Carcinoma of the Pharynx

Anatomy & Pathophysiology:

The pharynx is divided into three broad subregions: the nasopharynx, the oropharynx, and the hypopharynx. The nasopharynx begins at the skull base and extends inferiorly to the soft palate. Important landmarks within the nasopharynx include the Eustachian tube orifices, the torus tubarius (cartilaginous structure posterosuperior to the Eustachian tube opening), and fossa of Rosenmüller (also known as the pharyngeal recess). Subsites of the nasopharynx include lateral walls, roof and the posterior wall. A wide variety of benign and malignant tumors can arise in the nasopharynx. A common benign lesion of the nasopharynx seen in adolescent males is juvenile nasal angiofibroma (JNA), which is described in detail in Tumors of the Nose and Paranasal Sinuses.

The most common malignancy of the nasopharynx is nasopharyngeal carcinoma (NPC). Histologically, NPC is divided into three types: keratinizing squamous cell carcinoma (SCC), nonkeratinizing SCC, and undifferentiated carcinoma. Keratinizing SCC is sporadic and behaves similarly to SCC of other regions of the head and neck (including increased risk with tobacco and alcohol use). Nonkeratinizing and undifferentiated carcinoma are by far the most common forms and are associated with genetic and environmental risk factors, notably Epstein-Barr virus (EBV) infection and dietary habits (such as increased nitrosamine consumption). Cervical lymph node metastases are common in NPC, most frequently involving the retropharyngeal, high level V, and level II lymph nodes.

The oropharynx extends from the level of the palate to the vallecula (level of the hyoid bone). It is contiguous with the oral cavity. Subunits of the oropharynx include the base of tongue, soft palate and uvula, palatine tonsils and tonsillar fossae, and pharyngeal wall. Of these, the tonsillar fossa is the most common site of tumor origin, followed by the base of tongue. Malignancy in the oropharynx is predominantly squamous cell carcinoma (90%), followed by lymphoma. Pathogeesis of oropharyngeal SCC today is usually related to human papillomavirus (HPV) infection, particularly subtype 16. Tobacco and alcohol use are also strongly associated risk factors. Cervical lymph node metastases are very common in oropharyngeal carcinoma, most commonly involving the jugulodigastric, retropharyngeal, and parapharyngeal nodes (levels II-IV). Bilateral cervical nodal involvement is more common in tongue base, soft palate, and posterior pharyngeal wall tumors.

The hypopharynx is located lateral, and partially posterior, to the larynx. It extends from the level of the hyoid bone to the esophageal introitus (level of the cricoid cartilage). Subunits of the hypopharynx include the pyriform sinuses, posterior hypopharyngeal wall, and postcricoid region. Squamous cell carcinoma is by far the most common hypopharyngeal malignancy. Tobacco and alcohol use are associated risk factors. The evidence that gastroesophageal reflux may play a small role in carcinogenesis remains controversial. The pyriform sinus is the most common location of hypopharyngeal carcinoma in the United States, accounting for 60-70% of cases. Tumors in this location can extend medially to or from the larynx. Postcricoid tumors are more common in European nations; these tumors may extend into the cricoid cartilage or posterior cricoarytenoid muscle, or they may involve the thyroid gland. Plummer-Vinson syndrome is a rare condition characterized by iron-deficiency anemia, angular stomatitis, and atrophic glossitis; it is associated specifically with postcricoid cancer. Lymphatic drainage of the hypopharynx is primarily to the jugulodigastric nodes, midjugular chain, retropharyngeal nodes, paratracheal nodes, and paraesophageal nodes. Hypopharyngeal carcinoma is notable for its propensity for submucosal spread.

Epidemiology:

Nasopharyngeal carcinoma is most prevalent among individuals with southern Chinese ancestry, including residents of Hong Kong and southeast Asia, as well as Chinese who have emigrated to the Unites States from southern China. In some regions of China, incidence is as high as 30 cases per 100,000 persons. The incidence of NPC is decreased in individuals of ethnic southern Chinese heritage but who are born and live in the United States, suggesting a possible environmental etiology in addition to a genetic component. NPC is more common in males and is most often diagnosed between the ages of 30 and 50 years.

