HPV-associated Oropharyngeal Squamous Cell Carcinoma Research Articles

Decreased overall survival in black patients with HPV-associated oropharyngeal cancer.

Racial disparities for overall survival (OS) in head and neck cancer have been well described. However, the extent to which these disparities exist for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC), and the contribution of demographic, clinical, and socioeconomic status (SES) variables, is unknown. Patients were identified from the Carolina Head and Neck Cancer Epidemiology Study (CHANCE), a population-based study in North Carolina. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for OS in black versus white patients with sequential adjustment sets. A total of 157 HPV-associated OPSCC patients were identified. Of these, 93% were white and 7% were black. Black patients with HPV-associated OPSCC were more likely to be younger, have an income <$20,000, live farther away from clinic where biopsy was performed, and have advanced T stage at diagnosis. Black patients had worse OS in the unadjusted analysis (HR 4.9, 95% CI 2.2-11.1, p<0.0001). The racial disparity in OS slightly decreased when sequentially adjusting for demographic, clinical, and SES variables. However, HR for black race remained statistically elevated in the final adjustment set which controlled for age, sex, stage, smoking, alcohol use, and individual-level household income, insurance, and education level (HR 3.4, 95% CI 1.1-10.1, p=0.028). This is the first population-based study that confirms persistence of racial disparities in HPV-associated OPSCC after controlling for demographic, clinical, and individual-level socioeconomic factors.

Prediction of post-radiotherapy locoregional progression in HPV-associated oropharyngeal squamous cell carcinoma using machine-learning analysis of baseline PET/CT radiomics

Locoregional failure remains a therapeutic challenge in oropharyngeal squamous cell carcinoma (OPSCC). We aimed to devise novel objective imaging biomarkers for prediction of locoregional progression in HPV-associated OPSCC. Following manual lesion delineation, 1037 PET and 1037 CT radiomic features were extracted from each primary tumor and metastatic cervical lymph node on baseline PET/CT scans. Applying random forest machine-learning algorithms, we generated radiomic models for censoring-aware locoregional progression prognostication (evaluated by Harrell's C-index) and risk stratification (evaluated in Kaplan-Meier analysis). A total of 190 patients were included; an optimized model yielded a median (interquartile range) C-index of 0.76 (0.66-0.81; p = 0.01) in prognostication of locoregional progression, using combined PET/CT radiomic features from primary tumors. Radiomics-based risk stratification reliably identified patients at risk for locoregional progression within 2-, 3-, 4-, and 5-year follow-up intervals, with log-rank p-values of p = 0.003, p = 0.001, p = 0.02, p = 0.006 in Kaplan-Meier analysis, respectively. Our results suggest PET/CT radiomic biomarkers can predict post-radiotherapy locoregional progression in HPV-associated OPSCC. Pending validation in large, independent cohorts, such objective biomarkers may improve patient selection for treatment de-intensification trials in this prognostically favorable OPSCC entity, and eventually facilitate personalized therapy.

Abstract 4739: The immunogenomic landscape of HPV-associated oropharyngeal squamous cell carcinoma by smoking and treatment response

