Laryngeal Carcinoma

Background: Laryngeal cancer is the most common cancer of the upper aerodigestive tract. The incidence of laryngeal tumors is closely correlated with smoking, as head and neck tumors occur 6 times more often among cigarette smokers than among nonsmokers. The age-standardized risk of mortality from laryngeal cancer appears to have a linear relationship with increasing cigarette consumption. Death from laryngeal cancer is 20 times more likely for the heaviest smokers than for nonsmokers.

Furthermore, active smoking by patients with head and neck cancer is associated with significant increases in the annual rate of second primary tumor development compared to former smokers or nonsmokers. The use of unfiltered cigarettes or dark, air-cured tobacco is associated with further increases in risk.

Although alcohol is a less potent carcinogen than tobacco, alcohol consumption is a risk factor for laryngeal tumors. In individuals who use both tobacco and alcohol, these risk factors appear to be synergistic, and they result in a multiplicative increase in the risk of developing laryngeal cancer.

Pathophysiology: Most squamous cell carcinomas of the larynx result from an exposure to carcinogens, such as tobacco and alcohol, which cause diffuse mucosal changes (field effect).

Frequency:

Mortality/Morbidity:

Race: Laryngeal carcinoma is more common in African Americans than in whites, with a ratio of 3.5:1.

Sex: In the 1950s, the male-to-female ratio in patients with laryngeal cancer was 15:1. This number had changed to 5:1 by the year 2000, and the proportion of women afflicted by the disease is projected to increase in years to come. These changes are likely a reflection of shifts in smoking patterns, with women smoking more in recent years.

Age: Laryngeal cancer most commonly affects men middle-aged or older who are smokers and who use alcohol. The peak incidence is in those aged 50-60 years.

Anatomy:

Cartilage

The cartilaginous framework of the larynx includes the thyroid cartilage, cricoid cartilage, arytenoid cartilage, and corniculate cartilage.

The conus elasticus (cricovocal ligament) is an elastic membrane that joins the upper surface of the cricoid cartilage, the vocal process of the arytenoid, and the lower thyroid cartilage. It serves as a barrier against inferior invasion of pre-epiglottic fat disease. The anterior commissure tendon extends from the anterior commissure and inserts into the thyroid cartilage.

Regions of the larynx

The larynx is divided into 3 anatomic regions: the supraglottic larynx, the glottis, and the subglottic region.

The supraglottic larynx consists of epiglottis, false vocal cords, ventricles, aryepiglottic folds, and arytenoids. The anatomic borders are as follows: superior, epiglottis; inferiorly, point at which the vocal cord epithelium turns upward to form the lateral wall of the ventricle; anterior, posterior edge of the vallecula superiorly and anterior false cord inferiorly; and posterior, the arytenoids.

The glottic larynx consists of the true vocal cords and anterior commissure. The anatomic borders are as follows: superior, point at which the vocal cord epithelium turns upward to form the lateral wall of the ventricle; inferior, 5 mm below the free margin of the vocal cords; anterior, the anterior commissure, which is usually located within 1 cm of the skin surface (an important consideration in planning for radiation therapy); and posterior, the posterior commissure.

The subglottic larynx consists of the region between the vocal cords and the trachea. The anatomic borders are as follows: superior, 5 mm below the free margin of the vocal cords, and inferior, the inferior aspect of the cricoid cartilage.

Pre-epiglottic fat space

The pre-epiglottic fat is located in the anterior and lateral aspects of the larynx and is often invaded by advanced cancers. The anatomic borders are as follows: superior, hyoid bone and hyoepiglottic ligament; inferior, conus elasticus; anterior, thyrohyoid membrane; posterior, anterior wall of the pyriform sinus; and lateral, thyroid cartilage wall. Invasion of the pre-epiglottic fat has significant surgical implications, so evaluation of this space should be part of any radiologic analysis.

Nerves

The recurrent laryngeal nerve innervates the intrinsic laryngeal muscles. Damage to this nerve causes hoarseness clinically and medialization of the arytenoid cartilage radiographically. Enlargement of the pyriform sinus is an important secondary sign of recurrent laryngeal nerve paralysis. The superior laryngeal nerve innervates the cricothyroid muscle, an extrinsic laryngeal muscle that tenses the true vocal cords. Damage to this nerve produces bowing of the vocal cord.

