AUTHOR AND EDITOR INFORMATION

Section 1 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

INTRODUCTION

Section 2 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

Hypopharyngeal cancer is a term used for tumors of a subsite of the upper aerodigestive tract, and like most other subsite designations, the distinction is anatomic rather than pathophysiologic within the group of head and neck malignancies. The hypopharynx is the region between the oropharynx above (at the level of the hyoid bone) and the esophageal inlet below (at the lower end of the cricoid cartilage). Embryologically, the larynx interjects into the hypopharynx anteriorly and is therefore considered a separate structure.

Hypopharyngeal cancers are often named for their location, including pyriform sinus, lateral pharyngeal wall, posterior pharyngeal wall, or postcricoid pharynx (see Images 1-2). Most arise in the pyriform sinus. In the United States and Canada, 65-85% of hypopharyngeal carcinomas involve the pyriform sinuses, 10-20% involve the posterior pharyngeal wall, and 5-15% involve the postcricoid area.¹

As in other head and neck cancer sites, more than 95% of hypopharyngeal malignancies arise from the epithelium of the mucosa and, therefore, are squamous cell cancers. Premalignant mucosal lesions evolve into hyperproliferative lesions that develop the capacity to enlarge, to invade local structures, to invade lymphatics to spread to regional lymph nodes, and to invade vascular channels to metastasize to other organs.

See the following related CME: 

New Insights and New Challenges in Head and Neck Carcinoma

Multidisciplinary Approaches to Supportive Care of Patients With Head and Neck Cancer 

Epidemiology and prognosis

Race

African Americans have had an increasing incidence of cancers of all pharyngeal subsites since the early 1970s.

Sex

US incidence indicates an approximate male-to-female ratio of 3:1. Women have a higher incidence of postcricoid cancers related to nutritional deficiencies (Plummer-Vinson syndrome) than men. The prognosis for women generally is better than that for men.

Prognosis

The biological behavior of carcinoma of the hypopharynx differs greatly from that of carcinoma of the larynx. Carcinomas of the hypopharynx are usually poorly differentiated and patients are usually asymptomatic; early presentations are unfortunately uncommon. In fact, T1 N0 cases (see Staging in Workup) account for only 1-2% of all patients seen.

Most patients have no symptoms to bring them to medical attention until their disease is advanced, at which point the prognosis is poor. The rate of metastases is high, with nodal involvement present in 50-70% of cases at presentation. Of patients with hypopharyngeal cancers, 70% have stage III disease at presentation. Cervical lymph node metastases occur as the presenting symptom in approximately 50% of cases. The frequency of distant metastases is also among the highest of all head and neck cancers.²

Prognosis varies with the stage. The 5-year survival rate with small (T1-T2) lesions is about 60%, but with T3-T4 lesions or multiple node involvement, survival falls to 17-32%. Five-year survival for all stages is approximately 30%.

Morbidity is predominantly due to the primary tumor itself causing pain, bleeding, poor swallowing (with subsequent malnutrition), or aspiration. Very advanced tumors may cause airway obstruction as they grow into the larynx. Laryngectomy is often needed, leading to permanent loss of voice and permanent tracheostomy. Functional problems from surgical or radiation treatment can include swallowing dysfunction, recurrent aspiration pneumonias, neck fibrosis, facial edema, and pain.

CLINICAL

Section 3 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

History

In general, hypopharyngeal cancers involve a tumor that is relatively more silent than other head and neck cancer tumors. Larger lesions are required to produce symptoms. The time between initial symptoms and diagnosis is longer than that for laryngeal tumors or other cancers because of the relatively few early symptoms and the difficulty of physical examination in this region.

Symptoms of hypopharyngeal cancer include dysphagia, chronic sore throat, and foreign body sensation in the throat or referred otalgia. (Otalgia is pain referred to the ear via the Arnold nerve, a division of the 10th cranial nerve. It suggests an underlying malignancy.) For hypopharyngeal cancer, a metastatic node in the neck is often the presenting symptom. An asymptomatic mass in the neck, usually a jugulodigastric or jugulo-omohyoid lymph node, is present in 20% of patients. The average duration of symptoms before presentation is 2-4 months.

Other symptoms, which usually develop later, include weight loss, hemoptysis, laryngeal stridor, and hoarseness when the vocal cord becomes affected by direct extension into the arytenoid cartilage or the recurrent laryngeal nerve. Of patients with hypopharyngeal cancers, 70% have stage III disease at presentation.

• Neck mass: Cervical lymph node metastases occur as the presenting symptom in approximately 50% of cases. As many as 70% of patients with pyriform sinus lesions have palpable lymph nodes upon initial clinical examination.
• Sore throat
• • Typically, pain is unilateral and well localized.
  • Often, pain radiates to the ears.
  • Patients commonly undergo one or more courses of empiric antibiotics without response.
• Hoarseness: This indicates either involvement of the recurrent laryngeal nerve, which runs deep to the anterior wall of the pyriform sinus, or direct invasion of the larynx (see Image 4).
• Dysphagia (Image 5. See related CME at Diagnostic Evaluation of Dysphagia.)
• • Tumor invasion often causes a combination of painful swallowing (odynophagia) and neuromuscular dysfunction (dysphagia). Patients frequently report food sticking in the upper esophagus or upper throat; this is because the hypopharynx is involved in the coordination of the swallowing function around the larynx.
  • Aspiration is occasionally seen.
  • Weight loss and malnutrition are common at presentation.
• Otalgia: Referred pain to the ear is mediated by branches of the tenth cranial nerve (see Image 6). Invasion of the laryngeal nerve causes spread of neuropathic impulses to the auricular nerve (sensory to posterior external auditory canal and back of pinna).
• Hemoptysis
• Halitosis: Fetid breath is due to saprophytic bacterial overgrowth in fungating necrotic tumors.

