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NCI/PDQ^® Health professionals: Oropharyngeal Cancer Treatment (PDQ®)

National Cancer Institute
Last Modified: July 16, 2012

TABLE OF CONTENTS

• General Information About Oropharyngeal Cancer

• Cellular Classification of Oropharyngeal Cancer

• Stage Information for Oropharyngeal Cancer
  • Definitions of TNM

• Treatment Option Overview

• Stage I Oropharyngeal Cancer
  • Current Clinical Trials

• Stage II Oropharyngeal Cancer
  • Current Clinical Trials

• Stage III Oropharyngeal Cancer
  • Current Clinical Trials

• Stage IV Oropharyngeal Cancer
  • Resectable Oropharyngeal Cancer
  • Unresectable Oropharyngeal Cancer
  • Current Clinical Trials

• Recurrent Oropharyngeal Cancer
  • Current Clinical Trials

• Changes to This Summary (07/16/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Oropharyngeal Cancer

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Oropharyngeal cancer is uncommon and typically involves patients in the fifth through seventh decades of life; men are afflicted three to five times more often than women. 1 2 3

Similar to other cancers of the head and neck, tobacco and alcohol abuse represent the most significant risk factors for the development of oropharyngeal cancer. 3 4 (Refer to the PDQ® summaries on Hypopharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.) Other risk factors may include: 5

• A diet poor in fruits and vegetables. 6
• The consumption of maté, a stimulant beverage commonly consumed in South America. 7
• The chewing of betel quid, a stimulant preparation commonly used in parts of Asia. 8
• Infection with the human papillomavirus (HPV), especially HPV-type-16, also known as HPV-16. 9 10 11

Defective elimination of acetaldehyde, a carcinogen generated by alcohol metabolism, poses an additional risk factor for oropharyngeal cancers. In individuals, primarily East Asians, carrying an inactive mutant allele of alcohol dehydrogenase-2, alcohol consumption is associated with a susceptibility to multiple metachronous oropharyngeal cancers that are caused by the decreased elimination of acetaldehyde. 12

Anatomically, the oropharynx is located between the soft palate superiorly and the hyoid bone inferiorly; it is continuous with the oral cavity anteriorly and communicates with the nasopharynx superiorly and the supraglottic larynx and hypopharynx inferiorly. The oropharynx is divided into the following sites: 13

• Base of the tongue, which includes the pharyngoepiglottic folds and the glossoepiglottic folds.
• Tonsillar region, which includes the fossa and the anterior and posterior pillars.
• Soft palate, which includes the uvula.
• Pharyngeal walls, that is, posterior and lateral.

The regional lymph node anatomy of the head and neck contains lymph nodes that run parallel to the jugular veins, spinal accessory nerve, and facial artery and into the submandibular triangle; an understanding of this anatomy and the status of regional lymph nodes is critical to the care of head and neck cancer patients. 3 14 The regions of the neck have been characterized by levels (IV) to facilitate communication regarding the lymph node anatomy:

• Level I contains the submental and submandibular lymph nodes.
• Level II contains the upper jugular lymph nodes, which are above the digastric muscle.
• Level III contains the mid-jugular lymph nodes, which are between the omohyoid muscle and the digastric muscle.
• Level IV contains the lower jugular lymph nodes.
• Level V contains the lymph nodes of the posterior triangle.

Histologically, almost all oropharyngeal cancers are squamous cell carcinomas (SCCs). 3 Other cancers in this area include minor salivary gland carcinomas, lymphomas, and lymphoepitheliomas, also known as tonsillar fossa. (Refer to the PDQ® summaries on Salivary Gland Cancer Treatment, Adult Hodgkin Lymphoma Treatment, and Adult Non-Hodgkin Lymphoma Treatment for more information.)

The concept of field cancerization may be responsible in part for the multiple, synchronous primary SCCs that occur in oropharyngeal cancer. This concept, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue chronically exposed to carcinogens. 15 Molecular studies detecting genetic alterations in histologically normal tissue from high-risk individuals have provided strong support for the field cancerization concept. 16 17 18 19 20

Clinically, cancers of the base of the tongue are insidious. These cancers can grow in either an infiltrative or exophytic pattern. Because the base of the tongue is devoid of pain fibers, these tumors are often asymptomatic until they have progressed significantly. 13

Symptoms of base-of-the-tongue cancers may include the following: 3 13

• Pain.
• Dysphagia.
• Weight loss.
• Referred otalgia secondary to cranial nerve involvement.
• Trismus secondary to pterygoid muscle involvement.
• Fixation of the tongue that is caused by infiltration of the deep muscle.
• A mass in the neck.

