Neoplasms of the Hypopharynx and Cervical Esophagus

Anatomy of the Hypopharynx and Cervical Esophagus

The hypopharynx is a subsite of the pharynx that extends superiorly from the oropharynx to the cervical esophagus inferiorly. The cervical esophagus is the portion of the esophagus that extends from the hypopharynx to the thoracic inlet. The superior extent of the hypopharynx is radiographically defined at the level of the hyoid bone or clinically defined at the level of the pharyngoepiglottic folds. Inferiorly, the hypopharynx tapers to the esophageal introitus at the cricopharyngeus muscle. It is bordered anteriorly by the larynx and posteriorly by the retropharyngeal space. The hypopharynx is subdivided into three regions: the piriform sinuses, the postcricoid region, and the posterior pharyngeal wall ( Fig. 101.1 ).

The piriform sinuses are the most common subsite of hypopharyngeal malignancies. They are paired and comprise anterior, medial, and lateral walls of the hypopharynx, forming an inverted pyramid; the base is at the level of the pharyngoepiglottic fold, and the apex extends to just below the cricoid cartilage. This lower region is lateral to the aryepiglottic folds and just medial to the thyroid lamina. Because of this close relationship of the piriform apex to the thyroid lamina, tumors of the hypopharynx can often extend to invade the larynx. In addition, the medial piriform mucosa forms the posterolateral wall of the paraglottic space and is separated from the endolarynx by the aryepiglottic folds and the lateral cricoarytenoid muscles. This is another common pattern of spread for hypopharyngeal tumors.

The postcricoid region is a midline, inferiorly located subsite of the hypopharynx and extends from just below the posterior aspect of the arytenoid cartilages to the esophageal introitus. Postcricoid tumors commonly invade the cricoid cartilage and the posterior cricoarytenoid muscle. Because the postcricoid region lies just medial to the tracheoesophageal groove, tumors that arise from this area can involve the recurrent laryngeal nerve, paratracheal nodes, and the thyroid gland.

The third region of the hypopharynx, the posterior hypopharyngeal wall , is separated from the vertebral and paravertebral structures by the potential retropharyngeal space. The posterior wall extends from the level of the hyoid bone to the superior aspect of the cricopharyngeus muscle. The close relationship of the retropharyngeal space and paravertebral structures allows these tumors to invade the prevertebral tissues early in the disease course.

The aryepiglottic folds separate the endolarynx from the medial wall of the piriform sinus bilaterally and form what has been termed the marginal area . Although the aryepiglottic folds are actually part of the supraglottic larynx, tumors that arise at this site behave aggressively, such as hypopharyngeal cancers rather than supraglottic carcinomas.

The cross-sectional and histology of the hypopharynx is composed of four layers: a mucosal lining , formed by stratified squamous epithelium over loose stroma; a fibrous layer , formed by the pharyngeal aponeurosis; a muscular layer ; and a fascial layer , which arises from the buccopharyngeal fascia. The muscular layer is composed of the posterior cricoarytenoid muscles anteriorly and the middle and inferior constrictor muscles posteriorly. The inferior constrictor condenses into the cricopharyngeus muscle distally. At the superior aspect of this junction, there is a potential area of weakness known as the Killian triangle , through which posterior pharyngeal wall tumors can extend outside the hypopharynx. Similarly, there are weaknesses in the middle and inferior constrictor just inferior to the hyoid bone at the thyrohyoid membrane. Hypopharyngeal tumors may extend through the area and spread laterally along the vascular pedicle and the superior laryngeal nerve.

The arterial blood supply to the hypopharynx is primarily through the superior thyroid arteries. Branches from the lingual and ascending pharyngeal arteries also form collaterals that supply this area. The venous drainage mirrors the arterial blood supply.

