Molecular and immunologic analysis of laryngeal squamous cell carcinoma in smokers and non-smokers.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is strongly associated with tobacco use, but recent reports suggest an increasing incidence of LSCC in patients without traditional risk factors, suggesting an alternative etiology of tumorigenesis. The purpose of this study is to characterize this non-smoking population and to compare immunohistochemical markers in tumor specimens from non-smokers and smokers with LSCC. METHODS: A retrospective chart review of patients with LSCC at Johns Hopkins Hospital (JHH) was performed. A tissue microarray (TMA) was constructed with tumor specimen from non-smokers with stage and age-matched smokers and stained for a variety of immunologic and molecular targets. RESULTS: In the JHH cohort of 521 patients, 12% (n = 63) were non-smokers. Non-smokers were more likely to be <45 years old at time of diagnosis (OR 4.13, p = 0.001) and to have glottic tumors (OR 2.46, p = 0.003). The TMA was comprised of tumors from 34 patients (14 non-smokers, 20 smokers). Only 2 patients (6%) were human-papillomavirus (HPV) positive by high-risk RNA in situ hybridization (ISH). There was no correlation between smoking status and p16 (p = 0.36), HPV-ISH positivity (p = 0.79), phosphatase and tensin homolog (PTEN, p = 0.91), p53 (p = 0.14), or programmed death-ligand 1 (PD-L1, p = 0.27) expression. CONCLUSIONS: Non-smokers with LSCC are more likely to be younger at the time of diagnosis and have glottic tumors than smokers with LSCC. In TMA analysis of stage and age-matched specimens from smoker and non-smokers with LSCC, the pattern of expression for common molecular and immunologic markers is similar. Further, HPV does not appear to be a major causative etiology of LSCC in either smokers or non-smokers in our cohort of patients.

Facial Asymmetry Index: Validation and Applications in Various Smile Restoration Techniques.

Consistent and objective evaluation of the paralyzed face is imperative for documenting preoperative findings and assessing postoperative outcomes of reanimation techniques. Static and dynamic facial asymmetry are the key features of the paralyzed face. To date, there is no consensus among surgeons on how best to document facial asymmetry. The authors propose a Facial Asymmetry Index (FAI) as an objective measure of facial asymmetry and validate its use and reliability across numerous reanimation techniques. Frontal photographs of patients with unilateral facial nerve paralysis were analyzed. The length from the medial canthus to the ipsilateral oral commissure was compared between affected and nonaffected sides. The FAI is the difference between the two values, with a higher value reflecting poorer facial symmetry. Validation and reliability testing was then performed. There was a consistent decrease in the FAI with procedural intervention (FAI pre = 10.1, FAI post = 3.17; p < 0.0001). Furthermore, there was excellent inter- and intrarater reliability among independent judges. The FAI is a powerful and accessible tool to quantify operative outcomes for many lower facial nerve reanimation techniques.

Evaluation of proposed staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma.

BACKGROUND: Patients with human papillomavirus (HPV)-related oropharyngeal cancer (OPC) have improved survival when compared with those with HPV-negative OPC. Unfortunately, the American Joint Committee on Cancer seventh edition (AJCC-7ed) staging system does not account for the prognostic advantage observed with HPV-positive OPC. The purpose of the current study was to validate and compare 2 recently proposed staging systems for HPV-positive OPC. METHODS: Patients treated for HPV-positive OPC from 2005 to 2015 at Johns Hopkins Hospital (JHH) were included for analysis. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) and The University of Texas MD Anderson Cancer Center (MDACC) staging systems were applied and survival was calculated using Kaplan-Meier methods. Cox proportional hazard regression was used to determine the relationship between stage of disease and survival. Models were compared using the Akaike information criterion (AIC). RESULTS: A total of 435 patients were eligible for analysis. There was a dramatic shift in lymph node category and overall stage of disease when ICON-S and MDACC stage were applied to the JHH cohort. There was superior stratification of overall survival and progression-free survival by ICON-S stage. Both proposed models had an improved fit based on AIC scores (P<.001 for both) over the AJCC-7ed. The ICON-S staging system had the lowest AIC score, and thus a better fit within the JHH population. CONCLUSIONS: The current analysis provides external validation for both staging systems in an independent and heterogeneously treated patient population. Although the MDACC staging system is an improvement over the AJCC-7ed, the ICON-S stage provides superior stratification of overall and progression-free survival, thereby supporting its use as the updated AJCC staging system for OPC. Cancer 2017;123:1768-1777. © 2017 American Cancer Society.

A case of congenital agenesis of the common carotid artery associated with an ectopic parathyroid adenoma mimicking a carotid body tumor.

Ectopic parathyroid adenomas can be encountered during four gland explorations, but nearly 80% of adenomas are localized with ultrasound and sestamibi imaging. Ectopic adenomas are thought to arise from abnormal migration during development. As a cervical congenital anomaly, common carotid artery agenesis is an extremely rare anomaly characterized by separate origins of the internal and external carotid arteries directly from the aortic arch. Here we present a case of a 75 year old man with primary hyperparathyroidism who was found to have congenital agenesis of the common carotid artery associated with an ectopic parathyroid adenoma within the parapharyngeal space, which mimicked a carotid body tumor based on location and imaging. The successful identification and resection of the ectopic parathyroid adenoma presented here demonstrate the importance of preoperative imaging studies to allow appropriate operative planning as well as the utility of intraoperative parathyroid hormone assay in predicting cure during surgery.

Nonuniform Distribution of High-risk Human Papillomavirus in Squamous Cell Carcinomas of the Oropharynx: Rethinking the Anatomic Boundaries of Oral and Oropharyngeal Carcinoma From an Oncologic HPV Perspective.

