V - Head and Neck
Editors: Mills, Stacey E.
Title: Histology for Pathologists, 3rd Edition
Copyright 2007 Lippincott Williams & Wilkins
> Table of Contents > V - Head and Neck > 17 - Major Salivary Glands
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17
Major Salivary Glands
Fernando Mart nez-Madrigal
Jaques Bosq
Odile Casiraghi
Introduction
The primary function of the salivary glands is to moisten the mucous membranes of the upper aerodigestive tract. In humans, this function is fulfilled by the continuous exocrine secretion of numerous minor salivary glands. These glands are located in the submucosa throughout the oral cavity, pharynx, and upper airways. In developed species, most of the saliva is elaborated by three pairs of major glands, or salivary glands, named by their location: the parotid, the submaxillary or submandibular, and the sublingual glands. They are connected symmetrically to the oral cavity, where they empty their secretion only under specific stimuli. The saliva produced by these glands (750 1000 mL/24 hours) plays an important role in preparing food for digestion, as well as in controlling the bacterial flora of the mouth. The quality of the saliva produced by the major glands is variable and depends on both the stimuli and the predominant participating gland.
Embryologic and Postnatal Developmental Changes
Parotid Gland
During embryologic life, the parotid is the first of the three major glands to appear and is seen by the sixth week. It derives from the ectoderm as an epithelial bud from the primitive oral epithelium, at the angle between the maxillary
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process and the mandibular arch (1). As the primordia grow, they ramify into a bushlike system surrounded by mesenchymal tissue. This mesenchyma and, particularly, the basal lamina play an important role in the lobular organization of the gland (2,3,4,5), and in vascular and neural development. By the seventh week, the primitive gland moves in a dorsal and lateral direction and reaches the preauricular region. Development of the facial nerve divides the gland by approximately the tenth week into superficial and deep portions (6).
By the third month, the gland has attained its general pattern of organization. The epithelial structures are arranged in lobules, limited by a capsule of loose connective tissue (Figure 17.1A). The mesenchyma is then colonized by numerous lymphocytes that are later disposed in intraglandular and extraglandular lymph nodes. By the sixth month, the epithelial cordons are canalized and exhibit a double-cell ciliated cover. Cell differentiation begins in the excretory ducts with the progressive transformation of ciliated cells by columnar, squamous, and goblet cells (Figure 17.1B) (7). Intralobular duct and acinar differentiation, including myoepithelial cell formation, begins about the eighth month (8) and myoepithelial cell differentation by the nineteenth- to twenty-fourth week period. These cells, arranged in the basal portions of the acini and intercalated ducts, appear as clear cells with electron microscopy. Between 25 and 32 weeks, the myoepithelial cells become flattened and show cytoplasmal prolongations (9,10,11). Saliva production starts as a mucinous liquid at this time; but several studies in rodents suggest that full maturation is completed only after birth (12,13,14,15).
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Figure 17.1 Development and histogenesis of the epithelial constituents of the salivary gland. A. Fetal parotid gland at 4 months; a lobular architecture is present. B. Drawing of (A), showing the cellular lines of differentiation for the excretory ducts, (1); excretory ducts, (2); intralobular ducts, (3); and acini. |
The definitive location of the parotid is behind the inferior facial nerve maxillary branch, below and in front of the external ear. It is enclosed within a fibroadipose capsule in a depression whose anterior limit is the masseter muscle. Its superior limit is the zygomatic arch; the posterior limit is the tragus, and the inferior limit is the anterior border of the sternocleidomastoid muscle (16). The adult parotid is the largest of the three major salivary glands and weighs between 14 and 28 g. The gland is surrounded by a fine capsule and is divided into two portions by the facial nerve. The main portion, or superficial lobe, is flattened and quadrilateral; it is here that the majority of salivary tumors develop. This observation has permitted the development of conservative surgical treatment of many parotid tumors. The rest of the gland, called the deep lobe, is irregularly wedge-shaped in anatomic relationship with the parapharyngeal space (17).
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The surgical anatomic area where the parotid gland is located, is called the parotid region. In this region it is important to keep in mind the anatomical relations between the facial nerve, the gland, and the subcutaneous planes. The facial nerve has four parts, designated as retro-, inter-, intra-, and preglandular. The parotid gland is covered by a superficial musculoaponeurosis and the skin (18). Accessory parotid tissue is found in approximately 20% of cases. Nevertheless, in a recent study, the incidence was found to be 56% with no differences between right and left sides or between sexes (19). This accessory tissue may be found on the anterior surface of the gland, as well as along the parotid duct (20).
Like all the exocrine glands, the parotid is composed of numerous tubuloacinar units connected through the excretory ducts to a main duct (Stensen's duct) located in the anterior portion of the gland. The parotid duct follows a twisted course of 7 cm, crossing the masseter muscle, the corpus adiposum of the cheek, and the buccinator muscle before opening into the oral vestibule. The secretion of the accessory parotid is emptied by an independent duct reaching the parotid duct in the masseter portion.
Blood supply is by arterial branches from the external carotid. The veins are tributaries of the external jugular, and the lymphatics join the superficial and deep cervical lymph nodes. Innervation is derived from the sympathetic and auriculotemporal nerves.
Submaxillary Gland
In the submaxillary gland, the primordia appear at the end of the sixth week and, unlike the parotid, are probably of endodermal derivation (21,22). However, a recent study suggests that the sublingual process of the submandibular gland originates from a lateral ectodermal bud of the anlage of the submandibular gland (23). The epithelial bud appears in the groove between the lower jaw and tongue, at one side of the midplane. Extension of the glandular tissue in the mesenchyma goes backward beneath the lower jaw. Subsequent maturation and cell differentiation are similar to those of the parotid gland except for the lymphoid tissue, which is less obvious than in the parotid. In addition, there is no lymph node formation inside the gland. Recent studies have demonstrated that the extracellular matrix protein fibronectin is essential for cleft formation during the initiation of epithelial branching in submaxillary gland. It has also been demonstrated that inhibition of fibronectin blocks cleft formation and branching (24,25). This mechanism could be applied for other salivary glands and other exocrine glands (such as the mammary glands).
The submaxillary gland is finely encapsulated; it lies inside the submandibular triangle, an osteofibrous cavity from which it takes the form of a triangular prism. This gland weighs approximately 7 to 8 g and, like the other major salivary glands, is organized in lobules connected to a main excretory duct the submaxillary duct (Wharton's duct) which measures 5 cm in length and 2 to 3 mm in diameter. The duct originates near the surface; runs between the mylohyoideus, the hyoglossus, and genioglossus muscles; and finally opens through a narrow orifice in a small papilla called the caruncula sublingualis on each side of the frenulum linguae. A submandibular gland having three ducts that open separately into the oral cavity has also been reported (26). The blood supply is from branches of the facial and sublingual arteries. The secretomotor nerves are fibers from the cranial parasympathetic branch of the facial nerve; the vasomotor nerves are derived from the superior cervical ganglion. The lymph nodes are arranged in a row in the spaces between the mandible and the gland and are disposed in anterior, medial, and posterior groups (16,17).
