11 - Central Nervous System

Editors: Mills, Stacey E.

Title: Histology for Pathologists, 3rd Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > V - Head and Neck > 15 - Mouth, Nose, and Paranasal Sinuses

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15

Mouth, Nose, and Paranasal Sinuses

Karoly Balogh

Liron Pantanowitz

Embryology and Prenatal Changes

The development of this highly specialized part of the head is restricted to structures of importance to the surgical pathologist. For details, the reader is referred to other sources (1,2).

The oral region develops from an ectodermal depression, the stomodeum. The deep oral cavity is formed by the forward growth of structures about the margins of the stomodeum, giving rise to superficial parts of the face and jaws, as well as the walls of the oral cavity. The stomodeal prominence is surrounded bilaterally by the maxillary and mandibular processes and rostrally by the unpaired frontal prominence. The upper lip, maxilla, and nose are derived from structures surrounding the stomodeum. The caudal boundary of the oral cavity is formed by the paired mandibular processes, which, during the second year of life, fuse in the midline to form the mandible. The paired maxillary processes likewise meet in the midline, crowding the nasal elevation to ultimately form the maxilla and, by fusion in the midline, the palate. The contours of the face change with the rapid growth of the nose and jaws (2). The nose is formed on either side of the frontonasal elevation by an invagination of ectoderm into the mesoderm to form two nasal pits that gradually converge toward the midline, where they merge with each other. The underlying mesenchyme develops into bone, cartilage, and skeletal muscle.

At the end of the second month of fetal life, the formation of the bony structures begins; the maxilla is one of the first bones to calcify. Simultaneously, the nasal pits become progressively deeper and extend downward toward the oral cavity. Later, elevations appear on the lateral walls of the right and left nasal cavity that will become the scroll-like nasal turbinates (conchae). The nasal cavities communicate with chambers in the adjacent bones known as paranasal sinuses. Named for the bones in which they lie, they comprise the frontal, maxillary, sphenoidal, and ethmoidal sinuses. The paranasal sinuses can be first identified around the fourth month of fetal life, but most of their expansion occurs after birth, and they attain full size many years later. The mucosa lining the nasal cavities invaginates into the surrounding bone, thereby lining the expanding sinus. While the palate has been taking shape from the roof of the mouth, the tongue has been forming in the floor. The posterior part of the tongue (behind the sulcus terminalis)

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is derived from the midventral areas of branchial arches II, III, and IV.

The tonsils first develop as endodermal epithelial buds that arise from the lining of the primitive oronasal cavity and grow into the subjacent mesenchyme to eventually give rise to the tonsillar crypts. Crypt formation may be simple, as in the lingual tonsil, or more complex, as in the palatine tonsils. Lymphoid tissue begins to accumulate and organize around the crypts at around the time when secondary budding of the crypts takes place. This development occurs in close association with mucous glands, which explains the close anatomic proximity of such glands to the tonsils.

Tooth development (odontogenesis) is of considerable importance to an understanding of the pathogenesis of odontogenic tumors and cysts. Odontogenesis is a highly coordinated and complex process that relies upon several genes, growth factors, structural proteins (e.g., amelogenin, tuftelin, predentin, cementum, enamelin), and extracellular matrix molecules being expressed in temporal- and space-specific patterns (3). The teeth begin to develop inside the gums of the upper and lower jaw (Figure 15.1). Such regulatory interactions occur during the early stages of morphogenesis, particularly when the dental epithelium induces the condensation of mesenchymal cells around the epithelial bud. Teeth pass through three stages of development: growth, mineralization, and eruption. The growth period is further subdivided into the bud, cap, and bell stages.

Initially, the oral epithelium shows definite thickening and begins to grow into the subjacent mesenchyme around the entire arc of each jaw. The free margin of this epithelial band gives rise to two invaginating processes. The outer process (vestibular lamina) will form the vestibule that demarcates the cheeks and lips. From the inner horseshoe-shaped process (dental lamina), tooth buds (bud stage) arise at the site of each future tooth. Thus, the primordia for the temporary deciduous (primary) teeth are formed. Shortly afterward, the primordia of the succedaneous (permanent) teeth develop in the same way. The permanent tooth germs lie in a hollow of the alveolar sockets on the lingual side of the deciduous teeth. The developing enamel organ of each tooth takes the shape of a goblet with the dental lamina as its stem. As the dental lamina disintegrates, the inner lining cells (inner enamel epithelium) of the enamel organ differentiate to become columnar epithelial cells called ameloblasts, whereas the outer layer of cells (outer enamel epithelium) flatten into a layer of closely packed cells. Between the ameloblasts and the outer enamel epithelium is the loosely arranged epithelium of the stellate reticulum. Inside the goblet-shaped enamel organ, the mesenchymal cells proliferate to form a dense aggregate, the dental papilla (cap stage).

Figure 15.1 Coronal section of head of a human fetus about 30 weeks of age (284 mm crown-rump length). The bell-shaped enamel organs are present in each quadrant. The tongue is relatively large. The paranasal sinuses are not yet discernible at this stage of fetal development.

The dental papilla will form the dentin, cementum, and pulp. The dentin is the internal layer of the tooth, the cementum is the bony tissue covering the root of the tooth, and the pulp is the soft inner part of the tooth. More peripherally, the condensing mesenchymal cells extend around the enamel organ as the dental follicle. The cells of the dental follicle eventually produce alveolar bone and collagen fibers of the periodontium. In the final

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(bell) stage of growth, the epithelium of the cap will form the enamel. During this stage, the outer and inner enamel epithelium meet at their apical ends, where they proliferate to form Hertwig's epithelial root sheath, which initiates the differentiation of the outermost cells of the papilla to become arranged in a row of single columnar cells to form the odontoblasts (Figures 15.2,15.3). Nerves and blood vessels in the dental papilla begin to form the primitive dental pulp. The dental papilla grows toward the gum, crowding in on the enamel organ, which by then has lost its connection with the oral epithelium. During dentinogenesis nonmineralized predentin is produced by the odontoblasts against the inner surface of the enamel organ. As the odontoblasts produce predentin, their cell bodies recede toward the center of the tooth, so that each odontoblast leaves behind a thin process (Tomes' fiber) that occupies a dentinal tubule. The organic matrix of the predentin eventually mineralizes to become dentin, which is arranged in the shape of tubules running from the pulp chamber toward the periphery. Meanwhile the enamel cap of the tooth is being formed (amelogenesis) by the ameloblasts (4). The formation of dentin and enamel begins at the tip of the crown and progresses toward the root of the tooth (5). As the developing root increases in length, the previously formed crown moves closer to the surface of the gum. Even when the crown of the tooth begins to erupt, the root is still incomplete and continues growing until the crown has completely emerged (6,7) (Figures 15.4,15.5). The

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enamel is made by differentiated ameloblasts that produce long, thin enamel prisms, or rods; these rods become calcified and are surrounded by a thin organic matrix. Enamel production is completed when the crown is mineralized and its final size attained (8). At this point in time, the flattened ameloblasts and remainder of the cells of the enamel organ form a cuticle on the surface of the enamel; this membrane is then shed (9).

Figure 15.2 Enamel organ of deciduous tooth. Formation of enamel and dentin has begun at the crown area of the tooth. [Arrow, remnants of dental lamina; arrowhead, a small epithelial cyst (rest of Serres)]

Figure 15.3 Enamel organ. Amelogenesis and dentinogenesis progress from crown to root. Early enamel and dentin appear as black bands, widest at the crown area and become thinner toward the root. [Ex, external enamel epithelium; In, inner enamel epithelium; SR, stellate reticulum; H, Hertwig's epithelial root sheath; P, dental papilla; *, artifact (separation)]

Figure 15.4 Developing tooth, sagittal section. Ameloblasts (A) line the surface of the enamel matrix (E) which is partly mineralized. Dentin (D) is not mineralized (predentin) and has been separated by an artifact (*) from pulp (missing).

Figure 15.5 Developing tooth. Layer of polarized odontoblasts with Tomes' fibers (arrow) extending into tubules of predentin. Fibroblasts of pulp (P) are loosely arranged. (E, enamel matrix)

After the root has attained its full length and definitive position in the jaw, a bone-like hard substance, cement, is deposited on it (cementogenesis). Cement is produced by the mesenchymal cells adjacent to the root. These cells become differentiated into a cementoblast layer that resembles the osteogenic (cambial) layer of the periosteum (10,11). Fibers from the rest of the dental sac form the periodontal ligament, which firmly attaches the tooth in the bony alveolar socket (12).

As the jaws approach their adult size, the latent primordia of the permanent teeth follow the same developmental process as did the deciduous teeth (13) (Figure 15.6). When a developing permanent tooth increases in size, the root of the corresponding deciduous tooth is partly resorbed by osteoclastic activity (Figure 15.7). Thus, the anchorage of the deciduous tooth becomes weakened and the tooth is shed, permitting the underlying permanent tooth to erupt.

The minor salivary glands in the mouth develop following a pattern of epithelial-mesenchymal interactions between the outgrowth of an ectodermal bud from the lining of the stomodeum and the underlying mesenchyme. The proliferation, differentiation, and morphogenesis of these glands depend on intrinsic (programmed pattern of cell-specific gene expression) and extrinsic factors. The extrinsic factors include cell-cell and cell-matrix interactions, as well as growth factors (14).

Figure 15.6 Deciduous and unerupted permanent teeth in a 10-year-old child. Perpendicular section through the roots of two deciduous teeth with underlying permanent molar tooth. Empty space was left by enamel that was dissolved by decalcification. Note relationship between teeth and bone, respectively.

