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Nature Reviews. Clinical Oncology May 2022Human papillomavirus (HPV)-positive (HPV) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income... (Review)
Review
Human papillomavirus (HPV)-positive (HPV) oropharyngeal squamous cell carcinoma (OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the UICC/AJCC staging system separates HPV OPSCC from its HPV-negative (HPV) counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment de-intensification as a means to improve quality of life while maintaining acceptable survival outcomes. In addition, owing to the distinct biology of HPV OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage owing to a lack of symptoms in the early stages; therefore, a need exists to identify and validate possible diagnostic biomarkers to aid in earlier detection. In this Review, we provide a summary of the epidemiology, molecular biology and clinical management of HPV OPSCC in an effort to highlight important advances in the field. Ultimately, a need exists for improved understanding of the molecular basis and clinical course of this disease to guide efforts towards early detection and precision care, and to improve patient outcomes.
Topics: Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Molecular Epidemiology; Oropharyngeal Neoplasms; Papillomavirus Infections; Quality of Life; Squamous Cell Carcinoma of Head and Neck
PubMed: 35105976
DOI: 10.1038/s41571-022-00603-7 -
Annual Review of Pathology Jan 2023Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries.... (Review)
Review
Human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV-OPSCC) has one of the most rapidly increasing incidences of any cancer in high-income countries. The most recent (8th) edition of the Union for International Cancer Control/American Joint Committee on Cancer staging system separates HPV-OPSCC from its HPV-negative counterpart to account for the improved prognosis seen in the former. Indeed, owing to its improved prognosis and greater prevalence in younger individuals, numerous ongoing trials are examining the potential for treatment deintensification as a means to improve quality of life while maintaining acceptable survival outcomes. Owing to the distinct biology of HPV-OPSCCs, targeted therapies and immunotherapies have become an area of particular interest. Importantly, OPSCC is often detected at an advanced stage, highlighting the need for diagnostic biomarkers to aid in earlier detection. In this review, we highlight important advances in the epidemiology, pathology, diagnosis, and clinical management of HPV-OPSCC and underscore the need for a progressive understanding of the molecular basis of this disease toward early detection and precision care.
Topics: Humans; Papillomavirus Infections; Quality of Life; Oropharyngeal Neoplasms; Carcinoma, Squamous Cell; Squamous Cell Carcinoma of Head and Neck; Prognosis; Head and Neck Neoplasms
PubMed: 36693202
DOI: 10.1146/annurev-pathmechdis-031521-041424 -
The Lancet. Oncology Aug 2010A rise in incidence of oropharyngeal squamous cell cancer--specifically of the lingual and palatine tonsils--in white men younger than age 50 years who have no history... (Review)
Review
A rise in incidence of oropharyngeal squamous cell cancer--specifically of the lingual and palatine tonsils--in white men younger than age 50 years who have no history of alcohol or tobacco use has been recorded over the past decade. This malignant disease is associated with human papillomavirus (HPV) 16 infection. The biology of HPV-positive oropharyngeal cancer is distinct with P53 degradation, retinoblastoma RB pathway inactivation, and P16 upregulation. By contrast, tobacco-related oropharyngeal cancer is characterised by TP53 mutation and downregulation of CDKN2A (encoding P16). The best method to detect virus in tumour is controversial, and both in-situ hybridisation and PCR are commonly used; P16 immunohistochemistry could serve as a potential surrogate marker. HPV-positive oropharyngeal cancer seems to be more responsive to chemotherapy and radiation than HPV-negative disease. HPV 16 is a prognostic marker for enhanced overall and disease-free survival, but its use as a predictive marker has not yet been proven. Many questions about the natural history of oral HPV infection remain under investigation. For example, why does the increase in HPV-related oropharyngeal cancer dominate in men? What is the potential of HPV vaccines for primary prevention? Could an accurate method to detect HPV in tumour be developed? Which treatment strategies reduce toxic effects without compromising survival? Our aim with this review is to highlight current understanding of the epidemiology, biology, detection, and management of HPV-related oropharyngeal head and neck squamous cell carcinoma, and to describe unresolved issues.
Topics: Biomarkers, Tumor; Carcinoma, Squamous Cell; Female; Human papillomavirus 16; Humans; In Situ Hybridization; Incidence; Male; Middle Aged; Oropharyngeal Neoplasms; Papillomavirus Infections; Polymerase Chain Reaction; Risk Factors; Sex Distribution; Survival Rate; Tumor Virus Infections
PubMed: 20451455
DOI: 10.1016/S1470-2045(10)70017-6 -
Nature Genetics Apr 2023Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both...
Head and neck squamous cell carcinoma (HNSCC) includes a subset of cancers driven by human papillomavirus (HPV). Here we use single-cell RNA-seq to profile both HPV-positive and HPV-negative oropharyngeal tumors, uncovering a high level of cellular diversity within and between tumors. First, we detect diverse chromosomal aberrations within individual tumors, suggesting genomic instability and enabling the identification of malignant cells even at pathologically negative margins. Second, we uncover diversity with respect to HNSCC subtypes and other cellular states such as the cell cycle, senescence and epithelial-mesenchymal transitions. Third, we find heterogeneity in viral gene expression within HPV-positive tumors. HPV expression is lost or repressed in a subset of cells, which are associated with a decrease in HPV-associated cell cycle phenotypes, decreased response to treatment, increased invasion and poor prognosis. These findings suggest that HPV expression diversity must be considered during diagnosis and treatment of HPV-positive tumors, with important prognostic ramifications.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms; Carcinoma, Squamous Cell; Human Papillomavirus Viruses; Papillomavirus Infections; Oropharyngeal Neoplasms; Genomics; Papillomaviridae
PubMed: 37012457
DOI: 10.1038/s41588-023-01357-3 -
Clinical & Translational Oncology :... May 2021Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than...