Sublingual Gland
The sublingual glands are the last of the three major salivary glands to appear. Their primordia are located immediately lateral to the submaxillary glands for the greater sublingual glands and in the linguogingival sulcus for the lesser sublingual glands. The epithelial buds grow downward from the groove between the lower jaw and the tongue. Parenchymal organization and differentiation are similar to those of the submaxillary gland and are also probably of endodermal derivation.
The principal sublingual gland weighs 3 g. It lies in the sublingual fossa of the mandible and is surrounded by loose connective tissue. Its secretion is drained through a main duct called the Bartholin's duct, which opens into the submandibular duct, and various small ducts (Rivinus' ducts) that open separately into the mouth in the plica sublingualis or join the submandibular duct (16,17).
Vascular supplies come from the sublingual and submental arteries; the veins are tributaries of the external jugular. Innervation is similar to that of the submaxillary gland.
Apoptosis
In the literature, studies concerning apoptosis in salivary glands are not very frequent. Contrary to other glandular tissue, programmed cell death in the salivary glands has been sporadically studied in less-developed and developed species, using experimental animals such as rats or monkeys and, less frequently, humans (27,28,29).
In normal salivary glands, apoptosis was uncommon when observed in acinar cells and epithelial duct cells and never observed in myoepithelial cells. In specific pathologic contexts, such as duct obstruction or irradiation of the salivary glands, programmed cell death was observed with
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many significant changes in the structure of the glands (30,31). In some salivary gland diseases, such as Sj gren's syndrome, accelerated apoptosis may explain acinar and ductal cell loss with the typical functional loss of the secretory activity seen in patients with this disease.
In experimental models, apoptosis is regulated by two kinds of protein families, bcl-2-related proteins and the inhibitor of apoptosis proteins (IAP). Activation of caspase-3 is inhibited by bcl-2 or Bcl-XL and accelerated by Bax. In addition, an X chromosome linked inhibitor of apoptosis called XIAP inhibits caspase-3 activation. Several gene products induce apoptosis in salivary gland diseases (32,33,34). A particular focus has been put on the expression of Fas (CD95) and its ligand FasL (CD95L), which are members of the TNF (tumor necrosis factor) receptors superfamily. In Sj gren syndrome, contradictory results have been found so the importance of apoptosis in epithelial cell loss in these patients remains speculative (35,36,37).
Duct obstruction due to calculi or strictures induces salivary gland atrophy. Histologically, the disappearance of acinar cells within the presence of groups of ductlike structures in a fibrous and inflammatory stroma was observed. The acinar cells had disappeared by apoptosis; this acinar cell death was observed a few hours after duct obstruction. In the first cell death, a few days after duct obstruction, the number of intraepithelial macrophages located in the acinar and duct epithelium of a normal salivary gland multiplied. These macrophages removed the dying cells and apoptotic cellular fragments by phagocytosis, and then they migrated to the interstitium. Simultaneous proliferation of duct epithelial cells by an increase in mitosis contributed to the groups of ductlike structures with some features of squamous metaplasia. Myoepithelial cells became more prominent at the periphery of residual ducts. According to many experimental studies, myoepithelial cells become more prominent as the epithelial cell loss increases, and no myoepithelial cell apoptosis has been observed (38,39,40,41,42,43,44,45).
Irradiation of the major salivary glands is unavoidable during radiotherapy for many head and neck cancers. In fact, radiotherapy induced dryness of the oral cavity, contributing to deterioration of oral mucosa and loss of teeth.
The death of salivary gland acinar cells by apoptosis was observed within 24 hours after irradiation. This mode of cell death occurs with relatively low doses of radiation. An acute inflammatory response located among the destroyed acini was observed.
In normal adult salivary glands, cell division is infrequent in the acini. Development and replenishment of acini destroyed by low doses of radiation comes from stem cells that are located in the terminal intralobular ducts. It is possible that radiation-induced apoptosis of acinar cells could be a stimulus for replication of duct stem cells. However, the death of the ductal stem cells by high-dose radiation did not induce complete regeneration of the destroyed acini and resulted in atrophy of the salivary glands (46).
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Figure 17.2 Serous-type acini of a parotid gland, with dense secretory granules. |
Light Microscopy
The salivary glands are compound exocrine tubuloacinar glands characterized by the aggregation of numerous secretory units. These units consist of acini, where secretion is produced, and a duct system that carries the secretion to the oral cavity and regulates the concentration of water and electrolytes. There are three types of salivary secretory units: the serous ones that contain amylase; the mucous ones that secrete sialomucins; and mixed units made up of mucous and serous cells. According to the predominance of these types of secretory units, the salivary glands may be classified into three categories: serous, mucous, and mixed glands.
With the exception of some mucous units, the parotid gland is of the serous type (Figure 17.2). The submaxillary and the sublingual glands are mixed, with a predominance of serous units in the submaxillary glands (Figure 17.3) and
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a mucous predominance in the sublingual glands (Figure 17.4). Mixed secretory units can be found in accessory parotid glands (19).
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Figure 17.3 Histologic section of a submaxillary gland. In mixed units (arrows), serous cells are grouped in a crescent-shaped formation on the periphery of the acini, whereas the mucous cells (m) are in direct contact with the duct system. |
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Figure 17.4 Mucous-type acini of the sublingual gland; they are larger and more irregular than the serous and mixed types. Note an inconspicuous duct system. |
The lobular architecture of the glands is well defined by the anastomosed connective tissue trabeculae carrying the vascular and neural branches, as well as by the excretory ducts.
Secretory Units
Acini
Serous acini consist of pear-shaped groups of epithelial cells surrounded by a distinct basement membrane. The epithelial cells have a basal nucleus and dense cytoplasm packed with basophilic [periodic acid-Schiff (PAS)-positive] zymogen granules. They vary in number, depending on the different phases of the secretory cycle (Figure 17.2) (46). The primary enzyme present in the zymogen granules is amylase, or amylase, which splits starch into smaller water-soluble carbohydrates. However, there are other proteins in these granules, including agglutinin, proline-rich proteins, and histatins (47). Other enzymes, such as nonspecific antibacterial lysozyme, lactoferrin, trypsin- and chymotrypsin-like proteases, lysine endopeptidase, and histidine peptidase, also have been shown in the cytoplasm of acinar cells (47,48,49,50,51). Each acinus has a central lumen, rarely visible by light microscopy, through which the secretion drains into the intercalated ducts. The excretion seems to be promoted by the contraction of myoepithelial cells that lie between the outer surface of the acinus and the basement membrane. (Given the importance of myoepithelial cells in the pathology of salivary glands, a separate section, below, is devoted to their description.)
