Primary Oropharyngeal Squamous Cell Carcinoma Research Articles

Evaluation of an E6/E7 PCR-capillary electrophoresis fragment analysis in the genotyping of human papillomavirus in archival FFPE samples of oropharyngeal cancer.

Accumulating evidence has demonstrated that high-risk human papillomaviruses (HR-HPVs) are involved in the etiology of a subset of oropharyngeal squamous cell carcinoma (OPSCC). In this regard, the International Agency for Research on Cancer (IARC) has recommended direct molecular HPV testing. So far, there is no agreement on the most appropriate method for HPV detection on OPSCC formalin-fixed paraffin-embedded (FFPE) materials. In this study, we aimed to evaluate the performance of the high-sensitive SureX HPV assay in OPSCC FFPE tissues compared with LiPA-25 and p16ink4a immunostaining. A retrospective series of FFPE primary OPSCC cases were diagnosed between 2008 and 2019 and provided by the Henan Cancer Hospital, China. The level of agreement of two assays was determined using Cohen's Kappa (κ) statistics. A total of 230 FFPE OPSCC samples from tumor resections (n = 160) and diagnostic biopsies (n = 70) were detected. Sixty-six (28.7%) and 70 (30.4%) samples were identified as HPV-DNA-positive by LiPA-25 and SureX, respectively, of which HPV16 was largely the most common type (95.5% vs 94.3%). We found a perfect concordance between LiPA-25 and SureX for HPV-DNA status (κ = 0.906, 95% CI: 0.875-0.937) and for HPV16 (κ = 0.925, 95% CI: 0.897-0.953). In addition, SureX and p16ink4a immunostaining had a perfect concordance (κ = 0.917, 95% CI: 0.888-0.946). Moreover, the HPV-driven fraction, based on double positivity for HPV-DNA and p16ink4a, was similar between SureX (63 of 230, 27.4%) and LiPA-25 (60 of 230, 26.1%). Similar results were found in samples from resections and biopsies. SureX and LiPA-25 are comparable. SureX could be used for routine HPV-DNA detection and genotyping on archival OPSCC FFPE tissues.

Fibroblasts from HPV-negative oropharynx squamous cell carcinomas stimulate the release of osteopontin from cancer cells via the release of IL-6.

HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) shows distinct biological and clinical behaviour when compared to HPV-negative OPSCC. The overall role of the tumour microenvironment (TME) in head and neck cancer progression and metastasis has been studied intensively, but differences in HPV-negative and HPV-positive OPSCCs are less understood. To investigate the role of cancer-associated fibroblasts (CAFs) and the functional interactions of normal tonsil fibroblasts (NTFs) and OP CAFs with HPV+ and HPV- OPSCC cells and explore novel candidates in tumour-fibroblast crosstalk. A retrospective cohort of 143 primary OPSCCs was characterised using HPV16/18 RNAScope assay, p16 IHC and ɑ-SMA. Four OPSCC, three NTF and 2 new OPSCC CAF cultures were used to assess the cytokine-based interactions using cytokine arrays on conditioned media (CM), followed by co-culture approaches to identify the role of individual cell types and the role of OPN (SPP1) and IL-6 in SCC/fibroblast communication. HPV status was associated with better overall survival. Although ɑ-SMA expression was observed in both OPSCC subtypes, it provided survival stratification only in the HPV-positive group (Log-Rank p = 0.02). Three normal tonsillar fibroblast cultures (NTFs) were characterised by induction of myofibroblastic and senescent phenotypes with similar reactivity to our published NOF phenotype. The OPSCC-derived CAF cultures were characterised and their baseline myofibroblastic and senescence phenotypes varied. Cytokine array analysis of CM to identify novel candidates in the crosstalk between OPSCC tumour cells and NTFs/CAFs identified differences in the cytokine profiles on comparison of HPV+ and HPV- OPSCC cells. Osteopontin (OPN/SPP1) was identified, particularly in HPV-negative OPSCC cell analyses. We have demonstrated that OPN was produced by the OPSCC cells and revealed an associated upregulation of IL-6 in fibroblasts. Treatment of NTFs with rOPN showed alteration in phenotype, including increased contraction and IL-6 production. Antibody-mediated inhibition of CD44v6 attenuated the production of IL-6 by OPN in NTFs. This investigation with OPSCC fibroblasts provides novel insights into the role of CAFs in OPSCC mediated by IL-6 stimulated release of OPN from HPV negative OPSCC cells. The details of HPV-positive SCC cell/fibroblast cytokine crosstalk remain elusive.