Physical examination

Assessment begins in the office with a thorough head and neck examination, including inspection, palpation, and indirect or fiberoptic examination. Flexible fiberoptic endoscopic examination is important to attempt to localize and stage the primary tumor. Because of the patient's gag reflex, a flexible fiberoptic examination is the preferred examination technique and often allows the mucosa of the hypopharynx to be well examined. Hypopharyngeal cancer is typically advanced at presentation, and an obvious abnormality is usually present in either the pharynx or the neck. Occasionally, only subtle signs such as submucosal fullness or unilateral pooling of saliva are present. Typical findings of hypopharyngeal cancer include mucosal ulceration; pooling of the saliva in the pyriform fossa; edema of the arytenoids; or fixation of the cricoarytenoid joint, true vocal cords, or both.

During the flexible laryngoscopy, the assessment of vocal cord mobility or fixation is important for staging purposes. The patient who puffs out his or her cheeks or performs a Valsalva maneuver may distend the pyriform fossae for inspection.

The neck should be examined in a systematic fashion. Any lymph nodes should be assessed with regard to size, location, and mobility. On neck examination, loss of the grating sensation (laryngeal crepitus) of the laryngeal cartilages over the prevertebral tissues may indicate deep pharyngeal wall involvement.

• Oral examination
• • The hypopharynx is not visible directly, but other regional pathologies, including the synchronous oral cavity or oropharyngeal tumors, might be seen.
  • Asymmetry of tonsillar pillars can be a clue to a tumor invading the palatopharyngeus muscle at insertion to the inferior constrictor muscle.
• Larynx and pharynx examinations
• • The mirror examination is the quickest and simplest screening tool, but it cannot reveal lower pyriform sinus or postcricoid lesions. Fiberoptic laryngoscopy is the examination of choice.
  • Findings include mass lesions, hyperkeratotic or erythematous mucosal lesions, ulcerations, and vocal cord paralysis.
• Neck examination
• • Examine and document the size, location, and number of palpable lymph nodes in all cervical and supraclavicular node-bearing areas.
  • Palpate and wiggle the larynx from side to side. Tenderness suggests invasion, while loss of normal tracheal crepitus suggests invasion of prevertebral tissue or a large postcricoid tumor.
• Head examination
• • Assess cranial nerve function.
  • Assess jaw mobility. Trismus suggests invasion of pterygoid muscles.
  • Areas of mass lesions or tenderness are suggestive of regional metastases.
• General examination for distant metastases and comorbidities
• • Examination of the lungs may reveal chronic obstructive pulmonary disease (COPD). Chest x-ray films may demonstrate metastases, synchronous lesions, or effusions suggesting metastases to pleura or lymphatic obstruction.
  • Examination of the heart may demonstrate congestive heart failure (CHF) or right-sided failure and pulmonary hypertension.
  • Examination of the extremities may reveal peripheral vascular disease or clubbing suggestive of advanced lung disease or synchronous lung cancer.
  • Hepatomegaly with a hard irregular contour suggests metastatic disease.
  • General neurologic examination may show toxic or metabolic encephalopathy or neuropathy. Focal neurologic findings suggest brain metastases or prior cerebrovascular accident (CVA).
  • Perform a peripheral lymph node examination to assess for possible distant lymph node metastases. 

Natural history of hypopharyngeal squamous cell carcinomas

• In general, 30% of patients have local disease at the time of diagnosis, 60% have local regional disease, and 10% present with distant metastases. In the United States, most hypopharyngeal tumors (60-70%) arise in the pyriform sinus, 25% are found in the posterior pharyngeal wall, and 5% are found in the posterior cricoid region.
• Most patients present with large T3 or T4 tumors (see Staging in Workup).
• Medial wall pyriform sinus tumors usually spread along the mucosal surface to the aryepiglottic folds and can invade into the larynx by involving the paraglottic space.
• Tumors of the lateral wall and apex commonly invade the thyroid cartilage.
• Once the tumor penetrates the constrictor muscle, it can spread along the fascial planes to the base of skull.
• Because of the abundant lymphatics in the region and the extent of the primary tumor at diagnosis, metastasis to the regional lymph nodes is common.

Pathology

More than 95% of hypopharyngeal tumors are squamous cell carcinoma, less than 60% are keratinizing, 33% are nonkeratinizing, and all are usually poorly differentiated. Variants include basaloid squamous cell carcinoma, superficial spreading cancer, sebaceous cancer, adenosquamous cancer, and signet-ring and verrucous types. Uncommon histologic types include adenocarcinoma, lymphoma, and sarcoma.

Studies have reported that tumor margins are usually infiltrating (80%) but can be pushing (20%). Unsuspected submucosal spread can extend beyond 1 cm of visible tumor margins. Skip lesions or multifocal areas of disease are not unusual.

ETIOLOGY AND RISK FACTORS

Section 4 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

Patients diagnosed with hypopharyngeal cancer are typically men aged 55-70 years with a history of tobacco use, alcohol ingestion, or both. The combined use of tobacco and alcohol has a synergistic effect on the incidence of hypopharyngeal cancer.

One exception is an increased incidence of postcricoid cancer in women aged 30-50 years with Plummer-Vinson or Paterson-Kelly syndrome. This syndrome includes dysphagia, hypopharyngeal and esophageal webs, weight loss, and iron deficiency anemia. Currently in the United States, because of the reduced incidence of Plummer-Vinson syndrome, postcricoid carcinoma is more common in men.

Asbestos may pose an independent risk for the development of hypopharyngeal cancer.³

The etiology of squamous cell cancers is similar for most anatomic subsites. Tobacco and ethanol are the principle carcinogens responsible. Long-term exposure causes progressive cellular dysregulation by alteration of tumor suppressor genes such as TP53, amplification of proto-oncogenes such as cyclin D1, and damage to regulatory factors such as transforming growth factor–beta (TGF-beta) and retinoic acid receptors. The progression from normal mucosa to cancer correlates with accumulation of genetic abnormalities.

