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Cancer May 2021Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct...
BACKGROUND
Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification.
METHODS
Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema.
RESULTS
Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+.
CONCLUSION
HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis.
LAY SUMMARY
The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy.
Topics: Carcinoma; Humans; Neoplasm Staging; Oropharyngeal Neoplasms; Papillomavirus Infections; Prognosis
PubMed: 33595897
DOI: 10.1002/cncr.33414 -
Cancer Journal (Sudbury, Mass.)The global incidence of human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has surged in recent decades, with HPV+ HNSCC accounting for... (Review)
Review
The global incidence of human papillomavirus-positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has surged in recent decades, with HPV+ HNSCC accounting for >70% of oropharynx cancers in the United States. Its incidence in men has surpassed that of HPV+ cervical cancer in women, and reliable assays are needed for early detection and to monitor response to therapy. Human papillomavirus-positive OPSCC has a more favorable response to therapy and prognosis than HPV-negative (HPV-) HNSCC, motivating regimens to deintensify curative surgery or chemoradiotherapy protocols. A barrier to deintensifying and personalizing therapy is lack of reliable predictive biomarkers. Furthermore, HPV- HNSCC survival rates are static without reliable surveillance biomarkers available. The emergence of circulating plasma-based biomarkers reflecting the tumor-immune microenvironment heralds a new era in HNSCC diagnosis and therapy. We review evidence on tumor-derived extracellular vesicles (exosomes) as biomarkers for diagnosis, prognostication, and treatment in HPV+ and HPV- HNSCC.
Topics: Male; Female; Humans; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Human Papillomavirus Viruses; Carcinoma, Squamous Cell; Papillomavirus Infections; Exosomes; Oropharyngeal Neoplasms; Biomarkers; Liquid Biopsy; Tumor Microenvironment
PubMed: 37471614
DOI: 10.1097/PPO.0000000000000671 -
Journal of Experimental & Clinical... Sep 2022Immune checkpoint inhibitors (ICI) are approved for treatment of recurrent or metastatic oropharyngeal head and neck squamous cell carcinoma in the first- and...
The immune microenvironment of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma: a multiparametric quantitative and spatial analysis unveils a rationale to target treatment-naïve tumors with immune checkpoint inhibitors.
BACKGROUND
Immune checkpoint inhibitors (ICI) are approved for treatment of recurrent or metastatic oropharyngeal head and neck squamous cell carcinoma in the first- and second-line settings. However, only 15-20% of patients benefit from this treatment, a feature increasingly ascribed to the peculiar characteristics of the tumor immune microenvironment (TIME).
METHODS
Immune-related gene expression profiling (GEP) and multiplex immunofluorescence (mIF) including spatial proximity analysis, were used to characterize the TIME of 39 treatment-naïve oropharyngeal squamous cell carcinomas (OPSCC) and the corresponding lymph node metastases. GEP and mIF results were correlated with disease-free survival (DFS). HPV-positive tumors disclosed a stronger activation of several immune signalling pathways, as well as a higher expression of genes related to total tumor-infiltrating lymphocytes, CD8 T cells, cytotoxic cells and exhausted CD8 cells, than HPV-negative patients. Accordingly, mIF revealed that HPV-positive lesions were heavily infiltrated as compared to HPV-negative counterparts, with a higher density of T cells and checkpoint molecules. CD8+ T cells appeared in closer proximity to tumor cells, CD163+ macrophages and FoxP3+ cells in HPV-positive primary tumors, and related metastases. In HPV-positive lesions, PD-L1 expression was increased as compared to HPV-negative samples, and PD-L1+ tumor cells and macrophages were closer to PD-1+ cytotoxic T lymphocytes. Considering the whole cohort, a positive correlation was observed between DFS and higher levels of activating immune signatures and T cell responses, higher density of PD-1+ T cells and their closer proximity to tumor cells or PD-L1+ macrophages. HPV-positive patients with higher infiltration of T cells and macrophages had a longer DFS, while CD163+ macrophages had a negative role in prognosis of HPV-negative patients.
CONCLUSIONS
Our results suggest that checkpoint expression may reflect an ongoing antitumor immune response. Thus, these observations provide the rationale for the incorporation of ICI in the loco-regional therapy strategies for patients with heavily infiltrated treatment-naïve OPSCC, and for the combination of ICI with tumor-specific T cell response inducers or TAM modulators for the "cold" OPSCC counterparts.
Topics: B7-H1 Antigen; Carcinoma, Squamous Cell; Forkhead Transcription Factors; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Oropharyngeal Neoplasms; Papillomavirus Infections; Programmed Cell Death 1 Receptor; Spatial Analysis; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment
PubMed: 36123711
DOI: 10.1186/s13046-022-02481-4 -
Radiotherapy and Oncology : Journal of... Jan 2020The aim was to evaluate in oropharyngeal carcinoma the: (1) incidence and predictors of retropharyngeal (RP) lymph node (LN) involvement, (2) pattern of...
INTRODUCTION
The aim was to evaluate in oropharyngeal carcinoma the: (1) incidence and predictors of retropharyngeal (RP) lymph node (LN) involvement, (2) pattern of ipsilateral/bilateral/contralateral-only RP LNs (3) location of RP LNs in relation to contouring guidelines.
