Head and neck squamous cell carcinoma

Daniel E Johnson, Barbara Burtness, C René Leemans, Vivian Wai Yan Lui, Julie E Bauman, Jennifer R Grandis, Daniel E Johnson, Barbara Burtness, C René Leemans, Vivian Wai Yan Lui, Julie E Bauman, Jennifer R Grandis

Abstract

Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.

Conflict of interest statement

Competing interests

D.E.J. and J.R.G. are co-inventors of cyclic STAT3 decoy and have financial interests in STAT3 Therapeutics. STAT3 Therapeutics holds an interest in cyclic STAT3 decoy. B.A.B. has received honoraria for consulting from Merck and AstraZeneca. C.R.L. serves on the Advisory Board of Merck & Co. and Rakuten Medical. V.W.Y.L. receives grant support from Lee’s Pharmaceutical, Hong Kong Limited, via the University-Industry Collaboration Program (UIM/329; from the Innovation and Technology Fund, Hong Kong government; in 2018–2020), and served as a scientific consultant for Novartis Pharmaceutical (Hong Kong) Limited (Oct 2015-Oct 2016). J.E.B. serves as a scientific consultant to CUE Pharmaceuticals and Astra Zeneca and has research grant support from the IST programs of Aveo and Novartis.

Figures

Figure 1.. Anatomical sites of HNSCC development.
Figure 1.. Anatomical sites of HNSCC development.
Head and neck squamous cell carcinoma (HNSCC) arises from the mucosal epithelium of the oral cavity (lips, buccal mucosa, hard palate, anterior tongue, floor of mouth and retromolar trigone), nasopharynx, oropharynx (palantine tonsils, lingual tonsils, base of tongue, soft palate, uvula and posterior pharyngeal wall), hypopharynx (the bottom part of the throat, extending from the hyoid bone to the cricoid cartilage) and larynx. Human papilloma virus-associated HNSCCs arise primarily from the palantine and lingual tonsils of the oropharynx, whereas tobacco-associated HNSCCs arise primarily in the oral cavity, hypopharynx and larynx.
Figure 2.. Global incidence of head and…
Figure 2.. Global incidence of head and neck squamous cell carcinoma.
The estimated age-standardized rate (ASR) of HNSCC incidence worldwide is shown for men and women combined–. Data from GLOBOCAN, 2018 . Map was generated using the GLOBOCAN website mapping tool (https://gco.iarc.fr/today/online-analysis-map) by selecting the ‘hypopharynx’, ‘larynx’, ‘lip, oral cavity’, ‘nasopharynx’ and ‘oropharynx’ cancer sites.
Figure 3.. Progression of HNSCC and key…
Figure 3.. Progression of HNSCC and key genetic events.
The mucosal epithelium lining the oral cavity, pharynx, larynx and sinonasal tract is the site of origin for head and neck squamous cell carcinoma (HNSCC). In a model of ordered histological progression of HNSCC, mucosal epithelial cell hyperplasia is followed by dysplasia, and carcinoma in situ precedes the development of invasive carcinoma. Specific genetic events have been found to be enriched at each stage of progression and are indicated. Of note, unlike in most cancers in which oncogenic mutations typically drive tumorigenesis, HNSCC formation usually involves the inactivation of tumour suppressor genes, such as CDKN2A and TP53 (encoding p16INK4A and p53, respectively) in early stages and PTEN (encoding phosphatase and tensin homologue (PTEN)) at later stages. LOH, loss of heterozygosity. Histopathology images of hyperplasia, dysplasia, carcinoma in situ and invasive carcinoma are reprinted from ref. 250, Springer Nature Limited. Histopathology image of normal mucosa courtesy of R. Jordan, University of California, San Francisco.
Figure 4.. Development of carcinogen-associated, HPV-negative HNSCC.
Figure 4.. Development of carcinogen-associated, HPV-negative HNSCC.
Consumption of tobacco products or betel quid (the leaf of Piper betle) and areca nut (Areca catechu), exposure to environmental pollutants or excessive alcohol consumption are primary factors in the development of human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). Tobacco and tobacco smoke, in particular, are rich in polycyclic aromatic hydrocarbons and nitrosamines, which are known human carcinogens and are associated with a strongly increased risk of HNSCC. Metabolic activation of carcinogens results in the formation of reactive metabolites, which, if not detoxified and excreted, can damage DNA, typically by generating bulky DNA adducts. If the DNA damage is faithfully and accurately repaired, there may be no lasting consequences. However, if the damaged DNA is not promptly repaired, or is repaired errantly by lower fidelity repair mechanisms, then permanent damage in the form of mutations, deletions and amplifications can occur. The accumulation of alterations in key tumour suppressor genes (such as TP53 and CDKN2A, which encode p53 and p16INK4A, respectively) or signalling pathways (such as PI3K–AKT–mTOR and RAS–MAPK pathway genes) is associated with the onset, progression and poor prognosis of HPV-negative HNSCC.
Figure 5.. HPV infection of the tonsil…
Figure 5.. HPV infection of the tonsil crypt and development of HPV-positive HNSCC.
a | Throughout the tonsil epithelium, proliferating basal epithelial cells constitute the cell layer adjacent to the basement membrane. Differentiation of basal epithelial cells leads to their detachment from the basement membrane and upward migration, with progressively increasing differentiation leading to the sloughing off of terminally differentiated, non-proliferating cells. The palatine and lingual tonsils are also characterized by numerous tissue invaginations, commonly termed crypts, which are particularly enriched in stem cells at their base. A unique, reticulated squamous epithelium lines the crypt structure and gaps or fissures in the basement membrane and basal layer also occur. The presence of these fissures allows lymphocytes to enter the crypts and directly interact with foreign, external antigens. b | During infection with human papilloma virus (HPV), the reticulated and disrupted nature of the crypt squamous epithelium allows viral access to stem cells, proliferating basal cells and the basement membrane. Infiltrating immune cells also make contact with the viral particles. In the case of a productive infection, distinct viral genes and proteins are induced and/or activated during the different stages of epithelial cell differentiation, culminating in the production and shedding of new viral particles. c | Stem cells or proliferating basal cells represent probable cells of origin for HPV-positive head and neck squamous cell carcinoma (HNSCC). Stable integration of the viral genome into the host genome, and the concerted action of HPV E6 and E7 proteins on cellular p53 and RB levels, respectively, acts to promote cellular transformation. The accumulation of additional genetic alterations is needed to induce full transformation, including the acquisition of invasive and metastatic phenotypes.
Figure 6.. Histopathology of HNSCC.
Figure 6.. Histopathology of HNSCC.
a | Well-differentiated squamous cell carcinoma of the oral tongue, demonstrating mature cells with semi-organized keratinization and featuring a ‘keratin pearl’ (10x). b | A poorly differentiated squamous cell carcinoma of the base of tongue (10x). Inset shows immature cells with nuclear polymorphism and atypical mitoses without apparent stratification or keratinization (40x). c | A p16INK4A-positive oropharyngeal squamous cell carcinoma characterized by diffuse nuclear and cytoplasmic staining for the cell-cycle protein p16INK4A by immunohistochemistry, indicative of HPV-positive disease (10x). d | A p16INK4A-negative oropharyngeal squamous cell carcinoma demonstrates minimal staining by the same anti-p16INK4A antibody, a staining intensity that is indicative of HPV-negative disease (40x). In parts a and b, staining is with haematoxylin and eosin. HNSCC, head and neck squamous cell carcinoma.
