Laryngeal barriers to tumor spread are a product of laryngeal development, anatomic barriers, and enzymatic activity. Supraglottic and glottic/subglottic development is distinct and partially explains the metastatic behavior of laryngeal carcinoma. Dense connective tissues and elastic fibers provide anatomic barriers within the larynx. Laryngeal cartilage contains dense cartilage, enzyme inhibitors, and an intact perichondrium making it relatively resistant to tumor invasion; however, focal areas of vulnerability are created by ossified cartilage and natural interruptions in the perichondrium. Local inflammation and the enzymatic interplay between tumor and host are important factors in the spread of laryngeal tumor.
Key points
- •
Supraglottic development is distinct from glottic and subglottic development, which partially explains the metastatic behavior of laryngeal carcionoma.
- •
Dense connective tissues and elastic fibers provide anatomic barriers within the larynx.
- •
Ossified cartilage and interruptions in the perichondrium create vulnerable points to tumor spread.
- •
Tumor spread is not purely mechanical.
- •
Tumor stimulates the host to activate enzymes that break down the body’s natural barriers to invasion.
Laryngeal anatomy
Laryngeal Regions
The larynx is dived into 3 regions (supraglottis, glottis, and subglottis). The supraglottis is subdivided into 5 segments (suprahyoid epiglottis, infrahyoid epiglottis, laryngeal surface of the aryepiglottic folds, arytenoids, and false vocal cords). A horizontal plane through the lateral margin of the ventricle marks the inferior extent of the supraglottis. Below this plane marks the beginning of the glottis. The glottis is composed of the true vocal folds and the space between them, which is called the rima glottidis. The true vocal folds include the epithelium, superficial lamina propria, vocal ligament (intermediate and deep lamina propria), and the vocalis muscle. The glottis extends from the anterior commissure, the junction of the vocal folds and vocal ligaments with the thyroid cartilage, to the vocal process of the arytenoid cartilage. The glottis continues in the caudal direction for a distance of approximately 1 cm. The subglottis begins at the inferior border of the glottis and continues caudally to the inferior border of the cricoid cartilage.
Borders of the Larynx
The superior surfaces of the epiglottis and aryepiglottic folds correspond to the cranial boundary of the larynx. The lingual surfaces of the suprahyoid epiglottis and the hyoepiglottic ligament form the anterosuperior limit of the larynx and form the roof of the preepiglottic space. The anterior border of the larynx is bounded to the thyrohyoid membrane and thyroid cartilage at the level of the supraglottis, the thyroid cartilage at the level of the glottis, and the cricothyroid membrane and cricoid cartilage at the level of the subglottis. The inferior edge of the cricoid cartilage marks the inferior limit of the larynx. The laryngeal surfaces of the aryepiglottic folds and arytenoid cartilages mark the lateral and posterolateral borders of the larynx. The interarytenoid space and the posterior wall of the cricoid ring mark the posterior border of the larynx. The lateral surfaces of the aryepiglottic folds are not part of the larynx. They belong to the pyriform sinus, which is a subdivision of the hypopharynx.
Laryngeal Spaces
The laryngeal aperture is the superior laryngeal inlet and is bounded by the epiglottis anteriorly, the aryepiglottic folds laterally, and the interarytenoid space posteriorly. The larynx openly communicates with the pharynx at the superior and posterosuperior laryngeal aperture. Caudal to the laryngeal aperture is the laryngeal vestibule, which corresponds to the space between the laryngeal aperture and the vestibular folds (false vocal folds). The laryngeal vestibule is bounded anteriorly by the epiglottis and laterally by the aryepiglottic folds. The laryngeal ventricle, also referred to as Morgagni sinus, is the space between the vestibular folds (false vocal folds) superiorly and the true vocal folds inferiorly. At the anterior roof of the ventricle lies a pouchlike structure called the saccule, which functions to lubricate the ipsilateral vocal fold. The lateral most aspect of the ventricle is the embryologic fusion point of the buccopharyngeal and the tracheobronchial primordium, which marks the border between the supraglottis and glottis. The glottic opening is called the rima glottidis. The rima glottidis is divided into the intermembranous space between the true vocal folds and the intercartilaginous space between the vocal processes of the arytenoids. The rima glottidis is the narrowest part of the laryngeal cavity.
