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Supplementary Table S1. Age and gender comparison between the current study and the UK incidence data (2002-2011); Supplementary Table S2. Comparison of age distribution in cases from 2002-2006 vs. 2007-2011; Supplementary Table S3. Type-specific HPV prevalence among single infected HPV-positive tumours

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002–2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3–54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99–1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9–2.2); 2011: 4.1 (95% CI, 4.0–4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV− cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598–606. ©2016 AACR.

Background The contemporary treatment of oropharyngeal squamous cell carcinoma (SCC) is an area of debate. We report outcomes of a minimally invasive approach involving transoral laser microsurgery (TLM). Methods A consecutive series of patients (n = 153) undergoing primary TLM for oropharyngeal SCC from 2006 to 2013 was studied. Human papillomavirus (HPV) status was determined by p16 immunohistochemistry and high-risk HPV DNA in situ hybridization. Survival analyses were evaluated using Kaplan–Meier statistics. Results Tumor subsites included tonsil (n = 94; 61.5%), tongue base (n = 38; 24.8%), and soft palate (n = 21; 13.7%), with the majority being American Joint Committee on Cancer (AJCC) stage III/IVa (n = 124; 81.0%) and HPV-positive (n = 101; 66.0%). Three-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were 84.5%, 91.7%, and 78.2%, respectively. HPV-positivity portended favorable oncologic outcomes. One-year gastrostomy tube (G-tube) dependency was 1.3%. Conclusion To the best of our knowledge, this is the largest single-center TLM oropharyngeal SCC series to date. Our data suggest that TLM +/− postoperative radiotherapy (PORT) results in at least as good oncologic outcomes as chemoradiotherapy (CRT), while conferring swallowing function advantages. © 2016 Wiley Periodicals, Inc. Head Neck , 2016 © 2016 Wiley Periodicals, Inc. Head Neck 38:1263–1270, 2016

BackgroundAlternative splicing of the vascular endothelial growth factor (VEGF) gene results in a family of antiangiogenic isoforms (VEGF(xxx)b), not yet investigated in squamous cell carcinoma of the head and neck (SCCHN). We examined, therefore, the prognostic value of the relative expression of VEGF isoforms in SCCHN. MethodsA tissue microarray comprising 187 SCCHNs was studied by immunohistochemistry with total VEGF (panVEGF) and VEGF(xxx)b-specific antibodies, and scored by 2 assessors for intensity and proportion. Scores were combined and expression ratios calculated. ResultsNo meaningful significant differences were observed between panVEGF, VEGF(xxx)b, or expression ratio, and presence of lymphatic metastasis, or overall survival. This held true when tumor subsites were analyzed independently and when human papillomavirus (HPV) was accounted for in the oropharyngeal subgroup. ConclusionDifferential VEGF isoform expression is not a reliable prognostic biomarker for either the clinically node negative/pathologically node-positive neck or overall survival in pharyngeal and laryngeal SCCHNs. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 775-781, 2016

Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.

Objectives/Hypothesis The incidence of human papillomavirus (HPV)-driven disease beyond the oropharynx varies greatly in the reported literature. Study Design Case series. Methods Two hundred twenty-one samples were strictly classified to the subsites of oral cavity, larynx, or hypopharynx at the time of primary surgery. Formalin-fixed paraffin-embedded samples were subjected to a validated, tiered, diagnostic algorithm of p16 immunohistochemistry, high-risk HPV in situ hybridization, and quantitative polymerase chain reaction for HPV E6 DNA. An additional 60 oropharyngeal cases acted as an internal biological control. Results An incidence of 4% of HPV-driven cases was observed across the subsites outside the oropharynx compared to 70% of tumors confined within it. Conclusions This is the first reporting of a broad range of nonoropharyngeal HPV rates using this validated diagnostic algorithm. It remains unclear whether patients with HPV-driven disease originating outside the oropharynx enjoy the same survival advantage apparent in those patients with oropharyngeal squamous cell carcinomas. Level of Evidence 4 Laryngoscope, 124:2739–2744, 2014

The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC.Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases.A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort.Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002–2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3–54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99–1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9–2.2); 2011: 4.1 (95% CI, 4.0–4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV− cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598–606. ©2016 AACR.

