Histology for Pathologists

Editors: Mills, Stacey E.

Title: Histology for Pathologists, 3rd Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > V - Head and Neck > 16 - Larynx and Pharynx

16

Larynx and Pharynx

Stacey E. Mills

Larynx

Definition and Boundaries

The larynx is a complex organ with numerous connective tissue elements and a variety of epithelia. The superior border of the larynx is the tip of the epiglottis and the aryepiglottic folds. The inferior limit is the inferior rim of the cricoid cartilage. The anterior boundary is composed of the lingual surface of the epiglottis, the thyroid cartilage, the anterior arch of the cricoid cartilage, the thyrohyoid membrane, and the cricothyroid membrane. The posterior boundary is the cricoid cartilage and the arytenoid region. The piriform fossa is frequently, and erroneously, considered to be a part of the larynx. In reality, it is a pouch of the hypopharynx that passes on each side of the larynx. It is, thus, a conduit for food and water, not air.

Although not part of the larynx per se, the pre-epiglottic space is an important area for the spread of carcinoma. This more or less triangular space is filled with fat and loose connective tissue. It is bounded posteriorly by the epiglottis, anteriorly by the thyroid cartilage and thyrohyoid membrane, and superiorly by the hyoepiglottic ligament.

Embryology

The supraglottic portion of the larynx is derived from the third and fourth branchial arches and is, therefore, related to the development of the oral cavity and oropharynx. The glottis and subglottis arise from the sixth branchial arch, which also give rise to the trachea and lungs. Bocca et al. (1) have demonstrated that the larynx virtually consists of two hemilarynges (superior and inferior), each of them with its own different derivation and its own largely independent lymphatic circulation. These authors also discuss the importance of this embryologic derivation with respect to the origin and spread of laryngeal carcinoma. Each of these hemilarynges may become invaded by cancer independent of one another. The extension of cancer is often limited within the boundaries of this embryologic demarcation (1).

The first embryologic appearance of the respiratory apparatus occurs at approximately 21 days in the 3-mm embryo. At this time, an evagination, or groove, forms adjacent to the superior portion of the foregut, above the fourth branchial arch. The inferior portion of this evagination is the pulmonary anlage. The first portion of the larynx to develop is the epiglottis, but this does not appear as a definitively formed structure until approximately the fifth week of intrauterine development.

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The outline of the larynx is recognizable in the 6-mm embryo. At this time, the respiratory groove described previously begins to close; this closure is completed with the formation of the arytenoid cartilages. By 60 to 70 days, at the stage of the 30-mm embryo, the vocal cords begin to differentiate. The embryonic development of the larynx is complex, and it is not surprising that at least 30 different congenital malformations have been described (2).

Gross and Functional Anatomy

The larynx is composed of an elastic cone, cartilages, intrinsic and extrinsic muscles, submucosa, and an overlying mucous membrane (Figures 16.1,16.2,16.3). The elastic cone provides most of the structural strength to support the true vocal cords. The elastic tissue is thickened just under the mucosa of the free edge of the cord. This portion of the elastic cone is referred to as the vocal ligament. It is visible grossly as a white band beneath the mucous membrane (Figure 16.3). The vocal ligament inserts on the thyroid cartilage anteriorly and the vocal process of the arytenoid cartilage posteriorly (Figure 16.4).

The major cartilages of the larynx are the cricoid, thyroid, and the paired arytenoid cartilages (Figure 16.5). These major structural cartilages are all of hyalin type. The epiglottis, in contrast, is composed of elastic cartilage containing numerous fenestrations. Calcification of the thyroid and cricoid cartilages begins during the second decade of life in males and somewhat later in females. In older individuals, the thyroid cartilage is frequently ossified, replete with fibrofatty and hematopoietic bone marrow elements. The ossification of the thyroid cartilage is important in regard to the spread of laryngeal carcinoma. This cartilage is involved by continuous or metastatic carcinoma only when ossified. Hyalin cartilage, perhaps because of its elaboration of angiogenesis inhibiting factors, is remarkably resistant to the spread of neoplasia.

