The prognostic effect of radiological extranodal extension in HPV-positive oropharyngeal squamous cell carcinomas: a retrospective cohort analysis.

PURPOSE: Radiological extranodal extension (rENE) is a well-known negative prognosticator in head and neck squamous cell carcinoma (HNSCC). However, controversy remains regarding the prognostic effect of rENE in HPV-positive oropharyngeal SCCs (OPSCC). This single-center retrospective cohort analysis assessed the prognostic role of rENE in an HPV + OPSCC population and tried to validate a recently proposed modification of the TNM8 N-classification. METHODS: 129 patients with HPV + OPSCC, of whom 106 cN + patients, were included. Radiological imaging (CT, MRI or both) was reanalyzed by a senior head and neck radiologist. Overall survival (OS), disease-free survival (DFS), locoregional recurrence-free survival (LRFS), and disease-specific survival (DSS) were evaluated. Cox proportional hazard models were used for estimating hazard ratios (HR). RESULTS: A non-significant trend towards better outcomes in the rENE- group, as compared to the rENE + population, was observed for 5 year OS [80.99% vs 68.70%, HR: 2.05, p = 0.160], 5 year RFS [78.81% vs 67.87%, HR: 1.91, p = 0.165], 5 year DFS [77.06% vs 60.16%, HR: 2.12, p = 0.0824] and 5 year DSS [88.83% vs 81.93%, HR: 2.09, p = 0.195]. OS declined with ascending levels of rENE (p = 0.020). Multivariate analysis identified cT-classification and smoking as independent negative predictors for OS/DFS. The proposed modification of the TNM8 N-classification could not be validated. CONCLUSIONS: Although rENE could not be identified as an independent negative prognosticator for outcome in our HPV + OPSCC population, outcomes tend to deteriorate with increasing rENE.

Sequencing Analysis of MUC6 and MUC16 Gene Fragments in Patients with Oropharyngeal Squamous Cell Carcinoma Reveals Novel Mutations: A Preliminary Study.

The growing incidence of oropharyngeal squamous cell carcinoma (OPSCC) calls for better understanding of the mutational landscape of such cases. Mucins (MUCs) are multifunctional glycoproteins expressed by the epithelial cells and may be associated with the epithelial tumour invasion and progression. The present study aimed at the analysis of the sequence of selected MUC6 and MUC16 gene fragments in the tumour, as well as the margin, samples obtained from 18 OPSCC patients. Possible associations between the detected mutations and the clinicopathological and demographic characteristics of the study group were analysed. Sanger sequencing and bioinformatic data analysis of the selected MUC6 and MUC16 cDNA fragments were performed. Our study found 13 and 3 mutations in MUC6 and MUC16, respectively. In particular, one novelty variant found that the MUC6 gene (chr11:1018257 A>T) was the most frequent across our cohort, in both the tumour and the margin samples, and was then classified as a high impact, stop-gain mutation. The current study found novel mutations in MUC6 and MUC16 providing new insight into the genetic alternation in mucin genes among the OPSCC patients. Further studies, including larger cohorts, are recommended to recognise the pattern in which the mutations affect oropharyngeal carcinogenesis.

Sex-specific aspects in patients with oropharyngeal squamous cell carcinoma: a bicentric cohort study.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is the only subgroup of head neck cancer that presents with an increased incidence. Gender-specific studies in other cancer entities have revealed differences in treatment response and prognosis. However, only limited data in OPSCC according to gender and human papillomavirus (HPV) status exist. Therefore, we aimed to investigate sex-specific differences in OPSCC and how these may be distributed in relation to HPV and other risk factors. METHODS: This retrospective, bicentric study included 1629 patients with OPSCC diagnosed between 1992 and 2020. We formed subgroups based on TNM status, American Joint Cancer Committee 8th edition (AJCC8), HPV status, treatment modality (surgery (± radio(chemo)therapy (RCT) vs. definitive RCT) and patient-related risk factors and investigated gender differences and their impact on patients survival via descriptive-,uni- and multivariate analysis. RESULTS: With the exception of alcohol abuse, no significant differences were found in risk factors between men and women. Females presented with better OS than males in the subgroup T1-2, N + , independent of risk factors (p = 0.008). Males demonstrated significant stratification through all AJCC8 stages (all p < 0.050). In contrast, women were lacking significance between stage II and III (p = 0.992). With regard to therapy (surgery (± R(C)T) - vs. definitive RCT) women treated with surgery had better OS than men in the whole cohort (p = 0.008). Similar results were detected in the HPV-negative OPSCC sub-cohort (p = 0.042) and in high-risk groups (AJCC8 stage III and IV with M0, p = 0.003). CONCLUSION: Sex-specific differences in OPSCC represent a health disparity, particularly according to staging and treatment, which need to be addressed in future studies.

