HPV-negative Oropharyngeal Carcinoma Research Articles

Predictive potential of dynamic contrast-enhanced MRI and plasma-derived angiogenic factors for response to concurrent chemoradiotherapy in human papillomavirus-negative oropharyngeal cancer.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT). Twenty-five patients with locally advanced HPV-negative oropharyngeal carcinoma were prospectively enrolled in the study. DCE-MRI and blood plasma sampling were conducted before cCRT, after receiving a radiation dose of 20 Gy, and after the completion of cCRT. Perfusion parameters ktrans, kep, Ve, initial area under the curve (iAUC) and plasma expression levels of angiogenic factors (vascular endothelial growth factor [VEGF], connective tissue growth factor [CTGF], platelet-derived growth factor [PDGF]-AB, angiogenin [ANG], endostatin [END] and thrombospondin-1 [THBS1]) were measured at each time-point. Patients were stratified into responders and non-responders based on clinical evaluation. Differences and correlations between measures were used to generate prognostic models for response prediction. Higher perfusion parameter ktrans and higher plasma VEGF levels successfully discriminated responders from non-responders across all measured time-points, whereas higher iAUC and higher plasma PDGF-AB levels were also discriminative at selected time points. Using early intra-treatment measurements of ktrans and VEGF, a predictive model was created with cut-off values of 0.259 min-1 for ktrans and 62.5 pg/mL for plasma VEGF. Early intra-treatment DCE-MRI parameter ktrans and plasma VEGF levels may be valuable early predictors of response to cCRT in HPV-negative oropharyngeal cancer.

Neoadjuvant adebrelimab plus dalpiciclib in HPV-negative locally advanced head and neck squamous cell carcinoma: A phase II clinical trial.

TPS6129 Background: The efficacy and safety of neoadjuvant immunotherapy (NAI) for treating resectable locally advanced head and neck squamous cell carcinoma (LAHNSCC) remain uncertain, and the comprehensive protocol of NAI needs further explored. The tumor suppressor gene CDKN2A plays a pivotal role in cell cycle regulation by modulating cyclin-dependent kinase (CDK) activity. Mutations in CDKN2A lead to continuous activation of CDK4/6, resulting in uncontrolled cell proliferation and tumor growth. Approximately 35.7% of HNSCC patients exhibit CDKN2A mutations, with the incidence rising to 58% among HPV-negative LAHNSCC patients. Studies have shown that combining immunotherapy with a CDK4/6 inhibitor produces a synergistic anti-tumor effect. This study aims to assess the efficacy and safety of combining anti-PD-L1 (adebrelimab) with a CDK4/6 inhibitor (dalpiciclib) as NAI in resectable LAHNSCC patients. Methods: This open-label, single-arm, prospective phase II trial will enroll LAHNSCC patients eligible for surgery. Inclusion criteria include: being 18 to 75 years old at study entry; pathologically confirmed HPV-negative HNSCC (oral, laryngeal, hypopharyngeal, and HPV-negative oropharyngeal carcinoma), determined via p16 immunohistochemistry or HPV DNA tests; with CDKN2A mutation; resectable LAHNSCC, staged III-IVB according to the UICC/AJCC 8th edition TNM system; an ECOG Performance Status score of 0 or 1; no prior relevant anti-tumor treatments; intent for curative treatment; and adequate organ function. Key exclusion criteria are active autoimmune diseases, use of immunosuppressive drugs, or systemic corticosteroids. Eligible patients receive 3 cycles of adebrelimab (1200 mg intravenously every 3 weeks, Day 1, 22 and 43) and 2 cycles of dalpiciclib (150 mg, po, every 4 weeks, day 1-21 and 29-49) before surgery. Dose adjustments are allowed based on toxicity. Surgery will follow 2-4 weeks post-NAI, with subsequent adjuvant radiotherapy or chemoradiotherapy based on risk factors after surgery. The primary endpoints are 1-year disease-free survival (defined as the time from surgical resection to local recurrence) and major pathological response (MPR, defined as ≤10% residual viable tumor cells), with secondary endpoints focusing on safety and predictive biomarkers. Clinical trial information: NCT06199271 .