The cricoid and thyroid cartilages articulate with one another, but their motion is limited by several dense ligaments that anchor the cartilages together. The arytenoid cartilages articulate with the cricoid cartilage. Both the cricothyroid and cricoarytenoid joints are diarthrodial and lined by flattened synovial cells. These tiny joints are susceptible to conditions that more commonly affect larger synovial-lined spaces, such as gout and rheumatoid arthritis.

Each arytenoid cartilage attaches to the thyroarytenoid muscle and has a protrusion, the vocal process, that is the posterior point of insertion of the vocal ligament. The position of the arytenoid cartilage determines the tension of the vocal ligament. During adduction of the cords, the arytenoid cartilages move medially along the facets of the cricoid cartilage; they also pivot or rock (Figure 16.4). The rocking motion causes the vocal processes to move downward and toward the midline to complete the adduction of the vocal cords.

The muscles of the larynx can be divided into two groups. The extrinsic muscles originate from neighboring structures outside the larynx and insert on the thyroid, cricoid, or hyoid cartilages. These muscles include the omohyoid, sternohyoid, sternothyroid, and thyrohyoid muscles; they act as a whole upon the larynx during swallowing.

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The principle intrinsic muscles of the larynx are the cricothyroid, posterior cricoarytenoid, lateral cricoarytenoid, and thyroarytenoid. There are also small strands of muscle that are in continuity with the thyroarytenoid muscle and insert along the length of the vocal ligaments. This is frequently referred to as the vocalis muscle. It should be remembered that the vocalis muscle is actually a component of the thyroarytenoid muscle, and some authors use these names interchangeably.

The lateral cricoarytenoid muscle adducts the vocal cord, and the posterior cricoarytenoid muscle abducts the cord. During phonation, the thyroarytenoid muscle slightly moves the thyroid cartilage. The degree of contraction of the thyroarytenoid muscle determines the length and tension of the vocal cord.

The larynx can be divided into three major compartments (supraglottic, glottic, subglottic) for purposes of discussing its submucosal and mucosal components. The supraglottic larynx extends from the tip of the epiglottis to the true cord (3). This portion of the larynx also includes the aryepiglottic (arytenoepiglottic) folds, false vocal cords, and ventricles. The arytenoepiglottic folds run posteriorly from the base of the epiglottis to the region of the arytenoid cartilages. The false vocal cords are soft, rounded protrusions of the mucous membrane that lie superior to the true cords. The ventricles form the lower boundary of the false cords and separate them from the inferiorly located true cords. The ventricles extend upward behind the false cords as elliptical pouches. The greatest extension of the ventricles is slightly forward, where they end as dilated, blind pouches called the saccules. Involvement of the ventricle is a frequent route of superior spread by glottic carcinoma, and this spread may be difficult to detect clinically.

The glottic compartment consists of the true vocal cords and the narrow band of mucous membrane called the anterior commissure, which bridges the vocal cords anteriorly (4,5). The subglottic compartment is the area between the lower border of the true vocal cords, where the squamous epithelium normally ends, and the first tracheal cartilage (6).

Microscopic Anatomy

Studies of larynges from newborns have shown that, except for the true vocal cords, the larynx initially is lined by ciliated epithelium (7) (Figures 16.6,16.7). Squamous epithelium begins to appear on the false vocal cords by about 6 months of age but does not necessarily completely replace the ciliated respiratory mucosa (8,9). The lingual, or anterior, surface of the epiglottis is invariably covered by stratified squamous epithelium. The posterior, or laryngeal, surface of the epiglottis is covered by stratified squamous epithelium in its upper portion, but this merges with

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The normal ciliated epithelium of the larynx has an innermost layer of small, round cells the basal, or reserve, cell layer. This single cell layer of basal cells is overlaid by a second row of ciliated columnar cells. Variation in the position of the nuclei within the columnar cell layer imparts a pseudostratified appearance to the epithelium. The ciliated layer may vary considerably in thickness (Figure 16.8). Mucus-secreting cells may be numerous or rare. When there is abundant mucin, the cells assume a goblet configuration and may be located either within the middle portion of the epithelium or near the surface (Figure 16.9). Other mucus-secreting cells are barely recognizable and have only a few faintly discernible vacuoles within otherwise eosinophilic columnar cells.