Post radiation mucosal ulcer risk after a hypofractionated stereotactic boost and conventional fractionated radiotherapy for oropharyngeal carcinoma.

BACKGROUND/PURPOSE: Post radiation mucosal ulcers (PRMU) after treatment for oropharyngeal squamous cell carcinoma (OPSCC) can have a huge negative impact on patients' quality of life, but little is known concerning risk factors and the impact of fraction size. Therefore, the goal of this study was to determine the pattern of PRMU development and to identify risk factors after a hypofractionated stereotactic body radiotherapy boost (SBRT) compared to conventionally fractionated radiotherapy for OPSCC. MATERIAL AND METHODS: We performed a retrospective cohort study (N = 332) of OPSCC patients with ≥ 1-year disease-free survival, treated with 46 Gy Intensity Modulated Radiotherapy (IMRT) (2 Gy fractions) followed by either an SBRT boost of 16.5 Gy (5.5 Gy fractions) (N = 180), or 24 Gy IMRT (2 Gy fractions) (N = 152). PRMU (grade ≥ 2) was scored when observed > three months after the last radiotherapy (RT) fraction (CTCAE v5.0). Potential risk factors were analyzed with Cox regression models using death as competing risk. Dose at the PRMU site was calculated by projecting delineated PRMU on the planning CT. RESULTS: All cases of PRMU (N = 64) occurred within 24 months; all were grade 2. The cumulative incidence at 2 years in the SBRT boost group was 26% (N = 46) vs. 12% (N = 18) for conventional fractionation (p = 0.003). Most PRMU developed within nine months (N = 48). PRMU occurring > nine months (N = 16) were mainly observed in the SBRT boost group (N = 15). Sex (p = 0.048), acute tube feeding (p = < 0.001), tumor subsite tonsil (p = 0.001), and N stage (p = 0.017) were associated with PRMU risk at multivariable regression in the hypofractionated SBRT boost group. All 25 delineated PRMU were located within the high dose regions. CONCLUSION: The risk of PRMU should be included in the cost benefit analysis when considering future research using a hypofractionated SBRT boost for OPSCC patients.

Level IV neck dissection in cN0 HPV-negative oropharyngeal squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: As opposed to observation of the neck, elective neck dissection has a survival benefit for cN0 oropharyngeal squamous cell carcinoma (OPSCC). However, there are limited date on level IV neck dissection in human papillomavirus (HPV)-negative OPSCC because most earlier studies did not stratify by P16 or HPV status. Thus, whether to exclude level IV from selective dissection (SND) of cN0 HPV-negative OPSCC remains controversial. METHODS: In this single-center retrospective cohort study, disease-free survival (DFS) was estimated as the primary endpoint for 124 cN0 HPV-negative OPSCC patients who received SND of levels I-III (Group A) and I-IV (Group B). Overall survival (OS) and disease-specific survival (DSS) were considered secondary endpoints. RESULTS: For the entire cohort, the 5-year DFS rates of Groups A and B were 55.0% and 60.1%, respectively. Five-year OS rates were 58.9% and 61.5%, and 5-year DSS rates were 74.0% and 64.8%, respectively. Group B did not show higher 5-year DFS, OS, or DSS than Group A. CONCLUSIONS: This retrospective cohort study validated that in cN0 HPV-negative OPSCC, SND including level IV does not have substantial benefits regarding DFS, OS or DSS.