Mucous acini are larger than the serous type and have an irregular pattern (Figure 17.4). The secretory cells have abundant cytoplasm filled with clear mucous substance. They contain acid sialomucins (Alcian blue and mucicarmine-positive) and neutral sialmucins (PAS-positive) in different concentrations (52). The characteristics of these sialomucins also differ between submandibular and sublingual glands (53).
Mixed acini (Figure 17.3) are typically found in the submaxillary gland. These structures are characterized by the concentration of mucous cells near the intercalated duct and bordered by a crescent-shaped formation of serous cells. In mixed acini, the serous cells are more or less conspicuous, according to the amount of secretion accumulated in the mucous cells.
Ducts
A peculiar duct system transports the saliva from the gland to the oral cavity and modifies its water and electrolyte concentration. The first two segments, the intercalated and the striated ducts, are intralobular (Figure 17.5). They are also known as secretory ducts because of their metabolic activity (54). The other segments are interlobular and are called excretory ducts (54).
The intercalated duct lies directly in contact with the acinus. It is lined with a single layer of cuboidal epithelium and an irregular layer of myoepithelial cells. The epithelial cells show a progressive transformation between the secretory and ductal cells and a strong cytoplasmic activity of lactoferrin and lysozyme (55). The lengths of the intercalated ducts are variable in the three major glands (Figure 17.6). In the parotid gland, because they are relatively long, they are easy to recognize in the histologic sections (Figure 17.5A). In contrast, they are short in the submaxillary gland and hardly visible in the sublingual gland (Figure 17.4). Some authors have found undifferentiated cells on the basal side of the intercalated and striated ducts (56). These cells are positive for cytokeratins 13 and 16 on immunohistochemical staining (57,58).
The striated ducts are obvious in routine sections, particularly in the submaxillary gland, where they are relatively longer (Figures 17.3, 17.6). The epithelial lining is simple columnar. On the basal side, it has characteristic parallel striations caused by the deep cell membrane invaginations and mitochondria (Figure 17.5B). This structure represents a specialized surface on the epithelia involved in the transport of water and electrolytes. The numerous mitochondria are correlated with the strong eosinophilia of the duct. Various enzymes such as adenosine triphosphatase (ATPase), succinyl dehydrogenase, and carbonic anhydrase (59) are present in the cytoplasm of the striated ducts and provide them with a metabolic and energy system capable of concentrating some of the elements present in the saliva.
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Figure 17.5 Parotid intralobular ducts. A. The intercalated ducts (arrows) (sectioned longitudinally) lie in contact with the acinus. B. The striated ducts (sectioned transversely) are lined with a columnar epithelium of basal-striated appearance. |
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The striated ducts are connected with the interlobular ducts located in the septal connective tissue. These ducts are lined with a columnar pseudostratified epithelium with sparse goblet cells (Figure 17.7). They become progressively larger before joining the principal duct. The principal function of interlobular ducts is to transport saliva, but their role in regeneration is proposed by means of the hypothetical undifferentiated pluripotential cells. In theory, these cells may follow the same cellular lines as in embryonic development (Figure 17.1B) and are perhaps implicated in the metaplastic and neoplastic alterations of salivary glands (60), which are more frequent in these ducts.
The principal duct consists of a thick external fibrous coat of collagen (similar to dermal collagen) and elastic fiber bundles. The epithelium is pseudostratified columnar and becomes squamous and stratified near the opening in the mucous membrane (Figure 17.8).
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Figure 17.6 The morphology of the major salivary glands is characterized by three types of secretory unit. In the parotid (A) the intercalated duct (I) is longer than in the submaxillary (B) and sublingual glands (C). In contrast, the striated duct (S) is longer in the submaxillary gland. Sebaceous glands are more frequent in the parotid gland; in the sublingual gland. the intralobular ducts are inconspicuous. |
Ultrastructure
At the electron microscopy level, the serous cells show all the characteristics of a specialized cell for secretion and export of proteins. The cytoplasm possesses abundant endoplasmic reticulum, Golgi vesicles, mitochondria, lipid droplets, and secretory granules (Figure 17.9). The last are more common on the apical side of the cell. They consist of a membrane, which encloses the secretion, and a matrix of low-electron density and homogeneous aspect in immature granules and high-electron density in mature granules (61,62). The electron density of the granules differs according to the package of the different proteins within the same granule (46). All the cytoplasmic organelles increase during protein synthesis and decrease during discharge (59). The basal surface of the cell shows numerous folds of plasma and basal membranes. They cover the entire cell base and
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extend beyond the lateral margins in the manner of foot processes. Therefore, the basal surface of the cell is greatly expanded, facilitating diffusion of materials into the cell (59). Most of the cytoplasm in mucous cells is occupied by mucous vacuoles and Golgi apparatus. Only a small basal and lateral portion of the cytoplasm contains endoplasmic reticulum and mitochondria (63).
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Figure 17.7 Interlobular duct adjacent to vessels in the septal connective tissue. |
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Figure 17.8 Main excretory duct in the caruncula sublingualis. Near the oral surface, the duct is lined with a squamous stratified epithelium. |
At the apical pole, the secretory cells are joined by an adhesive zone, whereas the basal side is adhered by desmosomes (62). Between the junctions, virtual spaces form the secretory capillaries, which are in continuation with the acinar lumen. Numerous microvilli protrude into the capillary lumen (Figure 17.9).
The cytoplasm of myoepithelial cells may be separated into two portions (61): one, in contact with the basal lamina, is occupied by myofilaments and pinocytotic vesicles; the other portion is in contact with the secretory cell and contains mitochondria, endoplasmic reticulum, lysosome-like complexes, and Golgi vesicles. The visualization of myofilaments may vary in different myoepithelial cells; some of them have only focal aggregates of myofilaments, while others show a typical basal distribution resembling
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smooth muscle cells (62). The junction between myoepithelial and secretory cells is ensured by desmosomes.
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Figure 17.9 A. Ultrastructure of a parotid acinus: lumen (L), secretory granules (SG), lipid droplets (LD), secretory capillaries (SC), and myoepithelial cell (MC) ( 6000). B. Drawing of an acinar cell. |
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Figure 17.10 A. Intercalated duct of parotid gland. Some secretory granules (SG) and secretory capillaries (SC) are present on the apical side. On the external surface, myoepithelial cell prolongations (MC) are found ( 10,300). B. Drawing of an intercalated ductal cell. |
Transition from acinus to intercalated duct is gradual. In the latter, epithelial cells have relatively large nuclei and few cytoplasmic organelles, consisting principally of mitochondria, some cisternae of endoplasmic reticulum, lipid droplets, and a few apical secretory granules (54,58) (Figure 17.10). Scattered secretory capillaries may be found, as well. On the external surface, myoepithelial cell prolongations are usually present.