Figure 7.. Algorithm for treatment-decision making for…
Figure 7.. Algorithm for treatment-decision making for recurrent and/or metastatic HNSCC.
After a diagnosis of recurrent disease or distant metastasis, patients with disease that is amenable to local therapy receive resection, radiation or limited volume irradiation and are then subject to observation. However, in patients who are not amenable to these therapies, systemic therapy is indicated. Pembrolizumab is chosen for those with expression of programmed cell death 1 ligand 1 (PDL1) expression (composite positive score (CPS)>1; CPS is: (the number of PDL1-staining tumor and immune cells/total number of viable tumour cells counted)X100), given alone for those with high expression and asymptomatic disease (CPS>20), or given with platinum-based chemotherapy for those with lower PDL1 expression (CPS 1–19) or higher symptom burden. If PDL1 expression is absent (CPS
All figures (7)

References

    1. Stein AP et al. Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review. Cancer J 21, 138–146, doi:10.1097/PPO.0000000000000115 (2015).
    1. Isayeva T, Li Y, Maswahu D & Brandwein-Gensler M Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 6 Suppl 1, S104–120, doi:10.1007/s12105-012-0368-1 (2012).
    1. Michaud DS et al. High-risk HPV types and head and neck cancer. Int J Cancer 135, 1653–1661, doi:10.1002/ijc.28811 (2014).
    1. Bonner JA et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354, 567–578 (2006).
    1. Gillison ML et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 393, 40–50, doi:10.1016/S0140-6736(18)32779-X (2019).
    1. Mehanna H et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet 393, 51–60, doi:10.1016/S0140-6736(18)32752-1 (2019).
    1. Ferris RL et al. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med 375, 1856–1867, doi:10.1056/NEJMoa1602252 (2016).
    1. Seiwert TY et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol 17, 956–965, doi:10.1016/S1470-2045(16)30066-3 (2016).
    1. Burtness B et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 394, 1915–1928, doi:10.1016/S0140-6736(19)32591-7 (2019).
    1. Ferlay J et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. Int J Cancer 144, 1941–1953, doi:10.1002/ijc.31937 (2019).
    1. Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394–424, doi:10.3322/caac.21492 (2018).
    1. Ferlay J, Ervik M, Lam F, Colombet M, Mery L, Pineros M, Znaor A, Soerjomataram I, Bray F Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer, <> (2018).
    1. Hashibe M et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99, 777–789, doi:99/10/777 [pii] 10.1093/jnci/djk179 (2007).
    1. Mehanna H et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck 35, 747–755, doi:10.1002/hed.22015 (2013).
    1. Jiang H et al. Can public health policies on alcohol and tobacco reduce a cancer epidemic? Australia’s experience. BMC Med 17, 213, doi:10.1186/s12916-019-1453-z (2019).
    1. Windon MJ et al. Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. Cancer 124, 2993–2999, doi:10.1002/cncr.31385 (2018).
    1. Fung SY, Lam JW & Chan KC Clinical utility of circulating Epstein-Barr virus DNA analysis for the management of nasopharyngeal carcinoma. Chin Clin Oncol 5, 18, doi:10.21037/cco.2016.03.07 (2016).
    1. Pulte D & Brenner H Changes in survival in head and neck cancers in the late 20th and early 21st century: a period analysis. Oncologist 15, 994–1001, doi:10.1634/theoncologist.2009-0289 (2010).
    1. Chaturvedi AK et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29, 4294–4301, doi:10.1200/JCO.2011.36.4596 (2011).
    1. Osazuwa-Peters N et al. Suicide risk among cancer survivors: Head and neck versus other cancers. Cancer 124, 4072–4079, doi:10.1002/cncr.31675 (2018).
    1. Cancer, I. A. f. R. o. List of Classifications by cancer sites with sufficient or limited evidence in humans, Volumes 1 to 127. IARC Monographs On The Identification Of Carcinogenic Hazards To Humans, <> (
    1. Blot WJ et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 48, 3282–3287 (1988).
    1. Zhang LW et al. Incidence and mortality trends in oral and oropharyngeal cancers in China, 2005–2013. Cancer Epidemiol 57, 120–126, doi:10.1016/j.canep.2018.10.014 (2018).
    1. Organization, W. H. WHO global report on trends in prevalence of tobacco smoking 2015. Geneva. WHO Press; (2015).
    1. Wong IC, Ng YK & Lui VW Cancers of the lung, head and neck on the rise: perspectives on the genotoxicity of air pollution. Chin J Cancer 33, 476–480, doi:10.5732/cjc.014.10093 (2014).
    1. Mishra A & Meherotra R Head and neck cancer: global burden and regional trends in India. Asian Pac J Cancer Prev 15, 537–550, doi:10.7314/apjcp.2014.15.2.537 (2014).
    1. Guha N et al. Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. Am J Epidemiol 166, 1159–1173, doi:10.1093/aje/kwm193 (2007).
    1. Freedman ND et al. Fruit and vegetable intake and head and neck cancer risk in a large United States prospective cohort study. Int J Cancer 122, 2330–2336, doi:10.1002/ijc.23319 (2008).
    1. Hennessey PT, Westra WH & Califano JA Human papillomavirus and head and neck squamous cell carcinoma: recent evidence and clinical implications. J Dent Res 88, 300–306, doi:10.1177/0022034509333371 (2009).
    1. Tsang CM, Lui VWY, Bruce JP, Pugh TJ & Lo KW Translational genomics of nasopharyngeal cancer. Semin Cancer Biol 61, 84–100, doi:10.1016/j.semcancer.2019.09.006 (2020).
    1. Viens LJ et al. Human Papillomavirus-Associated Cancers - United States, 2008–2012. MMWR Morb Mortal Wkly Rep 65, 661–666, doi:10.15585/mmwr.mm6526a1 (2016).
    1. Gillison ML et al. Prevalence of oral HPV infection in the United States, 2009–2010. JAMA 307, 693–703, doi:10.1001/jama.2012.101 (2012).
    1. Chaturvedi AK et al. NHANES 2009–2012 Findings: Association of Sexual Behaviors with Higher Prevalence of Oral Oncogenic Human Papillomavirus Infections in U.S. Men. Cancer Res 75, 2468–2477, doi:10.1158/0008-5472.CAN-14-2843 (2015).
    1. Gillison ML, Chaturvedi AK, Anderson WF & Fakhry C Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma. J Clin Oncol 33, 3235–3242, doi:10.1200/JCO.2015.61.6995 (2015).
    1. Gillison ML, Chaturvedi AK & Lowy DR HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer 113, 3036–3046, doi:10.1002/cncr.23764 (2008).