Population-based utility scores for HPV infection and oropharyngeal squamous cell carcinoma among Indigenous Australians.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is associated with high mortality. Human papillomavirus (HPV) infection is a significant risk factor for OPSCC. Utilities are fundamental values representing the strength of individuals' preferences for specific health-related outcomes. Our study aim was to work in partnership with Indigenous communities in South Australia to develop, pilot test and estimate utility scores for health states related to HPV, HPV vaccination, precursor OPSCC and its treatment, and early stage OPSCC among Indigenous Australians. METHODS: Development and pilot testing of hypothetical HPV and OPSCC health states, specifically through the lens of being Indigenous Australian, was conducted with an Indigenous Reference Group. Six health states were decided upon, with utility scores calculated using a two-stage standard gamble approach among a large convenience sample of Indigenous Australians aged 18+ years residing in South Australia. The rank, percentage of perfect health and utility score of each health state was summarised using means, and medians at 12 months and lifetime duration. Potential differences by age, sex and residential location were assessed using the Wilcox Rank Sum test. RESULTS: Data from 1011 participants was obtained. The mean utility scores decreased with increasing severity of health states, ranging from 0.91-0.92 in 'screened, cytology normal, HPV vaccination' and 'screened, HPV positive, endoscopy normal', to less than 0.90 (ranging from 0.87-0.88) in lower grade conditions (oral warts and oral intraepithelial neoplasia) and less than 0.80 (ranging from 0.75-0.79) in 'early stage throat cancer'. Higher utility scores were observed for 'screened, cytology normal and HPV vaccination' among younger participants (18-40 years), for 'early stage invasive throat cancer' among females, and for 'oral intraepithelial neoplasia' and 'early stage invasive throat cancer' among metropolitan-dwelling participants. CONCLUSION: Among a large sample of Indigenous Australians, utility for oral HPV infection and OPSCC decreased with severity of health states. Older participants, as well as males and those residing in non-metropolitan locations, had decreased utility for high-grade cytology and early invasive cancer states. Our findings are an important contribution to cost-utility and disease prevention strategies that seek to inform policies around reducing HPV infection and OPSCC among all Australians.

Multiple imputation and clinico-serological models to predict human papillomavirus status in oropharyngeal carcinoma: An alternative when tissue is unavailable.

In cancer epidemiological studies, determination of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) typically depends on the availability of tumor tissue testing, and/or tumor tissue access. Identifying alternative methods for estimating HPV status can improve the quality of such studies when tissue is unavailable. We developed multiple predictive models for tumor HPV status and prognosis by combining both clinico-epidemiological variables and either serological multiplex assays of HPV or multiple imputation of HPV status (HPVmi ). Sensitivity, specificity and accuracy of these methods compared to either p16 immunostaining (p16 IHC) or survival were assessed. When compared to a reference of tumor tissue p16 IHC in 783 OPSCC patients, the clinic-HPVsero model incorporating a composite of 20 HPV serological antibodies (HPVsero ) and 4 clinical factors (c-index: 0.96) performed better than using HPVsero (c-index: 0.92) or HPVmi (c-index: 0.76) alone. However, the model that contained a single HPV16 E6 antibody combined with four clinical variables, performed extremely well (clinic-s1-16E6; c-index: 0.95). When defining HPV status by HPVsero , s1-16E6, HPVmi or through p16 IHC, each of these definitions demonstrated improved overall and disease-free survival in HPV-positive OPSCC patients, when compared to HPV-negative patients (adjusted hazard ratios between 0.25 and 0.63). Our study demonstrates that when blood samples are available, a model that utilizes a single s1-16E6 antibody combined with several clinical features has excellent test performance characteristics to estimate HPV status and prognosis. When neither blood nor tumor tissue is available, multiple imputation, calibrated on local population characteristics, remains a viable, but suboptimal option.

Extracapsular extension of neck nodes and absence of human papillomavirus 16-DNA are predictors of impaired survival in p16-positive oropharyngeal squamous cell carcinoma.

