Head and Neck Cancer

Squamous cell carcinoma (SCC) of the head and neck is the most common malignancy (90%) of the upper aerodigestive tract. Cancer can develop in several different parts of the head and neck; some of the most common include oral cancer, laryngeal cancer, pharyngeal (throat) cancer, nasal cavity and paranasal sinus cancers, thyroid cancer, and parathyroid tumors. 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.

Key Points

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


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


  • Gold standard for diagnosis – usually obtained via endoscopy, biopsy, fine needle aspiration of mass
  • Immunohistochemistry and in situ hybridization
  • 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


  • 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 (NIH, 2015)
    • 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



  • 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


  • 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

ARUP Laboratory Tests

Preferred in situ hybridization (ISH) test

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

Test for human papillomavirus (HPV) genotype 16 and 18 in patients previously diagnosed with head and neck squamous cell carcinoma

Aid in histologic diagnosis of head and neck cancer

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

HPV ISH testing recommended to confirm HPV

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

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

Measure protein expression

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

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

Adjunct test for diagnosing nasopharyngeal carcinoma

Related Tests

Aid in histologic diagnosis of head and neck cancer

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

Useful as a tumor marker for squamous cell carcinomas of the head and neck

Medical Experts



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