HPV – A different view on Head and Neck Cancer

Abstract

Head and neck cancer is the sixth most common cancer with over 500000 annually reported incident cases worldwide. Besides major risk factors tobacco and alcohol, oropharyngeal squamous cell carcinomas (OSCC) show increased association with human papillomavirus (HPV). HPV-associated and HPV-negative OSCC are 2 different entities regarding biological characteristics, therapeutic response, and patient prognosis. In HPV OSCC, viral oncoprotein activity, as well as genetic (mutations and chromosomal aberrations) and epigenetic alterations plays a key role during carcinogenesis. Based on improved treatment response, the introduction of therapy de-intensification and targeted therapy is discussed for patients with HPV OSCC. A promising targeted therapy concept is immunotherapy. The use of checkpoint inhibitors (e.g. anti-PD1) is currently investigated. By means of liquid biopsies, biomarkers such as viral DNA or tumor mutations in the will soon be available for disease monitoring, as well as detection of treatment failure. By now, primary prophylaxis of HPV OSCC can be achieved by vaccination of girls and boys.

Key words

Head and neck cancer - Oropharyngeal squamous cell carcinoma - Carcinogenesis - Human Papillomavirus - Immunotherapy

• Literatur

• 1 Javadi P. et al. Evolving disparities in the epidemiology of oral cavity and oropharyngeal cancers. Cancer Causes Control 2017; 28: 635-645
• 2 Mifsud M. et al. Evolving trends in head and neck cancer epidemiology: Ontario, Canada 1993–2010. Head Neck 2017; 39: 1770-1778
• 3 Chaturvedi AK. et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29: 4294-4301
• 4 Nasman A. et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma?. Int J Cancer 2009; 125: 362-366
• 5 Wittekindt C. et al. Expression of p16 protein is associated with human papillomavirus status in tonsillar carcinomas and has implications on survival. Adv Otorhinolaryngol 2005; 62: 72-80
• 6 Quabius ES. et al. Geographical and anatomical influences on human papillomavirus prevalence diversity in head and neck squamous cell carcinoma in Germany. Int J Oncol 2015; 46: 414-422
• 7 Wurdemann N. et al. Prognostic Impact of AJCC/UICC 8th Edition new staging rules in oropharyngeal squamous cell carcinoma. Front Oncol 2017; 7: 129
• 8 Klussmann JP. et al. Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus. Am J Pathol 2003; 162: 747-753
• 9 Saraiya M. et al. US assessment of HPV types in cancers: implications for current and 9-valent HPV vaccines. J Natl Cancer Inst 2015; 107: djv086
• 10 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 2013; 35: 747-755
• 11 Abogunrin S. et al. Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis. BMC Cancer 2014; 14: 968
• 12 Isayeva T. et al. Human papillomavirus in non-oropharyngeal head and neck cancers: a systematic literature review. Head Neck Pathol 2012; 6 (Suppl. 01) S104-S120
• 13 Ndiaye C. et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol 2014; 15: 1319-1331
• 14 Castellsague X. et al. HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 Patients. J Natl Cancer Inst 2016; 108: djv403
• 15 Lassen P. et al. Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol 2014; 113: 310-316
• 16 Chung CH. et al. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. J Clin Oncol 2014; 32: 3930-3938
• 17 Scheel A. et al. Classification of TP53 mutations and HPV predict survival in advanced larynx cancer. Laryngoscope 2016; 126: E292-E299
• 18 Mork J. et al. Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344: 1125-1131
• 19 Anantharaman D. et al. Human papillomavirus infections and upper aero-digestive tract cancers: the ARCAGE study. J Natl Cancer Inst 2013; 105: 536-545
• 20 Kreimer AR. et al. Oral human papillomavirus in healthy individuals: a systematic review of the literature. Sex Transm Dis 2010; 37: 386-391
• 21 Gillison ML. et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012; 307: 693-703
• 22 Giuliano AR. et al. Incidence, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women's Health Study. J Infect Dis 2002; 186: 462-469
• 23 Pickard RK. et al. The prevalence and incidence of oral human papillomavirus infection among young men and women, aged 18-30 years. Sex Transm Dis 2012; 39: 559-566
• 24 Kreimer AR. et al. Incidence and clearance of oral human papillomavirus infection in men: the HIM cohort study. Lancet 2013; 382: 877-887