Figure 15.7 Roots of deciduous molar tooth before shedding. Resorption of dentin is indicated by numerous Howship's lacunae and osteoclasts (arrows). The thin band (bottom) is the reduced internal enamel epithelium that covered the crown of the underlying permanent tooth; the enamel dissolved with decalcification.

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Gross Anatomy

In this chapter we will consider only those features that are important for the surgical pathologist.

Jawbone

The mandible is a horseshoe-shaped bone; its horizontal part forms the body, which is continuous with the vertical parts of the two sides, the rami. The bone of the body has a thick cortex, and the compact shell contains plates of cancellous bone arranged along the trajectories. The upper part of the body is hollowed into sockets that carry eight teeth on each side. Each ramus is a nearly vertical, flattened, oblong plate of bone surmounted by two processes. The posterior articular process ends in the condyle, articulating with the articular disk of the temporomandibular joint. The anterior (coronoid) process serves for the insertion of the temporal muscle.

The right and left maxillae jointly form the upper jaw; they participate in forming boundaries of four cavities: the roof of the mouth, the floor and lateral wall of the nose, the floor of the maxillary sinus, and the floor of the orbit. The alveolar processes of the maxillae together form the alveolar arch.

Nose

The external nose and nasal septum are partly composed of hyaline cartilage and bone. The two orifices of the external nose, the nares (nostrils), are separated from each other by the median vertical soft tissue columella. The columella is attached posteriorly to the nasal septum, which forms the medial wall of the two approximately symmetrical chambers, the right and left nasal cavities. The nasal cavity extends from the nares anteriorly to the choanae posteriorly. Just behind the nares, the nasal cavity widens to form the vestibule. A ridge (limen nasi) on the lateral nasal wall separates the vestibule from the rest of the nasal cavity proper. In each nasal fossa is an olfactory region that occupies the superior part of the nasal cavity. The rest of the nasal fossa consists of the respiratory region. On the lateral wall of each nasal fossa are the superior, middle, and inferior turbinates. A fourth supreme turbinate may be present at the uppermost portion of the lateral nasal wall. The scroll-shaped turbinates hang over the corresponding funnel-shaped nasal passages, or meatuses, into which the various paranasal sinuses open. The nasal mucosa is in continuity with the mucosa of these sinuses through their corresponding openings. The nasal mucous membrane is most vascular and thickest over the turbinates and is also relatively thick over the nasal septum.

Paranasal Sinuses

The air-filled paranasal cavities (sinuses) are located in the bones around the nasal cavity. The maxillary and frontal sinuses open into the middle meatus of the nose. The sphenoidal sinus opens into the sphenoethmoidal recess above the superior turbinate. There are numerous ethmoidal sinuses that form small communicating cavities, also called ethmoid air cells (or ethmoid labyrinth). The ethmoid air cells have thin bony walls. According to their location, the ethmoidal sinuses can be divided into three groups: the anterior and middle ethmoidal sinuses, which open into the middle meatus, and the posterior ethmoidal sinus, which opens into the superior meatus of the nose. There are many variations in size, shape, and location of all paranasal sinuses. One or more of them may even be underdeveloped or absent.

Blood Vessels

The nasal cavity has an extraordinarily rich blood supply. The anterior and posterior ethmoidal branches of the ophthalmic artery supply the frontal and ethmoidal sinuses, as well as the roof of the nasal cavity. The sphenopalatine branch of the maxillary artery supplies the mucosa of the turbinates, meatuses, and the nasal septum. The mucosa of the maxillary sinus is supplied by branches of the maxillary artery and the sphenoidal sinus by the pharyngeal artery. The branches of all these vessels form a plexiform network in and below the mucous membrane. The veins of the nasal mucosa are well developed, particularly in the inferior turbinate and in the posterior part of the nasal fossa, where they form a cavernous plexus. The veins of the lower jaw drain via the inferior central vein into the pterygoid plexus. Blood from the upper jaw and facial structures drains in two directions: the more anterior parts into the anterior facial vein and the more posterior parts into the pterygoid plexus. The pterygoid plexus drains the teeth, soft palate, fauces, and pharynx. These anatomic relationships are particularly important because infections and tumors of the face, mouth, nose, and paranasal sinuses can reach the intracranial cavernous sinus either via the emissary vein of Vesalius or by way of veins communicating with the inferior or superior ophthalmic veins. The latter veins drain the structures of the anterior face, such as lips, cheek, and external nose, as well as the mucosa of the frontal sinuses, ethmoidal cells, and upper lateral nasal wall. The cavernous sinus also receives venous blood from the mucosa of the sphenoidal sinus.

Nerves

The regions discussed here have a rich and complex innervation, the description of which is beyond the scope of this

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chapter. However, many nerves of the head lie in close proximity to the mucosa and submucosa of the upper aerodigestive tract and are therefore prone to early invasion by carcinoma.

Lymph Nodes

Lymph nodes of the head and neck are abundant and can be divided into 10 groups: the occipital, mastoid, parotid, facial, sublingual, submaxillary, submental, retropharyngeal, anterior cervical, and lateral cervical nodes. Only those lymph nodes related to the regions covered in this chapter are discussed here. There are three principal parotid lymph node groups: superficial (suprafascial or preauricular) nodes; subfascial (extraglandular) nodes contained in the parotid sheath; and deep intraglandular nodes. The parotid lymph nodes drain the parotid gland, external ear, frontotemporal facial region, eyelids, upper lip, root of the nose, floor of the nasal cavity, soft palate, and buccal mucosa. Their efferents pass into the superior deep cervical nodes.

The small superficial group of facial nodes include, from rostral to caudal, the infraorbital (nasolabial) nodes situated in the nasolabial fold, the buccal nodes placed external to the buccinator muscle and its fascia, and the mandibular nodes located external to the mandible. The facial nodes receive afferent lymphatics from the eyelids, nose, cheek, upper lip, and subjacent nodes, and they empty into the submaxillary nodes. There are also deep facial nodes situated deep to the ramus of the mandible near the maxillary artery. Heterotopic buccal nodes may rarely be encountered immediately beneath the buccal mucosa near the orifice of Stensen's duct, giving the false clinical impression of a neoplasm (15,16). The sublingual (or lingual) nodes are intercalated along the course of the collecting lymph trunks of the tongue. The submaxillary (submandibular) nodes, situated in the space lodging the submaxillary salivary gland, are located around or within the fascial sheath of this gland. They receive lymph vessels from the chin, lips, cheeks, nose (including the anterior nasal cavity), gums, teeth, floor of the mouth, hard palate, tongue, and other nearby nodes. The submental nodes receive lymphatics from similar regions. Their afferent vessels connect partly with the submaxillary and internal jugular nodes. The retropharyngeal nodes, which lie between the posterior wall of the pharynx and prevertebral fascia, may project anteriorly onto the soft palate and therefore may be mistaken for palatine tonsils. The more lateral retropharyngeal nodes atrophy with age. These nodes drain the nasal cavities, palate, middle ear, nasopharynx, and orophrynx. They send efferent vessels to the internal jugular chain of nodes.

Lymphatics

For a detailed description of the lympahtic system draining the head and neck, the reader is referred to the compendium by Tobias, which is a translation of the original work by Rouvi re (17). Lymphatics arising from the upper lip terminate in the parotid, submental, and submaxillary lymph nodes. Central lymphatics from the lower lip drain into the submental node, while those originating more laterally empty into the submaxillary nodes. Lymphatics arising from the mucosa of the cheeks traverse the buccinator muscle to eventually terminate in the submaxillary nodes. Their course may be interupted by the buccinator nodes. Cutaneous lymphatics of the cheek end in the submaxillary, submental, and parotid nodes. The lymphatic network of the tongue is divided into a superficial and deep (muscular) set. They drain to the linguinal and submaxillary nodes but end mainly in the deep cervical lymph nodes. The node at the bifurcation of the common carotid artery is considered to be the principal lymph node of the tongue (17). Lymphatics in the region of the tongue may cross the midline to reach nodes of the opposite side. The gingiva contain a similar superficial and deep anastomosing lymphatic network that drains into the sublingual, submental, submaxillary, internal jugular, and occasionally the retropharyngeal nodes. Lymphatic vessels that exit from the dental pulp of the teeth are in direct communication with those of the gingiva. Lymphatics from the floor of the mouth are continuous with those from the tongue and gums. Afferent lymphatics from the floor of the mouth drain into the sublingual, submental, and deep cervical nodes, while those from the posterolateral region terminate in the submaxillary and deep cervical nodes. The draining lymphatics of the palate, which are continuous with those of the gums and palatine tonsils, reach the submaxillary, retropharyngeal, and deep nodes of the neck.

The cutaneous lymphatics of the nose terminate in the submaxillary lymph nodes. Lymph from the nasal vestibule goes to the parotid and submaxillary nodes. Lymphatics originating from the anterior nasal cavities drain to the submental nodes, while those from the posterior cavities pass to the retropharyngeal and deep superior cervical nodes. The lymphatics from the olfactory region do not communicate with those of the respiratory region (17). Lymphatics arising from the olfactory region communicate to the subarachnoid space of the brain via small cannaliculi passing through the foramina of the cribiform plate along with the olfactory nerve filaments. The lower aspect of the inferior turbinate drains to the internal jugular lymph nodes. The upper portion of the inferior turbinate, along with lymphatics from the middle turbinate, drain into the retropharyngeal and internal jugular lymph nodes. The superior turbinates drain to the retropharyngeal and deep cervical nodes. Lymphatics from the frontal and maxillary sinuses, along with the anterior and medial group of ethmoidal sinuses, drain to the submaxillary nodes. The posterior ethmoidal group and sphenoidal sinuses drain lymph into the retropharyngeal nodes.