Abstract Background: Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is an increasingly common malignancy and public health epidemic. Overall, outcomes in HPV-associated OPSCC are very good but treatment failure is associated with a devastating prognosis. Although tobacco use is one of the few clinical biomarkers associated with worse prognosis, the mechanisms underlying this disparity are not well understood. The goal of this study was to investigate the genomic and immune related alterations associated with tobacco use in HPV-associated OPSCC. Methods: We prospectively identified a cohort of 53 patients with HPV-associated OPSCC with corresponding clinical and demographic data. Tumor DNA and RNA were extracted from FFPE samples along with whole blood as a control for variant calling. We performed whole exome sequencing, mutational signature analysis and a 770 gene RNA-based NanoString immuno-oncology assay to further interrogate these tumors. Results: We identified that smokers and non-smokers had remarkably well conserved copy number alterations and mutational alterations. Mutational alterations in tumors across the cohort including in heavy smokers had frequent mutations in PIK3CA, FGFR3, ZNF750 that largely reflect the known alterations common in HPV-associated OPSCC. Regardless of smoking status, we rarely observed mutations typical of non-HPV associated head and neck cancers such as TP53, CDKN2A, and FAT1. COSMIC mutational signature analysis revealed that a majority of the tumors expressed an APOBEC signature (#2 and #13) consistent with viral etiology of tumorigenesis. Strikingly, none of the tumors expressed mutational signatures associated with tobacco use (#4 and #29). We then performed an RNA-based NanoString immuno-oncology assay to investigate differences within the immune microenvironment. We identified significantly upregulated expression of genes associated with myeloid derived suppressor cell (MDSC) recruitment and activity including S100A8/A9, S100A12, CXCR2, CXCL1, and ARG2, suggesting a potential association between tobacco use, MDSC-driven immunosuppression and poorer prognosis. Conclusion: In this genomic analysis of HPV-associated OPSCC, we demonstrate that tobacco use does not clearly induce structural or mutational differences within the tumor cells. Even in heavy tobacco users, the mutational signatures reflect a tumor driven by its viral etiology and more closely aligns to non-tobacco using HPV-associated OPSCC than it does HPV-negative OPSCC. The poorer prognosis in smokers may be related to alterations in the immune microenvironment including the recruitment and activity of MDSCs. This provides further evidence that strategies to target MDSC activity in the immune microenvironment may be effective in high-risk HPV-OPSCC smokers. Citation Format: Paul Zolkind, Ben Wahle, Zachary Skidmore, Angela Mazul, Obi Griffith, Malachi Griffith, Jose P. Zevallos. The immunogenomic landscape of HPV-associated oropharyngeal squamous cell carcinoma by smoking and treatment response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4739.

Abstract 154: Genetic and epigenetic analysis of HPV-positive and HPV-negative Oropharyngeal squamous cell carcinoma

Abstract Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing in these two decades, primarily due to human papillomavirus (HPV). Whereas HPV-associated OPSCC generally correlates with better prognosis, approximately 20% of the patients do not show good prognosis or response to treatment. Appropriate molecular markers have not been available to stratify OPSCC into distinct molecular subtypes reflecting these different clinicopathological features, making treatment stratification difficult, while de-escalation strategies for better prognosis group are expected to decrease the long-term chemoradiation-related morbidities. Methods: We performed DNA methylome analysis using Infinium 450k for 89 OPSCC cases and targeted exon sequencing for 86 OPSCC cases, and analyzed the data together with 81 cases reported by The Cancer Genome Atlas. We stratified OPSCC by hierarchical clustering analysis using methylome data. Methylation levels of classifier markers were validated quantitatively using pyrosequencing, and area under the curve (AUC) values of receiver operating characteristics (ROC) curves were calculated. Association between clinicopathological factors and DNA methylation or mutation status was statistically analyzed. Results: OPSCC was stratified into four epigenotypes: HPV(+) high-methylation (OP1), HPV(+) intermediate-methylation (OP2), HPV(−) intermediate-methylation (OP3), and HPV(−) low-methylation (OP4). Ten methylation marker genes were generated: five to classify HPV(+) cases into OP1 and OP2, and five to classify HPV(−) cases into OP3 and OP4. AUC values of ROC curves were 0.969 and 0.952 for the two marker panels, respectively. While significantly higher TP53 mutation and CCND1 copy number gains were observed in HPV(−) than in HPV(+) groups (P&amp;lt;0.01), no significant difference of genomic aberrations was observed between OP1 and OP2, or OP3 and OP4. The four epigenotypes showed significantly different prognosis (P=0.0006), distinguishing the most favorable OPSCC subgroup (OP1) among generally favorable HPV(+) cases, and the most unfavorable OPSCC subgroup (OP3) among generally unfavorable HPV(−) cases. Generally favorable HPV-associated OPSCC as well as generally unfavorable HPV-negative OPSCC can be successfully subdivided into two different epigenotypes each, reflecting significantly distinct prognosis. Conclusions: HPV(+) and HPV(−) OPSCC are further divided into distinct DNA methylation epigenotypes, showing significantly different prognosis. These findings will contribute to greater understanding of the molecular basis of OPSCC and de-escalation treatment strategies. Citation Format: Takuya Nakagawa, Keisuke Matsusaka, Kiyoshi Misawa, Masaki Fukuyo, Tomoya Kurokawa, Masato Mima, Hisahiro Matsubara, Toyoyuki Hanazawa, Atsushi Kaneda. Genetic and epigenetic analysis of HPV-positive and HPV-negative Oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 154.