The striated ducts (Figure 17.11) are composed of tall cylindrical cells with central nuclei. On the basal side, the cell membrane is extensively folded into fingerlike structures. The space between these folds is occupied by vertically oriented mitochondria. This cytoplasmic organization is specialized in the active transport of water and electrolytes from the vascular system to the lumen of the duct; the rest of the cytoplasm contains mitochondria and scattered endoplasmic reticulum (63,64,65).
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Figure 17.11 A. Striated duct cells possess vertically oriented mitochondria and extensively folded plasma membrane; the basal side is in close relationship to the blood capillary ( 7920). B. Drawing of a striated duct cell. |
Sebaceous Glands
In 1931, Hamperl (66) described the presence of sebaceous glands histologically similar to those of the cutaneous adnexa. Other authors have indeed recognized such structures, which appear as isolated cells in the wall of either an intercalated or a striated duct (Figure 17.12A) (67,68,69,70). Larger cell accumulations form a sebaceous gland limited by a well-defined basal membrane (Figure 17.12B C). They vary in size, have a diverticular aspect, and are permanently linked to an interlobular duct. At the periphery of the gland, the cells are flattened with round or oval nuclei. The central cells have an abundant vacuolated cytoplasm rich in lipids, which may be stained, in frozen sections, with fat colorations (Sudan III and IV, oil red O, osmic acid). The nuclei become irregular or pyknotic and finally disappear. When the gland reaches a certain size, the holocrine-type secretion is emptied into the ductal system and is mixed with the saliva (Figure 17.12D).
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Figure 17.12 Sebaceous elements in a parotid gland. A. Isolated sebaceous cells can be seen in the duct wall (arrow). They proliferate to form a well-defined gland (B, C); secretion is present in the lumen of the duct (D) (arrows). E. Drawing illustrates the previous features. |
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The number of sebaceous glands in major salivary glands varies; they are common in the parotid gland, rare in the submaxillary gland, and probably absent in the sublingual gland. They are diffusely scattered throughout the parenchyma, where their numbers also vary greatly. Their presence or absence in the different lobules is not related to either age or sex (70).
In a review of 100 parotid glands selected at random from our material, we found sebaceous glands in 42% of cases. They were also found in 5% of 100 submaxillary glands. These findings are in agreement with other authors. Thus, we conclude that their incidence in the parotid gland is more frequent than imagined. The more sections that are examined, the more sebaceous glands are found; it is, therefore, merely a question of looking for them. If the entire parotid gland were examined meticulously, it would be difficult not to find a sebaceous gland (69).
The presence of sebaceous glands in the salivary tissue has not been satisfactorily explained. A heterotopic phenomenon (67,68) similar to the occurrence of sebaceous glands in the oral mucosa (Fordyce's disease) seems unlikely. In the mouth, this condition may result from aberrant buds along the fetal line of closure (70,71,72); but in the parotid and submaxillary glands, there are no lines of closure. Metaplasia (66,70) beginning in the ducts does not explain the high frequency of sebaceous glands in parotid parenchyma. Therefore, it seems reasonable to consider the sebaceous glands as a normal holocrine differentiation. Their occurrence in the parotid gland appears to be related to a specific function that is not yet understood. Sebaceous glands analogous to those of the salivary glands have been found in the oral mucosa. In the oral mucosa, androgen receptors participate in the histogenesis of sebaceous glands (73,74). A similar mechanism may be proposed for the histogenesis of sebaceous glands in salivary glands.
The belief that a potential for sebaceous differentiation exists in the salivary parenchyma is further supported by the fact that salivary tumors or tumorlike conditions with a sebaceous character or sebaceous gland participation have been described. These rare lesions include sebaceous adenoma, sebaceous lymphadenoma, sebaceous carcinoma, and parotid cyst. They have also been noted in pleomorphic adenoma and mucoepidermoid carcinoma (69,74,75,76,77,78,79,80,81,82,83,84,85,86,87).
Myoepithelial Cells
Myoepithelial cells (basket cells) are derived from early modification and differentiation of primitive pluripotential salivary duct cells by the tenth week of gestation. It has also been suggested that the precursor of myoepithelial cells are the clear cells located in the terminal and striated ducts (63). In regeneration, these cells migrate from the acinar periphery to the duct-acinar region (32).
These cells lie between the epithelial cells and the basal lamina of acini, in the intercalated ducts, and probably also in the union of the striated and intercalated ducts (56,87,88). The cells are flat and have long cytoplasmic processes extending over the epithelial surface (Figure 17.13) in a network that makes it difficult to discern them in routine histologic sections. However, myoepithelial cells may assume morphologic modification at different anatomic locations within the ductal acinar structure (56,64). These cells are best studied by electron microscopy.
The most outstanding characteristic is the presence of cytoplasmic filaments on the basal side. Most of these consist of the myofilaments actin, tropomyosin, and myosin (63,88,89,90), which are arranged in a pattern similar to that of the smooth muscle. Tonofibril-like bundles of intermediate filaments are attached to the cellular junctions, particularly in desmosomes where the filaments are cytokeratin. Some forms of myoepithelial cells may also show scattered, rather than basal, cytoplasmic distribution of these filaments, which may reflect structural and functional
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differences (64). The presence of vimentin is not constant, and the filament desmin is absent in normal myoepithelium (91). The cytoplasm shows a strong activity of ATPase and alkaline phosphatase (92,93).
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Figure 17.13 Myoepithelial cells (arrows) on the acinic surface (semithin section, toluidine blue). |
It is generally accepted that myoepithelial cells are contractile. This function speeds up the outflow of the saliva by increasing the pressure on the excretory unit (94). It has been extensively studied in the mammary gland of the rat, where these cells are more frequently found. Oxytocin-induced contraction in the myoepithelial cells is similar to that of true muscle cells (95). The presence of myofilaments in the cytoplasm of these cells correlates strongly with this function. In addition, myoepithelial cells support the underlying parenchyma and participate in the elaboration of the basal lamina. This last function is important in some hyperplastic and neoplastic alterations, where the myoepithelial cells produce fibronectin, laminin, and type III collagen (96,97,98,99,100,101,102,103). All these proteins are constituents of the basal lamina (104). In addition, myoepithelial cells are also involved in the production of tenascin, an extracellular matrix glycoprotein (105,106).
