Malignant Tumors of the Larynx

Embryology

The embryologic development of the larynx influences the pattern of metastatic spread of laryngeal cancer. The supraglottic larynx is derived from the buccopharyngeal primordium, which develops from the third and fourth branchial arches. The glottis and subglottis are derived from the tracheobronchial primordium from the sixth branchial arch and are formed by the union of lateral furrows that develop on each side of the tracheobronchial primordium. Analogous to the embryology, the larynx has a dual blood supply and lymphatic drainage. The supraglottis is supplied by the superior laryngeal arteries from the superior thyroid artery, and its lymphatic drainage follows these vessels to the carotid sheath to drain into deep cervical chain nodes in Levels II and III. The glottis and subglottis are supplied by the inferior laryngeal arteries emanating from the inferior thyroid artery, and similarly, lymphatic drainage from these two regions follows these arteries to drain into prelaryngeal and pretracheal nodes (Level VI) before it reaches the deep cervical chain nodes in Level IV.

The glottis is formed by paired structures that fuse in the midline. The lymphatics drain unilaterally and the vocal folds have sparse lymphatics; therefore glottic cancers must invade deeply before they gain access to lymphatic channels. These factors explain the lower incidence of lymphatic metastasis in glottic SCC and the propensity for unilateral metastases. Because the supraglottis is formed without a midline union, its lymphatics drain bilaterally. The increased likelihood of bilateral lymphatic metastases from supraglottic carcinoma is ascribed to this embryologic factor. Pressman and colleagues noted that the inferior extent of supraglottic injection was the inferior false vocal cord; the ventricle defines an anatomic barrier that halts further inferior flow of the dye.

Anatomy

A complete description of the anatomy of the larynx is beyond the scope of this chapter, so the following discussion is limited to a description of the boundaries of the larynx, its compartments, and its lymphatic drainage. The laryngeal framework is formed by three unpaired cartilages—the epiglottis, thyroid, and cricoid—and the paired arytenoid cartilages. The superior boundary of the larynx consists of the tip and lateral margin of the epiglottis and the superior edge of the aryepiglottic folds. The anterosuperior limit is formed by the lingual surface of the suprahyoid epiglottis and the hyoepiglottic ligament, which forms the superior boundary of the preepiglottic space. The anterior boundary of the larynx is formed by the thyrohyoid membrane and thyroid cartilage in the supraglottis, thyroid cartilage in the glottis, and cricothyroid membrane and anterior arch of the cricoid cartilage in the subglottis. The inferior limit of the larynx is defined by the horizontal plane, which passes through the inferior edge of the cricoid cartilage. The posterior and lateral borders of the larynx are composed of the laryngeal surface of the aryepiglottic folds, arytenoid cartilages, interarytenoid space, and the posterior surface of the subglottic space, defined as the mucosa that covers the surface of the cricoid cartilage.

The larynx is divided into three regions: the supraglottis, the glottis, and the subglottis ( Fig. 105.1 ). This division reflects the embryologic structure of the larynx and the anatomic barriers to spread of laryngeal cancer outlined earlier. The tumor/node/metastasis (TNM) staging system further subdivides the supraglottis and glottis of the larynx into multiple subsites, which are used to define the T stage ( Box 105.1 ). The supraglottis is composed of the suprahyoid and infrahyoid epiglottis, both the lingual and the laryngeal surfaces; laryngeal surfaces of the aryepiglottic folds; the arytenoids; and the false vocal cords. The boundary between the suprahyoid and infrahyoid epiglottis is a horizontal plane that passes through the hyoid bone. This separation is important because the infrahyoid epiglottis communicates anteriorly with the preepiglottic space (PES), whereas the suprahyoid epiglottis does not. The inferior limit of the supraglottis is a horizontal plane through the lateral margin of the ventricle at its junction with the superior surface of the true vocal cord. The glottis is composed of the true vocal cords, both the superior and inferior surfaces, and includes the anterior and posterior commissures. The inferior boundary of the glottis is a horizontal plane 1 cm inferior to the inferior limit of the supraglottis, defined as the lateral margin of the ventricle at its junction with the superior surface of the vocal cord. The subglottis extends from the inferior limit of the glottis to the inferior edge of the cricoid cartilage; it is not divided further into any subsites.

The mucosal lining of the larynx differs in the three regions. The epithelium of the supraglottis is predominantly of the pseudostratified columnar type, except at the edges of the aryepiglottic folds and the lateral borders of the epiglottis, which are stratified squamous epithelium. The supraglottic mucosa has an abundance of mucous glands and lymphatic vessels. The true vocal cords have a unique structure: stratified squamous epithelium covers a three-layered lamina propria composed of superficial, intermediate, and deep layers. The intermediate and deep layers of the lamina propria make up the vocal ligament, which forms the superior border of the conus elasticus and interdigitates with the vocalis muscle. The glottis has few lymphatic vessels. The subglottis is lined by pseudostratified columnar epithelium, which is in close approximation to the cricoid cartilage and cricothyroid membrane.

