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Importance: The assessment and management of surgical margins in stage I and II oral cavity squamous cell carcinoma is one of the most important perioperative aspects of oncologic care, with profound implications for patient outcomes and adjuvant therapy. Understanding and critically reviewing the existing data surrounding margins in this context is necessary to rigorously care for this challenging group of patients and minimize patient morbidity and mortality., Observations: This review discusses the data related to the definitions related to surgical margins, methods for assessment, specimen vs tumor bed margin evaluation, and re-resection of positive margins. The observations presented emphasize notable controversy within the field about margin assessment, with early data coalescing around several key aspects of management, although studies are limited by their design., Conclusions and Relevance: Stage I and II oral cavity cancer requires surgical resection with negative margins to obtain optimal oncologic outcomes, but controversy persists over margin assessment. Future studies with improved, well-controlled study designs are required to more definitively guide margin assessment and management.

Background: Oral proliferative verrucous leukoplakia (OPVL) is a chronic form of oral leukoplakia that progresses to a multifocal disease with confluent, exophytic and proliferative features. The clinical differential diagnosis for OPVL includes frictional keratosis, leukoplakia, chronic hyperplastic candidiasis, squamous papilloma, verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma. In this study, we aimed to delineate the dynamic changes in molecular signature during OPVL progression. We compare to a cohort of oral cavity keratinizing squamous cell carcinoma (OSCC) patients covering the spectrum of verrucous carcinoma to invasive squamous cell carcinoma including cytologically bland cuniculatum variant., Methods: Samples from a large OPVL lesion that exhibited a histopathologic continuum of OPVL progression., Results: Canonical hotspot TERT promoter mutations were identified in all patients. TERT C228T was dominant and mutually exclusive with TERT C250T. In patients with TERT C250T, there was concurrent PI3 point mutation. TP53 mutations were also consistently found (8/10). At the protein level, p53 was abnormal, with loss of function and gain of function., Conclusions: OPVL is a pathology that shows proximity to the gene expression profile of OSCC, highlighting signatures in common that can be important targets for drug treatment, as well as in the development of diagnostic and prognostic strategies for this disease., Competing Interests: Declaration of competing interest We have no financial interest or conflict of interest in association with this work., (Published by Elsevier Inc.)

Background: The prognostic impact of human papillomavirus (HPV) infection or smoking on oropharyngeal high-grade neuroendocrine carcinoma (HG-NEC) is not established., Methods: Retrospective study with patients with oropharyngeal HG-NEC seen at MD Anderson Cancer Center from 1997 to 2020, and previously reported patients with oropharyngeal HG-NEC and known p16 and HPV status from the literature review. Survival was estimated with the Kaplan-Meier method, and survival differences assessed with the log-rank test and Cox proportional hazards models., Results: Thirty patients were included; most had a heavy (≥10 pack-years) smoking history (52%), locoregional disease (stage III-IVB; 77%), and p16-positive tumor (92%). HPV was positive in 65% of tested samples (15/23). Of 24 patients treated with curative intent, the objective response rates was 90% (9/10) and 81% (17/21), respectively, for induction chemotherapy and definitive radiotherapy. During follow-up, 54% (13/24) recurred, mostly (11/13) at distant sites. Median overall survival (OS) was 46 months (95% CI, 14.3 - NA). OS was not associated with HPV status (HR 0.73, P = 0.6) or smoking (HR 1.16, P = 0.8). Among 63 patients with known HPV status after the literature review (19 HPV- and 44 HPV + ), HPV status remained unassociated with OS (P = 0.92)., Conclusions: This is the largest retrospective cohort of oropharyngeal HG-NEC. Distant recurrence rate after curative treatment was high, suggesting that multimodality treatment including systemic therapy may benefit patients with locally advanced disease. HPV infection did not affect survival outcomes, therefore should not lead to therapy de-intensification for this histology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