Regardless of endodermal or ectodermal origin, the myoepithelial cells share an epithelial and mesenchymal structure and function. Altered myoepithelial cells may manifest (in neoplastic proliferation) one or both characteristics. These cells are now considered the key factor in the morphology of many salivary neoplasms and in the morphologic variability of some tumors (106).
The Role of Myoepithelial Cells in Salivary Gland Tumors
The presence of myoepithelial cells in different histologic types of salivary gland tumors (Table 17.1) is well documented, as is the role of these cells in the pathogenesis and in its biologic behavior.
The role of myoepithelial cells in the histogenesis of the pleomorphic adenoma has been extensively studied. This tumor, sometimes called a mixed tumor because of the epithelial and mesenchymal mixture of tissues, is the most frequent neoplasm of the major salivary glands (107,108). It is now accepted that myoepithelial cells play a crucial role in the neoplastic process by expressing both epithelial and mesenchymal structures in the majority of pleomorphic adenomas (109,110,111,112,113,114,115,116,117). The participation of the contractile elements is also accepted in epithelial-myoepithelial carcinoma [clear cell carcinoma, a malignant tumor that mimics the normal structure of the intercalated duct (118,119,120,121,122,123)] and myoepithelioma [in which the myoepithelial cells are the only tumoral element showing different cellular forms (124,125,126,127,128,129)]. They also have been demonstrated in terminal duct adenocarcinoma (polymorphous low-grade adenocarcinoma) (130,131); monomorphic adenoma, which includes basaloid monomorphic adenoma (132,133,134); adenoid cystic carcinoma (96,100,113,135,136,137,138); and basaloid adenocarcinoma (139). Myoepithelial cell participation is also present in congenital tumors of salivary gland origin, such as sialoblastoma (140) and the salivary gland anlage tumor (141). Although there are rare reports of myoepithelial cells in mucoepidermoid carcinoma (135,142), it is difficult to fully accept these statements because mucoepidermoid carcinoma arises from a ductal segment that lacks myoepithelial cells.
Table 17.1 Salivary Gland Tumors with Myoepithelial Cell Participation | ||||||
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Figure 17.14 Morphology and histologic markers of the normal (A) and modified myoepithelial cells (B E). The most constant markers are present in order of frequency: chondromyxoid type (B), spindle-shaped type (C), hyalin or plasmocytoid type (D), and epithelial (clear) type (E). |
The principal morphologic types of altered myoepithelial cells are (Figure 17.14):
Stellate or myxoid cells, which are typically present in chondromyxoid areas of pleomorphic adenoma.
Spindle-shaped or myoid cells, which can be identified in pleomorphic adenoma and some types of myoepithelioma.
Hyalin or plasmocytoid cells (143), which can be seen in pleomorphic adenomas and can be present in myoepitheliomas. These cells show abundant cytoplasmic filaments that give a hyalin eosinophilic aspect.
Clear or epithelial cells, which are found in many salivary tumors on the external surface of ducts or ductlike structures. This is also characteristic in epithelial-myoepithelial carcinoma.
Bidirectional differentiation of the modified myoepithelium has been well documented. Myoepithelial cells with mesenchymal characteristics secrete mesenchymal mucins such as the acid glycosaminoglycans (hyaluronic acid, heparin sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate) (144,145), basement membrane constituents, elastin (111,112), and tenascin (105). In addition to contractile filaments (actin and myosin) and related proteins such as calponin, vimentin becomes strongly positive, particularly in spindle-shaped form (138,139,140,146,147,148). The S-100 protein, which is a common marker used for the myoepithelium, enhances its positivity in chondroid, myxoid, and stellate cells, particularly if they are associated with a myxoid stroma (104,149,150). Plasmocytoid myoepithelial cells are frequently negative for the muscular markers (151). However, these cells express several ultrastructural and immunomarkers characteristic of myoepithelial cells (127). On the other hand, epithelial differentiation may take the form of clear or squamous cells, which can contain both vimentin and keratin filaments in the same cell (110). Figure 17.14 illustrates the histologic and immunohistochemical patterns of modified myoepithelium.
Myoepithelial cells are a central element in the histologic formation and organization of different salivary gland tumors. The cytomorphologic features and the variability of the extracellular products account for the morphologic heterogeneity of these lesions. The presence of these cells varies widely, from minimal as in monomorphic adenomas (136), to marked, as in myoepitheliomas. Evidence of the protective effect of myoepithelial cells in malignant tumors is growing. Protease inhibitors like maspin, 1-antitrypsin, TIMP-1, and nexin II are anti-invasive factors produced by the myoepithelial cells in myoepithelial cells rich tumors (152,153). Now it is well accepted that malignant tumors with important myoepithelial cell components behave less aggressively. Myoepithelial carcinoma tends to be lobulated tumors rather than infiltrating, and patients with myoepithelial carcinoma show a better survival when they are compared to carcinomas that do not express myoepithelial cell differentiation. In addition, there is also evidence that myoepithelial cells may inhibit angiogenesis (154).
Lymphoid Tissue
The immune system of salivary glands comprises two elements of the mucosa-associated immune system. One is the secretory component, a glycoprotein receptor for dimeric IgA and pentameric IgM that is produced by epithelial cells in the acini, intercalated ducts, and striated ducts (155,156). The other element is lymphoid tissue, which is either distributed diffusely or organized in lymph nodes. Isolated
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lymphoid cells are present in the connective tissue near the acini and ducts. They are variable in number in the different glands (157) and yield principally IgA (nearly 80% of the immunoglobulins in saliva), along with a lesser quantity of IgG and IgM (159). Small lymph nodes are usually present near the surface of the parotid gland but not in the other salivary glands. Nevertheless, lymphoid cell aggregates are present in fetal submandibular and sublingual glands (158). These nodes usually contain salivary ducts and acini in the medullary region (Figure 17.15A), a phenomenon probably due to the close relationship between developing gland and lymphoid tissue during embryonic life.
 |
Figure 17.15 Lymph node of the parotid gland. A. Presence of glandular ducts in the medullary region (arrows). B. Duct dilatation and oncocytic transformation in another lymph node of the same patient. |
Lymph nodes are thought to participate in the histogenesis of Warthin's tumor. Although they have been pinpointed as the origin of the lymphoid tissue that characterizes this neoplasm, the hypothesis is still under debate. Different mechanisms have been proposed, but the most widely accepted one states that the lesion originates from the ducts inside lymph nodes within or adjacent to the parotid gland (85,160,161,162). According to this concept, the epithelial component of the tumor corresponds to altered ducts inside a lymph node, and the lymphatic component is, in fact, a lymph node. The following arguments support this hypothesis: salivary tissue is frequently present in intraparotid or periparotid lymph nodes (Figure 17.15A); with the exception of a few cases, this tumor is exclusive to the parotid region; it is common to find early stages of oncocytic and papillary transformation in lymph nodes of the parotid region (Figure 17.15B); and, finally, tumors identical to the epithelial structure of Warthin's tumor occur outside the lymph nodes but without lymphocytic components (160).