    1. Rowhani-Rahbar A et al. Antibody responses in oral fluid after administration of prophylactic human papillomavirus vaccines. J Infect Dis 200, 1452–1455, doi:10.1086/606026 (2009).
    1. Velleuer E & Dietrich R Fanconi anemia: young patients at high risk for squamous cell carcinoma. Mol Cell Pediatr 1, 9, doi:10.1186/s40348-014-0009-8 (2014).
    1. Fang M, Huang W, Mo D, Zhao W & Huang R Association of Five Snps in Cytotoxic T-Lymphocyte Antigen 4 and Cancer Susceptibility: Evidence from 67 Studies. Cell Physiol Biochem 47, 414–427, doi:10.1159/000489953 (2018).
    1. Niu YM et al. Increased risks between Interleukin-10 gene polymorphisms and haplotype and head and neck cancer: a meta-analysis. Sci Rep 5, 17149, doi:10.1038/srep17149 (2015).
    1. Wang Y, Yang H, Duan G & Wang H The association of the CYP1A1 Ile462Val polymorphism with head and neck cancer risk: evidence based on a cumulative meta-analysis. Onco Targets Ther 9, 2927–2934, doi:10.2147/OTT.S106264 (2016).
    1. Cadoni G et al. A review of genetic epidemiology of head and neck cancer related to polymorphisms in metabolic genes, cell cycle control and alcohol metabolism. Acta Otorhinolaryngol Ital 32, 1–11 (2012).
    1. Chan KCA et al. Analysis of Plasma Epstein-Barr Virus DNA to Screen for Nasopharyngeal Cancer. N Engl J Med 377, 513–522, doi:10.1056/NEJMoa1701717 (2017).
    1. Krishnamurthy S et al. Endothelial cell-initiated signaling promotes the survival and self-renewal of cancer stem cells. Cancer Res 70, 9969–9978, doi:10.1158/0008-5472.CAN-10-1712 (2010).
    1. Faber A et al. CD44 as a stem cell marker in head and neck squamous cell carcinoma. Oncol Rep 26, 321–326, doi:10.3892/or.2011.1322 (2011).
    1. Yu SS & Cirillo N The molecular markers of cancer stem cells in head and neck tumors. J Cell Physiol 235, 65–73, doi:10.1002/jcp.28963 (2020).
    1. Zhang Q et al. A subpopulation of CD133(+) cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett 289, 151–160, doi:10.1016/j.canlet.2009.08.010 (2010).
    1. Chiou SH et al. Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clin Cancer Res 14, 4085–4095, doi:10.1158/1078-0432.CCR-07-4404 (2008).
    1. Leon X et al. Second, third, and fourth head and neck tumors. A progressive decrease in survival. Head Neck 34, 1716–1719, doi:10.1002/hed.21977 (2012).
    1. Leon X et al. Risk of onset of second neoplasms and successive neoplasms in patients with a head and neck index tumour. Acta Otorrinolaringol Esp 71, 9–15, doi:10.1016/j.otorri.2018.11.003 (2020).
    1. Slaughter DP, Southwick HW & Smejkal W Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).
    1. Ryser MD, Lee WT, Ready NE, Leder KZ & Foo J Quantifying the Dynamics of Field Cancerization in Tobacco-Related Head and Neck Cancer: A Multiscale Modeling Approach. Cancer Res 76, 7078–7088, doi:10.1158/0008-5472.CAN-16-1054 (2016).
    1. Sheth SH, Johnson DE, Kensler TW & Bauman JE Chemoprevention targets for tobacco-related head and neck cancer: past lessons and future directions. Oral Oncol 51, 557–564, doi:10.1016/j.oraloncology.2015.02.101 (2015).
    1. Hecht SS Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91, 1194–1210, doi:10.1093/jnci/91.14.1194 (1999).
    1. Hoffmann D & Hoffmann I The changing cigarette, 1950–1995. J Toxicol Environ Health 50, 307–364, doi:10.1080/009841097160393 (1997).
    1. Warnakulasuriya S & Straif K Carcinogenicity of smokeless tobacco: Evidence from studies in humans & experimental animals. Indian J Med Res 148, 681–686, doi:10.4103/ijmr.IJMR_149_18 (2018).
    1. Talamini R et al. Combined effect of tobacco and alcohol on laryngeal cancer risk: a case-control study. Cancer Causes Control 13, 957–964, doi:10.1023/a:1021944123914 (2002).
    1. Pai SI & Westra WH Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol 4, 49–70, doi:10.1146/annurev.pathol.4.110807.092158 (2009).
    1. Brooks PJ & Theruvathu JA DNA adducts from acetaldehyde: implications for alcohol-related carcinogenesis. Alcohol 35, 187–193, doi:10.1016/j.alcohol.2005.03.009 (2005).
    1. Cancer Genome Atlas N Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517, 576–582, doi:10.1038/nature14129 (2015).
    1. Scheffner M, Huibregtse JM, Vierstra RD & Howley PM The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75, 495–505 (1993).
    1. White EA et al. Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J Virol 86, 13174–13186, doi:10.1128/JVI.02172-12 (2012).
    1. Tomaic V Functional Roles of E6 and E7 Oncoproteins in HPV-Induced Malignancies at Diverse Anatomical Sites. Cancers (Basel) 8, doi:10.3390/cancers8100095 (2016).
    1. Eckhardt M et al. Multiple Routes to Oncogenesis Are Promoted by the Human Papillomavirus-Host Protein Network. Cancer Discov 8, 1474–1489, doi:10.1158/-17-1018 (2018).
    1. Dyson N, Howley PM, Munger K & Harlow E The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243, 934–937, doi:10.1126/science.2537532 (1989).
    1. White EA et al. Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proc Natl Acad Sci U S A 109, E260–267, doi:10.1073/pnas.1116776109 (2012).
    1. Venuti A et al. Papillomavirus E5: the smallest oncoprotein with many functions. Mol Cancer 10, 140, doi:10.1186/1476-4598-10-140 (2011).
    1. Estevao D, Costa NR, Gil da Costa RM & Medeiros R Hallmarks of HPV carcinogenesis: The role of E6, E7 and E5 oncoproteins in cellular malignancy. Biochim Biophys Acta Gene Regul Mech 1862, 153–162, doi:10.1016/j.bbagrm.2019.01.001 (2019).
    1. Califano J et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 56, 2488–2492 (1996).
    1. Lui VW et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 3, 761–769, doi:10.1158/-13-0103 (2013).
    1. Nichols AC et al. High frequency of activating PIK3CA mutations in human papillomavirus-positive oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg 139, 617–622, doi:10.1001/jamaoto.2013.3210 (2013).
    1. Agrawal N et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333, 1154–1157, doi:10.1126/science.1206923 (2011).
    1. Stransky N et al. The mutational landscape of head and neck squamous cell carcinoma. Science 333, 1157–1160, doi:10.1126/science.1208130 (2011).
    1. Alsahafi E et al. Clinical update on head and neck cancer: molecular biology and ongoing challenges. Cell Death Dis 10, 540, doi:10.1038/s41419-019-1769-9 (2019).