Oropharyngeal carcinoma accounts for 10-12% of all head and neck cancers. The reported incidence of oropharyngeal carcinoma (1-3 cases per 100,000 persons) has been increasing in the past two decades, during which time the association with human papillomavirus (HPV) infection has been studied extensively. There is a male predominance, and tumors are most often diagnosed between 40 and 65 years of age.

Hypopharyngeal carcinoma accounts for approximately 4% of all head and neck cancers. Overall incidence rates are around 1 case per 100,000 persons for males and 0.5 cases per 100,000 persons in females. An exception to the male predominance is in patients with Plummer-Vinson syndrome, which primarily affects women. Cancer of the hypopharynx has been reported to have a higher incidence in the African American population, particularly among African American males.

Natural History:

Although anatomically adjacent, tumors of the nasopharynx, the oropharynx, and the hypopharynx are best considered as three distinct entities, with different populations, etiologies, intervention strategies, and prognoses. Typical NPC occurs in patients of southern Chinese ancestry and is treated with chemoradiation with good control at the primary site, but has significant rates of distant metastases. The majority of tonsillar fossa and base of tongue tumors today are HPV-related and have excellent prognoses; current studies aim at minimizing the complications and side effects of different intervention strategies. Hypopharyngeal tumors are similar to laryngeal tumors in etiology, present late, and carry a poorer prognosis than either OP carcinomas or NPC.

Presentation:

The most common presenting signs and symptoms of NPC are neck mass and unilateral middle ear effusion presenting as decreased hearing. Epistaxis is uncommon, as bleeding is usually posterior, but blood-tinged saliva may be noted. Pain and nasal obstruction may occur. In advanced cases with skull base extension, the patient may exhibit headache or cranial nerve neuropathies (such as V2, VI, and XII).

Presenting symptoms in oropharyngeal carcinoma include dysphagia, odynophagia, foreign body sensation in the throat, oral bleeding, referred otalgia, change in speech, or neck mass. Trismus may be present if there is involvement of the pterygoid muscles. Tumors involving the soft palate may be initially detected during dental examination.

Hypopharyngeal cancers typically present late, with dysphagia, neck mass, dysphonia, hemoptysis, hoarseness, or referred otalgia. Dyspnea or other signs of airway obstruction may be present in late stage disease.

Differential Diagnosis of Nasopharyngeal Mass:

Differential Diagnosis of Oropharyngeal/Hypopharyngeal Mass:

Evaluation:

History

The patient history in suspected pharyngeal carcinoma should include the timing of symptom onset and progression and details of tobacco and alcohol use.

Physical Examination

Examination should include cranial nerve assessment, a bimanual oral cavity examination including the base of tongue and tonsillar fossae, and palpation of the neck for cervical lymphadenopathy. For nasopharyngeal masses, otoscopy may reveal otitis media with effusion.

Endoscopy should be performed in any case of suspected pharyngeal tumor to inspect the nose and nasopharynx, oropharynx, hypopharynx, and larynx. In NPC, an exophytic mass is generally seen, but occasionally the tumor may be submucosal, wherein the overlying mucosa appears normal or with only minimal contour irregularity or erythema. In addition to masses, endoscopy should also assess for airway patency, vocal cord mobility (cranial nerve X function), and tongue mobility (cranial nerve XII function).

Biopsy

Tissue biopsies are required for pathologic diagnosis of pharyngeal cancers; this may be via a fine needle aspiration biopsy of an involved neck node or via a biopsy of the primary site. Nasopharyngeal tumors may be transnasally biopsied in the office under local anesthesia with endoscopic guidance. Biopsy of oropharyngeal tumors may be performed under local anesthesia or may require general anesthesia in an operating room setting. Hypopharyngeal tumors are biopsied as part of a panendoscopy (direct laryngoscopy, fiberoptic bronchoscopy, and fiberoptic esophagoscopy). Histological staining for HPV (or p16) in oropharyngeal tumors and EBV for NPC tumors is indicated.