The squamous epithelium of the larynx has a basal layer of small cells with scant cytoplasm and ovoid nuclei that are typically oriented perpendicular to the surface. Mitotic figures are normally confined to this layer. Dendritic melanocytes may be present in the basal layer, especially in African Americans (11,12). The frequency with which this

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As the squamous cells in laryngeal mucosa mature and migrate toward the lumen, the nuclei enlarge, assume a more spherical shape, and have more vesicular chromatin. The eosinophilic cytoplasm becomes abundant, and slight cell shrinkage during fixation produces numerous, thin strands of cytoplasm from adjacent cells that remain attached by desmosomes. Because of these thin cytoplasmic strands between cells, the term prickle cell layer (malpighian layer) has been applied to this zone. This is the broadest component of the squamous epithelium. The superficial layer is composed of one to three flattened cells with small, condensed nuclei. The squamous epithelium of the larynx can vary from about 5 cells in total thickness to over 25 cells (Figure 16.10). Normally, the larynx lacks a layer of parakeratotic surface cells. Continued exposure to irritants, such as cigarette smoke, may lead to foci of parakeratosis that may also be associated with orthokeratin formation.

The lamina propria of the true vocal cord is loose or dense connective tissue that lies between the vocal ligament and the squamous epithelium (Reinke's space) (Figure 16.11). Reinke's space contains a few capillaries but lacks lymphatics and only rarely has sparse seromucinous glands. As a result of this limited vascular access, carcinomas confined to the true vocal cords tend to remain localized and are amenable to curative radiation or surgical therapy. The poor lymphatic drainage of Reinke's space also probably contributes to the development of vocal cord nodules and polyps when abnormal amounts of edemalike fluid collect in this region. Likewise, vocal abuse or upper respiratory tract infections frequently produce edema in this region and manifest clinically as hoarseness or dysphonia. The anterior commissure, unlike the true cords, contains more abundant capillaries, lymphatics, and seromucinous glands.

The junction between the ciliated columnar epithelium, inferior and superior to the squamous epithelium of the true vocal cords, may be abrupt, but usually there is a transitional zone that varies from several cells to a width of 1 to 2 mm. The transitional zone consists of columnar cells that are gradually replaced by small, basaloid or immature squamous cells (Figure 16.12). In effect, this is a zone of immature squamous metaplasia in which the cells become progressively larger until they reach the size of the fully mature squamous epithelium that lines the true vocal cord.

The transitional zone often has a microscopically disorganized appearance when compared to the adjacent squamous and ciliated epithelium (Figure 16.12). Furthermore, the epithelium in this zone may be thickened and consist predominantly of basaloid cells. The latter

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Human papillomavirus (HPV) subtypes have been implicated in the pathogenesis of a variety of squamous proliferations in the larynx and elsewhere in the head and neck. Using sensitive polymerase chain reaction (PCR) techniques, studies are beginning to document some HPV subtypes, such as type 11 in approximately 25% of light microscopically normal laryngeal specimens (13). Thus, the finding of this HPV subtype adjacent to a laryngeal carcinoma cannot be assumed to represent a causative assocation. HPV subtypes more commonly associated with malignancy (HPV-16, HPV-18) have not yet been demonstrated in light-microscopically normal laryngeal mucosa.