Sensory innervation from the hypopharynx that assists in swallowing passes through the glossopharyngeal nerve (cranial nerve [CN] IX) and the vagus nerve (CN X) to the nucleus solitarius in the brainstem. The sensory input is connected to the nearby CN motor nuclei by interneurons and assists in the coordination of deglutition. The internal branch of the superior laryngeal nerve passes through the superior portion of the lateral wall of the piriform sinus and through the thyrohyoid membrane to join the vagus nerve. These sensory fibers then synapse in the jugular ganglion within the jugular foramen along with sensory fibers of the Arnold nerve from the external auditory canal. This juxtaposition accounts for the referred otalgia that is often experienced by patients with tumors of the piriform sinus.

Lymphatic drainage is separate for the different subsites of the hypopharynx. The piriform sinus lymphatics pass through the thyrohyoid membrane primarily to the jugulodigastric lymph node and to the midjugular and spinal accessory chains ( Fig. 101.2 ). Lymphatic vessels from the inferior portion of the hypopharynx (piriform apex) and the postcricoid region drain to the paratracheal and paraesophageal nodes and to nodes in the supraclavicular fossa. Lymphatic drainage from the posterior hypopharyngeal wall is primarily to the retropharyngeal nodes and to the midjugular chain. The retropharyngeal nodes are divided into a medial and lateral group. Lateral retropharyngeal nodes, also known as the nodes of Rouvière , are present at the level of the skull base.

The cricopharyngeus muscle represents the transition between the hypopharynx and the cervical esophagus, a muscular tube that also has a squamous epithelial layer, a submucosa rich in lymphatics, a muscular layer, and an adventitial layer. The muscular layer is divided into an inner circular and outer longitudinal layer. The trachea and thyroid are anterior to the cervical esophagus, and the lobes of the thyroid also extend laterally. The retroesophageal space is contiguous with the retropharyngeal space above and the posterior mediastinum below.

The lymphatics of the cervical esophagus are almost coincident with the hypopharyngeal lymphatics and include drainage to the recurrent laryngeal, paratracheal, and jugular chain nodes. The lymphatic drainage of the cervical esophagus also involves the superior mediastinal lymph nodes. The vascular supply is derived from the inferior thyroid arteries with some contribution from the high thoracic vasculature. Finally, innervation to the cervical esophagus is provided by sympathetics, parasympathetics, and CNs IX, X, and XI (the spinal accessory nerve). The recurrent laryngeal nerve and the pharyngeal plexus provide innervation to the cricopharyngeus.

Epidemiology

Squamous cell carcinoma (SCC) of the hypopharynx is associated with the worst prognosis of any squamous cell cancer of the head and neck. Although adenocarcinoma, sarcomata, and lymphoma can also affect the hypopharynx, SCC comprises 95% of hypopharyngeal tumors. Regardless, hypopharyngeal SCC is a relatively uncommon cancer and represents only 3% to 5% of all SCCs of the head and neck. There is geographic variation in incidence, possibly related to smoking prevalence and diet, with the highest incidences reported in Asia and parts of Europe. Thirty percent of patients diagnosed with hypopharyngeal SCC die within a year of diagnosis, and less than 40% of all patients survive to 5 years, making it a particularly devastating disease. The majority of hypopharyngeal cancers present at an advanced stage, with more than 75% stage III or greater. In addition, most patients with hypopharyngeal SCC are older (average age, 66 years), from a lower socioeconomic status (80% unemployed, retired, or on disability), and have a history of heavy alcohol use.

Because of the rarity of the disease, data on cancer of the cervical esophagus are more limited. SCC is the predominant histologic subtype and comprises 85.7% of newly diagnosed cancers of the cervical esophagus; the rate of adenocarcinoma is slightly higher in this anatomic site (9.4%). SCC of the cervical esophagus, even as a subsite of esophageal cancers, is a rare cancer that represented only 5.4% (9/168 patients) of all esophageal cancers in one series. Given this low frequency, the data are limited on the incidence and optimal treatment of this cancer.