The laryngeal cartilages, hyoepiglottic ligament, thyrohyoid membrane, quadrangular membrane, conus elasticus, anterior commissure, and cricothyroid membrane form natural barriers to the spread of tumor. Within the larynx, the PES and the paraglottic space (PGS) provide pathways for spread of laryngeal tumors ( Fig. 105.2 ). The boundaries of the PES are anteriorly, the thyroid cartilage and thyrohyoid membrane; superiorly, the hyoid bone, hyoepiglottic ligament, and valleculae; and posteriorly, the anterior surface of the epiglottic cartilage and the thyroepiglottic ligament; laterally, the PES is open and continuous with each of the two paraglottic spaces. The PES contains fat and areolar tissue and is frequently invaded by tumors, because the cartilage of the epiglottis has multiple small fenestrations through which cancers that arise from the infrahyoid epiglottis may pass. Superiorly, the hyoepiglottic ligament provides a barrier to spread of tumor to the tongue base ( Fig. 105.3 ). The lymphatics of the PES drain through the thyrohyoid membrane and spread to lymph nodes on both sides of the neck, primarily in Levels II and III ( Fig. 105.4 ). Supraglottic tumors with PES involvement are staged as T3 lesions.

The PGS lies lateral to the true and false vocal folds and extends laterally to the thyroid cartilage ( Fig. 105.5 ). The boundaries of each PGS are medially (from superior to inferior), the quadrangular membrane, laryngeal ventricle, and conus elasticus; laterally, the thyroid cartilage anteriorly and the mucosa of the medial wall of the piriform sinus posteriorly; and inferolaterally, the cricothyroid membrane. Anteriorly, each PGS is continuous with the PES, and tumors may spread along this pathway (see Fig. 105.2 ). PGS involvement in either a glottic or supraglottic tumor is staged as T3 and is significant, because the extent of the PGS means that tumors in this space may spread to involve any or all of the three regions of the larynx ( Fig. 105.6 ).

Conservation laryngeal surgery is undertaken on the basis of the theory of compartmentalization of the larynx, which evolved from the work of Frazer, Pressman and colleagues, and Tucker and Smith. Pressman and colleagues found that this separate embryologic derivation explained why supraglottic tumors of substantial bulk do not spread across the laryngeal ventricle to the vocal cord. In experiments using submucosal vital dyes and radioisotopes, they also noted that the inferior extent of supraglottic injection was the inferior false vocal cord; the ventricle was an anatomic barrier to the inferior flow of the dye and thus was confirmed as a barrier to tumor spread. Using animals, cadavers, and whole-organ serial sections of human tumor specimens, Tucker and Smith confirmed that elastic tissue barriers within the larynx explain the findings of the dye studies. Although these studies confirm compartmentalization of the larynx, and clinically, supraglottic tumors are uncommonly observed to invade the glottis (and vice versa), no true anatomic barrier separates the supraglottis from the glottis.

Treatment of Precursor Lesions

The treatment of a precursor lesion should aim to eradicate the lesion while preserving voice quality and laryngeal function. Accurate diagnosis is critical for proper decision making, and a number of factors related to the characteristics of the lesion, as well as patient factors, affect the treatment decision-making process ( Table 105.3 ).

Patients with concerning vocal fold lesions should undergo microdirect laryngoscopy with directed biopsies. Critical to this is the use of high-power magnification, fine microsurgical instruments, and meticulous surgical techniques to remove the entire lesion and preserve the underlying lamina propria. Treatment options include microflap and full-thickness excision, ablation with carbon dioxide laser and excision with photoangiolytic lasers such as the 585-nm pulsed dye laser (PDL) and the 532 nm pulsed potassium-titanyl-phosphate (KTP) laser. Historically, vocal fold stripping was performed, in which the mucosa and underlying lamina propria were removed. This, however, causes vocal fold scarring and poor voice outcomes; hence this technique is no longer advocated and has been abandoned. After treatment, patients should be followed closely in the office to monitor for recurrence. Lesions that recur should be treated again, with the understanding that some patients may have lesions that recur more than once.

Lesions that are high-grade dysplasia and CIS have an increased risk of progressing to malignancy. Close follow-up is required because of the risk of recurrence of the lesion and possible malignant transformation. CIS may be treated with surgery or by RT. The recurrence rate for CIS treated with surgery is greater than that for neoplasms treated with RT and is reported to be approximately 20% after initial excision. With repeated surgical excision, the ultimate local control rate is excellent and is at least equivalent to that of RT. Surgical treatment is preferred for focal lesions in patients who are reliable and will attend routine follow-up.