NUT carcinoma (NC) is a rare subtype of squamous cell carcinoma defined by NUTM1 rearrangements encoding NUT fusion oncoproteins (the most frequent fusion partner being BRD4 ) that carries a very poor prognosis, with most patients dying in under 1 year. Only rare primary thyroid NCs have been reported. Here, we evaluated a series of 14 cases. The median patient age at diagnosis was 38 years (range: 17 to 72 y). Eight of 13 cases with slides available for review (62%) showed a morphology typical of NC, whereas 5 (38%) had a non-NC-like morphology, some of which had areas of cribriform or fused follicular architecture resembling a follicular cell-derived thyroid carcinoma. For cases with immunohistochemistry results, 85% (11/13) were positive for NUT on biopsy or resection, though staining was significantly decreased on resection specimens due to fixation; 55% (6/11) were positive for PAX8, and 54% (7/13) for TTF-1. Tumors with a non-NC-like morphology were all positive for PAX8 and TTF-1. The fusion partner was known in 12 cases: 9 (75%) cases had a NSD3-NUTM1 fusion, and 3 (25%) had a BRD4-NUTM1 fusion. For our cohort, the 2-year overall survival (OS) was 69%, and the 5-year OS was 58%. Patients with NC-like tumors had a significantly worse OS compared with that of patients with tumors with a non-NC-like morphology ( P =0.0462). Our study shows that NC of the thyroid can mimic other thyroid primaries, has a high rate of NSD3 - NUTM1 fusions, and an overall more protracted clinical course compared with nonthyroid primary NC., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a research grant from the National Institutes of Health (NCI, CA124633 to C.A.F.) and Cancer Center Support Grant of the National Institutes of Health/National Cancer Institute under award number P30CA008748 (R.A.G and B.X.). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Patients with advanced cutaneous squamous cell carcinoma (CSCC) have a poor prognosis. Blocking the PD-1-PD-L1 axis has shown promising activity in this patient population. We assessed the safety and antitumor activity of PD-1 inhibitor pembrolizumab in patients with refractory advanced CSCC., Methods: This was a prespecified subgroup analysis of patients with advanced CSCC who enrolled in an open-label, phase II clinical trial for pembrolizumab in patients with refractory rare cancers during 2016-2018. Patients received pembrolizumab 200 mg intravenously every 21 days until progressive disease, unacceptable adverse event, or completion of 24 months of treatment. The primary endpoint was nonprogression rate (NPR) at 27 weeks; secondary endpoints included safety, objective response rate (ORR) per irRECIST, clinical benefit rate (CBR), progression-free survival, and overall survival., Results: Twenty patients with refractory CSCC enrolled; 19 were evaluable for efficacy. Median follow-up time was 44.1 months. The NPR at 27 weeks was 37% (95% CI 0.16-0.62). Three patients had a complete response (CR), three had a partial response, and one had stable disease, for an ORR of 32% and a CBR of 37%; median duration of response was 27.3 months. All three patients with a CR remained free of recurrence at the time of writing. Severe treatment-related adverse events (grade ≥ 3) occurred in 10% of patients (2/20). PD-L1 expression was not correlated with response to pembrolizumab., Conclusion: A long-term follow-up confirms pembrolizumab's antitumor activity and safety profile in patients with refractory CSCC. Patients with a CR may experience cure., Trial Registration: ClinicalTrials.gov, NCT02721732, Registered March 29, 2016., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

We have previously demonstrated that PD-1 blockade decreased the incidence of high-grade dysplasia in a carcinogen-induced murine model of oral squamous cell carcinoma (OSCC). It remains unknown, however, whether there are additional factors involved in escape from immune surveillance that could serve as additional targets for immunoprevention. We performed this study to further characterize the immune landscape of oral premalignant lesions (OPL) and determine the impact of targeting of the PD-1, CTLA-4, CD40, or OX40 pathways on the development of OPLs and oral carcinomas in the 4-nitroquinoline 1-oxide model. The immune pathways were targeted using mAbs or, in the case of the PD-1/PD-L1 pathway, using PD-L1-knockout (PD-L1 ko ) mice. After intervention, tongues and cervical lymph nodes were harvested and analyzed for malignant progression and modulation of the immune milieu, respectively. Targeting of CD40 with an agonist mAb was the most effective treatment to reduce transition of OPLs to OSCC; PD-1 alone or in combination with CTLA-4 inhibition, or PD-L1 ko , also reduced progression of OPLs to OSCC, albeit to a lesser extent. Distinct patterns of immune system modulation were observed for the CD40 agonists compared with blockade of the PD-1/PD-L1 axis with or without CTLA-4 blockade; CD40 agonist generated a lasting expansion of experienced/memory cytotoxic T lymphocytes and M1 macrophages, whereas PD-1/CTLA-4 blockade resulted in a pronounced depletion of regulatory T cells among other changes. These data suggest that distinct approaches may be used for targeting different steps in the development of OSCC, and that CD40 agonists merit investigation as potential immunoprevention agents in this setting. PREVENTION RELEVANCE: PD-1/PD-L1 pathway blockade, as well as activation of the CD40 pathway, were able to prevent OPL progression into invasive OSCC in a murine model. A distinct pattern of immune modulation was observed when either the CD40 or the PD-1/PD-L1 pathways were targeted., (©2020 American Association for Cancer Research.)

