Pharynx and Esophagus

Radiographic Evaluation

The lining of the upper aerodigestive tract, including the nasopharynx, oropharynx, and hypopharynx, is radiographically termed the pharyngeal mucosal space. Radiographic imaging is crucial for delineating the third dimension of the primary tumor and the extent of its local invasion, whereas clinical examination is more reliable for assessment of its surface extent. Although MRI is superior for assessment of the soft tissue extent of the tumor, its utility is limited by motion artifact if the patient cannot control swallowing during the examination because of a bulky tumor at the base of the tongue or hypopharynx. In contrast, new generation CT scanners allow rapid acquisition of data that can be reconstructed in coronal and sagittal planes, which is particularly useful in patients who are unable to tolerate an adequate MRI examination.

When evaluating the nasopharynx, MRI is the modality of choice. Although CT is excellent for assessment of cortical bone and foramina at the skull base, nasopharyngeal tumors have a tendency to invade the medullary space of the clivus, and bone involvement therefore is detected earlier on MRI than on CT. Benign lesions of the nasopharynx such as a Thornwaldt cyst and retention cysts have characteristic imaging features that are helpful in making a diagnosis. Thornwaldt cysts arise from the notochord remnant and are located submucosally in the midline. They are very well defined and generally are bright on T2-weighted MRI ( Fig. 9.29 ). Retention cysts, generally located paramedian or laterally, are also bright on T2-weighted MRI and do not enhance with contrast ( Fig. 9.30 ).

The presence of an asymmetric mass in the nasopharynx is an obvious feature that should raise suspicion for a tumor in adults, especially if unilateral opacification of the ipsilateral mastoid air cells is noted. However, adenoidal tissue can be a source of confusion, especially in children. The presence of certain other features such as skull base invasion can point to the diagnosis of malignancy in these situations. Invasion of the skull base is seen frequently in patients with NPC, because the pharyngobasilar fascia acts as a barrier to lateral spread and funnels the tumor cephalad toward the central skull base. Early clival invasion is nicely seen on precontrast T1-weighted MRI, because normal bright adult fatty marrow provides contrast for grayish tumor infiltration. The tumor generally has a high signal on T2-weighted MRI and enhances on postcontrast images ( Fig. 9.31 ). Another feature of NPC is infiltration of the petroclival fissure, which is best demonstrated on bone windows of a CT scan ( Fig. 9.32 ). Gross extension into the parapharyngeal space occurs with breach of the pharyngobasilar fascia ( Fig. 9.33 ). The tumor can directly involve the lower cranial nerves, or perineural spread of tumor can occur along the branches of the trigeminal nerve. A tumor also can extend into the pterygopalatine fossa, gaining access to the vidian nerve and V2 ( Fig. 9.34 ), and it can involve the muscles of mastication in the masticator space ( Fig. 9.35 ), although this happens rarely.

Small and superficial tumors of the base of the tongue can be difficult to differentiate from lingual tonsillar tissue. The diagnosis of malignancy is obvious if infiltration into the base of tongue musculature is seen, but tumors of minor salivary gland origin can be well defined and difficult to differentiate from benign lesions ( Fig. 9.36 ). Imaging for lesions of the base of the tongue can be helpful in delineating the relationship of the tumor to the neurovascular bundles and for assessment of submucosal spread to the tonsillar fossa, soft palate, and pharyngeal wall ( Fig. 9.37 ). Sagittal T1-weighted precontrast MRI is useful for assessment of preepiglottic space invasion by a base of tongue tumor. Tumors of the tonsil also can spread submucosally to the base of the tongue via the glossotonsillar fold or to the soft palate ( Fig. 9.38 ). More advanced tumors can extend into the masticator space, involve the mandible, or encase the internal carotid artery.

Early staged carcinomas of the hypopharynx are rare but are evident on CT scans as an area of thickened, enhancing mucosa ( Fig. 9.39 ). Tumors of the medial wall of the pyriform sinus can extend into the paraglottic space and cause vocal cord fixation ( Fig. 9.40 ). Laterally, the thyroid cartilage is located immediately beneath the pyriform mucosa and is at risk for invasion by cancer. Involvement of the apex of the pyriform sinus places the cricoid cartilage at risk for invasion, and the adjacent recurrent laryngeal nerve can be directly invaded by tumor in the upper tracheoesophageal groove ( Fig. 9.41 ). Early carcinomas of the posterior pharyngeal wall appear as an area of subtle thickening with enhancement on contrast-enhanced CT, but more advanced tumors are readily apparent because of asymmetry ( Fig. 9.42 ). Imaging can be useful in delineating the relationship of these tumors to the prevertebral musculature if obvious infiltration is present, but early invasion often is difficult to define. Postcricoid tumors can spread submucosally to involve the circumference of the hypopharynx and often extend caudally into the cervical esophagus ( Fig. 9.43 ). Involvement of the cervical esophagus appears as asymmetric thickening of its wall, which is more easily seen on T2-weighted MRI. Extraluminal spread is indicated by obliteration of fat in the upper tracheoesophageal groove.

