General Information About Oropharyngeal Cancer
Incidence and Mortality Risk Factors
Oropharyngeal squamous cell carcinoma (SCC) risk factors may include:
- A smoking history of more than 10 pack years.
- Infection with the human papillomavirus (HPV), especially HPV type16, also known as HPV-16.[5-7]
Similar to other cancers of the head and neck, tobacco and alcohol abuse represent significant risk factors for the development of oropharyngeal cancer.[3,8] (Refer to the PDQ summaries on Hypopharyngeal Cancer Treatment and Lip and Oral Cavity Cancer Treatment for more information.)
Because of the decreased incidence of smoking in the United States, HPV-negative, smoking-related oropharyngeal cancer is decreasing and HPV-associated oropharyngeal cancer is increasing in incidence. The prevalence of HPV in oropharyngeal cancers has increased by 225% from 1988 to 2004, and the HPV-negative cancers have declined by 50% according to the Surveillance, Epidemiology, and End Results (SEER) tissue repository data.[Level of Evidence: 3iii]
HPV-positive oropharyngeal cancers may represent a distinct disease entity that is causally associated with HPV infection and is also associated with an improved prognosis. Several studies indicate that individuals with HPV-positive tumors have significantly improved survivals.[6,10-12] 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 the presence of HPV.
The prognosis of oropharyngeal carcinoma is based on HPV status, smoking history (pack-year smoking history of 10 or more years), tumor stage, and nodal stage. The following criteria are used to determine whether patients have low-, intermediate-, or high-risk oropharyngeal carcinoma and have been defined using recursive partitioning analysis in a retrospective analysis of a randomized trial of stage III and IV oropharyngeal SCC patients treated with chemoradiation:
- Low-risk patients include those with HPV-positive tumors, a smoking history of 10 or fewer pack years, and N0 to N2a nodal disease.
- Intermediate-risk patients include those with HPV-positive tumors, a smoking history of more than 10 pack years, and N2b–N3 disease; or, for those with HPV-negative tumors, a smoking history of 10 or fewer pack years, N2b or N3 disease, or T2–3 tumors.
- High-risk patients include those with HPV-negative tumors and a smoking history of more than 10 pack years; or, for those with HPV-negative tumors, a smoking history of 10 or fewer pack years, and T4 disease.
The 3-year rates of overall survival (OS) were 93.0% (95% confidence interval [CI], 88.3–97.7) in the low-risk group, 70.8% (95% CI, 60.7–80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7–57.7) in the high-risk group.
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.[13,14] Because of this risk, patients require lifelong surveillance. Patients need counseling about continued smoking and alcohol consumption after treatment, which has been associated with the development of second primary tumors of the aerodigestive tract.[15-17] (Refer to the PDQ Smoking Cessation and Continued Risk in Cancer Patients summary for more information.)
An analysis studied 2,230 patients with index SCC of the oropharynx to determine the likelihood of developing second primary malignancies compared with index SCC of nonoropharyngeal sites (i.e., oral cavity, larynx, and hypopharynx). The second primary malignancy rate was lower for patients with index oropharyngeal SCC than for patients with index nonoropharyngeal cancer (P < .001). Among patients with oropharyngeal SCC, former smokers had a 50% greater risk of second primary malignancy and current smokers had a 100% greater risk than never-smokers (P trend = .008). These data suggest that patients who fit the typical HPV phenotype have a very low, second-primary malignancy risk.
To date, SCC of the oropharynx has not been associated with any specific chromosomal or genetic abnormalities. Genetic and chromosomal aberrations in these cancers are complex.[19,20] 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.
Other risk factors may include the following:
- A diet poor in fruits and vegetables.
- The consumption of maté, a stimulant beverage commonly consumed in South America.
- The chewing of betel quid, a stimulant preparation commonly used in parts of Asia.
- Defective elimination of acetaldehyde, a carcinogen generated by alcohol metabolism. In individuals, primarily East Asians, 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.
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:
- 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, i.e., 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.[3,27] The regions of the neck have been characterized by levels (I–V) 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.
- Retropharyngeal lymph nodes.
Traditionally, the retropharyngeal lymph nodes are at risk for nodal spread in oropharyngeal cancer; this incidence has not been well established until recently.
In a large, retrospective cohort from the MD Anderson Cancer Center, 981 oropharyngeal patients who underwent primary radiation therapy were analyzed. The base of the tongue (47%) and the tonsil (46%) were the most common primary sites. The majority of patients had stage T1 to T2 primary tumors (64%), and 94% had stage 3 to 4B disease. The incidence of radiographic retropharyngeal–nodal 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, distant metastases-free, and OS on multivariate analysis.[Levels of evidence: 3iiA, 3iiDii] Histologically, almost all oropharyngeal cancers are SCCs. 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 and are associated with a smoking history. This concept, originally described in 1953, proposes that tumors develop in a multifocal fashion within a field of tissue chronically exposed to carcinogens. Molecular studies detecting genetic alterations in histologically normal tissue from high-risk individuals have provided strong support for the concept of field cancerization.[30-34]
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.Symptoms
- 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 the patients have ipsilateral cervical nodal metastases; 30% or fewer of the patients have bilateral, cervical lymph–node metastases.[26,35] The cervical lymph nodes involved commonly include levels II, III, IV, V, and retropharyngeal lymph nodes.
- 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. 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.[3,26] 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.[3,26] 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.
Symptoms of pharyngeal wall tumors may include:
- 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. These are clinical terms that have no specific histopathologic connotations. 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.” 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.
The prevalence of leukoplakia in the United States is decreasing; this decline has been related to reduced tobacco consumption. Although erythroplakia is not as common as leukoplakia, it is much more likely to be associated with dysplasia or carcinoma.[4,39]Imaging Work-up
The clinical anatomic staging of oropharyngeal cancers involves both clinical assessment and imaging techniques.[3,27] Standard imaging techniques include a dedicated head and neck computed tomography (CT) scan with contrast, positron emission tomography (PET)-CT scan, and magnetic resonance imaging. A PET-CT scan yields morphologic 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 morphologic and PET-glycolytic parameters, which are measured in fluorodeoxyglucose PET-CT, are significantly larger in HPV-negative disease compared with HPV-positive disease in the primary tumor for oropharyngeal carcinoma. However, the same PET parameters are frequently larger in the regional nodal disease in patients with HPV-positive disease.[Level of evidence: 3iiDiv]References
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