overall survival remained stable over time., (© 2013 American Cancer Society.)

Purpose: We investigated the efficacy and underlying molecular mechanism of a novel chemopreventive strategy combining EGF receptor (EGFR) tyrosine kinase inhibitor (TKI) with cyclooxygenase-2 inhibitor (COX-2I)., Experimental Design: We examined the inhibition of tumor cell growth by combined EGFR-TKI (erlotinib) and COX-2I (celecoxib) treatment using head and neck cancer cell lines and a preventive xenograft model. We studied the antiangiogenic activity of these agents and examined the affected signaling pathways by immunoblotting analysis in tumor cell lysates and immunohistochemistry (IHC) and enzyme immunoassay (EIA) analyses on the mouse xenograft tissues and blood, respectively. Biomarkers in these signaling pathways were studied by IHC, EIA, and an antibody array analysis in samples collected from participants in a phase I chemoprevention trial of erlotinib and celecoxib., Results: The combined treatment inhibited head and neck cancer cell growth significantly more potently than either single agent alone in cell line and xenograft models, and resulted in greater inhibition of cell-cycle progression at G1 phase than either single drug. The combined treatment modulated the EGFR and mTOR signaling pathways. A phase I chemoprevention trial of combined erlotinib and celecoxib revealed an overall pathologic response rate of 71% at time of data analysis. Analysis of tissue samples from participants consistently showed downregulation of EGFR, pERK, and pS6 levels after treatment, which correlated with clinical response., Conclusion: Treatment with erlotinib combined with celecoxib offers an effective chemopreventive approach through inhibition of EGFR and mTOR pathways, which may serve as potential biomarkers to monitor the intervention of this combination in the clinic. Clin Cancer Res; 19(5); 1244-56. ©2013 AACR., (©2013 AACR.)

To accurately interpret pretreatment and posttreatment imaging in patients with hypopharyngeal squamous cell carcinoma (SCC), one must understand the complex anatomy of this part of the aerodigestive system. Common patterns of spread must be recognized, andpitfalls in imaging must be understood. This article reviews the epidemiology, anatomy, staging, treatment, and pitfalls in imaging of hypopharyngeal SCC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To investigate whether patients treated with laryngectomy had less comorbidity than those treated with chemoradiation, which could help explain the improved survival for the laryngectomy cohorts in recent studies., Design: Observational cross-sectional study., Patients: Patients receiving diagnoses of primary invasive advanced squamous cell carcinoma of the larynx between 2003 and 2008 were selected from the National Cancer Database, which collects information from more than 1400 facilities accredited by the American College of Surgeons' Commission on Cancer. Patient-level independent variables included age at diagnosis, sex, diagnosis year, race/ethnicity, primary payer status, and zip code-level education., Main Outcome Measures: Primary treatment information. The association between treatment and patient clinical, sociodemographic, and facility-level and zip code-level socioeconomic status variables were analyzed using univariate statistics and multivariate models. Charlson Deyo Comorbidity and The Washington University Head and Neck Comorbidity Index scores were calculated from the hospital face sheet., Results: The study demonstrated that receipt of treatment (chemoradiation vs total laryngectomy) was significantly associated with comorbidity. Treatment was not significantly associated with insurance status, race/ethnicity, or age. Patients with comorbidity were less likely to receive chemoradiation than subtotal or total laryngectomy, with a risk ratio (RR) of 0.84 (95% CI, 0.81-0.87) for patients with 1 or more comorbidities compared with those without any comorbidity, after controlling for factors such as tumor stage, age, race/ethnicity, insurance, and socioeconomic status. Patients were also less likely to receive chemoradiation than total laryngectomy if they had stage IV disease (RR, 0.81; 95% CI, 0.79-0.83) and if they had been diagnosed at a teaching or research institution (RR, 0.80; 95% CI, 0.77-0.84). Patients were more likely to receive chemoradiation if they were diagnosed after 2003 (RR, 1.37; 95% CI, 1.30-1.45) or if they lived in a zip code with a high percentage of high school graduates (RR, 1.1; 95% CI, 1.05-1.15)., Conclusions: This is the first study, to our knowledge, that demonstrates that patients with advanced laryngeal cancer with 1 or more comorbidities are more likely to receive surgery than chemoradiation compared with patients without any comorbidity, independent of numerous clinical and nonclinical variables among a large national cohort. A limitation of this study is the use of comorbidity data from the National Cancer Database, which gathers its information from hospital discharge face sheets. We recognize that the National Cancer Database may be an imperfect system for the collection of comorbidity data and encourage discussion on different methods to improve the system, including incorporating comorbidity data from the Surveillance, Epidemiology, and End Results Medicare Database and medical chart-based comorbidity data collection by cancer registrars.

