Cancer (Head and Neck)

Squamous cell carcinomas of the head and neck collectively refers to cancers arising from the squamous cell layer of the mucosal surfaces in the oral cavity and oropharynx.¹  Head and neck cancers can also begin in the salivary glands, but are relatively uncommon.¹  Although they border each other, the oral cavity (OC) and oropharynx (OP) are separate, non-overlapping anatomic regions (Table; Figure).^{2, 3}

Anatomic Distinctions Between the Oral Cavity and the Oropharynx

Oral Cavity (OC)	Oropharynx (OP)
Anatomic border between from above: Junction of the hard and soft palate
Hard palate	Soft palate
Retromolar trigone	Palatine tonsils
Floor of the mouth	Palatoglossal folds
Anterior two-thirds of the tongue (i.e., anterior to the circumvallate papillae)	Posterior one-third of the tongue (i.e., base of the tongue)
Alveolar ridge and gingiva	Valleculae
Buccal mucosa	Posterior pharyngeal wall
Labial mucosa
Anatomic border between from below: Circumvallate papillae

  

Diagram of the oral cavity and oropharynx. The oral cavity includes the lips, the labial and buccal mucosa, the front two-thirds of the tongue, the retromolar pad, the floor of the mouth, the gingiva, and the hard palate. The oropharynx includes the palatine and lingual tonsils, the back one-third base of the tongue, the soft palate, and the posterior pharyngeal wall. Source: Centers for Disease Control and Prevention

Squamous cell carcinoma (SCC) is the most common malignancy in the OC and OP, accounting for 90% of cancers of the head and neck, after excluding nonmelanoma skin cancers.² The American Cancer Society estimated number of new oral cavity (OC) and oropharynx (OP) cancer cases in the U.S. in 2018 is 51,540, while the estimated number of deaths from OP/OC-related cancers in 2018 is 10,030.⁴  These estimates account for 3% of all cancers diagnosed and 1.6% of all cancer deaths.⁵  The SEER data show that in the U.S. there has been a statistically significant increase in the annual percent change in the incidence of OP-SCC cancer of the tonsil of 2.7% and oropharynx of 1.6%; and a statistically significant decrease in the annual percent change in the incidence of cancer of the lip of 2.5%, floor of the mouth of 2.7% and hypopharynx (sometimes defined as laryngeal cancer) of 2.6%.⁶

The 5-year relative survival rate for those with localized disease at diagnosis is 83%, compared with only 38% in patients whose cancer has metastasized.⁷

The major risk factors for OC-SCC and OP-SCC are tobacco use,^{2, 8, 9} alcohol consumption,^{2, 8, 10} interaction between heavy use of tobacco and alcohol together,^{11, 12} and chewing betel quid (“paan,” often practiced in Asian, migrant Asian, and other communities).² Ultraviolet exposure may be the likely risk factor associated with SCC of the lip.¹³  Older age and male sex also increase the risk of OC/OP-SCC.⁶  Smoking-associated risk appears to be dose dependent and correlates with daily or cumulative cigarette consumption.² For patients who quit smoking, the risk for OC-SCC and OP-SCC declines over time and may approach that of nonsmokers after 10 or more years of cessation.^{2, 14}  The risk of head and neck cancer 20 or more years following cessation of alcohol consumption appears to approach the risk of those who have never consumed alcohol.¹⁵  Human papillomavirus (HPV) infection² is a major risk factor for oropharyngeal cancer, rather than oral cancer (see following section “Focus on HPV in Oropharyngeal Cancer”).^{2, 16, 17} The HPV vaccine was developed to prevent cervical and other cancers of the reproductive system. The vaccine protects against the types of HPV that can cause oropharyngeal cancers, so it may also prevent oropharyngeal cancers; however, studies have not been done to show this.¹⁸

The increase of oral tongue SCC seen among young white women does not appear to be associated with either tobacco or alcohol use or HPV infection and has been suggested to have a different causative mechanism (e.g., genetic abnormalities such as Fanconi anemia, other oncogenic viral infections, or other environmental exposures).¹⁹ There is an increased risk for OC/OP-SCC in patients with certain rare heritable conditions, including Fanconi anemia, dyskeratosis congenita, and Bloom syndrome.²