(Refer to the PDQ® summary on Pain and for more information on weight loss, refer to the Nutrition in Cancer Care summary.)

Lymph node metastasis is common because of the rich lymphatic drainage of the base of the tongue. Approximately 70% or more of the patients have ipsilateral cervical nodal metastases; 30% or fewer of the patients have bilateral cervical lymph node metastases. 13 21 The cervical lymph nodes involved commonly include levels II and III.

The symptoms of tonsillar lesions may include the following: 3 13

• Pain.
• Dysphagia.
• Weight loss.
• Ipsilateral referred otalgia.
• A mass in the neck.

The anterior tonsillar pillar and tonsil is the most common location for a primary tumor of the oropharynx. 13 Lesions involving the anterior tonsillar pillar may appear as areas of dysplasia, inflammation, or a superficial spreading lesion. These cancers can progress across a broad region including the lateral soft palate, retromolar trigone and buccal mucosa, and tonsillar fossa. 3 13 The lymphatic drainage is primarily to level II nodes.

Lesions of the tonsillar fossa may be either exophytic or ulcerative and have a pattern of extension similar to those of the anterior tonsillar pillar. These tumors present in advanced-stage disease more often than cancers of the tonsillar pillar. Approximately 75% of patients will present with stage III or stage IV disease. 3 13 The lymphatic drainage is primarily to level V nodes. Tumors of the posterior tonsillar pillar can extend inferiorly to involve the pharyngoepiglottic fold and the posterior aspect of the thyroid cartilage. These lesions more frequently involve level V nodes.

Soft palate tumors are primarily found on the anterior surface. 13 Lesions in this area may remain superficial and in early stages. 3 The lymphatic drainage is primarily to level II nodes.

Tumors of the pharyngeal wall are typically diagnosed in an advanced stage because of the silent location in which they develop. 3 13

Symptoms of pharyngeal wall tumors may include:

• Pain.
• Bleeding.
• Weight loss.
• A neck mass.

These lesions can spread superiorly to involve the nasopharynx, posteriorly to infiltrate the prevertebral fascia, and inferiorly to involve the pyriform sinuses and hypopharyngeal walls. Primary lymphatic drainage is to the retropharyngeal nodes and level II and III nodes. Because most pharyngeal tumors extend past the midline, bilateral cervical metastases are common.

Precancerous lesions of the oropharynx include leukoplakia, erythroplakia, and mixed erythroleukoplakia. 5 These are clinical terms that have no specific histopathologic connotations. 22 Leukoplakia, the most common of the three conditions, is defined by the World Health Organization as a white patch or plaque that cannot be characterized clinically or pathologically as any other disease. 23 The diagnosis of leukoplakia is one of exclusion; conditions such as candidiasis, lichen planus, leukoedema, and others must be ruled out before a diagnosis of leukoplakia can be made. 5

The prevalence of leukoplakia in the United States is decreasing; this decline has been related to a reduction of tobacco consumption. 24 Although erythroplakia is not as common as leukoplakia, it is much more likely to be associated with dysplasia or carcinoma. 5 25

The clinical anatomic staging of oropharyngeal cancers involves both clinical assessment and imaging techniques. 3 14 One study has reported that positron emission tomography scans are more accurate than computed tomographic scans or magnetic resonance imaging in detecting occult nodal disease. 26 Diagnostic methods involve the molecular analysis of tissue from the margins of lip and oral cavity SCCs (i.e., molecular staging) to detect tumor-associated genetic alterations in cells that appear normal by conventional light microscopy. Molecular staging may predict the likelihood of recurrence and may help to establish the relationship between index lesions of SCCs and subsequent lesions. 27 28