Background: Laryngeal preservation programs for patients with advanced laryngeal squamous cell carcinomas (SCC) have generally excluded patients with T4 disease. The accuracy of preoperative imaging in evaluating thyroid cartilage penetration and extralaryngeal spread (ELS) has previously been questioned. Clinically, SCC spread into noncartilaginous structures may have less of a functional impact when compared with thyroid cartilage penetration. The current study was designed to characterize and quantify the routes and frequency of ELS., Methods: A total of 103 laryngectomy specimens with preoperative contrast-enhanced neck computed tomography scans were coded according to the observed extent of disease by pathological and radiological data. Previously irradiated tumors or those of pyriform sinus origin were omitted. Routes of spread were categorized as anterior (thyroid cartilage penetration), posterior (arytenoid cartilage destruction and thyroarytenoid space widening), inferior (conus elasticus penetration), and superior (base of tongue, thyrohyoid membrane or thyroid notch penetration involvement)., Results: Sixty-three cases of ELS were identified. Anterior spread by thyroid cartilage penetration occurred in 44% of all instances of ELS, followed by both inferior and posterior spread each representing 33% of ELS cases. Superior spread occurred with a frequency of 24%., Conclusions: Although thyroid cartilage penetration is a common route of ELS of glottic and supraglottic SCC, ELS into surrounding structures with thyroid cartilage penetration was found to occur in only 44% of the cases of ELS in the current study. As illustrated, advanced SCC spreads in a variety of pathways. Once these patterns are better understood and identified at the time of initial evaluation, subgroups of patients with ELS who may still be candidates for laryngeal preservation may be identified., (Copyright © 2011 American Cancer Society.)

Background: Because of the multidisciplinary nature of treatment for advanced laryngeal cancer, the authors hypothesized that treatment at high-volume teaching/research facilities is associated with improved survival., Methods: After exclusions, 19,326 patients who were diagnosed with advanced laryngeal cancer (stage III and IV) between 1996 and 2002 and who received treatment (chemoradiotherapy [CRT], total laryngectomy [TL], or radiotherapy [RT]) were analyzed from the National Cancer Database (NCDB). Facilities were classified into 6 groups (low-volume and high-volume teaching/research facilities, low-volume and high-volume community cancer centers, and low-volume and high-volume community facilities). Multivariate proportional hazards regression modeling was used to determine 90-day, 365-day, and 4-year hazard ratio (HR) estimates., Results: Treatment included TL (37.6%), CRT (29.4%), and RT alone (33%). Overall, 36.2% of patients were treated at high-volume teaching/research centers (average, 17.1 cases per year). Among all patients, 20% died within the first year. In multivariate models that were controlled for covariates, 90-day, 365-day, and 4 year HR estimates for death were lowest for high-volume teaching/research centers., Conclusions: Receiving treatment at high-volume teaching/research facilities was associated with improved survival. Undergoing total laryngectomy also was associated with improved survival. The current results suggested that the regionalization of care for patients with advanced-stage laryngeal cancer has occurred, because most patients were treated either at high-volume teaching/research facilities or at high-volume community cancer centers. Future studies should investigate the factors associated with better survival at high-volume teaching/research facilities, such as quality of care, processes of care, and referral patterns., (© 2010 American Cancer Society.)