HPV infection^{2, 20} is a major risk factor for oropharyngeal cancer, rather than oral cancer, per se.^{2, 16, 17, 21}  HPV has emerged as an etiologic factor for OP-SCC of the tonsil and oropharynx,^{16, 21, 22} but not for the totality of tongue cancers.^{23, 24}  Based on data from U.S. cancer registries, an estimated 63% of OP-SCC each year—or over 11,000 cases—are associated with HPV infection.²⁵  The vast majority (~85 to 90%) of HPV-positive OP-SCC are associated with HPV-16 and HPV-18, two high-risk, HPV types that are commonly associated with cervical cancer and other anogenital cancers.^{7, 16, 25}

Examination of the demographics find that younger, non-Hispanic whites and Hispanics have higher incidence of HPV-positive OP-SCC.  Prevention of OP-SCC has not been evaluated in randomized trials designed for this purpose.  Data suggest that oral HPV infection prevalence is lower in men and women who have received HPV vaccine than those who have not.²⁶  Although it is possible that the HPV vaccine might also ultimately prevent OP cancers, as the vaccine prevents an initial infection with HPV types that can cause these cancers, current data are lacking regarding prevention of HPV-associated OP cancer.¹⁸ Clinical trials designed to answer these questions are currently underway.

In 2017, the American Academy of Pediatric Dentistry (AAPD) issued a policy statement on HPV vaccination²⁷ as follows:

The AAPD supports measures that prevent [oral and oropharyngeal cancers], including the prevention of HPV infection, a critical factor in the development of oral squamous cell carcinoma.

The AAPD encourages oral health care providers to:

• Educate patients, parents, and guardians on the serious health consequences of [oral and oropharyngeal cancers] and the relationship of HPV to [oral and oropharyngeal cancers].
• Counsel patients, parents, and guardians regarding the HPV vaccination, in accordance with CDC recommendations, as part of anticipatory guidance for adolescent patients.

On October 5, 2018, the U.S. Food and Drug Administration (FDA) approved a supplemental application for Gardasil 9® (HPV 9 valent-vaccine, recombinant; Merck & Co., Inc.) expanding the approved use of the vaccine to include women and men aged 27 through 45 years.²⁸  Gardasil 9® was previously approved for use in males and females aged 9 through 26 years.

In 2020, Villa et al.²⁹ published an umbrella review of systematic reviews, summarizing evidence on the safety, efficacy, and effectiveness of HPV vaccines.  The review compiled findings from 30 systematic reviews and found evidence that available HPV vaccines “are safe, effective, and efficacious against vaccine-type HPV infection and HPV-associated cellular changes, including precancerous and benign lesions.”

Two oral lesions that could be precursors to cancer are leukoplakia (white patches) and erythroplakia (red patches).^{2, 7} Although there is a known potential for malignant transformation, the majority of leukoplakias will not progress to cancer.² Some oral lesions will show a combination of red and white features, termed erythroleukoplakia, speckled leukoplakia, or speckled erythroplakia.² Although less common than leukoplakia, erythroplakia and lesions with erythroplakic components have a much greater potential for becoming cancerous.⁷ 

Because these white and/or red mucosal patches have an increased risk of becoming or already harboring invasive carcinoma, they have collectively been classified as “potentially malignant disorders.”² Any white or red patch/lesion that does not resolve in 2 weeks should be reevaluated and considered for biopsy to obtain a definitive diagnosis.⁷

Other possible signs and symptoms of head and neck cancers that patients may report include:⁷

• a lump or thickening in the oral soft tissues
• soreness or a feeling that something is caught in the throat
• difficulty chewing or swallowing
• ear pain
• difficulty moving the jaw or tongue
• hoarseness
• numbness of the tongue or other areas of the mouth
• swelling of the jaw that causes dentures to fit poorly or become uncomfortable