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Tonsils

Nonencapsulated lymphoid tissue present in the oropharynx is normally organized into epithelial-covered lymphoid aggregates termed tonsils. Tonsils are typically softer than lymph nodes on palpation because they lack a fibrous capsule or trabeculae. The word tonsil has also been used to refer to the palatine tonsils. Waldeyer's ring, described by the nineteenth century anatomist Wilhelm von Waldeyer, refers to the circular collection of submucosal lymphoid tissue that gaurds the opening into the upper aerodigestive tract (18). Waldeyer's ring is comprised of the palatine, pharyngeal, tubal, and lingual tonsils, as well as the lateral pharyngeal lymphoid bands and intervening isolated lymphoid follicles (pharyngeal granulations) (19,20). The pharyngeal bands are located on the posterolateral wall of the oropharynx, just behind the posterior tonsillar pillar. The oval shaped palatine (faucial) tonsils are situated laterally in the oropharynx within the triangular tonsillar fossa, which is bound by the palatoglossal arch anteriorly and palatopharyngeal arch posteriorly. Their tonsillar crypts usually become occupied with desquamated epithelium, debris, and microorganisms that are grossly visible on the surface as white spots (follicles). Such crypt plugs may calcify. The palatine tonsils are the only tonsils with a partial capsule, which is formed by compressed connective tissue on their attached side. This capsule separates the tonsils from the underlying musculature of the pharyngeal wall. The tonsils are largest in early childhood; after about four years of age, they begin to gradually atrophy. Following puberty, the tonsils become increasingly fibrotic. The pharyngeal tonsil (adenoid, or tonsil of Luschka) is a single pyramidal-shaped aggregate of lymphoid tissue located superiorly in the midline of the nasopharyngeal wall. Unlike the other tonsils, the adenoid does not have typical crypts, but rather numerous surface folds extending from the tonsillar base anterolaterally. The surface of the pharyngeal tonsil also forms a median recess known as the pharyngeal bursa. The tubal tonsil (eustachian tonsil or Gerlach's tonsil) is that small portion of the pharyngeal tonsil that is located behind the pharyngeal opening of the eustachian tube. The lingual tonsil is situated on the dorsum of the tongue posteriorly, between the sulcus terminalis and the valleculae. In most individuals the median glossoepiglottic ligament divides the lingual tonsil into bilateral lobes.

Additional tonsillar structures may also be found in the normal human oropharynx. These include the so-called oral tonsils, which are structurally similar to the palatine tonsils (21). Oral tonsils occur chiefly in the palate, floor of the mouth, and on the ventral surface of the tongue. They are small (1 3 mm in diameter), firm, circumscribed, mobile lymphoid aggregates present under intact oral mucosa. Oral tonsils contain a single central crypt. It has been proposed by some authors that intraoral lymphoepithelial cysts originate from occluded crypts of oral tonsils (22,23). Reactive tonsillar tissue has also been noted in the region of the pyriform sinus, palate, and lateral surface of the tongue (24,25).

Microscopy

Mouth

Lips and Vermilion Border

The entrance to the digestive tract is surrounded by two fleshy folds of skin, the lips. They are partly covered by skin that bears hairs, sweat glands, and sebaceous glands and is richly endowed with sensory nerves. The inner surface of the lips is covered by the oral mucosa and forms a part of the wall of the oral cavity. Between the external integument and the oral mucosa are the orbicularis oris muscle, the labial vessels, nerves, and adipose tissue with numerous minor salivary glands. The latter are easily accessible for biopsies to diagnose Sj gren's syndrome. The junction between the skin and oral mucosa is known as the vermilion border, where the keratinized squamous epithelium of the skin changes to the mucous membrane of the oral cavity. The squamous epithelium of the vermilion border is thin, and the tall connective tissue papillae are close to the surface. The blood in the rich capillary network shows through the thin epithelium, accounting for the redness of the lips. The transition zone has no hairs. In adults, ectopic sebaceous glands are commonly observed in the vermilion border, at the corners of the mouth, or in the buccal mucosa; these are termed Fordyce's spots (or Fox-Fordyce granules) and increase with age, so that 70 to 80% of elderly persons have them. These ectopic sebaceous glands are considered normal (Figure 15.8) (26,27). Like the skin, the vermilion border

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is exposed to physical forces and chemical agents. For this reason, actinic keratosis and solar elastosis can be seen on the vermilion border. The squamous epithelium of the transitional zone imperceptibly merges with the stratified squamous epithelium of the oral mucosa.

Figure 15.8 Ectopic sebaceous glands in the vermilion border (Fox-Fordyce granule).

Oral Mucosa and Submucosa

The oral mucosa consists of an epithelial layer and an underlying layer of connective tissue, the lamina propria (Figure 15.9). The mucosa of the oral cavity shows regional modifications in structure and cytokeratin expression that correspond to functional requirements. The stratified squamous epithelium of the oral mucosa has three functional types: the lining mucosa, masticatory mucosa, and specialized mucosa (28). Most of the oral mucosa is lined by nonkeratinized squamous epithelium, representing the lining mucosa. The palate, gingiva, and dorsum of the tongue are exposed to the forces of mastication and are covered by keratinized epithelium of the masticatory mucosa type. The mucosa of the palate is orthokeratinized, whereas the epithelium of the gingiva is often parakeratinized. Details of the specialized mucosa are described with the tongue. Throughout the oral cavity the epithelium is worn off by mastication and speaking; hence, exfoliated epithelial cells are a normal constituent of the saliva and are frequently encountered by the pathologist in sputum or as contaminants in bronchoscopic specimens. Squamous cells of the buccal mucosa have also been a convenient source for the microscopic demonstration of the sex chromosome (Barr body) (Figure 15.10). The shed epithelial cells are replaced by the basal cells, which divide then migrate to the surface and are themselves eventually worn off. The renewal of the oral mucosa takes about 12 days (29). As the name implies, the squamous epithelium of the mucosa is kept moist and glistening by mucus that is secreted by the numerous minor and paired major salivary glands. This thin film of mucus covers and protects all intraoral structures, including the teeth, which are bathed by saliva. Saliva rinses away bacteria, provides buffering agents (e.g., phosphate and bicarbonate) that neutralize acids created by bacteria that inhabit dental plaque, contains antibacterial agents, and minerals required for tooth remineralization. Hence, xerostomia promotes tooth decay

Figure 15.9 Inner aspect of cheek, cross section. Left to right: cross-striated muscle, adipose tissue, lamina propria, buccal mucosa.

Figure 15.10 Cytologic image of a scraping of the buccal mucosa. Intermediate squamous cell with sex chromatin body (Barr body) (arrow) lying against the inner nuclear membrane (Papanicolaou stain).

The interface of the epithelium and lamina propria is delineated by the basal lamina, or basement membrane. In hematoxylin and eosin (H&E) stained sections, it is sometimes hard to see the basal lamina, but special stains (e.g., reticulin) demonstrate it well (Figure 15.11). The basal lamina is secreted by the epithelial cells and serves supportive and filtering functions. It also regulates differentiation, migration, and polarity of the epithelial cells. The basal lamina is composed of type IV collagen and heparan sulfate, as well

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as the two glycoproteins, laminin and entactin, that interact with other components of the extracellular matrix. A single layer of basal cells rests on the basal lamina. The basal cells continuously divide, and the new cells push the overlying ones toward the surface. During this process of differentiation, the small cuboidal basal cells become polyhedral and larger, forming the stratum spinosum. These cells contain abundant intracytoplasmic fibrils (tonofilaments) that attach to desmosomes, connecting the squamous epithelial cells with each other. Toward the superficial layers the cells gradually become flat. The nonkeratinized squamous epithelium lacks a stratum granulosum and stratum corneum. The surface cells may retain their nuclei, and their cytoplasm does not contain keratin filaments (Figure 15.12) (30). In keratinizing epithelium, the cells form a stratum granulosum, which is a prominent layer three to five cells thick. The cells of this layer have numerous intracytoplasmic granules, called keratohyalin granules, which stain with hematoxylin. As the process of keratinization advances, the nucleus and cytoplasmic organelles become disrupted and disappear while the cell becomes filled with an intracellular protein, keratin. Thus, the surface layer, the stratum corneum, is formed.

Figure 15.11 Buccal mucosa. Reticulin stain delineates the cell membrane of nonkeratinized squamous epithelial cells and the delicate basement membrane. Papillae of the lamina propria contain blood vessels.

Figure 15.12 Buccal mucosa showing maturation of squamous epithelium: there is a row of small basal cells, larger cells of stratum spinosum, and parallel arranged flat surface cells. No keratinization is seen. Lamina propria shows delicate strands of connective tissue, blood vessels, and a few lymphocytes. (Mallory's trichrome.)

Table 15.1 Cytokeratin Expression Profiles of Different Oral Epithelia, as Determined by Immunohistochemical and Electrophoretic Studies.

