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FeedbackSquamous 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
- 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
- In situ hybridization (ISH) for HPV DNA
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
- PET
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
- Much higher rate of other mutations for those who smoke >10 pack years
- Smokers with HPV may have more aggressive tumors (ASCO, 2016)
- 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
- Human papillomavirus (HPV) – positive tumors have improved 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
- Parasitic
- Systemic disease
- Sjögren syndrome
- Kimura disease
- Castleman disease
- Congenital
- Neoplastic
- Benign
- Lipoma
- Salivary tumor
- Thyroid goiter
- Paragangliomas
- Malignant
- Benign
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
ARUP Laboratory Tests
Preferred in situ hybridization (ISH) test
Detects high-risk HPV subtypes 16, 18 to determine potential cancer risk
In situ Hybridization
Test for human papillomavirus (HPV) genotype 16 and 18 in patients previously diagnosed with head and neck squamous cell carcinoma
Qualitative Polymerase Chain Reaction
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
Immunohistochemistry
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
Fluorescence in situ Hybridization (FISH)
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
Immunohistochemistry
Quantify Epstein-Barr virus (EBV) viral load as an aid in monitoring EBV-related disease
Quantitative Polymerase Chain Reaction
Adjunct test for diagnosing nasopharyngeal carcinoma
In situ hybridization (ISH)
Aid in histologic diagnosis of head and neck cancer
Stained and returned to client pathologist for interpretation; consultation available if needed
Immunohistochemistry
Useful as a tumor marker for squamous cell carcinomas of the head and neck
Immunofluorescence
Medical Experts
Deftereos
Miles
References
ASCO - Mutational Profile May Impact Treatment Decisions for Smokers With Human Papillomavirus-Positive Oropharyngeal Cancer
Barbor M. Mutational Profile May Impact Treatment Decisions for Smokers With Human Papillomavirus-Positive Oropharyngeal Cancer. ASCO Post. [ Accessed: Dec 2016]
CAP - Larynx
College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Carcinomas of the Larynx. [Posted: Oct 2013; Accessed: Mar 2020]
CAP - Lip and Oral Cavity
College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Carcinomas of the Lip and Oral Cavity, Version 3.3.0.0. [Posted: Aug 2016; Accessed: Mar 2020]
CAP - Nasal Cavity and Paranasal Sinus
College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Carcinomas of the Nasal Cavity and Paranasal Sinuses. [Posted: Oct 2013; Accessed: Mar 2020]
CAP - Pharynx
College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Carcinomas of the Pharynx. [Posted: Oct 2013; Accessed: Mar 2020]
CAP - Major Salivary Glands
College of American Pathologists (CAP). Protocol for the Examination of Specimens from Patients with Carcinomas of the Salivary Glands. [Posted: Oct 2013; Accessed: Mar 2020]
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