The contemporary treatment of oropharyngeal squamous cell carcinoma (SCC) is an area of debate. We report outcomes of a minimally invasive approach involving transoral laser microsurgery (TLM).A consecutive series of patients (n = 153) undergoing primary TLM for oropharyngeal SCC from 2006 to 2013 was studied. Human papillomavirus (HPV) status was determined by p16 immunohistochemistry and high-risk HPV DNA in situ hybridization. Survival analyses were evaluated using Kaplan-Meier statistics.Tumor subsites included tonsil (n = 94; 61.5%), tongue base (n = 38; 24.8%), and soft palate (n = 21; 13.7%), with the majority being American Joint Committee on Cancer (AJCC) stage III/IVa (n = 124; 81.0%) and HPV-positive (n = 101; 66.0%). Three-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS) were 84.5%, 91.7%, and 78.2%, respectively. HPV-positivity portended favorable oncologic outcomes. One-year gastrostomy tube (G-tube) dependency was 1.3%.To the best of our knowledge, this is the largest single-center TLM oropharyngeal SCC series to date. Our data suggest that TLM +/- postoperative radiotherapy (PORT) results in at least as good oncologic outcomes as chemoradiotherapy (CRT), while conferring swallowing function advantages. © 2016 Wiley Periodicals, Inc. Head Neck , 2016 © 2016 Wiley Periodicals, Inc. Head Neck 38:1263-1270, 2016.

The incidence of human papillomavirus (HPV)-driven disease beyond the oropharynx varies greatly in the reported literature.Case series.Two hundred twenty-one samples were strictly classified to the subsites of oral cavity, larynx, or hypopharynx at the time of primary surgery. Formalin-fixed paraffin-embedded samples were subjected to a validated, tiered, diagnostic algorithm of p16 immunohistochemistry, high-risk HPV in situ hybridization, and quantitative polymerase chain reaction for HPV E6 DNA. An additional 60 oropharyngeal cases acted as an internal biological control.An incidence of 4% of HPV-driven cases was observed across the subsites outside the oropharynx compared to 70% of tumors confined within it.This is the first reporting of a broad range of nonoropharyngeal HPV rates using this validated diagnostic algorithm. It remains unclear whether patients with HPV-driven disease originating outside the oropharynx enjoy the same survival advantage apparent in those patients with oropharyngeal squamous cell carcinomas.4 Laryngoscope, 124:2739-2744, 2014.

The subcellular localization of WT1 is controversial and has received little attention in the epithelial tumors of salivary glands. Paraffin-embedded, surgical specimens from 80 salivary tumors were investigated by immunohistochemistry using a monoclonal, anti-WT1 antibody (6F-H2, Dako). Immunostaining was seen in 14/14 pleomorphic adenomas (PAs), 6/6 myoepitheliomas, 4/4 basal cell adenomas, 4/4 canalicular adenomas, 0/7 Warthin tumors, 0/1 oncocytoma, 1/6 acinic cell carcinomas (Cas), 0/11 mucoepidemoid Cas, 1/11 adenoid cystic Cas, 11/12 polymorphous low-grade adenocarcinomas (PLGAs), 1/2 Ca ex PA, 0/1 salivary duct Ca and 0/1 clear cell adenocarcinoma. Stained-cell subpopulations up to 90% were not uncommon in the benign tumors. Up to 80% of cells in PLGA could be stained. Staining was weak to intense and confined to the cytoplasm of preferentially non-luminal or adjacent to stroma cells. One adenoid cystic Ca showed nuclear staining. The results suggest that WT1 is often highly expressed in benign non-oncocytic salivary tumors whereas the malignant tumors show decreased expression, the exception being PLGA. The expression is usually cytoplasmic and associated with non-luminal cells. PLGA immunoreactivities could be useful in histological differential diagnosis.

