Head and Neck Cancer

Throat Cancer

Primary Author: Schlaberg, Robert, MD, MPH.
  • Key Points
  • Diagnosis
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

HPV Testing in Head and Neck Cancer

Within the head and neck squamous cell cancers (HNSCC), those that are human papillomavirus positive (HPV+) are recognized as a distinct subset based on etiology, molecular-genetic aberrations, and favorable clinical outcomes. The overall incidence of HPV+ head and neck cancers is increasing in the U.S., while the incidence of HPV negative (HPV-) cancers (primarily tobacco- and alcohol-related) is decreasing. HPV+ tumors are more common in the tongue and tonsils (lingual and palatine) and tend to occur in younger individuals who do not have typical risk factors for head and neck cancer (tobacco smoking and alcohol consumption) (NCCN, 2017).

NCCN recommends that oropharyngeal SCCs (OSCCs) be tested for high-risk oncogenic HPV (NCCN, 2017). Oral HPV type 16 infection increases the risk of oropharyngeal cancer (OC), and a strong causal relationship has been established. HPV types 18, 31, and 33 are responsible for the vast majority of the remaining fraction. Either immunohistochemistry (IHC) for analysis of p16 expression or in situ hybridization (ISH) for detection of HPV DNA in tumor cell nuclei is recommended.

Detection of Oncogenic HPV Infection in Tumors

  • Available options for detecting HPV DNA in tumor cell nuclei
    • ISH for HPV DNA
    • IHC for p16 expression  (alternate name is CDKN2A immunostaining)
      • Protein p16 is usually overexpressed in HPV-associated oropharyngeal squamous cell cancer (HPV-OSCC)
      • Serves as a reliable surrogate marker; does not confirm presence of HPV genome
      • FFPE specimen acceptable
      • ARUP test  – p16 by Immunohistochemistry

Indications for Testing

  • Nonhealing ulcers in oropharynx
  • Sore throat
  • Hoarseness
  • Palpable mass in neck
  • Enlarged lymph nodes
  • Difficulty swallowing

Laboratory Testing

Refer to Key Points section

Histology

  • Gold standard for diagnosis – usually obtained via endoscopy, biopsy, fine needle aspiration of mass
  • Immunohistochemistry and in situ hybridization
    • Refer to Key Points section
  • Epstein-Barr virus (EBV) for nasopharyngeal carcinomas

Imaging Studies

  • CT/MRI/positron emission tomography (PET) – establish local and regional extent of disease
    • PET
      • Useful in treatment planning and monitoring
      • Good sensitivity/specificity for detection of nodal metastases

Prognosis

  • Markers
    • Human papillomavirus (HPV) – positive tumors have improved prognosis
      • Smokers with HPV may have more aggressive tumors (ASCO, 2016)
        • Much higher rate of other mutations for those who smoke >10 pack years
          • Associated with worst prognosis
    • EGFR
      • FISH is sensitive for amplification
      • High levels associated with poor prognosis
      • May be useful in establishing treatment regimens
    • HER2 – variably expressed; may be associated with improved prognosis
    • p53 – may predict poor prognosis
  • Stage at diagnosis
    • Earlier stage associated with higher rate of survival
  • Presence of comorbidity – strong predictor of mortality in head and neck cancers
  • Nature and location of tumors
    • May determine treatment options that ultimately affect patient mortality

Differential Diagnosis

Screening for risk factor human papillomavirus (HPV) oropharyngeal infection is not currently recommended – virus resides in the tonsils and is not highly accessible by swab

  • Squamous cell carcinoma (SCC) antigen
    • Monitoring test only – not intended for use in diagnosis
    • Serial determinations (pre- and postsurgery) are necessary – most useful in monitoring for cancer recurrence
    • Antigen levels decrease to normal levels ~96 hours after removal of lesion
  • Epstein-Barr virus DNA quantitative polymerase chain reaction (PCR) – useful for monitoring treatment response and disease progression in nasopharyngeal carcinoma

Squamous cell carcinoma (SCC) of the head and neck is the most common malignancy (90%) of the upper aerodigestive tract. These carcinomas have historically been associated with substance use (tobacco and alcohol). Currently, there has been an epidemiological shift with up to 70% of these cancers being associated with human papillomavirus (HPV). All head and neck SCCs should be tested for HPV, as these cancers have a different course and prognosis.

Epidemiology

  • Incidence
    • >63,000 estimated new U.S. cases of oral cavity, pharyngeal, and laryngeal cancers – represents ~3.7% of new cancers (NCCN, 2017)
    • >600,000 new cases worldwide
    • Increased incidence over the past 10 years – attributed to increasing prevalence of HPV
  • Age – peaks in 50s
    • Tumors associated with HPV peak in mid 40s
  • Sex – M>F, 3:1
  • Ethnicity – occurs more often in African Americans than Caucasians

Risk Factors

  • Substance abuse
    • Tobacco use – increases risk 5- to 25-fold
    • Alcohol abuse – when combined with smoking, risk increases geometrically
  • HPV types 16, 18, 31 – associated with carcinoma of tonsils and base of tongue
    • Associated with oral sex
    • Risk increased by multiple oral sex partners
  • Other viral infection
  • Occupational exposures
    • Nickel refining, chromium, mustard gas, radium
    • Woodworking and tanning byproducts
  • Family history – 1.2- to 2.3-fold higher risk
  • Betel nut chewing