Etiology and Biology

The causal relationship between alcohol and tobacco intake, genetic predisposition, diet, and socioeconomic conditions in the development of SCC of the head and neck applies to hypopharyngeal cancer. Of the known carcinogens, alcohol intake has the strongest association to hypopharyngeal SCC. The causality for the development of hypopharyngeal cancer greater than the other subsites of head and neck cancer is unclear. Alcohol may have direct carcinogenic effects or act synergistically with tobacco at this subsite to potentiate tumor formation. In addition to alcohol, two studies have shown that chewing tobacco products and exposure to wood smoke were associated with hypopharyngeal cancers in India.

Although a growing body of evidence suggests that human papillomavirus (HPV) can be detected in hypopharyngeal cancers, it is unclear whether this represents transcriptionally active HPV. In a series of 64 patients from South Korea with hypopharyngeal cancer, seven tested positive for HPV with in situ hybridization, and all seven cancers were located in the piriform sinus. The interesting finding from this study was that similar to HPV-positive oropharyngeal cancer (HPV-OPC), improved survival was noted in the HPV-positive hypopharyngeal cancer patients. In addition, the authors noted a more exophytic appearance in this subset of tumors. The number of patients in the study was small; however, this finding is likely to be replicated in larger studies. The use of p16 overexpression, a robust marker in HPV-OPC, may not be as applicable in hypopharyngeal cancer.

A condition associated with postcricoid and upper esophageal carcinoma is Plummer-Vinson or Paterson-Brown-Kelly syndrome, which primarily affects women (85% of cases). This syndrome represents the combination of dysphagia, iron deficiency anemia, and hypopharyngeal and esophageal webs. It is hypothesized that chronic irritation results in the hypopharyngeal webs that then progress to carcinoma. The syndrome is also geographically biased in that patients are predominantly located in the United States, Wales, and Sweden. The etiology is believed to be due to a nutritional deficiency. Improved nutrition and better prenatal care have resulted in a decline in the incidence of postcricoid carcinomas in Sweden.

Clinical Evaluation

Imaging

Imaging of hypopharyngeal malignancies examines the extent of the primary tumor, regional lymphatic disease, and the development of distant disease, if any. Hypopharyngeal tumors have a propensity for submucosal spread that may be undetectable on clinical or radiographic examination. Causes for surgical failure include submucosal extension, involvement of the thyroid gland, and metastasis to paratracheal and upper mediastinal lymph nodes. Thus imaging is essential to assess tumor extent or recurrence. Although the topic of imaging hypopharyngeal and esophageal cancer is covered in Chapter 100 , a short summary is provided here.

Although a barium swallow has been historically used to identify malignancies in this region, its use is now more limited. Some centers continue to utilize the swallow to evaluate for second primary malignancies in the esophagus. In the case of a cervical esophageal cancer where an endoscope cannot be passed distally, a barium swallow can be used for imaging the distal extent of disease. Another use of a barium study is in the postoperative setting to examine the deglutition process or to identify treatment complications such as stricture or fistula.

The primary imaging modality for pretreatment evaluation of the hypopharynx is cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI). A number of studies examining the impact of cross-sectional imaging on the staging of hypopharyngeal and/or esophageal cancer have shown the clinical tumor stage was upstaged in up to 90% of patients. The accuracy of tumor staging, determined by comparison with pathologic findings, is 58% for clinical examination, 80% for CT, and 85% for MRI. CT is often preferred to MRI to assess cartilage invasion; however, an increased T2 and decreased T1 signal intensity on MRI, which indicates cartilage involvement, can achieve a very high degree of sensitivity (89% to 100%). However, the specificity of MRI for cartilage invasion is inferior to that of CT (62% vs. 84%). A wide variability in specificity reflects differences in cartilaginous ossification and the degree of inflammation, edema, and/or fibrosis at the tumor site. The specificity for cartilage invasion is lowest for the thyroid cartilage (57%), highest for the arytenoid cartilages (95%), and intermediate for the cricoid cartilage (87%).