Signs and symptoms that persist for 2 weeks or more merit further investigation, such as a biopsy or referral to a specialist.⁷

OP-SCC develops most frequently in the tonsillar region and base of the tongue, often appearing as an ulcerated mass, fullness, or irregular erythematous mucosal change.²  OP-SCC tumors are thought to present at a more advanced stage than OC-SCC because of their ability to grow undetected (i.e., without overt symptoms) and their propensity for metastasis.² The most common chief complaints are the presence of a neck mass (from metastatic disease), sore throat, and dysphagia.²

In 2017, an expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs published a systematic review/meta-analysis and clinical practice guideline called the "Evidence-Based Clinical Practice Guideline for the Evaluation of Potentially Malignant Disorders in the Oral Cavity."^30,31 The goal of this clinical practice guideline is to inform clinicians about the potential use of adjuncts as triage tools for the evaluation of lesions, including potentially malignant disorders, in the oral cavity. Among the guideline's recommendations:

• Clinicians should obtain an updated medical, social, and dental history and perform an intraoral and extraoral conventional visual and tactile examination in all adult patients.
• For patients with suspicious lesions, clinicians should immediately perform a biopsy of the lesion or refer the patient to a specialist.
• Salivary and light-based adjuncts are not recommended for evaluating lesions for malignancy.

The U.S. Preventive Services Task Force (USPSTF)³² concluded in 2013 that “current evidence is insufficient to assess the balance of benefits and harms of screening for oral cancer in asymptomatic adults,” although the statement specifically clarifies that, “This recommendation is intended for primary care providers and does not pertain to dental providers or otolaryngologists. Dental care providers and otolaryngologists may conduct a comprehensive examination of the oral cavity and pharynx during the clinical encounter.”

ADA Current Dental Terminology (CDT) code D0120 for “periodic oral evaluation” (established patient) includes “an oral cancer evaluation … where indicated.”  CDT code D0150 for “comprehensive oral evaluation” (new or established patient) also includes “an evaluation for oral cancer where indicated.”  The National Institute for Dental and Craniofacial Research (NIDCR)⁷ provides a protocol for dental practitioners for an oral cancer examination based on the standardized oral examination method recommended by the World Health Organization.  The NIDCR examination method is “consistent with those followed by the Centers for Disease Control and Prevention and the National Institutes of Health” and requires adequate lighting, a dental mouth mirror, two 2" x 2" gauze squares, and gloves and should take approximately 5 minutes.⁷  The NIDCR provides the examination protocol in poster form and also has a pamphlet on oral cancer for patients and a patient education resource for oral cancer and the oral cancer exam; these items are not copyrighted and can be reproduced freely.  An additional resource is the video posted by the ADA demonstrating the evaluation of a patient for potentially malignant disorders, showing inspection and palpation elements of the intra- and extraoral examination.

The NIDCR⁷ suggests that a thorough head and neck examination should be a routine part of each patient's dental visit, as follows. Clinicians should be particularly vigilant in checking those who use tobacco or excessive amounts of alcohol.

• Examine your patients using the head and neck examination protocol described by the NIDCR.
• Take a history of their alcohol and tobacco use.
• Inform your patients of the association between tobacco use, alcohol use, and oral cancer.
• Follow-up to make sure a definitive diagnosis is obtained on any possible signs or symptoms of oral cancer.

A 2014 ADA Policy statement on “Early Detection and Prevention of Oral Cancer” supports routine examinations and prevention education. ³³  

Given that mortality rates from OC/OP-SCC have been fairly stable,³³ it has been posited that earlier detection of oral cancers will improve prognosis.  A 2015 systematic review and meta-analysis by Seoane et al.³⁵ found that a longer time interval from a patient’s first symptom to referral for diagnosis was a “risk factor for advanced stage and mortality of oral cancer.”