Traditionally, surgery and/or radiation therapy have been the standards for treatment of oropharyngeal cancers; these treatment modalities are frequently complicated by suboptimal control of locoregional disease and significant long-term functional deficits. 3 29 Although specific indications for primary surgical resection exist, some investigators suggest that the concurrent use of multiagent chemotherapy and radiation has become the standard of care for the management of patients with late-stage disease, and surgery is often reserved for salvage of those patients who fail definitive nonoperative treatment. 27 29 30 Studies using aggressive and uncompromised radiation therapy with concurrent multiagent chemotherapy have consistently demonstrated a survival and locoregional control benefit. 31 32 33 34 35 This treatment approach emphasizes organ preservation and functionality. New treatments under development include various biologic therapies (i.e., vaccines, growth factor-receptor antagonists, cyclin-dependent kinase inhibitors, oncolytic viruses, and others) and photodynamic therapy. 27 36 37 38 39 40 41 42 43

The rate of curability of cancers of the oropharynx varies depending on the stage and specific site. Local control rates for early base-of-tongue cancers approximate 85%. 3 In a large retrospective study involving 262 patients with base-of-tongue cancer, the overall 5-year disease-specific survival rate for patients with all stages of disease was approximately 50%. Treatment modalities included surgery with and without radiation therapy and radiation therapy alone. None of the treatment modalities had a significant survival advantage either overall or within the stages. 44 45

In a retrospective study involving 162 patients with tonsil carcinoma, 84 patients were treated with primary surgery, which was followed by radiation therapy and/or chemotherapy if histologic signs of aggressive behavior were identified. Survival rates were 89% for stage I, 91% for stage II, 79% for stage III, and 52% for stage IV. 46 In a retrospective study of 188 patients with SCC of the soft palate, uvula, and anterior tonsillar pillar, treatment to the primary site consisted of radiation therapy for 150 patients, surgery for 28 patients, and combined therapy for 10 patients. The overall determinant survival was 80% at 2 years, but it fell to 67% at 5 years. 47 In another retrospective study, 148 patients received definitive radiation therapy for SCC of the pharyngeal wall. Cause-specific survival rates were 89% for stage I, 88% for stage II, 44% for stage III, and 34% for stage IV. Twice-daily fractionation, stage I to stage II disease, and an oropharyngeal primary site were associated with improved locoregional control. 48

HPV-positive oropharyngeal cancers may represent a distinct disease entity that is causally associated with HPV infection and that is also associated with an improved prognosis. Several studies indicate that individuals with HPV-positive tumors have significantly improved survivals. 10 49 50 51 In a prospective study involving 253 patients with newly diagnosed or recurrent head and neck SCC, HPV was detected in 25% of the cases. Poor tumor grade and an oropharyngeal site independently increased the probability of HPV presence. 10

The risk of developing a second primary tumor in patients with tumors of the upper aerodigestive tract has been estimated to be 3% to 7% per year. 52 53 Because of this risk, surveillance of these patients should be lifelong. Patients should be counseled that continued smoking and alcohol consumption after treatment has been associated with the development of second primary tumors of the aerodigestive tract. 54 55 56 (Refer to the PDQ® Smoking Cessation and Continued Risk in Cancer Patients summary for more information.)

To date, SCC of the oropharynx has not been associated with any specific chromosomal or genetic abnormalities. Genetic/chromosomal aberrations in these cancers are complex. 57 58 Despite the lack of specific genetic abnormalities, testing for genetic alterations or ploidy in early oropharyngeal lesions may identify patients who are at the greatest risk for progression and may lead to more definitive therapy. 27

References:

1. American Cancer Society.: Cancer Facts and Figures 2004. Atlanta, Ga: American Cancer Society, 2004. Also available online. [PUBMED Abstract]
2. Parkin DM, Bray F, Ferlay J, et al.: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94 (2): 153-6, 2001. [PUBMED Abstract]
3. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80. [PUBMED Abstract]
4. Licitra L, Bernier J, Grandi C, et al.: Cancer of the oropharynx. Crit Rev Oncol Hematol 41 (1): 107-22, 2002. [PUBMED Abstract]
5. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]
6. Sánchez MJ, Martínez C, Nieto A, et al.: Oral and oropharyngeal cancer in Spain: influence of dietary patterns. Eur J Cancer Prev 12 (1): 49-56, 2003. [PUBMED Abstract]
7. Goldenberg D, Golz A, Joachims HZ: The beverage maté: a risk factor for cancer of the head and neck. Head Neck 25 (7): 595-601, 2003. [PUBMED Abstract]
8. Ho PS, Ko YC, Yang YH, et al.: The incidence of oropharyngeal cancer in Taiwan: an endemic betel quid chewing area. J Oral Pathol Med 31 (4): 213-9, 2002. [PUBMED Abstract]
9. Mork J, Lie AK, Glattre E, et al.: Human papillomavirus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 344 (15): 1125-31, 2001. [PUBMED Abstract]
10. Gillison ML, Koch WM, Capone RB, et al.: Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92 (9): 709-20, 2000. [PUBMED Abstract]
11. D'Souza G, Kreimer AR, Viscidi R, et al.: Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356 (19): 1944-56, 2007. [PUBMED Abstract]
12. Yokoyama A, Watanabe H, Fukuda H, et al.: Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers. Cancer Epidemiol Biomarkers Prev 11 (9): 895-900, 2002. [PUBMED Abstract]
13. Choi WH, Hu KS, Culliney B, et al.: Cancer of the oropharynx. In: Harrison LB, Sessions RB, Hong WK, eds.: Head and Neck Cancer: A Multidisciplinary Approach. 3rd ed. Philadelphia, PA: Lippincott, William & Wilkins, 2009, pp 285-335. [PUBMED Abstract]
14. Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56. [PUBMED Abstract]
15. Slaughter DP, Southwick HW, Smejkal W: Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer 6 (5): 963-8, 1953. [PUBMED Abstract]
16. Braakhuis BJ, Tabor MP, Leemans CR, et al.: Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck 24 (2): 198-206, 2002. [PUBMED Abstract]
17. Braakhuis BJ, Tabor MP, Kummer JA, et al.: A genetic explanation of Slaughter's concept of field cancerization: evidence and clinical implications. Cancer Res 63 (8): 1727-30, 2003. [PUBMED Abstract]
18. Tabor MP, Brakenhoff RH, van Houten VM, et al.: Persistence of genetically altered fields in head and neck cancer patients: biological and clinical implications. Clin Cancer Res 7 (6): 1523-32, 2001. [PUBMED Abstract]
19. Tabor MP, Brakenhoff RH, Ruijter-Schippers HJ, et al.: Multiple head and neck tumors frequently originate from a single preneoplastic lesion. Am J Pathol 161 (3): 1051-60, 2002. [PUBMED Abstract]
20. Ha PK, Califano JA: The molecular biology of mucosal field cancerization of the head and neck. Crit Rev Oral Biol Med 14 (5): 363-9, 2003. [PUBMED Abstract]
21. Lindberg R: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29 (6): 1446-9, 1972. [PUBMED Abstract]
22. Oral cavity and oropharynx. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 223-55. [PUBMED Abstract]
23. Kramer IR, Lucas RB, Pindborg JJ, et al.: Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 46 (4): 518-39, 1978. [PUBMED Abstract]
24. Scheifele C, Reichart PA, Dietrich T: Low prevalence of oral leukoplakia in a representative sample of the US population. Oral Oncol 39 (6): 619-25, 2003. [PUBMED Abstract]
25. Shafer WG, Waldron CA: Erythroplakia of the oral cavity. Cancer 36 (3): 1021-8, 1975. [PUBMED Abstract]
26. Ng SH, Yen TC, Chang JT, et al.: Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol 24 (27): 4371-6, 2006. [PUBMED Abstract]
27. Forastiere A, Koch W, Trotti A, et al.: Head and neck cancer. N Engl J Med 345 (26): 1890-900, 2001. [PUBMED Abstract]
28. Brennan JA, Mao L, Hruban RH, et al.: Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 332 (7): 429-35, 1995. [PUBMED Abstract]
29. Adelstein DJ: Oropharyngeal cancer: the role of chemotherapy. Curr Treat Options Oncol 4 (1): 3-13, 2003. [PUBMED Abstract]
30. Forastiere AA, Trotti A: Radiotherapy and concurrent chemotherapy: a strategy that improves locoregional control and survival in oropharyngeal cancer. J Natl Cancer Inst 91 (24): 2065-6, 1999. [PUBMED Abstract]