• 25 D'Souza G. et al. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol 2014; 32: 2408-2415
• 26 D'Souza G. et al. Six-month natural history of oral versus cervical human papillomavirus infection. Int J Cancer 2007; 121: 143-150
• 27 D'Souza G. et al. Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection. PLoS One 2014; 9: e86023
• 28 Partridge JM. et al. Genital human papillomavirus infection in men: incidence and risk factors in a cohort of university students. J Infect Dis 2007; 196: 1128-1136
• 29 Poethko-Muller C, Buttmann-Schweiger N, Ki G.G.S.S.G. [HPV vaccination coverage in German girls: results of the KiGGS study: first follow-up (KiGGS Wave 1)]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2014; 57: 869-877
• 30 Armstrong EP. Prophylaxis of cervical cancer and related cervical disease: a review of the cost-effectiveness of vaccination against oncogenic HPV types. J Manag Care Pharm 2010; 16: 217-230
• 31 Drolet M. et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis 2015; 15: 565-580
• 32 Novakovic D. et al. Juvenile recurrent respiratory papillomatosis: 10-year audit and Australian prevalence estimates. Laryngoscope 2016; 126: 2827-2832
• 33 Matys K. et al. Mother-infant transfer of anti-human papillomavirus (HPV) antibodies following vaccination with the quadrivalent HPV (type 6/11/16/18) virus-like particle vaccine. Clin Vaccine Immunol 2012; 19: 881-885
• 34 Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70
• 35 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646-674
• 36 Napier SS, Speight PM. Natural history of potentially malignant oral lesions and conditions: an overview of the literature. J Oral Pathol Med 2008; 37: 1-10
• 37 van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; terminology, classification and present concepts of management. Oral Oncol 2009; 45: 317-323
• 38 Zhang L. et al. Loss of heterozygosity (LOH) profiles--validated risk predictors for progression to oral cancer. Cancer Prev Res (Phila) 2012; 5: 1081-1089
• 39 Ha PK, Califano JA. The role of human papillomavirus in oral carcinogenesis. Crit Rev Oral Biol Med 2004; 15: 188-196
• 40 Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 1953; 6: 963-968
• 41 Califano J. et al. Genetic progression model for head and neck cancer: implications for field cancerization. Cancer Res 1996; 56: 2488-2492
• 42 van Houten VM. et al. Mutated p53 as a molecular marker for the diagnosis of head and neck cancer. J Pathol 2002; 198: 476-486
• 43 Leemans CR, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer 2011; 11: 9-22
• 44 Rietbergen MM. et al. No evidence for active human papillomavirus (HPV) in fields surrounding HPV-positive oropharyngeal tumors. J Oral Pathol Med 2014; 43: 137-142
• 45 Watson IR. et al. Emerging patterns of somatic mutations in cancer. Nat Rev Genet 2013; 14: 703-718
• 46 Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol 2010; 2: a001008
• 47 Seiwert TY. et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res 2015; 21: 632-641
• 48 Lechner M. et al. Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Med 2013; 5: 49
• 49 Wagner S. et al. [HPV-associated head and neck cancer: mutational signature and genomic aberrations]. HNO 2015; 63: 758-767
• 50 Cancer Genome Atlas, N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015; 517: 576-582
• 51 Gaykalova DA. et al. Novel insight into mutational landscape of head and neck squamous cell carcinoma. PLoS One 2014; 9: e93102
• 52 Keating PJ. et al. Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression. Br J Cancer 1995; 72: 405-411
• 53 Gollin SM. Cytogenetic alterations and their molecular genetic correlates in head and neck squamous cell carcinoma: a next generation window to the biology of disease. Genes Chromosomes Cancer 2014; 53: 972-990
• 54 Noutomi Y. et al. Comparative genomic hybridization reveals genetic progression of oral squamous cell carcinoma from dysplasia via two different tumourigenic pathways. J Pathol 2006; 210: 67-74
• 55 Wreesmann VB. et al. Genetic abnormalities associated with nodal metastasis in head and neck cancer. Head Neck 2004; 26: 10-15
• 56 Klussmann JP. et al. Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res 2009; 15: 1779-1786