Seromucinous glands are present throughout most of the larynx and communicate with the surface epithelium by ducts that are lined either by squamous cells, columnar epithelium (Figures 16.13 and 16.14), or a mixture of the two (14). The columnar epithelial component may or may not be ciliated. The glands are most abundant in the false cords (Figure 16.15), and there is also an extensive group of seromucinous glands just below the anterior commissure. Just superior to the anterior commissure is a narrow zone that is devoid of glands. In most cases, no glands are found beneath the squamous epithelium lining the free edge of the true vocal cords. Glands are present, however, beginning immediately at the squamocolumnar junction, both above and below the squamous epithelium of the true cords. Occasionally, there are glands in the stroma of the true vocal cord, and glands may be present in the underlying vocalis muscle (Figure 16.16).

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Laryngeal biopsies, particularly from the region of the false cords, will often contain seromucinous gland ducts lined by squamous epithelium and located deep beneath the surface mucosa (Figure 16.17). Because of tangential sectioning, these ducts may appear as seemingly isolated squamous nests. Distinction from infiltrating carcinoma should not be a problem in adequately prepared sections. However, changes of basal cell hyperplasia or dysplasia also can involve these ducts. Fortuitous sections of such ducts may then result in seemingly isolated nests of basaloid or overtly dysplastic epithelium that are much more likely to be mistaken for invasive carcinoma (Figure 16.18).

Oncocytic metaplasia of ductal and acinar cells in the seromucinous glands of the larynx is a common, age-related change. Oncocytes are not seen in the seromucinous glands of individuals younger than 18 years of age, but oncocytes are present in these glands in approximately 80% of people over the age of 50 (15,16). Uncomplicated oncocytic metaplasia is asymptomatic; but, occasionally, oncocytic metaplasia may become cystic (Figure 16.19) and, if sufficiently large, produce symptoms.

The seromucinous glands of the larynx may also undergo infarction and associated squamous metaplasia (Figures 16.20,16.21). The resultant process, termed necrotizing sialometaplasia, is much more common in the oral cavity and probably results from a traumatic or spontaneous ischemic event (17). The islands of metaplastic cells may be mitotically active and exhibit mild-to-moderate nuclear atypia. Confusion with mucoepidermoid or squamous cell carcinoma is common, particularly in frozen section specimens. At low-power magnification, the preservation of the acinar pattern, in association with infarction, inflammation, and extravasation of mucin, will aid in the correct diagnosis.

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If the external surface of the larynx is carefully sampled, it is not unusual to find microscopic islands of normal thyroid tissue within the fibrous capsule of the larynx and trachea, just external to the cricothyroid membrane (18). The thyroid follicles are small and appear normal, with well-formed colloid. Continuity with the main thyroid gland is not usually demonstrable (19). Less commonly, microscopic foci of thyroid tissue will be encountered internal to the cartilage of the larynx and trachea, usually at the junction of the cricoid cartilage and the first tracheal ring (18,20). These isolated foci of extrathyroidal thyroid tissue probably lose their connection to the main portion of the thyroid gland during embryologic development (18). Awareness of this phenomenon and attention to the microscopic features will avoid confusion with invasive or metastatic thyroid carcinoma.

The normal larynx contains at least two pairs of paraganglia. The superior, supraglottic paraganglia are sharply localized to the upper, anterior third of the false cords, in close approximation to the margin of the thyroid cartilage and the internal branch of the superior laryngeal nerves (21,22). The paired inferior paraganglia are more variably situated and may be found between the thyroid and cricoid cartilages or just below the cricoid cartilage (21,22). They are closely associated with the inferior laryngeal nerves. Aberrant or ectopic paraganglia have been described in various sites throughout the larynx. Laryngeal paraganglia are minute, neuroendocrine structures (0.1 0.4 mm) of unknown physiologic activity. Their close association with neurovascular bundles suggests chemoreceptor function, but this has not been proved. Laryngeal paraganglia presumably give rise to the rare paragangliomas of the larynx.