Dual-energy CT is a relatively new imaging modality that may offer increased specificity for the detection of cartilage invasion. Using a combination of weighted-average and iodine overlay images, the technique is so named because of the use of CT imaging with varying tube voltages and the use of iodine enhancement. This technique offers improved visualization of true cartilage invasion by exploiting the fact that iodine enhances tumor tissue but not cartilage. Fig. 101.3 demonstrates a T4 right piriform sinus SCC that has invaded the arytenoid cartilage and the thyroid lamina. The incidence of a second neoplasm of the aerodigestive tract, either synchronous or metachronous to an index tumor of the hypopharynx, has been reported to be 16% to 18% ; therefore a thorough radiographic evaluation of the entire aerodigestive tract, including the esophagus, is necessary.

No data are available to support the routine use of imaging with CT or MRI in the posttreatment period to follow disease-free status. Typically, patient symptoms or clinical endoscopic findings will dictate the utilization of specific imaging. The role of positron emission tomography (PET) has been explored as a modality to assist in the detection of locoregional recurrence and/or persistent disease, and several studies have reported on the improved sensitivity of PET over MRI in the evaluation of response to therapy. Although this modality appears to have an increased sensitivity (86%) for recurrence over CT or MRI (57%), the measured specificity is lower with PET (75% vs. 92% for CT/MRI). An improvement in specificity with PET may be achieved as newer tracers are studied. In addition to the routinely used ¹⁸ F-fluorodeoxyglucose (FDG), new compounds have shown some promise, including ¹¹ C-methionine for following postchemotherapy tumor response and ¹⁸ F-misonidazole / ¹⁸ F-fluoroazomycin-arabinoside for identifying hypoxic tumors and predicting their response to chemotherapy. The combination of PET and CT (PET-CT) scans provides significant advantages because of the ability to correlate FDG-avid lesions with anatomic findings, and it is increasingly used in all phases of hypopharyngeal tumor management. Fig. 101.4 illustrates the use of PET-CT in a patient with an advanced left piriform sinus SCC with cervical lymphadenopathy. The fused scan not only shows the primary FDG-avid lesion but highlights the left cervical lymph node with obvious tumor involvement. Thus the combination of CT, MRI, and PET scanning can be used in all phases of the management of hypopharyngeal and cervical esophageal carcinoma.

Pathology

Although the vast majority of neoplasms in the hypopharynx and cervical esophagus are SCCs, other rare pathologic entities, as well as variants of SCCs, have been described. Unusual malignant lesions include lymphomas, which can present in the hypopharynx as the primary tumor or can secondarily involve the hypopharynx and cervical esophagus after systemic presentation. Subtypes include angiocentric T-cell lymphomas, non-Hodgkin extranodal lymphomas, and mucosa-associated lymphoid tissue lymphomas. A high index of suspicion for lymphoma should be maintained in patients with HIV/AIDS and a hypopharyngeal mass. Lymphomas need to be extensively staged (multiple imaging modalities), and depending on subtype, they are treated with a combination of radiation and/or chemotherapy.

Adenocarcinomas and neuroendocrine tumors are other rare malignant entities seen in the hypopharynx and cervical esophagus. These lesions may initiate in the minor salivary glands within the hypopharynx or ectopic gastric mucosa in the cervical esophagus. Neuroendocrine tumors are typically managed nonsurgically with chemotherapy and radiation and have a high propensity to metastasize. The outgrowth of adenocarcinomas from ectopic gastric mucosa is a rare event. In addition, thyroid malignancies may secondarily involve the hypopharynx or cervical esophagus via direct invasion. Other extremely rare malignancies include sarcomas such as liposarcomas, angiosarcomas, and synovial sarcomas.

Of the squamous cell cancers, three histologic subtypes deserve special attention. First is basaloid SCC, a bimorphic variant of SCC that has distinct pathologic features. Clinically, these lesions appear primarily in the supraglottis, piriform sinus, and tongue base and have a distinctly more aggressive clinical course. Second, lymphoepitheliomas are the hypopharyngeal counterpart of nasopharyngeal cancers. They more often arise within the Waldeyer ring associated with Epstein-Barr virus, but the link between Epstein-Barr virus and hypopharyngeal lesions is controversial. These tumors are treated with radiation and chemotherapy, similar to nasopharyngeal carcinoma. Finally, adenosquamous carcinoma is another rare variant that also behaves clinically in an aggressive manner.