The role of human papilloma virus (HPV) in cancers of the hypopharynx is unclear, although it may play more of a role in cancers of the oropharynx and oral cavity. Nonsmokers with cancers of the head and neck are more likely to have detectable HPV, although this is less common than hypopharyngeal cancer in persons who smoke.

• Clinically, the mucosa first develops dysplastic lesions that may appear white (leukoplakia) or red (erythroplasia), and with time and continued carcinogen exposure, lesions can develop into frank malignancy.
• Nutritional and metabolic deficiencies are implicated in rare instances. Plummer-Vinson syndrome, mucosal webbing of the postcricoid area with iron deficiency, is associated with a higher incidence of cancer in that region. This is most common in women from northern Europe, including nonsmokers. The pathophysiology is not clear.
• Genetic factors are under investigation. Heritable polymorphisms of expression of enzymes that activate tobacco-related protocarcinogens (eg, aryl hydrocarbon hydroxylase) and detoxify carcinogens (eg, glutathione S-transferase) have been identified. Certain polymorphisms in the alcohol dehydrogenase genes may increase the risk of oral and pharyngeal cancers related to alcohol consumption. Racial differences in the metabolism of carcinogens may be a possible cause of the increasing incidence in African Americans.
• Clinical testing for peripheral blood lymphocyte chromosome fragility shows promise for identifying individuals at high risk of primary and secondary head and neck cancers, but it is still investigational.
• Deficient DNA repair mechanisms increase susceptibility to head, neck, and other cancers. Clinically recognized syndromes include xeroderma pigmentosum, Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia. Head and neck cancers are not constituents of the most common cancer family syndromes, which include nonpolyposis colorectal cancer, Li-Fraumeni, or BRCA1/BRCA2 mutation kindreds.

Risk factors

• The main risk factors associated with this disease are alcohol and tobacco use. Alcohol is a significant cofactor in the development of hypopharyngeal cancer. It can act as a promoter of the mutagenic effects of tobacco-derived substances. Smoking cessation is associated with improved response to radiation, improved survival, and lower risk of second primary cancers.
• Lower hypopharyngeal tumors can be associated with iron and vitamin C deficiencies. For example, Plummer-Vinson syndrome is characterized by hypopharyngeal webs, dysphagia, weight loss, and iron deficiency anemia. This syndrome has historically been associated with a high incidence of postcricoid carcinomas in Northern European women who do not smoke.
• Chronic irritation of the pharynx from gastroesophageal or laryngotracheal reflux of the gastric contents has also been associated with the development of tumors in the posterior cricoid region, and such symptoms need to be addressed in the overall management of the tumor.
• Regional differences have been reported and are apparent when cases in the United States are compared with those in Europe, Asia, or Africa.
• • In the United States, two thirds of tumors arise in the pyriform sinus region.
  • Women in Northern European countries who do not smoke develop postcricoid squamous cell carcinoma because of its association with Plummer-Vinson syndrome. This cause has greatly decreased with improved nutrition.
  • A report from Egypt indicated that postcricoid tumors were the most common (50%) hypopharyngeal tumors in the patients studied, but no clear evidence was available to explain why this site predominated.⁴
• Ultimately, the possible biologic factors responsible for the development of these tumors await further investigation. Genetic deficiencies that affect the metabolism of tobacco-related and other carcinogens and malfunctions in DNA repair mechanisms and cell-cycle regulation may play a role.

WORKUP

Section 5 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

The workup consists of an initial history and physical examination, including a well conducted flexible fiberoptic endoscopic examination, as mentioned in Clinical. The flexible fiberoptic examination is the preferred examination to determine the mucosal anatomy because of the location of the hypopharynx and the patient's gag reflex. This examination is complementary to imaging studies, which permit an evaluation of deeper anatomic structures but do not allow an adequate view of the mucosal anatomy. Imaging studies should be not be considered as a replacement for a flexible fiberoptic examination.

See related CME at New Ways to Investigate Esophageal Function: pH, Impedance, Manometry, Capsules, and More. (Slides With Transcript).

Differentials

Lab studies

• Complete blood count (CBC)
• • During general assessment of bone marrow function, check for the presence of anemia due to chronic disease, metabolic derangements, or occult blood loss. Macrocytic RBCs may hint at chronic alcohol abuse common in this population. Thrombocytopenia may suggest hypersplenism or nutritional deficiency.
  • A CBC helps to assess the patient's ability to tolerate myelosuppressive chemotherapy and radiotherapy.
• Hepatic enzymes: Check for underlying liver disease or liver metastases.
• Serum creatinine
• • Assess renal function for general tolerance to therapy.
  • Measure 24-hour creatinine clearance if the serum creatinine concentration is elevated and cisplatin chemotherapy is under consideration.
• Prothrombin time (PT) and activated partial thromboplastin time (aPTT): These are used to assess the safety of biopsy and other surgical procedures. Prolonged results may indicate hepatic insufficiency.
• Serum albumin: Assess the nutritional status.
• Serum calcium: Paraneoplastic hypercalcemia is common with head and neck cancer, even if it is not metastatic.
• Thyroid stimulating hormone (TSH): Check for underlying hypothyroidism. Radiation induces hypothyroidism in approximately 30-40% of patients. This risk may be greater in the era of intensity-modulated radiation therapy (IMRT). This may happen more quickly and more severely in those with hypothyroidism prior to treatment.