Cytokeratin Type CK1 CK4 CK5 CK6 CK7 CK8 CK10 CK13 CK14 CK16 CK18 CK19
Epidermis (for comparison) ++ / ++ + / - ++ / ++ + / /
Oral lining mucosa / ++ ++ + / - - ++ + - - +
Oral gingival epithelium ++ + ++ + - - ++ + ++ ++ - +
Epithelium of oral sulcus - ++ ++ / - + - ++ ++ ++ + ++
Junctional epithelium - - ++ / - + - ++ ++ + + ++
Masticatory mucosa (e.g., hard palate) ++ / ++ / / / / / ++ ++ / /
Epithelia of enamel organ / - ++ / + + - - / / - ++
Rests of Malassez / - ++ / - - - - + - - ++
+ (weak or occasional expression); ++ (strong expression); - (expression absent); / (no data)
(Modified from: Mackenzie IC, Rittman G, Gao Z, Leigh I, Lane EB. Patterns of cytokeratin expression in human gingival epithelia. J Periodontal Res 1991;26:468 478.)

All oral epithelia show expression of cytokeratin 5 and 14 (CK5 and CK14, respectively), the keratin pair typically expressed by basal cells of stratifying epithelium. The oral mucosa from various sites exhibits striking differences in cytokeratin synthesis (Table 15.1) (31,32). Such differences usually appear in the fetus by 23 weeks. The differences in the distribution of these cytoskeletal proteins reflect the relationship between morphology and function of these epithelia (33). The gingiva expresses a great complexity of cytokeratins, similar to that of the epidermis. For example, gingival epithelia are immunoreactive for CK1 and CK10 (differentiation that is associated with epithelial properties of toughness and rigidity), as well as CK4 and CK13 (differentiation associated with epithelial properties of flexibility and elasticity). In contrast, the lining mucosa shows a paucity of cytokeratins, resembling stratified nonkeratinizing squamous epithelium of the esophagus. Malignant transformation is often associated with alterations in the cytokeratin pattern.

Normal oral mucosal epithelial cells, even in the fetus, express the ABO blood group antigens (34). In fact, the oral mucosa has become a model for studying cellular glycosylation. In general, the blood group antigen expression on epithelial cells follows the general phenotype of the host individual as determined by routine serologic methods. The loss of these antigens on malignant epithelial cells may be a valuable marker for primary carcinoma. All epithelial

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cell layers of the enamel organ, however, are normally devoid of the blood group antigens.

The lamina propria is a delicate layer of connective tissue situated beneath the squamous epithelium. It contains few elastic and collagenous fibers and is rich in blood vessels, lymphatics, and nerves. The nerves belong to the sensory branches of the trigeminal nerve. The lamina propria also contains scattered lymphocytes, which are often found migrating through the epithelium. Consequently, few lymphocytes are a normal constituent of the saliva (salivary corpuscles).

The submucosa under the lining mucosa is composed of fairly loosely arranged connective tissue, which contains larger blood vessels, lymphatics, nerves, adipose tissue, and numerous minor salivary glands. Where the mucosa is in close proximity to the underlying bone (e.g., the hard palate), there is no submucosa and the fibers of the lamina propria are directly and tightly attached to bone. In these areas, the mucosa, lamina propria, and periosteum are joined together as one membrane and are generally referred to as a mucoperiosteum.

Palate and Uvula

The roof of the oral cavity is formed by the palate; the anterior two-thirds consists of the hard palate, and the posterior one-third is comprised of the soft palate. The palate separates the oral and nasal cavities. Anteriorly and laterally, the palate is bounded by the alveolar arches and gums; posteriorly, it is continuous with the soft palate. The hard palate is covered by masticatory mucosa, which has a series of ridges (palatal rugae) running across, but not crossing, the midline. The ridges are easily seen and palpated and can be felt with the tongue. The supporting dense connective tissue fibers of these ridges pass directly from the papillary layer of the lamina propria into the underlying bone. In the anterior lateral regions of the hard palate, the submucosa contains fat tissue, whereas more posteriorly its lateral regions contain minor salivary glands (palatine glands), which are pure mucous glands (Figure 15.13).

The soft palate is the mobile portion. With no bony support, it is suspended from the posterior border of the hard palate like a curtain. Its oral surface is covered by lining mucosa, and its nasal surface, which is continuous with the floor of the nasal cavity, is mostly lined by ciliated respiratory epithelium. The soft palate contains fibers of striated muscle, blood vessels, and nerves (Figure 15.14). Larger mucous glands underlie the oral epithelium of the soft palate, whereas smaller groups of mixed glands are present on the nasal surface under the respiratory epithelium. From the middle of the posterior border of the soft palate hangs a small, conical process of soft tissue, the uvula. The uvula is microscopically similar to the

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soft palate (Figure 15.15). It contains predominantly mucous glands and muscle fibers that become more sparse from the proximal to the distal end. The musculus uvulae muscle inserts into the actual mucosa of the uvula. Mast cells, usually located around blood vessels, are a frequent finding (35).

Figure 15.13 Hard palate with pure mucous minor salivary glands and duct. Note dense connective tissue of lamina propria (H&E).

Figure 15.14 Soft palate sectioned in the coronal plane. Nasal respiratory mucosa (top), oral squamous mucosa (bottom). Fascicles of pharyngopalatine muscle are to the right and left of the midline. Fibers of levator veli palatini muscle (*) are obliquely descending. Ducts of minor salivary glands are near the oral mucosa (arrow), respectively.

Figure 15.15 Sagittal section of uvula with numerous mucous glands and bundles of cross-striated muscle. More glands are seen near the oral surface (right).

Floor of the Mouth

The mucous membrane of the floor of the mouth is thin and loosely attached to the underlying structures. The rete ridges are short. The submucosa contains some adipose tissue and numerous minor salivary glands (sublingual mucous glands).

Tonsils

The tonsils are organized aggregates of lymphoid tissue covered on their luminal surface by a mucous membrane. The close proximity of lymphocytes to the surface epithelium facilitates the direct internal transport of foreign material from the exterior. Epithelial-lined crypts and folds further aid in trapping foreign material. Tonsils normally lack a prominent fibrous capsule. This is in contrast to lymph nodes, which have a capsule and subcapsular sinus that reflects the antigenic delivery through afferent lymphatics. The mucosa lining the palatine and lingual tonsils consists of stratified squamous epithelium, whereas the mucosa overlying the pharyngeal tonsil is pseudostratified ciliated respiratory type epithelium that contains occasional goblet cells. The epithelium lining the crypts or folds represents an extension of the regional surface epithelium. However, the epithelial lining of some crypts in the palatine tonsil may occasionally consist of respiratory mucosa. The palatine tonsil contains 10 to 30 crypts that may extend to the deep juxtacapsular region. In the lingual tonsil (Figure 15.16) and pharyngeal tonsil, the lining epithelium forms only shallow folds 0.5 to 1.0 cm deep. Sulfur granules comprised of Actinomyces and other Actinomyces-like oral flora are a frequent finding within tonsillar crypts. As in lymph nodes, the lymphoid component may contain lymphoid follicles, some with active germinal centers. Intraepithelial lymphocytes within the surface and crypt-lining epithelium (called lymphoepithelium) is commonly observed (Figures 15.17,15.18) and merely reflects the normal passage of lymphocytes. Sometimes the epithelium is so heavily infiltrated by lymphocytes that it is scarcely

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distinguishable. Intraepithelial lymphocyte trafficking primarily overlies subepithelial lymphoid follicles (Figures 15.19,15.20), resembling Peyer's patches of the small intestinal mucosa. Intraepithelial lymphocytes of the surface mucosa are predominantly T cells (CD3+, CD5+, CD7+, and CD8+), whereas those present within the crypt epithelium include both T cells and B cells (36). The epithelial cells of lymphoepithelium (known as M cells) exhibit numerous surface microvilli and microfolds. At the ultrastructural level, intraepithelial lymphocytes have been shown to be located within intracytoplasmic compartments that communicate with each other to form an intraepithelial network of channels (37).

Figure 15.16 Lingual tonsil. Low-power view of lymphoid tissue and underlying mucous glands that appear as pale areas among bundles of skeletal muscle.

Figure 15.17 Lingual tonsil. The mucosa (nonkeratinized stratified squamous epithelium) is infiltrated with numerous lymphocytes that obscure the basement membrane.

Figure 15.18 Lingual tonsil. Squamous epithelium of crypt is disrupted by lymphocytes that have migrated into it.

Figure 15.19 Tonsil lymphoepithelium overlying a secondary lymphoid follicle with a germinal center. The CD3 (T-cell marker) immunostain highlights abundant T cells trafficking through the epithelium. (We acknowledge Christopher N. Otis for his help with this photomicrograph.)

Figure 15.20 Tonsil showing CD20 (B-cell marker) immunoreactive lymphocytes located within a lymphoid follicle. B cells focally pass through the lymphoepithelium. (We acknowledge Christopher N. Otis for his help with this photomicrograph.)

Tonsils are normally found in close association with minor salivary glands (Figure 15.21). Frequently, the excretory ducts of these mucous glands empty into the tonsillar crypts. The minor salivary glands (Weber's glands) adjacent to the palatine tonsils are thought to be a putative reservoir of pathogenic bacteria and therefore should be removed along with the tonsil during a tonsillectomy. Small foci of elastic cartilage and even bone may be present close to the

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fibrous capsule of the palatine tonsil, which has been proposed by some authors to represent metaplasia or heteretopia (38) but more than likely is an embryological remnant of Reichert's cartilage that originates from the second branchial arch.

Figure 15.21 Lingual tonsil. Lymphoid tissue with follicles under mucosa and around its infolding (crypt). Note mucous glands and ducts.