31. Adelstein DJ, Saxton JP, Lavertu P, et al.: A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck 19 (7): 567-75, 1997. [PUBMED Abstract]
32. Wendt TG, Grabenbauer GG, Rídel CM, et al.: Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol 16 (4): 1318-24, 1998. [PUBMED Abstract]
33. Brizel DM, Albers ME, Fisher SR, et al.: Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med 338 (25): 1798-804, 1998. [PUBMED Abstract]
34. Denis F, Garaud P, Bardet E, et al.: Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol 22 (1): 69-76, 2004. [PUBMED Abstract]
35. Staar S, Rudat V, Stuetzer H, et al.: Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 50 (5): 1161-71, 2001. [PUBMED Abstract]
36. Chang AE, Li Q, Jiang G, et al.: Generation of vaccine-primed lymphocytes for the treatment of head and neck cancer. Head Neck 25 (3): 198-209, 2003. [PUBMED Abstract]
37. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21 (14): 2787-99, 2003. [PUBMED Abstract]
38. Senderowicz AM: Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. Cancer Chemother Pharmacol 52 (Suppl 1): S61-73, 2003. [PUBMED Abstract]
39. Chiocca EA: Oncolytic viruses. Nat Rev Cancer 2 (12): 938-50, 2002. [PUBMED Abstract]
40. Copper MP, Tan IB, Oppelaar H, et al.: Meta-tetra(hydroxyphenyl)chlorin photodynamic therapy in early-stage squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 129 (7): 709-11, 2003. [PUBMED Abstract]
41. Biel MA: Photodynamic therapy and the treatment of head and neck neoplasia. Laryngoscope 108 (9): 1259-68, 1998. [PUBMED Abstract]
42. Lou PJ, Jones L, Hopper C: Clinical outcomes of photodynamic therapy for head-and-neck cancer. Technol Cancer Res Treat 2 (4): 311-7, 2003. [PUBMED Abstract]
43. Hopper C: Photodynamic therapy: a clinical reality in the treatment of cancer. Lancet Oncol 1: 212-9, 2000. [PUBMED Abstract]
44. Sessions DG, Lenox J, Spector GJ, et al.: Analysis of treatment results for base of tongue cancer. Laryngoscope 113 (7): 1252-61, 2003. [PUBMED Abstract]
45. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006. [PUBMED Abstract]
46. Galati LT, Myers EN, Johnson JT: Primary surgery as treatment for early squamous cell carcinoma of the tonsil. Head Neck 22 (3): 294-6, 2000. [PUBMED Abstract]
47. Weber RS, Peters LJ, Wolf P, et al.: Squamous cell carcinoma of the soft palate, uvula, and anterior faucial pillar. Otolaryngol Head Neck Surg 99 (1): 16-23, 1988. [PUBMED Abstract]
48. Hull MC, Morris CG, Tannehill SP, et al.: Definitive radiotherapy alone or combined with a planned neck dissection for squamous cell carcinoma of the pharyngeal wall. Cancer 98 (10): 2224-31, 2003. [PUBMED Abstract]
49. Ringstrím E, Peters E, Hasegawa M, et al.: Human papillomavirus type 16 and squamous cell carcinoma of the head and neck. Clin Cancer Res 8 (10): 3187-92, 2002. [PUBMED Abstract]
50. Schwartz SR, Yueh B, McDougall JK, et al.: Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg 125 (1): 1-9, 2001. [PUBMED Abstract]
51. Ang KK, Harris J, Wheeler R, et al.: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363 (1): 24-35, 2010. [PUBMED Abstract]
52. Khuri FR, Lippman SM, Spitz MR, et al.: Molecular epidemiology and retinoid chemoprevention of head and neck cancer. J Natl Cancer Inst 89 (3): 199-211, 1997. [PUBMED Abstract]
53. León X, Quer M, Diez S, et al.: Second neoplasm in patients with head and neck cancer. Head Neck 21 (3): 204-10, 1999. [PUBMED Abstract]
54. Do KA, Johnson MM, Doherty DA, et al.: Second primary tumors in patients with upper aerodigestive tract cancers: joint effects of smoking and alcohol (United States). Cancer Causes Control 14 (2): 131-8, 2003. [PUBMED Abstract]
55. Khuri FR, Kim ES, Lee JJ, et al.: The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial. Cancer Epidemiol Biomarkers Prev 10 (8): 823-9, 2001. [PUBMED Abstract]
56. Day GL, Blot WJ, Shore RE, et al.: Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst 86 (2): 131-7, 1994. [PUBMED Abstract]
57. Tremmel SC, Gítte K, Popp S, et al.: Intratumoral genomic heterogeneity in advanced head and neck cancer detected by comparative genomic hybridization. Cancer Genet Cytogenet 144 (2): 165-74, 2003. [PUBMED Abstract]
58. Brieger J, Jacob R, Riazimand HS, et al.: Chromosomal aberrations in premalignant and malignant squamous epithelium. Cancer Genet Cytogenet 144 (2): 148-55, 2003. [PUBMED Abstract]