RT is also an effective treatment for CIS; a recent review of 16 studies of CIS treated with RT determined that the local control rate was 93.5%. RT is particularly useful for multiple recurrences following surgical excision; for diffuse lesions that extend beyond the vocal cords that cannot be excised without inducing significant morbidity; for patients who are unlikely or unable to attend follow-up; and for medically infirm patients unfit for general anesthesia. Voice quality is well preserved following RT. The primary disadvantage of RT is that it cannot be repeated if there is a recurrence or second tumor in the irradiated field. Long-term side effects of RT should be considered as well. Successful management of premalignant laryngeal lesions also requires the implementation of tobacco and alcohol cessation strategies and treatment of laryngopharyngeal reflux when present.

In-Office Treatment of Premalignant Lesions

Over the past two decades, in-office management of precursor lesions has become more common. Initially this was performed with the 585-nm PDL, but more recently, the 532-nm pulsed KTP laser has been used more commonly. In a pilot study, Franco and colleagues used PDL for the treatment of dysplasia in the operating room under general anesthesia. In most cases, the treated lesions were then excised and sent for histologic examination. This treatment was effective: 81% of patients had greater than 70% regression of their lesions. The authors also noted that regression occurred in treated lesions that were not excised. A subsequent report from the same group demonstrated the efficacy of PDL delivered via a flexible endoscope in the office for the treatment of dysplasia. Koufman and colleagues found that 64% (16/25) of their patients with dysplasia required no further treatment during the follow-up period of their study. Franco has also described favorable experience with the use of PDL for dysplasia. Zeitels and colleagues subsequently adopted the pulsed KTP laser for in-office use, citing smaller fiber diameter, greater reliability, improved intralesional energy absorption, and improved hemostasis as advantages of the pulsed KTP system over PDL.

The energy from these lasers is preferentially absorbed by oxyhemoglobin; the absorption of energy from the pulsed KTP is superior to that of PDL and causes photoangiolysis of the sublesional blood vessels. Preferential destruction of intraepithelial desmosome junctions and separation of the treated epithelial cells from the basement membrane have also been observed microscopically. Apart from the obvious advantages of in-office procedures—avoidance of general anesthesia, lower cost, improved efficiency, and patient preference—these lasers have minimal effect on the surrounding tissue, and scarring is uncommon. The bilateral simultaneous treatment of lesions in and around the anterior commissure is possible, with minimal risk of web formation.

While performing in-office biopsy at the time of laser surgery is possible, specimens are often small and difficult to analyze and, as such, biopsy is rarely performed. This being the case, a concern of office-based surgery is that no specimen is obtained for pathologic examination, and therefore a definitive assessment of the tumor extent and margin status is not possible. In the reports published to date, a biopsy was obtained in all patients before the commencement of treatment. It bears repeating that all patients should first be taken to the operating room for microdirect laryngoscopy, and subsequent recurrences can be treated in the office if desired. Potential limitations of in-office treatment include poor exposure of the lesion, difficulty treating medial edge of infraglottic lesions, and decreased freedom in fiber positioning compared to suspension laryngoscopy. Serial, outpatient office-based laser treatment has been shown to be effective in management of these lesions in study with long follow-up. Treatment in the operating room should always be reserved for patients with concern of progression of disease.

Risk Factors

Second Primary Tumors

The single greatest risk factor for head and neck SCC is prior head and neck SCC. The annual risk of a second primary tumor (SPT) following an index head and neck SCC is 1% to 7%, and this risk persists for at least 10 years. The cumulative risk of developing an SPT is at least 20% and is greater for those who continue to use tobacco and alcohol. An individual with stage I or II head and neck SCC is more likely to die of an SPT than from the index tumor. The majority of SPTs develop in the head and neck, but a significant proportion occur in the esophagus or lung. Second primary tumors may be synchronous, identified within 6 months of the index tumor, or metachronous, diagnosed more than 6 months after the index tumor. In a study of 875 patients with SCC of the head and neck, SPTs had developed in 207 patients within 5 years of the index tumor. Of these patients, 31% developed a third primary malignancy, and 10% had a fourth primary malignancy. For laryngeal cancer, the lung is a significant site for synchronous and metachronous SPTs. An isolated lung malignancy in a patient with larynx cancer is more likely to be an SPT than a metastasis from the laryngeal cancer; therefore an isolated pulmonary nodule should be considered an SPT until proven otherwise. Prior RT is associated with SPTs in a small number of cases. Slaughter and associates examined clinically normal tissue adjacent to head and neck cancers and identified many histologic changes seen in the malignant cells in the adjacent normal-appearing tissue, which led to the proposal of the concept of “field cancerization.” Improved understanding of head and neck carcinogenesis has provided a molecular explanation for these observations. Bedi and colleagues examined X-chromosome inactivation and performed microsatellite analysis to evaluate allelic loss at chromosomes 3p and 9p in females with multiple primary head and neck cancers. Both the original cancer and the second malignancy arose from a single clone. Califano and coworkers similarly observed that tissues adjacent to malignant and premalignant lesions shared common genetic changes. Multiple tumors generally do not arise from multiple transforming events; rather, a single transforming event produces a cell with a growth advantage that spreads throughout the mucosal surface. The tumor may accumulate further genetic damage and ultimately result in additional malignancies that are geographically distinct but genetically related to the original cancer.