Imaging studies     

• Chest x-ray films
• • Check for lung metastases, synchronous lung cancer, and comorbid heart or lung disease. Because of the morbidity associated with definitive treatment in the neck, excluding the presence of distant metastasis (especially to the lungs) is often advisable in patients who present with significant cervical nodal metastasis, which increases the risk of distant metastasis.
  • If hypopharynx cancer is aggressive (T4, N2-N3, or poorly differentiated histology), consider chest CT scan or positron emission tomography (PET) scan for most sensitive detection of metastases.
  • Barium swallow is not usually used unless the lesion is too large to introduce a scope, but its findings can help determine the inferior border of the lesion and the involvement of the esophageal inlet. If used, perform this test after the physical examination and with anesthesia because it can obscure tissues until the barium passes.
• • This may be helpful in patients with no obvious abnormality found on physical examination.
  • Negative swallow study findings with progressive or continuous symptoms should not preclude an endoscopic examination.
  • Superficial mucosal lesions in the pyriform sinus are seen on barium studies, although this is not the imaging modality of choice.
• CT scan or MRI of oral cavity and neck
• • In patients with hypopharyngeal cancer, CT scan and MRI are used to visualize the primary tumor and regional lymph nodes prior to definitive treatment. These modalities provide information about the location and extent of tumor involvement and demonstrate the interface of tumor with bone, fat, muscles, soft tissues, blood vessels, dura, and brain.
  • The contrast-enhanced CT scan is typically used as the initial imaging modality to assess local tumor extent and evaluate lymph nodes. Perform a CT scan of the head and neck with contrast to assist with delineation of cartilage and bone invasion, lymph node metastasis, and extralaryngeal invasion. As a single modality, this is generally more useful for staging hypopharyngeal cancers.
  • MRI provides no clear superiority to CT scan in all cases. MRI (with gadolinium) is better for delineating soft tissue extension, while CT scan (with bone windows) is better for delineating bone invasion. MRI is most often used to study lesions that suggest submucosal spread toward the esophagus on CT scans.
• PET scan: The role of PET scanning is emerging in initial assessment of patients with head and neck cancer, especially those with locally advanced disease, nodal involvement (particularly when MRI or CT scan findings are equivocal), suspicion of metastatic disease, or for evaluation of an unknown primary site. The use of fluorodeoxyglucose positron emission tomography (FDG-PET) has been demonstrated to be useful in staging head and neck carcinomas, including squamous cell carcinoma of the hypopharynx. FDG-PET may improve pretreatment staging, identification of an occult primary site, estimation of treatment response, and differentiation of early recurrence from scar tissue.
• • Integrated PET/CT overcomes poor anatomic localization of PET together with the morphologic data revealed by CT.
  • PET/CT is helpful in locating and localizing occult primary and regional disease and differentiating between malignant disease and posttreatment changes.
• Abdominal CT scan: If alkaline phosphatase and gamma-glutamyltransferase (GGT) levels are elevated, consider an abdominal CT scan to rule out liver metastases.
• Bone scan: If alkaline phosphatase levels are elevated and GGT levels are normal, consider a bone scan to rule out bone metastases.

Other tests

Perform an ECG because a high incidence of cardiovascular disease exists in this patient population.

A full dental evaluation is required before radiotherapy is initiated. This step is critical because of xerostomia caused by radiotherapy, which can lead to dental decay and osteoradionecrosis. Nonrestorable teeth should be extracted, and fluoride trays should be made. If teeth are extracted, include a healing period of 10-14 days before initiating radiotherapy. Good dental and oral hygiene should be emphasized during and after radiotherapy.

If a partial laryngeal surgery is being considered as part of the management plan, pulmonary function tests should be obtained.

Diagnostic procedures

• Biopsy is necessary to establish the diagnosis. It is usually performed during a triple endoscopy.
• An examination under anesthesia is critical for obtaining a biopsy and defining the anatomic extent of disease, particularly the superior and inferior extent, as well as the involvement of the prevertebral fascia. Posterior pharyngeal wall lesions are better visualized using direct laryngoscopy.
• Triple endoscopy, also known as panendoscopy, can be used to assist in defining the inferior extent of the tumor (ie, involvement of the esophageal inlet) and to look for skip lesions and second primary tumors. However, it can be controversial. The necessity of triple endoscopy is being debated; an integrated PET/CT may obviate the need for triple endoscopy. The use of triple endoscopy is based more on symptoms. Esophagoscopy can be difficult to perform if the tumor is large and has caused significant stenosis. In addition, in the absence of findings or symptoms, routine bronchoscopy may not be cost effective.
• • It is an operating room procedure, performed by an otolaryngologist surgeon.   
  • With the patient under mask general anesthesia, the entire oral cavity and throat are palpated and visually inspected, including direct-vision laryngoscopy. The extent of the tumor can be most accurately ascertained in this manner.
  • Biopsies of all suspicious lesions are taken. Bronchoscopy and esophagoscopy are performed to rule out synchronous cancers.
  • Multiple synchronous pharyngeal tumors can be found in approximately 15% of cases.
  • Synchronous lung or esophageal tumors can be found in approximately 5-10% of cases.

Histologic findings

Most hypopharyngeal cancers are squamous cell neoplasms. Nearly 100% of head and neck cancers overexpress epidermal growth factor receptor (EGFR), although the clinical significance is still unclear. Sarcomas, plasmacytomas, non-Hodgkin lymphomas, and metastatic lesions can be encountered in rare instances.

Histologic factors that denote a higher risk tumor include lymphovascular invasion, perineural invasion, or poorly differentiated cell morphology.

Staging

T stage and risk of nodal disease

Summation of examination and radiographic findings into prognostic categories, using the American Joint Committee on Cancer (AJCC) designations of tumor (T), nodal (N), and metastatic (M) categories, assists in treatment selection and planning.

The staging of primary hypopharyngeal tumors is as follows (see Image 3):

• TX: The primary tumor cannot be assessed.
• T0: No evidence of primary tumor is present.
• TIS: The tumor is carcinoma in situ.
• T1: The tumor is limited to one subsite of the hypopharynx and is 2 cm or less at its greatest dimension.
• T2: The tumor involves more than one subsite of the hypopharynx or an adjacent site or is larger than 2 cm but not larger than 4 cm at its greatest diameter without fixation of the hemilarynx.
• T3: The tumor is larger than 4 cm at its greatest dimension or involves fixation of the hemilarynx.
• T4: In 2003, the sixth edition of the tumor, node, metastasis (TNM) classification introduced a subdivision of T4 into T4a (low risk) and T4b (high risk) to reflect the probability of a reasonable opportunity for disease control (T4a) compared with a near certainty of a poor outcome (T4b).
• • T4a – The tumor invades the thyroid/cricoid cartilage, hyoid bone, thyroid gland, esophagus, or central compartment soft tissues, including prelaryngeal strap muscles and subcutaneous fat.
  • T4b - The tumor invades the prevertebral fascia, encases the carotid artery, or involves mediastinal structures.