Non-melanoma skin cancer (NMSC) is the most common malignancy in the world and is reaching epidemic proportions. The most common types of NMSC include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). The head and neck is the most common site for NMSC, and surgery remains the mainstay of treatment. We review the etiology, risk factors, pathogenesis as well as the preoperative, operative, and postoperative considerations in the management of NMSC. Multidisciplinary evaluation and attention to each of these phases is imperative for favorable oncologic and functional patient outcomes., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Sinonasal papilloma has a tendency toward local destruction, recurrence, and malignant transformation. This study aimed to unravel mechanisms in the malignant transformation of sinonasal papillomas using RNA-seq., Methods: The cohort consisted of 37 consecutive patients; tumor histology included a continuum spectrum (sinonasal papillomas/dysplastic/carcinomas-in-situ/invasive squamous cell carcinomas). These were microdissected and RNA was subjected to whole-transcriptome shotgun sequencing., Results: RNA-seq and pathway analysis showed that the highest expressed genes/potential drivers were development- and differentiation-related genes. The protein expression of six highly upregulated genes (HOXA9, EN1, DUX4, CA9, CD1a, and CK5/6) validated the RNA-seq results. HOXA9 and CA9 were found to be expressed in most of the carcinoma samples but were largely negative in papillomas; all of the CA9-negative carcinomas were recurrent., Conclusions: We conclude that sinonasal carcinomas arising from papillomas are mainly defined by overexpressed developmental/homeobox genes, which provide the potential for transformation/plasticity, along with differentiation and proliferation behavior of neoplastic cells. Our results support HOXA9 and CA9 as biomarkers for carcinomas, with CA9 emerging as a predictive marker of recurrence., (© 2019 Wiley Periodicals, Inc.)

Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer. It is often difficult to determine whether SNUC is a distinct pathologic entity with poorly differentiated neuroendocrine features or it represents an undifferentiated tumor of squamous lineage. Also, reliable histopathologic markers that distinguish SNUC from poorly differentiated sinonasal squamous cell carcinoma (SNSCC) are lacking. Therefore, identification of new diagnostic molecular markers for SNUC is needed., Methods: Treatment-naïve tumor specimens obtained from 15 SNUC and 6 SNSCC patients were used. Gene expression analysis was performed using an oncology panel., Results: An unsupervised cluster analysis divided the patients into the one with only SNUCs and the one with mainly SNSCCs. Of 132 differentially expressed genes, 7 genes completely distinguished SNUCs from SNSCCs. SNUCs were enriched in sets of genes related to DNA repair, synthesis/replication, and cell division., Conclusions: Our study identified new diagnostic markers and potential therapeutic targets for SNUC., (© 2019 Wiley Periodicals, Inc.)

Objectives: To determine the sensitivity and specificity of magnetic resonance imaging (MRI) for the detection of perineural spread (PNS) along the intratemporal facial nerve (ITFN) in patients with head and neck cancers., Study Design: Case series with chart review., Setting: Tertiary care center., Subjects and Methods: We included 58 patients with head and neck malignancies who underwent sacrifice of the ITFN between August 1, 2002, and November 30, 2015. Demographics, preoperative facial nerve function, prior oncologic treatment, and timing between MRI and surgery were recorded. Histopathology slides and preoperative MRI were reviewed retrospectively by a neuropathologist and a neuroradiologist, respectively, both blinded to clinical data. The mastoid segment of the facial nerve (referred to as the descending facial nerve [DFN]) and stylomastoid foramen (SMF) were evaluated separately. A grading system was devised when radiographically assessing PNS along the DFN., Results: Histopathologic evidence of PNS was found in 21 patients (36.2%). The sensitivity and specificity of MRI in detecting PNS to the DFN were 72.7% and 87.8%, respectively. MRI showed higher sensitivity but slightly lower specificity when evaluating the SMF (80% and 82.8%, respectively). Prior oncologic treatment did not affect the false-positive rate ( P = .7084). Sensitivity was 100% when MRI was performed within 2 weeks of surgery and was 62.5% to 73.3% when the interval was greater than 2 weeks. This finding was not statistically significant (SMF, P = .7076; DFN, P = .4143)., Conclusion: MRI shows fair to good sensitivity and good specificity when evaluating PNS to the ITFN.