A number of adjuncts to the standard clinical examination have been developed and are intended to improve disease detection. These include oral brush cytology, toluidine blue staining, and light-based detection systems to increase the visibility of oral mucosal lesions or provide real-time data on suspicious mucosal lesions.³⁶  Diagnostic performance in clinical studies has been inconsistent because results vary according to study settings and the sample populations enrolled.³⁶ As noted in the 2017 ADA clinical practice guideline,^{30, 31} it is not yet clear whether these ancillary tests are helpful in triaging which patients need diagnostic or therapeutic follow-up, in part because these tests also cause false-positive results. Diagnostic adjuncts have been evaluated primarily in referral clinic settings or cancer centers and in patients at high baseline risk of disease.³⁶  Data from studies in general clinic settings and in patients at low baseline risk of disease are more limited and additional data are needed to characterize test performance in these populations and settings.³⁶

EARLY DETECTION AND PREVENTION OF ORAL CANCER
(Trans.2014:506)

Resolved, that the American Dental Association recognizes that early oral cancer diagnosis has the potential to have a significant impact on treatment decisions and outcomes, and supports routine visual and tactile examinations, particularly for patients who are at risk including those who use tobacco or who are heavy consumers of alcohol, and be it further

Resolved, that the Association supports state and local Association sponsored education activities to promote the prevention and early detection of oral cancer to those who use tobacco, alcohol or both.

American Dental Association
Adopted 2014

HUMAN PAPILLOMAVIRUS (HPV) VACCINATION FOR THE PREVENTION OF INFECTION WITH HPV TYPES ASSOCIATED WITH OROPHARYNGEAL CANCER
(Trans.2018:XXX)

The American Dental Association (ADA) adopts the position that HPV vaccination, as recommended by the CDC Advisory Committee on Immunization Practices, is a safe and effective intervention to decrease the burden of oral and oropharyngeal HPV infection; and be it further

Resolved, that the ADA urges dentists, as well as local and state dental societies, to support the use and administration of the HPV vaccine as recommended by the CDC Advisory Committee on Immunization Practices; and

Resolved, that the ADA encourages appropriate external agencies to support research to improve understanding of the natural history of oral HPV infection, transmission risks, screening and testing.