    1. Rocco JW & Ellisen LW p63 and p73: life and death in squamous cell carcinoma. Cell Cycle 5, 936–940, doi:10.4161/cc.5.9.2716 (2006).
    1. Rocco JW, Leong CO, Kuperwasser N, DeYoung MP & Ellisen LW p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer Cell 9, 45–56 (2006).
    1. Yang X et al. DeltaNp63 versatilely regulates a Broad NF-kappaB gene program and promotes squamous epithelial proliferation, migration, and inflammation. Cancer Res 71, 3688–3700, doi:10.1158/0008-5472.CAN-10-3445 (2011).
    1. Lu H et al. TNF-alpha promotes c-REL/DeltaNp63alpha interaction and TAp73 dissociation from key genes that mediate growth arrest and apoptosis in head and neck cancer. Cancer Res 71, 6867–6877, doi:10.1158/0008-5472.CAN-11-2460 (2011).
    1. Si H et al. TNF-alpha modulates genome-wide redistribution of DeltaNp63alpha/TAp73 and NF-kappaB cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer. Oncogene 35, 5781–5794, doi:10.1038/onc.2016.112 (2016).
    1. Lu H et al. CK2 phosphorylates and inhibits TAp73 tumor suppressor function to promote expression of cancer stem cell genes and phenotype in head and neck cancer. Neoplasia 16, 789–800, doi:10.1016/j.neo.2014.08.014 (2014).
    1. Hu Z et al. Polo-like kinase 2 acting as a promoter in human tumor cells with an abundance of TAp73. Onco Targets Ther 8, 3475–3488, doi:10.2147/OTT.S90302 (2015).
    1. Foy JP et al. New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development. Cancer Prev Res (Phila) 8, 1027–1035, doi:10.1158/1940-6207.CAPR-14-0179 (2015).
    1. Viswanathan M, Tsuchida N & Shanmugam G Promoter hypermethylation profile of tumor-associated genes p16, p15, hMLH1, MGMT and E-cadherin in oral squamous cell carcinoma. Int J Cancer 105, 41–46, doi:10.1002/ijc.11028 (2003).
    1. Ha PK & Califano JA Promoter methylation and inactivation of tumour-suppressor genes in oral squamous-cell carcinoma. Lancet Oncol 7, 77–82, doi:10.1016/S1470-2045(05)70540-4 (2006).
    1. Rubin Grandis J et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 90, 824–832 (1998).
    1. Zhu X et al. Prognostic role of epidermal growth factor receptor in head and neck cancer: a meta-analysis. J Surg Oncol 108, 387–397, doi:10.1002/jso.23406 (2013).
    1. Madoz-Gurpide J et al. Activation of MET pathway predicts poor outcome to cetuximab in patients with recurrent or metastatic head and neck cancer. J Transl Med 13, 282, doi:10.1186/s12967-015-0633-7 (2015).
    1. Arnold L, Enders J & Thomas SM Activated HGF-c-Met Axis in Head and Neck Cancer. Cancers (Basel) 9, doi:10.3390/cancers9120169 (2017).
    1. Karakasheva TA et al. IL-6 Mediates Cross-Talk between Tumor Cells and Activated Fibroblasts in the Tumor Microenvironment. Cancer Res 78, 4957–4970, doi:10.1158/0008-5472.CAN-17-2268 (2018).
    1. Tsai MS, Chen WC, Lu CH & Chen MF The prognosis of head and neck squamous cell carcinoma related to immunosuppressive tumor microenvironment regulated by IL-6 signaling. Oral Oncol 91, 47–55, doi:10.1016/j.oraloncology.2019.02.027 (2019).
    1. Marsit CJ, Black CC, Posner MR & Kelsey KT A genotype-phenotype examination of cyclin D1 on risk and outcome of squamous cell carcinoma of the head and neck. Clin Cancer Res 14, 2371–2377, doi:10.1158/1078-0432.CCR-07-4368 (2008).
    1. Wang Z, Valera JC, Zhao X, Chen Q & Gutkind JS mTOR co-targeting strategies for head and neck cancer therapy. Cancer Metastasis Rev 36, 491–502, doi:10.1007/s10555-017-9688-7 (2017).
    1. Squarize CH et al. PTEN deficiency contributes to the development and progression of head and neck cancer. Neoplasia 15, 461–471, doi:10.1593/neo.121024 (2013).
    1. Geiger JL, Grandis JR & Bauman JE The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations. Oral Oncol 56, 84–92, doi:10.1016/j.oraloncology.2015.11.022 (2016).
    1. Johnson DE, O’Keefe RA & Grandis JR Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15, 234–248, doi:10.1038/nrclinonc.2018.8 (2018).
    1. Lui VW et al. Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer. Proc Natl Acad Sci U S A 111, 1114–1119, doi:10.1073/pnas.1319551111 (2014).
    1. Peyser ND et al. Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer. PLoS One 10, e0135750, doi:10.1371/journal.pone.0135750 (2015).
    1. Alamoud KA & Kukuruzinska MA Emerging Insights into Wnt/beta-catenin Signaling in Head and Neck Cancer. J Dent Res 97, 665–673, doi:10.1177/0022034518771923 (2018).
    1. Augsten M Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol 4, 62, doi:10.3389/fonc.2014.00062 (2014).
    1. Canning M et al. Heterogeneity of the Head and Neck Squamous Cell Carcinoma Immune Landscape and Its Impact on Immunotherapy. Front Cell Dev Biol 7, 52, doi:10.3389/fcell.2019.00052 (2019).
    1. Peltanova B, Raudenska M & Masarik M Effect of tumor microenvironment on pathogenesis of the head and neck squamous cell carcinoma: a systematic review. Mol Cancer 18, 63, doi:10.1186/s12943-019-0983-5 (2019).
    1. Marsh D et al. Stromal features are predictive of disease mortality in oral cancer patients. J Pathol 223, 470–481, doi:10.1002/path.2830 (2011).
    1. Amit M et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature 578, 449–454, doi:10.1038/s41586-020-1996-3 (2020).
    1. Partlova S et al. Distinct patterns of intratumoral immune cell infiltrates in patients with HPV-associated compared to non-virally induced head and neck squamous cell carcinoma. Oncoimmunology 4, e965570, doi:10.4161/21624011.2014.965570 (2015).
    1. Mandal R et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 1, e89829, doi:10.1172/jci.insight.89829 (2016).
    1. Chen YP et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol 30, 68–75, doi:10.1093/annonc/mdy470 (2019).
    1. Brooks JM et al. Development and Validation of a Combined Hypoxia and Immune Prognostic Classifier for Head and Neck Cancer. Clin Cancer Res 25, 5315–5328, doi:10.1158/1078-0432.CCR-18-3314 (2019).
    1. Feng B et al. Integrative Analysis of Multi-omics Data Identified EGFR and PTGS2 as Key Nodes in a Gene Regulatory Network Related to Immune Phenotypes in Head and Neck Cancer. Clin Cancer Res 26, 3616–3628, doi:10.1158/1078-0432.CCR-19-3997 (2020).