Background: The 8th edition of the American Joint Committee on Cancer's (AJCC) staging system for oral cavity cancer incorporates pathological features. We aimed to assess whether these changes results in better risk stratification of patients with early oral tongue squamous cell carcinoma (OTSCC)., Methods: Overall survival (OS) and disease-specific survival (DSS) of 244 patients were calculated using the Kaplan-Meier method. Multivariate analysis with stepwise selection was performed using Cox proportional hazards regression., Results: Sixty-two patients (25%) were upstaged using the 8th edition. Multivariate analysis revealed that overall stage using the 8th edition of the AJCC staging system but not using the 7th edition was a significant predictor for both OS and DSS. The 8th edition had lower Akaike information criterion and improved concordance index values compared with the 7th edition., Conclusion: The 8th edition of AJCC allows better risk stratification and more precise counseling of patients with OTSCC who were previously considered at low risk., (© 2018 Wiley Periodicals, Inc.)

Background: Depth of invasion (DOI) in oral cavity cancer is important in determining prognosis. This study aims to determine optimal cut-points of DOI for detection of occult disease and survival., Methods: A retrospective cohort study was completed of previously untreated early stage lateral oral tongue cancer. DOI cut-points were computed. Multiple logistic regression and multivariate Cox proportional hazards models were used to assess predictors of occult nodal disease and overall survival (OS) and disease-specific survival (DSS)., Results: Occult nodal disease was found in 55 (26%) of the 212 patients. DOI of 7.25 mm was most predictive for occult nodal disease and 8 mm for OS and DSS. DOI was an independent predictor of OS and DSS., Conclusion: The optimal DOI cut-point for detection of occult nodal metastasis was 7.25 and 8 mm for OS and DSS at 5 years. DOI is an independent predictor of OS and DSS., (© 2018 Wiley Periodicals, Inc.)