Table 15.2 Minor Salivary Glands of the Mouth, Nose, and Paranasal Sinuses

Name Location Type of Acini
Labial (superior and inferior) Lips Mixed (predominantly mucous)
Buccal Cheek Mixed (predominantly mucous)
Glossopalatine Anterior faucial pillar
Glossopalatine fold
Pure mucous
Palatine Hard palate
Soft palate
Pure mucous (mixed in avula)
  Uvula Mixed (predominantly mucous)
Palatine tonsil (Weber's glands) Subjacent to tonsil capsule Pure mucous
Sublingual Floor of mouth Mixed (predominantly mucous)
Lingual (glands of Blandin and Nuhn) Anterior tongue Mixed (predominantly mucous)
Tongue (Ebner's glands) Circumvallate papillae Pure serous
Lingual tonsil Base of tongue Pure mucous
Nasal and paranasal Nose and sinuses Mixed

Minor Salivary Glands

Numerous small salivary glands are scattered throughout the submucosa of the oral cavity, nose, and paranasal sinuses, as well as adjacent to the palatine and pharyngeal tonsils. These glands are not encapsulated and are named by their location. They can be classified as mucous, serous, and mixed seromucinous types (Table 15.2). These glands produce secretions similar to those of the major salivary glands, which empty onto the mucosal surface through numerous small excretory ducts. The secretory activity of these glands appears to be continuous, although they can respond to specific local chemical or physical stimuli.

Figure 15.22 Minor salivary glands in the uvula are surrounded by cross-striated muscle. The gland with the distinct duct is of the pure mucous type. The other gland is seromucinous, with the serous cells forming darker staining crescents (arrows).

Structurally, the minor salivary glands are compound tubular or tubuloacinar glands. Their secretory portions are the acini that are designated according to their secretion as mucous, serous, or mixed. Within mixed acini, the mucous cells are nearest to the excretory duct, whereas the serous cells are at the cul-de-sac of the acini and appear as crescents, called the demilunes of Giannuzzi (Figures 15.22,15.23). The mucous acini are more tubular than those of the serous type. The mucous cells are also larger,

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and their flattened nuclei are present at the cell bases. The mucous cells have a pale-appearing cytoplasm in H&E-stained sections (Figure 15.13) and will also stain with Alcian blue, periodic acid-Schiff (PAS), or mucicarmine (39,40). The smaller serous cells have more rounded basal nuclei and have an eosinophilic cytoplasm that contains zymogen granules. Contractile myoepithelial cells are wrapped around the acinus and assist by squeezing the secretion from the acinar cells into the excretory ducts (41). The myoepithelial cells of the minor salivary glands are variably immunoreactive with antibodies to cytokeratin (CK5, CK14, and CK17), to smooth muscle markers (smooth muscle actin, h-caldesmon, calponin), p63 (nuclear immunoreactivity), and, rarely, to S-100 protein (42). It should be noted that melanocytes may be found in a small proportion (<2%) of minor salivary glands (43).

Figure 15.23 Mixed minor salivary gland of the uvula. Acid mucopolysaccharides in mucous cells are stained turquoise (Alcian blue at pH 2.6).

It is important to note that the minor salivary glands, wherever they occur in the mouth, nose, or paranasal sinuses, can become involved by the same pathologic processes as the major salivary glands. This is especially true for neoplasms, which arise from various cellular components of the minor salivary glands.

The surgical pathologist must be well aware of the fact that squamous metaplasia can occur in the excretory ducts and acini of minor salivary glands. For instance, epithelial regeneration after injury of various types may lead to squamous metaplasia that can mimic squamous cell carcinoma. A good example of this is seen in necrotizing sialometaplasia or in irradiated salivary glands. In the latter case, the diagnostic dilemma is usually compounded by the possibility of a recurrence of previous squamous cell carcinoma. Oncocytic cells may be found in minor salivary glands in varying numbers and distribution patterns (Figure 15.24). Oncocytes ( swollen cells ) are large, cuboidal, or columnar epithelial cells with a finely granular eosinophilic cytoplasm that have been identified in many exocrine or endocrine glands (44). Up to 60% of their cytoplasm is usually occupied by mitochondria that can be visualized after long-term (48 hours) staining with phosphotungstic acid-hematoxylin on fresh-frozen sections incubated for the histochemical demonstration of mitochondrial enzyme activity, by means of immunohistochemistry (e.g., antimitochondrial antibody), or by electron microscopy. Oncocytes are benign cells that occur with increasing frequency in older persons. They develop due to metaplasia of ductal and acinar epithelium. However, the etiology and functional significance of oncocytic metaplasia is not clear. In the minor salivary glands, oncocytes can be seen in nodular or diffuse oncocytosis, oncocytoma (45,46), and even oncocytic carcinomas (47).

Figure 15.24 Oncocytes in minor salivary gland appear as cuboidal swollen cells with a finely granular oxyphilic cytoplasm.

Cheeks

The skin of the cheek is part of the facial skin. The inner surface of the cheeks is covered by squamous lining mucosa. The submucosa contains some fat cells and many minor salivary glands of the mixed type, embedded in loose connective tissue. The mucosa and submucosa are bound to the underlying buccal musculature by connective tissue fibers.

Juxtaoral Organ of Chievitz

Deep in the wall of the cheeks overlying the angle of the mandible sits an anatomically well-defined small fusiform structure, the juxtaoral organ (JOO) of Chievitz, which is normally present in the buccotemporal space (48,49). In adults, it measures 0.7 to 1.7 cm in length and 0.1 to 0.2 cm in diameter and persists throughout life. It is multilobulated, has a dense fibrous capsule, and consists of round or elongate nests of nonkeratinizing squamouslike epithelial cells embedded in an organized connective tissue stroma that is rich in small nerves and sensory receptors innervated by two to four branches of the buccal nerve (50). The connective tissue envelope is divided into a thin inner stratum fibrosum internum, middle stratum nervosum, and outer stratum fibrosum externum. These nests of epithelial cells appear in a cluster on histologic sections, but serial sectioning shows them to be small sprouts and folds in continuity with a mass of epithelium (49). Thus, cross sections through different portions of the JOO can show considerable variation in number and shape of epithelial sprouts (Figure 15.25). The larger nests of epithelium are composed of cells with a clear PAS-positive cytoplasm and round or oval nuclei, forming light centers. Intercellular bridges can be seen toward the center of the cell nests. The cells in the smaller nests can show a whorl-like or concentric arrangement. Occasionally, a glandlike lumen or a follicle filled with colloidlike mucin-negative material is encountered. Melanin pigmentation has been reported in the JOO (51). The central epithelial cells of the JOO appear to be immunoreactive for cytokeratins, whereas the outer

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more basaloid cells are usually keratin negative. The cell nests are also positive for vimentin and epithelial membrane antigen (EMA) but are negative for S-100 protein, glial fibrillary acidic protein (GFAP), neurospecific enolase (NSE), synaptophysin, and chromogranin (52,53).

Figure 15.25 Juxtaoral organ of Chievitz. Small nests of nonkeratinized squamous epithelial cells are delineated by basement membrane. The elongated cells outside the epithelial islands are fibroblasts and Schwann cells. Nerve is seen below and to the right.

The seemingly esoteric and minute JOO has considerable importance for the surgical pathologist because the presence of squamous epithelial nests intimately admixed with numerous small nerves may be misinterpreted as perineural invasion by squamous cell carcinoma (54). On the other hand, astute pathologists aware of this pitfall have, in a case of a mucoepidermoid carcinoma with lymphatic spread in the retromolar region, correctly recognized the epithelial nests of the juxtaoral organ (55). Such cases unequivocally demonstrate the importance of awareness of this small organ. Cases of clinically enlarged (56) and hyperplastic JOOs have been described (57), but so far no carcinoma originating from it has been reported. The function of the JOO is unknown. Since Johan Henrik Chievitz, a Danish anatomist, described this structure in 1885 in a 10-week-old human embryo (58), it has been widely believed that the organ of Chievitz is a rudimentary structure, representing an abortive salivary gland anlage. More recently, the possibility of a neurosecretory and receptor function of the organ has been raised (59). The JOO has been shown to contain pacinian corpuscles (60), supporting its mechanosensory function. For a thorough review of the literature, the reader is referred to the small monograph by Zenker (49) or review paper by Pantanowitz and Balogh (59). Finally, we would like to alert our readers to the fact that similar benign epithelial islands may reside within peripheral nerves in the maxilla (61) and mandible (62).

Tongue

Situated in the floor of the mouth, the tongue is an organized mass of cross-striated muscle invested by mucous membrane. Its muscles are partly extrinsic (i.e., have their origins outside the tongue) and partly intrinsic, being contained entirely within it. The bundles of cross-striated muscle are embedded in connective tissue with some adipocytes and are arranged three-dimensionally. The tongue is well-supplied with blood vessels that form numerous anastomoses. The tongue is richly endowed with myelinated and nonmyelinated nerves containing motor, sensory, and vegetative nerve fibers, some with ganglion cells. The ventral (under) surface of the tongue is covered by smooth lining mucosa that has short, blunt rete ridges (Figure 15.26). Its submucosa merges with the connective tissue that intersects with the ventral muscle bundles of the tongue.