Imaging Studies

Radiographic imaging is essential in cases of pharyngeal carcinoma for establishing tumor extent, evaluating locoregional and distant spread, and, if applicable, preoperative planning. Magnetic resonance imaging (MRI) is the preferred modality for nasopharyngeal and oropharyngeal tumors. Computed tomography (CT) may occasionally be preferable in evaluating hypopharyngeal tumors, such as when there is marked motion artifact with swallowing. Positron emission tomography (PET)-CT is helpful in assessing regional and distant metastases, as well as for radiation planning.

Other Studies

An audiologic assessment may also be performed during the diagnostic evaluation, especially if cisplatin is to be used as part of the chemoradiation protocol.

Staging

Note that the staging of nodal metastasis in NPC is different than for other common sites of squamous cell carcinoma. In the future it is anticipated that HPV staining will formally become part of oropharyngeal staging as it is critically correlated with prognosis (HPV-positive tumors do better).

AJCC TNM Staging for Nasopharyngeal Carcinoma
Primary Tumor (T)
T1	Tumor confined to nasopharynx OR tumor extends to nasal cavity or oropharynx without parapharyngeal extension
T2	Tumor extends to parapharyngeal space
T3	Tumor involves bony structures of paranasal sinuses or skull base
T4	Tumor extends intracranially and/or involves cranial nerves, hypopharynx, or orbit OR tumor extends to infratemporal fossa or masticator space
Nodal Metastasis (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in ipsilateral lymph node(s), none >6 cm in greatest dimension
N2	Metastasis in bilateral lymph node(s), none >6 cm in greatest dimension
N3	Metastasis in lymph node >6 cm in greatest dimension OR supraclavicular node
Distant Metastasis (M)
Mx	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis present (includes mediastinal lymph nodes)
Staging Groups
Stage	T	N	M
I	T1	N0	M0
II	T2	N0	M0
	T1-2	N1	M0
III	T3	N0-2	M0
	T1-2	N2	M0
IVA	T4a	Any N	M0
IVB	Any T	N3	M0
IVC	Any T	Any N	M1

AJCC TNM Staging for Oropharyngeal and Hypopharyngeal Carcinoma
Oropharynx
T1	Tumor ≤2 cm in greatest dimension
T2	Tumor >2 cm but ≤4 cm in greatest dimension
T3	Tumor >4 cm in greatest dimension
T4a	Tumor invades larynx, deep or extrinsic muscle of the tongue, medial pterygoid, hard palate, or mandible
T4b	Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base OR tumor encases carotid artery
Hypopharynx
T1	Tumor limited to one subsite of hypopharynx and ≤2 cm in greatest dimension
T2	Tumor invades more than one subsite of hypopharynx or an adjacent site OR tumor measures > 2 cm but not >4 cm in greatest dimension; no fixation of hemilarynx is present
T3	Tumor >4 cm in greatest dimension OR fixation of hemilarynx is present
T4a	Tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissue (including prelaryngeal strap muscles and subcutaneous fat)
T4b	Tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures
Nodal Metastasis (N)
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
N2a	Metastasis in a single ipsilateral lymph node, >3 cm but <6 cm in greatest dimension
N2b	Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension
N2c	Metastasis in bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N3	Metastasis in a lymph node >6 cm in greatest dimension
Distant Metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis present
Staging Groups
Stage	T	N	M
I	T1	N0	M0
II	T2	N0	M0
	T1-2	N1	M0
III	T3	N0-2	M0
	T1-2	N2	M0
IVA	T4a	Any N	M0
IVB	Any T	N3	M0
IVC	Any T	Any N	M1

Treatment:

Nasopharyngeal carcinoma

Radiation is the primary treatment modality for NPC. For early stage (stage I/II) disease, radiotherapy is employed as the sole therapy. Chemoradiation (such as with cisplatin) is typically given for advanced stage disease. Following chemoradiation, neoadjuvant chemotherapy using cisplatin and 5-fluorouracil was shown in a randomized prospective trial to be effective for stage IV NPC, although several subsequent studies have called that into question. Surgical resection of NPC is reserved for selected cases of recurrent disease; re-irradiation is an alternative for locally recurrent tumors, or when surgery is not appropriate. Nasopharyngectomy for recurrent local disease may be approached via endoscopic or open approaches, depending on the extent of disease and the experience of the surgeon. Resectable recurrent regional (cervical) disease is treated with a modified radical neck dissection.