Findings from a Malaysian multicentre study on oropharyngeal squamous cell carcinoma

BackgroundIn addition to the conventional aetiologic agents of oropharyngeal squamous cell carcinoma (OPSCC) such as tobacco usage, alcohol consumption and betel quid usage, it has been established that a proportion of OPSCC are driven by persistent oncogenic human papillomavirus (HPV) infections. Currently, there is a lack of data on the burden of HPV- associated OPSCC in Asian countries including Malaysia.MethodsA cross-sectional multicentre study with tissue analysis of Malaysian patients diagnosed with primary OPSCC within a five-year period, from 2015 to 2019 between 01/01/2015 to 31/12/2019 was undertaken. Determination of HPV status was carried out using p16INK4a immunohistochemistry on tissue microarrays constructed from archived formalin-fixed paraffin-embedded tissue.ResultsFrom the cases identified, 184 cases had sufficient tissue material for analysis. Overall, median age at diagnosis was 63.0 years (IQR = 15) and 76.1% of patients were males. In our cohort, 35.3% of patients were Indian, 34.2% were Chinese, 21.2% were Malay and 9.2% were from other ethnicities. The estimated prevalence of HPV-associated OPSCC in our cohort was 31.0% (CI 24.4–38.2%). The median age for the HPV-associated OPSCC sub-group of patients was not significantly lower than the median age of patients with HPV-independent OPSCC. More than half of HPV-associated OPSCC was seen in patients of Chinese ethnicity (54.4%). Patients with HPV-associated OPSCC had a much better overall survival than patients with HPV-independent OPSCC (Log rank test; p < 0.001). Patients with HPV-associated OPSCC with no habit-related risk factors such as smoking, were found to have much better overall survival when compared to all other sub-groups.ConclusionsThe findings from our study suggests that prevalence of HPV-associated OPSCC in Malaysia, though not as high as some developed countries, is however on an upward trend. HPV-associated OPSCC appears to be more frequently encountered in patients of Chinese ethnicity. Conventional risk-factors associated with OPSCC such as smoking, alcohol consumption and betel quid chewing should still be considered when estimating prognosis of patients with HPV-associated OPSCC.

Risk Stratification for Oropharyngeal Squamous Cell Carcinoma Using Texture Analysis on CT - A Step Beyond HPV Status.

Background and Purpose: Human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC) is increasingly prevalent. Despite the overall more favorable outcome, the observed heterogeneous treatment response within this patient group highlights the need for additional means to prognosticate and guide clinical decision-making. Promising prediction models using radiomics from primary OPSCC have been derived. However, no model/s using metastatic lymphadenopathy exist to allow prognostication in those instances when the primary tumor is not seen. The aim of our study was to evaluate whether radiomics using metastatic lymphadenopathy allows for the development of a useful risk assessment model comparable to the primary tumor and whether additional knowledge of the HPV status further improves its prognostic efficacy. Materials and Methods: 80 consecutive patients diagnosed with stage III-IV OPSCC between February 2009 and October 2015, known human papillomavirus status, and pre-treatment CT images were retrospectively identified. Manual segmentation of primary tumor and metastatic lymphadenopathy was performed and the extracted texture features were used to develop multivariate assessment models to prognosticate treatment response. Results: Texture analysis of either the primary or metastatic lymphadenopathy from pre-treatment enhanced CT images can be used to develop models for the stratification of treatment outcomes in OPSCC patients. AUCs range from .78 to .85 for the various OPSCC groups tested, indicating high predictive capability of the models. Conclusions: This preliminary study can form the basis multi-centre trial that may help optimize treatment and improve quality of life in patients with OPSCC in the era of personalized medicine.

Radiofrequency Coblation-Assisted Transoral Surgery for the Treatment of Oropharyngeal Squamous Cell Carcinoma: A Comparative Study with Open Surgery.