Cellular Classification of Oropharyngeal Cancer

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Most oropharyngeal cancers are squamous cell carcinomas (SCCs). 1 2 Other oropharyngeal cancers include:

• Minor salivary gland tumors.
• Lymphomas.
• Lymphoepitheliomas (e.g., tonsillar fossa).

(Refer to the PDQ® summaries on Salivary Gland Cancer Treatment, Adult Hodgkin Lymphoma Treatment, and Adult Non-Hodgkin Lymphoma Treatment for more information.)

SCCs may be noninvasive or invasive. For noninvasive SCC, the term carcinoma in situ is used. Histologically, invasive carcinomas are well-differentiated, moderately differentiated, poorly differentiated, or undifferentiated. SCCs are usually moderately or poorly differentiated. 2 Grading the deep invasive margins (i.e., invasive front) of SCC may provide better prognostic information than grading of the entire tumor. 3

Immunohistochemical examination of tissues for the expression of the biomarker Ki-67, a proliferation antigen, may complement histologic grading. As a molecular indicator of epithelial dysplasia of the oropharynx, Ki-67 expression appears to correlate well with loss of heterozygosity (LOH) in tumor cells. In a retrospective study involving 43 tissue samples from 25 patients, the assessment of proliferation with Ki-67 was found to be a better surrogate for LOH than histologic grading. 4

Leukoplakia should be used only as a clinically descriptive term meaning that the observer sees a white patch that does not rub off, the significance of which depends on the histologic findings. 5 Leukoplakia can range from hyperkeratosis to an actual early invasive carcinoma or may only represent a fungal infection, lichen planus, or other benign oral disease. (Refer to the General Information About Oropharyngeal Cancer section of this summary for more information.)

References:

1. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 729-80. [PUBMED Abstract]
2. Oral cavity and oropharynx. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 223-55. [PUBMED Abstract]
3. Bryne M, Boysen M, Alfsen CG, et al.: The invasive front of carcinomas. The most important area for tumour prognosis? Anticancer Res 18 (6B): 4757-64, 1998 Nov-Dec. [PUBMED Abstract]
4. Tabor MP, Braakhuis BJ, van der Wal JE, et al.: Comparative molecular and histological grading of epithelial dysplasia of the oral cavity and the oropharynx. J Pathol 199 (3): 354-60, 2003. [PUBMED Abstract]
5. Neville BW, Day TA: Oral cancer and precancerous lesions. CA Cancer J Clin 52 (4): 195-215, 2002 Jul-Aug. [PUBMED Abstract]

Stage Information for Oropharyngeal Cancer

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Note: The American Joint Committee on Cancer has recently published a new edition of the AJCC Cancer Staging Manual, which includes revisions to the staging for this disease. The PDQ® Adult Treatment Editorial Board, which is responsible for maintaining this summary, is currently reviewing the new staging to determine the changes that need to be made in the summary. In addition to updating this Stage Information section, additional changes may need to be made to other parts of this summary to ensure that it is up-to-date. The changes will be made as soon as possible.

The staging systems for oropharyngeal cancer are all clinical, based on the best possible estimate of the extent of disease before treatment. The assessment of the primary tumor is based on inspection and palpation, when possible, and by indirect mirror examination. The appropriate nodal drainage areas are examined by careful palpation.