The diffuse lymphoid tissue may increase in chronic sialadenitis, particularly in immunologic reactions such as the benign lymphoepithelial lesion associated with Sj gren's syndrome. In these instances, lymphoid tissue may obscure the glandular parenchyma in a diffuse or nodular manner, and epimyoepithelial islands may be formed (91,160). The polyclonal character of the lymphoid cells and the presence of epimyoepithelial islands are useful criteria in the differential diagnosis of malignant lymphoma, which can occur in a preexisting benign lymphoepithelial lesion (162).
The Heterotopic Salivary Tissue and its Significance
The presence of salivary tissue outside the major salivary glands and the oral cavity, pharynx, and upper airways is considered heterotopia. This heterotopia may be classified as intranodal and extranodal in a number of locations in the head and neck.
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Heterotopia is common in the lymph nodes near the parotid gland but is much less frequent in the submaxillary region and in other upper cervical nodes (163,164). The glandular elements are either normal or atrophic; they consist mainly of ducts, but acini are also found. They are localized in the medullary region and comprise a variable proportion of lymphoid and salivary tissues. Although all types of secretory units are found, serous ones are predominant. The histologic architecture is similar to a normal gland. The lymph nodes exhibit a normal structure or some degree of lymphoreticular hyperplasia.
The incidence of heterotopic salivary tissue in the lymph nodes has been well documented (165). It is typically found in the parotid region of fetuses during various stages of development, usually in more than one lymph node. In adults, although the incidence is not constant, it is nonetheless frequent (166). In most of the reports, the histogenetic mechanisms of this phenomenon have been related to embryonic development. From this point of view, the salivary tissue is trapped during embryologic development. In the fetus, the parotid gland is closely related to lymphoid tissue from the beginning of the second month. Moreover, Bairati (166) found that, at least in the first years of life, this salivary tissue is connected to the parotid gland. Although lymphatic dissemination has been proposed as a mechanism of salivary heterotopia in lymph nodes, in particular when they are located in the lower neck, this hypothesis is only speculative (167).
Extralymphatic heterotopias are rare and often latent but may be responsible for symptomatology. Heterotopic salivary tissue has been described in several sites, including head and neck, thorax, and abdomen (Table 17.2). In the upper neck, heterotopia is limited to the mandible, ear, palatine tonsil, mylohyoid muscle, pituitary gland, and cerebellopontine angle (164,168,169). All these sites, with the exception of the last, may be related to the embryonic migration of the salivary glands. In the lower neck, heterotopias are localized in the base of the neck, particularly around the sternoclavicular joint and in the thyroid gland and parathyroid glands (Figure 17.16) (167,171).
Table 17.2 Salivary Gland Heterotopias | |
|---|---|
|
 |
Figure 17.16 Extranodal salivary heterotopias. Pituitary gland (1), middle ear (2), external auditory canal (3), cerebellopontine angle (4), mandible (5), oropharynx (6), cervical superior (7), thyroid capsule (8), and lower anterolateral neck (9). |
Most examples of high salivary heterotopia are explained in relation to lines of migration of the parotid and submaxillary glands. In the mandible, the presence of salivary heterotopia may be related to a bone cavity and usually contains submandibular gland tissue. These inclusions are most common in the posterior lower jaw, near the angle. Originally described in 1942 by Stafne, they are often considered as heterotopias (172). This defect may be found in the anterior position (173). A recent study showed the heterotopic salivary tissue is present in 0.3% of maxillofacial marrow samples. The origin of this tissue is a matter of debate, but the most accepted hypothesis is the metaplasia of the odontogenic epithelial lesions (174). In the lower neck, an association with cysts and sinuses is frequent. This condition, along with the topographic presentation, has been related to the branchial apparatus (164,170) and, in particular, to a defective closure of the precervical His's sinus. The different abnormalities related to this defect (175) correspond embryologically to topographic distribution
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through the neck from the ear to the clavicle. When this defect occurs, the salivary tissue is the result of abnormal tissue differentiation (heteroplasia). Willis (176) has argued that this is the mechanism of heterotopia. This mechanism may also account for the salivary tissue in remnants of Rathke's pouch (169) and the thyroglossal duct.
Neoplastic transformation in heterotopic salivary tissue may pose a problem in differential diagnosis of metastasis in a cervical lymph node (163). Pleomorphic adenoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma are the most frequent tumors arising in heterotopic salivary tissue. In fact, heterotopia is an explanation for many aberrant salivary tumors (167,177) and some cervical lymph node metastases that are thought to be metastases of an unknown primary tumor (178). Primary salivary tumors of the mandible may originate in this aberrant tissue (179).
Aging Changes
Oncocytes
The oncocyte is an altered swollen epithelial cell characterized by an abundant eosinophilic granular cytoplasm that is rich in altered mitochondria and enzymes (Figure 17.17A) (180). This cell is frequently present in interlobular ducts and is less frequent in acinar cells. Oncocytes are more common in the parotid gland. They are rare before 50 years of age, increase in frequency with advancing years, and become constant after 70 years (66,181). Oncocytes may be detected by histochemical methods using phosphotungstic-acid hematoxylin or by more specific immunohistochemical methods with antibodies to human mitichondria (182).
 |
Figure 17.17 A. Oncocytes in intralobular ducts of a normal submaxillary gland. Note the abundant and granulated cytoplasm. B. Nodular oncocytic hyperplasia. C. Diffuse oncocytosis. |
The nature and function of oncocytes are unknown. Their proliferative character is a common finding in organs with endocrine function or endocrine dependence (183). Numerous researchers are presently interested in the production of various peptides with endocrine function in the intralobular ducts of rodent salivary glands (184,185,186). On the other hand, a number of workers are investigating the presence of neuroendocrine peptides such as the substance P like, -endorphin like (187,188), and a calcitonin-related peptide (189). In addition, neuroendocrine regulation of inflammation by the submandibular gland has been explained by an immunoneuroendocrine communication controlled by cervical sympathetic nerves (190).
The proliferation of oncocytes is called oncocytosis or oncocytic metaplasia when it is diffuse and generally without pathologic significance. In other cases, this proliferation presents a nodular pattern known as nodular hyperplasia (191). Histologically, it is easy to distinguish in the
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salivary parenchyma as one or several small foci of oncocytes that are well circumscribed but not encapsulated. The cells may be arranged in solid cords or ductal structures and, in rare cases, may replace most of the gland (Figure 17.17B C). Oncocytes participate in various salivary gland tumors in approximately 10% of cases (192); the most common is Warthin's tumor, and they are also observed in basal cell adenoma, pleomorphic adenoma, myoepithelioma, polymorphous low-grade adenocarcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma (193,194,195,196). The neoplastic proliferation called oncocytoma is rarely found in salivary glands (197).