1676: Unexpected correlation between DWI and treatment response in HPV negative oropharyngeal carcinoma

1676: Unexpected correlation between DWI and treatment response in HPV negative oropharyngeal carcinoma

Analysis of cells of epithelial, connective tissue and immune differentiation in HPV-positive-, HPV-negative oropharyngeal carcinoma and normal oropharyngeal tissue by immunofluorescence multiplex image cytometry: a preliminary report

BackgroundEpithelial, connective tissue and immune cells contribute in various ways to the pathophysiology of HPV positive (HPV+) and HPV negative (HPV-) oropharyngeal squamous cell carcinoma (OPSCC). We aimed to investigate the abundance of these cell lineages and their coexpression patterns in patients with HPV + and HPV- OPSCC.MethodsWe used a 4-channel immunofluorescence-microscopy technique for the simultaneous detection of three direct-conjugated antibodies (pancytokeratin, vimentin and CD45/CD18) and DAPI (4’,6-Diamidin-2-phenylindole) in formalin fixed paraffin-embedded tissue samples (FFPE) of patients with HPV + and HPV- OPSCC, and of control patients. Image acquisition and analysis were performed with TissueFAXS and StrataQuest (TissueGnostics, Vienna, Austria), respectively, in tumor cell clusters/stroma in OPSCC specimens and epithelial layer/lamina propria in control specimens. Cell populations were created based on antibodies’ coexpression patterns. Isotype and positive controls were examined for plausibility.ResultsThe proportion of cells of epithelial differentiation in tumor cell clusters was higher in HPV + OPSCC (55%) than in HPV- OPSCC samples (44%). The proportion of connective tissue cells in tumor cell cluster was lower in HPV + OPSCC patients (18%) than in HPV- OPSCC patients (26%). The proportion of immune cells in tumor cell clusters was higher in HPV + OPSCC patients (25%) than in HPV- OPSCC patients (18%). The percentage of anaplastic, potentially de-differentiated cells, was 2% in control patients, and it was higher in HPV- OPSCC (21%) than in HPV + OPSCC samples (6%).ConclusionsThis study provided the first quantitative data for the abundance of cells of epithelial, connective tissue and immune differentiation, in patients with OPSCC and control patients. The abundance of these different crucial cell populations was consistently originating from the same tissue sample. De-differentiation of tumor cells was higher in HPV- OPSCC than in HPV + OPSCC. In tumor cells clusters, the antitumoral host immune response was higher in HPV + OPSCC than in HPV- OPSCC, whereas the fibroblast response was higher in HPV- OPSCC than in HPV + OPSCC. This study contributed to the understanding of histopathologic differences between HPV + OPSCC and HPV- OPSCC patients.

