Primary Site and Regional Lymphatics

Larynx

The larynx is divided into three regions: the supraglottis, glottis, and subglottis. The supraglottic larynx lies above the level where the mucosa of the upper surface of the true vocal cords turns upward to form the lateral wall of the ventricle. It consists of the false vocal cords, arytenoids, aryepiglottic folds, and infrahyoid and suprahyoid epiglottis. The glottic region by definition includes the true vocal cords and extends 0.5 cm inferiorly, and the subglottic region extends from there to the superior aspect of the trachea (Fig. 33-1).

Figure 33-1 Anatomy of the larynx and its subdivisions.

Primary glottic cancers are about three times more common than supraglottic carcinomas, whereas subglottic carcinomas are extremely rare (about 2% of larynx cancers). At diagnosis, nearly two thirds of patients with laryngeal cancer have their disease confined to the laryngeal structures and less than 10% present with distant metastases. The patterns of spread, presentations, and management of cancers arising from these three subsites are very different.

Glottis

Most glottic lesions arise on the free margin and upper surface of the anterior two thirds of the true cord. These tumors tend to grow slowly and remain confined to the mucosa of the true cords. Eventually they will spread superiorly or inferiorly onto the mucosa of the supraglottic or subglottic structures. Some tumors may grow outward, in an exophytic fashion, leading to voice changes and subsequently respiratory obstruction. Invasion into the intrinsic musculature and joints of the larynx decreases vocal cord mobility and ultimately causes vocal cord fixation. Noteworthy is that tumor bulk alone can cause impaired mobility. Less commonly, infiltration of the recurrent laryngeal nerve may also cause impairment of mobility.

Infiltrative tumors will breach into the paraglottic and pre-epiglottic spaces. These spaces lie between the external frame of the larynx (thyroid-cricoid cartilages and hyoid bone) and the internal components of the larynx (epiglottis, muscles, and ligaments) and are filled with fat and hence offer little resistance to infiltration. From these spaces, infiltrative tumors may break through ligaments above or below the thyroid cartilage into the neck or may invade the cartilage directly.

The mucosa of the true vocal cords has a sparse lymphatic supply. Thus, glottic carcinomas have a low propensity for lymphatic spread. The incidence of lymphadenopathy at diagnosis is approximately 5% for T1 and T2 lesions and approximately 20% for T3 and T4 tumors.³⁸ The frequency of occult nodal involvement is also low. Byers and colleagues³⁹ found microscopic nodal involvement in 9 of 57 patients who underwent elective nodal dissection for T3 or T4 vocal cord lesions; most frequently involved nodes were the upper jugular (level II), midjugular (level III), and paratracheal groups (level VI).

Supraglottis

There are some variations of growth patterns within subsites of the supraglottic larynx. Suprahyoid epiglottic tumors sometimes grow in an exophytic pattern off the tip of the epiglottis, causing no symptoms until they become quite large. At other times they spread inferiorly, infiltrating and eroding the epiglottis. These lesions can eventually autoamputate the tip of the epiglottis. Complete regression of these tumors after RT may leave only a small epiglottic stump. Such an anatomic aberration increases the risk for aspiration.

Infrahyoid epiglottic lesions tend to spread anteriorly or circumferentially They can invade directly through the base of the epiglottis into the pre-epiglottic space and spread onto the lingual epiglottis and subsequently invade the vallecula, pharyngoepiglottic folds, and tongue base. At other times they spread onto the aryepiglottic folds, usually spreading from their midline position in both directions to involve both folds, producing a horseshoe-like appearance. They then spread either inferiorly onto the false vocal cords or over the aryepiglottic folds onto the piriform sinuses.

Lesions originating on the aryepiglottic folds can spread in all directions, that is, anteromedially onto the epiglottis, posteriorly to the arytenoids, inferiorly to the false cords, or laterally into the piriform sinus. Similar to lesions of the false vocal cords, they have variable growth patterns but often are infiltrative with easy access to the paraglottic space. They can frequently involve the cricoarytenoid joints or the musculature of the larynx, impairing mobility.