The staging of the regional lymph nodes is as follows:

• NX: The regional lymph nodes cannot be assessed.
• N0: No regional lymph node metastasis is present.
• N1: Metastasis is found in a single ipsilateral node (£3 cm at its greatest dimension).
• N2: Metastasis is found in a single ipsilateral lymph node (>3 cm but <6 cm in greatest dimension) or in multiple ipsilateral lymph nodes (none >6 cm at greatest dimension).
• • N2a - Metastasis in a single ipsilateral lymph node (>3 cm but <6 cm at its greatest dimension)
  • N2b - Metastasis in multiple ipsilateral lymph nodes (none >6 cm at greatest dimension)
  • N2c - Metastasis in bilateral or contralateral lymph nodes (none >6 cm at greatest dimension)
• N3: Metastasis is found in a lymph node larger than 6 cm at its greatest dimension.

The staging of distant metastasis is as follows:

• M0: No distant metastasis is present.
• M1: Distant metastasis (eg, lung, mediastinal lymph nodes, skeletal, hepatic) is present.

Table 1. Hypopharyngeal Cancer Staging

• T1 - Risk of nodal disease 60%
• T2 - Risk of nodal disease 60-70%
• T3 - Risk of nodal disease 84%
• T4 - Risk of nodal disease 84%

ANATOMY

Section 6 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

The hypopharynx, or laryngopharynx, is the longest and most inferior portion of the 3 segments of the pharynx and links the oropharynx to the esophagus (see Images 1-2). It is located posterior to the cartilaginous structures of the larynx. It is wide superiorly and progressively narrows toward the level of the cricopharyngeal muscle. The hypopharynx is a continuous area; the oropharynx is above it and the cervical esophagus through the cricopharyngeal sphincter is below it. This region is known as the pharyngoesophageal junction or postcricoid area. It is bounded anteriorly by the posterior face of the cricoid cartilage. The hypopharynx extends from the hyoid bone to the cricoid cartilage and is further subdivided into the regions of the pyriform sinus, pharyngeal wall, and posterior cricoid.  

• Pyriform sinuses: The parts of the hypopharynx that lie partly to each side of the larynx form the pyriform sinuses or fossae, so named for their pear shape. The pyriform sinuses are bound laterally by the thyroid cartilage and medially by the lateral surface of the aryepiglottic fold, arytenoids, and cricoid cartilages. It is posteriorly open. The apex, or most inferior extent, lies below the vocal cords and, occasionally, below the cricoid cartilage. The superior extent is bordered by the pharyngoepiglottic mucosal fold that extends from the lateral pharyngeal wall to the epiglottis. The pyriform sinuses extend from the glossoepiglottic folds to the upper esophagus.
• Posterior pharyngeal wall: The posterior pharyngeal wall extends from the level of the hyoid bone to the inferior aspect of the cricopharyngeus muscle. It is formed by the constrictor muscles and is in direct contact with the prevertebral fascia.
• Pharyngoesophageal junction (postcricoid area): The posterior cricoid area is the posterior surface of the larynx and extends from the arytenoids to the inferior edge of the cricoid cartilage and beginning of the esophagus. The superior laryngeal nerve lies deep to the mucosa of the lateral wall of the pyriform fossa. The constrictor muscles, covered with mucous membrane, form the posterior wall of the hypopharynx. It extends from the level of the floor of the vallecula to the level of the cricoarytenoid joint. The anterior wall of the hypopharynx is bounded by the larynx.

The pharyngeal plexus of nerves, which receives contributions from the glossopharyngeal and vagus nerves, supplies the innervation of the hypopharynx. The vagus nerve supplies motor innervation to the constrictors. Sensory information from the hypopharynx travels along the glossopharyngeal nerve and the internal laryngeal branch of the superior laryngeal nerve, which arises from the vagus nerve. 

The primary lymphatic drainage of the hypopharynx includes the jugulodigastric lymph nodes and middle jugular chains. The spinal accessory and retropharyngeal and paratracheal lymph nodes communicate freely.

The pyriform sinuses are drained by a network of lymphatics, which drain primarily to the upper and middle jugular nodes, posterior cervical nodes, and retropharyngeal lymph nodes. Lymphatics of the posterior wall of the hypopharynx drain to the jugular nodes and retropharyngeal nodes. Postcricoid lymphatics drain to the middle and lower jugular nodes and to the paratracheal nodes.⁵

Table 2. Distribution of Involved Lymph Nodes

• In recent years, conformal radiotherapy techniques such as intensity-modulated radiotherapy (IMRT) have placed an emphasis on axial anatomy. An understanding of the axial anatomy is especially important in the accurate delineation of the nodal regions at risk for occult nodal metastasis. The nomenclature used is analogous to the surgical nomenclature used to delineate the nodal groups in the cervical neck. The anatomic delineation of nodal groups in the neck is as follows:
• • Level I: The posterior border is defined by the posterior edge of the submandibular gland.
  • Level II: The superior extent is defined by the mastoid tip and the caudal edge of the lateral C1 process. The inferior extent is defined by the cranial edge of the hyoid bone. The lateral edge is bordered by the sternocleidomastoid muscle.
  • Level III: This cervical nodal group is bordered anterolaterally by the sternocleidomastoid muscle and begins superiorly at the cranial edge of the hyoid bone. The inferior edge is bordered by the inferior edge of the cricoid cartilage.
  • Level IV: This cervical nodal group is bordered by the sternocleidomastoid muscle, begins at the inferior edge of the cricoid cartilage, and extends to 2 cm superior to the supraclavicular joint.
  • Level V: This posterior neck chain is defined anteriorly by the posterior edge of the sternocleidomastoid and the scalene muscle. It begins superiorly at the cranial edge of the hyoid bone and inferiorly at the transverse cervical vessels.
  • Level VI: This nodal group is defined superiorly by the caudal edge of the thyroid gland and inferiorly by the sternal manubrium. It is defined laterally by the medial edge of the sternocleidomastoid muscle and medially by the trachea. It is limited posteriorly by the common carotid artery.