Radiographic imaging with CT or MRI is especially important in the evaluation of the regional lymph nodes in patients with cancer of the pharynx, because retropharyngeal lymph nodes are not amenable to clinical evaluation or ultrasound examination. The lateral retropharyngeal lymph nodes (which have a normal size of less than 8 mm in adults) are located between the prevertebral musculature (longus colli and capitis muscles) and the internal carotid artery. These lymph nodes are at risk for involvement by tumors of the nasopharynx and tonsil ( Fig. 9.44 ). Cystic cervical nodal metastases are a hallmark of primary cancer of Waldeyer's ring and should not be confused with “branchial cleft cyst.” A cystic neck mass in an adult always should be considered indicative of metastatic disease unless proven otherwise. Branchial cleft cysts have homogeneous content and a thin and smooth wall that does not enhance unless the cyst is infected. Cystic metastases, on the other hand, usually have a thick wall with rim enhancement, may be multiple, and are most often associated with a demonstrable primary tumor ( Fig. 9.45 ).

Positron emission tomography (PET) scanning has become essential in pretreatment assessment of the extent of primary tumor and regional lymph node metastases ( Fig. 9.46 ). It is regularly used for radiation treatment planning and is an essential imaging study for evaluating response to therapy in cancers of the oropharynx and other sites treated by chemoradiotherapy. Generally, PET scan assessment should be done at least 3 months following completion of treatment.

Pathologic Evaluation

Nasopharynx

Nasopharyngeal squamous cell carcinoma is classified by the World Health Organization into keratinizing, nonkeratinizing, and undifferentiated types ( Table 9.1 ). Nonkeratinizing carcinoma is further subclassified into differentiated and undifferentiated subtypes. The undifferentiated subtype of nonkeratinizing carcinoma is particularly common in southeast Asia, where it represents 15% to 20% of all cancers and is thought to be associated with EBV infection. EBV can be detected in the tumor cells of almost all nonkeratinizing carcinoma but rarely in keratinizing NPC ( Fig. 9.47 ).

Table 9.1

The World Health Organization (WHO) Classification of Nasopharyngeal Carcinoma (2005)

WHO 1978	WHO 1991	WHO 2005
I Squamous cell carcinoma	I Squamous cell carcinoma	Keratinizing squamous cell carcinoma
II Nonkeratinizing carcinoma III Undifferentiated carcinoma	II Nonkeratinizing carcinoma a Differentiated nonkeratinizing carcinoma b Undifferentiated carcinoma	Nonkeratinizing carcinoma Differentiated Undifferentiated
		Basaloid squamous cell carcinoma

Differentiated nonkeratinizing nasopharyngeal carcinomas display a stratified appearance and distinct cell margins. By contrast, undifferentiated tumors exhibit clusters of poorly delineated or syncytial cells bearing large vesicular oval nuclei and scant eosinophilic cytoplasm. The undifferentiated variant often features a conspicuous lymphoid infiltrate, accounting for the obsolete (and misleading) term “lymphoepithelioma” ( Fig. 9.48 ). Both subtypes are immunoreactive with cytokeratin. The epithelial nature of this tumor is underscored by the fact that tumor cells express cytokeratin but no hematologic or lymphoid markers.

Oropharynx

Worldwide, up to 25% of head and neck squamous cell carcinomas are associated with high-risk HPV, the great majority of which are HPV 16. However, HPV serotypes 18, 31, 33, and 35 also have been associated with oropharyngeal squamous cell carcinoma. The HPV oncoproteins (E6 and E7) transform oral squamous epithelial cells. These proteins bind with p53 and Rb, respectively, interfering with their tumor suppressor functions and leading to cell cycle dysregulation and genetic instability. Immunohistochemistry for p16 is commonly used as a surrogate marker to identify HPV infection. Diffuse (>70%) and strong nuclear and cytoplasmic immunoreactivity is required to label a tumor as positive for that marker. In situ hybridization for HPV DNA ( Fig. 9.49 ) and RNA are now available. The latter has high sensitivity and specificity and localizes to the nucleus and cytoplasm.