The vocal process of the arytenoid cartilage is a normal structure that is occasionally encountered in biopsy specimens from the posterior portion of the true cord. It is a sharply circumscribed nodule of uniformly mature, elastic-type cartilage (Figure 16.22). Its elastic nature, demonstrable with appropriate elastin stains, allows distinction from cartilaginous neoplasms of the larynx, all of which are composed of hyalin-type cartilage. The sharp circumscription of the cartilaginous arytenoid process allows it to be differentiated from chondroid metaplasia of the vocal ligament. Chondroid metaplasia of the vocal cord is a common, usually asymptomatic, finding that typically affects the mid- and posterior portions of the vocal cord (23,24). The margins of the cartilage are blurred, and there is a peripheral zone of connective tissue that is rich in acid mucopolysaccharides (Figure 16.23) (24). The metaplastic nodules contain dense aggregates of elastic fibers throughout the lesion. The multilobular pattern, typical of cartilaginous neoplasms, is absent. Chondroid metaplasia can occur

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Neural, Vascular, and Lymphatic Components

The intrinsic laryngeal muscles are innervated by branches of the vagus nerve. The cricothyroid muscle is supplied by the superior laryngeal branch of the vagus, and the remainder of the intrinsic musculature has been conventionally viewed as being innervated by the recurrent laryngeal branch of the vagus nerve. The terminal portion of the recurrent laryngeal nerve is referred to as the inferior laryngeal nerve (25). More recently, it has been shown that branches of the superior and recurrent laryngeal nerves form anastomoses, most commonly within the interarytenoid muscle but less consistently in the piriform sinus. Branches from the superior laryngeal nerve, referred to as the communicating nerve, may pass through the cricothyroid muscle to partially innervate the vocalis muscle (26,27). It has been suggested that the communicating nerve may be the nerve of the elusive fifth branchial arch (27).

The lower portions of the larynx are supplied with blood from the inferior laryngeal artery, a small branch of the inferior thyroid artery that accompanies the inferior laryngeal nerve. The inferior laryngeal artery has anastomoses with the larger superior laryngeal artery, derived from the superior thyroid artery. The laryngeal arteries are accompanied by similarly named veins. The superior laryngeal vein joins the superior thyroid vein and drains into the internal jugular vein (25). The inferior laryngeal vein joins the inferior thyroid vein. Numerous anastomoses across the front of the trachea between the left and right inferior laryngeal veins may lead to contralateral venous return (25).

The lymphatics of the larynx tend to drain along with the vasculature. Therefore, supraglottic lymphatics drain superiorly, and subglottic lymphatics drain inferiorly (1,25). As discussed earlier, lymphatics are scarce in the glottis. Some of the laryngeal lymphatics end in very small lymph nodes on the thyrohyoid membrane, cricotracheal ligament, or superior trachea (25). These nodes, however, drain into the deep cervical nodes (25). Lymphatics in the supraglottic larynx are prominent and, typically, terminate in the anterior jugular chain (28). Subglottic lymphatics terminate in the midline pretracheal nodes or, less commonly, in the lower cervical lymph nodes (28).

Pharynx

Definition and Boundaries

The pharynx has three functionally and structurally dispersed subparts the nasopharynx, oropharynx, and hypopharynx (Figure 16.24). The nasopharynx is the portion of the pharynx that lies above the soft palate. It has anterior, posterior, and lateral walls. The anterior wall is perforated by the posterior nares (choanae). The posterior wall is an arch that includes the roof of the nasopharynx, as well as the posterior portion against the base of the skull. The posterior wall extends inferiorly and, at the level of the horizontal projection of the soft palate, continues inferiorly as the posterior wall of the oropharynx. The anterior and posterior walls are connected by the lateral walls into which the eustachian (pharygotympanic, or auditory) tubes empty.

The oropharynx lies between the soft palate and the tip of the epiglottis. By definition, its superior boundary is a horizontal projection of the soft palate. Anteriorly, it is bounded by the fauces or opening from the mouth and, below this, the posterior aspect of the dorsum of the tongue. The inferior margin of the anterior portion of the oropharynx is marked by the opening of the piriform recess at the level of the tip of the epiglottis. A horizontal projection posteriorly from this point, marks the posterior aspect of the inferior margin, which is continuous with the hypopharynx.