Differences in Survival Outcomes among Racial Minorities with Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> While disparities in patient outcomes for head and neck squamous cell carcinoma (HNSCC) have been documented, the specific drivers of inferior outcomes among racial/ethnic (R/E) minorities remain poorly understood. Our objective was to identify the defining prognostic factors for survival outcomes among R/E minority HNSCC patients in the United States. <h3>Materials/Methods</h3> We identified HNSCC patients of all the major mucosal head and neck subsites treated with surgery, radiation, chemotherapy or a combination of modalities between 2004-2016 using the National Cancer Database (NCDB). Patient outcomes were stratified by R/E groups including White, Black, Hispanic, Native American/Other, and Asian. Covariates analyzed include ethnicity, race, insurance type, income, age, sex, stage, cancer site, co-morbidity status, treatment modality, and HPV status. Kaplan Meier analysis and log-rank test were used to estimate overall survival (OS) outcomes between strata. Cox proportional hazard regression models were used to assess the association between co-variates and risk of death. <h3>Results</h3> 311,032 HNSCC patients were treated between 2004-2016, of which 269,166 (86.5%) were White, 32,871 (10.5%) were Black, 6,285 (2%) were Asian, and 2,710 (0.8%) were Native American. By ethnicity, 12,379 (4%) were Hispanic. Compared to White HNSCC patients, Black patients were more likely to have Medicaid insurance (22% vs 8%, p<0.001), lower income (<30,000, 42% vs 13%, p<0.0001), Stage IV disease (39% vs 29%, p<0.0001), less likely to be treated with surgery (26% vs 15%, p<0.0001), and had a higher proportion of HPV negative oropharyngeal carcinoma (18% vs 21%, p<0.0001). Among patients treated with surgery, Black patients had a longer time to initiation of adjuvant RT compared to White patients (mean 58 vs 53 days, p<0.0001). Among all patients, 5-year OS for White, Black, Hispanic, Native American/Other, and Asian was 50.8%, 38.5%, 51.5%, 51.2%, and 57.2%, respectively (log rank, p<0.0001). Black patients had an inferior 5-year OS for the majority of HNSCC subsites, including the oral cavity, hypopharynx, larynx, nasal cavity, and oropharynx (all log-rank p<0.0001). Even among favorable HPV positive oropharynx cancer patients, Black patients had a significantly inferior OS compared to White patients (log-rank, p<0.0001). On multivariable analysis, Black patients had a higher mortality (HR:1.09, 95% CI, 1.02-1.155, P=0.003) after adjusting for income, insurance type, co-morbidity status, treatment modality, clinical stage, and HPV status. <h3>Conclusion</h3> This large cohort of HNSCC patients demonstrates that Black race is independently associated with worse OS. Efforts should be made to reduce clinical and non-clinical factors in racial minorities to further narrow the survival gaps in HNSCC. Further work is needed to better understand the biological basis for the worse outcomes seen after accounting for social determinants of health.

Use of positron emission tomography/ computed tomography in the initial staging of head and neck squamous cell carcinoma: Accuracy in evaluation of the primary site of the tumor, metastases to cervical lymph nodes, and distant metastases.

Our study aimed to evaluate the use of positron emission tomography/computed tomography (PET/CT) in the initial staging of head and neck squamous cell carcinoma (HNSCC), including assessment of local and distant spread of the disease. We also aimed to compare the accuracy of PET/CT in the evaluation of human papillomavirus (HPV) positive and HPV-negative oropharyngeal carcinoma. This single-center, prospective study was conducted between August 2016 and September 2021. A total of 198 patients with HNSCC who underwent PET/CT within the primary staging were included. We compared PET/CT results with histological findings. We calculated the accuracy, sensitivity, specificity, and positive and negative predictive values to assess the primary tumor, cervical lymph nodes, and distant metastases. PET/CT showed a high success rate (32%) in revealing the primary site of carcinoma of unknown primary (CUP). The accuracy of PET/CT in displaying the primary tumor, cervical lymph node metastases, and distant metastases was 89.4%, 85.4%, and 87.4%, respectively. The method provided high sensitivity but lower specificity in all three areas. Specifically, PET/CT showed low specificity in the assessment of small tumors (75%), metastatic involvement of cervical lymph nodes (69.6%), and HPV-positive oropharyngeal carcinoma (55.6%). The high accuracy of PET/CT to identify distant metastases and whole-body staging in one diagnostic step accelerated primary staging and resulted in earlier commencement of therapy. However, it also led to an overestimation of clinical findings and thus to extensive surgical treatment, especially in patients with small tumors, metastatic involvement of cervical lymph nodes, and HPV- positive oropharyngeal carcinoma. PET/CT is also useful for CUP diagnostics.

Patterns of disease events and causes of death in patients with HPV-positive versus HPV-negative oropharyngeal carcinoma