The primary difference between supraglottic cancers and true glottic cancers is the likelihood of developing cervical nodal metastases. At diagnosis, 55% of patients with supraglottic cancers have clinically involved lymph nodes. Lymphatic vessels in the supraglottic larynx collect in channels that pass through the piriform sinuses to drain to nodes along the jugular chain, particularly the upper (level II) and midjugular (level III) lymph nodes. Lee and associates⁴⁰ reported on the data of a subgroup of patients with intermediate-stage disease who underwent supraglottic laryngectomy with neck dissections. One third of patients had palpable nodes on presentation, and nearly an additional third of patients had pathologic nodal involvement.

Subglottis

Subglottic tumors spread inferiorly to the trachea, extend through the cricothyroid membrane into the neck, or directly invade the cricoid cartilage. Superiorly, they almost always involve the undersurface of the true glottis; and from a staging perspective, it is sometimes difficult to differentiate between a tumor truly originating from the subglottis and a glottic tumor with significant subglottic extension.

Hypopharynx

The hypopharynx is the inferior portion of the three divisions of the pharynx (Fig. 33-2). It extends from the hyoid bone superiorly to the cricoid inferiorly. Valleculae, pharyngoepiglottic fold, and lateral projections of aryepiglottic folds are considered the superior border separating the hypopharynx from oropharynx. Inferiorly, the hypopharynx ends at the cervical esophageal inlet. The hypopharynx is subdivided into three components: the pharyngeal walls, the piriform sinus, and the postcricoid pharynx. The hypopharyngeal walls are a continuation of the lateral and posterior oropharyngeal walls. The pair of piriform sinuses is created by the invagination of the larynx into the hypopharynx. They are conical (more truly pear shaped, hence the derivation of its name). Each sinus (or recess) consists of three walls. The medial wall is essentially the lateral aspect of the larynx; superiorly, it becomes the aryepiglottic fold. The lateral wall is a continuation of the lateral wall of the oropharynx. Anteriorly, the medial and lateral walls converge to form the narrow anterior wall. Superior is the base or vestibule formed by the rim of the three walls. Inferiorly, the three walls merge to form the apex.

Figure 33-2 Anatomic relationship of the hypopharynx to the pharyngeal axis.

The postcricoid pharynx begins superiorly at the level of the arytenoids and ends inferiorly at the esophagus. The posterior larynx makes its anterior border, and posteriorly it again is a continuation of the posterior pharyngeal wall.

Hypopharyngeal cancers also commonly present as nodal metastases. Lindberg⁴¹ reported a 75% incidence of nodal metastases in patients presenting to the M.D. Anderson Cancer Center (MDACC) with hypopharyngeal tumors. Level II and III nodes were most frequently involved, and bilateral lymphadenopathy was seen in 15% of patients. These tumors also have access to deep jugular and retropharyngeal lymph nodes.

Piriform Sinus Tumors

Piriform sinus tumors account for 70% of cancers originating in the hypopharynx. Tumors originating from the medial wall of the piriform sinus behave similarly to supraglottic tumors arising from the aryepiglottic folds, and it is often difficult to know the true origin of some of these lesions. Posteriorly, there is little to impede tumor extension into the postcricoid space or crossing from the ipsilateral arytenoid to the contralateral arytenoid. Lateral wall tumors also have few barriers to growth. They can extend medially along the mucosa to involve the posterior hypopharyngeal wall or anteromedially to involve the other two walls of the piriform sinus. Inferiorly, they have quick access to the apex and usually extend deep to the sinus submucosally to involve other adjacent structures, including the thyroid and cricoid cartilages, or directly into the thyroid gland. It is not uncommon to see advanced tumors from this location that have direct soft tissue extension into the neck. These tumors can also extend into the cervical esophagus, primarily through submucosal routes, making a true definition of disease extent extremely difficult. They can also behave similarly to more classic esophageal tumors with extensive spread along lymphatic spaces and with skip lesions.