Lymphatics

The first-echelon lymphatics for the supraglottic larynx are the subdigastric nodes and the middle anterior cervical nodes (level 3), and the second-echelon lymphatics are the lower anterior cervical nodes (level 4).

The glottic larynx contains few lymphatics, and nodal spread occurs only with primary extension to the supraglottis or subglottis. For tumors with spread to the supraglottis, the subdigastric nodes are at risk. For tumors with spread to the anterior commissure and anterior subglottis, the middle and lower anterior cervical nodes, the Delphian node, and the lateral paratracheal nodes are at risk.

The first-echelon lymphatics for the subglottic larynx are the Delphian node, the lower anterior cervical nodes and paratracheal nodes, and the supraclavicular nodes, and the second-echelon lymphatics are the mediastinal nodes.

Glottic and subglottic tumors metastasize to ipsilateral lymph nodes, but supraglottic tumors often spread to nodes on both sides of the neck.

Levels of the neck

The anatomy of the cervical lymph nodes is relevant to the treatment of all laryngeal cancer. The American Joint Committee on Cancer (AJCC) and the American Academy of Otolaryngology–Head and Neck Surgery classification systems are widely used.

The neck is divided into 5 levels: level I includes the submental and submandibular triangles; level II, the superior jugular chain nodes extending from the skull base down to the carotid bifurcation and posteriorly to the posterior border of the sternocleidomastoid muscle; level III, the jugular nodes from the carotid bulb inferiorly to the omohyoid muscle; level IV, the jugular nodes from the omohyoid muscle to the clavicle; and level V, the posterior triangle bounded by the sternocleidomastoid anteriorly, the trapezius posteriorly, and the omohyoid inferiorly.

Radiologists use the hyoid bone as a marker for the carotid bifurcation, and the inferior cricoid cartilage as a marker for the omohyoid muscle, which may be difficult to discern radiographically. The Radiation Therapy Oncology Group , in collaboration with 2 European research groups, has established guidelines for delineation of nodal levels.

Clinical Details: Most laryngeal cancers arise in the glottic region and are symptomatic early as a result of hoarseness and changes in the voice.

Clinical presentation

For supraglottic tumors, common symptoms include mild odynophagia, mild dysphagia, and mass sensation. Uncommon symptoms include severe dysphagia and aspiration and referred ear pain. The mechanism of the referred ear pain is through the activation of the internal branch of the superior laryngeal branch of cranial nerve X with referral to the auricular nerve of Arnold. The pain is located in the posterior wall of the external auditory canal and posterior pinna.

For glottic and subglottic tumors, the most common presenting symptom is hoarseness of the voice. Uncommon symptoms include odynophagia, referred ear pain, thyroid cartilage pain, and airway obstruction.

Staging system

The AJCC has designated staging by using the tumors, nodes, and metastases (TNM) classification. Definitions for the stages are described below.

Primary tumor, T stage

TX indicates that the primary tumor cannot be assessed; T0 means no evidence of primary tumor; and Tis indicates carcinoma in situ.

In the supraglottis, the T stages are as follows: T1, tumor limited to 1 subsite of the supraglottis with normal vocal cord mobility; T2, tumor invasion of the mucosa of more than 1 adjacent subsite of the supraglottis or glottis or of a region outside the supraglottis (eg, mucosa of base of tongue, vallecula, medial wall of pyriform sinus), without fixation of the larynx; T3, tumor limited to the larynx with vocal cord fixation and/or invasion of any of the postcricoid area or pre-epiglottic tissues; T4, tumor invasion through the thyroid cartilage and/or extension into soft tissues of the neck, thyroid, and/or esophagus.

Subsites include the following: false cords, arytenoids, suprahyoid epiglottis, infrahyoid epiglottis, and aryepiglottic folds (laryngeal aspect).

In the glottis, the T stages are as follows: T1, tumor limited to the vocal cord (may involve anterior or posterior commissure) with normal mobility; T2, tumor extension to the supraglottis and/or subglottis and/or impaired vocal cord mobility; T3, tumor limited to the larynx with vocal cord fixation; and T4, tumor invasion through the thyroid cartilage and/or other tissues beyond the larynx (eg, trachea or soft tissues of the neck, including the thyroid and pharynx).

Stage T1 can be subdivided into T1a, in which the tumor limited to 1 vocal cord and T1b, in which the tumor involves both vocal cords.