    1. Nguyen N et al. Tumor infiltrating lymphocytes and survival in patients with head and neck squamous cell carcinoma. Head Neck 38, 1074–1084, doi:10.1002/hed.24406 (2016).
    1. Fang J et al. Prognostic significance of tumor infiltrating immune cells in oral squamous cell carcinoma. BMC Cancer 17, 375, doi:10.1186/s12885-017-3317-2 (2017).
    1. Whiteside TL Immunobiology of head and neck cancer. Cancer Metastasis Rev 24, 95–105, doi:10.1007/s10555-005-5050-6 (2005).
    1. Ward MJ et al. Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer 110, 489–500, doi:10.1038/bjc.2013.639 (2014).
    1. Costa NL et al. Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. Oral Oncol 49, 216–223, doi:10.1016/j.oraloncology.2012.09.012 (2013).
    1. Ferris RL, Hunt JL & Ferrone S Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res 33, 113–133, doi:10.1385/IR:33:2:113 (2005).
    1. Ferris RL, Whiteside TL & Ferrone S Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 12, 3890–3895, doi:10.1158/1078-0432.CCR-05-2750 (2006).
    1. Grabowska AK & Riemer AB The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J 6, 249–256, doi:10.2174/1874357901206010249 (2012).
    1. DiMaio D & Petti LM The E5 proteins. Virology 445, 99–114, doi:10.1016/j.virol.2013.05.006 (2013).
    1. Karim R et al. Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte’s innate immune response. PLoS Pathog 9, e1003384, doi:10.1371/journal.ppat.1003384 (2013).
    1. Gu Z, Shi W, Zhang L, Hu Z & Xu C USP19 suppresses cellular type I interferon signaling by targeting TRAF3 for deubiquitination. Future Microbiol 12, 767–779, doi:10.2217/fmb-2017-0006 (2017).
    1. Sorensen BS et al. Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother Oncol 108, 500–505, doi:10.1016/j.radonc.2013.06.011 (2013).
    1. Brizel DM, Sibley GS, Prosnitz LR, Scher RL & Dewhirst MW Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 38, 285–289, doi:10.1016/s0360-3016(97)00101-6 (1997).
    1. Swartz JE et al. Poor prognosis in human papillomavirus-positive oropharyngeal squamous cell carcinomas that overexpress hypoxia inducible factor-1alpha. Head Neck 38, 1338–1346, doi:10.1002/hed.24445 (2016).
    1. Gottgens EL, Ostheimer C, Span PN, Bussink J & Hammond EM HPV, hypoxia and radiation response in head and neck cancer. Br J Radiol, 20180047, doi:10.1259/bjr.20180047 (2018).
    1. Nordsmark M et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy. An international multi-center study. Radiother Oncol 77, 18–24, doi:10.1016/j.radonc.2005.06.038 (2005).
    1. Linge A et al. Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(−) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG. Clin Cancer Res 22, 2639–2649, doi:10.1158/1078-0432.CCR-15-1990 (2016).
    1. Bornigen D et al. Alterations in oral bacterial communities are associated with risk factors for oral and oropharyngeal cancer. Sci Rep 7, 17686, doi:10.1038/s41598-017-17795-z (2017).
    1. Mager DL et al. The salivary microbiota as a diagnostic indicator of oral cancer: a descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects. J Transl Med 3, 27, doi:10.1186/1479-5876-3-27 (2005).
    1. Banerjee S et al. Microbial Signatures Associated with Oropharyngeal and Oral Squamous Cell Carcinomas. Sci Rep 7, 4036, doi:10.1038/s41598-017-03466-6 (2017).
    1. Luukkaa M et al. Association between high collagenase-3 expression levels and poor prognosis in patients with head and neck cancer. Head Neck 28, 225–234, doi:10.1002/hed.20322 (2006).
    1. Patel BP, Shah SV, Shukla SN, Shah PM & Patel PS Clinical significance of MMP-2 and MMP-9 in patients with oral cancer. Head Neck 29, 564–572, doi:10.1002/hed.20561 (2007).
    1. Viros D et al. Prognostic role of MMP-9 expression in head and neck carcinoma patients treated with radiotherapy or chemoradiotherapy. Oral Oncol 49, 322–325, doi:10.1016/j.oraloncology.2012.10.005 (2013).
    1. Samanna V, Ma T, Mak TW, Rogers M & Chellaiah MA Actin polymerization modulates CD44 surface expression, MMP-9 activation, and osteoclast function. J Cell Physiol 213, 710–720, doi:10.1002/jcp.21137 (2007).
    1. Sterz CM et al. A basal-cell-like compartment in head and neck squamous cell carcinomas represents the invasive front of the tumor and is expressing MMP-9. Oral Oncol 46, 116–122, doi:10.1016/j.oraloncology.2009.11.011 (2010).
    1. Nijkamp MM et al. Expression of E-cadherin and vimentin correlates with metastasis formation in head and neck squamous cell carcinoma patients. Radiother Oncol 99, 344–348, doi:10.1016/j.radonc.2011.05.066 (2011).
    1. Yang MH et al. Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10, 295–305, doi:10.1038/ncb1691 (2008).
    1. Zhang Z, Filho MS & Nor JE The biology of head and neck cancer stem cells. Oral Oncol 48, 1–9, doi:10.1016/j.oraloncology.2011.10.004 (2012).
    1. Williams ED, Gao D, Redfern A & Thompson EW Controversies around epithelial-mesenchymal plasticity in cancer metastasis. Nat Rev Cancer 19, 716–732, doi:10.1038/s41568-019-0213-x (2019).
    1. Puram SV et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell 171, 1611–1624 e1624, doi:10.1016/j.cell.2017.10.044 (2017).
    1. Nirmala JG & Lopus M Cell death mechanisms in eukaryotes. Cell Biol Toxicol 36, 145–164, doi:10.1007/s10565-019-09496-2 (2020).
    1. Zeng Q et al. Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B. J Biol Chem 277, 25203–25208, doi:10.1074/jbc.M201598200 (2002).
    1. Neiva KG et al. Cross talk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT3/Akt/ERK signaling. Neoplasia 11, 583–593, doi:10.1593/neo.09266 (2009).
    1. Huang SH et al. Refining American Joint Committee on Cancer/Union for International Cancer Control TNM stage and prognostic groups for human papillomavirus-related oropharyngeal carcinomas. J Clin Oncol 33, 836–845, doi:10.1200/JCO.2014.58.6412 (2015).
    1. Hashibe M et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 18, 541–550, doi:1055–9965.EPI-08–0347 [pii] 10.1158/1055-9965.EPI-08-0347 (2009).
    1. Taberna M et al. Human papillomavirus-related oropharyngeal cancer. Ann Oncol 28, 2386–2398, doi:10.1093/annonc/mdx304 (2017).
