Faculty Bibliography

While sinonasal intestinal type adenocarcinoma (ITAC) is defined by an intestinal phenotype, non-intestinal type adenocarcinoma (non-ITAC) is traditionally viewed as a diagnosis of exclusion, despite previous implication of a seromucinous phenotype and similarity to sinonasal seromucinous hamartomas (SSH). We performed a comparison of clinicopathologic and immunophenotypic features of ITAC, non-ITAC and SSH using traditional discriminatory markers and new markers of seromucinous differentiation. Twenty-three non-ITAC, 17 ITAC, and 5 SSH were retrieved (1987-2014). As expected, ITAC occurred predominantly in the nasal cavity in elderly patients (mean age 65 years) with a striking male predilection (15:2). Regardless of grade/subtype, all ITAC were invariably CK20 and CDX2 positive, and many (11/15) showed some CK7 positivity. Non-ITAC occurred in younger individuals (mean age 51 years) with a slight female predilection (male to female ratio: 10:13) and showed diverse morphologic patterns and grades, some with morphologic similarity to SSH. SSH occurred in younger individuals (mean age 33 years). Non-ITAC and SSH were invariably CK7 positive and CK20 negative, however, 4/22 non-ITAC and 2/5 SSH showed squamoid morular metaplasia that aberrantly expressed CDX2 and co-expressed nuclear β-catenin. Markers of seromucinous differentiation (S100, DOG1, and SOX10) were essentially absent in ITAC, but present to varying degrees in the majority of non-ITAC and all SSH. Thus, the term 'seromucinous adenocarcinoma' is the more appropriate designation for non-ITAC. Squamoid morules in non-ITAC and SSH may be an immunophenotypic pitfall given the aberrant CDX2 expression.

IMPORTANCE/OBJECTIVE:Positive margins are associated with poor prognosis among patients with oral tongue squamous cell carcinoma (SCC). However, wide variation exists in the margin sampling technique. OBJECTIVE:To determine the effect of the margin sampling technique on local recurrence (LR) in patients with stage I or II oral tongue SCC. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A retrospective study was conducted from January 1, 1986, to December 31, 2012, in 5 tertiary care centers following tumor resection and elective neck dissection in 280 patients with pathologic (p)T1-2 pN0 oral tongue SCC. Analysis was conducted from June 1, 2013, to January 20, 2015. INTERVENTIONS/METHODS:In group 1 (n = 119), tumor bed margins were not sampled. In group 2 (n = 61), margins were examined from the glossectomy specimen, found to be positive or suboptimal, and revised with additional tumor bed margins. In group 3 (n = 100), margins were primarily sampled from the tumor bed without preceding examination of the glossectomy specimen. The margin status (both as a binary [positive vs negative] and continuous [distance to the margin in millimeters] variable) and other clinicopathologic parameters were compared across the 3 groups and correlated with LR. MAIN OUTCOMES AND MEASURES/METHODS:Local recurrence. RESULTS:Age, sex, pT stage, lymphovascular or perineural invasion, and adjuvant radiation treatment were similar across the 3 groups. The probability of LR-free survival at 3 years was 0.9 and 0.8 in groups 1 and 3, respectively (P = .03). The frequency of positive glossectomy margins was lowest in group 1 (9 of 117 [7.7%]) compared with groups 2 and 3 (28 of 61 [45.9%] and 23 of 95 [24.2%], respectively) (P < .001). Even after excluding cases with positive margins, the median distance to the closest margin was significantly narrower in group 3 (2 mm) compared with group 1 (3 mm) (P = .008). The status (positive vs negative) of margins obtained from the glossectomy specimen correlated with LR (P = .007), while the status of tumor bed margins did not. The status of the tumor bed margin was 24% sensitive (95% CI, 16%-34%) and 92% specific (95% CI, 85%-97%) for detecting a positive glossectomy margin. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:The margin sampling technique affects local control in patients with oral tongue SCC. Reliance on margin sampling from the tumor bed is associated with worse local control, most likely owing to narrower margin clearance and greater incidence of positive margins. A resection specimen-based margin assessment is recommended.

