Oropharyngeal Cancer Treatment (Adult) (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Oropharyngeal Cancer

Incidence and Mortality

Estimated new cases and deaths from cancer of the oral cavity and pharynx in the United States in 2025:[1]

• New cases: 59,660.
• Deaths: 12,770.

The increasing incidence of oropharyngeal cancer is attributed to the rise in human papillomavirus (HPV)-associated cases. Men are almost three times as likely as women to have oropharyngeal cancer.[1,2,3]

Anatomy

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 parts:[4]

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

Regional lymph node anatomy of the head and neck

The regional lymph nodes of the head and neck include the lymph nodes that run parallel to the jugular veins, spinal accessory nerve, and facial artery and into the submandibular triangle. An understanding of regional anatomy and the status of regional lymph nodes is critical to the care of patients with head and neck cancer.[3,5,6] To facilitate communication regarding lymph node anatomy, the regions of the neck are described as levels I to V and retropharyngeal:

• 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 midjugular 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.
• Retropharyngeal lymph nodes.

The retropharyngeal lymph nodes are a possible site for nodal spread in oropharyngeal cancer. A large retrospective cohort study from the MD Anderson Cancer Center described the clinical features of 981 patients with oropharyngeal cancer who underwent primary radiation therapy.[7][Level of evidence C1][Level of evidence C2]

• The base of the tongue (47%) and the tonsil (46%) were the most common primary sites.
• Most patients had stage T1 to T2 primary tumors (64%) and stage III to IVB disease (94%).
• The incidence of radiographic retropharyngeal node involvement was 10% and was highest for the pharyngeal wall (23%) and lowest for the base of the tongue (6%).
• Retropharyngeal lymph node involvement was associated with inferior 5-year local control and inferior recurrence-free survival, distant metastases−free survival, and overall survival on multivariate analysis.

Risk Factors

Risk factors for oropharyngeal squamous cell carcinoma (SCC) include:[8]

• Smoking history of more than 10 pack years and other tobacco use.[9,10]
• Heavy alcohol use.
• HPV infection, especially HPV type 16, also known as HPV-16.[11,12,13]
• Personal history of head and neck cancer.
• Betel quid chewing.

For more information, see Oral Cavity, Oropharyngeal, Hypopharyngeal, and Laryngeal Cancers Prevention.

HPV infection

Because of the decreased incidence of smoking in the United States, HPV-negative, smoking-related oropharyngeal cancer is decreasing; however, HPV-positive oropharyngeal cancer is increasing. According to the Surveillance, Epidemiology, and End Results (SEER) Program's tissue repository data from 1988 to 2004, the prevalence of HPV-negative oropharyngeal cancer declined by 50%, while HPV-positive oropharyngeal cancers increased by 225%.[14][Level of evidence C1]

HPV-positive oropharyngeal cancers may represent a distinct disease entity that is caused by HPV infection and associated with an improved prognosis. Several studies indicate that individuals with HPV-positive tumors have significantly improved survival.[12,15,16,17] Due to the prognostic impact of the HPV status in oropharyngeal cancer, the American Joint Committee on Cancer 8th edition staging separates oropharyngeal staging by HPV status.[5,6] In a prospective study of 253 patients with newly diagnosed or recurrent head and neck SCC, HPV was detected in 25% of the patients. Poor tumor grade and an oropharyngeal site independently increased the probability of the presence of HPV.[12] Oropharyngeal tumors are more likely to be HPV positive (57%) than oral cavity (12%) tumor sites and non-oropharyngeal (14%) sites. HPV-positive oropharyngeal cancers predominantly arise in the palatine or lingual tonsils. For tonsil or base-of-tongue sites, 62% of tumors were HPV positive, compared with 25% for other oropharyngeal sites.

Personal history of head and neck cancer

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.[18,19] Because of this risk, patients require lifelong surveillance. Smoking and alcohol consumption after treatment are associated with the development of second primary tumors of the aerodigestive tract.[20,21,22] Patients may need counseling to discontinue smoking and alcohol consumption.

The process of field cancerization may be partly responsible for the multiple, synchronous, primary SCCs that occur in oropharyngeal cancer and that are associated with a smoking history. Originally described in 1953, the concept of field cancerization holds that tumors develop in a multifocal fashion within a field of tissue chronically exposed to carcinogens.[23] Molecular studies that detect genetic alterations in histologically normal tissue from high-risk individuals have provided strong support for this concept.[24,25,26,27,28]

A comparison of patients (N = 2,230) with index SCC of the oropharynx site and index SCC of non-oropharyngeal sites (i.e., oral cavity, larynx, and hypopharynx) was performed to determine the likelihood of developing second primary malignancies. The second primary malignancy rate was lower for patients with index oropharyngeal SCC than for patients with index non-oropharyngeal cancer (P < .001). Among patients with oropharyngeal SCC, former smokers had a 50% higher risk of second primary malignancy than never-smokers, and current smokers had a 100% higher risk than never-smokers (P trend = .008). These data suggest that patients who fit the typical HPV phenotype have a very low risk of second primary malignancy.[29]