The dorsal (upper) surface of the tongue is divided into an anterior and posterior part by a V-shaped shallow groove, the sulcus terminalis. The anterior two-thirds of the dorsum of the tongue is lined by specialized mucosa, which is bound by connective tissue fibers to the underlying skeletal muscle of the tongue. This specialized mucosa is modified keratinized squamous epithelium covered with small projections (papillae) that are visible to the naked eye. The pathologist has to be aware of these papillae so as not to mistake them for papillary epithelial hyperplasia, papillomas, or oral hairy leukoplakia. According to their shape, the papillae can be filiform, fungiform, foliate, or circumvallate. The great majority are filiform papillae, conical projections of the keratinized epithelium (Figure 15.27). Among these are scattered the fungiform papillae, which are rounded elevations above the surface of the tongue; their surface is not keratinized (Figure 15.28). Clinically, fungiform papillae appear as small red nodules because the thin epithelium does not mask the underlying vascular connective tissue. Microscopically, fungiform papillae should not be misinterpreted as denture-induced fibrous hyperplasia or small traumatic fibromas. The foliate papillae are located posteriorly along the sides of the tongue. At

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the junction of the anterior two-thirds and the posterior one-third of the tongue are the circumvallate papillae. These are the largest papillae, measuring 0.1 to 0.2 cm in diameter and are arranged in a V-shape immediately anterior to the sulcus terminalis. The circumvallate papillae number 6 to 12. A small, ring-shaped furrow surrounds each circumvallate papilla and separates it from a circular, palisade-like mucosal elevation (vallum), which is the outer border of the circumvallate papilla (Figure 15.29).

Figure 15.26 Ventral surface of tongue. The stratified nonkeratinized squamous epithelium of the lining mucosa has a slightly wavy interface with the lamina propria. A few scattered lymphocytes are seen in the lamina propria and in the epithelium.

Figure 15.27 Dorsal surface of tongue. Filiform papillae have a connective tissue core beset with secondary papillae with pointed ends. The superficial squamous cells are keratinized. Note the slender, pointed rete ridges.

Taste buds are present in large numbers on the side of the circumvallate papillae and in lesser numbers on the fungiform and foliate papillae, as well as elsewhere on the dorsal and lateral aspects of the tongue. These small epithelial organs stain lighter than the surrounding epithelium. Like other simple epithelia, taste buds express low-molecular weight keratins such as CK18, and, accordingly, they are immunoreactive with the antibody CAM5.2 (Figure 15.30). Numerous small serous glands (Ebner's glands) are located under the circumvallate papillae. The ducts of these glands empty their secretion into the small furrow around each papilla; this serous secretion flushes out the furrows, thus facilitating perception of new tastes (Figure 15.29). The taste buds are barrel-shaped intramucosal sensory receptors that occupy the full thickness of the mucosa and communicate with the surface through a small opening, the gustatory pore (Figure 15.31). The taste buds are composed of three types of cells: (a) gustatory or taste cells, (b) supporting, or sustentacular, cells, and (c) basal cells. The taste cells are crescent-shaped, have lightly staining cytoplasm, and possess numerous

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fine microvilli that protrude through the taste pore as gustatory hairs. The basal end of the taste cells has intimate contact with many fine nerve terminals that leave through the basement membrane and become myelinated outside the taste bud. The supporting cells are likewise crescentic, extending between the basement membrane and the surface; they form a shell for the taste bud and are also scattered between the gustatory cells. The supporting cells have a dark cytoplasm and possess microvilli that also protrude through the taste pore. The small basal cells, situated between the bases of the other cells, give rise to the other cells of the taste bud (63,64).

Figure 15.28 Fungiform papillae. Slightly rounded, elevated structures with a larger connective tissue core. Smaller connective tissue papillae project into the base of the surface epithelium.

Figure 15.29 Circumvallate papilla. Numerous taste buds are on the lateral walls of the papilla and on the epithelium facing the papilla within the furrow. Ducts of serous glands open into the furrow surrounding the circumvallate papilla.

Figure 15.30 Taste buds showing immunoreactivity for CAM 5.2.

Figure 15.31 Taste buds on the side of a circumvallate papilla. The cells of the intraepithelial taste buds are spindle-shaped and oriented at a right angle to the surface. The cell nuclei are elongated and are situated mainly in the basal half of the buds. Nerve fibers ending on the sensory (gustatory) cells cannot be seen with H&E stain.

The apex of the V-shaped sulcus terminalis projects backward and is marked by a small pit, the foramen cecum, which is an embryologic remnant indicating the upper end of the thyroglossal duct. Correspondingly, ectopic thyroid tissue can occur at the base of the tongue (lingual thyroid) or anywhere along the tract of the thyroglossal duct caudally (Figure 15.32). Microscopically, ectopic thyroid resembles normal thyroid tissue. However, the surgical pathologist should be aware that the presence of thyroid glands within muscle may mimic carcinoma. Ectopic thyroid tissue may undergo all the physiologic and pathologic changes of the thyroid gland proper.

Figure 15.32 Lingual thyroid. The glandular parenchyma is embedded in skeletal muscle. The thyroid tissue is not encapsulated, and care should be taken to avoid mistaking it for invasive growth.

Gingiva

The gingiva (gum) is that portion of the oral mucosa that surrounds the neck of the teeth like a collar. Masticatory mucosa (i.e., parakeratinized or keratinized stratified squamous epithelium) covers the gum. There is no submucosal layer. Instead, the connective tissue of the lamina propria contains collagenous fibers that bind the epithelium tightly to the underlying alveolar periosteum and bone. The gingival epithelium interdigitates with the underlying connective tissue, forming long, interconnected rete ridges that are separated by connective tissue plates and papillae (Figures 15.33,15.34). The gingival epithelium is divided anatomically into oral gingival, oral sulcular, and junctional epithelia. The cytokeratin expression profile of gingival epithelium corresponds to this anatomical division (Table 15.1).

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Oral gingival epithelium that extends onto the oral surface of the gum best fits the general pattern of masticatory mucosa. The short portion of gingiva apposed to the tooth (sulcular gingiva) differs from the rest of gingival epithelium in that it is thinner, lacks the characteristic rete ridges, and is not keratinizing (65,66).

Figure 15.33 Gingiva (gum). The masticatory mucosa has tall rete ridges. A dense network of collagen fibers (blue) tightly anchors the epithelium to the underlying bone (not shown); the keratin layer (orange band) on the surface of the epithelium imparts further strength to it (Mallory's trichrome).

Figure 15.34 Gingiva. Tall rete ridges and dense lamina propria with blood vessels in papillae.

The gingiva is highly vascular; its vessels originate in the periodontium and extend into the lamina propria, forming well-organized capillary loops. Occasionally random biopsies of gingiva have been performed to support the diagnosis of systemic diseases (e.g., amyloidosis).

Intraepithelial Nonkeratinocytes

Four different nonepithelial cell types normally occur in the oral mucosa: melanocytes, Merkel cells, Langerhans cells, and lymphocytes.

Melanocytes are found mainly in a basal location in the oral mucosa; they are more common in people with darker complexions (67,68). Small areas of melanin pigmentation, mostly less than 10 mm in diameter, may occur. They are most common on the gingiva but are also seen in the lips, palate, and buccal mucosa and are called mucosal melanosis (melanotic macules) (69) (Figure 15.35). Melanin pigment formed by melanocytes in the basal layer is transferred to adjacent epithelial cells. Such changes can sometimes occur after inflammatory reactions, in smokers, with Peutz-Jeghers syndrome and Addison's disease, or secondary to drugs and human immunodeficiency virus (HIV) infection. Melanocytic hyperplasia (lentigo) and pigmented nevi may also occur in the oral mucosa but less commonly than on the skin (70,71,72,73). Histologically, a lentigo shows increased melanin pigmentation in the basal cell layer without an increase in the number of melanocytes. Intramucosal nevi, similar to intradermal nevi, are the most common type of nevus. Other types of nevi, such as compound nevi, junctional nevi, blue nevi, and combined forms can be observed on the vermilion border, cheek mucosa, gingiva, palate, and tongue. Understandably, primary malignant melanomas can arise anywhere from the oral mucosa (74).

Merkel cells also occur in the basal layer of the oral epithelium, either individually or in clusters (75). Clusters are preferentially located in masticatory mucosa in close contact with the tongue, which supports the notion that they have a mechanoreceptor function. On routine H&E-stained sections, their cytoplasm appears lighter than that of the surrounding basal cells. These neuroendocrine cells are morphologically and functionally identical to those in the skin. They are immunoreactive with antibodies to S-100 protein, chromogranin, CK20, and villin. Their ultrastructure is characterized by many intracytoplasmic dense-core, membrane-bound granules, 80 to 100 m in diameter (Figure 15.36).

Langerhans cells, mostly located suprabasally, are microscopically similar to melanocytes and cannot be distinguished with certainty in routine H&E-stained sections. In the gingiva, the Langerhans cells are structurally and functionally similar to those in the skin (76,77). Their cytoplasm appears clear, and their small indented ( coffee bean ) nucleus stains heavily with hematoxylin. Their dendritic processes, spread among the cells of the stratum spinosum, can be seen well with the immunohistochemical stain for S-100 protein (Figure 15.37), as well as CD1a, the MHC class II

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molecules (e.g., HLA-DR), and various adhesion molecules (78). Electron microscopy shows characteristic Birbeck granules in their cytoplasm and a lack of tonofilaments and desmosomes. The frequency of oral mucosal Langerhans cells varies inversely with the degree of keratinization. They are quantitatively lowest in the floor of the mouth and do not occur only around the basal portion of the taste buds and in epithelium lining periodontal pockets.

Figure 15.35 Mucosal melanosis of the lip. Numerous melanocytes above the basal lamina appear as a brown ribbon.