Background and purposeThere have been no studies to date of patterns of events after oropharyngeal squamous cell carcinoma (OPC) treatment comprising disease progression immediately after treatment or after a disease-free interval (DFI), and causes of death, according to HPV status. Materials and methodsPatients with a T1-4, N0-3, M0 OPC who completed treatment in a curative intent at our center between 2011 and 2020 were analyzed. A DFI was defined as the absence of the disease confirmed by both physical and radiological evaluation. ResultsWe analyzed 888 patients, of who 451 were p16-positive and 437 were p16-negative. The 5-year survival rates were 82.4% vs. 44%, respectively (p < 0.0001, HR 0.24). The rates of disease progression at the end of the treatment without a DFI were 7.8% vs. 21.1% in the p16-positive vs. the p16-negative patients (p < 0.0001, OR 0.38). The 5-year competing risks of disease recurrence after a DFI were 5.6% vs. 20.5%, respectively (p < 0.0001, HR 0.26). Patients who were p16-positive had a lower risk of death from OPC disease (p < 0.0001, HR 0.23). The 5-year competing risks of a second primary cancer during follow-up were 16.1% vs. 49.9% (p = 0.0002) in the p16-positive vs. the p16- negative patients. Patients who were p16-positive had a lower risk of death from intercurrent causes (p < 0.0001, HR 0.17). ConclusionClinical trials and medical interventions dedicated to each category of events and causes of death are needed to improve survival in HPV-positive and HPV-negative OPC patients.

Clinical Validity of a Prognostic Gene Expression Cluster-Based Model in Human Papillomavirus-Positive Oropharyngeal Carcinoma.

PURPOSEUnder common therapeutic regimens, the prognosis of human papillomavirus (HPV)–positive squamous oropharyngeal carcinomas (OPCs) is more favorable than HPV-negative OPCs. However, the prognosis of some tumors is dismal, and validated prognostic factors are missing in clinical practice. The present work aimed to validate the prognostic significance of our published three-cluster model and to compare its prognostic value with those of the 8th edition of the tumor-node-metastasis staging system (TNM8) and published signatures and clustering models.METHODSPatients with HPV DNA-positive OPCs with locoregionally advanced nonmetastatic disease treated with curative intent (BD2Decide observational study, NCT02832102) were considered as validation cohort. Patients were treated in seven European centers, with expertise in the multidisciplinary management of patients with head and neck cancer. The median follow-up was 46.2 months (95% CI, 41.2 to 50), and data collection was concluded in September 2019. The primary end point of this study was overall survival (OS). Three-clustering models and seven prognostic signatures were compared with our three-cluster model.RESULTSThe study population consisted of 235 patients. The three-cluster model confirmed its prognostic value. Two-year OS in each cluster was 100% in the low-risk cluster, 96.6% in the intermediate-risk cluster, and 86.3% in the high-risk cluster (P = .00074). For the high-risk cluster, we observed an area under the curve = 0.832 for 2-year OS, significantly outperforming TNM 8th edition (area under the curve = 0.596), and functional and biological differences were identified for each cluster.CONCLUSIONThe rigorous clinical selection of the cases included in this study confirmed the robustness of our three-cluster model in HPV-positive OPCs. The prognostic value was found to be independent and superior compared with TNM8. The next step includes the translation of the three-cluster model in clinical practice. This could open the way to future exploration of already available therapies in HPV-positive OPCs tailoring de-escalation or intensification according to the three-cluster model.

Prognostic value of clinical and radiologic extranodal extension and their role in the 8th edition TNM cN classification for HPV-negative oropharyngeal carcinoma.

We evaluate the performance between the TNM-8 versus TNM-7 cN-classification and explore the relative prognostic contribution of radiologic extranodal extension (rENE) for HPV-negative oropharyngeal cancer (HPV-OPC). All HPV- OPC treated with IMRT between 2005 and 2016 were included. cENE was defined as unambiguous "fixation" of a neck mass or "skin involvement" on clinical examination. rENE was recorded by re-reviewing pre-treatment CT/MR. Disease-free survival (DFS) stratified by cENE or rENE were compared. Multivariable analyses (MVA) calculated the adjusted hazard ratio (aHR) for the separate cENE and rENE attributes and their combination. A refined cN-category incorporating both cENE and rENE parameters was proposed. The performance of the revision was compared to TNM-8 and TNM-7. Of 361 HPV- OPC, 97 were cN0 and 264 were cN+ with 48 cENE+ and 72 rENE+ respectively. Median follow-up was 5.4years. The 3-year DFS was lower in cENE+ vs cENE-negative (cENE-) (23% vs 45%; aHR=1.68, p=0.008) and rENE+ vs rENE-negative (rENE-) patients (29% vs 45%; aHR=1.44, p=0.037). The cENE+/rENE+ subset had the worse DFS vs cENE-/rENE+ or cENE-/rENE- (24%/37%/46%, p=0.005). We propose a refined cN-category wherein any cENE-/rENE+ case is reclassified one N-stratum higher while any cENE+ case remains cN3b. The stage schema with the refined N-categorization outperformed TNM-8, and both outperformed TNM-7. cENE and rENE are both prognostic but the cENE+/rENE+ subset has the worst outcome. The TNM-8 cN-categories improves outcome prediction compared to the TNM-7. Incorporation of rENE into TNM-8 cN-categories may further augment performance.