Pathophysiology

  • Aerodigestive tract is lined with squamous and respiratory epithelium
  • Premalignant disease (epithelial dysplasia) may precede frank malignancy

Clinical Presentation

  • Oral cavity – nonhealing ulcers on the floor of the mouth, tongue, buccal mucosa, hard palate; persistent sore throat
  • Hypopharynx – hoarseness, dysphagia, otalgia, enlarged cervical nodes
  • Oropharynx – sore throat, otalgia, odynophagia, chronic dysphagia
  • Larynx – hoarseness, shortness of breath; supraglottic (neck mass)
  • Nasopharynx – usually late symptoms of bleeding, obstruction, cranial nerve palsy; otitis media unresponsive to antibiotics
  • Salivary glands – swelling, adenopathy
  • Paranasal sinuses – obstructions, symptoms occur usually late in disease
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Human Papillomavirus (HPV), High Risk by in situ Hybridization, Paraffin 2002899
Method: In situ Hybridization

Recommended Use 

Preferred in situ hybridization (ISH) test

Detects high-risk HPV subtypes 16, 18 to determine potential cancer risk

p16 by Immunohistochemistry 2004064
Method: Immunohistochemistry

Recommended Use 

Aid in histologic diagnosis of head and neck cancer

Stained and returned to client pathologist for interpretation; consultation available if needed

Follow-up 

HPV ISH testing recommended to confirm HPV

EGFR Gene Amplification by FISH 2008605
Method: Fluorescence in situ Hybridization

Recommended Use 

Aid in prognostication and therapeutic decision making for neoplasms where amplification has been demonstrated

Limitations 

Tissues fixed in alcohol-based or nonformalin fixatives have not been tested using this method

ERBB2 (HER2) (HercepTest) by Immunohistochemistry 2007332
Method: Immunohistochemistry

Recommended Use 

Measure protein expression

Limitations 

Testing using tissue fixed in alcohol-based or nonformalin fixatives has not been validated using this method

Specimens placed in decal may have a false-negative result

Repeat testing is recommended for discordant results

Epstein-Barr Virus by Quantitative PCR 0051352
Method: Quantitative Polymerase Chain Reaction

Recommended Use 

Quantify Epstein-Barr virus (EBV) viral load as an aid in monitoring EBV-related disease

Epstein-Barr Virus (EBV) by in situ Hybridization, Paraffin 2002902
Method: In situ Hybridization

Recommended Use 

Adjunct test for diagnosing nasopharyngeal carcinoma

Guidelines

NCCN Clinical Practice Guidelines in Oncology, Head and Neck Cancers. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Larynx. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Lip and Oral Cavity. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Apr 2016. College of American Pathologists (CAP). Northfield, IL [Revised Aug 2016; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Nasal Cavity and Paranasal Sinuses. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Pharynx . Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Jun 2017]

Protocol for the Examination of Specimens from Patients with Carcinomas of the Salivary Glands. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Jun 2017]

General References

Barbor M. Mutational Profile May Impact Treatment Decisions for Smokers With Human Papillomavirus–Positive Oropharyngeal Cancer. ASCO Post. [Accessed: Dec 2016]

Hunt JL. An update on molecular diagnostics of squamous and salivary gland tumors of the head and neck. Arch Pathol Lab Med. 2011; 135(5): 602-9. PubMed

Leemans R, Braakhuis BJ, Brakenhoff RH. The molecular biology of head and neck cancer. Nat Rev Cancer. 2011; 11(1): 9-22. PubMed

Marur S, D'Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010; 11(8): 781-9. PubMed

Mehanna H, Paleri V, West CM, Nutting C. Head and neck cancer--Part 1: Epidemiology, presentation, and prevention. BMJ. 2010; 341: c4684. PubMed

Mehanna H, West CM, Nutting C, Paleri V. Head and neck cancer--Part 2: Treatment and prognostic factors. BMJ. 2010; 341: c4690. PubMed

Robinson M, Sloan P, Shaw R. Refining the diagnosis of oropharyngeal squamous cell carcinoma using human papillomavirus testing. Oral Oncol. 2010; 46(7): 492-6. PubMed

Smeets SJ, Hesselink AT, Speel EM, Haesevoets A, Snijders PJ, Pawlita M, Meijer CJ, Braakhuis BJ, Leemans R, Brakenhoff RH. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer. 2007; 121(11): 2465-72. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Jarboe EA, Hunt JP, Layfield LJ. Cytomorphologic diagnosis and HPV testing of metastatic and primary oropharyngeal squamous cell carcinomas: a review and summary of the literature. Diagn Cytopathol. 2012; 40(6): 491-7. PubMed

Layfield LJ. Fine-needle aspiration in the diagnosis of head and neck lesions: a review and discussion of problems in differential diagnosis. Diagn Cytopathol. 2007; 35(12): 798-805. PubMed

Willmore-Payne C, Holden JA, Layfield LJ. Detection of EGFR- and HER2-activating mutations in squamous cell carcinoma involving the head and neck. Mod Pathol. 2006; 19(5): 634-40. PubMed

Medical Reviewers

Ellis, Gary L., DDS, Medical Director, Head and Neck Pathology at ARUP Laboratories; Professor of Pathology, University of Utah

Salama, Mohamed E., MD, Medical Director, Hematopathology and Immunohistochemistry Staining at ARUP Laboratories; Associate Professor of Clinical Pathology, Director of Hematopathology Fellowship Program, University of Utah

Content Reviewed: 
June 2017

Last Update: September 2017