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.

Tabs Content

Clinical Overview

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

ARUP Lab Tests

Preferred in situ hybridization (ISH) test

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

Human Papillomavirus (HPV) High Risk by in situ Hybridization, Paraffin 3002008

Method: In situ Hybridization

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

Human Papillomavirus (HPV) Genotype 16 and 18 by PCR, Head and Neck 3000414

Method: 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

p16 by Immunohistochemistry 2004064

Method: 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

EGFR Gene Amplification by FISH 3001310

Method: Fluorescence in situ Hybridization

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

ERBB2 (HER2) (HercepTest) by Immunohistochemistry 2007332

Method: Immunohistochemistry

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

Epstein-Barr Virus by Quantitative PCR 0051352

Method: Quantitative Polymerase Chain Reaction

Adjunct test for diagnosing nasopharyngeal carcinoma

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

Method: In situ Hybridization

Related Tests

Aid in histologic diagnosis of head and neck cancer

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

p53 with Interpretation by Immunohistochemistry 0049250

Method: Immunohistochemistry

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

Squamous Cell Carcinoma Antigen, Serum 0081054

Method: Quantitative Enzyme-Linked Immunosorbent Assay

Medical Experts

Deftereos, Georgios, MD, FCAP, FASCP, Medical Director and Laboratory Section Chief, Molecular Oncology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

Miles, Rodney R., MD, PhD, Laboratory Section Chief, Hematopathology, at ARUP Laboratories; Assistant Professor of Clinical Pathology, University of Utah

References

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 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]
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]

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

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Cannon RB, Dundar Y, Thomas A, Monroe MM, Buchmann LO, Witt BL, Sowder AM, Hunt JP. Elective Neck Dissection for Head and Neck Cutaneous Squamous Cell Carcinoma with Skull Base Invasion. Otolaryngol Head Neck Surg. 2017; 156(4): 671-676. PubMed

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

Educational Videos

Content Review:

June 2017

Last Update: November 2019

Head and Neck Cancer

Key Points

HPV Testing in Head and Neck Cancer

Detection of Oncogenic HPV Infection in Tumors

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Imaging Studies

Prognosis

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult


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Head and Neck Cancer

Key Points

HPV Testing in Head and Neck Cancer

Detection of Oncogenic HPV Infection in Tumors

Diagnosis

Indications for Testing

Laboratory Testing

Histology

Imaging Studies

Prognosis

Differential Diagnosis

Screening

Monitoring

Background

Epidemiology

Risk Factors

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

Guidelines

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

ARUP Laboratories

ARUP Websites

ARUP Consult