Radiofrequency coblation (RFC) is a relatively new method that has opened up new perspectives in treating oropharyngeal squamous cell carcinoma (OPSCC). Our study was designed to explore the feasibility and effectiveness of RFC-assisted transoral surgery (RFC-TOS) for primary OPSCC. Sixty-nine cases of OPSCC from February 2005 to November 2020 were retrospectively analyzed, including 31 in the RFC-TOS group and 38 in the open surgery group. No difference was observed in demographic and oncological characteristics. The significance between the RFC-TOS group and the open surgery group was proved in intraoperative bleeding volume (34.10 ± 10.10 ml vs. 193.68 ± 21.00 ml, P < 0.001), durations of surgery (79.58 ± 8.45 min vs. 217.87 ± 17.65 min, P < 0.001), time to resume oral feeding (1.64 ± 0.41 d vs. 11.58 ± 1.41 d, P < 0.001), duration of hospitalization (7.84 ± 0.66 d vs. 15.66 ± 1.62 d, P < 0.001), and the total costs (22846.22 ± 1821.55¥ vs. 41792.24 ± 4150.86¥, P < 0.001). The rates of 5-year overall survival (OS), 5-yeardisease-specific survival (DSS), and 5-year local control rate (LC) were 69.1%, 71.7%, and 75.7%, respectively, in the RFC-TOS group and 71.0%, 73.4%, and 73.7% in the open surgery group (P > 0.05). RFC-TOS is a feasible alternative transoral approach for OPSCC. The reported perioperative and oncologic outcomes are satisfactory.

Magnetic resonance imaging based radiomics prediction of Human Papillomavirus infection status and overall survival in oropharyngeal squamous cell carcinoma

ObjectivesHuman papillomavirus- (HPV) positive oropharyngeal squamous cell carcinoma (OPSCC) differs biologically and clinically from HPV-negative OPSCC and has a better prognosis. This study aims to analyze the value of magnetic resonance imaging (MRI)-based radiomics in predicting HPV status in OPSCC and aims to develop a prognostic model in OPSCC including HPV status and MRI-based radiomics. Materials and methodsManual delineation of 249 primary OPSCCs (91 HPV-positive and 159 HPV-negative) on pretreatment native T1-weighted MRIs was performed and used to extract 498 radiomic features per delineation. A logistic regression (LR) and random forest (RF) model were developed using univariate feature selection. Additionally, factor analysis was performed, and the derived factors were combined with clinical data in a predictive model to assess the performance on predicting HPV status. Additionally, factors were combined with clinical parameters in a multivariable survival regression analysis. ResultsBoth feature-based LR and RF models performed with an AUC of 0.79 in prediction of HPV status. Fourteen of the twenty most significant features were similar in both models, mainly concerning tumor sphericity, intensity variation, compactness, and tumor diameter. The model combining clinical data and radiomic factors (AUC = 0.89) outperformed the radiomics-only model in predicting OPSCC HPV status. Overall survival prediction was most accurate using the combination of clinical parameters and radiomic factors (C-index = 0.72). ConclusionPredictive models based on MR-radiomic features were able to predict HPV status with sufficient performance, supporting the role of MRI-based radiomics as potential imaging biomarker. Survival prediction improved by combining clinical features with MRI-based radiomics.

The Incidence, Survival, and HPV Impact of Second Primary Cancer following Primary Oropharyngeal Squamous Cell Carcinoma: A 20-Year Retrospective and Population-Based Study.

Second primary cancer (SPC) is the second most common cause of death among patients diagnosed with head and neck cancer. This study examined the risk of SPC following oropharyngeal squamous cell carcinoma (OPSCC) and the impact of human papillomavirus (HPV) on survival following SPC. The study was a population-based, retrospective study including all patients diagnosed with OPSCC in eastern Denmark from 2000-2020 who received curative intended treatment. The incidence rate ratio (IRR), age-adjusted incidence rates (AAIR), and hazard ratios (HR) were calculated. A total of 2584 patients with primary OPSCC were included (median follow-up time: 3.1 years), with 317 patients (12.3%) diagnosed with SPC. The risk of SPC was approximately five times the occurrence of cancer in the general population (IRR: 4.96). The median time to SPC after a primary OPSCC was 2.0 years (interquartile range (IQR) = 0.6-4.2 years). HPV-positive (HPV+) patients had a significantly longer median time to SPC, and a significant better survival compared to HPV-negative (HPV-) patients. SPC was most frequently found in lungs, head, and neck (LHN) for HPV- OPSCC patients and lungs followed by gender-specific (prostate, ovaries, or endometrium) for HPV+ OPSCC. There was a significant difference between the two groups when distributed between "within" or "outside" LHN. Patients with SPC outside LHN had a significant better overall survival. This knowledge should be considered during post-treatment surveillance and might guide targeted imaging.