Location of Tumors and Patterns of Spread

An understanding of the site of initiation and patterns of spread of hypopharyngeal carcinoma is critical in treatment decision making. A number of studies have shown significant variation in the subsite of origin in hypopharyngeal SCC. Kirchner described experience at the Yale University hospitals in managing hypopharyngeal carcinoma. In their patient population, 152 carcinomas (86%) arose in the piriform sinus, 17 (10%) were in the posterior pharyngeal wall, and 8 (5%) were in the postcricoid region. In the series of Carpenter and colleagues, 117 carcinomas (72%) arose in the piriform sinus, 37 (23%) were in the posterior pharyngeal wall, and 8 (5%) were located in the postcricoid region. In contrast, Saleh and colleagues described their series of patients from Egypt and found that postcricoid cancers were the majority of presenting lesions (50.1%), followed by piriform sinus (26.5%) and finally posterior pharyngeal wall tumors (23.4%). A European cancer registry review demonstrated the highest rates of piriform sinus cancer in France (78%) and the lowest rates in Sweden (5%). Although it is difficult to identify the precise reason for these subsite differences, one explanation is the possibility that an assignment of the exact origin of these tumors may be difficult except in the earliest stages.

The histologic spread of hypopharyngeal SCC has been carefully studied by Kirchner, who performed whole-organ serial sections on 51 surgically resected piriform sinus carcinoma specimens. He found a number of tumors were able to leave the hypopharynx at a number of locations. Tumors were able to infiltrate the larynx and behave as transglottic cancers, they were able to invade the lateral and posterior pharyngeal walls, and they also spread into the supraglottis and base of tongue. Invasion inferiorly into the cervical esophagus was not a common finding in these specimens. Twenty-two specimens invaded the thyroid cartilage at its posterior border, and all were found to have lateral pharyngeal wall involvement. Kirchner demonstrated in this study that the exclusion of tumors with piriform apex involvement from conservation surgery was indeed appropriate because all tumors with inferior extent into the piriform apex had laryngeal framework invasion.

A distinct feature in the surgical treatment of hypopharyngeal SCC was its tendency to spread in a submucosal fashion. Ho and colleagues performed a detailed analysis of submucosal extension by serial sectioning of 57 specimens of hypopharyngeal cancer. Three classes of submucosal extension were identified. Type 1 was a direct submucosal extension visible on gross inspection as elevated mucosa, type 2 was direct submucosal extension that was only visible on histologic examination, and type 3 was a true “skip” lesion with no connection to the primary. Only 1 of 57 specimens had type 3 extension; however, 33 patients (58%) did have submucosal extension of some type. There was significant inferior extension toward the cervical esophagus in a number of patients, although this finding has not been observed in all studies. In addition, patients treated with preoperative radiotherapy had significantly increased amounts of type 2 extension. Interestingly, no differences were found in overall 5-year survival between patients with and without submucosal extension. In addition, submucosal extension was not associated with increased locoregional recurrences. Thus, although it is true that submucosal extension occurs in a significant number of patients with hypopharyngeal cancer, most of it is detectable clinically, and at least in one study, poorer prognosis was not seen in patients with submucosal extension of tumor.

Included in the data from serial sectioning by Ho and colleagues and Wei was the finding that submucosal extension was greatest in the inferior direction, followed by lateral extension, and finally superior extension. Based on these data, they recommended that resection margins should be 3 cm inferiorly, 2 cm laterally, and 1.5 cm superiorly in patients who have not received previous radiation. For those previously irradiated, these margins were recommended to be 4, 3, and 2 cm, respectively. The deep margin was recommended to be greater than 1 mm in all patients.