Impact of Lymph Node Yield on Survival in Surgically Treated Oropharyngeal Squamous Cell Carcinoma.

(1) To estimate the association between neck dissection lymph node yield (LNY) and survival among patients with surgically treated human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). (2) To identify a clinically relevant quality metric for surgical treatment of HPV-related OPSCC. Retrospective cohort study. National Cancer Database. From the National Cancer Database, 4130 patients were identified with HPV-associated OPSCC treated with primary surgery from 2010 to 2016. Based on prior literature, an adequate neck dissection LNY was defined as ≥18 lymph nodes. To determine whether LNY is associated with survival, univariable and multivariable Cox proportional hazards regression was performed. Analysis was stratified by adjuvant therapy regimen. A total of 2113 patients (51.2%) underwent surgery with or without adjuvant radiation (S ± RT), and 2017 patients (48.8%) underwent surgery with adjuvant chemoradiation. LNY ≥18 was associated with a 5-year survival benefit of 7.15% (91.7% for LNY ≥18, 84.5% for LNY <18, P = .004) for the S ± RT cohort on unadjusted survival analysis. For the S ± RT group, LNY ≥18 was associated with decreased hazard of death (hazard ratio, 0.45; 95% CI, 0.29-0.70; P < .001) after adjustment for patient characteristics, TNM staging, surgical margins, extranodal extension, and treating facility characteristics. For surgery with adjuvant chemoradiation, the adjusted hazard ratio estimate for LNY ≥18 was 0.64 (95% CI, 0.41-1.00), but the result was not statistically significant (P = .052). An adequate LNY from a neck dissection may affect survival when HPV-related OPSCC is treated with up-front surgery.

Improving post-CRT neck assessment in patients with HPV-associated OPSCC (Review).

The positive predictive value (PPV) of 12-week post-therapy FDG-PET/CT is low in patients with Human Papillomavirus (HPV)-associated Oropharyngeal Squamous Cell Carcinoma (OPSCC) after treatment with definitive chemoradiation (CRT). Moreover, the diagnostic performance of post-CRT fine needle aspiration (FNA) in detecting persistent disease is unknown in this population. Given these important shortcomings in post-CRT treatment assessment, head and neck oncologists are limited in appropriately selecting patients for consolidative neck dissection, which results in over-treatment of a favorable risk population. Using the PubMed database, we performed a literature review of published series in HPV-associated OPSCC to investigate potential strategies for improvement of post-CRT neck assessment. Several different approaches were found, including continued surveillance with PET/CT, delayed timing of restaging PET/CT, initial response evaluation with multimodality or alternative imaging, and detection of circulating HPV DNA. At present, the optimal approach to post-CRT treatment assessment is unclear; further investigation and incorporation of new technologies and surveillance protocols will be highly beneficial for patients with HPV-associated OPSCC.

Potential Added Value of PET/CT Radiomics for Survival Prognostication beyond AJCC 8th Edition Staging in Oropharyngeal Squamous Cell Carcinoma.