The hypopharynx is the portion of the pharynx below the tip of the epiglottis and extending downward to the beginning of the esophagus. The hypopharynx is wide superiorly, but rapidly narrows as it approaches the level of the cricoid cartilage and becomes continuous with the esophagus. The hypopharynx partially surrounds the larynx laterally and is separated from it by the aryepiglottic folds. The latter extend from the upper posterior border of the larynx to the side of the epiglottis. The lateral extensions of the hypopharynx are called the piriform recesses or sinuses (25) (Figure 16.25).

Embryology

The embryologic pharynx is of endodermal derivation and, at its cephalic end, is in direct continuity with the ectoderm forming the stomodeum. Recent observations have

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Thus, the lining of the nasal cavity and paranasal sinuses is of ectodermal origin and constitutes the so-called schneiderian membrane. The nasopharynx, oropharynx, and hypopharynx are, at least in large part, of endodermal origin. The sharp demarcation between endoderm and ectoderm at the level of the nasal cavity is of considerable practical importance. Certain neoplasms, such as angiofibromas and lymphoepitheliomas, are virtually confined to the endodermally derived nasopharynx. In contrast, schneiderian papillomas and intestinal-type adenocarcinomas arise from the ectodermally derived lining of the nasal cavity and paranasal sinuses; they do not occur in the nasopharynx.

Gross Anatomy

By nature of their boundaries and lack of resectability, the nasopharynx and oropharynx are practically never encountered as gross specimens. The roof of the nasopharynx is composed of mucosa overlying the basal portions of the sphenoid and occipital bones (25). The lateral and posterior walls of the nasopharynx are composed of the superior constrictor muscles and the pharyngobasilar fascia. The soft palate is the floor of the anterior portion of the nasopharynx: the only truly mobile portion of the nasopharynx (25). Although the opening between the nasopharynx and oropharynx is normally patent, the soft palate can be moved posteriorly and superiorly to completely separate the nasal and oral segments. This is important as a component of proper speech and to keep food and water out of the nasal region during eating and drinking.

The most important gross features of the nasopharynx encountered by pathologists are the pharyngeal tonsil, pharyngeal recess, and the eustachian tube openings. The pharyngeal tonsil, or adenoids, is a prominent, convoluted mass in the roof of the nasopharynx in children. (It typically atrophies in adults.) The pharyngeal recess, or Rosenm ller's fossa, is a mucosal-lined depression in the posterolateral portion of the nasopharynx. Just anterior to the recess, located in the lateral wall, is the ostium of the eustachian tube. This opening is surrounded on its superior and posterior aspects by mucosa-covered cartilage, the tubal torus, from the eustachian tube wall (25).

The superior portion of the anterior oropharynx is bounded by the fauces, or opening of the mouth into the oropharynx. The lateral walls of the fauces are composed, on each side, of the two tonsillar pillars, between which lies the palatine tonsil in the tonsillar fossa. The anterior tonsillar pillar is the palatoglossal arch. This structure curves downward and forward, from the soft palate to the tongue. The posterior tonsillar pillar, or palatopharyngeal arch, extends downward from the posterolateral border of the soft palate laterally along the pharyngeal wall. Each of the arches contains a similarly named muscle (25).

The palatine tonsil, more commonly referred to as simply the tonsil, varies tremendously in size, depending on its state of lymphoid reactivity. The surface of the tonsil is covered with epithelial-lined pits, the tonsillar crypts that pass into the underlying lymphoid tissue. Beneath the tonsil is the pharyngobasilar fascia, which sends branches of fibrous tissue into and around the tonsil, forming the so-called tonsillar capsule. Loose connective tissue between this capsule and the deeper superior constrictor muscle forms a plane of cleavage that facilitates surgical removal (25).