Betel quid

The chewing of betel quid, a stimulant preparation commonly used in parts of Asia, increases the risk of oropharyngeal cancer.[30]

Other risk factors

Other risk factors may include:[8]

• Defective elimination of acetaldehyde, a carcinogen generated by alcohol metabolism. In individuals, primarily those of East Asian race, who carry 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.[31]

SCC of the oropharynx has not been associated with any specific chromosomal or genetic abnormalities. Genetic and chromosomal aberrations in these cancers are complex.[32,33] 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 of disease progression and may lead to more-definitive therapy.[34]

Clinical Presentation

The clinical presentation of oropharyngeal cancer depends on the tumor's location in the oropharynx. Oropharyngeal cancer may present in the following locations:

• Tonsil, tonsillar fossa, tonsillar pillars, or glossotonsillar sulci.
• Base of the tongue (posterior one-third of the tongue posterior to the circumvallate papillae).
• Vallecula.
• Soft palate, inferior surface, or uvula.
• Posterior pharyngeal wall.

Tonsil

The anterior tonsillar pillar and tonsil are the most common location for a primary tumor of the oropharynx.[4] Lesions involving the anterior tonsillar pillar may appear as areas of dysplasia, inflammation, or a superficial spreading lesion. These cancers can spread across a broad region, including the lateral soft palate, retromolar trigone and buccal mucosa, and tonsillar fossa.[3,4] The lymphatic drainage is primarily to level II 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.

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 as advanced-stage disease more often than do cancers of the tonsillar pillar. Approximately 75% of patients will present with stage III or stage IV disease.[3,4] 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.

Signs and symptoms of tonsillar lesions may include:[3,4]

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

Base of the tongue

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 there is significant tumor progression.[4]

Signs and symptoms of advanced base-of-the-tongue cancers may include:[3,4]

• 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.

Lymph node metastasis is common because of the rich lymphatic drainage of the base of the tongue. Approximately 70% or more of patients with advanced base-of-the-tongue cancers have ipsilateral cervical nodal metastases; 30% or fewer of such patients have bilateral, cervical lymph–node metastases.[4,35] The cervical lymph nodes involved commonly include levels II, III, IV, and V and retropharyngeal lymph nodes.

Soft palate

Soft palate tumors are primarily found on the anterior surface.[4] Lesions in this area may remain superficial and in early stages.[3] The lymphatic drainage is primarily to level II nodes.

Pharyngeal wall

Pharyngeal wall 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.

Early-stage tumors are often asymptomatic. Tumors of the pharyngeal wall are typically diagnosed in an advanced stage.[3,4]

Signs and symptoms of advanced pharyngeal wall tumors may include:

• Pain.
• Bleeding.
• Dysphagia.
• Weight loss.
• A mass in the neck.

Leukoplakia

Leukoplakia is 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 histological findings.[8] Leukoplakia can range from hyperkeratosis to an actual early invasive carcinoma or may represent a fungal infection, lichen planus, or other benign oral disease.

Diagnostic Evaluation

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 presence of tumor must be confirmed histologically. Any other pathological data obtained from a biopsy and additional radiographical studies are also considered.

The following procedures may be done to evaluate the primary tumor:

• Positron emission tomography–computed tomography (PET-CT) scan.
• Magnetic resonance imaging.
• Endoscopy.
• Laryngoscopy.
• Biopsy and p16 testing to assess for HPV status.

A PET-CT scan yields morphological and metabolic data to assess the detection of primary tumor, nodal disease, and distant metastatic disease. It may also be used to guide radiation therapy planning. Retrospective data demonstrate that morphological and PET-glycolytic parameters (as measured by fluorodeoxyglucose PET-CT) are significantly larger (as measured by Response Evaluation Criteria In Solid Tumors [RECIST] longest diameter) and more heterogenous in HPV-negative disease than in HPV-positive disease in the primary tumor for oropharyngeal carcinoma. These PET-CT parameters also show higher standardized uptake value (SUV) max, SUV mean, and metabolic tumor volume in HPV-negative disease. However, the same PET parameters are frequently larger in the regional nodal disease in patients with HPV-positive disease.[36][Level of evidence C3]

Prognostic Factors and Survival

Prognostic factors for oropharyngeal carcinoma include:

• HPV status.
• Smoking history (10 or more pack-years).
• Tumor stage and nodal status.

The criteria described in Table 1 are used to determine whether patients have low-, intermediate-, or high-risk oropharyngeal carcinoma. These criteria have been defined by using recursive partitioning analysis in a retrospective analysis of a randomized trial of patients with stage III and IV oropharyngeal SCC treated with chemoradiation.[17]

Follow-Up After Treatment

A careful examination of the patient's head and neck allows the physician to look for recurrence every 6 to 12 weeks for the first posttreatment year, every 3 months for the second year, every 3 to 4 months for the third year, and every 6 months thereafter.

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