Figure 15.36 Merkel cell surrounded by keratinocytes in the basal layer. Transmission electron micrograph shows the lighter-staining cytoplasm with characteristic and subplasmalemmal, membrane-bound, dense-core granules. The nucleus has no fibrous lamina, unlike melanocytes. The adjacent dermis contains fibroblasts. (Original magnification 11,500.)

Langerhans cells play an important role in the immune response, being involved in the processing and presentation of antigens to subjacent lymphocytes. An increased number of Langerhans cells is seen in biopsy samples of the oral mucosa in oral lichen planus, associated with dental caries, with tobacco and alcohol consumption, and in tumor epithelium of invasive oral squamous cell carcinoma.

Teeth and Supporting Structures

The deciduous and permanent teeth have a similar microscopic appearance. The teeth are set in bony sockets on the alveolar processes of the maxillae and the mandible. The part of the tooth that lies within the socket is called the root; there may be multiple roots. The tip of each root is called the apex. The alveolar processes are covered by the gum, and the crowns of the teeth project above the gums. The roots of the teeth are held securely in their sockets by bundles of collagen fibers called the periodontal ligament (periodontal membrane) (12,66). The periodontium includes the tissues investing and supporting the teeth: the cementum, periodontal membrane, alveolar bone, and gingiva (Figures 15.38,15.39). The center of each tooth has a

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pulp chamber, or pulp cavity, that is filled with dental pulp containing loosely arranged fibroblasts, nerves, blood vessels, and lymphatics (79) (Figure 15.40). The pulp chamber narrows toward the root and becomes the root canal. The vessels and postganglionic sympathetic and sensory nerve fibers enter and leave the root canal through a small opening, the apical foramen. The pulp chamber of the growing tooth is lined by a single continuous layer of odontoblasts, which are tall columnar cells with oval nuclei. An elongated cell process, also known as Tomes' fiber, reaches from each odontoblast into the extracellular matrix secreted by them (Figure 15.5). The matrix around the odontoblastic process eventually mineralizes, so that Tomes' fiber comes to lie within a dentinal tubule (80,81). Besides the odontoblastic process, the tubules also contain 200 m-long unmyelinated nerve fibers, which account for the well-known sensitivity of dentin. Dentin is arranged in the shape of tubules running from the pulp chamber toward the periphery. The dentinal tubules and the meshwork of collagen between them are embedded in hydroxyapatite crystals. On a weight basis, 80% of dentin consists of inorganic calcium salts and 20% of organic material. It is harder than bone but softer than enamel. Dentin makes up most of the wall of the tooth. In the mature tooth, many odontoblasts become inactive, but some continue producing predentin at a reduced rate throughout the life of the tooth. In response to physiologic or pathologic stimuli, odontoblasts can upregulate their protein synthetic activity.

Figure 15.37 Langerhans cells in mucosa of tongue. Dendritic cells in the suprabasal epidermis demonstrate immunoreactivity for S-100 protein.

As the dental pulp ages, the number of fibroblasts decreases and, concomitantly, the number and size of collagen fibers increases. Pulp stones (denticles) are commonly observed in the dental pulp of aging individuals. True denticles contain dentinal tubules within a mineralized matrix and are surrounded by odontoblasts. False denticles are composed of a mineralized matrix arranged in concentric lamellae. Most denticles are asymptomatic.

Enamel covers the crown of the tooth. It is the hardest material found in the body and consists of 99.5% apatite crystals (82). Mature enamel is made up of long thin rods that dissolve during decalcification and are therefore not seen on conventional histologic sections. The dentin-enamel junction lies at the former interface between the inner enamel epithelium and dental mesenchyme. Coronal dentin is covered with enamel, and radicular dentin is covered with cementum. Thus, cementum covers the root of the tooth. A slight indentation (cervical line) encircles the tooth and marks the junction of the crown with the root.

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The cementum joins the enamel at this junction (cementoenamel junction). Cementum is similar in structure and composition to bone but has fewer cells, called cementocytes, that occupy lacunae (10,11). It is composed of 55% organic material (mainly calcium) and 45% inorganic material. Cementum is attached by the periodontal ligament to the surrounding bone (Figure 15.39). In older persons, many cementocytes die, and only the surface layer appears viable. Another aging phenomenon are cementicles, which are small round calcified bodies on or in the cementum and in the periodontal ligament. Cementicles are of no clinical significance.

Figure 15.38 Schematic drawing depicts the periodontium including the gingiva, alveolar bone, periodontal ligament, and cementum.

Figure 15.39 Root of tooth and supporting structures, perpendicular section. Dentin is covered by a thin layer of cementum (appearing as a blue band). The periodontal ligament (L) holds the tooth in the bony socket of the alveolar process (B).

Figure 15.40 Pulp of developing tooth. Odontoblasts (arrows) line dentin. The pulp consists mostly of loosely arranged fibroblasts. Note the delicate wall of blood vessels.

From the pathologist's point of view, it is noteworthy that examination of teeth involved in neoplastic growth in most cases shows tumor invading the periodontal ligament and the alveolar bone, destroying these structures. The roots of the teeth may remain intact or may undergo resorption. However, the dental pulp is rarely invaded by neoplasm.

Odontogenic epithelium changes over time. Before tooth eruption, it consists of the external enamel epithelium, inner enamel epithelium, stellate reticulum, Hertwig's epithelial root sheath, and dental lamina; after complete tooth formation, it comprises the epithelial rests of Malassez. Most odontogenic epithelia express cytokeratins 5, 8 and 19 (83). In addition, the external enamel epithelium and stellate reticulum also express cytokeratins 7, 13, 14, 17, and 18; the inner enamel epithelium, cytokeratins 14 and 18; dental lamina, cytokeratins 7, 13, and 14; and epithelial rests of Malassez, cytokeratins 14 and 19. During odontogenesis, CK14 expression in ameloblasts is gradually replaced by CK19. Odontogenic epithelium is the source of odontogenic cysts and some neoplasms, which explains why CK19 is present in almost all epithelial cells of odontogenic cysts.

Pathologic Correlates of the Rests of Serres and Rests of Malassez

Developmental remnants of the dental lamina, called the rests of Serres, commonly occur under the gum as small nests of squamous epithelium (10,14) (Figures 15.2, 15.41). These epithelial islands may proliferate and undergo cystic degeneration, which leads to the formation of gingival cysts. Similarly, epithelial remnants of Hertwig's root sheath, called the rests of Malassez, are universally present in the periodontal membrane and, exceptionally, even in the bone of the alveolar ridge. When dental caries cause a bacterial infection and necrosis of the pulp, the infection usually spreads toward the apical foramen, and a periapical granuloma may develop. As a result of the inflammatory stimulus, the nearby epithelium of the rests of Malassez begins to proliferate and forms an epithelial lining in these apical granulomas (Figure 15.41). It is also assumed that the rests of Serres and the rests of Malassez are potential sources of ameloblastomas and odontogenic cysts.

Nose and Paranasal Sinuses

External Nose and Nasal Vestibule

The external nose is covered by skin that is rich in sebaceous glands, sweat glands, and small hairs. The anterior skin of the nares and widened nasal vestibule, lined by skin that is

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continuous with the integument of the nose, similarly contains many hair follicles and sebaceous and sweat glands. The squamous epithelium of the vestibule merges with the respiratory mucosa, which covers the respiratory portion of the nasal cavity and all of the paranasal sinuses.

Figure 15.41 Rests of Malassez in periodontium near the apical granuloma.

Nasal Mucosa

At the level of the limen nasi, the lining of the nasal cavity gradually changes from squamous epithelium to nonciliated cuboidal or columnar epithelium. Farther into the nasal cavity, this becomes continuous with the pseudostratified ciliated columnar epithelium (respiratory epithelium). The mucosa of the respiratory portion is continuous with that of the ostia and contiguous paranasal sinuses. The mucosal lining contains three main cell types: basal (reserve) cells, goblet cells, and ciliated cells (Figure 15.42). Basal cells, confined to the vicinity of the basal lamina, divide to produce new daughter cells that differentiate to become mucous or ciliated cells. The mucous cells rest on the basement membrane with a slender stem, and the cytoplasm of their apical portion contains varying amounts of mucus. As these cells fill up with mucus, they resemble a goblet with a foot and a stem. The cells discharge their contents to form a blanket of mucus that covers the surface of the respiratory epithelium. Another source of this mucous coat is the secretion from the seromucinous glands in the lamina propria.

Figure 15.42 Pseudostratified respiratory mucosa of the nose with predominantly ciliated cells. Goblet cells have clear cytoplasm. The basal cells (arrow) are lying on thin basal lamina.

The majority of the cells of the respiratory epithelium are normally made up of ciliated cells bearing small fingerlike cell processes, the cilia, which project into the lumen. Each cell has over 200 cilia, each about 5 m long. Ultrastructurally, on cross section the ciliary shafts show a highly characteristic circular arrangement of nine pairs of microtubules (doublets), which are arranged symmetrically around two central microtubules (Figure 15.43). Longitudinal sections of the cilia show that the ciliary shaft ends in a basal body (kinetosome), from which it is derived (84). The nasal mucosa is a convenient site to biopsy when ultrastructural abnormalities of cilia are suspected, such as in immotile-cilia syndrome (85,86). The function of the ciliated cells in the nose is to constantly move the protective mucous blanket by the coordinated sweeping motion of the cilia toward the pharynx. In order to perform this function, the cilia beat at 10 to 20 cycles/second. They have an effective whiplike stroke forward and a recovery stroke backward. The propulsive forward phase is much faster and more vigorous than the recovery phase (87). Ciliary activity is optimal at the normal nasal temperature of about 30 C. However, cilia are hardy and persist under unfavorable conditions, including under extreme cold and heat. They will also beat normally and forcefully in a pus-filled cavity. When injured or destroyed by an acute infection, they regenerate rapidly. They do not, however, tolerate excessive drying. Accordingly, they are dependent always upon a coating of moisture for their activity and preservation. The blanket of mucus covering the nasal mucosa and paranasal sinuses forms a conveyor of the bacteria and other foreign matter. The nasal mucociliary layer is the first line of defense against bacterial invasion in this location.