IMPORTANCE/OBJECTIVE:Large patient cohorts are necessary to validate the efficacy of transoral robotic surgery (TORS) in the management of head and neck cancer. OBJECTIVES/OBJECTIVE:To review oncologic outcomes of TORS from a large multi-institutional collaboration and to identify predictors of disease recurrence and disease-specific mortality. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A retrospective review of records from 410 patients undergoing TORS for laryngeal and pharyngeal cancers from January 1, 2007, through December 31, 2012, was performed. Pertinent data were obtained from 11 participating medical institutions. INTERVENTIONS/METHODS:Select patients received radiation therapy and/or chemotherapy before or after TORS. MAIN OUTCOMES AND MEASURES/METHODS:Locoregional control, disease-specific survival, and overall survival were calculated. We used Kaplan-Meier survival analysis with log-rank testing to evaluate individual variable association with these outcomes, followed by multivariate analysis with Cox proportional hazards regression modeling to identify independent predictors. RESULTS:Of the 410 patients treated with TORS in this study, 364 (88.8%) had oropharyngeal cancer. Of these 364 patients, information about post-operative adjuvant therapy was known about 338: 106 (31.3) received radiation therapy alone, and 72 (21.3%) received radiation therapy with concurrent chemotherapy. Neck dissection was performed in 323 patients (78.8%). Mean follow-up time was 20 months. Local, regional, and distant recurrence occurred in 18 (4.4%), 15 (3.7%), and 10 (2.4%) of 410 patients, respectively. Seventeen (4.1%) died of disease, and 13 (3.2%) died of other causes. The 2-year locoregional control rate was 91.8% (95% CI, 87.6%-94.7%), disease-specific survival 94.5% (95% CI, 90.6%-96.8%), and overall survival 91% (95% CI, 86.5%-94.0%). Multivariate analysis identified improved survival among women (P = .05) and for patients with tumors arising in tonsil (P = .01). Smoking was associated with worse overall all-cause mortality (P = .01). Although advanced age and tobacco use were associated with locoregional recurrence and disease-specific survival, they, as well as tumor stage and other adverse histopathologic features, did not remain significant on multivariate analysis. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:This large, multi-institutional study supports the role of TORS within the multidisciplinary treatment paradigm for the treatment of head and neck cancer, especially for patients with oropharyngeal cancer. Favorable oncologic outcomes have been found across institutions. Ongoing comparative clinical trials funded by the National Cancer Institute will further evaluate the role of robotic surgery for patients with head and neck cancers.

OBJECTIVES/OBJECTIVE:Children with obstructive sleep apnea/hypopnea syndrome (OSAHS) as a result of base of tongue (BOT) or lingual tonsillar hypertrophy do not improve following adenotonsillectomy. In adults, transoral robotic surgery (TORS) offers a means of treating such patients, however the efficacy of this technique for children is not known. In this study, we examine the effectiveness of TORS BOT reduction and lingual tonsillectomy for treatment of pediatric OSAHS. METHODS:This was a retrospective study of nine patients (5 non-syndromic; 4 syndromic) who underwent isolated BOT reduction and lingual tonsillectomy for OSAHS between 2012 and 2014 at a tertiary care pediatric medical center. Differences between pre and post surgical polysomnograms (PSGs) were utilized to measure the procedural effectiveness. Patient age, sex, body mass index (BMI), developmental status, and comorbid conditions were also examined. RESULTS:The average patient age was 10.5 years (range 5.2-18.5). There were 5 males and 4 females. The mean pre-operative obstructive AHI (O-AHI) was 27.1 compared to 10.9 post-operatively (mean difference=16.1, t=2.27, p≤0.05). Statistically significant reductions were also noted in hypopneic events (mean difference=61.3, t=2.64, p<0.05) and lowest oxygen saturation (mean difference=9.0, t=-3.29, p≤0.01). One patient developed a post-operative bleed that was controlled operatively. CONCLUSIONS:In children with airway obstruction associated with BOT and lingual tonsillar hypertrophy, TORS is a useful and effective tool. Patients' who underwent TORS demonstrated a significant decrease in obstructive events. All patients reviewed exhibited at least a 50% reduction in O-AHI.