Objectives:We examined the accuracy of magnetic resonance imaging in assessing thyroid cartilage and thyroid gland invasion in patients undergoing total laryngectomy for squamous cell carcinoma, by comparing histopathology results with imaging findings.Study design:A retrospective study reviewed histology and magnetic resonance scan results for all total laryngectomies performed between 1998–2008 at University Hospital Aintree, Liverpool.Methods:Pre-operative magnetic resonance images were reviewed independently by two consultant head and neck radiologists masked to the histology; their opinions were then compared with histology findings.Results:Eighty-one magnetic resonance scans were reviewed. There were 22 laryngectomy patients with histologically verified thyroid cartilage invasion and one patient with thyroid gland invasion. There were 31 patients with apparent radiological thyroid cartilage invasion pre-operatively (with 17 false positives), giving sensitivity, specificity, and positive and negative predictive values of 64, 71, 45 and 84 per cent, respectively. On assessing thyroid gland invasion, there were nine false positive scans and no false negative scans, giving sensitivity, specificity, and positive and negative predictive values of 100, 89, 10 and 100 per cent, respectively.Conclusion:Magnetic resonance scanning over-predicts thyroid cartilage and gland invasion in patients undergoing total laryngectomy. Magnetic resonance scans have limited effectiveness in predicting thyroid cartilage invasion by squamous cell carcinoma in laryngectomy patients.

Purpose: Human papillomavirus-16 (HPV16) is the causative agent in a biologically distinct subset of oropharyngeal squamous cell carcinoma (OPSCC) with highly favorable prognosis. In clinical trials, HPV16 status is an essential inclusion or stratification parameter, highlighting the importance of accurate testing. Experimental Design: Fixed and fresh-frozen tissue from 108 OPSCC cases were subject to eight possible assay/assay combinations: p16 immunohistochemistry (p16 IHC); in situ hybridization for high-risk HPV (HR HPV ISH); quantitative PCR (qPCR) for both viral E6 RNA (RNA qPCR) and DNA (DNA qPCR); and combinations of the above. Results: HPV16-positive OPSCC presented in younger patients (mean 7.5 years younger, P = 0.003) who smoked less than HPV-negative patients (P = 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P = 0.001) between 1988 and 2009. A combination of p16 IHC/DNA qPCR showed acceptable sensitivity (97%) and specificity (94%) compared with the RNA qPCR “gold standard”, as well as being the best discriminator of favorable outcome (overall survival P = 0.002). p16 IHC/HR HPV ISH also had acceptable specificity (90%) but the substantial reduction in its sensitivity (88%) impacted upon its prognostic value (P = 0.02). p16 IHC, HR HPV ISH, or DNA qPCR was not sufficiently specific to recommend in clinical trials when used in isolation. Conclusions: Caution must be exercised in applying HPV16 diagnostic tests because of significant disparities in accuracy and prognostic value in previously published techniques. Clin Cancer Res; 17(19); 6262–71. ©2011 AACR.

The presence of tyrosine-rich crystalloids in salivary neoplasms is well known, but such crystals have rarely been described in other sites. To our knowledge, the presence of tyrosine-rich crystals in vocal cord mucosa has not been previously described. A 61-year-old man presented with hoarseness of voice for 12 months. He also complained of coughing, which had improved after he had stopped smoking. There was no history of any treatment to the vocal cords. His medical history included hypertension, anxiety, vasectomy and tonsillectomy. Microlaryngoscopy revealed Reinke’s oedema of the right vocal cord and a polyp of the left true vocal cord, which was removed. An H&E-stained section showed normal non-keratinising squamous epithelium covering oedematous vocal cord mucosa with …