• 57 Hopman AH. et al. Genomic integration of oncogenic HPV and gain of the human telomerase gene TERC at 3q26 are strongly associated events in the progression of uterine cervical dysplasia to invasive cancer. J Pathol 2006; 210: 412-419
• 58 Mooren JJ. et al. Chromosome stability in tonsillar squamous cell carcinoma is associated with HPV16 integration and indicates a favorable prognosis. Int J Cancer 2013; 132: 1781-1789
• 59 Prigge ES. et al. p16(INK4a) /Ki-67 co-expression specifically identifies transformed cells in the head and neck region. Int J Cancer 2015; 136: 1589-1599
• 60 Mooren JJ. et al. P16(INK4A) immunostaining is a strong indicator for high-risk-HPV-associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low-risk-HPV-infection in head and neck papillomas and laryngeal dysplasias. Int J Cancer 2014; 134: 2108-2117
• 61 Reimers N. et al. Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 2007; 120: 1731-1738
• 62 Vent J. et al. p16 expression in carcinoma of unknown primary: diagnostic indicator and prognostic marker. Head Neck 2013; 35: 1521-1526
• 63 Jung AC. et al. Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma. Int J Cancer 2010; 126: 1882-1894
• 64 Gao G, Smith DI. Very large common fragile site genes and their potential role in cancer development. Cell Mol Life Sci 2014; 71: 4601-4615
• 65 Karim R. et al. Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte's innate immune response. PLoS Pathog 2013; 9: e1003384
• 66 Olthof NC. et al. Comprehensive analysis of HPV16 integration in OSCC reveals no significant impact of physical status on viral oncogene and virally disrupted human gene expression. PLoS One 2014; 9: e88718
• 67 Olthof NC. et al. Viral load, gene expression and mapping of viral integration sites in HPV16-associated HNSCC cell lines. Int J Cancer 2015; 136: E207-E218
• 68 Nulton TJ. et al. Analysis of The Cancer Genome Atlas sequencing data reveals novel properties of the human papillomavirus 16 genome in head and neck squamous cell carcinoma. Oncotarget 2017; 8: 17684-17699
• 69 Lace MJ. et al. Human papillomavirus type 16 (HPV-16) genomes integrated in head and neck cancers and in HPV-16-immortalized human keratinocyte clones express chimeric virus-cell mRNAs similar to those found in cervical cancers. J Virol 2011; 85: 1645-1654
• 70 Karunasinghe N et al. Influence of Aldo-keto reductase 1C3 in prostate cancer – a mini review. Curr Cancer Drug Targets 2017
• 71 Kostareli E. et al. HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest 2013; 123: 2488-2501
• 72 Minarovits J. et al. Epigenetic dysregulation in virus-associated neoplasms. Adv Exp Med Biol 2016; 879: 71-90
• 73 Reed AL. et al. High frequency of p16 (CDKN2/MTS-1/INK4A) inactivation in head and neck squamous cell carcinoma. Cancer Res 1996; 56: 3630-3633
• 74 McLaughlin-Drubin ME, Park D, Munger K. Tumor suppressor p16INK4A is necessary for survival of cervical carcinoma cell lines. Proc Natl Acad Sci U S A 2013; 110: 16175-16180
• 75 Munger K, Gwin TK, McLaughlin-Drubin ME. p16 in HPV-associated cancers. Oncotarget 2013; 4: 1864-1865
• 76 Schlecht NF. et al. Epigenetic changes in the CDKN2A locus are associated with differential expression of P16INK4A and P14ARF in HPV-positive oropharyngeal squamous cell carcinoma. Cancer Med 2015; 4: 342-353
• 77 Wijetunga NA. et al. Novel epigenetic changes in CDKN2A are associated with progression of cervical intraepithelial neoplasia. Gynecol Oncol 2016; 142: 566-573
• 78 Kostareli E. et al. Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients. Epigenetics 2016; 11: 61-73
• 79 Reuschenbach M. et al. Methylation status of HPV16 E2-binding sites classifies subtypes of HPV-associated oropharyngeal cancers. Cancer 2015; 121: 1966-1976
• 80 Chaiwongkot A. et al. Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions. Int J Cancer 2013; 132: 2087-2094
• 81 Wagner S. et al. Human papillomavirus-related head and neck cancer. Oncol Res Treat 2017; 40: 334-340
• 82 Mirghani H. et al. Comparative analysis of micro-RNAs in human papillomavirus-positive versus -negative oropharyngeal cancers. Head Neck 2016; 38: 1634-1642
• 83 Lajer CB. et al. Different miRNA signatures of oral and pharyngeal squamous cell carcinomas: a prospective translational study. Br J Cancer 2011; 104: 830-840
• 84 Lajer CB. et al. The role of miRNAs in human papilloma virus (HPV)-associated cancers: bridging between HPV-related head and neck cancer and cervical cancer. Br J Cancer 2012; 106: 1526-1534