Utility of PET-CT in Newly Diagnosed HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

To compare the utility of positron emission tomography-computed tomography (PET-CT) versus contrasted CT neck combined with routine chest imaging for disease staging and treatment planning in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC) with clinically evident sites of primary disease. All adult patients with primary HPV-associated OPSCC at a single quaternary care cancer center from 2018 to 2019 were reviewed, and those with images available for re-review were included. Primary outcomes included concordance in clinical staging between the 2 imaging modalities of interest (PET-CT vs CT), as well as independent agreement of each with pathologic staging. Analysis was performed via ordinal logistic regression. A secondary outcome was treatment selection after diagnostic imaging, analyzed via chi-squared testing. In total, 100 patients were included for evaluation, of which 89% were male, 91% Caucasian, and mean age was 61.2 years (SD 9.6). Clinical disease staging agreed between imaging modalities in 95% of cases (54 of 57 patients). Pathologic staging agreed with clinical staging from CT neck in 93% of cases (25 of 27 patients; P = .004), and with PET-CT in 82% (14 of 17 patients; P =.003). No differences were observed between the 2 imaging modalities for subsequent treatment selection (P = .39). In uncomplicated HPV-associated OPSCC, CT offers equivalent diagnostic accuracy to that of combined whole-body PET-CT for clinical staging, and has no appreciable impact on treatment selection. A reduced reliance on routine PET-CT during initial workup of HPV-associated OPSCC may be favorable for otherwise healthy patients with clinically evident sites of primary disease.

Does human papillomavirus modify the risk of oropharyngeal cancer related to smoking and alcohol drinking? A systematic review and meta-analysis.

ObjectiveTo synthesize evidence for interactions of traditional oropharyngeal squamous cell carcinoma (OPSCC) risk factors—tobacco smoking and alcohol drinking—with human papillomavirus (HPV).Data SourcesMEDLINE, Embase, Cochrane Database of Systematic Reviews, ProQuest, and Global Health were searched with no restrictions on language or publication date.MethodsAll case–control studies assessing interactions between these factors in OPSCC were considered. Quality was assessed using the Newcastle‐Ottawa Scale for case–control studies. The main outcome was the OR for developing OPSCC for the following interactions: (1) HPV and smoking, (2) HPV and alcohol drinking, and (3) HPV, alcohol drinking, and smoking. Interactions were assessed from stratified analysis (by HPV status) and/or joint effect analysis (synergy index and multiplicative index).ResultsThe search provided 3084 relevant studies, of which 9 were included. In the stratified analysis, the OR of developing OPSCC among smokers with HPV was less than that among smokers without HPV. A similar pattern was observed for alcohol drinking. This effect persisted among smokers and heavy alcohol drinkers with HPV compared with those without HPV. Joint effect analysis on the additive scale showed sub‐additive antagonistic interactions between HPV and smoking, and between HPV and alcohol. On the multiplicative scale, sub‐multiplicative interactions were found between HPV and smoking, and HPV and alcohol.ConclusionsThis meta‐analysis suggests a negative directed interaction of HPV and smoking; and HPV and heavy alcohol drinking in the development of primary OPSCC on stratified analysis and joint effect analysis.Level of Evidence3A.

OROPHARYNGEAL SQUAMOUS CELL CARCINOMA: A SERIES OF 152 CASES FROM RIO DE JANEIRO

<h3>Objectives</h3> The aim of the present study was to evaluate the clinicopathologic features of oropharyngeal squamous cell carcinoma (OPSCC) in a population from Rio de Janeiro, Brazil. <h3>Study Design</h3> One hundred fifty-two patients were diagnosed with primary OPSCC in an oral pathology laboratory between 2014 and 2020. Demographic and clinical data were retrospectively collected from the records and all cases were microscopically classified as keratinizing, nonkeratinizing, or nonkeratinizing with maturation. Immunohistochemistry for p16INK4a was performed in 46 cases (30.2%) and the positive ones were submitted to DNA in situ hybridization (ISH) for human papillomavirus (HPV). <h3>Results</h3> There were 29 females and 123 males, with a mean age of 61 years (range, 39-89). Most patients regularly consumed tobacco (69%) and alcohol (50.7%) and lived in low socioeconomic status areas. Most tumors measured more than 2 cm and were located mainly in the soft palate (48%), followed by unspecified oropharynx, tonsil, and base of the tongue. The 3 histologic subtypes were similarly distributed among the cases. Five cases were positive for p16INK4a (10.9%), and of these, 4 were positive for HPV by DNA ISH (8.7%), most of them nonkeratinizing. <h3>Conclusions</h3> HPV prevalence is low in OPSCC cases from this Brazilian population.