OBJECTIVE:The tumour-node-metastasis staging system has a dynamic structure that is continuously being updated as scientific data develops. This review discusses some suggested revisions on tumour-node-metastasis staging of human papillomavirus negative upper aerodigestive tract cancers. METHODS:The seventh edition of The American Joint Committee on Cancer Staging Manual was reviewed and important issues that could be considered for revision were identified and discussed. RESULTS:According to our assessment of the oncological outcomes of previous studies, the following factors should be considered for revision: anterior commissure involvement and subglottic extension in laryngeal cancers; underlying bone involvement in hard palate and upper alveolar ridge cancers; tumour thickness in oral cancers; and extracapsular spread and carotid artery involvement in neck metastases. CONCLUSION/CONCLUSIONS:Sufficient data on the prognostic importance of these issues have been reported. Suggested revisions in line with current knowledge on the clinical behaviour of upper aerodigestive tract cancers would improve the relevancy of staging.

Head and neck squamous cell carcinoma (HNSCC) has a variety of causes. Recently, the human papilloma virus (HPV) has been implicated in the rising incidence of oropharyngeal cancer and has led to variety of studies exploring the differences between HPV-positive and HPV-negative HNSCC. The calcium-activated chloride channel TMEM16A is overexpressed in a variety of cancers, including HNSCC, but whether or not it plays different roles in HPV-positive and HPV-negative HNSCC is unknown. Here, we demonstrate that TMEM16A is preferentially overexpressed in HPV-negative HNSCC and that this overexpression of TMEM16A is associated with decreased patient survival. We also show that TMEM16A expression is decreased in HPV-positive HNSCC at the DNA, RNA, and protein levels in patient samples as well as cell lines. We demonstrate that the lower levels of TMEM16A expression in HPV-positive tumors can be attributed to both a combination of copy number alteration and promoter methylation at the DNA level. Additionally, our cellular data show that HPV-negative cell lines are more dependent on TMEM16A for survival than HPV-positive cell lines. Therefore, we suspect that the down-regulation of TMEM16A in HPV-positive HNSCC makes TMEM16A a poor therapeutic target in HPV-positive HNSCC, but a potentially useful target in HPV-negative HNSCC.

OBJECTIVES/HYPOTHESIS/OBJECTIVE:Adenosquamous carcinoma (ASC) is a rare variant of head-and-neck squamous cell carcinoma (HNSCC) generally thought to be uniformly aggressive with poor prognosis. However, it remains unknown how overall survival compare with conventional HNSCC. Here we report for the first time that ASC does not necessarily indicate a worse prognosis than conventional HNSCC. STUDY DESIGN/METHODS:Case-control retrospective study. METHODS:Forty-two primary tumors of the head and neck, treated with curative intent, were identified. Next, 2:1 matching of HNSCC was performed using the following matching criteria: gender, site, pathologic tumor stage, and pathologic node stage. Successful matching was performed for 32 of 42 tumors. Additionally, 20 samples were sent for break-apart FISH testing to evaluate for the presence of the CRTC1-MAML2 translocation. RESULTS:There was a 1.8:1 male to female ratio, with a mean age of 62 years (range 38-84). The layrnx was the most common site (26%), followed by oropharynx (24%), oral cavity (19%), and sinonasal (17%). Kaplan-Meier analysis of adenosquamous and matched HNSCC showed similar survival curves. Median survival times for ASC and HNSCC were 4 and 6 years, respectively. A random-effects Cox model with Gamma frailty revealed no statistical difference between the two groups (P=0.25). All cases of ASC were negative for the CRTC1-MAML2 translocation. CONCLUSION/CONCLUSIONS:This study directly compares primary ASC with HNSCC. No difference in overall survival was detected in contradistinction to the previously thought uniformly poor prognosis. We also highlight the importance of the CRTC1-MAML2 translocation in distinguishing ASC from mucoepidermoid carcinoma. LEVEL OF EVIDENCE/METHODS:3b.