The parapharyngeal, or lateral pharyngeal, space is an important zone of loose connective tissue lying deep to the tonsil and lateral to the pharynx (Figure 16.26). This space is roughly pyramidal, with the base of the skull forming the base of the pyramid superiorly (18,25). Inferiorly, the apex

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Inferior to the fauces, the oropharynx is bounded anteriorly by the posterior aspect of the immobile portion of the tongue. The base of the tongue contains abundant submucosal lymphoid tissue that constitutes the lingual tonsil. Along with the palatine and pharyngeal tonsils, this structure forms an oblique wreath of lymphoid tissue that encompasses the oropharynx and nasopharynx and is often referred to as Waldeyer's ring.

The most important structures in the hypopharynx are the piriform sinuses (Figure 16.25). These elongated, pear-shaped gutters extend laterally along both sides of the larynx, and posteriorly from the pharyngoepiglottic fold to the opening of the esophagus (28). Laterally, the piriform sinus lies against the thyroid cartilage. Medially, it is separated from the laryngeal ventricle by a thin layer of muscles derived from the aryepiglottic fold and the opening of the esophagus (28). Just posterior and lateral to the piriform sinus is the common carotid artery. Because of their close association, tumors arising in the hypopharynx often invade the larynx secondarily. These tumors should be distinguished from primary laryngeal neoplasms because of their poorer prognosis.

Microscopic Anatomy

The nasopharyngeal mucosa in the adult has a surface area of about 50 cm². Most of it is lined by stratified squamous epithelium, and about 40% is covered by respiratory-type, columnar epithelium (31). Squamous epithelium predominantly lines the lower portion of the anterior and posterior nasopharyngeal walls, as well as the anterior half of the lateral walls. Ciliated respiratory epithelium predominantly carpets the region of the posterior nares (choanae) and the roof of the posterior wall. The remainder of the nasopharynx, including the posterior lateral walls and the middle-third of the posterior wall, has alternating islands of squamous and respiratory epithelium.

The junction between squamous and respiratory epithelium may be sharp, or there may be zones of transitional or intermediate epithelium as previously described in the larynx. We prefer the term intermediate epithelium, as opposed to transitional epithelium, because these cells lack the ultrastructural features of urinary tract epithelium. Intermediate epithelium primarily forms a wavy ring at the junction of the nasopharynx and oropharynx. The intermediate cells may be basaloid with minimal cytoplasm, and they typically have a cuboidal or round configuration. As discussed under the larynx, biopsy specimens containing intermediate epithelium must not be overly interpreted as areas of dysplasia or carcinoma in situ. This is most likely to be a problem when this zone is encountered in a frozen section.

In addition to the pharyngeal tonsil, less-prominent collections of lymphoid follicles may be present submucosally throughout the nasopharynx (Figure 16.27). These follicles are particularly abundant in the rim of the eustachian tube opening (Gerlach's, or tubal, tonsil), but they are also

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Throughout the nasopharynx, there are numerous submucosal seromucinous glands that produce predominantly mucin. These glands are particularly numerous in the region of the eustachian tube opening. As with the laryngeal seromucinous glands, oncocytic metaplasia in the glandular and ductal epithelium becomes increasingly frequent with advancing age (32,33).

The anterior portion of the pituitary gland forms from an intracranial invagination of epithelium in the form of Rathke's pouch. Microscopic remnants of Rathke's pouch epithelium are present in the roof of the nasopharynx in 95 to 100% of individuals (34,35,36). In most instances, this so-called pharyngeal pituitary is located in the midline, in the region of the vomerosphenoidal articulation. The nests of epithelial cells measure 0.2 mm to approximately 6 mm in greatest dimension. They are located deep in the mucosa or in the underlying periosteum (34). Most of the epithelial cells appear undifferentiated, but occasional basophilic and eosinophilic cells may be present (Figure 16.28). Although it is not entirely clear, the pharyngeal pituitary may not have any physiologic function. Most pituitary adenomas that involve the nasopharynx reach this location by invasion from the pituitary fossa. Occasionally, however, apparently ectopic pituitary adenomas present in the nasopharynx, and it is tempting to speculate that such lesions arise from the pharyngeal pituitary (37,38).