Expression patterns of uPAR, TF and EGFR and their potential as targets for molecular imaging in oropharyngeal squamous cell carcinoma.

The clinical introduction of molecular imaging for the management of oropharyngeal squamous cell carcinoma (OPSCC) relies on the identification of relevant cancer-specific biomarkers. The application of three membrane-bound receptors, namely urokinase-type plasminogen activator receptor (uPAR), tissue factor (TF) and EGFR have been previously explored for targeted imaging and therapeutic strategies in a broad range of solid cancers. The present study aimed to investigate the expression patterns of uPAR, EGFR and TF by immunohistochemistry (IHC) to evaluate their potential for targeted imaging and prognostic value in OPSCC. In a retrospective cohort of 93 patients with primary OPSCC, who were balanced into the 45 human papillomavirus (HPV)-positive and 48 HPV-negative groups, the IHC-determined expression profiles of uPAR, TF and EGFR in large biopsy or tumor resection specimens were analyzed. Using the follow-up data, overall survival (OS) and recurrence-free survival were measured. Specifically, associations between survival outcome, biomarker expression and clinicopathological factors were examined using Cox proportional hazards model and log-rank test following Kaplan-Meier statistics. After comparing the expression pattern of biomarkers within the tumor compartment with that in the adjacent normal tissues, uPAR and TF exhibited a highly tumor-specific expression pattern, whereas EGFR showed a homogeneous expression within the tumor compartment as well as a consistent expression in the normal mucosal epithelium and salivary gland tissues. The positive expression rate of uPAR, TF and EGFR in the tumors was 98.9, 76.3 and 98.9%, respectively. No statistically significant association between biomarker expression and survival outcome could be detected. Higher uPAR expression levels had a trend towards reduced OS according to results from univariate analysis (P=0.07; hazard ratio=2.01; 95% CI=0.92-4.37). Taken together, these results suggest that uPAR, TF and EGFR may be suitable targets for molecular imaging and therapy in OPSCC. In particular, uPAR may be an attractive target owing to their high positive expression rates in tumors and a highly tumor-specific expression pattern.

Diffusion-Weighted Imaging to Assess HPV-Positive versus HPV-Negative Oropharyngeal Squamous Cell Carcinoma: The Importance of b-Values.

Controversy exists as to whether ADC histograms are capable to distinguish human papillomavirus-positive (HPV+) from human papillomavirus-negative (HPV-) oropharyngeal squamous cell carcinoma. We investigated how the choice of b-values influences the capability of ADC histograms to distinguish between the two tumor types. Thirty-four consecutive patients with histologically proved primary oropharyngeal squamous cell carcinoma (11 HPV+ and 23 HPV-) underwent 3T MR imaging with a single-shot EPI DWI sequence with 6 b-values (0, 50, 100, 500, 750, 1000 s/mm2). Monoexponentially calculated perfusion-sensitive (including b=0 s/mm2) and perfusion-insensitive/true diffusion ADC maps (with b ≥ 100 s/mm2 as the lowest b-value) were generated using Matlab. The choice of b-values included 2 b-values (ADCb0-1000, ADCb100-1000, ADCb500-1000, ADCb750-1000) and 3-6 b-values (ADCb0-750-1000, ADCb0-500-750-1000, ADCb0-50-100-1000, ADCb0-50-100-750-1000, ADCb0-50-100-500-750-1000). Readers blinded to the HPV- status contoured all tumors. ROIs were then copied onto ADC maps, and their histograms were compared. ADC histogram metrics in HPV+ and HPV- oropharyngeal squamous cell carcinoma changed significantly depending on the b-values. The mean ADC was lower, and skewness was higher in HPV+ than in HPV- oropharyngeal squamous cell carcinoma only for ADCb0-1000, ADCb0-750-1000, and ADCb0-500-750-1000 (P < .05), allowing distinction between the 2 tumor types. Kurtosis was significantly higher in HPV+ versus HPV- oropharyngeal squamous cell carcinoma for all b-value combinations except 2 perfusion-insensitive maps (ADCb500-1000 and ADCb750-1000). Among all b-value combinations, kurtosis on ADCb0-1000 had the highest diagnostic performance to distinguish HPV+ from HPV- oropharyngeal squamous cell carcinoma (area under the curve = 0.893; sensitivity = 100%, specificity = 82.6%). Acquiring multiple b-values for ADC calculation did not improve the distinction between HPV+ and HPV- oropharyngeal squamous cell carcinoma. The choice of b-values significantly affects ADC histogram metrics in oropharyngeal squamous cell carcinoma. Distinguishing HPV+ from HPV- oropharyngeal squamous cell carcinoma is best possible on the ADCb0-1000 map.

