Head and Neck Cancer

Key Points

HPV Testing in Head and Neck Cancer

Within the head and neck squamous cell cancers (HNSCC), those that are human papilloma virus positive (HPV+) are recognized as a distinct subset based on etiology, molecular-genetic aberrations, and favorable clinical outcomes.  The recent NCCN Clinical Practice Guidelines in Oncology recommend that oropharyngeal SCCs are tested for high risk oncogenic HPV (NCCN guidelines, 2012).   Either immunohistochemistry (IHC) for analysis of p16 expression or in situ hybridization (ISH) for detection of HPV DNA in tumor cell nuclei is recommended.  HPV+ tumors are more common in the tongue and tonsils (lingual and palatine) and tend to occur in younger individuals who do not have the typical risk factors of tobacco smoking and alcohol consumption.

Detection of oncogenic HPV infection in tumors

• Best method for detection not established; choice depends on specimen available
• Available options for detecting HPV DNA in tumor cell nuclei
  • ISH for HPV DNA
    • Sensitive
    • Formalin-fixed, paraffin-embedded (FFPE) specimen acceptable
    • ARUP test  –  Human Papillomavirus (HPV) High Risk in situ Hybridization, Paraffin
  • IHC for p16 expression  (alternate name is  CDKN2A immunostaining)
    • Serves as a surrogate marker; does not confirm presence of HPV genome
    • FFPE specimen acceptable
    • ARUP test  – p16 by Immunohistochemistry

Diagnosis

Indications for Testing

• Persistence of symptoms listed in clinical presentation (see Clinical Background tab), particularly hoarseness, sore throat, or dysphagia

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
• Epstein-Barr virus (EBV) for nasopharyngeal carcinomas

Imaging Studies

• CT/MRI/PET – establish local and regional extent of disease
  • PET – 90% sensitivity and 94% specificity in detecting nodal metastases
    • Useful in treatment planning and monitoring
  • CT – 82% sensitivity and 85% specificity

Prognosis

• Markers
  • HPV – HPV+ tumors have improved prognosis
  • EGFR – high levels indicate poor prognosis
    • May be useful in establishing treatment regimens
  • p53 – may predict poor prognosis
  • HER2 – variably expressed but may be associated with improved prognosis
• Stage at diagnosis helps predict survival
• Presence of comorbidity – strong predictor of mortality in head and neck cancers
• Nature and location of tumors
  • Great impact on patient perceptions for future quality of life
  • May determine treatment options that ultimately affect patient mortality

Differential Diagnosis

• Non-neoplastic
  • Congenital
    • Thyroglossal duct cyst
    • Branchial cleft cyst
    • Hemangioma
    • Lymphangioma
    • Dermoid
  • Infectious
    • Acute lymphadenitis
    • Abscess/deep-space neck infection
    • Sialadenitis
    • Viral
      • EBV
      • Cytomegalovirus
      • HIV
    • Bacterial
      • M. tuberculosis
      • Bartonella spp
    • Parasitic
      • Toxoplasma gondii
  • Systemic disease
    • Sjögren syndrome
    • Kimura disease
    • Castleman disease
• Neoplastic
  • Benign
    • Lipoma
    • Salivary tumor
    • Thyroid goiter
    • Paragangliomas
  • Malignant
    • Salivary
    • Thyroid
    • Metastatic carcinoma
    • Sarcoma
    • Lymphoma
      • B cell
      • T/NK cell
    • Melanoma

Monitoring

Clinical Background

Squamous cell carcinoma (SCC) of the head and neck is the most common malignancy (90%) of the upper aerodigestive tract. Less common malignancies include melanoma, sarcoma, lymphoma, and oral metastases.

Epidemiology

• Incidence
  • >49,000 new U.S. cases during 2010 – represents 3% of new cancers
  • >600,000 new cases worldwide
  • Increased incidence over the past 10 years – attributed to increasing prevalence of human papillomavirus (HPV)
    • HPV infection linked to practice of oral sex with multiple sex partners  
    • Cancer of the base of the tongue and tonsils (especially in <45 age group) is the most common etiology of this increased incidence – these cancers are highly related to 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

• Tobacco use – increases risk five- to 25-fold
• Alcohol use – when combined with smoking, risk increases geometrically 
• Occupational exposures
  • Nickel refining, chromium, mustard gas, radium
  • Woodworking and tanning byproducts
• Viral infection
  • Epstein-Barr virus – associated with nasopharyngeal carcinoma
  • HPV types 16, 18, 31 – highly associated with carcinoma of lingual and palatine tonsils
    • Tend not to be associated with smoking or alcohol consumption
• Betel nut chewing
• Family history – 1.2- to 2.3-fold higher risk
• Primary head and neck tumor increases risk for secondary tumors in other head and neck sites and for tumors of lung, esophagus, and other sites sharing similar risk factors

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, and 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
• See Thyroid Cancer for information on thyroid tumors

Prevention

• Benefit of HPV vaccination in reducing head and neck cancer risk is unknown

Indications for Laboratory Testing

• 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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Lipid Associated Sialic Acid 0080467 Method: Quantitative Spectrophotometry	Limited use as a marker in squamous cell cancer
p53 with Interpretation by Immunohistochemistry 0049250 Method: Immunohistochemistry	Prognostic marker
Squamous Cell Carcinoma Antigen, Serum 0081054 Method: Quantitative Enzyme-Linked Immunosorbent Assay	Limited use as a marker for monitoring