The tumor must be confirmed histologically, and any other pathologic data obtained from a biopsy may be included. Additional radiographic studies may be included. As an adjunct to clinical examination, magnetic resonance imaging is used to evaluate the extent of disease in the soft tissues; computed tomography is used to evaluate the mandible and maxilla. 1 Positron emission tomography has been investigated as an imaging modality for recurrent oropharyngeal cancer. 2

Complete endoscopy, typically under general anesthesia, is performed after completion of other staging studies to assess the surface extent of the tumor accurately, to assess deep involvement by palpation for muscle invasion, and to facilitate biopsy. Because of the incidence of multiple primary tumors occurring simultaneously, a careful search for other primary tumors of the upper aerodigestive tract is indicated. 3

Definitions of TNM

The American Joint Committee on Cancer has designated staging by TNM classification to define oropharyngeal cancer. 3 Nonepithelial tumors such as those of lymphoid tissue, soft tissue, bone, and cartilage are not included.

Table 1. Primary Tumor (T)^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.^bMucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of larynx.

TX	Primary tumor cannot be assessed.
T0	No evidence of primary tumor.
Tis	Carcinoma in situ.
T1	Tumor 2 cm in greatest dimension.
T2	Tumor >2 cm but 4 cm in greatest dimension.
T3	Tumor >4 cm in greatest dimension or extension to lingual surface of epiglottis.
T4a	Moderately advanced local disease. Tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible.b
T4b	Very advanced local disease. Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid artery.

Table 2. Regional Lymph Nodes (N)^a,b

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.^bMetastases at level VII are considered regional lymph node metastases.

NX	Regional lymph nodes cannot be assessed.
N0	No regional lymph node metastasis.
N1	Metastasis in a single ipsilateral lymph node, 3 cm in greatest dimension.
N2	Metastasis in a single ipsilateral lymph node, >3 cm but 6 cm in greatest dimension, or metastasis in multiple ipsilateral lymph nodes, 6 cm in greatest dimension, or in bilateral or contralateral lymph nodes, 6 cm in greatest dimension.
N2a	Metastasis in a single ipsilateral lymph node >3 cm but 6 cm in greatest dimension.
N2b	Metastases in multiple ipsilateral lymph nodes, 6 cm in greatest dimension.
N2c	Metastases in bilateral or contralateral lymph nodes, 6 cm in greatest dimension.
N3	Metastasis in a lymph node >6 cm in greatest dimension.

Table 3. Distant Metastasis (M)^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.

M0	No distant metastasis.
M1	Distant metastasis.

Table 4. Anatomic Stage/Prognostic Groups^a

^aReprinted with permission from AJCC: Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56.

Stage	T	N	M
0	Tis	N0	M0
I	T1	N0	M0
II	T2	N0	M0
III	T3	N0	M0
	T1	N1	M0
	T2	N1	M0
	T3	N1	M0
IVA	T4a	N0	M0
	T4a	N1	M0
	T1	N2	M0
	T2	N2	M0
	T3	N2	M0
	T4a	N2	M0
IVB	T4b	Any N	M0
	Any T	N3	M0
IVC	Any T	Any N	M1

References:

1. Weber AL, Romo L, Hashmi S: Malignant tumors of the oral cavity and oropharynx: clinical, pathologic, and radiologic evaluation. Neuroimaging Clin N Am 13 (3): 443-64, 2003. [PUBMED Abstract]
2. Wong RJ, Lin DT, Schíder H, et al.: Diagnostic and prognostic value of [(18)F]fluorodeoxyglucose positron emission tomography for recurrent head and neck squamous cell carcinoma. J Clin Oncol 20 (20): 4199-208, 2002. [PUBMED Abstract]
3. Pharynx. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 41-56. [PUBMED Abstract]

Treatment Option Overview

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On attempting to define the optimal therapeutic approach to the oropharynx, it becomes clear that no single therapeutic regimen offers a clear-cut superior survival over other regimens. The literature is filled with reports highlighting various therapeutic options but does not contain reports presenting any valid comparative studies of therapeutic options. The ultimate therapeutic choice will depend on a careful review of each individual case, paying attention to the staging of the neoplasm, the general physical condition of the patient, the emotional status of the patient, the experience of the treating team, and the available treatment facilities.