Females Have Worse Overall and Disease-Specific Survival in Human Papillomavirus–Negative Oropharyngeal Squamous Cell Carcinoma

Although sex (male vs female) has been identified as an independent prognostic factor in human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), the role of sex in HPV-negative OPSCC is less understood. The purpose of this study is to measure the association between sex and HPV-negative OPSCC disease-specific survival (DSS) and overall survival (OS). This longitudinal, retrospective study examined cases of HPV-negative OPSCC diagnosed in the United States between 2013 and 2016 from the Surveillance, Epidemiology, and End Results database. Patients with primary OPSCC and known HPV-negative status were included. Those with HPV-positive or unknown status and primary lesions located outside the oropharynx were excluded. The primary predictor variable was patient sex (male vs female). Primary outcome variables of interest included DSS and OS. The following patient-level covariates were also assessed: age, race, insurance status, primary anatomical site and histological type of lesion, histologic grade and stage, and disease outcome. A survival analysis was conducted using univariate and multivariate analyses via a cox proportional hazard regression model. An α value less than 0.05 was considered statistically significant. The study sample consisted of 2,565 cases (25.1% female) of HPV-negative OPSCC. Females presented with lower histologic grade (P=.015) and earlier stage (P=.003). Females demonstrated worse DSS (P<.001) and OS (P<.001). After multivariate adjustment, female sex (hazard ratio [HR]= 1.38; 95% confidence interval [CI], 1.13 to 1.67; P=.002), advanced age (HR= 1.672; 95% CI, 1.07 to 2.60; P=.023), advanced overall stage (HR= 4.69; 95% CI, 1.54 to 14.267; P=.006), TNM stage (T4: HR= 5.74; 95% CI, 3.86 to 8.55, P<.001, N3: HR= 3.48; 95% CI, 2.17 to 5.58; P<.001, and M1: HR= 2.80; 95% CI, 2.09 to 3.74; P<.001), subjects residing in counties with the highest rates of smoking (HR= 1.29; 95% CI, 1.01 to 1.65; P=.044), and the lack of surgical treatment in patients treated with radiation and/or chemotherapy (HR= 1.44; 95% CI, 1.08 to 1.91; P=.012) were correlated with poorer DSS and OS. Females with HPV-negative OPSCC demonstrated worse DSS and OS despite better typical prognostic signs such as histologic grade and clinical stage.

Post-Operative Hypothyroidism Predicts Fistula Development Following Salvage Oropharyngectomy

<h3>Purpose/Objective(s)</h3> Previous work has demonstrated post-operative hypothyroidism adversely affects wound healing in salvage laryngectomy. The purpose of this study is to evaluate the association between wound healing and hypothyroidism in patients undergoing salvage oropharyngectomy. <h3>Materials/Methods</h3> A single-institution retrospective case series was performed. Fifty-three patients who underwent salvage oropharyngectomy for recurrent or second primary oropharyngeal squamous cell carcinoma between 2001 and 2017 after radiation or chemoradiation were included. The principle explanatory variable was post-operative hypothyroidism, defined as thyroid stimulating hormone (TSH) greater than 5.5 mIU/L. The primary endpoints of the study were oropharyngocutaneous fistula development and fistula requiring operation within 30 days. Binary logistical regression multivariate analysis was performed. <h3>Results</h3> Post-operative fistula rate was 35% among hypothyroid patients which was significantly greater when compared to 9.1% among euthyroid patients. Moreover, 20% of patients with hypothyroidism developed a fistula requiring reoperation, while 3% of euthyroid patients developed a fistula requiring re-operative management. In a multivariate analysis, post-operative hypothyroid patients were at a 9.5-fold increased risk of developing a fistula (95% confidence interval [CI] 1.6 – 57.0, p = 0.013). Additionally, post-operative hypothyroid patients were at 13.6-fold increased risk for development of a fistula requiring reoperation (95% CI 1.2 – 160.5, p = 0.038). <h3>Conclusion</h3> Post-operative hypothyroidism in patients undergoing salvage oropharyngectomy is an independent predictor of fistula development and are more likely to require operative management after fistula development. These data support previously published work demonstrating post-operative hypothyroidism as an independent risk factor for fistula development in patients undergoing salvage laryngectomy. This study further supports the role of hypothyroidism management to modulate wound healing and post-operative wound complications.