Potential Spaces
The preepiglottic space is a potential space immediately in front of the epiglottis and is bound by the hyoepiglottic ligament (superior), the thyrohyoid membrane and the lamina of the thyroid cartilage (anterior), and the thyroepiglottic ligament (inferior). This potential space is composed of adipose tissue and is devoid of lymph nodes. The anterior aspect of the laryngeal saccule extends from the laryngeal ventricle into the preepiglottic space. The preepiglottic space extends slightly beyond the lateral margins of the epiglottis often referred to as horseshoe shaped. Therefore, the term periepiglottic space is a slightly more accurate description of this region. The caudal part of the periepiglottic space is subdivided into 1 median region and 2 lateral regions. The median region is immediately anterior to the epiglottis. The 2 lateral subdivisions correspond to the adipose and glandular tissue of the vestibular folds (false vocal folds) and are separated from the potential space of the paraglottic space by the thyroarytenoid muscle and the fibrous extensions of its muscle sheet.
The paraglottic space is a potential space bound by the thyroid cartilage and cricothyroid membrane (lateral), the quadrangular membrane and the conus elasticus (medial), and the pyriform sinus (posterior). Posteroinferiorly the paraglottic space extends to the cricothyroid joint. The paraglottic space, which is made up primarily of adipose tissue, contains the internal branch of the superior laryngeal nerve.
Just under the epithelial cover of the glottis is another potential space referred to as the Reinke space. This potential space corresponds to superficial lamina propria and is made up of a soft gelatinlike substance composed primarily of a loose fibrous and elastic matrix.
Laryngeal Structures
Cartilage and membranes
The laryngeal framework is composed of hyaline and elastic cartilage. It has 3 unpaired cartilages (epiglottis, thyroid, and cricoid cartilage) and 3 paired cartilages (arytenoid, corniculate, and cuneiform cartilage). Only epiglottis is composed of elastic cartilage, and the remaining cartilaginous structures are made up of hyaline cartilage. The larynx also has 6 fibrous membranes (hyoepiglottic ligament, thyroepiglottic ligament, thyrohyoid membrane, quadrangular membrane, conus elasticus, and cricothyroid membrane). With the exception of the thyroepiglottic ligament, the laryngeal cartilages and fibrous membranes form strong natural barriers to the spread of tumor. The larynx is devoid of a true bony structure. Although the hyoid bone functions as a point of stability to the larynx, it is not a laryngeal structure.
Muscles
The muscles of the larynx are separated into intrinsic and extrinsic laryngeal muscles. The intrinsic laryngeal muscles are responsible for varying the glottic opening, protecting the airway, and producing voice. The extrinsic laryngeal muscles support the position of the larynx by elevating or depressing the larynx and are used primarily in swallowing.
The intrinsic laryngeal muscles include the lateral cricoarytenoid and interarytenoid muscles, which adduct the vocal folds, the cricothyroid and thyroarytenoid muscles, which add tension to the vocal folds, and the posterior cricoarytenoid, which abducts the vocal folds. The posterior cricoarytenoid muscle is traditionally represented as one muscle; however, Sanders and colleagues showed the posterior cricoarytenoid muscle is composed of 3 muscle components (vertical, oblique, and horizontal component). They speculated that the vertical and oblique components are responsible for vocal fold abduction and the horizontal component is responsible for arytenoid stabilization during phonation.