A review of published, clinical results of radical radiation therapy for head and neck cancer suggests a significant loss of local control when the administration of radiation therapy was prolonged; therefore, lengthening of standard treatment schedules should be avoided whenever possible. 1 2 Patients who smoke during treatment with radiation therapy appear to have lower response rates and shorter survival durations than those who do not; 3 therefore, patients should be counseled to stop smoking before beginning radiation therapy. The posttherapy performance status of patients with base-of-tongue primary tumors appears to be better following radiation therapy than following surgery. Local control and survival is similar in both, which suggests that radiation therapy may be superior. 4 5

Accumulating evidence has demonstrated a high incidence (i.e., >30%40%) of hypothyroidism in patients who have received external-beam radiation therapy to the entire thyroid gland or to the pituitary gland. Thyroid function testing of patients should be considered prior to therapy and as part of posttreatment follow-up. 6 7

References:

1. Fowler JF, Lindstrom MJ: Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 23 (2): 457-67, 1992. [PUBMED Abstract]
2. Allal AS, de Pree C, Dulguerov P, et al.: Avoidance of treatment interruption: an unrecognized benefit of accelerated radiotherapy in oropharyngeal carcinomas? Int J Radiat Oncol Biol Phys 45 (1): 41-5, 1999. [PUBMED Abstract]
3. Browman GP, Wong G, Hodson I, et al.: Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 328 (3): 159-63, 1993. [PUBMED Abstract]
4. Harrison LB, Zelefsky MJ, Armstrong JG, et al.: Performance status after treatment for squamous cell cancer of the base of tongue--a comparison of primary radiation therapy versus primary surgery. Int J Radiat Oncol Biol Phys 30 (4): 953-7, 1994. [PUBMED Abstract]
5. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006. [PUBMED Abstract]
6. Turner SL, Tiver KW, Boyages SC: Thyroid dysfunction following radiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 31 (2): 279-83, 1995. [PUBMED Abstract]
7. Constine LS: What else don't we know about the late effects of radiation in patients treated for head and neck cancer? Int J Radiat Oncol Biol Phys 31 (2): 427-9, 1995. [PUBMED Abstract]

Stage I Oropharyngeal Cancer

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Surgery or radiation is equally successful in controlling this stage of oropharyngeal cancer.

Standard treatment options:

1. Radiation may be the preferred modality where the functional deficit will be great, such as the tongue base or tonsil, as shown in the RTOG-9003 trial, for example. 1
2. Surgery may be the preferred modality where the functional deficit will be minimal, such as tonsil pillar.

When radiation is given, careful choice of radiation technique by a radiation oncologist experienced in managing head and neck cancers is essential. The choice of treatment is dictated by the anticipated functional, cosmetic, and socioeconomic results of the treatment options as well as by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient.

Treatment options under clinical evaluation:

• Radiation clinical trials evaluating hyperfractionation schedules should be considered.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000. [PUBMED Abstract]

Stage II Oropharyngeal Cancer

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Surgery or radiation is equally successful in controlling this stage of oropharyngeal cancer.

Standard treatment options:

1. Radiation may be the preferred modality where the functional deficit will be great, such as the tongue base or tonsil, as shown in the RTOG-9003 trial, for example. 1 2 3
2. Surgery may be the preferred modality where the functional deficit will be minimal, such as tonsil pillar.

When radiation is given, careful choice of radiation technique by a radiation oncologist experienced in managing head and neck cancers is essential. Interstitial radiation techniques may be used when indicated. The choice of treatment is dictated by the anticipated functional, cosmetic, and socioeconomic results of the treatment options as well as by the available expertise of the surgeon or radiation therapist. Treatment is individualized for each patient.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage II oropharyngeal cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Mendenhall WM, Amdur RJ, Stringer SP, et al.: Radiation therapy for squamous cell carcinoma of the tonsillar region: a preferred alternative to surgery? J Clin Oncol 18 (11): 2219-25, 2000. [PUBMED Abstract]
2. Fu KK, Pajak TF, Trotti A, et al.: A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys 48 (1): 7-16, 2000. [PUBMED Abstract]
3. Mendenhall WM, Morris CG, Amdur RJ, et al.: Definitive radiotherapy for squamous cell carcinoma of the base of tongue. Am J Clin Oncol 29 (1): 32-9, 2006. [PUBMED Abstract]

Stage III Oropharyngeal Cancer

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The managem