Prognostic value of human papillomavirus detection and the eighth edition of the TNM classification staging system in oropharyngeal squamous cell carcinoma: A single-center Polish study

This study aimed to determine human papillomavirus (HPV) status and genotypes, the HPV status-dependent survival, and the applicability of the eighth TNM classification in Polish patients diagnosed with oropharyngeal squamous cell carcinoma (OPSCC). All patients with primary OPSCC, diagnosed and treated from 2007 to 2017 at the National Research Institute of Oncology, Warsaw, Poland, who underwent radical radiotherapy were included. The Kaplan-Meier method was deployed to produce 3- and 5-year observed survival (OS) estimates. A total of 110 OPSCC cases were identified. Double positivity for HPV (IHC p16INK4a and HPV-DNA) was recorded in 70.9% of cases, with HPV16 being the most prevalent genotype (96.2%). The disease stage was significantly less advanced in the HPV-related group than in the HPV-negative group (P < .001). Three- and 5-year OS in HPV-related carcinoma was 80.7% and 74.0%, respectively; in the HPV-negative group, OS was 52.9% and 48.5%. OS rates were associated with HPV status, tumor stage, and disease stage according to the eighth edition TNM classification. The majority of Polish patients with OPSCC are HPV16-positive. In HPV-related OPSCC, survival rates are significantly higher than in HPV-negative OPSCC. The findings support the requirement of HPV testing in Polish patients with OPSCC because HPV-positive status influences tumor prognosis.

Quality of life after radiation and transoral robotic surgery in advanced oropharyngeal cancer.

ObjectivesOropharyngeal squamous cell carcinoma (OPSCC) treatment results in impaired swallowing and quality of life (QOL). We analyzed a cross‐section of advanced stage OPSCC patients treated with multimodal therapies at our Survivorship Clinic to investigate treatment factors associated with QOL.MethodsRetrospective analysis of patient‐reported outcomes (PROMs) after primary OPSCC treatment using AJCC seventh edition staging.ResultsA total of 73 patients were included (90.1% human papillomavirus positive [HPV+]). There were no QOL differences between robotic surgery with radiation ± chemotherapy patients (n = 29) and those treated by radiation ± chemotherapy (n = 44). Radiation field analysis demonstrated significant correlations between increasing doses to larynx and contralateral parotid and submandibular gland and worse swallowing as measured by the Eating Assessment Tool‐10 (P = .02; P = .01; P = .01).ConclusionsIn advanced, mostly HPV+, OPSCC, we did not find clinically significant differences between QOL PROMs between surgical and radiation ± chemotherapy treatment groups. This highlights the need for continued therapy de‐escalation along with improved interventions for treatment related toxicities.Level of evidence4.

Prognostic significance of human papillomavirus 16 viral load level in patients with oropharyngeal cancer.

Human papillomavirus (HPV) infection in patients with oropharyngeal squamous cell carcinoma (OPSCC) is a major determinant for better prognosis. However, there remain HPV‐positive patients who have poor outcomes. The stratification strategy for detecting high‐risk patients among those with HPV‐positive OPSCC has not been well delineated, especially for Asian patients. We undertook a retrospective cohort study on the survival rate of 89 Japanese patients diagnosed with primary OPSCC. The tumors were concurrently analyzed for the presence of HPV E6 DNA/mRNA, viral DNA load, p16 expression, viral physical status, and viral variant lineage. Human papillomavirus 16 viral DNA was found in 45 (51%) OPSCCs. Human papillomavirus 16 DNA‐positive OPSCCs with higher viral load (classified as HPV16 DNA‐medium/high OPSCCs) showed significantly favorable overall survival and progression‐free survival compared with HPV16 DNA‐positive OPSCCs with lower viral load (<10 copies/cell; HPV16 DNA‐low OPSCCs) and HPV16 DNA‐negative OPSCCs. E6 mRNA expression was observed in all HPV16 DNA‐medium/high OPSCCs but not in HPV16 DNA‐low OPSCCs. Notably, p16‐positive and HPV16 DNA‐negative/low OPSCCs showed significantly worse survival than p16‐positive and HPV16 DNA‐medium/high OPSCCs and resembled HPV‐unrelated OPSCCs with regard to survival and risk factor profile. Although not significant, a trend toward shorter survival was observed for HPV16‐integrated OPSCCs. Phylogenetic analysis revealed two major types of HPV16 variants termed Asian (A4) and European (A1/A2/A3) variants, but no difference in survival between these variants was observed. Altogether, these findings suggest that HPV viral load is a potentially informative factor for more accurate risk stratification of patients with OPSCC.