Fatty Infiltration
Normally, some adipose cells are present in the areolar connective tissue of the salivary glands. This fatty tissue increases in adults; in the elderly, it forms an important proportion of salivary gland tissue. Fatty infiltration may reach huge proportions, especially in alcoholics and the malnourished (198).
Reactive Changes
Metaplasia
Squamous metaplasia may be present in larger salivary ducts in chronic inflammatory processes, particularly when associated with calculi (Figure 17.18A) (199). (Remember that when the major salivary ducts open into the oral cavity, they are lined with a stratified squamous epithelium). Metaplastic squamous transformation is also present in intralobular ducts and acini in ischemia and radiation injury (200,201).
Mucous metaplasia is found on interlobular ducts and, less frequently, on intralobular ducts in cases of obstructive and postradiotherapy forms of sialadenitis (202). An important proliferation of mucous goblet cells is accompanied by prominent ciliated cells mimicking the respiratory epithelium (Figure 17.18B). Necrotizing sialometaplasia is a type of metaplasia peculiar to salivary tissue, but it is exceptional in major salivary glands (Figure 17.19) (203). It consists of ischemic lobular infarction or necrosis of some acini, accompanied by extensive squamous metaplasia of salivary gland ducts and acini. Severe inflammation and granulation tissue are present. Necrosis of mucous acini is represented by small pools of mucin that, along with the squamous elements, may be mistaken for mucoepidermoid carcinoma (204). The preservation of general lobular morphology and prominent granulation tissue are criteria in favor of benignity. Subacute forms are also described (205).
 |
Figure 17.18 Metaplasia of excretory ducts. Squamous (A) and mucous metaplasia (B) showing cilliated cells simulating respiratory epithelium. |
Hyperplasia
Hyperplasia of mucous acini is an alteration exclusive to the minor salivary glands. In contrast, serous hyperplasia occurs in parotid and, rarely, in submaxillary and sublingual glands; it is called sialadenosis (206). This hyperplasia is associated with a number of metabolic, nutritional, and endocrine conditions or follows the ingestion of chemicals and drugs (207). In most cases, a bilateral swelling of the glands is caused by enlarged acini and an accumulation of secretory granules in the cytoplasm. In other cases, granulation is lost and the cytoplasm looks vacuolated (22). The myoepithelial cells may present nuclear pyknosis or cytoplasmic vacuolation. Adenomatoid salivary gland hyperplasia should be distinguished from true tumors. Recently, adenomatous ductal proliferation in salivary glands has been described; these cases may be misdiagnosed as true adenomas. Adenomatoid hyperplasia contains clusters or lobules of mucous or serous glands with normal or enlarged appearance, whereas adenomatous ductal proliferations show prominent ductal proliferation with some
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acinar cells complexes, but the normal lobular pattern is preserved (208,209).
 |
Figure 17.19 Necrotizing sialometaplasia of submaxillary gland. |
Atrophy
Atrophy of the salivary tissue is a common finding in surgical specimens of tumoral salivary glands that have one or more atrophied lobules. This atrophy is caused by partial or total obstruction of an excretory duct. Accordingly, secretory units distal to the obstructed duct are dilated, and the acinar lumina become visible. The secretory cells lose their granules and have a similar aspect to that of the intercalated duct. The atrophic lobule has an inflammatory component; the cells gradually disappear, and the parenchyma is replaced by adipose tissue and collagen fibers (Figure 17.20A). The extent of atrophy depends on the size of the affected duct. It is generally greater in lithiasic obstruction. The atrophy present in terminal stage chronic sialadenitis shows a diffuse pattern with prominent periductal sclerosis and dense inflammatory infiltration (Figure 17.20B) (202). In the submaxillary gland, diffuse atrophy is frequent after radiotherapy, and the gland has a firm consistency (Kuttner's tumor) that may be clinically mistaken for a submaxillary neoplasm. Atypical cells are often found in postradiotherapy atrophy. Dilated ducts lose cell polarity and exhibit hyperchromatic nuclei and prominent myoepithelium. In addition, interlobular ducts lose their continuity, and the interstitium is densely infiltrated with plasma cells (201). In experimental models, atrophy takes place after ligation of main salivary duct. Duct cells persist, in contrast to the disappearance of most acinar cells, which are deleted by apoptosis (210).
 |
Figure 17.20 Atrophy of the salivary parenchyma. A. Focal atrophy in the vicinity of a parotid tumor; note the duct dilatation. B. Diffuse atrophy in chronic sialadenitis showing prominent periductal sclerosis. |
Regeneration
The parenchyma of salivary glands have a capacity for regeneration. It is particularly notable in the salivary gland a few weeks after partial resection. In general, regenerating tissue follows an embryonic pattern, showing solid buds and branching columns of undifferentiated cells that eventually form excretory units (22) (Figure 17.21A). In some cases, such regenerating tissue exhibits an atypical appearance. Proliferating solid buds of undifferentiated cells may simulate basal cell adenoma (211) or other undifferentiated cell neoplasms (Figure 17.21B). However, unlike neoplasms, the regenerating tissue preserves the lobular architecture characteristic of the normal salivary gland (Figure 17.21B C) (22,39). Regeneration after atrophy due to duct obstruction is completed from residual parotid ducts that differentiate into acinar cells (212); this is probably achieved by a stem cell that resides in one of the ducts. The pattern is similar to the high proliferative activity of the terminal tubule, proacinar, and acinar cells during normal embryonic development of the rat submandibular gland (213).
 |
Figure 17.21 Regenerating salivary tissue of parotid gland. A. Formation of secretory units with an embryonic pattern. B. Atypical regenerating tissue; the lobular pattern is preserved. C. Infiltrating residual adenoid cystic carcinoma in a parotid gland. Solid buds consist of undifferentiated cells without lobular arrangement. |
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Correlative Normal and Neoplastic Histology
A characteristic of salivary glands is the ability to give rise to a large number of histologically distinct tumors (214). The histogenetic origin of these neoplasms is an interesting topic, but the numerous mechanisms that have been proposed remain hypothetical. The most attractive hypotheses attempt to relate this phenomenon to embryonic development and, particularly, to the presence of ductal reserve cells (56,60,193,214,215,216,217). A conjectural role of these reserve cells is the regeneration of salivary parenchyma, as well as the development of metaplastic tissue in reactive conditions. Batsakis (216) hypothesized two stem cells progenitors located at proximal and distal regions of the duct system that are related to tumors mimicking the terminal ductoacinar complex and the excretory ducts system, respectively. Some researchers have demonstrated, by immunohistochemical methods, the presence of basal cells with an undifferentiated aspect in salivary ducts (57,58). However, this does not prove that they act as reserve cells. Conversely, experimental evidence exists of the proliferative capacity of differentiated acinar and myepithelial cells (218,219,220).