BACKGROUND: Human papillomavirus (HPV)-driven oropharyngeal squamous cell carcinomas (OPSCCs) demonstrate superior outcome compared with HPV-negative OPSCCs. The eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, lymph node, metastasis (TNM) classification (TNM 2017) modifies OPSCC staging based on p16 positivity as a surrogate for HPV-driven disease. In p16-negative OPSCCs, lymph node (N) categories include extracapsular/extranodal extension (ECE); and, in p16-positive OPSCCs, N categories are based on the number of positive neck lymph nodes omitting ECE status. The objective of the current study was to assess the prognostic impact of positive ECE status and the detection of HPV16 DNA in patients with p16-positive OPSCC. METHODS: In a cohort of 92 patients with p16-positive, lymph node (N)-positive (stage III-IVB) OPSCC who underwent surgery and neck dissection, allowing for a pathologic examination of positive lymph nodes, 66 of 92 patients (71.4%) were p16-positive/HPV16 DNA-positive, 62 of 92 (67%) were ECE-positive, and 45 of 62 (72.6%) were ECE-positive, p16-positive, and HPV16 DNA-positive. Differences in outcome were assessed using Kaplan-Meier plots and Cox proportional hazard regression (CoxR) for tumor-specific survival and overall survival (OS). RESULTS: The mean numbers of positive lymph nodes in ECE-positive patients (5.0 positive lymph nodes; 95% CI, 3.8-6.4 positive lymph nodes) and ECE-negative patients (2.4 positive lymph nodes; 95% CI, 1.8-2.9 positive lymph nodes) were different (P = .0007). ECE affected OS and tumor-specific survival in p16-positive patients (P = .007 and P = .047, respectively) and in p16-positive/HPV16 DNA-positive patients (P = .013 and P = .026, respectively). Related to the unequal distributions of ECE-positive/HPV16 DNA-negative tumors, the TNM 2017 failed to discriminate OS in patients with UICC stage I, II, and III disease (mean OS, 54.5, 73.4, and 45 months, respectively; median OS, 64.7 months, not reached, and 41.1 months, respectively). According to a univariate CoxR, the presence of ECE predicted impaired OS in patients with p16-positive OPSCC (hazard ratio, 3.40; 95% CI, 1.17-9.89; P = .025) and even greater impaired OS in those with p16-positive/HPV16 DNA-positive OPSCC (HR, 8.64; 95% CI, 1.12-66.40; P = .038). Multivariate CoxR confirmed ECE and HPV16 DNA detection as independent predictors. CONCLUSIONS: ECE and HPV16 DNA status should be included in the prognostic staging of patients with p16-positive OPSCC because several lines of evidence demonstrate their impact on survival.

Individualized survival prediction for patients with oropharyngeal cancer in the human papillomavirus era.

BACKGROUND: Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation. METHODS: Four OPSCC calculators were identified that integrate HPV into their estimation of 5-year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan-Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots. RESULTS: Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan-Meier curves of calculator-defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes. CONCLUSIONS: Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers.

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

Identification of human papillomavirus (HPV) subtype in oral cancer patients through microarray technology.

PURPOSE: Human papilloma virus (HPV) is the main source of cervical cancer. Many recent studies have revealed the prevalence and prognosis of HPV associated with oropharyngeal squamous cell carcinoma, but fewer reports have evaluated HPV in oral squamous cell carcinoma (OSCC). The purpose of this study was to determine the prevalence and prognosis of HPV associated with OSCC according to HPV and tumor types. MATERIALS AND METHODS: We used a DNA chip kit (MY-HPV chip kit ®, Mygene Co., Korea) to detect high-risk HPV subtypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 54, 56, 58) and low-risk subtypes (6, 11, 34, 40, 42, 43, 44) among 187 patients. The prevalence was determined by Chi-square and Fisher's exact tests, and the prognosis was calculated by the Kaplan-Meier method and the log-rank test. RESULTS: The overall prevalence of HPV in OSCC was 7.0% for all HPV positives and 4.3% for high-risk HPV positives. The prevalence of HPV was significantly higher in individuals under 65 years old and in those with tumors in the tongue and gum regions. The prognosis did not differ between the HPV-positive and -negative groups. Although the prevalence of HPV-positive cases in OSCC was low (7.0, 4.3%) and the prognosis did not depend on HPV positivity, HPV-associated OSCC should be considered in the evaluation and treatment of oral cancer patients. In addition, separating high- and low-risk groups based on the HPV status of other body parts might not be appropriate. DISCUSSION: The DNA microarray method can accurately detect known HPV subtypes simultaneously, but has limitations in detecting new subtypes. Vaccines can also be used to prevent HPV-associated OSCC in patients, so further studies on the prognosis and efficacy of vaccines should be undertaken.

Human papillomavirus in oropharyngeal cancer: The changing face of a disease.

The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.

Variation in use of postoperative chemoradiation following surgery for T1 and T2 oropharyngeal squamous cell carcinoma; National Cancer Database.