Consensus guidelines for the accurate delineation of the clinical node-negative neck from several cooperative organizations (eg, Danish Head and Neck Cancer Group [DAHANCA], European Organization for Research and Treatment of Cancer [EORTC], French Head and Neck Cancer Group [GORTEC]) are available from the Radiation Therapy Oncology Group.

The intimate association between the hypopharynx and the larynx, oropharynx, and esophagus allows for certain dissemination routes of malignant disease. Pyriform sinus carcinomas may spread submucosally into the posterior wall of the hypopharynx, the postcricoid region, or the aryepiglottic fold. Large tumors also extend up into the paraglottic fat, the pre-epiglottic fat, and the base of the tongue. Tumors that arise from the lateral wall or apex of the pyriform sinus often have already invaded the thyroid cartilage. Lesions of the medial wall of the pyriform sinus may spread along the aryepiglottic fold into the false vocal cord and arytenoid cartilage. Medial wall lesions occasionally invade paraglottic and pre-epiglottic fat. They may also grow posteriorly into the postcricoid region and then cross the midline to involve the contralateral pyriform sinus.

MEDICAL TREATMENT

Section 7 of 15  

• Authors and Editors
• Introduction
• Clinical
• Etiology and Risk Factors
• Workup
• Anatomy
• Medical Treatment
• MEDICATION
• Surgical Treatment
• Follow-up and Complications
• Outcome and Prognosis
• Future Directions
• Medicolegal Pitfalls
• Multimedia
• References

Pretreatment care

• Dentist: Repair or extract damaged teeth prior to radiation therapy. The risk of osteoradionecrosis of bone is increased with poor dental hygiene or extractions performed after high-dose radiation. Dental prophylaxis with fluoride is important during and after radiation due to loss of saliva. Bisphosphonates should be used with caution in this population due to the risk of mandibular osteonecrosis.
• Nutritionist: Malnutrition is common at presentation and worsens following surgery, radiation, or both. At diagnosis, obtain nutritional evaluation and recommendations for ongoing nutrition support and follow-up.
• Speech/swallowing therapist: Specialists in this field should direct rehabilitation for speech and swallowing function. This can include training in electrolarynx use following laryngectomy, evaluation of posttreatment function (and risk of aspiration) by observation and barium swallow, and mouth and throat exercises to regain coordination of swallowing and phonation.

Consider feeding tube placement if oral feeding is likely to be disrupted by therapy. At least 75% of patients undergoing chemoradiotherapy require a feeding tube. Prophylactic placement is often recommended when a patient is unlikely to be able to complete therapy without nutritional support through a feeding tube. This has several advantages, including minimizing the risk of unnecessary interruptions in the radiotherapy, which can result in reduced efficacy of the radiotherapy. In addition, prophylactic feeding tube placement helps to minimize the weight loss that often occurs before a decision is made during a course of radiotherapy to place a feeding tube. 

In recent years, concerns have arisen that the sole reliance on a feeding tube, particularly when placed prophylactically, could contribute to postradiotherapy swallowing difficulties, possibly due to weakness of the swallowing muscles. When a feeding tube is placed, patients should be counseled to continue to swallow as much as possible during treatment and to use the feeding tube as part of a graduated strategy to provide increasing nutritional support with decreasing abilities to maintain a complete oral diet. A nutritionist should direct the choice and amount of tube feedings and supplements.

Emergency tracheotomy may be required in 5-15% of patients.

Chemotherapy, radiation therapy, and combined therapy

The traditional goal of hypopharyngeal cancer management is to achieve the highest locoregional control with the least functional injury, preserving respiratory function, deglutination, and phonation. In recent years, several new treatment options in the management of head and neck cancers have made this goal easier to achieve. This includes modern conservative surgical approaches that involve robotic assistance and laser dissection and new radiotherapy techniques such as intensity-modulated radiation therapy (IMRT) for increased conformal irradiation, including emerging techniques such as partial larynx radiation and the use of biologic agents such as the monoclonal antibody cetuximab (Erbitux), which specifically binds and prevents the activation of the epidermal growth factor receptor (EGFR).

Despite these new treatment modalities, an optimal treatment strategy for head and neck cancers, including hypopharyngeal cancers, is difficult to determine because no randomized study comparing outcomes following surgery with outcomes following radiation or chemoradiation has been completed. Randomized studies are needed because this study model minimizes the risk of skewed results; for example, if earlier-stage cancers are treated with one treatment approach while advanced-stage cancers are treated with a different approach, the study may incorrectly conclude that the two treatment approaches differ in efficacy.  This is commonly a problem with chart review studies from treating institutions because each institution has their bias when selecting particular stages of cancers for particular types of treatment. 

The management of hypopharyngeal cancer can be broken down based on stage, as follows:

• T1/T2 - Radiotherapy alone (commonly 66-70 Gy) or surgery (possibly with postoperative irradiation, depending on the pathology findings). Larynx preservation therapy is typically possible and is strongly favored.
• T3/T4 (resectable) - Partial or total laryngopharyngectomy, neck dissection, postoperative radiotherapy, or radiotherapy alone with altered fractionation or concurrent chemoradiotherapy or participation in prospective clinical trials.
• Unresectable or medically unstable - (1) Radiotherapy alone with altered fractionation or concurrent chemoradiotherapy or (2) participation in prospective clinical trials including the study of induction chemotherapy. 