METHODS
Single centre retrospective analysis of 402 patients with oropharyngeal carcinoma treated non-surgically between 2010 and 2017. All patients had a baseline FDG PET-CT and contrast-enhanced MRI and/or CT. All cases with reported abnormal RP LNs underwent radiology review.
RESULTS
Abnormal RP LNs were identified in 40/402 (10%) of patients. On multivariate analysis, RP LN involvement was associated with posterior pharyngeal wall/soft palate primaries (OR 10.13 (95% CI 2.29-19.08), p = 0.002) and contralateral cervical LN involvement (OR 2.26 (95% CI 1.05-4.86), p = 0.036). T stage, largest LN size, levels of ipsilateral LN level involvement, HPV and smoking status did not predict risk. 5/402 (1.2%) patients had bilateral RP involvement. 3/402 patients (0.7%) had contralateral-only RP LNs. All patients with contralateral RP LNs had contralateral neck nodes or primary cancers extending across midline. In 5/40 (12.5%) cases with involved RP LNs, the RP LNs were superior to hard palate/upper edge of body of C1 vertebra.
CONCLUSIONS
RP LNs were identified in 10% of oropharyngeal carcinoma patients, and were associated with contralateral neck disease and/or posterior pharyngeal wall/soft palate primary. Contralateral RP LN involvement was rare and associated with contralateral neck disease and/or primary crossing midline, suggesting potential for omission from target volumes for selected patients. Involvement of RP LNs close to the skull base highlights the need for generous elective outlining.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Incidence; Lymph Nodes; Lymphatic Metastasis; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Staging; Oropharyngeal Neoplasms; Positron Emission Tomography Computed Tomography; Retrospective Studies; Young Adult
PubMed: 31431388
DOI: 10.1016/j.radonc.2019.07.021 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Sep 2023To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor. A retrospective analysis was performed on 468 pathologically...
To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor. A retrospective analysis was performed on 468 pathologically confirmed oropharyngeal cancer as the primary tumor patients with p16 status, excluded distant metastasis, and admitted to the Chinese Academy of Medical Sciences from January 2010 to December 2020. The clinical features and prognosis of the secondary primary tumor were analyzed. Among 468 patients with oropharyngeal cancer treated at initial diagnosed, 222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6%(42/66) were synchronous and 36.4%(24/66) were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2%(=0.001); The second primary cancer accounted for 11.2%(12/107) of the deaths in the whole group, among them, the heterochronous second primary accounted for 75.0%(9/12). There were 246 patients with p16 positive, with a median follow-up time of 52.4 months, 20 patients developed second primary cancer(8.1%). Among them, 65.0%(13/20) were synchronous and 35.0%(7/20) were heterochronous. Esophagus was the most commonly involved site. The 4-year OS of p16-positive with synchronous, heterochronous and non-second primary cancer group were 51.9%, 80.7% and 83.3%. Secondary primary cancer accounted for 3.8%(2/52) of all deaths in p16 positvie group. The incidence of second primary cancer of p16 positive and negative oropharyngeal carcinoma were different. The esophagus was the most commonly involved site regardless of p16 status. Regardless of p16 status, the survival of patients with synchronous second primary cancer was worse than those without second primary cancer. For p16-negative oropharyngeal carcinoma, the prognosis was better in patients with heterogeneous second primary cancer, the second primary cancer is one of the main causes of death.
Topics: Humans; Carcinoma; Oropharyngeal Neoplasms; Retrospective Studies; Neoplasms, Second Primary
PubMed: 37640995
DOI: 10.13201/j.issn.2096-7993.2023.09.007 -
International Journal of Cancer Apr 2015Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of... (Review)
Review
Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.
Topics: Cancer Vaccines; Clinical Trials as Topic; Combined Modality Therapy; Humans; Oropharyngeal Neoplasms; Papillomavirus Infections; Treatment Outcome
PubMed: 24622970
DOI: 10.1002/ijc.28847 -
Journal of Global Oncology Sep 2018Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence in the United States and in many countries worldwide primarily as a result of increasing rates... (Review)
Review
Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence in the United States and in many countries worldwide primarily as a result of increasing rates of human papillomavirus (HPV) infection. HPV-positive OPSCC represents a distinct disease entity from head and neck squamous cell carcinoma caused by traditional risk factors such as tobacco and alcohol, with different epidemiology, patterns of failure, and expected outcomes. Because patients with HPV-positive OPSCC have a younger median age and superior prognosis compared with their HPV-negative counterparts, they live longer with the morbidity of treatment, which can be severe. Therefore, efforts are under way to de-escalate therapy in favorable-risk patients while maintaining treatment efficacy. Additional work is being undertaken to discover new therapies that may benefit both HPV-positive and HPV-negative patient subsets. Herein, we will review the available data for the evolving treatment paradigms in OPSCC as well as discuss ongoing clinical trials.