In the United States approximately 80% of oropharyngeal squamous cell carcinomas are associated with high-risk HPV. The tonsil is the most frequent site for these tumors, which have a basaloid morphologic appearance, are usually moderately to poorly differentiated, and have minimal to no associated keratin production. HPV-associated carcinomas in general carry a better prognosis than do their non-HPV–related counterparts. The histologic distinction between these tumors and the classic basaloid squamous cell carcinoma is not clear.

HPV-positive oropharyngeal squamous cell carcinomas are seen in a younger patient population, two to three decades earlier than the usual head and neck squamous cell carcinoma population. Patients usually do not have a history of smoking or heavy alcohol consumption. These patients have a better response to treatment with superior outcomes. On the other hand, heavy smokers and drinkers who also are HPV positive do not have the same favorable outcomes.

Hypopharynx

The majority of patients with hypopharyngeal squamous cell carcinoma have a history of tobacco and alcohol consumption. The risk is especially increased in patients with heavy alcohol consumption, as is observed in southern Europe. Historically, nutritional deficiency and anemia were said to be associated with postcricoid carcinoma, as reported from Scandinavia (Plummer-Vinson syndrome). Histologically, these tumors are moderate to poorly differentiated carcinomas with significant proclivity for submucosal spread, especially distally ( Fig. 9.50 ). Skip areas of tumor spread with additional lesions often are seen in the cervical esophagus. The hypopharynx is the most frequent site for synchronous primary tumors in the upper aerodigestive tract. Lymphatic drainage of the hypopharynx to the regional lymph nodes is profuse, and lymph node metastasis is a common feature at presentation. Consequently, management of cervical lymph nodes is integral in treatment planning.

Factors Affecting Choice of Treatment

The anticipated response to chemoradiation therapy is a key factor in the selection of initial definitive treatment. In general, early staged pharyngeal squamous cell carcinomas are responsive to radiation, with only a small proportion of patients requiring salvage surgery. Therefore most of these cancers, and particularly those where the larynx is at risk, are currently treated with radiation or chemoradiation therapy. This approach is supported by several prospective trials (see Chapter 20 ) and has become the standard of care.

Current treatment guidelines for oropharynx squamous cell carcinoma are in a state of evolution in light of the favorable prognostic influence of HPV status and with the goal of reducing treatment-related morbidity. Quantifying risk in this patient population has affected the choice of treatment. Specifically, risk stratification studies have attempted to identify “low-risk” patients who may be candidates for de-escalation of treatment. In the Radiation Therapy and Oncology Group trial (RTOG–0129), HPV-positive patients who were nonsmokers or with a smoking history of less than 10 pack-years and/or N0–N2a were considered “low risk” with a 3-year overall survival rate of 93%. T1-T3N0-N2b HPV-positive patients were identified as having a very low risk of distant metastases and therefore could be possible candidates for radiation alone. Surgery as a de-escalation strategy is also under evaluation. In 2009 the US Food and Drug Administration approved transoral robotic surgery for the treatment of T1–T2 oropharyngeal carcinoma. Proponents of surgery argue that TORS may achieve better functional outcomes compared with primary radiation approaches by reducing radiotherapy doses or eliminating chemotherapy. This is being tested in a randomized controlled trial at this time. TORS represents an attractive option in highly selected patients in whom surgery as a single modality of treatment may be all that is required for disease control. On the other hand, utilizing primary surgery as a deintensifying approach may be counterproductive if adjuvant radiation with possible concurrent chemotherapy is required based on the pathologic results of the resected primary tumor and neck nodes. This may be the case with a positive margin resection or if metastatic lymph nodes are found to have extranodal spread. Several de-escalation strategies are currently being evaluated in ongoing clinical trials, and they will need to show long-term better functional outcomes and at least equally good tumor control rates. Although concurrent chemoradiation is recommend for advanced stage tumors, selected deeply infiltrating endophytic tumors have a lower probability of complete response to chemoradiation and may be better treated with initial surgical resection. Very advanced tumors of the oropharynx with invasion of the mandible also are best treated with initial surgery. The factors that influence the choice of treatment for squamous cell carcinoma of the hypopharynx are related to the tumor, the patient, and the treatment team. Primary site, T stage, local extension, circumferential extent, cephalo-caudad extent, multifocality, extent of laryngeal invasion, histology, and involvement of regional lymph nodes are important tumor factors that would influence the decision regarding initial treatment. Invasion of the larynx with fixation of the vocal cords clearly puts the larynx in jeopardy. Early staged tumors of the hypopharynx may be treated by external beam radiation therapy alone or endoscopic laser resection with or without neck dissection and postoperative radiation therapy. Lesions that are not suitable for endoscopic resection where the larynx is not involved may be candidates for a partial laryngopharyngectomy. Patients in whom a laryngectomy is required for resection of a hypopharyngeal carcinoma are candidates for organ preservation treatment with chemoradiation given sequentially or concurrently. Very advanced tumors of the hypopharynx with invasion of the thyroid or cricoid cartilage require a pharyngolaryngectomy with appropriate reconstruction and postoperative adjuvant treatment. Tumors of the postcricoid region or lesions of the pharyngeal wall with circumferential involvement have a high risk of development of stricture following chemoradiation and should be considered for initial surgery.