Oropharyngeal carcinoma

Treatment options for oropharyngeal carcinoma depend on the site of tumor origin, extent of disease, and clinical staging. A common approach is concomitant chemoradiation, with surgery indicated if there is not a complete response. In cases where response clinically appears to be complete, a PET-CT is performed for verification three months after chemoradiation. For earlier disease, many centers have considered initial resection of a tonsillar fossa or base of tongue primary with neck dissection. If the pathology review is favorable, then a reduced dose of irradiation is given, without chemotherapy. The major questions to be ascertained are whether such an approach a) is associated with less long-term dysphagia, b) provides equivalent overall tumor control, and c) represents an acceptable surgical risk.

Hypopharyngeal carcinoma

Hypopharyngeal cancer in the early stages (I/II) is typically treated with radiation alone. As early presentation is uncommon, partial pharyngectomy is rarely employed as the primary treatment modality for early stage tumors. However, this might be a consideration if the tumor is confined to the posterior or lateral wall of the pyriform sinus. Other organ-preserving surgical approaches are similar to those used in laryngeal carcinoma (see Laryngeal Carcinoma). Alternatively, chemoradiation approaches are often used in an effort to avoid extensive laryngeal surgery, and to avoid a total laryngectomy, if possible. An initial total laryngectomy and partial or total pharyngectomy with postoperative chemoradiation may provide the best functional outcomes for more advanced lesions with impaired airway or poor swallowing. When a circumferential pharyngeal defect is created after an extensive pharyngectomy and laryngectomy, reconstruction must connect the oropharynx superiorly with the cervical esophagus inferiorly. Options include pectoralis major flap, gastric pull-up, and jejunal or anterolateral thigh microvascular free flap.

Complications, Prognosis & Follow-Up:

Nasopharyngeal carcinoma

Complications of radiotherapy for NPC include mucositis, xerostomia, sinusitis, otitis media with effusion, sensorineural hearing loss, trismus, and cranial nerve palsy. In addition, there may also be side effects and risks associated with any chemotherapeutic agent. The local recurrence rate after treatment in NPC is approximately 5-10%. Local recurrences may be effectively treated with salvage surgery or re-irradiation, depending on the extent of tumor. Neck persistence or recurrence is treated with neck dissection with overall good regional control. Prognosis in nasopharyngeal carcinoma is largely dependent on clinical stage. Early stage disease is associated with a 5-year survival rate of over 80%. With concurrent chemoradiation, 5-year survival rates for advanced stage disease may be as high as 70%; however, the risk of recurrence and distant metastasis result in reported 10-year survival rates of 10-40%. Distant metastases are common and difficult to manage successfully.

Oropharyngeal carcinoma

Complications of radiotherapy in oropharyngeal cancer include mucositis, dysphagia, xerostomia, gustatory dysfunction, dental problems, and osteoradionecrosis of the mandible. The prognosis for oropharyngeal carcinoma is dependent on HPV status and stage. Stage I-II, HPV-positive tumors are cured in 80-95% of cases. Stage I-II, HPV-negative tumors are cured somewhat less frequently–approximately 70-85% of cases. For stage III-IV, the difference is more striking, with cure rates of 20-50%, depending on HPV status. Treatment failure in advanced stage disease is usually a result of regional recurrence and, increasingly, because of distant metastases.

Hypopharyngeal carcinoma

Prognosis in hypopharyngeal carcinoma is poor, with overall data suggesting a survival rate of less than 40%. Survival has been reported to be higher in pyriform sinus tumors and lower in posterior hypopharyngeal wall tumors.