• 85 Wald AI. et al. Alteration of microRNA profiles in squamous cell carcinoma of the head and neck cell lines by human papillomavirus. Head Neck 2011; 33: 504-512
• 86 Melar-New M, Laimins LA. Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins. J Virol 2010; 84: 5212-5221
• 87 Srivastava K. et al. p63 drives invasion in keratinocytes expressing HPV16 E6/E7 genes through regulation of Src-FAK signalling. Oncotarget 2017; 8: 16202-16219
• 88 Qian K. et al. Identification and validation of human papillomavirus encoded microRNAs. PLoS One 2013; 8: e70202
• 89 Lin L. et al. Two less common human microRNAs miR-875 and miR-3144 target a conserved site of E6 oncogene in most high-risk human papillomavirus subtypes. Protein Cell 2015; 6: 575-588
• 90 Janssen HL. et al. Hypoxia in head and neck cancer: how much, how important?. Head Neck 2005; 27: 622-638
• 91 Lindel K. et al. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 2001; 92: 805-813
• 92 Aebersold DM. et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res 2001; 61: 2911-2916
• 93 Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer 2004; 4: 891-899
• 94 Denko NC. Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 2008; 8: 705-713
• 95 Mazurek S. Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells. Int J Biochem Cell Biol 2011; 43: 969-980
• 96 Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324: 1029-1033
• 97 Masoud GN, Li W. HIF-1alpha pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B 2015; 5: 378-389
• 98 Bardos JI, Ashcroft M. Negative and positive regulation of HIF-1: a complex network. Biochim Biophys Acta 2005; 1755: 107-120
• 99 Hoppe-Seyler K. et al. Induction of dormancy in hypoxic human papillomavirus-positive cancer cells. Proc Natl Acad Sci U S A 2017; 114: E990-E998
• 100 Nakamura M. et al. Hypoxia-specific stabilization of HIF-1alpha by human papillomaviruses. Virology 2009; 387: 442-448
• 101 Bodily JM, Mehta KP, Laimins LA. Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases. Cancer Res 2011; 71: 1187-1195
• 102 Cuninghame S, Jackson R, Zehbe I. Hypoxia-inducible factor 1 and its role in viral carcinogenesis. Virology 2014; 456-457: 370-383
• 103 Noch E, Khalili K. Oncogenic viruses and tumor glucose metabolism: like kids in a candy store. Mol Cancer Ther 2012; 11: 14-23
• 104 Amador-Molina A. et al. Role of innate immunity against human papillomavirus (HPV) infections and effect of adjuvants in promoting specific immune response. Viruses 2013; 5: 2624-2642
• 105 Orange JS. Natural killer cell deficiency. J Allergy Clin Immunol 2013; 132: 515-525 quiz 526
• 106 Viscidi RP. et al. Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica. Cancer Epidemiol Biomarkers Prev 2004; 13: 324-327
• 107 Woo YL. et al. Characterising the local immune responses in cervical intraepithelial neoplasia: a cross-sectional and longitudinal analysis. BJOG 2008; 115: 1616-1621 discussion 1621–1622
• 108 Cicchini L et al. Suppression of antitumor immune responses by human papillomavirus through Epigenetic Downregulation of CXCL14. MBio 2016; 7
• 109 Pacini L. et al. Downregulation of Toll-like receptor 9 expression by beta human papillomavirus 38 and implications for cell cycle control. J Virol 2015; 89: 11396-11405
• 110 Eggensperger S, Tampe R. The transporter associated with antigen processing: a key player in adaptive immunity. Biol Chem 2015; 396: 1059-1072
• 111 Richards KH. et al. The human papillomavirus (HPV) E7 protein antagonises an Imiquimod-induced inflammatory pathway in primary human keratinocytes. Sci Rep 2015; 5: 12922
• 112 Niebler M. et al. Post-translational control of IL-1beta via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53. PLoS Pathog 2013; 9: e1003536
• 113 Ashrafi GH. et al. E5 protein of human papillomavirus type 16 selectively downregulates surface HLA class I. Int J Cancer 2005; 113: 276-283
• 114 Ashrafi GH. et al. E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain. Int J Cancer 2006; 119: 2105-2112
• 115 Wagner S. et al. CD56-positive lymphocyte infiltration in relation to human papillomavirus association and prognostic significance in oropharyngeal squamous cell carcinoma. Int J Cancer 2016; 138: 2263-2273
• 116 Miura S. et al. CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV. J Virol 2010; 84: 11614-11623