With regard to patient factors, general status of health, airway compromise, and pulmonary function are vitally important. Patients with chronic obstructive pulmonary disease are poor candidates for consideration of an endoscopic or open partial laryngopharyngectomy because their ability to handle resulting postoperative aspiration is poor. Thus the possibility of extended pharyngeal resections with a partial laryngectomy is exceedingly small in patients who have poor pulmonary reserve. Similarly, the choice of reconstructive procedures for restoration of the anatomic continuity of the alimentary tract depends on various patient factors. These factors include availability of regional cutaneous and myocutaneous flaps, the status of peripheral vessels to permit the use of microvascular composite free flaps, and the availability of the stomach in patients who require a pharyngolaryngoesophagectomy for large tumors with extension to the cervical esophagus. In addition, a patient's habits, lifestyle, compliance, and preference are other factors to be considered.

Availability of a multidisciplinary surgical and comprehensive head and neck oncology team is the most important physician-related factor that influences the successful outcome of a comprehensive treatment program. These factors include surgical skills, especially endoscopic diagnostic capabilities; skills in laser resection and robotic surgery; experience in open conservation surgery; and experience in contemporary reconstructive techniques, including microvascular surgery as well as the availability of a postoperative swallowing and speech rehabilitation team. On the other hand, for nonsurgical organ preservation treatments, excellence in multidisciplinary management, including expertise in medical oncology and radiation oncology and availability of a speech and swallowing rehabilitation team, is essential for a successful outcome.

Surgical Anatomy

The nasopharynx begins at the posterior choana of the nasal cavity and extends up to the free border of the soft palate. The oropharynx extends from the plane of the superior surface of the soft palate to the plane of the superior surface of the hyoid bone. The hypopharynx extends from the plane of the superior surface of the hyoid bone to the plane corresponding to the lower border of the cricoid cartilage (C6 vertebra), where it continues into the cervical esophagus. The musculature of the pharynx consists of the pharyngeal constrictors and the pharyngeal elevators. The three pharyngeal constrictor muscles are oriented in a “cup within a cup” fashion, and their fibers insert posteriorly into a midline fibrous raphe, which is attached superiorly to the pharyngeal tubercle of the occipital bone. The pharyngeal mucosa immediately superior to the level of the superior constrictor muscle is in direct contact with and is supported by a thickened pharyngobasilar fascia. This fascia is attached at the skull base to the basilar portion of the occipital bone, the petrous temporal bone along the medial border of the pharyngotympanic tube, and the posterior border of the medial pterygoid plate and pterygomandibular raphe. The pharyngeal elevators attach to the skull base and help elevate the pharynx during swallowing and breathing.

The branches of the external carotid artery provide blood supply to the pharynx via the ascending pharyngeal artery, the ascending palatine and tonsillar branches of the facial artery, the greater palatine and pharyngeal branches of the maxillary artery, and the dorsal lingual branches of the lingual artery. The pharyngeal veins drain into the internal jugular vein and lymphatics drain into the retropharyngeal and parapharyngeal nodes and the nodes at levels II, III, and IV in the neck. The branches of the pharyngeal plexus (from the IX and X cranial nerves) provide sensory and motor innervation to the pharynx. The anatomic location of the major nerves and blood vessels in relation to the pharynx is shown in Fig. 9.51 .