American Dental Association
Adopted 2018

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3. Christopolous C, Moubayed SP, Nader ME, Ayed T, Ghannoum JE Mouth Anatomy: Overview. Medscape. "http://emedicine.medscape.com/article/1899122-overview". Accessed December 14, 2018.
4. American Cancer Society Cancer Statistics Center, Oral Cavity and Pharynx, 2018. "https://cancerstatisticscenter.cancer.org/?_ga=1.227218650.691950336.1464714768#/cancer-site/Oral%20cavity%20and%20pharynx". Accessed December 19, 2018.
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6. Howlader N, Noon AM, Krapcho M, et al. SEER Cancer Statistics Review 1975-2012: National Cancer Institute; 2015.
7. National Institute of Dental and Craniofacial Research. Detecting Oral Cancer: A Guide for Health Care Professionals. National Institutes of Health July 2013. "https://www.nidcr.nih.gov/sites/default/files/2017-09/detecting-oral-cancer-poster.pdf". Accessed December 19, 2018.
8. Hashibe M, Brennan P, Benhamou S, et al. Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 2007;99(10):777-89.
9. Centers for Disease Control and Prevention (CDC). The health consequences of smoking – 50 years of progress: a report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services, Office of the Surgeon General 2014. "http://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf". Accessed December 19, 2018.
10. Goldstein BY, Chang SC, Hashibe M, La Vecchia C, Zhang ZF. Alcohol consumption and cancers of the oral cavity and pharynx from 1988 to 2009: an update. Eur J Cancer Prev 2010;19(6):431-65.
11. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48(11):3282-7.
12. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev 2009;18(2):541-50.
13. Samarasinghe V, Madan V, Lear JT. Management of high-risk squamous cell carcinoma of the skin. Expert Rev Anticancer Ther 2011;11(5):763-9.
14. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum 2004;83:1-1438.
15. Kawakita D, Matsuo K. Alcohol and head and neck cancer. Cancer Metastasis Rev 2017;36(3):425-34.
16. Cleveland JL, Junger ML, Saraiya M, et al. The connection between human papillomavirus and oropharyngeal squamous cell carcinomas in the United States: implications for dentistry. J Am Dent Assoc 2011;142(8):915-24.
17. Lingen MW, Xiao W, Schmitt A, et al. Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas. Oral Oncol 2013;49(1):1-8.
18. Centers for Disease Control and Prevention Human Papillomavirus (HPV): HPV and Oropharyngeal Cancer Fact Sheet. "https://www.cdc.gov/cancer/hpv/basic_info/hpv_oropharyngeal.htm". Accessed December 19, 2018.
19. Patel SC, Carpenter WR, Tyree S, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol 2011;29(11):1488-94.
20. Viens LJ, Henley SJ, Watson M, et al. Human Papillomavirus–Associated Cancers — United States, 2008–2012. MMWR Morb Mortal Wkly Rep 2016;65:661–66.
21. Chaturvedi AK. Epidemiology and clinical aspects of HPV in head and neck cancers. Head Neck Pathol 2012;6 Suppl 1:S16-24.
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24. Sgaramella N, Coates PJ, Strindlund K, et al. Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1. Br J Cancer 2015;113(2):321-6.
25. Human papillomavirus-associated cancers - United States, 2004-2008. MMWR Morb Mortal Wkly Rep 2012;61:258-61.
26. Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of Prophylactic Human Papillomavirus (HPV) Vaccination on Oral HPV Infections Among Young Adults in the United States. J Clin Oncol 2018;36(3):262-67.
27. American Academy of Pediatric Dentistry Policy on human papilloma virus vaccinations.  2017. "http://www.aapd.org/media/Policies_Guidelines/P_HPV_Vaccinations.pdf". Accessed December 19, 2018.
28. U.S. Food and Drug Administration FDA News Release: FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old.  2018. "https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm622715.htm". Accessed October 8, 2018.
29. Villa A, Patton LL, Giuliano AR, et al. Summary of the evidence on the safety, efficacy, and effectiveness of human papillomavirus vaccines: Umbrella review of systematic reviews. J Am Dent Assoc 2020;151(4):245-54 e24. 
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35. Seoane J, Alvarez-Novoa P, Gomez I, et al. Early oral cancer diagnosis: The Aarhus statement perspective. A systematic review and meta-analysis. Head Neck 2015.
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Guidelines and Additional Clinician Resources:
Evaluation of Potentially Malignant Disorders in the Oral Cavity

• Clinical Recommendations
  
• Systematic Review
  
• Chairside Guide
• Instructional Video

Patient Education:

Reducing the Risk of Oral Cancer (JADA For the Patient Page 2020)

Oral cancer: What to do if something unusual shows up? (JADA For the Patient Page 2017)

Additional ADA Resources:

• Search JADA for articles related to oral or oropharyngeal cancer
• ADA Clinical Evaluators Panel Survey: Human Papillomavirus Vaccine (2020)
• ADA Council on Scientific Affairs Statement on Human Papillomavirus and Squamous Cell Cancers of the Oropharynx

ADA Store:

• The ADA Practical Guide to Soft Tissue Oral Disease (Item #P033)
• Oral Pathologist App (Item #P033i)

ADA CE Online: HPV Infection, Risk Factors, and HPV-Related Oropharyngeal Cancer

American Cancer Society:

• HPV (Human Papillomavirus)
• National HPV Vaccination Roundtable guide for dental healthcare providers

American Academy of Pediatrics: AAP HPV Champion Toolkit

Centers for Disease Control and Prevention resources:

• HPV and oropharyngeal cancers fact sheet
• 5 Ways to Boost Your HPV Vaccination Rates
• Human papillomavirus resources for parents and public, healthcare professionals, and partners and programs
• HPV vaccination: What can we do to bring specific partners to the table?
• Promotional flyers and posters regarding HPV vaccination for preteens and teens
• Vaccine “fact sheets” for preteens and teens (including HPV)

National Cancer Institute:  Head and Neck Cancer Fact Sheet

U.S. Department of Health and Human Services:  HPV Vaccine Promotional Toolkit