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 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
  • In situ hybridization (ISH) for HPV DNA
    • ARUP Laboratories’ only available HPV test for oropharyngeal specimens
    • Sensitive
    • Formalin-fixed, paraffin-embedded (FFPE) specimen acceptable
    • ARUP test  – Human Papillomavirus (HPV) High Risk in situ Hybridization, Paraffin
  • Polymerase chain reaction (PCR) for HPV DNA
    • FFPE specimen acceptable
    • ARUP test – Human Papillomavirus (HPV) Genotype 16 and 18 by PCR, Head and Neck
  • Immunohistochemistry (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

Diagnosis

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

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/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 (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

• Nonneoplastic
  • 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
    • Metastatic carcinoma
    • Sarcoma
    • Lymphoma
      • B cell
      • T/NK cell
    • Melanoma

Screening

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

Monitoring

• 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

Background

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
  • Epstein-Barr virus – associated with nasopharyngeal carcinoma
• 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