Human papillomavirus associated head and neck cancer
- Robert I Haddad, MD
Robert I Haddad, MD
- Associate Professor of Medicine
- Harvard Medical School
- Section Editors
- Bruce E Brockstein, MD
Bruce E Brockstein, MD
- Section Editor — Cancer of the Head and Neck
- Clinical Professor of Medicine
- University of Chicago Pritzker School of Medicine
- David M Brizel, MD
David M Brizel, MD
- Section Editor — Radiation Therapy
- Leonard R Prosnitz Professor of Radiation Oncology
- Professor of Otolaryngology Head & Neck Surgery
- Duke University Cancer Institute
- Marvin P Fried, MD, FACS
Marvin P Fried, MD, FACS
- Section Editor — Head and Neck Surgery
- Professor and University Chairman, Department of Otorhinolaryngology - Head and Neck Surgery
- Montefiore Medical Center, Albert Einstein College of Medicine
Human papillomavirus (HPV) infection is the most commonly diagnosed sexually transmitted disease in the United States. HPV infection has been etiologically linked with condyloma acuminatum, squamous intraepithelial lesions, and anogenital malignancy, including cervical, vaginal, vulval, penile, and anal carcinoma.
Many patients with oropharyngeal squamous cell carcinomas, particularly those arising in the base of the tongue and in the tonsillar region, do not have the traditional risk factors associated with head and neck cancers (eg, smoking, smokeless tobacco, alcohol consumption). Epidemiologic and molecular studies have identified the HPV-16 genotype of HPV as a causative agent in many of these patients . Other high-risk HPV genotypes, such as HPV-18, 31, or 33, are also causative but are less common. These high-risk HPV infections may also rarely cause cancers at other head and neck sites.
The role of HPV infection in head and neck squamous cell carcinoma is presented here. Other risk factors for head and neck cancer are discussed separately. (See "Epidemiology and risk factors for head and neck cancer", section on 'Risk factors'.)
BIOLOGY OF HPV
HPV are small deoxyribonucleic acid (DNA) viruses that are widely distributed in vertebrates. These viruses contain an 8 kilobase long, double-stranded, circular DNA genome. The papillomavirus genome comprises early and late genes that encode early proteins E1-E7 and late proteins L1-L2. The early proteins are nonstructural proteins involved in replication and transcription of the genome (E1-E5) or in host cell tumoral transformation (E6 and E7), whereas L1 and L2 are the structural capsid proteins of the virion.
The HPV E6 and E7 oncogenes encode proteins consisting of approximately 151 and 98 amino acids, respectively. These genes are largely responsible for the onset and persistence of the malignant process in both head and neck and anogenital cancers.
- Vokes EE, Agrawal N, Seiwert TY. HPV-Associated Head and Neck Cancer. J Natl Cancer Inst 2015; 107:djv344.
- Sturgis EM, Ang KK. The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms? J Natl Compr Canc Netw 2011; 9:665.
- Gillison ML, D'Souza G, Westra W, 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.
- Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011; 29:4294.
- O'Sullivan B, Huang SH, Su J, 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.
- Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013; 31:4550.
- Kreimer AR, Johansson M, Waterboer T, et al. Evaluation of human papillomavirus antibodies and risk of subsequent head and neck cancer. J Clin Oncol 2013; 31:2708.
- Ndiaye C, Mena M, Alemany L, 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.
- Castellsagué X, Alemany L, Quer M, et al. HPV Involvement in Head and Neck Cancers: Comprehensive Assessment of Biomarkers in 3680 Patients. J Natl Cancer Inst 2016; 108:djv403.
- Chakravarthy A, Henderson S, Thirdborough SM, et al. Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted the oropharynx. J Clin Oncol 2016.
- Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012; 307:693.
- D'Souza G, Gross ND, Pai SI, et al. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. J Clin Oncol 2014; 32:2408.
- Agalliu I, Gapstur S, Chen Z, et al. Associations of Oral α-, β-, and γ-Human Papillomavirus Types With Risk of Incident Head and Neck Cancer. JAMA Oncol 2016.
- Shi W, Kato H, Perez-Ordonez B, et al. Comparative prognostic value of HPV16 E6 mRNA compared with in situ hybridization for human oropharyngeal squamous carcinoma. J Clin Oncol 2009; 27:6213.
- Rischin D, Young R, Fisher R. Prognostic significance of HPV and p16 status in patients with oropharyngeal cancer treated on a large international phase III. J Clin Oncol 2009; 27:15s.
- Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006; 24:736.
- Pannone G, Rodolico V, Santoro A, et al. Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization. Infect Agent Cancer 2012; 7:4.
- Kraft S, Faquin WC, Krane JF. HPV-associated neuroendocrine carcinoma of the oropharynx: a rare new entity with potentially aggressive clinical behavior. Am J Surg Pathol 2012; 36:321.
- Näsman A, Attner P, Hammarstedt L, 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.
- Huang SH, Perez-Ordonez B, Liu FF, et al. Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 2012; 82:276.
- Stephen JK, Chen KM, Shah V, et al. Human papillomavirus outcomes in an access-to-care laryngeal cancer cohort. Otolaryngol Head Neck Surg 2012; 146:730.
- Lydiatt WM, Ridge JA, Patel SG, et al. Oropharynx (p16-) and Hypopharynx. In: AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), Springer, New York 2017. p.123.
- O'Sullivan B, Lydiatt WM, Haughey BH, et al. HPV-Mediated (p16+) Oropharyngeal Cancer. In: AJCC Cancer Staging Manual, 8th, Amin MB. (Ed), Springer, New York 2017. p.113.
- Rischin D, Young RJ, Fisher R, 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.
- Posner MR, Lorch JH, Goloubeva O, 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.
- Nguyen-Tan PF, Zhang Q, Ang KK, et al. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol 2014; 32:3858.
- Gillison ML, Zhang Q, Jordan R, 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.
- Marur S, Li S, Cmelak AJ, 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 2016; :JCO2016683300.
- Samuels SE, Vainshtein J, Spector ME, et al. Impact of retropharyngeal adenopathy on distant control and survival in HPV-related oropharyngeal cancer treated with chemoradiotherapy. Radiother Oncol 2015; 116:75.
- Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 2014; 32:3365.
- Kumar B, Cipolla MJ, Old MO, et al. Surgical management of oropharyngeal squamous cell carcinoma: Survival and functional outcomes. Head Neck 2016; 38 Suppl 1:E1794.
- Cmelak AJ, Li S, Goldwasser MA, et al. Phase II trial of chemoradiation for organ preservation in resectable stage III or IV squamous cell carcinomas of the larynx or oropharynx: results of Eastern Cooperative Oncology Group Study E2399. J Clin Oncol 2007; 25:3971.
- Chung CH, Zhang Q, Kong CS, 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.
- Lassen P, Primdahl H, Johansen J, et al. Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol 2014; 113:310.
- Nelson HH, Pawlita M, Michaud DS, et al. Immune Response to HPV16 E6 and E7 Proteins and Patient Outcomes in Head and Neck Cancer. JAMA Oncol 2016.
- BIOLOGY OF HPV
- HPV associated cancers
- - Oropharyngeal carcinoma
- - Non-oropharyngeal carcinoma
- Prevalence of oral HPV infection
- DIAGNOSIS AND BIOMARKER ANALYSIS
- OROPHARYNGEAL CARCINOMA
- Clinicopathologic features
- TNM staging system
- HPV positive versus HPV negative disease
- - Risk subgroup identification
- - Prognosis after recurrence
- NON-OROPHARYNGEAL CARCINOMA