Pre‐ and Post‐Radiotherapy Radiologic Nodal Features and Oropharyngeal Cancer Outcomes

To assess the prognostic value of pre-/post-radiotherapy (pre-/post-RT) radiologic lymph node (LN) features in human papillomavirus (HPV)-positive and HPV-negative oropharyngeal carcinoma (OPC) patients treated with definitive (chemo-)RT. Clinical node-positive OPCs treated from 2011 to 2015 were reviewed. Nodal features were reviewed by a radiologist on pre-/post-RT computed tomography (CTs). Univariable analysis calculated hazard ratio (HR) for regional failure (RF), distant metastasis (DM), and deaths. Multivariable analysis estimated adjusted HR (aHR) of significant nodal features identified in univariable analysis adjusting for confounders. Pre-RT CT was undertaken in 344 HPV-positive and 94 HPV-negative OPC patients, of whom 242 (70%) HPV-positive and 67 (71%) HPV-negative also had a post-RT CT. Median follow-up was 4.9 years. Pre-RT LN calcification (pre-RT_LN-cal) increased the risk of RF in HPV-negative (aHR: 5.3, P = .007) but not HPV-positive patients (P = .110). Pre-RT radiologic extranodal extension (pre-RT_rENE+) increased the risk of DM and death in both HPV-negative (DM: aHR 6.6, P < .001; death: aHR 2.1, both P = .019) and HPV-positive patients (DM: aHR 4.9; death: aHR 3.0, both P < .001). Increased risk of RF occured with < 20% post-RT LN size reduction in both HPV-negative (HR 6.0, P = .002) and HPV-positive cases (HR 3.0, P = .049). Post-RT_LN-cal did not affect RF, DM, or death regardless of tumor HPV status (all P > .05). Pre-RT_LN-cal is associated with higher RF risk in HPV-negative but not in HPV-positive patients. Pre-RT_rENE increases risk of DM and death regardless of tumor HPV status. Minimal post-RT LN size reduction (< 20%) increases risk of RF in both diseases. Post-RT_LN-cal + has no apparent influence on outcomes in either disease. 4 (a single institution case-control series) Laryngoscope, 131:E1162-E1171, 2021.

Sex-based differences in outcomes of patients with HPV-positive versus HPV-negative oropharyngeal carcinoma: a population-based study

ABSTRACT Objectives Prior studies have suggested that female sex is predictive of poor outcomes among patients with oropharyngeal carcinoma. The current study aims at elucidating whether this observation applies to both HPV-positive and HPV-negative subsets of the disease. Methods Surveillance, Epidemiology and End Results (SEER) - HPV specialized database was accessed. Cases with oropharyngeal squamous cell carcinoma and known HPV status were reviewed. Multivariable logistic regression analysis was used to evaluate factors predicting HPV positive status. The relationship between sex and overall and cancer-specific survival was further evaluated through multivariable Cox regression analysis. Results Female sex was associated with less probability of HPV positive status (OR: 0.55; 95% CI: 0.50-0.61; P<0.01). Using multivariable Cox regression analysis and among patients with HPV-negative disease, female patients have worse overall survival (HR: 1.24; 95% CI: 1.12-1.39; P<0.01) and cancer-specific survival (HR: 1.27; 95% CI: 1.08-1.50; P<0.01); while among patients with HPV-positive disease, there was no difference between males and females with regards to overall survival (HR: 1.05; 95% CI: 0.91-1.21; P= 0.45) or cancer-specific survival (HR: 1.17; 95% CI: 0.95-1.45; P= 0.12). Conclusions Among patients with HPV-positive oropharyngeal carcinoma, there is no difference in survival outcomes between women and men; while among patients with HPV-negative oropharyngeal carcinoma, women have worse survival outcomes compared to men.