The muscles of the supraglottis are formed from extensions of the intrinsic laryngeal muscles. The oblique arytenoid muscles have their origin at the posterior aspect of the arytenoid muscular process and cross midline to insert at the apex of the contralateral arytenoid cartilage. Some of the fibers then continue as the aryepiglottic muscle. The aryepiglottic muscles function primarily in narrowing the laryngeal vestibule. Similarly, some muscle fibers from the thyroarytenoid muscle extend into the lateral aspect of the aryepiglottic fold and epiglottis. These fibers are referred to as the thyroepiglottic muscles and function to widen the laryngeal vestibule.
The extrinsic laryngeal muscles are divided into the suprahyoid muscles that elevate the larynx (digastric, stylohyoid, mylohyoid, geniohyoid, and hyoglossus muscles) and the infrahyoid muscles that depress the larynx (thyrohyoid, sternothyroid, omohyoid, and sternohyoid muscles).
Mucosa and submucosal layers
The epithelium of the supraglottis is composed of respiratory pseudostratified columnar epithelium and has an abundance of mucous glands and lymphatic vessels. The only exception is at the edges of the aryepiglottic folds and at the lateral borders of the epiglottis, which are composed of stratified squamous epithelium.
The vocal folds are often wrongfully referred to as cords. This term came from the French anatomist, Antoine Ferrein, who named them cordes vocales when he thought the glottis generated sound by vibrating like strings of a violin. We now know that sound is generated by a mucosal wave formed by the glottic epithelium suspended over a vocal ligament. The glottis is, therefore, more accurately referred to as vocal folds. The epithelium is composed of stratified squamous epithelium. Deep to the epithelium lays the lamina propria, which is devoid of lymphatic vessels and is divided into superficial, intermediate, and deep layers. The superficial lamina propria is made up of a soft gelatinlike substance that is composed primarily of a loose fibrous and elastic matrix. The intermediate and deep layers of the lamina propria make up the vocal ligament. The intermediate lamina propria adds elastic mechanical integrity to the vocal fold and is made up primarily of elastic fibers. The deep lamina propria is made up primarily of collagenous fibers and adds durability to the ligament. The vocal ligament forms the superior border of the conus elasticus, which interlocks with the vocalis muscle.
At the anterior roof of the ventricle lies a pouchlike structure called the saccule. The saccule is made of both mucous and serous glands. In children the saccule may contain laryngeal lymphoid tissue, but in adults the presence of a lymphoid tissue in the saccule is pathologic and may indicate the presence of carcinoma. The function of the saccule is mainly to lubricate the ipsilateral vocal fold during speech and deglutition. The saccule may also contribute to increasing voice resonance.
The subglottis is lined by respiratory pseudostratified columnar epithelium. The subglottis is the only area of the larynx that is rigid because of the formation of a complete cartilaginous ring of the cricoid cartilage.
Barriers and pathways to tumor spread
Embryologic Barriers
Understanding laryngeal embryology can help explain the behavior of tumor spread within the larynx. The development of the supraglottis and glottis is distinct with each carrying an independent blood supply and lymphatic channel. The differentiation between the supraglottis and glottis was first described by Hajek, in 1932, when he observed that laryngeal edema was localized within compartments. In 1956 Pressman and colleagues elaborated on this observation by injecting dye into the larynx and found the junction of the vocal and vestibular folds to mark the border between the supraglottis and the glottis. At the infraglottis the dye would flow from the vocal fold to the end of the cricoid and stop at the midline. These boundaries correspond to the embryologic fusion points and help explain the behavior of tumor spread within the larynx.
The supraglottis is derived from the buccopharyngeal primordium, and its lymphatics flow laterally into the deep cervical lymph nodes of level II and level III bilaterally before reaching inferiorly to the lateral lymph nodes of level IV. The supraglottis is rich in lymphatic channels, which explains the propensity for supraglottic cancers to present with nodal metastasis. In addition, the supraglottis is formed from a single midline structure; its lymphatic drainage is, therefore, bilateral. The buccopharyngeal primordium of the supraglottis is derived from the third and fourth brachial arches, and its blood supply comes from the superior laryngeal artery.