BACKGROUND AND OBJECTIVES: Primary surgical treatment of patients with early T-classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC) has increased. We sought to determine how often these patients receive postoperative chemoradiation (CRT). METHODS: Patients with T1-T2 OPSCC in the National Cancer Database who underwent primary surgery were evaluated for receipt of postoperative CRT. Postoperative CRT use was examined among patients with high risk factors (positive margins and/or extracapsular spread [ECS]), intermediate risk factors (negative margins, no ECS, and either pT3-4 and/or N2-N3), and no apparent risk factors. RESULTS: Of 4833 patients with T1-T2 OPSCC who underwent primary surgery, 43% had high risk pathologic factors, of whom only 63% received postoperative CRT. Another 31% had no apparent risk factors, of whom 16% nonetheless received postoperative CRT. On multivariable analysis, in addition to tumor and demographic factors, patients treated at community hospitals were more likely to receive postoperative CRT (O.R. 1.41 C.I. 1.18-1.87, P = 0.001). CONCLUSIONS: Variation in postoperative CRT use indicates a lack of consensus and/or knowledge about its benefits and indications. Usage of postoperative CRT regardless of pathologic risk factors suggests an area where future efforts at implementation of best practices may be targeted.

Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base.

BACKGROUND: There has been increasing interest in the primary surgical treatment of patients with early T classification (T1-T2) oropharyngeal squamous cell carcinoma (OPSCC), with the stated goal of de-escalating or avoiding adjuvant treatment. Herein, the authors sought to determine the degree to which this interest has translated into changes in practice patterns, and the rates of adverse postoperative pathologic features. METHODS: Patients with T1 to T2 OPSCC in the National Cancer Data Base who were treated from 2004 through 2013 were categorized as receiving primary surgical or primary radiation-based treatment. Trends in treatment selection and factors related to the selection of primary surgery were examined. The rates of adverse pathologic features including positive surgical margins, extracapsular spread (ECS), and advanced T and N classifications after surgery were analyzed. RESULTS: Of 8768 patients with T1 to T2 OPSCC, 68% underwent primary surgical treatment, increasing from 56% in 2004 to 82% in 2013 (P<.0001). The highest versus lowest volume hospitals treated 78% versus 59% of patients with primary surgery (odds ratio, 2.23; 95% confidence interval, 1.55-3.22 [P<.0001]). Higher lymph node classification was found to be predictive of lower rates of primary surgery, but the majority of patients with clinical N2/N3 disease underwent primary surgery. Among patients treated with surgery, positive surgical margins were present in 24% and ECS in 25% of patients. The rate of positive surgical margins decreased over time (P<.0001) and was observed less often at high-volume centers (P<.0001). Among candidates for single-modality therapy (those with clinical T1-T2/N0-N1 disease), 33% had positive surgical margins and/or ECS and 47% had at least 1 adverse feature (T3-T4 disease, N2-N3 disease, positive surgical margins, and/or ECS). CONCLUSIONS: Primary surgical treatment among patients with early T classification OPSCC has become more widespread. Cancer 2016;122:1523-32. © 2016 American Cancer Society.

Best practice guidelines in the psychosocial management of HPV-related head and neck cancer: recommendations from the European Head and Neck Cancer Society's Make Sense Campaign.

Over the past three decades, oral human papillomavirus (HPV) has been associated with an increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in several countries. Specialist oncologists in head and neck cancer are observing a wider range of demographics, sexual behaviours, and survival outcomes with their patients. Additionally, there are fewer smokers, consumers of alcohol, or people of lower socioeconomic status than in previous decades. In order to support patients, the European Head and Neck Society's Make Sense Campaign aims to promote best practice in the management of head and neck cancer through the delivery of counselling, psychological assessment, support with the patient experience following HPV-related cancer diagnosis, sexual impact (in terms of communication, behaviour and prevention), facilitating access to educational resources about HPV in head and neck squamous cell carcinoma and OPSCC, and early referral if necessary. New concerns about psychosocial distress and unmet psychosocial needs following diagnosis, therefore, exist throughout the disease and treatment periods. Oncologists treating patients with HPV-related head and neck cancer must integrate new parameters focused on infection risk transmission and sexual topics. The development and dissemination of best practice guidelines through The European Head and Neck Cancer Society Make Sense Campaign will help healthcare professionals to be more confident and resourceful in supporting patients with HPV-related head and neck cancer.