The role of surgery and salvage surgery in the era of HPV-associated oropharyngeal carcinomas

The incidence of human papillomavirus (HPV)-positive oropharyngeal carcinomas is increasing worldwide. Due to amarkedly different response to treatment compared to HPV-negative oropharyngeal carcinomas, determining the ideal therapeutic approach can be challenging. Particularly in never-smokers, HPV-positive oropharyngeal carcinomas respond well to primary radiation therapy; at the same time recent studies indicate comparable survival after primary surgery. For stageI tumors according to TNM‑8, retrospective analyses show very good oncologic outcomes after surgery alone, and no added benefit of adjuvant radio- or chemotherapy. Results of prospective treatment deintensification trials are expected in the coming years. Minimally invasive transoral surgical approaches for selected oropharyngeal cancers can improve preservation of postoperative function and quality of life. For both HPV-positive and HPV-negative oropharyngeal carcinomas, salvage surgery is the treatment of choice for resectable recurrent locoregional disease and resectable distant metastases.

Prognostic Value of Nodal Involvement in Patients With Oropharyngeal Carcinoma According to the HPV Status

Background and objectiveDifferent studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection. Material and methodsRetrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990–2016 for whom information on HPV status was available. Results14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours. ConclusionsRegional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas.

Valoración de la capacidad pronóstica de la afectación ganglionar de los pacientes con carcinoma de orofaringe en función del estatus HPV

Background and objectiveDifferent studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection. Material and methodsRetrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990-2016 for whom information on HPV status was available. Results14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours. ConclusionsRegional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas.

HPV-negative oropharyngeal carcinoma as a separate prognostkally unfavorable form of cancer, requiring new approaches to treatment (case report)

The study objective is to demonstrate the difficulties associated with treatment of HPV-negative oropharyngeal cancer. Material and methods . A 52-year-old male patient visited a doctor in P.A. Herzen Moscow Oncology Research Institute in January 2017 with complaints of pain in the right part of the oropharynx irradiating to the right ear and difficulties with swallowing food and liquids. The patient was diagnosed with stage IVA oropharyngeal cancer (cT3N2bM0). Results. The patient underwent a course chemoradiotherapy (CRT); as a result, the tumor in the area of the right tonsil became indeterminable 2 weeks later. Three months after completing the course of CRT, the patient underwent modified radical right-sided lymph node dissection. Histological examination revealed metastases from poorly differentiated squamous cell carcinoma in 3 lymph nodes (LNs) with an invasion into adjacent adipose tissue. In October 2017, we received a histological confirmation of ongoing tumor growth in the area of the tongue root and LN metastases in the left side of the neck (yrpT4aN2cM0). We performed resection of the mandible, tongue, soft tissues of the oral floor, and right side of the oropharynx with installation of an oropharyngeal stoma, extended radical left-sided neck lym-phadenectomy with excision of soft tissues (levels I—V), defect repair using an autologous pectoral musculocutaneous flap, and tracheostomy. In March 2018, the patient was found to have continuing tumor growth in the area of the epiglottis and floor of the oral cavity. The patient underwent laryngectomy with oropharyngeal resection and end tracheostomy. In July 2018, we again received a histological confirmation of tumor growth in soft tissues of the anterior neck. We performed resection of the tumor and soft tissues with subsequent plastic reconstruction of the defect. In October 2018, the patient presented with multiple metastases in both lungs. He received a course of immune therapy. Positron emission tomography revealed neoplastic foci with pathological metabolic activity in the area of the alveolar process of the mandible (left side), soft tissues of the neck, lungs, left-sided axillary LNs, and mediastinal LNs. It was decided to continue immune therapy. Conclusion. HPV-negative oropharyngeal cancer requires an optimized treatment algorithm and, possibly, more aggressive therapeutic measures, such as increased radiation doses. Both overall management strategy and recommended standard scheme of CRT should be revised; the role of surgical and chemotherapeutic components of treatment should also be reassessed. We believe that surgical intervention should be considered regardless of the effect of radiation therapy, while the duration of follow-up after CRT should be reduced.