Hypopharyngeal Wall Tumors

Tumors originating from the hypopharyngeal walls are less common. Because early presentations are infrequent, it is unusual to see a lesion confined to and clearly originating from the lateral or posterior hypopharyngeal wall. Hypopharyngeal wall tumors frequently spread along the walls to involve either the posterior or lateral oropharyngeal walls. Posterior wall tumors can also invade the prevertebral tissues or invade even more deeply to the bones of the cervical spine.

Postcricoid Tumors

Postcricoid tumors are the least common hypopharyngeal tumors. They almost always present in advanced stages. They can extend laterally into one or both piriform sinuses or directly invade laryngeal structures.

Distant Metastases

The incidence of distant metastases from cancers of the head and neck and specifically laryngeal and hypopharyngeal cancers is low and is generally thought to be less than 10%. An often-referenced study by Crile in 1906⁴² reported an incidence of 1% distant metastases in 4500 patients with epidermoid cancers of the head and neck. In subsets of patients with head and neck squamous cell cancers, patients with glottic tumors usually have the lowest rates of distant metastases whereas patients with hypopharyngeal carcinomas often have the highest rates.

Merino and colleagues⁴³ analyzed the incidence of distant disease in over 5000 patients with head and neck squamous cell carcinomas treated from 1948 through 1967. Among patients with control of disease above the clavicle, the incidence of distant failure was 1%, 13%, and 23% for patients with carcinomas of the true vocal cords, supraglottic larynx, and hypopharynx, respectively. Similarly, Marks and associates⁴⁴ found that 23% of patients with piriform sinus cancers developed distant metastases, with a higher rate among patients who underwent total laryngectomies as part of their therapy. The incidence of metastases is associated with stage of disease, because the clinical incidence of metastases is approximately 20% in patients with stage IV disease.

The sites of presentation of distant metastases are similar for cancers of the larynx and hypopharynx.⁴³ The lungs are the most common site and are the first site of presentation in nearly 60% of patients. Bones are the next most common site, because 20% of patients with distant disease develop osseous metastases. Liver metastases are common in autopsy studies, but clinical liver metastases develop in only 10% of patients with hematogenous spread of disease from the larynx and hypopharynx.⁴⁵ Spread to mediastinal lymph nodes, the brain, or other organs is very uncommon.

Laryngeal Cancer

Clinical evaluation of laryngeal cancer includes indirect laryngoscopy with a mirror that is frequently supplemented by fiberoptic endoscopy (Table 33-1). Similar to other tumors in the head and neck, the examiner assesses the tumor size, morphology, infiltration (defect, distortion) of adjacent structures, and vocal cord mobility. It is important to palpate the base of the tongue to determine direct invasion from the supraglottic larynx and to look for indirect signs of pre-epiglottic space invasion such as fullness of the vallecula or ulceration of the infrahyoid epiglottis. A direct laryngoscopy is often the final step in evaluation. It is needed to further outline the disease extent and, in particular, to obtain biopsy specimens for tissue diagnosis.

TABLE 33-1 Evaluation of Patients with Suspected Laryngeal or Hypopharyngeal Cancer

* In patients with more advanced disease, these tests may augment the workup for metastatic disease; PET and barium studies may help better define the inferior extent of advanced hypopharyngeal cancers.

Examination of the neck is important to detect lymphadenopathy or direct tumor extension manifesting as tenderness of the thyroid cartilage or the presence of a subcutaneous mass. Firm fullness over the thyroid notch is suggestive for pre-epiglottic space involvement.

Radiologic studies are indicated when there is the suggestion of deep infiltration. CT (Fig. 33-3) or MRI is useful for the assessment of the pre-epiglottic space, tongue base, paraglottic region, and subglottis (which is sometimes difficult to evaluate from above with the mirror or fiberoptic scope). These images may help differentiate direct primary tumor extension to the soft tissue of the neck from nodal involvement. Anterior commissure lesions may have subtle thyroid cartilage invasion only detectable by CT.

Figure 33-3 CT of laryngeal cancers. A, Cancer of the supraglottis invades the pre-epiglottic space (left). B, Cancer of the epiglottis with direct extension into the base of the tongue. C, Cancer of the true vocal cord with subglottic extension (left). D, T4 laryngeal cancer, with destruction of the cartilage and invasion of the anterior strap muscles.