In the subglottis, the T stages are as follows: T1, tumor limited to the subglottis; T2, tumor extension to a vocal cord with normal or impaired mobility; T3, tumor limited to the larynx with vocal cord fixation; T4, tumor invasion through cricoid or thyroid cartilage and/or extension to other tissues beyond the larynx (eg, trachea or soft tissues of neck, including the thyroid and esophagus).

Regional lymph nodes, N stage

The N stages are as follows NX, regional lymph nodes cannot be assessed; N0, no regional lymph node metastasis; N1, metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension; N2, metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension, metastases in multiple ipsilateral lymph nodes with none more than 6 cm in greatest dimension, or metastases in bilateral or contralateral lymph nodes none more than 6 cm in greatest dimension; and N3, metastasis in a lymph node more than 6 cm in greatest dimension.

Stage N2 may be further subdivided as follows: N2a, metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension; N2b, metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension; and N2c, metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension.

Distant metastasis, M stage

MX indicates that distant metastasis cannot be assessed; M0, no distant metastasis; and M1, distant metastasis.

Preferred Examination:

Diagnostic workup

The diagnostic workup of an individual with a suspected laryngeal carcinoma should include history taking, physical examination, laboratory tests, and radiologic examination.

History taking should include an inquiry into hoarseness, odynophagia, dysphagia, referred ear pain, thyroid cartilage pain, aspiration, and dyspnea.

Physical examination should include a complete head and neck examination with fiberoptic endoscopy for an assessment of vocal cord fixation and the extent of primary disease. Subglottic disease is usually not well visualized endoscopically. Fullness between hyoid bone and thyroid cartilage suggests involvement of the pre-epiglottic space. Ulceration of the infrahyoid epiglottis or fullness of the vallecula suggests involvement of the pre-epiglottic space. Disappearance of a laryngeal click suggests postcricoid involvement. Localized pain over 1 ala of the thyroid cartilage suggests thyroid cartilage invasion.

Laboratory tests should include determination of the complete blood count and alkaline phosphatase level, and liver function tests should be performed.

Radiologic examination should include cross-sectional imaging (CT or MRI) of the head and neck to delineate the extent of primary disease, the presence of bone or cartilage invasion, and the presence of nodal disease. Imaging is particularly useful for submucosal regions such as the pre-epiglottic space and subglottis. T1 tumors of the glottis may not require imaging, though CT is often used to exclude nodal metastases. Plain chest radiography or chest CT may be used to rule out pulmonary metastasis. Although some authors claim that MRI provides a more accurate depiction of tumor extent, most institutions continue to use CT as the primary cross-sectional modality. Advances in high-resolution multi-channel helical CT have kept CT competitive with MRI. MRI is more sensitive, but less specific, than CT for the diagnosis of cartilage invasion.

Further assessment of carcinomas

Approximately 95% of all laryngeal and hypopharyngeal malignant tumors are squamous cell cancers. Almost all squamous cell carcinomas are diagnosed by means of direct visualization because they arise from the mucosal surface of the larynx. Biopsy performed with direct laryngoscopy can help confirm the diagnosis, but the otolaryngologist is usually sure of the diagnosis by simply visualizing the abnormality, even before the biopsy is performed. In the case of small tumors, the clinician can not only diagnose the problem but also obtain enough information by means of direct visualization to obviate the need for imaging. In some cases, however, landmarks important to therapeutic planning are deep to the mucosa; in these cases, imaging can be helpful.

The information sought at imaging depends on the size and position of the primary tumor and the type of therapy planned. A small tumor without evidence of deep extension does not require imaging because all information needed for the therapeutic decision may be obvious at endoscopy. Treatment options include cord stripping, laser excision or radiation therapy. Alternatively, the lesion may be so large that a total laryngectomy is the only option considered; thus, imaging of the primary lesion is of limited usefulness.

For intermediate-sized lesions, imaging can provide useful information. Radiation therapy remains an option. If surgery is considered, a decision must be made as to whether a patient is a candidate for a voice-sparing partial laryngectomy or whether total laryngectomy is required.

Supraglottic carcinomas are associated with a high incidence of nodal metastases at diagnosis; therefore, complete evaluation of the internal jugular lymph nodes with imaging studies is needed. The reported incidence of clinically positive lymph nodes is 55% at initial diagnosis, with a 16% incidence of bilateral involvement.