Combined anterior cervical spine fusion and total laryngopharyngectomy with free flap reconstruction: A technical note

Background and importanceIn complex cases such as dropped head cervical deformity due to post-radiation myopathy, anterior cervical discectomy and fusion (ACDF) could be done for deformity correction. In rare circumstances where there is a concurrent need for a total laryngopharyngectomy (TLP) and ACDF, there is a remarkable corridor for cervical discectomy and fusion from the extensive neck exposure. Clinical presentationWe present the case of a patient with history of primary oropharyngeal squamous cell carcinoma and left parotid carcinoma status post treatment, now with post-radiation laryngeal dysfunction and dropped head cervical spinal deformity. Patient underwent posterior fixation for deformity correction and also to create anterior access for total laryngopharyngectomy (TLP). He then underwent combined TLP with anterolateral thigh (ALT) free flap reconstruction and C3-5 ACDF with a vascularized pre-vertebral fascia flap coverage of the spinal hardware. ConclusionThis unique case report is the first of its kind where total laryngopharyngectomy with free flap reconstruction was performed together with an anterior cervical discectomy and fusion. Though complex, such procedures can be performed with satisfactory outcomes in well-established centers.

Pre-treatment PET/MRI based FDG and DWI imaging parameters for predicting HPV status and tumor response to chemoradiotherapy in primary oropharyngeal squamous cell carcinoma (OPSCC)

ObjectivesTo determine the feasibility of pre-treatment primary tumor FDG-PET and DWI-MR imaging parameters in predicting HPV status and the second aim was to assess the feasibility of those imaging parameters to predict response to therapy. Material and MethodsWe retrospectively analyzed primary tumors in 33 patients with proven OPSCC. PET/MRI was performed before and 6 months after chemo-radiotherapy for assessing treatment response. PET Standardized uptake value (SUVmax), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and apparent diffusion coefficient (ADC) from pre-treatment measurements were assessed and compared to the clinicopathological characteristics (T stages, N stages, tumor grades, HPV and post-treatment follow up). HPV was correlated to the clinicopathological characteristics. ResultsADCmean was significantly lower in patients with HPV+ve than HPV-ev, (P = 0.001), cut off value of (800 ± 0.44*10-3mm2/s) with 76.9% sensitivity, and 72.2% specificity is able to differentiate between the two groups. No significant differences were found between FDG parameters (SUVmax, TLG, and MTV), and HPV status, (P = 0.873, P = 0.958, and P = 0.817), respectively. Comparison between CR and NCR groups; ADCmean, TLG, and MTV were predictive parameters of treatment response, (P = 0.017, P = 0.013, and P = 0.014), respectively. HPV+ve group shows a higher probability of lymph nodes involvement, (P = 0.006) ConclusionOur study found that pretreatment ADC of the primary tumor can predict HPV status and treatment response. On the other hand, metabolic PET parameters (TLG, and MTV) were able to predict primary tumor response to therapy.

Salvage transoral robotic surgery in early-stage oropharyngeal recurrence

Limited data are currently available regarding outcomes following transoral robotic surgery (TORS) in the salvage setting. This study aims to investigate the functional and oncological outcomes following TORS in salvage oropharyngeal tumors. All patients undergoing salvage TORS for a residual, recurrent, or new primary oropharyngeal squamous cell carcinoma within a previously radiated field between March 2014 and October 2018 were included. Patients undergoing salvage TORS for other subsites were excluded. Margin status, complication rates, long-term tracheostomy, and gastrostomy requirements and overall and disease-free survival outcomes were recorded. A total of 26 patients were included. Three patients (11%) experienced a TORS-specific major complication. A gastrostomy tube was required in 42% of patients on discharge (n=11), and in 28% of patients on long-term follow-up (n=7) at a median of 34 (interquartile range, 11.8-47.8) months. A tracheostomy was placed in 5 patients and all were removed before discharge. The 3-year overall survival and disease-free survival were 74% and 70%, respectively. Salvage TORS is a viable and effective option in the management of selected tumors within a previously radiated field.