• 117 Zhang B. et al. The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-gamma. Virology 2003; 310: 100-108
• 118 Fahey LM. et al. A major role for the minor capsid protein of human papillomavirus type 16 in immune escape. J Immunol 2009; 183: 6151-6156
• 119 Hanna E. et al. A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck. Cancer Res 2001; 61: 2376-2380
• 120 Chung CH. et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell 2004; 5: 489-500
• 121 Walter V. et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS One 2013; 8: e56823
• 122 Wichmann G. et al. The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer. Int J Cancer 2015; 137: 2846-2857
• 123 Verhaak RG. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010; 17: 98-110
• 124 Wilkerson MD. et al. Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types. Clin Cancer Res 2010; 16: 4864-4875
• 125 Sorlie T. et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A 2003; 100: 8418-8423
• 126 Keck MK. et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin Cancer Res 2015; 21: 870-881
• 127 Saba NF. et al. Mutation and transcriptional profiling of formalin-fixed paraffin embedded specimens as companion methods to immunohistochemistry for determining therapeutic targets in Oropharyngeal Squamous Cell Carcinoma (OPSCC): A Pilot of Proof of Principle. Head Neck Pathol 2015; 9: 223-235
• 128 Alberico S. et al. [Maternal-fetal transmission of human papillomavirus]. Minerva Ginecol 1996; 48: 199-204
• 129 D'Souza G. et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356: 1944-1956
• 130 Hernandez BY. et al. Transmission of human papillomavirus in heterosexual couples. Emerg Infect Dis 2008; 14: 888-894
• 131 Gillison ML. et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 2008; 100: 407-420
• 132 Dahlstrom KR. et al. Socioeconomic characteristics of patients with oropharyngeal carcinoma according to tumor HPV status, patient smoking status, and sexual behavior. Oral Oncol 2015; 51: 832-838
• 133 Stenmark MH. et al. Influence of human papillomavirus on the clinical presentation of oropharyngeal carcinoma in the United States. Laryngoscope 2017; 127: 2270-2278
• 134 D'Souza G. et al. Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol 2010; 46: 100-410
• 135 Combes JD, Chen AA, Franceschi S. Prevalence of human papillomavirus in cancer of the oropharynx by gender. Cancer Epidemiol Biomarkers Prev 2014; 23: 2954-2958
• 136 Klussmann JP. et al. Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer 2001; 92: 2875-2884
• 137 Ng M. et al. Smoking prevalence and cigarette consumption in 187 countries, 1980-2012. JAMA 2014; 311: 183-192
• 138 Chaturvedi AK. et al. Burden of HPV-positive oropharynx cancers among ever and never smokers in the U.S. population. Oral Oncol 2016; 60: 61-67
• 139 Ang KK. et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010; 363: 24-35
• 140 Gillison ML. et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012; 30: 2102-2111
• 141 Maniakas A. et al. North-American survey on HPV-DNA and p16 testing for head and neck squamous cell carcinoma. Oral Oncol 2014; 50: 942-946
• 142 Prigge ES. et al. Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: A systematic review and meta-analysis. Int J Cancer 2017; 140: 1186-1198
• 143 Smith EM. et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 2004; 96: 449-455
• 144 Nordfors C. et al. Human papillomavirus prevalence is high in oral samples of patients with tonsillar and base of tongue cancer. Oral Oncol 2014; 50: 491-497
• 145 Chuang AY. et al. Presence of HPV DNA in convalescent salivary rinses is an adverse prognostic marker in head and neck squamous cell carcinoma. Oral Oncol 2008; 44: 915-919
• 146 Rotnaglova E. et al. HPV involvement in tonsillar cancer: prognostic significance and clinically relevant markers. Int J Cancer 2011; 129: 101-110
• 147 Kreimer AR. et al. Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol 2013; 31: 2708-2715
• 148 Beachler DC. et al. HPV16 E6 seropositivity among cancer-free men with oral, anal or genital HPV16 infection. Papillomavirus Res 2016; 2: 141-144
• 149 Nelson HH et al. Immune response to hpv16 e6 and e7 proteins and patient outcomes in head and neck cancer. JAMA Oncol 2016
• 150 Kreimer AR. et al. Kinetics of the human papillomavirus type 16 e6 antibody response prior to oropharyngeal cancer. J Natl Cancer Inst 2017; 109 DOI: 10.1093/jnci/djx005.