Accurate risk-stratification can facilitate precision therapy in oropharyngeal squamous cell carcinoma (OPSCC). We explored the potential added value of baseline positron emission tomography (PET)/computed tomography (CT) radiomic features for prognostication and risk stratification of OPSCC beyond the American Joint Committee on Cancer (AJCC) 8th edition staging scheme. Using institutional and publicly available datasets, we included OPSCC patients with known human papillomavirus (HPV) status, without baseline distant metastasis and treated with curative intent. We extracted 1037 PET and 1037 CT radiomic features quantifying lesion shape, imaging intensity, and texture patterns from primary tumors and metastatic cervical lymph nodes. Utilizing random forest algorithms, we devised novel machine-learning models for OPSCC progression-free survival (PFS) and overall survival (OS) using “radiomics” features, “AJCC” variables, and the “combined” set as input. We designed both single- (PET or CT) and combined-modality (PET/CT) models. Harrell’s C-index quantified survival model performance; risk stratification was evaluated in Kaplan–Meier analysis. A total of 311 patients were included. In HPV-associated OPSCC, the best “radiomics” model achieved an average C-index ± standard deviation of 0.62 ± 0.05 (p = 0.02) for PFS prediction, compared to 0.54 ± 0.06 (p = 0.32) utilizing “AJCC” variables. Radiomics-based risk-stratification of HPV-associated OPSCC was significant for PFS and OS. Similar trends were observed in HPV-negative OPSCC. In conclusion, radiomics imaging features extracted from pre-treatment PET/CT may provide complimentary information to the current AJCC staging scheme for survival prognostication and risk-stratification of HPV-associated OPSCC.

Machine Learning Prediction of Extracapsular Extension in Human Papillomavirus-Associated Oropharyngeal Squamous Cell Carcinoma.

To determine whether machine learning (ML) can predict the presence of extracapsular extension (ECE) prior to treatment, using common oncologic variables, in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). Retrospective database review. National Cancer Database study. All patients with HPV-associated OPSCC treated surgically between January 1, 2010, and December 31, 2015, were selected from the National Cancer Database. Patients were excluded if surgical pathology reports did not include information regarding primary tumor stage, number of metastatic regional lymph nodes, size of largest metastatic regional lymph node, and tumor grade. The data were split into a random distribution of 80% for training and 20% for testing with ML methods. A total of 3753 adults with surgically treated HPV-associated OPSCC met criteria for inclusion in the study. Approximately 38% of these patients treated with surgical management demonstrated ECE. ML models demonstrated modest accuracy in predicting ECE, with the areas under the receiver operating characteristic curves ranging from 0.58 to 0.68. The conditional inference tree model (0.66) predicted the metastatic lymph node number to be the most important predictor of ECE. Despite a large cohort and the use of ML algorithms, the power of clinical and oncologic variables to predict ECE in HPV-associated OPSCC remains limited.

Abstract A06: Interrogation of HPV-positive oropharyngeal squamous cell carcinomas with RNA-based Nanostring assay demonstrates expression profile associated with treatment resistance

Abstract Background: Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is an increasingly common malignancy and public health challenge. HPV-associated OPSCCs typically respond to treatment, and there is an increasing focus on deintensification trials to minimize treatment related morbidity. However, treatment failure rates in locally advanced HPV-associated OPSCC range from 14%-32%, and there is a need to interrogate potential biomarkers of treatment response and resistance to guide patient stratification for deintensification trials and to identify novel treatment targets for high-risk patients. Methods: We prospectively identified a cohort of 8 patients with HPV-associated OPSCC who subsequently developed a biopsy-proven tumor recurrence. We also identified 8 patients with HPV-associated OPSCC matched to the above cohort by gender, smoking history, TNM stage, and treatment modality who developed a complete response to treatment. The primary samples of each cohort were interrogated with an RNA-based Nanostring immuno-oncology assay. Results: We identified that treatment-responsive tumors had significantly higher expression of NK cell markers than nonresponders (KIR3DL2, q=0.003, KIR2DL3, q=0.04). These data may indicate a potential role of the innate immune system in tumor eradication. We also identified increased expression of CCL21 in treatment-resistant tumors (q=0.04), a biomarker that has been explored in colorectal cancer due to its association with cancer stem cell-like properties. Interrogation of the tumors by smoking status demonstrated that smokers had significantly higher expression of FGF18 (q=0.003), a fibroblast growth factor linked to epithelial-to-mesenchymal transition and cisplatin resistance. We also looked at the immune checkpoint B7-H3 (CD276), a novel immunotherapeutic target associated with worse outcomes in head and neck cancer. We demonstrate that B7-H3 expression is associated with expression of epithelial-to-mesenchymal transition markers such as TWIST1 (q= 0.01), SOX11 (q= 0.006), COL5A1 (q=0.0001), and CXCL8 (q=0.02). Interestingly, low expression of B7-H3 is associated with increased CD8B expression. Conclusion: In this genomic analysis of HPV-associated oropharyngeal squamous cell carcinomas, we identify an association between presence of NK cells in the tumor microenvironment and treatment responsiveness. We also identify CCL21 as a potential biomarker of treatment resistance. Further studies are needed to confirm these biomarkers and examine the link between smoking status and immune microenvironment. Finally, we demonstrate that the immune checkpoint B7-H3 is associated with markers of epithelial-to-mesenchymal transition and warrants further exploration as a novel therapeutic target. Citation Format: Zixing Liu, Angela Mazul, Malachi Griffith, Paul Zolkind. Interrogation of HPV-positive oropharyngeal squamous cell carcinomas with RNA-based Nanostring assay demonstrates expression profile associated with treatment resistance [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A06.