Melanocytes are also present in the normal mucosa of the upper airways. In the nasal cavity they can be seen in the respiratory epithelium and nasal glands. Melanocytes are commonly encountered in the lamina propria of the septum and turbinates, particularly in dark-skinned adults (88). This explains why primary malignant melanomas are well-known to arise in the nose and paranasal sinuses (89).

Intraepithelial lymphocytes are diffusely scattered throughout the nasal mucosa. These are uniformly CD8+ T cells (36). These T cells coexist with a population of dendritic cells that lack CD1a expression. The nasal mucosa and subepithelial tissue contain virtually no B cells. This

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finding may explain why most primary nasal lymphomas are of CD8+ T-cell derivation.

Figure 15.43 Transmission electron micrograph of nasal mucosa. Vertical section shows ciliated epithelial cells extending to the surface. The shafts of the slender long cilia have peripheral and central microtubules that appear as darker linear structures extending from the kinetosome (basal body) (B). Cross-banded filamentous rootlets (R) are associated with kinetosomes. Note junctional complexes (J). Inset: Cross section of the shaft of two cilia. Note the symmetrically arranged nine peripheral doublets and the central pair of single microtubules. (Original magnification 25,000; inset, original magnification 87,500.)

Beneath the mucous membrane is the lamina propria, containing numerous small mucous and serous glands that discharge their secretion through lobular ducts onto the surface (Figure 15.44). These glands are embedded in vascular fibroconnective tissue, which is attached to the perichondrium and periosteum of the cartilages and bones forming the nasal cavity (90,91,92).

The turbinates are somewhat curved structures that are supported by an osseous axis enveloped by relatively thick mucosa (Figures 15.1, 15.45). Their convex surface protrudes toward the nasal cavity. Located beneath their mucosa is a tunica propria or stroma that attaches the mucosa to the underlying structures. Their tunica propria is of variable thickness, being thickest in the areas more exposed to inhaled and exhaled air (i.e., over the nasal septum and medial aspects of the inferior and middle turbinates). In these areas, the epithelium contains many goblet cells and the basement membrane is prominent (93). These areas also have abundant blood vessels and clusters of mixed seromucinous glands (6 10 glands/mm2) (Figure 15.46). The glands vary from simple straight tubules lined with goblet cells to tubuloalveolar glands. The chief ducts of the latter open onto the mucosal surface by minute orifices. The glands tend to be at a level between the mucosa and the underlying bone.

The turbinates and the lower part of the septum are rich in venous sinuses, which are of variable size and shape, forming a dense network of large veins that resemble erectile tissue (Figure 15.47). These blood vessels are of irregular shape, have muscular walls, and can rapidly dilate and

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constrict, thereby permitting fast adjustments of mucosal temperature and secretion to climatic changes. It is important for the surgical pathologist to know about the normal rich vascular anatomy of the turbinates in order to avoid mistaking them for a hemangioma, angiofibroma, or angioleiomyoma. The stroma of the nasal mucosa also contains lymphatics, small nerves, and a sprinkling of lymphocytes and plasma cells but no lymphoid aggregates. A few mast cells and eosinophils are normally also present.

Figure 15.44 Nasal seromucinous gland with duct. Serous cells with darker staining cytoplasm are at the periphery of tubuloacinar glands and form the demilunes of Giannuzzi.

Figure 15.45 Middle turbinate, coronal section. Bone in the axis of the turbinate appears as a delicate, curled structure. The covering mucous membrane and tunica propria are rich in blood vessels and mucous glands, particularly on the convexity and inferior border of the turbinate, areas that are most exposed to the airstream in the nasal cavity. (Low-power view.)

Figure 15.46 Turbinate, coronal section. Mucosal blood vessels are surrounded by a thick sheath of connective tissue (blue); note the large artery near the bone (B) (Mallory's trichrome).

The osseous portion of the turbinates consists of thin, interconnecting laminae of lamellar bone, forming a continuous shell that is interconnected with bone trabeculae. The interosseous spaces contain numerous large veins, arteries, and some nerves. In contrast to the submucosal veins, the intraosseous veins have a rather large round or oval lumen on cross section and have proportionately thin walls. Occasional adipocytes, but no hematopoietic marrow, are seen in turbinated bone. The presence of prominent hematopoiesis in the facial and nasal bones or the paranasal sinuses is abnormal and may be observed in conditions such as thalassemia major.

The nasal septum consists of a large cartilaginous plate and four small osseous plates, all of which firmly unite with sutures (Figure 15.48). The nasal mucosa is closely apposed to the underlying structures of the nasal septum. The periosteum and perichondrium of the nasal septum attach so closely to the overlying submucosa as to constitute one

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membrane, called the mucoperiosteum. A common site of nosebleed is Little's area (or Kiesselbach's area) on the anterior part of the cartilaginous nasal septum above the intermaxillary line. The submucosa of this area is richly supplied with thin-walled dilated blood vessels (Figure 15.49). Although rarely seen in surgical specimens, Little's area should not be mistaken for a pyogenic granuloma, which frequently occurs in this location.

Figure 15.47 Inferior turbinate. Numerous larger blood vessels of variable size and shape are closely packed and form a spongelike vascular system resembling erectile tissue. The endothelial cells are evenly distributed. Capillaries are lacking.

Figure 15.48 Suture (S) in the nasal septum. Parallel edges of the vomer (top) and maxilla are connected by parallel, densely arranged collagen fibers that are anchored in the bones.

Vomeronasal Organ of Jacobson

The vestigial remains of a paired embryonic structure, the vomeronasal organ of Jacobson, are situated under the mucosa of the lower anterior side of the nasal septum covering an area of 0.2 to 0.6 cm. In adults, it consists of a small tubular sac lined by columnar epithelium with microvilli, but it has no sensory cells with cilia and lacks other well-differentiated olfactory structures (Figure 15.50). The organ is best developed in the twentieth week of embryonic life, after which regressive changes occur and it becomes rudimentary. In humans it has no known function and is of no pathologic significance (94). In many vertebrates, Jacobson's organ is highly developed, particularly in animals of keen olfactory sensibility (95,96,97).

Figure 15.49 Little's area. Teleangiectatic, thin-walled blood vessels are clustered under the epithelium in the anterior portion of the nasal septum. This area is above the level of mucous glands.

Figure 15.50 Vomeronasal organ of Jacobson in a 22-week-old embryo (180 mm crown-rump length), including a cross section of the tubular structure adjacent to vomeronasal cartilage. In humans the columnar epithelium has microvilli but no sensory epithelium.

Olfactory Mucosa

The roof of the nasal cavity and contiguous portions of the nasal septum and superior turbinate form the olfactory region (98). Here, the ciliated columnar epithelium of the nasal mucosa is modified by liberally scattered cells of the sensory organ of smell. The olfactory epithelium consists of three types of cells: (a) olfactory nerve cells, (b) supporting, or sustentacular, cells, and (c) basal cells that lie on the basal lamina (99,100) (Figure 15.51). The olfactory nerve cells are spindle-shaped and have a spherical nucleus. The dendrites of these bipolar cells extend to the surface of the pseudostratified olfactory epithelium and send out a tuft of fine processes known as olfactory cilia (hairs). The cilia, which function as receptors for the detection of odorants, are 2 m long and lie along the surface of the mucosa embedded in mucus. The deep processes of these bipolar cells form axons that find their way through the basal lamina and join neighboring processes to become bundles of unmyelinated olfactory nerve fibers (100). These fibers collect to form myelinated nerves, which then pass through the cribriform plate of the ethmoid bone to end on the mitral cells in the olfactory bulb. The supporting cells are tall, cylindrical cells that in the elderly contain lipofuscin, giving the yellow hue characteristic of the olfactory mucous membrane. The free surface of these cells possesses many slender microvilli that protrude into the covering mucus. The basal cells are small and conical, lying with their base on the basement membrane. They are believed to represent

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stem cells that can give rise to new supporting and sensory cells. Under the mucosa is the lamina propria, composed of loose connective tissue in which are found the olfactory glands of Bowman (101). The secretion of these tubuloalveolar glands is carried to the surface of the mucosa by narrow ducts.

Figure 15.51 Olfactory mucosa. The population of olfactory nerve cells and supporting cells forms a pseudostratified columnar epithelium with distinct microvilli. Basal cells lie on basal lamina (arrow). Bowman's glands (G) with excretory ducts and nerves are between the epithelium and bone of nasal septum (B).

Paranasal Sinuses

The sinuses are lined with a mucous membrane that is continuous with the nasal mucosa. The mucosa is therefore similar to that of the nasal cavity. However, the epithelium (schneiderian epithelium) and lamina propria are thinner and less vascular. Seromucous glands present in the sinuses are more sparse compared to in the nasal mucosa and are largely concentrated at the ostium of the maxillary sinus. The mucus formed in the sinuses is moved by the action of the cilia through the apertures to the nasal cavities.

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Histology for Pathologists
Histology for Pathologists
ISBN: 0781762413
EAN: 2147483647
Year: 2004
Pages: 53

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