Cervical Nodal Metastases

The incidence of cervical metastases from SCC of the larynx, as well as the nodal groups involved, varies according to the site of the primary tumor ( Fig. 105.8 ). Because of its rich network of lymphatics, supraglottic SCC has the highest incidence of regional metastases, both clinically apparent and occult metastases. Cervical metastasis has been confirmed pathologically in 10% of T1, 29% of T2, 38% of T3, and 57% of T4 supraglottic lesions. The incidence of occult metastases (cN0, pN+) in supraglottic SCC varies from 12% to 40% for all T stages. The incidence of occult metastases is greater in tumors with a higher T stage; the rate for T1 staging is 0% to 14%; for T2, the rate is 20% to 21%; for T3, it is 28% to 35%; and for T4 lesions, it is 40% to 75%. Supraglottic SCC usually metastasizes to Levels II, III, and IV. Levels I and V are involved by metastases rarely and only when other nodal levels are also involved. Bilateral metastases, both palpable and occult, occur frequently in supraglottic SCC and are more common in midline or bilateral tumors. Therefore in cases of supraglottic SCC, surgical treatment of the N0 and N1 neck is usually with a bilateral selective neck dissection (Levels II through IV). For N2 or N3 disease, a comprehensive neck dissection (Levels I through V) is indicated.

Glottic SCC has a low risk of cervical metastasis. In a series of 910 patients, the overall incidence of pathologically confirmed nodal metastasis was 5.9%, with an incidence of occult metastasis of 18%. Similar to supraglottic SCC, the incidence of regional metastasis correlates with T stage. In the same series, nodal metastases were found in 0.1% of T1 (one patient only), 5% of T2, 18% of T3, and 32% of T4 tumors. The nodes at risk of metastasis from glottic SCC are those in Levels II, III, IV, and VI—the prelaryngeal, pretracheal, and paratracheal nodes. Bilateral or contralateral metastases are rare.

Primary subglottic carcinoma is rare, and descriptions of the clinical behavior of these tumors are based on a small number of patients. The paratracheal nodes (Level VI) are most frequently involved with metastases, including contralateral or bilateral metastases. Metastases to Levels III, IV, and V are uncommon. Although these tumors are aggressive and have a poor prognosis, the incidence of cervical metastasis is generally reported to be low, with a range of 4% to 27%. However, Harrison detected metastatic tumor in approximately 50% of serially sectioned paratracheal nodes. Metastases to mediastinal lymph nodes are common (up to 46%), but they are classified as distant metastases.

Distant Metastases

Distant metastases from laryngeal SCC include not only hematogenous metastases to distant organs but also lymphatic metastases to nodal groups outside the neck. The most common site for distant hematogenous metastasis is the lung. The liver and skeletal system (ribs, vertebrae, and skull) are affected less often. The mediastinum is the most common site for distant lymphatic metastases, which are uncommon at initial presentation. Patients who develop distant metastases have almost always had regional metastases diagnosed at some stage in the course of their disease. The incidence of distant metastasis varies according to the site of the primary tumor: the rate is 3.1% to 8.8% in glottic SCC and 3.7% to 15% in supraglottic SCC. Supraglottic SCC usually has a higher incidence of distant metastases compared with glottic SCC. The frequency of distant metastases from subglottic SCC is less certain, because primary tumors in this site are rare; however, Spector and colleagues observed that 14.3% of subglottic SCCs developed distant metastases. Clinical and pathologic factors associated with an increased risk of distant metastases include an advanced-stage primary tumor, especially stage T4; the presence of cervical metastases, especially N2 and N3 disease; the duration, level, and extracapsular spread of cervical metastases; and locoregional recurrence. Lymphatic metastasis to the skin is also a sign of advanced disease and, similar to distant metastases, portends a grave prognosis.