Predicting late radiation-induced xerostomia with parotid gland PET biomarkers and dose metrics

PurposeTo assess associations between parotid gland PET biomarkers and late radiation-induced xerostomia, and to validate improvement of xerostomia predictive models by adding pre-treatment PET features to models based on dose and pre-treatment xerostomia. Materials and MethodsIntensity PET features from 47 patients treated on institutional prospective clinical trials for HPV-associated oropharyngeal squamous cell carcinoma with uniform chemoRT were analyzed. Associations between 90th percentile of the parotid gland standardized uptake values (P90) from pre-treatment and post-treatment PET scans, mean parotid gland doses, and late xerostomia defined by the Xerostomia Questionnaire (XQ) and salivary flow rates were quantified. Multivariable analysis was applied for dose and PET features using penalized logistic regression for feature selection and generation of predictive models using the LASSO technique, and optimism bias was estimated by bootstrap resampling. ResultsSignificant associations between late xerostomia and both mean parotid gland dose and P90 were demonstrated, and were generally stronger for post-treatment PET scans. The addition of P90 from pre-treatment PET scans improved the prediction model for late moderate or severe xerostomia compared to the base model, from AUC = 0.74 to 0.78 (p-value <0.001) for XQ summary score and from 0.77 to 0.84 (p-value <0.001) for the single eating-related XQ item with the largest inter-patient variability; however, only the latter remained significant on cross validation (AUC = 0.69 to 0.70 and 0.73 to 0.80, respectively). ConclusionsThe addition of pre-treatment parotid gland PET biomarkers improved a predictive model for late patient-reported xerostomia over dose and pre-treatment xerostomia.

The Evolution of Intermediate Risk Oropharyngeal Cancer in a Veteran Population: a 15 Year Study

Oropharyngeal squamous cell carcinoma (OPSCC) incidence is increasing at an epidemic rate, fueled by human papillomavirus (HPV) infections. Whereas HPV-associated OPSCC (HPV+OPSCC) often occurs in non-smokers in the general population, smoking prevalence is much higher in the Veteran population resulting in a large intermediate-risk (HPV+ tumors in patients with significant smoking history) OPSCC cohort whose outcomes remain poorly described to date. Our goal was to evaluate oncologic and functional outcomes for OPSCC in a Veteran population and ascertain shifts in survival and relative disease burden within this intermediate-risk cohort. We hypothesized that intermediate-risk OPSCC represents a majority of new OPSCC diagnoses among Veterans.

PET Imaging Biomarkers and Clinical Features to Predict Locoregional and Distant Failures in HPV-Associated Oropharyngeal Squamous Cell Carcinoma

PET Imaging Biomarkers and Clinical Features to Predict Locoregional and Distant Failures in HPV-Associated Oropharyngeal Squamous Cell Carcinoma

Primary chemoradiotherapy or transoral robotic surgery for Stage I-II HPV-associated oropharyngeal squamous cell carcinoma

Primary chemoradiotherapy or transoral robotic surgery for Stage I-II HPV-associated oropharyngeal squamous cell carcinoma

Knowledge Gaps among Patients and Providers in HPV-Related Oropharyngeal Cancer: A Systematic Review.