The IL-1/IL-1R axis induces greater fibroblast-derived chemokine release in human papillomavirus-negative compared to positive oropharyngeal cancer.

Human papillomavirus (HPV) is now recognised as a major aetiological agent in the pathogenesis of oropharyngeal carcinoma (OPC). HPV‐positive tumours are associated with better outcomes compared to HPV‐negative tumours, possibly due to differences in their aetiology and/or the tumour microenvironment. Increased numbers of tumour‐associated leukocytes have been observed in many cancers including OPC, with variable influence on prognosis depending on the leukocyte subpopulation investigated. Whether HPV status influences leukocyte recruitment to OPC remains unknown. This in‐vitro study examined differences in the chemoattractant capacity of HPV‐positive and HPV‐negative OPC cell lines. Gene and protein expression analysis demonstrated that whilst both monocultures of HPV‐positive and HPV‐negative cell lines, along with normal tonsillar fibroblasts (NTF), expressed low chemokine levels, NTF cultured with conditioned medium from HPV‐negative OPC cells expressed significantly higher levels of all chemokines tested compared to NTF incubated with the medium from HPV‐positive OPC cell lines. HPV‐negative OPC lines expressed IL‐1β mRNA whereas HPV‐positive cells did not, and NTF constitutively expressed IL‐1R1. Pre‐treatment with the IL‐R antagonist, anakinra or siRNA to IL‐1R1 significantly reduced chemokine secretion from NTF stimulated with conditioned medium from HPV‐negative tumour cells or recombinant IL‐1β (p < 0.05). These data suggest that secretion of chemokines is driven by the interaction between HPV‐negative OPC cells and stromal fibroblasts through an IL‐1/IL‐1R‐mediated mechanism that is less prominent within the HPV‐positive tumour microenvironment. These observations may explain differences in leukocyte sub‐populations recruited to HPV‐positive versus negative OPC and indicate that HPV status is a key determinant in controlling the inflammatory tumour microenvironment.

An NCDB Analysis Investigating Outcomes in HPV Negative Oropharyngeal Carcinoma - An Attempt to Bridge the Gap Due to Lack of Accrual in RTOG 1221

Transoral robotic surgery (TORS) represents a considerable technological advance in surgical technique in head and neck squamous cell carcinoma (HNSCC). RTOG 1221 was a proposed study of intensified local therapy for T1-2, N0-2b, HPV negative HNSCC of the oropharynx with TORS; this study closed after 15 months due to zero patient accrual1. In place of the prospective trial, the National Cancer Database (NCDB) can be utilized to follow survival outcomes in this patient population. Retrospective review was performed of the National Cancer Data Base 2004 – 2015 data for T1-2, N0-2b, oropharynx HNSCC. Patients were included for analysis if they were treated according to the regimens of RTOG1221 with TORS +/- adjuvant therapy, or chemoRT alone. Adjuvant treated must have been started within 3 months of TORS. Kaplan Meier overall survival (OS) estimates and log rank analysis was performed. A total of 1698 T1-2, N0-2b patients with HPV negative oropharyngeal HNSCC were analyzed. Median survival was not reached in either cohort. 126 patients had TORS +/- adjuvant therapy, with a median follow-up of 36.55 months (SD 17.53 months). This cohort had a 2-year survival estimate of 88.2% with standard error of 0.03. 1572 patients had chemoRT alone, with a median follow-up of 33.15 months (SD 18.33 months). This cohort had a 2-year survival estimate of 84.1% with standard error of 0.009. Log rank analysis of these groups demonstrates no statistically significant difference in OS, with a chi-square of 1.754 and a p-value of 0.185. OS outcomes of HPV negative patients treated with TORS +/- adjuvant therapy were not statistically significantly different than those treated with concurrent chemoRT alone. This NCDB data may offer insight into the role of TORS in treatment escalation for HPV negative oropharyngeal HNSCC, especially as this data matures over the next several years.