• 151 Guardiola E. et al. Is there still a role for triple endoscopy as part of staging for head and neck cancer?. Curr Opin Otolaryngol Head Neck Surg 2006; 14: 85-88
• 152 Martel M. et al. The role of HPV on the risk of second primary neoplasia in patients with oropharyngeal carcinoma. Oral Oncol 2017; 64: 37-43
• 153 Jain KS. et al. Synchronous cancers in patients with head and neck cancer: risks in the era of human papillomavirus-associated oropharyngeal cancer. Cancer 2013; 119: 1832-1837
• 154 Sharma SJ. et al. [Current practice of tumour endoscopy in German ENT-clinics]. Laryngorhinootologie 2013; 92: 166-169
• 155 Graves EE. et al. Quantitative and qualitative analysis of [(18)F]FDG and [(18)F]FAZA positron emission tomography of head and neck cancers and associations with HPV status and treatment outcome. Eur J Nucl Med Mol Imaging 2016; 43: 617-625
• 156 Hanns E. et al. Human Papillomavirus-related tumours of the oropharynx display a lower tumour hypoxia signature. Oral Oncol 2015; 51: 848-856
• 157 Schouten CS. et al. Interaction of quantitative (18)F-FDG-PET-CT imaging parameters and human papillomavirus status in oropharyngeal squamous cell carcinoma. Head Neck 2016; 38: 529-535
• 158 Thorwarth D. et al. Combined uptake of [18 F]FDG and [18 F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol 2006; 80: 151-156
• 159 Mortensen LS. et al. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol 2012; 105: 14-20
• 160 Mehanna H. et al. PET-NECK: a multicentre randomised Phase III non-inferiority trial comparing a positron emission tomography-computerised tomography-guided watch-and-wait policy with planned neck dissection in the management of locally advanced (N2/N3) nodal metastases in patients with squamous cell head and neck cancer. Health Technol Assess 2017; 21: 1-122
• 161 Bogowicz M et al. Computed tomography radiomics predicts hpv status and local tumor control after definitive radiochemotherapy in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2017
• 162 Parmar C. et al. Radiomic machine-learning classifiers for prognostic biomarkers of head and neck cancer. Front Oncol 2015; 5: 272
• 163 Aerts HJ. et al. Decoding tumour phenotype by noninvasive imaging using a quantitative radiomics approach. Nat Commun 2014; 5: 4006
• 164 Ou D. et al. Predictive and prognostic value of CT based radiomics signature in locally advanced head and neck cancers patients treated with concurrent chemoradiotherapy or bioradiotherapy and its added value to Human Papillomavirus status. Oral Oncol 2017; 71: 150-155
• 165 Klozar J. et al. Nodal status is not a prognostic factor in patients with HPV-positive oral/oropharyngeal tumors. J Surg Oncol 2013; 107: 625-633
• 166 Straetmans JM. et al. Human papillomavirus reduces the prognostic value of nodal involvement in tonsillar squamous cell carcinomas. Laryngoscope 2009; 119: 1951-1957
• 167 Sedaghat AR. et al. Prognostic significance of human papillomavirus in oropharyngeal squamous cell carcinomas. Laryngoscope 2009; 119: 1542-1549
• 168 Wittekindt C, Klussmann JP. Tumor staging and HPV-related oropharyngeal cancer. Recent Results Cancer Res 2017; 206: 123-133
• 169 O'Sullivan B. et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study. Lancet Oncol 2016; 17: 440-451
• 170 Sinha P. et al. High metastatic node number, not extracapsular spread or N-classification is a node-related prognosticator in transorally-resected, neck-dissected p16-positive oropharynx cancer. Oral Oncol 2015; 51: 514-520
• 171 Coatesworth AP, MacLennan K. Squamous cell carcinoma of the upper aerodigestive tract: the prevalence of microscopic extracapsular spread and soft tissue deposits in the clinically N0 neck. Head Neck 2002; 24: 258-261
• 172 Greenberg JS. et al. Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer 2003; 97: 1464-1470
• 173 Bernier J. et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 2005; 27: 843-850
• 174 Sinha P. et al. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer 2012; 118: 3519-3530
• 175 Maxwell JH. et al. Extracapsular spread in head and neck carcinoma: impact of site and human papillomavirus status. Cancer 2013; 119: 3302-3308
• 176 van den Brekel MW. et al. Observer variation in the histopathologic assessment of extranodal tumor spread in lymph node metastases in the neck. Head Neck 2012; 34: 840-845
• 177 Lewis Jr JS. et al. Extracapsular extension is a poor predictor of disease recurrence in surgically treated oropharyngeal squamous cell carcinoma. Mod Pathol 2011; 24: 1413-1420
• 178 Wittekindt C. et al. Basics of tumor development and importance of human papilloma virus (HPV) for head and neck cancer. GMS Curr Top Otorhinolaryngol Head Neck Surg 2012; 11: Doc09
• 179 El-Naggar AK, Westra WH. p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck 2012; 34: 459-461
• 180 Malm IJ. et al. Evaluation of proposed staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma. Cancer 2017; 123: 1768-1777