BACKGROUND:Fine-needle aspiration (FNA) cytology is a common approach to evaluate thyroid nodules. It offers definitive diagnosis of a benign or malignant nodule in the majority of cases. However, 10-25% of nodules yield one of three indeterminate cytologic diagnoses, leading to suboptimal management of these patients. Atypia of undetermined significance/follicular lesion of undermined significance (AUS/FLUS) is a common indeterminate diagnosis, with the cancer risk ranging from 6% to 48%. This study assessed whether a multi-gene next-generation sequencing (NGS) assay can offer significant improvement in diagnosis in AUS/FLUS nodules. METHODS:From May 2014 to March 2015, 465 consecutive FNA samples with the cytologic diagnosis of AUS/FLUS underwent prospective molecular testing using the ThyroSeq v2.1 panel. The panel included 14 genes analyzed for point mutations and 42 types of gene fusions occurring in thyroid cancer. In addition, eight genes were assessed for expression in order to evaluate the cell composition of FNA samples. Ninety-eight (21%) of these nodules had definitive surgical (n = 96) or nonsurgical (n = 2) follow-up and were used to determine the assay performance. RESULTS:Among 465 AUS/FLUS nodules, three were found to be composed of parathyroid cells and 462 of thyroid follicular cells. Of the latter, 31 (6.7%) were positive for mutations. The most frequently mutated genes were NRAS and HRAS, and overall point mutations in seven different genes and five types of gene fusions were identified in these nodules. Among 98 nodules with known outcome, histologic analysis revealed 22 (22.5%) cancers. ThyroSeq v2.1 was able to classify 20/22 cancers correctly, showing a sensitivity of 90.9% [confidence interval (CI) 78.8-100], specificity of 92.1% [CI 86.0-98.2], positive predictive value of 76.9% [CI 60.7-93.1], and negative predictive value of 97.2% [CI 78.8-100], with an overall accuracy of 91.8% [CI 86.4-97.3]. CONCLUSIONS:The results of the study demonstrate that the ThyroSeq v2.1 multi-gene NGS panel of molecular markers provides both high sensitivity and high specificity for cancer detection in thyroid nodules with AUS/FLUS cytology, which should allow improved management for these patients.

OBJECTIVE:To determine the accuracy of pretreatment, contrast-enhanced computed tomography (CT) in the diagnosis of extracapsular spread (ECS) in cervical lymph node metastases from p16-positive head-and-neck squamous cell carcinoma (HNSCC). STUDY DESIGN/METHODS:Retrospective observational study. METHODS:Sixty-five (n = 65) patients diagnosed between 2004 and 2013 with p16-positive HNSCC and with cervical lymph node metastases measuring at least 1 centimeter in diameter on pathological assessment were included. All patients underwent primary surgical treatment. Subjects' preoperative contrast-enhanced neck CT scans were independently assigned a score for the likelihood of ECS (5-point scale) by two board-certified neuroradiologists. Receiver-operating characteristic curves were generated, and optimal sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for each radiologist. RESULTS:On histological analysis, the majority of patients (58%; 38/65) were found to have ECS, and 29% (19/65) of patients had ≥ three metastatic lymph nodes. For radiologist 1, PPV and NPV for ECS detection were 72% (95% confidence interval (CI), 53%-87%) and 53% (95% CI, 36%-70%), respectively. For radiologist 2, PPV and NPV for ECS detection were 82% (95% CI, 60 %-95%) and 53% (95% CI, 38%-69%), respectively. CONCLUSION/CONCLUSIONS:CT is not a reliable method for determining the presence of ECS in p16-positive HNSCC patients.