Supraglottic carcinomas

Epiglottic carcinomas

The epiglottis is the most frequent location for cancers that arise in the supraglottic larynx. Tumors may arise from either the suprahyoid or infrahyoid epiglottis. Radiographically, these lesions are often exophytic and circumferential masses that, when detected early, are confined to the midline of the supraglottis. On MRI, these lesions are of intermediate signal intensity and homogeneously enhancing with the administration of contrast material.

Advanced lesions may extend superiorly to invade the vallecula and base of the tongue and also laterally to involve the aryepiglottic folds, false vocal cord, and paralaryngeal space. Direct inferior extension to involve the anterior commissure and subglottis is seen only in advanced lesions.

Tumors arising from the epiglottis may extend anteriorly to involve the pre-epiglottic space. This form of spread is facilitated by the presence of numerous foramina that provide access for tumoral invasion. Invasion of the pre-epiglottic space is often difficult to detect by means of clinical examination and, when present, alters the tumor stage (stage T3). Invasion of the pre-epiglottic space is readily seen on MRIs and best evaluated with nonenhanced T1 weighted /images, which show replacement of normal high-signal-intensity fat by intermediate-signal-intensity tumor.

Aryepiglottic fold carcinomas

Tumors of the aryepiglottic fold are typically exophytic lesions that, when detected early, are confined laterally along the aryepiglottic fold. Advanced lesions may extend laterally to involve the adjacent wall of the pyriform sinus or medially to invade the epiglottis. These malignancies may also grow superiorly to involve the pharyngoepiglottic folds, and they may eventually involve the suprahyoid portion of the epiglottis. Inferiorly, these lesions may involve the false vocal cords and ventricle.

Advanced lesions may extend to involve the cricoarytenoid joint, resulting in fixation of the true vocal cord. They may invade the laryngeal cartilages, and they may also extend into the base of the tongue and pharyngeal walls.

Radiographically, early lesions are identified as lobulated masses arising from the aryepiglottic fold. Early mucosal lesions may not be depicted on MRIs.

False vocal cord carcinomas

Squamous cell cancers that arise from the false vocal cords and laryngeal ventricle tend to be ulcerative and infiltrative with a limited exophytic component. Deep invasion by such tumors results in their access to the paraglottic space, and this may lead to fixation of the supraglottic larynx. Because of their close proximity, these tumors may extend inferiorly to involve the true vocal cords. Such submucosal spread is often occult on clinical examination, and understaging of the lesions is possible if this extension is undetected before surgery.

Tumors of the false vocal cords may extend laterally to involve the medial wall of the pyriform sinus and medially to the inferior portion of the epiglottis, thereby increasing the likelihood of invasion of the pre-epiglottic space. MRI is well suited for the imaging of false vocal cord carcinomas. Coronal imaging is beneficial for evaluating the superior and inferior extent of these lesions and for evaluating the presence of transglottic spread.

Glottic carcinomas

The true vocal cords are the most common site of laryngeal carcinomas; the ratio of glottic carcinomas to supraglottic carcinomas is approximately 3:1. The anterior portion of the true vocal cord is the most common location of squamous cell cancer, with most lesions occurring along the free margin of the vocal cord. Anteriorly, the tumor may extend to anterior commissure, where it may involve the contralateral true vocal cord.

Advanced lesions arising within the anterior aspect of the vocal cord or tumors arising along the posterior one third of the cord may extend posteriorly to involve the cricoarytenoid joint and interarytenoid region. Tumors may extend inferiorly, either mucosally or submucosally, to involve the subglottic region.

Early superficial mucosal lesions may not be detected with either CT or MRI. Larger lesions may result in thickening of the involved vocal cord.

The combination of coronal and axial /images may be used to determine the amount of subglottic extension and the presence of cartilage invasion. Because the mucosa is near the perichondrium of the thyroid cartilage anteriorly and the cricoid cartilage posteriorly, the presence of soft tissue thicker than 1 mm in both of these areas is considered abnormal.

Invasion of the cartilage may be detected with both CT and MRI, and is more common in glottic tumors than in subglottic carcinomas. MRI is more sensitive, but less specific, than CT in demonstrating cartilage involvement. The fatty marrow in the ossified cartilage has high signal intensity on T1-weighted /images. Tumor infiltration into the cartilage results in decreased signal intensity of the marrow. If the cartilage is nonossified, T2-weighted /images are more helpful because the tumor is usually hyperintense relative to the non-ossified cartilage. Unfortunately, edema may be mistaken for tumor invasion on T2-weighted /images.