    1. Fu TS, Foreman A, Goldstein DP & de Almeida JR The role of transoral robotic surgery, transoral laser microsurgery, and lingual tonsillectomy in the identification of head and neck squamous cell carcinoma of unknown primary origin: a systematic review. J Otolaryngol Head Neck Surg 45, 28, doi:10.1186/s40463-016-0142-6 (2016).
    1. Meccariello G et al. The emerging role of trans-oral robotic surgery for the detection of the primary tumour site in patients with head-neck unknown primary cancers: A meta-analysis. Auris Nasus Larynx 46, 663–671, doi:10.1016/j.anl.2019.04.007 (2019).
    1. Chen YP et al. Nasopharyngeal carcinoma. Lancet 394, 64–80, doi:10.1016/S0140-6736(19)30956-0 (2019).
    1. Pynnonen MA et al. Clinical Practice Guideline: Evaluation of the Neck Mass in Adults. Otolaryngol Head Neck Surg 157, S1–S30, doi:10.1177/0194599817722550 (2017).
    1. Yi CH, Jim Zhai Q & Wang BY Updates on Immunohistochemical and Molecular Markers in Selected Head and Neck Diagnostic Problems. Arch Pathol Lab Med 141, 1214–1235, doi:10.5858/arpa.2016-0245-RA (2017).
    1. Lewis JS Jr. et al. Human Papillomavirus Testing in Head and Neck Carcinomas: Guideline From the College of American Pathologists. Arch Pathol Lab Med 142, 559–597, doi:10.5858/arpa.2017-0286-CP (2018).
    1. Ang KK et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363, 24–35, doi:10.1056/NEJMoa0912217 (2010).
    1. Edge SB, B. D, Compton CC, Fritz AG, Greene FL, Trotti A, editors. . AJCC cancer staging manual (7th ed). . (New York, NY: Springer; ).
    1. Amin MB, et al. (eds). AJCC Cancer Staging Manual, 8th edn (American Joint Committee on Cancer and Springer International Publishing, 2017).
    1. Lydiatt W, O’Sullivan B & Patel S Major Changes in Head and Neck Staging for 2018. Am Soc Clin Oncol Educ Book 38, 505–514, doi:10.1200/EDBK_199697 (2018).
    1. van Gysen K et al. Validation of the 8(th) edition UICC/AJCC TNM staging system for HPV associated oropharyngeal cancer patients managed with contemporary chemoradiotherapy. BMC Cancer 19, 674, doi:10.1186/s12885-019-5894-8 (2019).
    1. Wurdemann N et al. Prognostic Impact of AJCC/UICC 8th Edition New Staging Rules in Oropharyngeal Squamous Cell Carcinoma. Front Oncol 7, 129, doi:10.3389/fonc.2017.00129 (2017).
    1. Lee VH et al. The addition of pretreatment plasma Epstein-Barr virus DNA into the eighth edition of nasopharyngeal cancer TNM stage classification. Int J Cancer 144, 1713–1722, doi:10.1002/ijc.31856 (2019).
    1. Guo R et al. Proposed modifications and incorporation of plasma Epstein-Barr virus DNA improve the TNM staging system for Epstein-Barr virus-related nasopharyngeal carcinoma. Cancer 125, 79–89, doi:10.1002/cncr.31741 (2019).
    1. Pfister DG et al. Head and Neck Cancers, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 18, 873–898 (2020).
    1. Coca-Pelaz A et al. The risk of second primary tumors in head and neck cancer: A systematic review. Head Neck 42, 456–466, doi:10.1002/hed.26016 (2020).
    1. U.S. Department of Health and Human Services. Smoking Cessation: A report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, (2020).
    1. World Health Organization. Tackling NCDs: “Best buys” and other recommended interventions for the prevention and control of noncommunicable diseases. Geneva: World Health Organization; . License: CC BY-NC-SA 3.0 IGO (2017).
    1. Mehrtash H et al. Defining a global research and policy agenda for betel quid and areca nut. Lancet Oncol 18, e767–e775, doi:10.1016/S1470-2045(17)30460-6 (2017).
    1. Herrero R et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica. PLoS One 8, e68329, doi:10.1371/journal.pone.0068329 (2013).
    1. Hirth JM, Chang M, Resto VA & Group HPVS Prevalence of oral human papillomavirus by vaccination status among young adults (18–30years old). Vaccine 35, 3446–3451, doi:10.1016/j.vaccine.2017.05.025 (2017).
    1. Chaturvedi AK et al. Effect of Prophylactic Human Papillomavirus (HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States. J Clin Oncol 36, 262–267, doi:10.1200/JCO.2017.75.0141 (2018).
    1. Meites E, Kempe A & Markowitz LE Use of a 2-Dose Schedule for Human Papillomavirus Vaccination - Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 65, 1405–1408, doi:10.15585/mmwr.mm6549a5 (2016).
    1. Meites E et al. Human Papillomavirus Vaccination for Adults: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep 68, 698–702, doi:10.15585/mmwr.mm6832a3 (2019).
    1. Napier SS & Speight PM Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 37, 1–10, doi:10.1111/j.1600-0714.2007.00579.x (2008).
    1. Lee JJ et al. Predicting cancer development in oral leukoplakia: ten years of translational research. Clin Cancer Res 6, 1702–1710 (2000).
    1. Hong WK et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 315, 1501–1505, doi:10.1056/NEJM198612113152401 (1986).
    1. Hong WK et al. Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med 323, 795–801, doi:10.1056/NEJM199009203231205 (1990).
    1. Rosin MP et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 6, 357–362 (2000).
    1. Garland LL et al. Effect of Intermittent Versus Continuous Low-Dose Aspirin on Nasal Epithelium Gene Expression in Current Smokers: A Randomized, Double-Blinded Trial. Cancer Prev Res (Phila) 12, 809–820, doi:10.1158/1940-6207.CAPR-19-0036 (2019).
    1. Vitale-Cross L et al. Metformin prevents the development of oral squamous cell carcinomas from carcinogen-induced premalignant lesions. Cancer Prev Res (Phila) 5, 562–573, doi:10.1158/1940-6207.CAPR-11-0502 (2012).
    1. Bauman JE et al. Prevention of Carcinogen-Induced Oral Cancer by Sulforaphane. Cancer Prev Res (Phila) 9, 547–557, doi:10.1158/1940-6207.CAPR-15-0290 (2016).
    1. Hu L et al. Gene targets of sulforaphane in head and neck squamous cell carcinoma. Mol Med Rep 20, 5335–5344, doi:10.3892/mmr.2019.10766 (2019).
    1. Lee NCJ et al. Patterns of failure in high-metastatic node number human papillomavirus-positive oropharyngeal carcinoma. Oral Oncol 85, 35–39, doi:10.1016/j.oraloncology.2018.08.001 (2018).
    1. Lyhne NM et al. The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma. Radiother Oncol 117, 91–98, doi:10.1016/j.radonc.2015.07.004 (2015).
    1. Bledsoe TJ et al. Hypofractionated Radiotherapy for Patients with Early-Stage Glottic Cancer: Patterns of Care and Survival. J Natl Cancer Inst 109, doi:10.1093/jnci/djx042 (2017).