Hypopharyngeal Cancer

Evaluation of hypopharyngeal tumors is similar to that of larynx cancers. Because these lesions are typically at an advanced stage, it is not uncommon to palpate disease in the neck by direct extension. The thyroid click may be lost owing to anterior displacement of the larynx by a posteriorly located (particularly postcricoid) lesion. Phonation may provide better visualization of the piriform sinus on indirect mirror and fiberoptic examination. If unsuccessful, a Valsalva maneuver may open the sinus. Deep infiltrative lesions in the apex may be hard to see but are suspected by either pooling of secretions or arytenoid edema. Assessment of laryngeal mobility is important in medial wall lesions because they can invade directly into the laryngeal framework. In addition to CT (Fig. 33-4), combined ¹⁸F-fluorodeoxyglucose-labeled positron emission tomography and CT (FDG-PET/CT) may be helpful in defining tumor extent, particularly the inferior border where subtle changes in the inferior hypopharynx and superior cervical esophagus may be hard to identify solely on anatomic images.

Figure 33-4 CT of hypopharyngeal cancers. A, A small (<1-cm) lesion arises off the posterior hypopharyngeal wall (T1) with large (N3) neck metastases. The primary tumor was managed with irradiation only, and the neck was treated with combined irradiation and surgery. B, An exophytic lesion was confined to the walls of the left piriform sinus (T2) and was treated with hyperfractionated RT. C, An infiltrative lesion off the medial wall of the piriform sinus invaded and fixed the hemilarynx (T3). This patient was treated within the framework of a study of induction chemotherapy and irradiation. D, An advanced lesion of the piriform sinus extended directly into the soft tissues of the neck. This lesion required a resection with a free jejunal autograft repair followed by postoperative RT.

Larynx

Tumors are staged using the American Joint Committee for Cancer (AJCC) TNM system²⁷ (Table 33-2). The system is currently in its seventh iteration, most recently revised in 2010. The system classifies/categorizes larynx cancer primary tumors (T) by sites of extension and cord mobility but not size. For glottic tumors, stage T1 is disease limited to the vocal cord(s). The AJCC staging system further divides T1 glottic tumors into T1a for tumors confined to one true vocal cord and T1b for tumors involving both vocal cords. In general, this subdivision is more useful for communication and may influence the treatment decision (i.e., limited surgery vs. RT) but does not have a strong impact on prognosis. T2 glottic tumors have either supraglottic or subglottic extension and/or impaired mobility. Although not defined by the AJCC, T2 glottic lesions can be subdivided into T2a for normal mobility and T2b for impaired mobility. This subdivision is not uniformly used, however, because there is no general agreement that treatment outcomes differ among the substages.

TABLE 33-2 American Joint Committee on Cancer Staging of Laryngeal and Hypopharyngeal Cancers

Two significant revisions were made to the sixth edition of the staging system.⁶¹ Historically, the definition of T3 glottic disease has been fixation of the vocal cord. The sixth edition expanded on this definition and included paraglottic space invasion or minor thyroid cartilage invasion. Previous editions had defined T4 disease as invasion through the thyroid cartilage, but a common misinterpretation was to include any thyroid cartilage invasion into the T4 category. The new definition was made to clarify this point. The significance of this distinction is in the era of larynx preservation (see later); many still think that the presentation of invasion through the cartilage into the extralaryngeal tissues precludes a nonsurgical approach, but patients presenting with minimal invasion into the inner cortex may have disease suitable for larynx preservation.

The second modification is the subdivision of T4 disease. For head and neck cancers in general, the sixth edition had subdivided stage T4 into resectable (T4a) and unresectable (T4b) categories. Thus glottic cancer T4a disease has been defined as tumor that invades through the thyroid cartilage and/or invades tissues beyond the larynx (e.g., trachea, soft tissues of neck including deep extrinsic muscle of the tongue, strap muscles, thyroid, or esophagus), and T4b is tumor invading prevertebral space, encasing carotid artery, or invading mediastinal structures. Subsequently, the only change made in the seventh edition was descriptive. Stage T4a now describes moderately advanced local disease, and T4b describes very advanced local disease.