HPV-negative, but not HPV-positive, oropharyngeal carcinomas induce fibroblasts to support tumour invasion through micro-environmental release of HGF and IL-6.

Human papillomavirus (HPV) infection is causally related to a subset of oropharyngeal carcinomas (OPC) and is linked to a more favourable prognosis compared to HPV-negative OPC. The mechanisms underlying this effect on prognosis are not fully understood, but interactions with the tumour microenvironment may be pivotal. Here, we investigated the role of the tumour microenvironment in HPV-positive compared to HPV-negative cancer using 2D and 3D modelling of OPC interactions with stromal fibroblasts. HPV-negative, but not HPV-positive, OPC-derived cell lines induced a rapid fibroblast secretory response that supported 2D cancer cell migration and invasion in vitro. Array profiling of this HPV-negative induced fibroblast secretome identified hepatocyte growth factor (HGF) as the principal secreted factor that promoted cancer cell migration. The interaction between HPV-negative cell lines and fibroblasts in 2D was prevented using c-Met (HGF receptor) inhibitors, which further restricted both HPV-negative and positive cell invasion in 3D co-culture models. Furthermore, we discovered a synergistic relationship between HGF and IL-6 in the support of migration that relates JAK activation to HGF responsiveness in HPV-negative lines. In summary, our data show significant differences in the interactions between HPV-positive and HPV-negative OPC cells and stromal fibroblasts. In addition, we, provide in vitro evidence to support the clinical application of c-MET inhibitors in the control of early HPV-negative OPC.

Morphologic and topographic radiologic features of human papillomavirus-related and -unrelated oropharyngeal carcinoma.

The purpose of this study was to compare the clinicoradiologic characteristics of human papillomavirus (HPV)-related (HPV-positive) and HPV-unrelated (HPV-negative) oropharyngeal carcinoma (OPC). Primary tumor and lymph node features of HPV-positive and HPV-negative OPCs from 2008 to 2013 were compared on pretreatment CT/MRI. Intrarater/interrater concordance was assessed. Multivariable analyses identified factors associated with HPV-positivity to be used in nomogram construction. Compared to HPV-negative (n = 194), HPV-positive (n = 488) tumors were more exophytic (73% vs 63%; p = .02) with well-defined border (58% vs 47%; p = .033) and smaller axial dimensions; lymph node involvement predominated (89% vs 69%; p < .001) with cystic appearance (45% vs 32%; p = .009) but similar topography. Intrarater/interrater concordance varied (fair to excellent). Nomograms combining clinical (age, sex, smoking pack-years, subsite, T/N classification) and/or radiologic (nonnecrotic tumor and cystic lymph node) features were used to weigh the likelihood of HPV-driven tumors (area under the curve [AUC] = 0.84). HPV-positive OPC has different radiologic tumor (exophytic/well-defined border/smaller axial dimension) and lymph node (cystic) features but similar lymph node topography.

The Growing Epidemic of HPV-Positive Oropharyngeal Carcinoma: A Clinical Review for Primary Care Providers.

While the rate of head and neck cancer has decreased in recent decades, the prevalence of oropharynx cancer has dramatically increased due to human papillomavirus (HPV)-related oropharyngeal cancer. Three of 4 newly diagnosed oropharyngeal carcinomas are HPV-positive, and by 2020 it is projected that the prevalence of this disease will overtake that of HPV-related cervical cancer. Recognized in recent years as a malignant entity distinct from HPV-negative oropharyngeal carcinoma, HPV-positive oropharyngeal cancer is associated with younger age at diagnosis, oral sexual behavior as a primary risk factor, nonspecific presentation, and improved treatment response compared with HPV-negative disease. Early recognition and referral for definitive treatment are paramount in decreasing morbidity and mortality, as well as improving the quality of life of these patients. Primary care providers are in an ideal position to improve patient outcomes through early recognition and referral, as well as coordination of comprehensive care of patients with this potentially devastating disease. Awareness of risk factors, a high index of suspicion, counseling patients and parents on the importance of vaccination against HPV, and coordinated care between primary care providers and specialists are vital to achieving improved outcomes for patients with this increasingly prevalent cancer.