Background: SMARCB1 (INI-1)-deficient sinonasal carcinoma (IDSNC) is a newly described, poorly differentiated carcinoma. Herein, the authors describe the cytopathologic features of IDSNC in fine-needle aspiration (FNA) samples., Methods: The pathology archives of 2 academic institutions were searched for cases of IDSNC with available cytologic materials. All available slides were reviewed and a detailed morphological analysis was performed., Results: Six cases were identified from 6 patients. FNA specimens were obtained from metastatic sites (4 cases), a local disease recurrence (1 case), and a primary lesion extending into the orbit (1 case). The majority of cases had cellular specimens with features of nonkeratinizing squamous cell carcinoma composed of cohesive clusters and sheets of oval to polygonal cells with indistinct cell borders present within a background of necrotic debris. Two cases had single rhabdoid cells with more abundant cytoplasm. The nuclei generally were small and uniform with fine chromatin, small nucleoli, and mild nuclear membrane irregularities; moderate anisonucleosis and multinucleation were noted in one case. Apoptotic bodies were common in 5 of 6 cases, and readily identifiable mitoses in 3 of 6 cases. Immunohistochemistry demonstrated that all cases expressed cytokeratins, 4 of 5 cases expressed p63, and all cases demonstrated loss of INI-1 nuclear expression. All cases were negative for neuroendocrine markers and aberrant p16 staining., Conclusions: A diagnosis of IDSNC can be suspected on FNA specimens from patients with high-grade sinonasal carcinomas that have either a nonkeratinizing squamous cell carcinoma or rhabdoid morphology. Clinical history and the availability of material for immunohistochemistry are key in confirming the diagnosis. Cancer Cytopathol 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Purpose: Development of extranodal extension (ENE) has been associated with poor survival in patients with oral cavity squamous cell carcinoma (OSCC). Here, we sought to confirm the role of ENE as a poor prognostic factor, and identify genomic and epigenetic markers of ENE in order to develop a predictive model and improve treatment selection. Experimental Design: An institutional cohort (The University of Texas MD Anderson Cancer Center) was utilized to confirm the impact of ENE on clinical outcomes and evaluate the genomic signature of primary and ENE containing tissue. OSCC data from The Cancer Genome Atlas (TCGA) were analyzed for the presence of molecular events associated with nodal and ENE status. Results: ENE was associated with decreased overall and disease-free survival. Mutation of the TP53 gene was the most common event in ENE + OSCC. The frequency of TP53 mutation in ENE + tumors was higher compared with ENE - tumors and wild-type (WT) TP53 was highly represented in pN0 tumors. pN + ENE + patients had the highest proportion of high-risk TP53 mutations. Both primary tumors (PT) and lymph nodes with ENE (LN) exhibited a high rate of TP53 mutations (58.8% and 58.8%, respectively) with no significant change in allele frequency between the two tissue sites. Conclusions: ENE is one of the most significant markers of OSCC OS and DFS. There is a shift toward a more aggressive biological phenotype associated with high-risk mutations of the TP53 gene. Prospective clinical trials are required to determine whether TP53 mutational status can be used for personalized treatment decisions. Clin Cancer Res; 24(7); 1727-33. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Mucositis and dysphagia are common adverse effects of radiotherapy (RT) treatment of locally advanced squamous cell cancer of the head and neck (LA-SCCHN). Chemotherapy added to RT increases survival rates but causes worse mucositis and dysphagia. The aim of this analysis was to assess the impact of p16 status on mucositis, dysphagia, and feeding tube use in LA-SCCHN among patients treated with RT±cetuximab in the phase 3 IMCL-9815 trial., Methods: Patients received RT plus weekly cetuximab or RT alone. Subgroup analyses were conducted on patients with p16-positive (n=75) or p16-negative (n=106) oropharyngeal cancer (OPC), as determined by immunohistochemical analysis. The onset and duration of mucositis and dysphagia by treatment arm and p16 status were displayed using Kaplan-Meier curves and the log-rank test. P values for the incidence of mucositis and dysphagia were calculated using the Fisher exact test. Feeding tube use was assessed as the percent of patients reporting use., Results: The baseline characteristics of patients treated with RT±cetuximab were similar in both the p16-positive and p16-negative OPC subgroups. Patients within the p16-positive OPC subgroup had higher Karnofsky scores and were more likely to have stage T1-T3 cancer and be from the United States. Regardless of p16 status, there was no difference in the onset or duration of grade 3/4 mucositis or dysphagia in patients receiving RT plus cetuximab compared with those receiving RT alone. In the overall population, and the p16-positive and p16-negative OPC subpopulations, feeding tube use was not different for patients receiving RT plus cetuximab compared with RT alone., Conclusion: Regardless of p16 status, the addition of cetuximab to RT did not alter the incidence, time to onset, severity, or duration of mucositis and dysphagia and did not impact the frequency of feeding tube use., Competing Interests: J.A.B. receives honorarium from Merck Serono, Eli Lilly, and Bristol-Myers Squibb. J.B. is a consultant for Merck and in the advisory boards for Eli Lilly. J.L. is an employee of Merck Serono, Beijing, China. J.S. is an employee of Merck KGaA, Darmstadt, Germany. D.I.R. receives research funding (grant) from Merck Serono and is in the advisory boards for Merck Serono and Bristol-Myers Squibb. All other authors have no conflicts to report., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone., Patients and Methods: In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA., Results: Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared., Conclusion: p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