The oral cavity and oropharynx have historically been viewed as a single anatomic compartment of the head and neck. The practice of combining the oral cavity and oropharynx has recently been revised, largely owing to the observation that human papillomavirus (HPV)-related carcinogenesis has a strong predilection for the oropharynx but not the oral cavity. The purpose of this study was to determine whether HPV is evenly distributed across squamous cell carcinomas of the oropharynx including those sites that do not harbor tonsillar tissues such as the soft palate. A search of the medical records of the Johns Hopkins Hospital identified 32 primary squamous cell carcinomas of the soft palate (n=31) and posterior pharyngeal wall (n=1). All were evaluated with p16 immunohistochemistry and high-risk HPV in situ hybridization (ISH) (29 by RNA ISH and 3 by DNA ISH). For comparison, we also reviewed the medical records to obtain the HPV status of patients who had undergone HPV testing of primary tonsillar carcinomas over the same time interval as part of their clinical care. High-risk HPV as detected by ISH was present in just 1 (3.1%) of the 32 oropharyngeal squamous cell carcinomas, including 1 of 2 p16-positive carcinomas. The difference in HPV detection rates between tonsillar and nontonsillar sites was significant (1/32, 3.1% vs. 917/997, 92%; P<0.0001). HPV is not frequently detected in squamous cell carcinomas arising from nontonsillar regions of the oropharynx. Indeed, squamous cell carcinomas of the soft palate more closely resemble those arising in the oral cavity than those arising in areas of the oropharynx harboring tonsillar tissue. This finding not only further sharpens our understanding of site-specific targeting by HPV, but may have practical implications regarding HPV testing and even the way the oral vault is oncologically compartmentalized to partition HPV-positive from HPV-negative cancers.

Expression profile and in vitro blockade of programmed death-1 in human papillomavirus-negative head and neck squamous cell carcinoma.

BACKGROUND: Treatment with a blocking programmed death-1 (αPD-1) antibody recently showed clinical efficacy for various tumor types. In this study, we characterized the expression profile of PD-1/programmed death-ligand-1 (PD-L1) and the potential of PD-1 blockade in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). METHODS: Lymphocytes from peripheral blood, draining lymph nodes, and the tumor were phenotyped for PD-1 expression, and their proliferative activity was assessed in the presence of blocking αPD-1 treatment. Primary tumor expression of PD-L1 was also analyzed using immunohistochemistry (IHC). RESULTS: Lymphocyte PD-1 expression was abundant with highest expression in the tumor, and in vitro mixed lymphocyte reaction demonstrated that PD-1 blockade could induce T cell proliferation. Furthermore, tumor cells were found to have 3 distinct patterns of PD-L1 expression with over 78% of the specimens demonstrating strong PD-L1 positivity. CONCLUSION: Our data strongly supports the use of αPD-1 blockade in patients with HPV-negative HNSCC that are refractory to standard treatments.

Otolaryngological progression of granulomatosis with polyangiitis after systemic treatment with rituximab.

OBJECTIVE: Rituximab is used for the treatment of granulomatosis with polyangiitis (GPA), historically known as Wegener's granulomatosis. However, the otolaryngological progression of GPA after systemic treatment with rituximab (Rituxan) is unclear. We therefore examined the disease sequelae of patients with GPA who were treated with rituximab. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care medical center. SUBJECTS AND METHODS: Patients with a diagnosis of GPA who were treated with rituximab between 2006 and 2012 were included in this study. Systemic and otolaryngological symptomatology, prednisone usage, and procedural interventions following B-cell depletion were analyzed. RESULTS: We identified 11 patients who met our inclusion criteria. The average length of follow-up after treatment with rituximab was 23.5 months. After treatment with rituximab, there was a significant decrease in daily prednisone dose at 3, 12, and 18 months postinfusion (P < .05). However, there was no observed improvement in patients' otolaryngological complaints as measured by the Birmingham Vasculitis Activity Score. Furthermore, patients treated with rituximab underwent numerous otolaryngological interventions during follow-up. Patients with a history of subglottic stenosis (n = 6) underwent an average of 3.40 laryngoscopies and 0.58 dilations per year during rituximab remission, and patients with sinusitis also underwent multiple nasal endoscopies (4.54 per year, n = 9) and nasal debridements (1.34, n = 9). CONCLUSIONS: While rituximab has been shown to be noninferior to cyclophosphamide with respect to remission from systemic GPA, these patients continue to have chronic otolaryngological manifestations of their disease. Otolaryngologists must continue to play a supportive role throughout their maintenance period.

Preclinical evidence that PD1 blockade cooperates with cancer vaccine TEGVAX to elicit regression of established tumors.

Biomarker studies have shown that expression of the T-cell coregulatory ligand PDL1 on tumor cells correlates with clinical responsiveness to the PD1 antibody nivolumab. Here, we report the findings of a preclinical cancer vaccine study demonstrating vaccine-dependent PDL1 upregulation in the tumor microenvironment. We formulated an IFNγ-inducing cancer vaccine called TEGVAX that combined GM-CSF and multiple Toll-like receptor agonists to increase the number of activated dendritic cells. Treatment of established tumors with TEGVAX retarded tumor growth in a manner associated with enhanced systemic antitumor immunity. Unexpectedly, TEGVAX also upregulated PDL1 expression in the tumor microenvironment, possibly explaining why tumors were not eliminated completely. In support of this likelihood, PDL1 upregulation in this setting relied upon IFNγ-expressing tumor-infiltrating CD4(+) and CD8(+) T cells and administration of a PD1-blocking antibody with TEGVAX elicited complete regression of established tumors. Taken together, our findings provide a mechanistic rationale to combine IFNγ-inducing cancer vaccines with immune checkpoint blockade.