The pharyngeal bursa is a normal embryonic structure situated posterior to Rathke's pouch. Remnants of this bursa may be found in approximately 3% of normal adults (39,40). Cysts derived from this structure may be found in all ages, occasionally as an incidental finding, and occur in the regions of the adenoid (41). The cysts are separated from the adenoid by a fibrous membrane and will not be removed with routine adenoidectomy specimens (Figure 16.29) (10). The median pharyngeal recess is a shallow depression formed normally in association with the pharyngeal tonsil. Unlike cysts derived from the pharyngeal bursa, those formed from the median pharyngeal recess are located within the adenoid and will be removed with it (10).

The cranial end of the embryonic notochord is closely associated with the roof of the developing nasopharynx (42). Although most of the notochord degenerates during embryonic and fetal development, notochordal remnants have been demonstrated in the submucosa of the nasopharynx and other closely adjacent locations (10,43). Most chordomas involving the nasopharynx are downgrowths of cranio-occipital tumors, but rare primary nasopharyngeal tumors presumably arise from these nasopharyngeal notochord remnants (42,43).

Both the oropharynx and hypopharynx are lined continuously by stratified squamous epithelium. This mucus is typically nonkeratinizing, although areas of parakeratin or orthokeratin may be seen secondary to chronic irritation. As in the nasopharynx, the submucosa of the oropharynx and hypopharynx contains scattered lymphoid aggregates, as well as prominent submucosal seromucinous glands.

The stratified squamous epithelium covering the tonsils extends into the tonsillar crypts for considerable distances. As these cords of epithelium merge with the underlying lymphoid tissue, the epithelial cells assume a more basaloid appearance and have uniform but vesicular nuclei. The junction between the lymphoid cells and the islands of squamous cells is often blurred (Figure 16.30). Apparently isolated, irregular nests of basaloid, focally keratinized squamous cells, often with vesicular nuclei, are common deep within the tonsil (Figure 16.31), and such nests must not be confused with carcinoma. Attention to the low-power

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Occasionally, islands of metaplastic cartilage and bone are encountered within or immediately adjacent to the tonsils (18,44). This presumably represents a secondary, reactive change to prior inflammation. Eggston and Wolff (44) described this change in about one-fifth of all resected tonsils. These authors noted that patients with this change had an average age of 24 years and, therefore, were older than most individuals undergoing tonsillectomy (44).

Neural, Vascular, and Lymphatic Components

The nerves supplying the constrictor muscles of the phaynrx, the stylopharyngeus muscle, and the muscles of the soft palate are derived almost entirely from the pharyngeal plexus. The latter structure is formed by the union of the pharyngeal branches of the glossopharyngeal and vagus nerves. The inferior constrictor muscle may receive a portion of its innervation from the external laryngeal nerve, a separate branch of the vagus that primarily supplies the larynx (25).

The blood supply to the superior portion of the pharynx is from the ascending pharyngeal artery, which runs upward along the posterior lateral wall of the pharynx (25) (Figure 16.32). The inferior portion of the pharynx is supplied by branches from the superior and inferior thyroid arteries. The veins draining the pharynx merge posteriorly to form the pharyngeal plexus, which in turn drains at irregular intervals into the pterygoid plexus and the superior and inferior thyroid veins (25).

The lymphatics from the roof and posterior wall of the nasopharynx join in the midline, and pass through the pharyngeal fascia. They then split to the right or left retropharyngeal lymph nodes. Some of the nasopharyngeal lymphatics terminate in the highest lymph nodes of the internal jugular and spinal chains (28). Most of the

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Acknowledgments

The author thanks Linda Hamme for her expert artistic assistance and Joshua Weikersheimer, director of the American Society of Clinical Pathologists Press, for obtaining and allowing the use of several illustrations from Mills and Fechner (45).

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