• 181 Husain ZA. et al. A comparison of prognostic ability of staging systems for human papillomavirus-related oropharyngeal squamous cell carcinoma. JAMA Oncol 2017; 3: 358-365
• 182 Arenz A. et al. Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis. Strahlenther Onkol 2014; 190: 839-846
• 183 Rieckmann T. et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 2013; 107: 242-246
• 184 Petrelli F, Sarti E, Barni S. Predictive value of human papillomavirus in oropharyngeal carcinoma treated with radiotherapy: An updated systematic review and meta-analysis of 30 trials. Head Neck 2014; 36: 750-759
• 185 Lassen P. et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009; 27: 1992-1998
• 186 Semrau R. et al. Prognostic impact of human papillomavirus status, survivin, and epidermal growth factor receptor expression on survival in patients treated with radiochemotherapy for very advanced nonresectable oropharyngeal cancer. Head Neck 2013; 35: 1339-1344
• 187 Garden AS. et al. Radiation therapy (with or without neck surgery) for phenotypic human papillomavirus-associated oropharyngeal cancer. Cancer 2016; 122: 1702-1707
• 188 O'Sullivan B. et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013; 31: 543-550
• 189 Sinha P. et al. Does elimination of planned postoperative radiation to the primary bed in p16-positive, transorally-resected oropharyngeal carcinoma associate with poorer outcomes?. Oral Oncol 2016; 61: 127-134
• 190 Al-Mamgani A, Verheij M, van den Brekel MWM. Elective unilateral nodal irradiation in head and neck squamous cell carcinoma: A paradigm shift. Eur J Cancer 2017; 82: 1-5
• 191 Tassone P. et al. Pathologic markers in surgically treated hpv-associated oropharyngeal cancer: retrospective study, systematic review, and meta-analysis. Ann Otol Rhinol Laryngol 2017; 126: 365-374
• 192 Huang YH. et al. Cystic nodal metastasis in patients with oropharyngeal squamous cell carcinoma receiving chemoradiotherapy: Relationship with human papillomavirus status and failure patterns. PLoS One 2017; 12: e0180779
• 193 Wuerdemann N. et al. Risk factors for overall survival outcome in surgically treated human papillomavirus-negative and positive patients with oropharyngeal cancer. Oncol Res Treat 2017; 40: 320-327
• 194 Lohaus F. et al. HPV16 DNA status is a strong prognosticator of loco-regional control after postoperative radiochemotherapy of locally advanced oropharyngeal carcinoma: results from a multicentre explorative study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG). Radiother Oncol 2014; 113: 317-323
• 195 Posner MR. et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 2011; 22: 1071-1077
• 196 Toustrup K. et al. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 2012; 102: 122-129
• 197 Rischin D. et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol 2010; 28: 4142-4148
• 198 Ziemann F. et al. Increased sensitivity of HPV-positive head and neck cancer cell lines to x-irradiation +/- Cisplatin due to decreased expression of E6 and E7 oncoproteins and enhanced apoptosis. Am J Cancer Res 2015; 5: 1017-1031
• 199 Rosenthal DI. et al. Association of human papillomavirus and p16 status with outcomes in the IMCL-9815 phase iii registration trial for patients with locoregionally advanced oropharyngeal squamous cell carcinoma of the head and neck treated with radiotherapy With or Without Cetuximab. J Clin Oncol 2016; 34: 1300-1308
• 200 Ang KK. et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32: 2940-2950
• 201 Chera BS. et al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys 2015; 93: 976-985
• 202 Molony P. et al. Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status. Head Neck 2017; 39: 1680-1688
• 203 Kharytaniuk N. et al. Association of extracapsular spread with survival according to human papillomavirus status in oropharynx squamous cell carcinoma and carcinoma of unknown primary site. JAMA Otolaryngol Head Neck Surg 2016; 142: 683-690
• 204 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 2008; 100: 261-269
• 205 Inhestern J. et al. A two-arm multicenter phase II trial of one cycle chemoselection split-dose docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy before two cycles of split TPF followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1). Ann Oncol 2017; 28: 1917-1922
• 206 Topalian SL. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-2454
• 207 Hong AM. et al. PD-L1 expression in tonsillar cancer is associated with human papillomavirus positivity and improved survival: implications for anti-PD1 clinical trials. Oncotarget 2016; 7: 77010-77020
• 208 Scheel AH. et al. Interlaboratory-concordance of PD-L1 immunohistochemistry for non-small cell lung cancer. Histopathology 2017; DOI: 10.1111/his.13375. [Epub ahead of print]
• 209 Scheel AH. et al. [Predictive PD-L1 immunohistochemistry for non-small cell lung cancer: Current state of the art and experiences of the first German harmonization study]. Pathologe 2016; 37: 557-567