    1. Weinstein GS et al. Transoral robotic surgery: a multicenter study to assess feasibility, safety, and surgical margins. Laryngoscope 122, 1701–1707, doi:10.1002/lary.23294 (2012).
    1. Forastiere AA et al. Use of Larynx-Preservation Strategies in the Treatment of Laryngeal Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol 36, 1143–1169, doi:10.1200/JCO.2017.75.7385 (2018).
    1. D’Cruz AK et al. Elective versus Therapeutic Neck Dissection in Node-Negative Oral Cancer. N Engl J Med 373, 521–529, doi:10.1056/NEJMoa1506007 (2015).
    1. Forastiere AA et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med 349, 2091–2098, doi:10.1056/NEJMoa031317 (2003).
    1. Cooper JS et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 350, 1937–1944, doi:10.1056/NEJMoa032646 (2004).
    1. Bernier J et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350, 1945–1952, doi:10.1056/NEJMoa032641 (2004).
    1. Forastiere AA et al. Long-term results of RTOG 91–11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31, 845–852, doi:10.1200/JCO.2012.43.6097 (2013).
    1. Kelly JR et al. Upfront surgery versus definitive chemoradiotherapy in patients with human Papillomavirus-associated oropharyngeal squamous cell cancer. Oral Oncol 79, 64–70, doi:10.1016/j.oraloncology.2018.02.017 (2018).
    1. Kann BH et al. Pretreatment Identification of Head and Neck Cancer Nodal Metastasis and Extranodal Extension Using Deep Learning Neural Networks. Sci Rep 8, 14036, doi:10.1038/s41598-018-32441-y (2018).
    1. Lowe VJ et al. Multicenter Trial of [(18)F]fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Staging of Head and Neck Cancer and Negative Predictive Value and Surgical Impact in the N0 Neck: Results From ACRIN 6685. J Clin Oncol 37, 1704–1712, doi:10.1200/JCO.18.01182 (2019).
    1. Adelstein DJ et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol 21, 92–98, doi:10.1200/JCO.2003.01.008 (2003).
    1. Bauml JM et al. Cisplatin Every 3 Weeks Versus Weekly With Definitive Concurrent Radiotherapy for Squamous Cell Carcinoma of the Head and Neck. J Natl Cancer Inst 111, 490–497, doi:10.1093/jnci/djy133 (2019).
    1. Worden FP et al. Chemoselection as a strategy for organ preservation in patients with T4 laryngeal squamous cell carcinoma with cartilage invasion. Laryngoscope 119, 1510–1517, doi:10.1002/lary.20294 (2009).
    1. Blanchard P et al. Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 16, 645–655, doi:10.1016/S1470-2045(15)70126-9 (2015).
    1. Zhang Y et al. Gemcitabine and Cisplatin Induction Chemotherapy in Nasopharyngeal Carcinoma. N Engl J Med 381, 1124–1135, doi:10.1056/NEJMoa1905287 (2019).
    1. Chan ATC et al. Analysis of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Cancer After Chemoradiation to Identify High-Risk Patients for Adjuvant Chemotherapy: A Randomized Controlled Trial. J Clin Oncol, JCO2018777847, doi:10.1200/JCO.2018.77.7847 (2018).
    1. Trotti A et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol 8, 613–624, doi:10.1016/S1470-2045(07)70144-4 (2007).
    1. Haddad R et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol 14, 257–264, doi:10.1016/S1470-2045(13)70011-1 (2013).
    1. Cohen EE et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol 32, 2735–2743, doi:10.1200/JCO.2013.54.6309 (2014).
    1. Posner MR et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 357, 1705–1715, doi:10.1056/NEJMoa070956 (2007).
    1. Kowalski LP et al. COVID-19 pandemic: effects and evidence-based recommendations for otolaryngology and head and neck surgery practice. Head Neck, doi:10.1002/hed.26164 (2020).
    1. Fakhry C et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100, 261–269, doi:djn011 [pii] 10.1093/jnci/djn011 (2008).
    1. Marur S et al. E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. J Clin Oncol 35, 490–497, doi:10.1200/JCO.2016.68.3300 (2017).
    1. Chen AM et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol 18, 803–811, doi:10.1016/S1470-2045(17)30246-2 (2017).
    1. Lee AW et al. Retrospective analysis of patients with nasopharyngeal carcinoma treated during 1976–1985: survival after local recurrence. Int J Radiat Oncol Biol Phys 26, 773–782, doi:10.1016/0360-3016(93)90491-d (1993).
    1. Fakhry C et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 32, 3365–3373, doi:10.1200/JCO.2014.55.1937 (2014).
    1. Saada-Bouzid E et al. Hyperprogression during anti-PD-1/PD-L1 therapy in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol 28, 1605–1611, doi:10.1093/annonc/mdx178 (2017).
    1. Saleh K et al. Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Eur J Cancer 121, 123–129, doi:10.1016/j.ejca.2019.08.026 (2019).
    1. Puzanov I et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5, 95, doi:10.1186/s40425-017-0300-z (2017).
    1. Vermorken JB et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 359, 1116–1127, doi:359/11/1116 [pii] 10.1056/NEJMoa0802656 (2008).
    1. Cohen EEW et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet 393, 156–167, doi:10.1016/S0140-6736(18)31999-8 (2019).
    1. Mehra R et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer 119, 153–159, doi:10.1038/s41416-018-0131-9 (2018).
    1. Haddad R et al. Nivolumab treatment beyond RECIST-defined progression in recurrent or metastatic squamous cell carcinoma of the head and neck in CheckMate 141: A subgroup analysis of a randomized phase 3 clinical trial. Cancer 125, 3208–3218, doi:10.1002/cncr.32190 (2019).
    1. Taylor MH et al. Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. J Clin Oncol 38, 1154–1163, doi:10.1200/JCO.19.01598 (2020).
    1. Verdonck-de Leeuw IM et al. The course of health-related quality of life in head and neck cancer patients treated with chemoradiation: a prospective cohort study. Radiother Oncol 110, 422–428, doi:10.1016/j.radonc.2014.01.002 (2014).
    1. Rettig EM et al. Health-related quality of life before and after head and neck squamous cell carcinoma: Analysis of the Surveillance, Epidemiology, and End Results-Medicare Health Outcomes Survey linkage. Cancer 122, 1861–1870, doi:10.1002/cncr.30005 (2016).
    1. Quinten C et al. Baseline quality of life as a prognostic indicator of survival: a meta-analysis of individual patient data from EORTC clinical trials. Lancet Oncol 10, 865–871, doi:10.1016/S1470-2045(09)70200-1 (2009).
    1. Rogers SN et al. Quality of life, cognitive, physical and emotional function at diagnosis predicts head and neck cancer survival: analysis of cases from the Head and Neck 5000 study. Eur Arch Otorhinolaryngol 277, 1515–1523, doi:10.1007/s00405-020-05850-x (2020).
    1. Hammerlid E, Silander E, Hornestam L & Sullivan M Health-related quality of life three years after diagnosis of head and neck cancer--a longitudinal study. Head Neck 23, 113–125, doi:10.1002/1097-0347(200102)23:2<113::aid-hed1006>;2-w (2001).