A correlation between the normal structure of the salivary gland and the histologic appearance of salivary tumors can help us to understand morphologic classifications. Nevertheless, we must realize that this histologic similarity does not necessarily imply that a particular tumor arises from the structure that it mimics (217). However, the morphogenetic approach proposed by Dardick relates morphology to cell differentiation derived from different genes' expression of a stem cell (221,222).
The intercalated duct represents the most important segment of the salivary gland in the morphologic organization of many salivary tumors (217). Many distinctive tumors have been related to it, including pleomorphic adenoma, adenoid cystic carcinoma, basal cell adenoma, epithelial-myoepithelial carcinoma, terminal duct carcinoma, basal cell carcinoma, and embryonic tumors (Figure 17.22). These tumors show both epithelial and myoepithelial cell differentiation (93,109,112,113,118,131,132,134,136,139,148,149,217,222,223), as does the normal intercalated duct. According to Batsakis (216), these tumors develop from intercalated duct reserve cells that follow the same direction as the embryonic terminal tubular cell. Statistically, approximately 80% of salivary tumors develop in the parotid gland, where the intercalated ducts are relatively long (Figure 17.6). In contrast, in the sublingual gland, which gives rise to less than 1% of salivary tumors (22), intercalated ducts are hardly visible.
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 |
Figure 17.22 Morphologic similarity of some salivary tumors and the different epithelial structures of the salivary gland: acinus (A), intercalated duct (I), striated duct (S), sebaceous gland (SG), and excretory ducts (E). Not necessarily related to histogenesis. |
A similar morphologic link exists between the acini, the most differentiated structure of the gland, and the acinic cell tumor, a well-differentiated neoplasm (Figure 17.23A B) (224); between the mitochondria-rich cells of the striated duct, Warthin's tumor, and oncocytomas (180,181); and between the sebaceous glands and sebaceous tumors (69,76,86). A morphologic analogy also may be found between the larger excretory ducts and mucoepidermoid carcinoma, salivary duct adenocarcinoma, epidermoid carcinoma, adenosquamous carcinoma, and papillary tumors (Figure 17.22) (225,226,227,228,229,230,231,232,233).
Immunohistochemistry
An important aspect of cytodifferentiation in normal and neoplastic salivary tissue is the expression of different intermediate filaments, enzymes, immunologic components, and other proteins. These proteins may be stained by immunohistochemical methods.
 |
Figure 17.23 A. Acinic cell carcinoma of tha parotid gland (arrow), mimicking the normal gland. B. Epithelial-myoepithelial carcinoma of parotid gland, showing both epithelial and myoepithelial cells of the intercalated duct. |
In normal salivary glands, the immunohistochemistry may be summarized as follows (Table 17.3): the expression of cytokeratin varies according to individual cell types of the secretory unit. Acinar cells are stained by several types of lower weight cytokeratins such as CK7, CK8, and CK19. In addition, these cells may be marked by the enzymes usually present in the normal acinus, such as amylase and lysozyme (234). Cytokeratins 6 and 12 are weakly positive in acinar cells but strongly positive in ductal cells, especially in excretory ducts (Figure 17.24) (57). Basal cells are stained with anticytokeratin 19 and 18. Myoepithetial cells may coexpress cytokeratins 14, 17, 19, and vimentin (57,146,148). The most specific markers for myoepithelial cells are S-100 protein, -smooth muscle actin, calponin, caldesmon, and myosin heavy chain (149,235). In addition, normal myoepithelial cells are
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sometimes stained with glial fibrillary protein (236). The secretory component, except for the mucous units, is present in acinar cells and intercalated and striated ducts (55,237). Carcinoembryonic antigen (CEA) is present in acinar and intercalated duct cells; it is strongly positive in inflamed glands (238). Basal cells are stained with CK14, CK17, and p63 (234). Ductal epithelial cells of intercalated, striated, and interlobular ducts are strongly positive for epithelial membrane antigen (EMA) (239). Recently, the presence of -fetoprotein in the human submandibular gland has been documented (240). Used as functional markers, the following enzymes may be stained: amylase and lactoferrin in serous acinar cells (241), lysozyme in intercalated ducts (49,50), and alkaline phosphatase and ATPase in myoepithelial cells (92). When used as histologic markers, all these proteins have proven useful in surgical pathology.
Table 17.3 Immunohistochemical Markers of Salivary Glands | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
Figure 17.24 Immunostaining for high-molecular weight cytokeratin in a submaxillary gland. The acini are unstained, but intercalated, striated, and excretory ducts show a progressive immunoreaction (peroxidase-antiperoxidase method). |
Specimen Handling
The parotid gland is the most common location of major salivary gland tumors. Because most of them are benign and located on the superficial lobe, partial parotidectomy of the superficial lobe (lateral lobectomy) is the most common treatment. Superficial parotidectomy also suffices for small, well-differentiated, low-grade malignant neoplasms that have not compromised the facial nerve (242). The specimen should be sectioned horizontally, and the relationship between the tumor and the gland should be stated (Figure 17.25). The surgical limits should be described even in benign tumors (Figure 17.26). Total parotidectomy with preservation of the facial nerve is usually indicated in recurrent or multiple benign tumors and large benign tumors of the isthmus and deep lobe.
 |
Figure 17.25 Histologic section of a parotid gland showing a pleomorphic adenoma. The tumor is apparently well delimited; tumoral buds may be found separate from the principal tumor. |
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 |
Figure 17.26 Superficial parotidectomy for a pleomorphic adenoma. Note the tumor is well delimited within the normal gland. |
Total parotidectomy, including facial nerve resection (radical parotidectomy), is indicated in aggressive malignant tumors, malignant tumors situated in the deep lobe, or those that have compromised the facial nerve. All these specimens should be sectioned on their major axis to evaluate periparotid tissue infiltration (Figure 17.27). Intraparotid and periparotid lymph nodes should be identified; and, when radical parotidectomy includes neck dissection, the lymph nodes should be separated according to the different anatomical regions.
Benign and malignant submandibular gland tumors are rare. Single gland resection is indicated for benign tumors, whereas malignant tumors are treated by a monobloc resection of the gland lesion along with associated muscles, nerves, and mucous membrane.
Sublingual tumors are rare, and most (80%) are malignant. They are also treated by local monobloc resection, including the sublingual compartment and surrounding tissues (243).
 |
Figure 17.27 Radical parotidectomy for a high-grade mucoepidermoid carcinoma. Note the infiltration of the periparotid tissues. |
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