To describe the level of knowledge of human papillomavirus (HPV) and HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) among the general population and health care providers. Systematic search was performed on December 20, 2018, using MEDLINE (1966 to December 2018), EMBASE (1975 to December 2018), Web of Science (1900 to December 2018), and CENTRAL (1996 to December 2018) databases. English-language literature involving human subjects was used, and studies were limited to case series, case-control, cohort, and randomized controlled trial designs. Studies were included if they assessed knowledge of HPV and HPV-associated OPSCC. The primary outcome measure was the knowledge of HPV-associated OPSCC among the general population and with health care providers. Meta-analysis of proportions was attempted using random-effects model. The PRISMA guidelines were used for accuracy of reporting. Thirty-two studies were included with 17,288 participants. There was a high degree of heterogeneity preventing completion of a meta-analysis. Knowledge of HPV and HPV-associated OPSCC varied between the general population and health care providers. The proportion of the general population and health care providers with knowledge of HPV ranged from 16% to 75% and 21% to 84%, respectively. Knowledge of HPV-associated OPSCC was greater in health care providers and ranged from 22% to 100% compared with the general population, which ranged from 7% to 57%. There is a knowledge gap of HPV-associated OPSCC for both the general population and health care providers. Additional education may not only increase awareness but may also result in prevention and earlier detection.

Treatment de-escalation for HPV-associated oropharyngeal squamous cell carcinoma with radiotherapy vs. trans-oral surgery (ORATOR2): study protocol for a randomized phase II trial

BackgroundPatients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches.MethodsThis is a multicenter phase II study randomizing one hundred and forty patients with T1–2 N0–2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60 Gy) ± concomitant chemotherapy and TOS ± de-escalated adjuvant radiotherapy (50–60 Gy based on risk factors). Patients will be stratified based on smoking status (< 10 vs. ≥ 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity.DiscussionThis study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials.Trial RegistrationClinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.

Threshold for interpretation of p16 immunostaining in fine-needle aspirate specimens of metastatic oropharyngeal squamous cell carcinoma

Human papilloma virus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) has been recognized to have an excellent response to treatment and has a distinct pathologic staging. For this reason, HPV testing is recommended in cytology specimens of metastatic OPSCC, although the guidelines for testing are not clearly defined. The aim of the current study was to establish a threshold for interpretation of p16 in aspirates from metastatic OPSCC. Cases diagnosed as metastatic SCC by cytology in neck lymph nodes with concurrent p16 on cytology and on paired surgical specimen or an in situ hybridization (ISH) for HPV were included in the study. Stain intensity and percentage positive cells for p16 was compared with p16 on paired surgical pathology specimens and/or ISH RNA for HPV on cytology specimens. Of the 52 cases diagnosed as metastatic SCC on neck aspirates, paired surgical pathology specimens and/or ISH HPV was available in 17 cases. A p16 expression in ≥10%-15% cells resulted in asensitivity and negative predictive value of 66% and 37%, respectively. However, when even minimalexpression in tumor fragments is considered positive, the negative predictive value increases to 100%. We recommend that even minimal nuclear expression for p16 in viable tumor fragments must be considered as positive in cytology specimens. Expression limited to only background single tumorcells or in a necrotic specimen must be interpreted with caution.

Factors associated with the quality of life for hospitalized patients with HPV-associated oropharyngeal squamous cell carcinoma.

Oropharynx squamous cell cancer (OPSCC) is a type of head and neck squamous cell carcinoma. The raising OPSCC incidence is mainly attributed to human papillomavirus (HPV). HPV-related OPSCC has a relatively good prognosis, the concerns are focused on the improvement of quality-of-life (QOL). We aimed to figure out the factors which may affect the QOL of HPV-related OPSCC patients after treatment. This study included patients with HPV-related OPSCC. The QOL of the patients were analyzed through the administration of European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)-Chinese version, the European Organization for Research and Treatment of Cancer Head and Neck Cancer Module-35 (EORTC QLQ-H&N-35)-Chinese version, and Eating Assessment Tool-10 (EAT-10). Multivariable regression analysis was employed to detect the influence of predictor variables on the QOL of patients. A total of 294 HPV-related OPSCC patients were involved in this research. The results of EORTC QLQ-C30, EORTC QLQ-H&N-35, and EAT-10 demonstrated that the treatment decreased the QOL of HPV-related OPSCC patients. Several different factors including marital status, consumption of tobacco and alcohol, tumor sites, clinical stages, therapeutic strategies, and neck dissection were proved to have influence on QOL of HPV-related OPSCC after treatment. Based on the analyzation of the QOL at baseline and after treatment, we demonstrated several factors which influenced the QOL of HPV-associated OPSCC patients after treatment. These results can make a great contribution to the improvement of the QOL after treatment.

Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer.

PURPOSEPlasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence.METHODS AND MATERIALSA prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance.RESULTSOne hundred fifteen patients were enrolled, and 1,006 blood samples were analyzed. After a median follow-up time of 23 months (range, 6.1-54.7 months), 15 patients (13%) developed disease recurrence. Eighty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 96% to 100%). Twenty-eight patients developed a positive ctHPVDNA during post-treatment surveillance, 15 of whom were diagnosed with biopsy-proven recurrence. Sixteen patients had 2 consecutively positive ctHPVDNA blood tests, 15 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 94% (95% CI, 70% to 99%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 3.9 months (range, 0.37-12.9 months).CONCLUSIONDetection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.

Impact of delayed adjuvant therapy after surgery in p16 positive oropharyngeal cancer: a retrospective analysis.

This study aimed to clarify the impact of delayed adjuvant therapy on the outcome of HPV associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). A total of 157 patients with HPV-OPSCC treated by surgery and adjuvant radiotherapy or chemoradiation therapy were analyzed retrospectively. We divided participants into two groups implementing adjuvant therapy within or after 50 days. Primary endpoints were the rates of locoregional recurrence and distant metastases, overall survival, and disease-specific survival. Adjuvant treatment began within 50 days (average: 38.8 days) in 79 cases compared to 78 cases after 50 days (average: 71.5 days). Five-year overall survival was 85.7% and 87.4% (p=0.588), the rates of local and regional recurrence were 3.8% and 6.4% (p=0.455) and of distant metastases 5.1% and 9% (p=0.369) implementing adjuvant treatment within or later than 50 days, respectively. These results suggest that adjuvant therapy initiated later than seven weeks after primary ablative surgery may still be effective HPV-OPSCC.

Factors influencing patient and health care delays in Oropharyngeal Cancer

BackgroundThe incidence of human papillomavirus (HPV)–associated oropharyngeal squamous cell carcinoma (OPSCC) is increasing. Patients with HPV-associated and HPV-unassociated OPSCC differ in many aspects, which may also impact their diagnostic and management timelines. This study aims at studying the patient, primary health care (PHC) and specialist-care (SC) delays and possible differences between these two patient groups in seeking medical care.MethodsWe reviewed all new patients with OPSCC treated between 2016 and 2018 at our institute, which covers a referral area of 1.6 million people. We collected data on patients’ symptoms and factors influencing why they sought medical care using a patient-reported questionnaire and hospital records. We compared delays based on patient and tumor characteristics.ResultsIn our study population of 83 patients, the median patient delay was 30 days (range, 0–366), with a median PHC delay of 15 days (range, 0 days–2.5 years), and a median SC delay of 54 days (range, 12–231). The SC delay was further divided into diagnostic hospital delay and treatment delay, each with a median length of 16 days (range, 0–237) and 29 days (range, 0–73), respectively. Furthermore, we found that p16 status did not associate with delays. A longer patient delay associated with specific tumor factors, such as a larger primary tumor and a lower UICC 7th edition stage. Patients that had multiple visits or did not have a follow-up visit scheduled at the initial appointment had longer PHC delays. Treatment delay was significantly longer for patients scheduled for (chemo-)radiotherapy than for those undergoing surgery with or without (chemo-)radiotherapy.ConclusionsAlthough delays remained short for the majority of OPSCC patients, long delays require further evaluation and improvement of management. Awareness of presenting symptoms among cancer risk patients and prompt referral practice or a follow-up visit at PHC represent key factors to shortening these delays. Ultimately, the causes for delays in SC appear multifactorial and require institutional quality control.