Radiotherapy, chemotherapy, and surgical treatment are summarized as follows (see below for further discussion):

• Radiation therapy
• • Radiation therapy as a curative treatment is feasible for T1 lesions and small T2 lesions. 
  • If a standard fractionation scheme is used, published experience supports the use of various total doses to the gross tumor ranging from 66-70 Gy with a conventional daily fractionation schedule. A dose of 70 Gy is generally favored. If the tumor involves the postcricoid region or the pyriform sinus, the posterior pharyngeal wall usually receives 50-55 Gy in order to treat the retropharyngeal nodes prophylactically. The nodes in the supraclavicular region usually receive prophylactic radiation to approximately 50 Gy.
  • Altered fractionation has also been recommended based on the results of a large multi-institutional study conducted by the Radiation Therapy Oncology Group (RTOG).⁸ See below. This trial enrolled patients with squamous cell carcinomas of various sites in the head and neck including the hypopharynx. The results demonstrated that both an accelerated schedule using a concomitant boost or a hyperfractionation schedule improved the probability of local-regional cancer control in the head and neck. This study validated the radiobiologic basis for these altered radiotherapy schedules. For the accelerated schedule, this was based on the hypothesis that a tumor stress response to the radiation would result in an increase in the number of tumor clonogens, hence benefiting from administering the planned total dose of radiation over a shorter treatment time to minimize the additional tumor cells. The basis of the hyperfractionation schedule was to achieve a safer increase in the total radiotherapy dose by administering smaller doses per fraction or treatment. To avoid the potential adverse effects of prolonging the overall duration of the radiotherapy as a result of the reduced dose per fraction, twice daily fractions were administered.
  • While both altered fractionation schedules appear to be superior to conventional daily fractionation schedules, the specific use for hypopharynx cancers must be carefully considered due to the potential for increased side-effects. Of the two schedules found to be superior when compared to once daily fractionation schedules, hyperfractionation is likely to be favored due to the results of a recent large individual patient-based meta-analysis.⁹ This meta-analysis demonstrated an improvement in survival and control of the local-regional cancer. Hyperfractionation schedules administer a typical total dose to the gross tumor between of 76.8–79.2 Gy in 64–66 fractions of 1.2 Gy each twice a day with 6 or more hours between treatments.
• Concurrent chemoradiation
• • Concurrent chemoradiotherapy is recommended for more advanced but resectable hypopharyngeal carcinomas (for organ preservation indications) and for unresectable indications. As with altered fractionation, the use of concurrent chemoradiation for resectable hypopharyngeal cancers must be carefully considered due to the increased acute toxicities and the potential for late injury to the normal tissues result in compromised organ function.
  • The basis for this comes from randomized trials including head and neck squamous cell carcinoma (HNSCC) from several tumor sites not restricted to the hypopharynx. A large patient-based meta-analysis¹ demonstrated a small but significant improvement in the overall survival of patients receiving concurrent chemotherapy to radiotherapy alone.
  • Cisplatin is considered the best agent to use with radiation in the treatment of hypopharyngeal cancer, though published experience with the combination of cisplatin and 5-fluorouracil (5-FU) also exist.  It is unclear if the addition of 5-FU increases the treatment benefits compared to cisplatin alone when it is administered together with radiotherapy. As such, these concerns must be balanced with the potential for increased side effects with the addition of 5-FU.
• Induction chemotherapy followed by radiation therapy alone
• • Historically, chemotherapy administered before definitive radiotherapy was used to improve on the results of conventionally fractionated radiotherapy alone. This was used for unresectable HNSCC and eventually for the use of resectable HNSCC as it has been observed that HNSCC that demonstrated a very good response to several cycles of induction chemotherapy before radiotherapy was associated with an improved probability for radioresponsiveness and improved overall survival. This lead to several randomized trials determining if induction chemotherapy followed by local-regional therapy, be it surgery or radiotherapy was beneficial or not to local-regional therapy alone.⁹ These trials were not specific for hypopharyngeal cancers alone. However, the general interpretation suggested that induction chemotherapy can reduce the risk of distant metastasis but that overall survival was only modestly improved in patients with unresectable cancer and not in resectable cancers. The use of induction chemotherapy did not improve the control of the local-regional cancer, which remained disappointing. As such, efforts have focused on the study of chemotherapy administered concurrently with radiotherapy (see above) and in recent years, the re-introduction of induction chemotherapy followed by concurrent chemoradiotherapy.
  • The European Organization for Research and Treatment of Cancer (EORTC) conducted a trial of voice preservation in patients with resectable advanced hypopharyngeal cancer. This study demonstrated that the larynx could be preserved with nonsurgical management without any compromise to the overall survival compared to treatment primarily via surgery. 
  • • This trial randomized 194 patients, of which 37% had stage IV disease. Only 3% of patients randomized to induction chemotherapy had stage T4 disease, whereas 23% had stage T2 cancers. Most patients were stage T3. Patients were randomized to surgery followed by postoperative radiotherapy or to induction chemotherapy consisting of cisplatin and 5-FU for a potential maximum of 3 cycles. Patients randomized to this arm were assessed after each cycle of chemotherapy to determine the clinical response.  Patients demonstrating either a complete response after 3 cycles went on to receive conventionally fractionated daily radiotherapy. Those who did not demonstrate a favorable response went to have surgery consisting of a total laryngectomy.
    • The incidence of nodal metastases was high. A complete response was achieved in the primary tumor in more than 50% of the patients randomized to chemotherapy, and 43% had no evidence of disease above the clavicles after chemotherapy.
    • In 1996, the EORTC published the preliminary results of their trial. Three-year survival rates were significantly better among patients randomized to chemotherapy (57%) compared with immediate surgery (43%). At 5 years, however, the differences were no longer significant. The 5-year survival rate with a functional larynx was 35%. The trial demonstrated a reduction of distant.¹⁰