Adoption of transoral robotic surgery compared with other surgical modalities for treatment of oropharyngeal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: Transoral robotic surgery (TORS) has increased for treatment of oropharyngeal squamous cell carcinoma (OPSCC). To define the adoption of TORS, we analyzed patterns of surgical treatment for OPSCC in the US. METHODS: Cases of T1-T3 OPSCC treated with surgery between 2010 and 2013 from the National Cancer Database were queried. RESULTS: Of 3,071 patients who underwent primary surgical management for T1-T3 OPSCC, 846 (28%) underwent TORS. On multivariable analysis, low tumor stage (T2 vs. T1: OR 0.75, CI 0.37-0.51, P < 0.0001; T3 vs. T1: O.R. 0.33, CI 0.28-0.38, P < 0.0001), treatment at an academic cancer center (O.R. 2.23, C.I. 1.29-3.88, P = 0.004) and treatment at a high volume hospital (34-155 cases vs. 1-4 cases: O.R. 9.07, C.I. 3.19-25.79, P < 0.0001) were associated with increased TORS approach. Significant geographic variation was observed, with high adoption in the Middle Atlantic. Positive margin rates were lower when TORS was performed at a high volume versus low volume hospital (8.2% vs. 16.7% respectively, P = 0.001). CONCLUSIONS: Tumor and non-tumor factors are associated with TORS adoption. This analysis suggests uneven diffusion of this technology in the treatment of OPSCC. J. Surg. Oncol. 2016;114:405-411. © 2016 Wiley Periodicals, Inc.

Multi-omics analysis of overexpressed tumor-associated proteins: gene expression, immunopeptide presentation, and antibody response in oropharyngeal squamous cell carcinoma, with a focus on cancer-testis antigens.

Introduction: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets. Materials and methods: Snap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins). Results: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels. Discussion: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy.

Early Improved Functional Outcomes in Head and Neck Cancer Patients with Primary Tumor Detection.

OBJECTIVES: We characterize functional outcomes in head and neck cancer of unknown primary (CUP) based on primary site identification. METHODS: In this retrospective study, CUP cases were categorized as known primaries (KP) if a tumor was localized after diagnostic workup or persisting unknown primaries (UP). Age, sex, HPV status, diagnostic methods, and treatments regimens were collected. Pretreatment and short-term posttreatment (3-6 months after completion of treatment) weights, PHQ-9, Eating Assessment Tool (EAT-10), and Voice Handicap Index (VHI-10) scores were compared between UP and KP. RESULTS: Among 67 CUP patients, 35 (52.2%) had identified primaries (91.4% oropharyngeal and 8.6% nasopharyngeal). KP patients were younger (58 vs. 64, p = 0.04) and more likely to be HPV-positive (88.6% vs. 50%, p = 0.002). Overall detection rates were 16.7% for PET/CT, 34.7% for direct laryngoscopy, and 46.6% for transoral robotic oropharyngectomy. Diagnostic workup was not significantly different between groups. Patients with KP received smaller intermediate radiation dose volumes (436.5 vs. 278.9 cc, p = 0.03) and lower doses to the cricopharyngeal muscle (41.6 vs. 24.6 Gy, p = 0.03).Pretreatment weights, PHQ-9, EAT-10, and VHI-10 scores did not differ between groups. However, posttreatment, UP had greater relative weight loss (-14.1% vs. -7.6%, p = 0.032), higher EAT-10 scores (12.5 vs. 3, p = 0.004), and higher PHQ-9 scores (6 vs. 1.4, p = 0.017). Specifically, UP reported more stressful swallowing, difficulty swallowing solids and pills, and swallowing affecting public eating. CONCLUSION: KP patients experienced less weight loss, depression, and reduced swallowing dysfunction, highlighting an early functional benefit of primary tumor identification likely driven by reduced radiation treatment volumes. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:701-707, 2024.

Automated AJCC Restaging for Oropharyngeal Cancer Research.

With the American Joint Committee on Cancer (AJCC) 8th edition staging guidelines update, human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) is now staged separately from its HPV-negative counterpart, preventing meaningful comparison of cases staged with the 7th versus 8th edition criteria. Manual restaging is time-consuming and error-prone, hindering multiyear analyses for HPV+ OPSCC. We developed an automated computational tool for re-classifying HPV+ OPSCC pathological and clinical tumor staging from AJCC 7th to 8th edition. The tool is designed to handle large data sets, ensuring comprehensive and accurate analysis of historic HPV+ OPSCC data. Validated against institutional and National Cancer Database data sets, the algorithm achieved accuracies of 100% (95% confidence interval [CI] 98.8%-100%) and 93.4% (95% CI 93.1%-93.7%), successfully restaging 326/326 and 26,505/28,374 cases, respectively. With its open-source design, this computational tool can enhance future HPV+ OPSCC research and inspire similar tools for other cancer types and subsequent AJCC editions.