Head and neck cancers (HNC) are defined as malignant tumours located in the upper aerodigestive tract and represents 5% of oncologic cases in adults in Spain. More than 90% of these tumours have squamous histology. In an effort to incorporate evidence obtained since 2017 publication, the Spanish Society of Medical Oncology (SEOM) presents an update of the squamous cell HNC diagnosis and treatment guideline. Most relevant diagnostic and therapeutic changes from the last guideline have been updated: introduction of sentinel node biopsy in early oral/oropharyngeal cancer treated with surgery, concomitant radiotherapy with weekly cisplatin 40 mg/m in the adjuvant setting, new approaches for HPV-related oropharyngeal cancer and new treatments with immune-checkpoint inhibitors in recurrent/metastatic disease.
Topics: Alphapapillomavirus; Chemoradiotherapy, Adjuvant; Cisplatin; Head and Neck Neoplasms; Humans; Immune Checkpoint Inhibitors; Medical Oncology; Mouth Neoplasms; Neoplasm Staging; Organ Sparing Treatments; Oropharyngeal Neoplasms; Radiation-Sensitizing Agents; Radiotherapy, Adjuvant; Sentinel Lymph Node Biopsy; Societies, Medical; Spain; Squamous Cell Carcinoma of Head and Neck
PubMed: 33635468
DOI: 10.1007/s12094-020-02533-1 -
Journal of Clinical Oncology : Official... Nov 2011Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical...
PURPOSE
Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.
PATIENTS AND METHODS
HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses.
RESULTS
HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020.
CONCLUSION
Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.
Topics: Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Incidence; Male; Middle Aged; Oropharyngeal Neoplasms; Papillomaviridae; SEER Program; United States
PubMed: 21969503
DOI: 10.1200/JCO.2011.36.4596 -
Journal of Clinical Oncology : Official... Mar 2021Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Reducing radiation treatment dose could improve the quality of life (QOL) of patients with good-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). Whether reduced-dose radiation produces disease control and QOL equivalent to standard chemoradiation is not proven.
PATIENTS AND METHODS
In this randomized, phase II trial, patients with p16-positive, T1-T2 N1-N2b M0, or T3 N0-N2b M0 OPSCC (7th edition staging) with ≤ 10 pack-years of smoking received 60 Gy of intensity-modulated radiation therapy (IMRT) over 6 weeks with concurrent weekly cisplatin (C) or 60 Gy IMRT over 5 weeks. To be considered for a phase III study, an arm had to achieve a 2-year progression-free survival (PFS) rate superior to a historical control rate of 85% and a 1-year mean composite score ≥ 60 on the MD Anderson Dysphagia Inventory (MDADI).
RESULTS
Three hundred six patients were randomly assigned and eligible. Two-year PFS for IMRT + C was 90.5% rejecting the null hypothesis of 2-year PFS ≤ 85% ( = .04). For IMRT, 2-year PFS was 87.6% ( = .23). One-year MDADI mean scores were 85.30 and 81.76 for IMRT + C and IMRT, respectively. Two-year overall survival rates were 96.7% for IMRT + C and 97.3% for IMRT. Acute adverse events (AEs) were defined as those occurring within 180 days from the end of treatment. There were more grade 3-4 acute AEs for IMRT + C (79.6% 52.4%; < .001). Rates of grade 3-4 late AEs were 21.3% and 18.1% ( = .56).
CONCLUSION
The IMRT + C arm met both prespecified end points justifying advancement to a phase III study. Higher rates of grade ≥ 3 acute AEs were reported in the IMRT + C arm.
Topics: Adult; Aged; Aged, 80 and over; Chemoradiotherapy; Female; Follow-Up Studies; Humans; Male; Middle Aged; Oropharyngeal Neoplasms; Papillomaviridae; Papillomavirus Infections; Prognosis; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Squamous Cell Carcinoma of Head and Neck; Survival Rate
PubMed: 33507809
DOI: 10.1200/JCO.20.03128 -
Current Treatment Options in Oncology Mar 2023Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced... (Review)
Review
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) incidence has been increasing in recent decades. Treatment of the locally advanced HPV-related OPSCC includes a multidisciplinary approach. Immunotherapy with immune checkpoint inhibitors is used in the treatment of patients with recurrent/metastatic head and neck squamous cell carcinomas (HNSCC), including HPV-related OPSCC patients. There is increasing knowledge of the role of HPV in the tumor immune microenvironment. Therefore, HPV status of OPSCC plays an essential role in the design of immunotherapy clinical trials in both curative intent and metastatic settings. Moreover, HPV has become a potential therapeutic target, with vaccines and adoptive T-cell therapies being developed against HPV for the treatment of OPSCC. Several novel studies are designed to target HPV in combination with immune checkpoint inhibitors. Thus, HPV-related OPSCC remains a unique subgroup in the immunotherapy era.
Topics: Humans; Human Papillomavirus Viruses; Carcinoma, Squamous Cell; Papillomavirus Infections; Immune Checkpoint Inhibitors; Neoplasm Recurrence, Local; Oropharyngeal Neoplasms; Head and Neck Neoplasms; Squamous Cell Carcinoma of Head and Neck; Immunotherapy; Tumor Microenvironment
PubMed: 36719604
DOI: 10.1007/s11864-023-01050-x -
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 -
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