Objectives: Patients with oropharyngeal cancer (OPC) have distinct risk factor profiles reflected in the human papillomavirus (HPV) status of their tumor, and these profiles may also be influenced by factors related to socioeconomic status (SES). The goal of this study was to describe the socioeconomic characteristics of a large cohort of patients with OPC according to HPV status, smoking status, and sexual behavior., Materials and Methods: Patients with OPC prospectively provided information about their smoking and alcohol use, socioeconomic characteristics, and sexual behaviors. HPV status was determined by a composite of immunohistochemistry for p16 expression, HPV in situ hybridization, and PCR assay in 356 patients. Standard descriptive statistics and logistic regression were used to compare socioeconomic characteristics between patient subgroups., Results: Patients with HPV-positive OPC had higher levels of education, income, and overall SES. Among patients with HPV-positive OPC, never/light smokers had more than 5 times the odds of having at least a bachelor's degree and being in the highest level of SES compared with smokers. Patients with HPV-positive OPC and those with higher levels of education and SES had higher numbers of lifetime any and oral sex partners, although not all of these differences were significant., Conclusion: Socioeconomic differences among subgroups of OPC patients have implications for OPC prevention efforts, including tobacco cessation, behavior modification, and vaccination programs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Little is known about the molecular signature of the rare tumor sinonasal squamous cell carcinoma (SNSCC). The purpose of this study was to comprehensively assess various molecular biomarkers in SNSCC., Methods: We chose 13 markers for this study, which have been known as prognostic markers in head and neck squamous cell carcinoma. Expression of these markers was examined by either in situ hybridization or immunohistochemical methods on tissue microarrays made from 70 SNSCC specimens and 28 matched-pair normal tissues from patients who underwent surgical resection at our institution. Expression data were correlated with patient clinicopathologic parameters and survival., Results: Of the 13 markers, only epidermal growth factor receptor (EGFR) protein expression was associated with significantly shorter disease-free survival (DFS; p = .01307). EGFR expression was also associated with shorter overall survival (OS), but the difference was not statistically significant., Conclusion: Targeted inhibition of tumor EGFR expression may be a new approach to treating SNSCC., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: The objectives of this study were to evaluate the validity of Cervista human papillomavirus (HPV) assays in head and neck fine-needle aspiration (FNA) specimens from patients with head and neck squamous carcinomas and to verify that the Cervista assay in FNA specimens is a valid option for determining HPV status in patients with oropharyngeal carcinomas., Methods: The authors retrospectively retrieved 64 head and neck FNA specimens from patients who had head and neck squamous carcinoma. The specimens were tested for HPV types 16 and 18 (HPV16/18) and for high-risk (HR) HPV DNA using the Cervista HPV16/18 and HPV HR assays, respectively. The results from those assays were compared with the results from polymerase chain reaction (PCR)-based HPV assays in the same tissues and with the results from HPV in situ hybridization assays/p16 immunostaining in the corresponding primary tumors., Results: In total, 64 FNA specimens were analyzed. The Cervista HPV16/18 and/or HPV HR assays were positive in 48 of 64 specimens (75%), and there was a predominance of HPV16 (42 of 48 specimens; 88%). In the 49 specimens that had PCR-based test results, overall agreement with Cervista assay results was 96% (47 of 49 specimens; κ = 0.883). In the 49 specimens that had PCR-based HPV16/18 genotyping results, overall agreement with the Cervista HPV16/18 results was 94% (46 of 49 specimens; κ = 0.847). In the 36 primary carcinoma specimens that had valid HPV in situ hybridization/p16 immunostaining results, overall agreement with the Cervista assay results was 92% (33 of 36 specimens; κ = 0.679)., Conclusions: Cervista HPV16/18 and Cervista HPV HR testing of head and neck FNA specimens is a valid option for determining HPV16/18 status in patients with oropharyngeal carcinoma., (© 2013 American Cancer Society.)

Background: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival., Methods: We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses., Results: Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pN+). pN+ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pN+. Contrasted posttreatment CT had low sensitivity and specificity., Conclusions: In advanced OPSCC pN+, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pN+, although increased use of modern imaging may reduce the rate of negative neck dissections., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: The patient-derived xenograft (PDX) model is likely to reflect human tumor biology more accurately than cultured cell lines because human tumors are implanted directly into animals; maintained in an in vivo, three-dimensional environment; and never cultured on plastic. PDX models of head and neck squamous cell carcinoma (HNSCC) have been developed previously but were not well characterized at the molecular level. HNSCC is a deadly and disfiguring disease for which better systemic therapy is desperately needed. The development of new therapies and the understanding of HNSCC biology both depend upon clinically relevant animal models. We developed and characterized the patient-derived xenograft (PDX) model because it is likely to recapitulate human tumor biology., Methods: We transplanted 30 primary tumors directly into mice. The histology and stromal components were analyzed by immunohistochemistry. Gene expression analysis was conducted on patient tumors and on PDXs and cell lines derived from one PDX and from independent, human tumors., Results: Five of 30 (17%) transplanted tumors could be serially passaged. Engraftment was more frequent among HNSCC with poor differentiation and nodal disease. The tumors maintained the histologic characteristics of the parent tumor, although human stromal components were lost upon engraftment. The degree of difference in gene expression between the PDX and its parent tumor varied widely but was stable up to the tenth generation in one PDX. For genes whose expression differed between parent tumors and cell lines in culture, the PDX expression pattern was very similar to that of the parent tumor. There were also significant expression differences between the human tumors that subsequently grew in mice and those that did not, suggesting that this model enriches for cancers with distinct biological features. The PDX model was used successfully to test targeted drugs in vivo., Conclusion: The PDX model for HNSCC is feasible, recapitulates the histology of the original tumor, and generates stable gene expression patterns. Gene expression patterns and histology suggested that the PDX more closely recapitulated the parental tumor than did cells in culture. Thus, the PDX is a robust model in which to evaluate tumor biology and novel therapeutics.