Objective: To examine whether patients with no insurance or Medicaid are more likely to present with advanced-stage laryngeal cancer., Design: Retrospective cohort study from the National Cancer Database, 1996-2003., Setting: Hospital-based practice., Participants: Patients with known insurance status diagnosed as having invasive laryngeal cancer at Commission on Cancer facilities (N = 61 131) were included. Adjusted and unadjusted logistic regression models analyzed the likelihood of presenting at a more advanced stage., Main Outcome Measures: Overall stage of laryngeal cancer (early vs advanced) and tumor size (T stage) at diagnosis., Results: Patients with advanced-stage laryngeal cancer at diagnosis were more likely to be uninsured (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.79-2.15) or covered by Medicaid (OR, 2.40; 95% CI, 2.21-2.61) compared with those with private insurance. Similarly, patients were most likely to present with the largest tumors (T4 disease) if they were uninsured (OR, 2.92; 95% CI, 2.60-3.28) or covered by Medicaid (OR, 3.97; 95% CI, 3.56-4.34). Patients who were black, between ages 18 and 56 years, and who resided in zip codes with low proportions of high school graduates or low median household incomes were also more likely to be diagnosed as having advanced disease and/or larger tumors., Conclusions: Individuals lacking insurance or having Medicaid are at greatest risk for presenting with advanced laryngeal cancer. Results for the Medicaid group may be influenced by the postdiagnosis enrollment of uninsured patients. It is important to consider the impact of insurance coverage on stage at diagnosis and associated morbidity, mortality, quality of life, and costs.

Objective: The aim of this study is to describe patterns of care of advanced oropharyngeal cancer during 1985 to 2001., Methods: We extracted oropharyngeal squamous cell cancer cases from the National Cancer Database. Type of initial treatment, type of facility, stage of tumor, payer status, and demographic variables were collected. Fisher exact test was used to compare the patient demographic and clinical characteristics across facility types. Weighted least squares regression analysis was used to analyze treatment trends over time and t-tests were done to test for significance in trends., Results: A total of 54,801 cases were available for analysis. Teaching/research facilities treated a disproportionately higher number of advanced-stage cancers (81%, P < .01). In addition, these facilities treat a higher percentage of uninsured (7%, P < .01) and nonwhite patients (27%, P < .01). The use of organ preservation protocols (chemoradiation) increased from 15% in 1985 to 29% in 2001 (beta1 = 0.0080, P < .05), whereas the use of radiation alone decreased from 42% in 1985 to 27% in 2001 (beta1 = -0.0118, P < .05). The use of cancer-directed surgery remained stable. There was no difference in rates of chemoradiation for advanced oropharyngeal cancer across facility types., Conclusions: Our results suggest that chemoradiation is increasingly becoming more prevalent at all facility types. The use of radiation alone as primary treatment significantly declined during the study period. In view of the complexity and multidisciplinary nature of treatment for oropharyngeal cancer, it is recommended that care of such patients be discussed at institutional tumor boards and that the recommendations be systematically recorded and documented in hospital cancer registries.

Purpose: The aim of our study was to assess the utility of positron emission tomography (PET) and 2 fluoro-2-deoxy-D-glucose coupled with neck CT compared with contrast-enhanced CT in predicting persistent cancer either at the primary site or cervical lymphatics in patients with oropharyngeal cancer treated with concurrent chemoradiation, Methods: Thirty consecutive patients underwent clinical examination, PET-CT, and contrast-enhanced CT to assess response after the completion of the treatment. The outcome variable was positive tissue diagnosis or negative disease at 6 months. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for the primary site as well as cervical disease., Results: Contrast-enhanced CT alone showed the best accuracy in detecting disease at the primary site after treatment (85.7%). Accuracy in evaluating residual tumor in the cervical lymphatics for contrast-enhanced CT and PET-CT was 59.3% and 74.1%, respectively. For evaluating the neck, PET-CT and contrast-enhanced CT demonstrated 100% NPV, but the PPV was 36.3% and 26.6%, respectively., Conclusions: In this preliminary study, PET-CT seems to be superior to contrast-enhanced CT in predicting persistent disease in the neck after chemoradiation for oropharyngeal or unknown primary cancer, but not at the primary site. However, the possibility of a false-positive result in the neck remains high, and thus overtreatment may result. Even more concerning are the false-negative results. Larger, prospective studies will be important in defining the role of PET-CT in obviating the need for salvage neck dissections after chemoradiation.

In this review, the authors outline the epidemiology, genetic factors, treatment and outcomes of head and neck cancer.