In contrast to the supraglottis, the glottis and subglottis are derived from 2 laterally based furrows of the tracheobronchial primordium that fuse at the midline with a median-based furrow. Its lymphatics, therefore, drain unilaterally. Additionally, the lymphatics to the glottis are sparse, which explains why glottic lesions rarely present with positive metastatic lymph nodes. The lymphatics of the glottis are focused centrally to the prelaryngeal and pretracheal nodes of level VI. The tracheobronchial primordium of the glottis and subglottis is derived from the sixth brachial arch, and its blood supply comes from the inferior laryngeal arteries.
These boundaries are distinct embryologic boundaries and are often respected by lymphatic metastases. Nevertheless, these embryologic boundaries alone are poor barriers to local tumor spread.
Anatomic Barriers and Facilitators to Tumor Spread
In addition to the developmental boundaries, the larynx has clear anatomic barriers to the spread of malignancy. Within the larynx, tumor spread is bounded by the ligaments, connective tissue membranes, and laryngeal cartilages and facilitated by soft tissue spaces and muscle.
Fibrous barriers to tumor spread
Tucker and Smith found elastic and dense connective tissues to be relatively resistant to tumor invasion. This finding explains why ligaments composed of ground substance, elastic fibers, and dense collagen are strong anatomic barriers to laryngeal tumors. Particularly effective barriers include the submucosal elastic layer, conus elasticus, quadrangular membrane, ventricular connective tissue, hyoepiglottic ligament, and glossoepiglottic ligament. Similarly, the vocal ligament tendon, also known as Broyles ligament, is a strong barrier to tumor invasion. However, as is discussed later in this article, the perichondrium at the anterior commissure is naturally interrupted by the muscular attachments to the thyroid cartilage at the vocal ligament tendon creating a focal area of vulnerability to tumor spread.
Beitler and colleagues described barriers to ventricular invasion from tumors of the paraglottic space. The barrier is formed by 2 subepithelial periventricular membranes referred to as the central periventricular membrane and the peripheral periventricular membrane. The central periventricular membrane is composed of elastic fibers. As is mentioned later, elastic fibers are naturally stable and serve as a relatively good barrier to invasion. The peripheral periventricular membrane, which is contiguous with the conus elasticus and quadrangular membranes, is composed of fibroelastic fibers. The quadrangular membrane is made up of closely woven undulating collagen and elastic fibers. Along with the conus elasticus, the quadrangular membrane provides a strong oncologic separation between the supraglottic and glottic and protects the glottis from carcinoma that is approaching from the vestibule. By contrast, the thyroepiglottic ligament is a relatively poor barrier to tumor spread with carcinoma of the vestibule often eroding upward through the thyroepiglottic ligament. The relative weakness of the thyroepiglottic ligament has to do with it microscopic composition. The thyroepiglottic ligament is made up of sagittally oriented collagen fiber bundles separated by adipose tissue, and tumor spread is facilitated in between these collagen fiber bundles. When compared with the dense interlaced fibrous mass of the hyoepiglottic ligament, the thyroepiglottic ligament seems weak.
The elastic fibers found in arteries make them a relatively resistant structure to tumor invasion. Malignant invasion is partially a result of the tumor’s ability to stimulate host-activated collagenase. However, tumor rarely elicits elastase activation. In addition, elastic fibers have a slow turnover rate making them less susceptible to exposures of damage and repair.
The laryngeal epithelium is also relatively resistant to tumor invasion, with laryngeal tumor often demonstrating subepithelial expansion before infiltration.
In addition, the dense fibrous layer encasing the surrounding viscera, like the thyroid gland, provides an additional barrier to tumor infiltration.
Cartilaginous barriers to tumor spread
Laryngeal cartilages are relatively resistant to tumor invasion often demonstrating extensive tumor spread along and around the laryngeal cartilage surfaces before invasion ( Fig. 1 ).