Topics: Carcinoma, Squamous Cell; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Humans; Oropharyngeal Neoplasms; Treatment Outcome
PubMed: 30241193
DOI: 10.1200/JGO.2016.006304 -
Folia Medica Cracoviensia Oct 2023Our umbrella review aimed to summarize and revisit the evidence from all of the meta-analyses and systematic reviews regarding the treatments of oropharyngeal squamous... (Review)
Review
INTRODUCTION
Our umbrella review aimed to summarize and revisit the evidence from all of the meta-analyses and systematic reviews regarding the treatments of oropharyngeal squamous cell carcinoma (OPSCC).
MATERIALS AND METHODS
Major medical databases such as PubMed, Scopus, Embase, Web of Science, Google Scholar, Cochrane Library, BIOSIS, and EBSCO were searched. The overall search process was conducted in 3 stages.
RESULTS
Finally, a total of 28 studies met the inclusion criteria and were included in this study. Out of those 28 meta-analyses, a total of 315 primary studies were screened in order to extract the data and perform the statistical analysis. In total, data from 22,619 patients was analyzed.
CONCLUSION
The main objective of the present umbrella review was to summarize and analyze all of the evidence-based data provided by numerous meta-analyses and systematic reviews regarding the treatment of OPSCC. Our study delivers the most up-to-date and evidence-based results regarding the different therapeutic modalities of this malignancy in one concise review, making it the ultimate tool for physicians treating OPSCC.
Topics: Humans; Carcinoma, Squamous Cell; Oropharyngeal Neoplasms; Systematic Reviews as Topic; Meta-Analysis as Topic
PubMed: 38310532
DOI: 10.24425/fmc.2023.147217 -
Lin Chuang Er Bi Yan Hou Tou Jing Wai... Oct 2022In recent years, the incidence of oropharyngeal carcinoma (OPC) is increasing, while the better prognosis of patients with Human papillomavirus (HPV) positive...
In recent years, the incidence of oropharyngeal carcinoma (OPC) is increasing, while the better prognosis of patients with Human papillomavirus (HPV) positive oropharyngeal carcinoma has been confirmed in a number of studies. There are a variety of detection methods for HPV-associated oropharyngeal carcinoma. Including P16 immunohistochemistry, Polymerase Chain Reaction (PCR) or In situ hybridization (ISH) detection of HPV DNA, HPV RNA, Revers transcriptase Polymerase Chain Reaction (RT PCR) was used to detect HPV RNA. The better prognosis of patients with HPV-positive oropharyngeal carcinoma has led to the emergence of a large number of degraded treatment trials. The traditional P16 test has certain limitations in the diagnosis of patients with HPV-positive oropharyngeal carcinoma. It is necessary to combine with other detection methods to accurately screen out patients with HPV-positive oropharyngeal carcinoma and better apply to degraded therapy. In this article, we will briefly introduce the trend of HPV-associated oropharyngeal carcinoma, the detection methods and the new progress of degraded treatment trials.
Topics: Carcinoma, Squamous Cell; Cyclin-Dependent Kinase Inhibitor p16; DNA, Viral; Humans; Oropharyngeal Neoplasms; Papillomaviridae; Papillomavirus Infections; RNA
PubMed: 36217663
DOI: 10.13201/j.issn.2096-7993.2022.10.015 -
BMC Cancer Jan 2021Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway,...
BACKGROUND
Despite reports of a link between human papillomavirus (HPV) infection and mechanistic target of rapamycin (mTOR) signaling activation, the role of the mTOR pathway, especially raptor and rictor, in HPV-related head and neck cancer is still unclear. The aim of the present study was to elucidate the role of the mTOR pathway in HPV-related oropharyngeal squamous cell carcinoma (OPSCC).
METHODS
The present study involved two strategies. The first was to investigate the activity of mTOR and mTOR-related complexes in high-risk HPV-positive (UM-SCC47 and CaSki) and HPV-negative (SCC-4 and SAS) cancer cell lines. The second was to elucidate mTOR complex expression in 80 oropharyngeal cancer tissues and to examine the relationship between mTOR complex expression and survival in patients with OPSCC.
RESULTS
The UM-SCC47 and CaSki cell lines showed high gene and protein expression of raptor. They also exhibited G1/S and G2/M phase cell cycle arrest following 24 h incubation with 6 μM temsirolimus, a rapamycin analog, and temsirolimus administration inhibited their growth. HPV-related OPSCC samples showed high gene and protein expression of raptor and rictor compared with HPV-unrelated OPSCC. In addition, HPV-related OPSCC patients with high raptor and rictor expression tended to have a worse prognosis than those with low or medium expression.
CONCLUSIONS
These results suggest that raptor and rictor have important roles in HPV-related OPSCC and that temsirolimus is a potential therapeutic agent for patients with HPV-related OPSCC. This is the first report to reveal the overexpression of raptor and rictor in HPV-related OPSCC.
Topics: Apoptosis; Biomarkers, Tumor; Carcinoma, Squamous Cell; Cell Cycle; Cell Movement; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Japan; Male; Middle Aged; Oropharyngeal Neoplasms; Papillomaviridae; Papillomavirus Infections; Prognosis; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; Survival Rate; Tumor Cells, Cultured
PubMed: 33482765
DOI: 10.1186/s12885-021-07794-9