The likelihood of nodal involvement associated with glottic carcinomas depends on the stage of the tumor. The incidence of early T1 lesions has been reported to be as low as 2%. This figure increases to approximately 20% for T3 and T4 lesions. The lymph nodes most at risk of metastases are those of the internal jugular chain. Paratracheal lymph nodes may be involved in glottic tumors that have significant subglottic spread.

Subglottic carcinomas

Subglottic carcinomas are rare and account for only 5% of all laryngeal carcinomas. The subglottic region is more commonly involved by the direct extension of a glottic or supraglottic carcinoma than by tumors elsewhere.

When present, these lesions are characteristically circumferential and often extend to involve the undersurface of the true vocal cords. They have a tendency for early invasion of the cricoid cartilage and extension through the cricothyroid membrane.

Primary subglottic carcinomas have a propensity to drain to the paratracheal lymph nodes. The reported incidence of clinically positive nodes in patients with subglottic carcinoma is 10%.

Hypopharyngeal carcinomas

Hypopharyngeal tumors can remain relatively asymptomatic for a long time. Extensive submucosal growth is common. At the time of diagnosis, as many as 75% of patients with hypopharyngeal tumors have metastases to cervical lymph nodes. Systemic metastases also develop in 20-40% of patients with hypopharyngeal tumors.

CT or MRI studies of hypopharyngeal cancer may demonstrate tumor that is more extensive than is apparent on clinical examination, usually because of submucosal spread of the cancer. Carcinoma of the hypopharynx is most common in the pyriform sinus (60%), followed by the postcricoid region (25%) and the post-pharyngeal wall (15%).

Tumors of the pyriform sinus

Superficial mucosal extension into the apex of the pyriform sinus is not well seen with cross-sectional imaging, and it is best evaluated by means of endoscopy. A pyriform sinus tumor 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. These tumors may erode the posterosuperior cricoid cartilage and invade the upper pole of the thyroid gland. Tumors arising from the lateral wall or apex of the pyriform sinus have often already invaded the thyroid cartilage at the time of diagnosis.

Lesions of the medial wall of the pyriform sinus may spread along the aryepiglottic fold into the false vocal cord and anterior cartilage. They also may grow posteriorly into the postcricoid region and then cross the midline to involve the contralateral pyriform sinus. Medial wall lesions also invade paraglottic and pre-epiglottic fat.

Tumors of the postcricoid region

Tumors confined to the postcricoid region are rare. The exception occurs in patients (mostly women) with Plummer-Vinson syndrome. Often, tumors of the posterior wall invade the posterior larynx (arytenoids and posterior cricoid cartilage), causing vocal cord paralysis and hoarseness. Large tumors concentrically infiltrate and narrow the lumen of the hypopharynx. These tumors may extend to the cervical esophagus. The junction of the postcricoid region with the esophageal verge should be evaluated for tumor involvement.

Degree of Confidence: MRI has several advantages over CT that may be helpful for presurgical planning. The multiplanar capabilities of MRI are superior to the reformations available with traditional CT, although multidetector-row CT shows early promise. Coronal imaging is helpful for determining involvement of the laryngeal ventricle and transglottic spread. Midsagittal /images are helpful for demonstrating the relationship between the tumor and the anterior commissure. MRI is also superior to CT for specific tissue characterization. However, the longer imaging time may contribute to image degradation by motion.

Focal sclerosis or low signal intensity on T1-weighted /images is suggestive of cartilage involvement. However, the only truly diagnostic finding is involvement of the strap muscles due to anterior extension of the tumor through the cartilage.

Interest in the use of dextran-coated ultrasmall supramagnetic iron oxide (USPIO) to detect metastatic nodal disease is growing. Patients are usually imaged 24-36 hours after the intravenous administration of USPIO. Compared with its noncontrast signal intensities, the signal intensity of a normally functioning lymph node after the administration of USPIO is markedly reduced on T1- and T2-weighted MRI as a result of both T2 relaxation and magnetic susceptibility effects due to the uptake of the iron particles by macrophages. A metastatic lymph node does not have a signal loss on contrast-enhanced /images because the macrophages of the node have been replaced.

The reported sensitivity and specificity in detecting nodal metastases are in the range of 87% to 90%, respectively. These results suggest that the use of USPIO contrast agents may become an important adjunct in evaluating metastatic nodal disease.