  • Despite the ability for induction chemotherapy to reduce the incidence of distant metastasis, the ability of induction chemotherapy to translate this into a consistent improvement in overall survival, especially in resectable HNSCC including the hypopharynx site, seems to be limited. This raises questions about its role in addition to local-regional therapy with radiotherapy alone. In fact, a large patient-based meta-analysis¹ of the EORTC trial (described above) and of two other larynx randomized trials studying induction chemotherapy in respectable HNSCC would support a lack of improvement in overall survival. In fact, the hazard ratio suggested the potential for an adverse impact on overall survival prompting the authors of the meta-analysis to recommend caution with regards to its routine generalized use. 
  • In recent years, the addition of Taxotere to the standard regimen of cisplatin and 5-fluorouracil has been demonstrated to have increased activity renewing interest in the use of docetaxel /cisplatin /fluorouracil (TPF) induction chemotherapy for locally advanced HNSCC. 
  • • The results of a large European trial randomizing patients with locally advanced unresectable stage III and IV HNSCC to TPF vs PF induction chemotherapy for 4 cycles followed by conventionally fractionated radiotherapy were recently reported (EORTC 24971).¹¹ Approximately 30% of the patients enrolled had a hypopharynx primary site carcinoma. Response was not used to determine if patients could proceed to radiotherapy. Rather, disease progression, inadequate bone marrow function, incomplete resolution of the mucositis, and non-healing dental wounds precluded local-regional radiotherapy. 
    • This study demonstrated an improvement in both the progression-free survival and overall survival. The incidence of distant metastasis was comparable between the two arms.
  • In summary, induction chemotherapy appears to have a more favorable therapeutic ratio (risk vs benefit) for unresectable HNSCC as compared to resectable HNSCC, including the hypopharynx site. How induction TPF followed by radiotherapy alone compares to concurrent chemoradiotherapy with regards to efficacy for unresectable HNSCC is unclear at this time.
• Induction chemotherapy followed by concurrent chemoradiation
• • Several completed and ongoing randomized trials are studying the role of induction chemotherapy to concurrent chemoradiotherapy for both resectable and unresectable HNSCC.
  • Spanish investigators reported the results of a phase III randomized trial of TPF vs PF induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced resectable and unresectable HNSCC.¹²  These investigators demonstrated an improvement in the overall survival only in patients with unresectable HNSCC. This finding is consistent with the findings by Vermorken et al¹¹ (see above) and would favor the addition of Taxotere in unresectable HNSCC as part of an induction regimen if this is elected. However, these investigators concluded that the role for induction chemotherapy would be significantly aided by the results of ongoing randomized trials evaluating induction chemotherapy followed by concurrent chemoradiation to patients receiving only concurrent chemoradiation.
  • A US study of TPF vs PF induction chemotherapy followed by concurrent chemoradiation with weekly carboplatin and standard fractionated radiotherapy was recently reported.¹³
  • • This trial randomized 501 patients with both resectable and unresectable locally-advanced HNSCC.  Approximately one third of the study patients were enrolled with resectable disease for organ preservation indications.
    • The incidence of distant metastasis was the same between the two induction chemotherapy arms. 
    • As with the Vermorken study,¹¹ the addition of Taxotere to the induction chemotherapy regimen improved the overall survival.
• Postoperative concurrent chemoradiation
• • The indications for postoperative radiotherapy have been the subject of a number of clinical studies attempting to define risk groups and to identify improvements with the use of postoperative radiotherapy with either altered fractionation or with concurrent chemotherapy. In general, studies have attempted to identify groups of patients with a low, intermediate, or high risk of cancer recurrence.
  • Determining which risk factors constitute a low and intermediate risk group is controversial. Despite this controversy, investigators from the MD Anderson Cancer Center demonstrated in a prospective trial that patients with an intermediate risk for cancer recurrence who received postoperative radiotherapy had the same local-regional control rates as patients who did not demonstrate any adverse pathologic factors in the resected cancer and who did not receive postoperative radiotherapy.¹⁴ Although patients in this portion of the study were not randomized, the strengths of these observations are that all patients were prospectively treated, observed, or both and that the outcome of the intermediate risk group did not significantly differ from that of the group with no risk factors for recurrence. This observation supports the use of postoperative radiotherapy using daily radiation treatments at a dose of 180-5760 cGy.
  • In general, patients who present with a positive surgical margin or with nodal extracapsular extension are at a high risk for recurrence. In this group of patients, 2 large randomized clinical trials have demonstrated that patients with these risk factors should receive concurrent chemoradiotherapy with cisplatin (100 mg/m² on days 1, 22, and 43 of radiotherapy) and that this results in cancer control rates that are superior to those of radiation alone.
  • In recent years, two significant independent randomized trials randomizing patients with head and neck cancers including hypopharyngeal carcinomas that demonstrated high-risk pathologic features following surgery, to either postoperative radiotherapy or postoperative chemoradiation have been reported.^{15, 16} Both trials randomized patients to conventionally fractionated radiotherapy or to the same radiotherapy schedule with concurrent high dose cisplatin (100 mg/m²) for 3 cycles during the radiotherapy. Both of these studies demonstrated that concurrent cisplatin improved both the probability of local-regional disease control and disease-free survival. 
• • While both trials were very similar in design showing benefit in patients with high-risk tumor features on pathologic evaluation, the study eligibility differed. This has contributed to the debate regarding which high-risk features should be considered for concurrent postoperative chemoradiation.¹⁷ In general, patients demonstrating a positive surgical margin (defined as cancer at the mucosal margin) or the presence of nodal metastasis with extracapsular extension (ECE) should be recommended to receive concurrent cisplatin. 
  • Debate exists as to the risk versus the benefit of concurrent chemoradiotherapy for patients with multiple nodal metastasis without ECE or tumors with a