The staging of supraglottic cancers requires the division of the supraglottis into five subsites: the suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds, arytenoids, and ventricular bands (false cords). T1 disease is disease confined to one subsite (with normal vocal cord mobility). T2 disease invades more than one adjacent subsite or region outside the supraglottis (mucosa of base of tongue, vallecula, or medial wall of the piriform sinus). T3 disease is similar to glottic carcinoma, although it also includes pre-epiglottic space invasion or postcricoid involvement. Last, in the newest edition, the definition of T4 supraglottic cancer is the same as that for glottic cancer with subdivisions into moderately advanced and very advanced (T4a and T4b) categories.

Hypopharynx

T category for hypopharyngeal tumors is also based on sites of involvement and larynx motion (an indirect measurement of disease extension). The fifth edition of this staging classification had a significant modification to also include the size of the tumor in staging.⁶² This change addressed a major deficiency in prior systems, because the older systems tended to understage hypopharynx tumors relative to other head and neck mucosal cancers. The hypopharyngeal T category still does not reflect morphology, which remains an important criterion for selection of local therapies, because exophytic tumors in this site are usually selected more frequently than infiltrative lesions for organ-preserving therapies. The sixth edition made one additional modification. As described for laryngeal cancers, resectable T4a and unresectable T4b categories were defined. T4a hypopharyngeal disease can invade thyroid or cricoid cartilages, hyoid bone, thyroid gland esophagus, or central compartment, while T4b disease invades prevertebral fascia, encases carotid artery, or involves mediastinal structures. The newest edition now defines T4a and T4b as moderately advanced and very advanced.

Regional Classification/Categorizaton

The nodal (N) category is uniform for all head and neck cancer, including laryngeal and hypopharyngeal tumors. No changes were made in the seventh edition. The details of T and N categories for laryngeal (glottic and supraglottic) and hypopharyngeal cancers are summarized in Table 33-2.

T1 and T2 Glottic Tumors

The management of early glottic carcinomas is controversial and is often determined by the preferences and expertise of the attending physicians. Oncologists advocate either irradiation or voice-preserving partial laryngectomy. Large published series have for all practical purposes demonstrated equivalent control rates with surgery (excision, cordectomy, or hemilaryngectomy) and RT. There has not been a true comparative study between these two modalities, and it is highly unlikely that a prospective trial will be performed.

There are several difficulties in comparing the results of various treatment options. Nearly all series are retrospective single-institutional studies. It is thus difficult to ascertain if small differences in control rates between series are real. Mendenhall and colleagues⁶³ address this issue by defining the surgical procedure that would have been recommended in their irradiated patients. They found that the surgical treatment option would have required total laryngectomy, rather than partial voice-conserving procedures, in 10% of patients with T1 disease and 55% of those with T2 disease. However, the supracricoid laryngectomy, a procedure that removes an entire circumferential portion of the larynx and subsequently reconstitutes the larynx, has largely been developed during the past decade.⁶⁴ Many patients described by Mendenhall and colleagues in 1993 deemed suitable only for total laryngectomy may now be managed with this voice-preserving surgery. Olsen⁶⁵ states that it is very unusual for disease that does not fix the arytenoids to require total laryngectomy. Although this is possibly true from a technical standpoint, many larynx cancer patients are older, have long histories of tobacco exposure, and medically may not be suitable for partial laryngeal surgery other than excisions of small T1 lesions on the midcord.

In general, T1 tumors can be treated effectively with laser excision,⁶⁶ laryngofissure,⁶⁷ partial laryngectomy,^68,69 or irradiation. Table 33-3 summarizes the results of RT. Local control rates of RT range from 85% to 95%, and ultimate control rates after salvage surgery for recurrences are greater than 95%. Surgical salvage for the uncommon local relapse often requires a total laryngectomy, but an occasional patient can have a lesion amenable to a voice-conserving partial laryngectomy.^70–74

TABLE 33-3 Results of Irradiation for T1 Carcinomas of the True Vocal Cords

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