Background: The local-regional failure of advanced oral squamous cell carcinoma (OSCC) after surgery results from the regrowth of residual tumor cells that may be stimulated by epidermal growth factor receptor (EGFR) ligands during the wound healing process., Methods: The level of EGFR ligands in human drain fluids (DFs) from OSCC resection and remote flap donor site were determined. A mouse model of microscopic residual OSCC was established and treated with cetuximab to measure tumor growth, survival, and cervical lymph node metastases. A mouse model of wound healing was also established to assess the effect of an EGFR antibody on the wound healing process., Results: EGFR ligands are found in sites from OSCC resection. EGFR targeted therapy can delay tumor regrowth in a microscopic residual disease model of OSCC without significant effects on local wound healing., Conclusion: These results provide a strong rationale for clinical evaluation of this approach to treat patients with local-regionally advanced OSCC., (Copyright © 2012 Wiley Periodicals, Inc.)

Head and neck squamous cell carcinoma (HNSCC) is a major cause of morbidity and mortality, and the alleviation thereof requires greater understanding of the pathobiologic behavior of HNSCC. Although the existence of cancer stem cells (CSCs) in most solid tumors has not been formally proven, application of the CSC concept has certainly enhanced understanding of HNSCC heterogeneity and progression. Recent data support the role of ALDH1(+) CD44(+) CSC in HNSCC, since the implantation of a few ALDH1(+) CD44(+) cells consistently gives rise to tumors that can be serially passaged in vivo. In addition to CSC biomarkers, recent explorations of CSC signaling pathways, gene expression, and localization in HNSCC carry significant clinical and therapeutic implications. Identification and characterization of CSC populations that regulate HNSCC growth, metastasis, and treatment resistance will facilitate development of novel diagnostic, therapeutic, and prognostic strategies. Furthermore, advances in multimodal imaging and nanotechnology, in conjunction with CSC models, may better elucidate the regulatory mechanisms that govern CSC biology in vivo, as well as develop platforms for targeted theragnostics. It is hoped that the promising applications of the CSC model in HNSCC will eventually alleviate the morbidity and mortality of this pervasive disease., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: The inhibition of c-Src results in a striking reduction in cancer cell invasion, but the effect on cell survival is modest. Defining mechanisms that limit apoptosis following c-Src inhibition could result in an ideal therapeutic approach that both inhibits invasion and leads to apoptosis. In this regard, we discovered a novel feedback loop that results in STAT3 reactivation following sustained c-Src inhibition. Here we define the mechanism underlying this feedback loop and examine the effect of inhibiting it in vivo., Experimental Design: We measured levels and activity of pathway components using PCR, Western blotting, and kinase assays following their manipulation using both molecular and pharmacologic approaches. We used a heterotransplant animal model in which human oral squamous cancer is maintained exclusively in vivo., Results: Following c-Src inhibition, STAT5 is durably inhibited. The inhibition of STAT5A, but not STAT5B, subsequently reduces the expression of suppressors of cytokine signaling 2 (SOCS2). SOCS2 inhibits Janus kinase 2 (Jak2) activity and Jak2-STAT3 binding. SOCS2 expression is necessary for STAT3 inhibition by c-Src inhibitors. Overexpression of SOCS2 is adequate to prevent STAT3 reactivation and to enhance the cytotoxic effects of c-Src inhibition. Likewise, the combination of Jak and c-Src inhibitors led to significantly more apoptosis than either agent alone in vivo., Conclusions: To our knowledge, ours is the first study that fully defines the mechanism underlying this feedback loop, in which sustained c-Src inhibition leads to diminished SOCS2 expression via sustained inhibition of STAT5A, allowing activation of Jak2 and STAT3, Jak2-STAT3 binding, and survival signals., (© 2011 AACR.)