• 210 Gandini S, Massi D, Mandala M. PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2016; 100: 88-98
• 211 Oguejiofor K. et al. Stromal infiltration of CD8 T cells is associated with improved clinical outcome in HPV-positive oropharyngeal squamous carcinoma. Br J Cancer 2015; 113: 886-893
• 212 Badoual C. et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 2013; 73: 128-138
• 213 Oguejiofor K. et al. Distinct patterns of infiltrating CD8+ T cells in HPV+ and CD68 macrophages in HPV- oropharyngeal squamous cell carcinomas are associated with better clinical outcome but PD-L1 expression is not prognostic. Oncotarget 2017; 8: 14416-14427
• 214 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 2016; 17: 956-965
• 215 Ferris RL. et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016; 375: 1856-1867
• 216 Addeo R, Caraglia M, Iuliano G. Pembrolizumab: the value of PDL1 biomarker in head and neck cancer. Expert Opin Biol Ther 2016; 16: 1075-1078
• 217 Kenter GG. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 2009; 361: 1838-1847
• 218 Reuschenbach M. et al. A phase 1/2a study to test the safety and immunogenicity of a p16(INK4a) peptide vaccine in patients with advanced human papillomavirus-associated cancers. Cancer 2016; 122: 1425-1433
• 219 Fakhry C. et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 2014; 32: 3365-3373
• 220 Huang SH. et al. Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncol 2013; 49: 79-85
• 221 Trosman SJ. et al. Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy. JAMA Otolaryngol Head Neck Surg 2015; 141: 457-462
• 222 Dave E. et al. The prognostic impact of human papillomavirus status following treatment failure in oropharyngeal cancer. PLoS One 2017; 12: e0181108
• 223 Sinha P. et al. Distant metastasis in p16-positive oropharyngeal squamous cell carcinoma: a critical analysis of patterns and outcomes. Oral Oncol 2014; 50: 45-51
• 224 Duprez F. et al. Distant metastases in head and neck cancer. Head Neck 2017; 39: 1733-1743
• 225 Sweeny L. et al. Outcomes after surgical salvage for recurrent oropharyngeal squamous cell carcinoma. Oral Oncol 2016; 60: 118-124
• 226 Patel SN. et al. Salvage surgery for locally recurrent oropharyngeal cancer. Head Neck 2016; 38 (Suppl. 01) E658-E664
• 227 Sims JR. et al. Management of recurrent and metastatic hpv-positive oropharyngeal squamous cell carcinoma after transoral robotic surgery. Otolaryngol Head Neck Surg 2017; 157: 69-76
• 228 Dang RP. et al. Clinical outcomes in patients with recurrent or metastatic human papilloma virus-positive head and neck cancer. Anticancer Res 2016; 36: 1703-1709
• 229 Etges CL. et al. Screening tools for dysphagia: a systematic review. Codas 2014; 26: 343-349
• 230 Colodny N. Interjudge and intrajudge reliabilities in fiberoptic endoscopic evaluation of swallowing (fees) using the penetration-aspiration scale: a replication study. Dysphagia 2002; 17: 308-315
• 231 Frakes JM. et al. Determining optimal follow-up in the management of human papillomavirus-positive oropharyngeal cancer. Cancer 2016; 122: 634-641
• 232 Sharma A. et al. Human papillomavirus-positive oral cavity and oropharyngeal cancer patients do not have better quality-of-life trajectories. Otolaryngol Head Neck Surg 2012; 146: 739-745
• 233 Stier-Jarmer M. et al. Assessment of functional outcomes in head and neck cancer. Eur Arch Otorhinolaryngol 2014; 271: 2021-2044
• 234 Morris LG. et al. Second primary cancers after an index head and neck cancer: subsite-specific trends in the era of human papillomavirus-associated oropharyngeal cancer. J Clin Oncol 2011; 29: 739-746
• 235 Wang Y. et al. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med 2015; 7: 293ra104
• 236 Cheng F, Su L, Qian C. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget 2016; 7: 48832-48841
• 237 Jahr S. et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61: 1659-1665
• 238 Bettegowda C. et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med 2014; 6: 224ra24
• 239 Haber DA, Velculescu VE. Blood-based analyses of cancer: circulating tumor cells and circulating tumor DNA. Cancer Discov 2014; 4: 650-661
• 240 Amirian ES. et al. Presence of viral DNA in whole-genome sequencing of brain tumor tissues from the cancer genome atlas. J Virol 2014; 88: 774
• 241 Lo YM. et al. Quantitative analysis of cell-free Epstein-Barr virus DNA in plasma of patients with nasopharyngeal carcinoma. Cancer Res 1999; 59: 1188-1191
• 242 Chan KCA. et al. Analysis of plasma epstein-barr virus dna to screen for nasopharyngeal cancer. N Engl J Med 2017; 377: 513-522
• 243 Cao H. et al. Quantitation of human papillomavirus DNA in plasma of oropharyngeal carcinoma patients. Int J Radiat Oncol Biol Phys 2012; 82: e351-e358
• 244 Yun CH. et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008; 105: 2070-2075