    1. Mehanna HM & Morton RP Deterioration in quality-of-life of late (10-year) survivors of head and neck cancer. Clin Otolaryngol 31, 204–211, doi:10.1111/j.1749-4486.2006.01188.x (2006).
    1. Verdonck-de Leeuw IM, van Nieuwenhuizen A & Leemans CR The value of quality-of-life questionnaires in head and neck cancer. Curr Opin Otolaryngol Head Neck Surg 20, 142–147, doi:10.1097/MOO.0b013e32834f5fd7 (2012).
    1. Singer S et al. International validation of the revised European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module, the EORTC QLQ-HN43: Phase IV. Head Neck 41, 1725–1737, doi:10.1002/hed.25609 (2019).
    1. List MA et al. The Performance Status Scale for Head and Neck Cancer Patients and the Functional Assessment of Cancer Therapy-Head and Neck Scale. A study of utility and validity. Cancer 77, 2294–2301, doi:10.1002/(SICI)1097-0142(19960601)77:11<2294::AID-CNCR17>;2-S (1996).
    1. Nekhlyudov L et al. Head and Neck Cancer Survivorship Care Guideline: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Cancer Society Guideline. J Clin Oncol 35, 1606–1621, doi:10.1200/JCO.2016.71.8478 (2017).
    1. Ringash J et al. Head and Neck Cancer Survivorship: Learning the Needs, Meeting the Needs. Semin Radiat Oncol 28, 64–74, doi:10.1016/j.semradonc.2017.08.008 (2018).
    1. Bonomo P et al. Quality Assessment in Supportive Care in Head and Neck Cancer. Front Oncol 9, 926, doi:10.3389/fonc.2019.00926 (2019).
    1. Rinkel RN et al. Prevalence of swallowing and speech problems in daily life after chemoradiation for head and neck cancer based on cut-off scores of the patient-reported outcome measures SWAL-QOL and SHI. Eur Arch Otorhinolaryngol 273, 1849–1855, doi:10.1007/s00405-015-3680-z (2016).
    1. Kraaijenga SA et al. Assessment of voice, speech, and related quality of life in advanced head and neck cancer patients 10-years+ after chemoradiotherapy. Oral Oncol 55, 24–30, doi:10.1016/j.oraloncology.2016.02.001 (2016).
    1. Hutcheson KA et al. Two-year prevalence of dysphagia and related outcomes in head and neck cancer survivors: An updated SEER-Medicare analysis. Head Neck 41, 479–487, doi:10.1002/hed.25412 (2019).
    1. Bjordal K & Bottomley A Making Advances in Quality of Life Studies in Head and Neck Cancer. Int J Radiat Oncol Biol Phys 97, 659–661, doi:10.1016/j.ijrobp.2016.11.051 (2017).
    1. Dawson C et al. Patient advocacy in head and neck cancer: Realities, challenges and the role of the multi-disciplinary team. Clin Otolaryngol 45, 437–444, doi:10.1111/coa.13508 (2020).
    1. van der Hout A et al. Role of eHealth application Oncokompas in supporting self-management of symptoms and health-related quality of life in cancer survivors: a randomised, controlled trial. Lancet Oncol 21, 80–94, doi:10.1016/S1470-2045(19)30675-8 (2020).
    1. Parke SC et al. Identifying Gaps in Research on Rehabilitation for Patients With Head and Neck Cancer: A Scoping Review. Arch Phys Med Rehabil 100, 2381–2388, doi:10.1016/j.apmr.2019.03.022 (2019).
    1. Kampshoff CS, Verdonck-de Leeuw IM, van Oijen MG, Sprangers MA & Buffart LM Ecological momentary assessments among patients with cancer: A scoping review. Eur J Cancer Care (Engl) 28, e13095, doi:10.1111/ecc.13095 (2019).
    1. David JM et al. Treatment at high-volume facilities and academic centers is independently associated with improved survival in patients with locally advanced head and neck cancer. Cancer 123, 3933–3942, doi:10.1002/cncr.30843 (2017).
    1. Wuthrick EJ et al. Institutional clinical trial accrual volume and survival of patients with head and neck cancer. J Clin Oncol 33, 156–164, doi:10.1200/JCO.2014.56.5218 (2015).
    1. Bossi P et al. Impact of treatment expertise on the outcome of patients with head and neck cancer treated within 6 randomized trials. Head Neck 40, 2648–2656, doi:10.1002/hed.25389 (2018).
    1. Ellington TD et al. Trends in Incidence of Cancers of the Oral Cavity and Pharynx - United States 2007–2016. MMWR Morb Mortal Wkly Rep 69, 433–438, doi:10.15585/mmwr.mm6915a1 (2020).
    1. Sonawane K et al. Oral Human Papillomavirus Infection: Differences in Prevalence Between Sexes and Concordance With Genital Human Papillomavirus Infection, NHANES 2011 to 2014. Ann Intern Med 167, 714–724, doi:10.7326/M17-1363 (2017).
    1. Tipifarnib Targets HRAS-Mutant Cancers. Cancer Discov 9, 1637–1638, doi:10.1158/-NB2019-129 (2019).
    1. Elkabets M et al. AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell 27, 533–546, doi:10.1016/j.ccell.2015.03.010 (2015).
    1. Merino DM et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer 8, doi:10.1136/jitc-2019-000147 (2020).
    1. Castellanos E & Baxi SS Letting the GENIE Out of Its Bottle: Examining the Potential of Real-World Clinicogenomic Data. Cancer Discov 10, 490–491, doi:10.1158/-20-0039 (2020).
    1. Cillo AR et al. Immune Landscape of Viral- and Carcinogen-Driven Head and Neck Cancer. Immunity 52, 183–199 e189, doi:10.1016/j.immuni.2019.11.014 (2020).
    1. Li H et al. Proteomic Characterization of Head and Neck Cancer Patient-Derived Xenografts. Mol Cancer Res 14, 278–286, doi:10.1158/1541-7786.MCR-15-0354 (2016).
    1. Karamboulas C et al. Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma. Cell Rep 25, 1318–1331 e1314, doi:10.1016/j.celrep.2018.10.004 (2018).
    1. Driehuis E et al. Oral Mucosal Organoids as a Potential Platform for Personalized Cancer Therapy. Cancer Discov 9, 852–871, doi:10.1158/-18-1522 (2019).
    1. Wang H et al. Immune Checkpoint Inhibitor Toxicity in Head and Neck Cancer: From Identification to Management. Front Pharmacol 10, 1254, doi:10.3389/fphar.2019.01254 (2019).
    1. Wang Z et al. Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4. Nat Commun 10, 5546, doi:10.1038/s41467-019-13471-0 (2019).
    1. Barry KC et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat Med 24, 1178–1191, doi:10.1038/s41591-018-0085-8 (2018).
    1. Shah FD et al. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem 26, 326–334, doi:10.1007/s12291-011-0149-8 (2011).

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever