Introduction : Our fascination with the marvelous machine that is our body predates Shakespeare by many, many centuries. From earliest times, we have attempted to understand anatomy and have tried to “map” the body and its systems. One such system for discussion today is the salivary glands. We have 3 pairs of major salivary glands – parotid, sub-mandibular and sub-lingual besides several minor glands which are scattered through out the mouth and pharynx. The human salivary glands are important organs of oral cavity that produce saliva and essential fluid required for normal speech, taste, mastication,
swallowing and in digestions. Saliva functions in the
maintainance of oral health through its anti microbial, cleansing, lubricating and buffering functions, as well as its role is digestion. Today i will be discussing the development structure, function, and developmental anomalies of the major and minor salivary gland is health. The majority of oral secretions are contributed by the sub-mandibular and parotid glands which equally provide 80-90% of saliva,reminder is formed by sub-lingual and minor salivary glands. In a day about 1000 ml – 1500 ml of salivary is produced which contributes to the digestions of food, to the maintainance of oral hygiene and speech. The development of these glands are principally induced to begin their characteristic branching morphogenesis through an interaction of the cells of the oral epithelium which is derived from the endoderm and the underlying mensenchyme.
DEVELOPMENT OF SALIVARY GLANDS 1) General development process Epithelial-mesenchymal interactions Neuro epithelial interactions 2) General development pattern of salivary glands. 3) Stages of development. 1) General development process ; i) Epithelial-Mesenchymal interactions : The development of glandular tissue in mammals involves the interactions of epithelium with the underlying mesenchyme to form functional part of the gland. They are also defined as proximate tissue interactions and also secondary induction â€“ in which the presence of mesenchyme in close proximity to epithelium is required for normal development of epithelium. The interactions regulate both initiation and growth of glandular tissue and cytodifferentiation of cells within salivary glands. The mesenchyme is therefore required for normal development as well as formation of supporting part of adult gland. Lawson studied rat sub-mandibular and parotid epithelium and found that both types can undergo differntiation with their own (or) reciprocal glandâ€™s mesenchyme. In those cases when epithelium of one gland was combined with mesenchyme of other gland (in vitro), growth and arrangements of acini were found to be governed by mesenchyme but not the function. Interaction between salivary epithelium and mesencyme is provided by recent studies describing the presence of an acid mucopolysaccharide (MPS) at the epithelio-mesenchymal interface. There is an increasing concentration of this material at the distal end of growing and branching lobules. So these authors are suggesting MPS may be involved in 2
morphogenesis. This MPS is located in the basal lamina and appears to be protein-bound, permits glandular primordial branching when it is retained in vitro. And if this MPS is removed, the epithelial growth produces only a spherical, unbranched structure. In growing of salivary epithelial cords is related to the contractile ability of intra epithelial microfilaments. Even though microfilaments are present the budding (clefting) will not occur unless specific salivary mesenchyme is present. ii) Mesenchyme : (composed of cells derived from neural crest) Extracellular matrix (ECM) and basal lamina. Mesenchyme consists of : a) Undifferentiated pluripotential connective tissue cells. b) ECM a) Undifferentiated pluedripotential C.T cells. - Fibroblasts - Macrophages - Mast cells b) ECM : - Glycosaminoglycans - Proteoglycans.
Gives gel like characteristic to ECM.
Glycosaminoglycans : - Chondroitin sulphate - Keratan sulphate - Hyaluronic acid â€“ gives gel like characteristic to ECM. These glycosamino glucans (1,2) are bound to a core protein to form proteoglycan sub units. These sub units are non-covalently bound to hyaluronic acid (another GAG) â€“ to form the bristle brush like structure of proteoglycan aggregate found in ECM. 3
Functions of proteoglycans : - Forms hydrated ground substance and also function in filtration (eg. Renal glomerular B.M). - “Bind signaling molecules (like growth factors to this target cells). Laminin – Entacin (glycoprotein) – interact with each other and other components of ECM through receptors, a family of transmembrance linker proteins – known as Integrins. Eg. Fibronectin receptors. They allow intra cellular adhesive molecules (ICAMs) facilitate communication within cell cytoplasm. (ECM to cytoskeleton). This communication / linked changes – cell shape - Motility - Migration - Proliferation - Differentiation All which occurs during salivary gland development. Influence of ECM on development : The ECM provides regulatory cues for - Cell proliferation - Cell differentiation - Morphogenesis, the major developmental process required for the formation of adult salivary gland structure. Cell proliferation : It is increased in number of cells that occurs during development as organs enlarge. Cells enter cell cycle, replicate DNA and undergo cytokinesis to form progeny (daughter cells) Cell differentiation : It describes process responsible for development of cell specificity and diversity as observed at the morphologic (or) molecular level. It expresses a specific portion of genome that is characteristic of that particular cell type. 4
Cell morphogensis : It describes those developmental process that are responsible for formation of shape and form of organ. Eg. Branding of salivary gland. Neuro epithelial interactions : Another study dealing with the events leading to the initiation of epithelial ingrowth has been under taken by DOZIN. The research demonstrates formation of both the human and mouse mandibular and sublingual glands is directly related to â€œGanglioneural recessâ€?. Ganglio neural recess is term descriptive of the developing sub-mandibular ganglion cells and their location. The further report demonstrated that both post ganglionic parasympathetic neurons as well as mesenchyme into which epithelium invagiantes are composed of ectomesenchyme, thus bringing salivary gland morphogenesis within the scope of developmental events that involve neural crest derivative cells. General development pattern and salivary glands : All salivary glands follow similar developmental pattern. The functional glandular tissue (parenchyma) develops as an epithelial out growth. (Glandular bud) of the buccal epithelium that invades the underlying mesenchyma. The connective tissue stroma (capsule and septa) and blood vessels form from the mesenchyme. The mesenchyme is composed of cells derived from the neural crest. It is essential for normal differentiation of the salivary glands. ECM components synthesized by mesenchymal
differentiation. Bud formation and gland origin : As the epithelial bud forms during development, the portions that are close to stomodeum (primitive and cavity) differentate into main excretory
duct of gland. The distal portions arborize to form the terminal portions of duct system, secretory end pieces or acini. The origin of epithelial buds is believed to be ectodermal in the parotid and minor salivary glands and endodermal in the sub-mandibular and sub-lingual glands. The break down of oropharyngeal (bucco pharyngeal) membrane during 4th week of development, permits the intermingling of stomodeal ectoderm and cranial forgut endoderm, which complicates identifications of specific germ layer origin of S.glands, parotid glands originate near corners of stomodeum by 6 th week of prenatal life. Sub-mandibular araise from floor of mouth at the end of 6 th or beginning of 7th week of utero. The sub lingual glands form lateral to sub-mandibular primordial at 8th week. Minor S.glands form from epithelium but donâ€™t develop until 12th prenatal week. STAGES OF DEVELOPMENT Salivary gland development may be divided into 6 stages. Stage I : Formation : induction of oral epithelium by underlying mesenchyma. The
proliferation in the epithelium, which results in the thickening and formation of epithelial bud. The growing bud is separated from the condensation of mesenchyme by basal lamina that is secreted by the epithelium. The process of development of all salivary glands is similar except the site and time of development. Stage II : Formation and growth of the epithelial cord : A solid cord of cells forms the epithelial bud by cell proliferation. Condensation and proliferation occur in the surrounding mesenchyme that is closely associated with the epithelial cord. The basal lamina is composed of GAGs, glycoproteins and collagen.
The basal lamina, as well as surrounding mesenchyme influences morphogenesis and differentiation of salivary glands throughout their development. Why mesenchyma induce proliferation there only + how ? Presence of 1st arch ecto-mesenchyme is essential for full salivary gland development. Eg. if non-salivary gland mesenchyme is combined with salivary gland epithelium, the epithelium does not differentiate into glandular epithelium. Stage III : Initiation of branching in terminal parts of the epithelial cord and continuation of glandular differentiation The epithelial cord proliferates rapidly and branches into terminal bulbs (presumptive acini). The growth in length of solid epithelial cords and differentiation of the berry like terminal bulbs are noticed. Stage IV : Repetative branching of epi-cord and lobule formation : The branching continues at terminal portions of the cord, forming an extensive trace like systems of the bulbs. As the branching occurs connective tissue differetate around the branches, eventually producing extensive lobulation. The glandular capsule forms from mesenchyme and surrounds the entire glandular parenchyma. Stage V : Canalization of presumptive ducts : Canalization of epithelial cord, with formation of hallow tube or duct usually occurs by 6th month in all 3 major salivary glands. Lumen appear 1st in the proimal (oral, terminal) and distal portions of the main excretory duct and in the branch ducts, then in the mid portion of main duct and lastly in the acini, all of which precede the formation of secretory granules. Lumen development occurs as a result of formation of tight junctions (zonular occludens) among the cells surrounding what was initially a simpler
intercellular space. Extensive branching of duct structure and growth of connective tissue septa continue at this stage of development. Stage VI : Cytodifferentiation : The final morphologic stage of salivary gland development is cytodifferentation of functional acini and intercalated ducts. During this period, mitotic activity shifts from the entire epithelial cord to the terminal bulb portions. Cells of the bulb region are the stem cells that undergo cell proliferation and subsequent differentiation into acinar cells as well as duct cells. Myo epithelial cells also arise from epithelial stem cells in the terminal bulbs of the developing duct system and development in contact with acinar cytodifferentation. Maturation of acinar cells occur in specific statges classified according to the morphology of secretory granules and cellular organells. Acinor development differs for serous and mucous cells. Therefore, the parodid, sub-mandibular and sublingual salivary glands show variations in cuto differentiation patterns. Terminal bulb cells differentiate into intercalcated duct cells of the acdulct glands and they serve as a stem cell for acinor, myoepthelial and ductal cells. Secretogogue stimulus-secretion coupling mechanisms and innervation of the gland continue to mature following cytodifferentiation. PATIENT DUCT SYSTEM In the formation of patient duct system of salivary glands it has been shown that (a) the mucous membrane at the end of the duct differentiates insitu into a papilla. (b) ducts are dilated initially by the secretion of water and of electrolytes by the cells themselves. Further, the prenatal duct cells, studies invitro, are sensitive to pharmocoliogic agents which tend to increase or decrease the transport of water and electrolytes. The later fetal stages of human sub-mandibular salivary gland differentiations have been studied and they reported that : at 4 months of 8
gestation only undifferentiated cells are present. Mucous like cells can be seen in striated ducts at 7 months and serous cells are found in the terminal portions of the gland at gestation. POSTNATAL DEVELOPMENT The postnatal developmental changes is the salivary glands was the work of Jacoby and Leeson with light microscope and electron microscope. In rat the sub mandibular and sub-lingual glands are more highly differentiated than the parotid at birth. In rat acinar cells are not present at birth as they are in man and in pig. Acinar cells are not present until 7 th day in the rat sub mandibular gland. Terminal ducts do not disappear and acini do not grow completely until 40th and 120th day. They (Jacoby and Leeson) described ultra structural changes in the terminal cells as secretory function is established. In the mouse, also, the post natal developmental changes include the opening of the secretory lumina and secretory cell differentiation. Functional influences on the initiations of salivary secretion is a postnatal event. Acinar transformation is induced and affected by cellular secretory activity. Secretion evokes a neural stimulation that effects acinar cyto differentiation. The further correlation between function and glandular development is reported by Redmass and Sreebny. They noted two early postnatal developmental stages 1. 1st from 1 to 12 days 2. 2nd from 15 to 25 days In first enzymatic concentration in the cells increase greater than cell number or size. During 2nd phase cell size in particular is increased. Further 1st phase correlates with the on set of suckling (enzymatic concentration) and 2nd phase with weaning, leading to suggestion that food substrates and
secretory stimuli may have â€œindictive significanceâ€? in salivary gland differatiation. PROCESS INVOLVED IN SALIVARY GLAND DEVELOPMENT 1) General Development of salivary glands is influenced by intrinsic and extrinsic factors that regulate the process of cells proliferation, differentation and morphogenesis. The intrinsic factors are defined as the programmed pattern of gene expression specific for each cell type. This programmed script, with gene turned-on and turned off at appropriate times, leads to the normal development and growth of tissues and organs and the differentiation of cells. Extrinsic factors are signals provided by cell-cell and cell-matrix interactions, as well as by cytokines, hormones and growth factors in extracellular milier. The extrinsic factors define boundaries between groups of cells during development. Eg. (Fruit fly) Drosaphila has been used as a model of embryonic development. There is a shift during development between 3 categories of genes. Maternal genes are expressed during oogenesis by the mother and act during oocyte maturation. They define broad regions with in the egg and regulate expression of the segmentation genes, that determine the number and / or polarity of segments. Segmentation genes define smaller regions of embryo. The last group, homeotic genes regulate development of 1 body part compared to other (same as other side). Homologous genes to those identified in drosophila are being identical in mammalian development with remarkable conservation of structure and regulatory functions.
2) Positioning of the glands : The formation of specialized structures (salivary glands) is regulated by homeotic genes. These genes contain – homeobox domain i.e. 60-amino acid, DNA binding domain. Much of informations is obtained from the studies of drosophila. In drosophila polarity is established initially along an anterior-posterior axis (head-tail)
development within each segment establishes a doral-ventral (backabdomen) gradient that is translated into specialized structures in each segment of the larua and eventually the adult segmented fly. In drosphila, the gene “SEX COMBS REDUCED” (sex) is a homeotic gene. It encodes a transcription factor that is responsible for the location of salivary glands. Scr is uniformly transcribed in the cells of posterior head segment where the drosophila suli.gland will develop. The dorso ventral boundaries of glands are established by genes homologous to mammalian genes, such as bone morphogenic protein – 4 (BMP-4) BMP-4 limit the permissibility of Scr expression in drosophilla also involved in cascode of gene expression that regulates epithelial mesenchymal interactions involved in branching and other morphogenetic events. The development of mammalian salivary glands mrophogenesis remain unclear. The correct patterning of vertebrate embryo is based upon expression of HOX genes. The expression and restriction of HOX genes are responsible for the differentiation of cells along the anterior-posterior axis of all metazoans. HOX-genes expression occurs in the vertebrate nervous system and its derivatives, including the neural crest cells.
The neural crest is instrumental in the formation of the salivary glands, teeth and over all craniofacial morphology through formation and differentiation of bronchial arches. 3) Branching of the epithelial cord : Branching is the primary morphogenetic process in salivary gland development. Cleft formation in distal buds initiates branching process that is followed by epithelial proliferation. Collagen type III accumulates at cleft points and appear to be critical for branching to occur. Type I and IV collagen appear to be more ruportant for the maintenance and support of established branches. Type I : Type III collagen ratio increases at the time of branching. Type Ileads to stabilization while type III is more involved in active branching. More recent studies also indicate that proteoglycan biosynthesis and deposition are required for branching but not growth of the rudiments. Chondroitin sulfates are the predominant GAGS in the basal lamina of actively branching young rudiments and appear to increase during stabilization. The independence of epithelial expansion and branding has been demonstrated by use of tunicamycin (in vitro). Tunicamycin inhibits Nlinked
accumulation and cell proliferation but epithelial branching is unaffected. After tunicamycin treatment branching accurs and lobules form normally with inhibited cell proliferations, resulting in smaller rudiment with miniature lobes. In contrast, the size and number of lobes increase in control cultures. Branching and proliferation must be coordinated processes for normal development. Mitotic activity is normally localized in the most peripheral regions of the bud. Treatment with hyaluronidase disrupts the basal lamina interfering with the signal required for cleft formation. Destabilization of 12
basal lamina there fore inhibits cleft development but also effects cell proliferation. In the absence of normal basal lamina there is an absence of branching and generalized cell proliferation replaces localized mitotic activity. So basal lamina is important in initiation and maintenance of lobular morphology. The basal lamina regulate morphogenetic changes by selective filtration or channeling of materials to the epithelium. For Eg : the regulation of the flow of ions such as Ca++ to epithelium may alter the function of micro tubules and microfilaments in cellular proliferation,
(collagenogentic) and selective break down of collagen (collagenolysis) play a critical role in salivary gland development. For example collagen synthesis by mesenchyme provides structural stabilization after branding has occurred. Stabilization appear to be provided by type I and IV collagen fibres. In addition, collagenolytic activity in the epithelium and mesenchyme may allow for selective breakdown of basal lamina and communicate between the epithelium, basal lamina, and surrounding mesenchyme at key stages of development. 4) Process involved in cyto differentiation : The interaction of the epithelium and mesenchyme is best stududied in a culture disb. Where epithelium can be grown in the presence of selected components of the basal lamina and specific growth factors. Salivary gland rudiments can branch invitro in the absence of mesenchymal cells, but in presence of other factors. A developing salivary gland rudiment have three clefts at the beginning of culture. The epithelium is grown in serum with the use of an artificial matrix known as Matrigel, composed of mainly laminin, type IV collagen, heparan sulfate, entactin, and nidogen. Using this they abserved that different growth factors appear to regulate distinct parts of 13
morphogenetic process. Fibroblast growth factor has bear shown to alter stalk elongation and epidermal growth factor (EGF) regulater branching. The FGF and EGF combination results in morphology similar to in vivo studies. ECM molecules regulate presentation and the distribution of growth factors to epithelium at appropriate time during in vivo. There for, the ECM in concern with specific growth factors appears to regulate the complex processes involved in branching morphogenesis. Cyto differentiation is believed as pre-programmed development occurring in early stages of morphogenesis. A period of in situ epithelial – mesenchymal contact is required for cyto differentiation. After this contact has taken place. Exocrine cell differentiation occurs without continued presence of mesenchyme. There fore it appears there is a partial coupling of morphogenesis and cyto differentiation. Full differentiation of secretory components is apparent at birth, but is complete until the onset of a solid diet and the presence of masticatory stimuli. This post natal development process includes the maturations of stimulus – secretion coupling that links secretagogue – membrane receptors to signal transudation pathways within the cell and control acinar cell secretion and establishment of neural connections from autonomic nervous system, the primary regulator of salivary gland function. Saliva formation : ionic transport : Saliva is formed in 2 stage. First stage – is production by acinar cells. Second stage – is the ducts that change isotonic solution to the hypotonic solution. Different systems involved are 1) Na+ K+ - ATpase 2) Na+ K+ Cl- co-trans port system. 3) Bicarbonate secretions – by Na+ / H+ exchanger. 14
4) Chloride secretions â€“ by Na+ / H+ and Cl- / Hco3 exchanger. 5) Ca++ regulated K+ and Cl- channels 6) Osmotic flow of water. 7) K+ / H+ exchangers. 8) Paracellular transport of Na+ and water. Saliva is primarily formed is the arrival cells and released into ducts where isotonic solution is modified into hypotonic solution by removal and addition of specific ions. Primary site of ionic transport is striated duct. Acinar secretion of saliva : I) On basolateral membrane Na+ K+ -ATpase exchanges 3Na+ in an outward direction towards the interstitions with 2 K + moving inward. The result is maintenance of high intracellular K+ and low intracellular. II) Due to this action it drives Na+ K+ Cl- co-transporter This Na+ K+ Cl- transporter necessary to transport Cl- into acinar cells III) Na+ / H+ and Cl- / HCO3- exchangers.o â†“
Hco3 to go out; while Cl- and
Allow transport of H+
Na+ are taken by the acinar cells. On the laminal surface chloride channels allow for rapid efflux of Cl following cellular stimulation. Activations of acetylcholine receptors Following para sympathetic nerve stimulation Result in increased inter cellular calcium (Ca+) This (Ca+) drives
apical Cl- channer. And also activate Ca+ activated K+ channel on the
baso lateral surface to preserve the membrane potential by giving the K + out into interstitium. 15
II Stage of salivary secretion : Here the isotonic saliva produced by acinar cells is modified into hypotonic saliva. The duct cells reobsorb Na + and Cl- and secrete K+ and Hco3- with out water reobsorption resulting in hypotonic saliva. The basolateral membrane of duct cells process high - Na+ - K+ - ATpase - Na+ / H+ - exchanger - Cl- / K+ channels The luminal surface processes - Na+ channels - Cl- channels - Na+ / H+ - Cl- / HCo3- H+ / K+ exchange A genetic mutation in cystic fibrosis (CF) gene alters Cl - and other channels in salivary glands and leads to following symptoms. Seen commonly among Caucasian children is characterized by general dysfunction of salivary and other exocrine glands and results in pulmonary, digestive and nutritional difficulties. Accumulations of glycoproteinaceous material in the acinar cells and ducts ďƒ leading to eventually obstructions of the ducts. During salivary secretion there is a rapid movement of water following stimulation. Since acinar cells shrink dramatically following secretions, it appears that most of water moves by osmosis in response to Na+ in primary saliva. There is also evidence for paracellular and transcellar movement of water. Aquaporins are membrane proteins that function as high selective water channels in fluid transporting epithelum. Aqua porins (AQPS) 1 and 5 are predominant inhuman salivary glands and mainly in serous acini. 16
CLASSIFICATION OF SALIVARY GLANDS The glands of the body may be classified into two general types : 1) Exocrine 2) Endocrine 1) Exocrine : Glands are those glands with a duct system to transport secretion from the glands. 2) Endocrine : Glands are those duct less glands dependent on blood supply for delivery of their secretary products. Salivary glands are classified as exocrine glands, but these glands are associated with a number of biologically active substances (Eg: nerve growth factor and epidermal growth factor) that may be secreted by an endocrine mechanism. They are classified as compound tubulo acinar glands, which indicates the presence of a branched duct system and secretory units with both tubular and acinar portions. I) The salivary glands of mammalian species may be divided into 1) Major salivary glands 2) Minor salivary glands. 1) Major salivary glands : These glands produce major part of salivary secretion most of the (0.5 to 0.75 lit.) saliva produced daily. These glands are located apart from oral cavity, they communicate with large excretory ducts. There are three pairs of major salivary glands : 1) Parotid 2) Sub mandibular (formely sub-maxillary) 3) Sub lingual 2) Minor salivary glands : They are found in the oral cavity and are named according to their location. - Buccal 17
- Labial - Lingual - Palative - Glasso palatine II) Salivary glands may also be classified by types of secretion. 1) Serous 2) Mucous 3) Mixed 1) Serous : serous secretion contains water, enzymes (primarily salivary amylase and some maltase), a variety of salts, and organic ions. i) Parotid gland ii) Lingual glands – circumvallate papillar (Von Ebner’s glands) 2) Mucous : Mucous secretion produces mucins, which act as lubricant to aid in mastication, deglutition and digestin. i) Glosso palatine –Anterior faucial pillar, and glasso palatine fold. ii) Palatine glands iii) posterior lingual glands 3) Mixed glands : i)
Sub lingual gland
Anterior lingual glands
GROSS ANATOMY OF SALIVARY GLANDS I. MAJOR SALIVARY GLANDS : 1) Parotid gland : Parotid gland is the largest of the salivary glands. It weight about 15gm. Situation : It is situated below external acoustic meatus, between the ramus of the mandible and the sternomastoid. A part of this forward extention is often detached, and is known as the accessory parotid. It lies between the zygomatic arch and parotid duct. Parotid capsule : The investing layer of the deep cervical fascia forms a capsule for the gland. The fascia splits to enclose the gland. The superficial lamina is thick and adherent to the gland is attached above to the zygonatic arch. The deep lamina is thin and is attached to the styloid process, the mandible and tympanic plate. A portion of deep lamina extending between styloid and mandible is thickened to form stylomandibular ligament which separate parotid from sub-mandibular gland. External features : The gland resembles a three sided pyramid with its apex down wards. The gland has 4 surfaces. 1) Superior (base of the pyramid) 2) Superficial 3) Anteromedial 4) Posteriomedial. The surfaces are separated by 3 borders : i)
Structures within parotid gland : 1) Arteries : The external carotid artery enters the gland through its postero medial surface. The maxillary artery leaves the gland through its anteromedial surface. The superficial temporal vessels emerge at the anterior part of the superior surface. The posterior auricular artery may araise with in the gland. 2) Veins : The retromandibular vein is formed with in the gland by the union of the superficial temporal and maxillary veins. In the lower part of gland the vein divides into anterior and posterior divisions which emerge at apex. 3) Nerves : The facial nerve enter the gland through the upper part of its posteriomedial surface and divides into its terminal branches with in the gland. The branches leave the gland through anteriomedial surface temporal, zygomatic, (upper buccal and lower buccal), buccal, mandibular and cervical branch. Parotid duct : It is thick walledand is about 5 cm long emerges form the middle of the anterior border of the gland. It runs forward and down wards on masseter. Here its relations are â€“ Superiorly : a) Accessory parotid gland b) Upper buccal branch of facial nerve c) Transverse facial vesels. At the anterior border of the masseter it turns medially and pierces a) Buccal pad of fat b) Buccal pharyngeal fasia c) Buccinator. 20
The duct runs forward for a short distance between buccinator and oral mucosa. Finally the duct turns medially and opens into the vestibule of the mouth opposite the crown of the upper second molar tooth. Blood supply : Parotid gland is supplied by the external carotid artery and its branches that araise near the gland. The veins drain into the external Jugular vein. Nerve supply : 1) Para sympathetic nerves are secretomotor. They reach the gland through the auriculotemporal nerve. The pre ganglionic fibres begins in the inferior salivary nucleus, pass through the 9 th nerve, its tympanic branch, the tympanic plexus, and the lesser petrosal nerve and relay in the otic ganglion. The post ganglionic fibres pass through the auriculotemporal nerve and reach the gland. 2) Sympathetic nerve supply : sympathetic nerves are vasomotor and are derived from the plexus around external carotid artery. 3) Sensory nerve Supply : Sensory nerve supply to gland comes from the auriculo temporal nerve, but parotid fascia is innervated by the sensory fibres of the greater auricular nerve (C2). Lymphatic drainage : Lymph drains first to parotid nodes and from there to the upper deep cervical nodes. 2) Sub â€“ mandibular salivary gland : This is large salivary gland. It is about size of a walnut. It is roughly â€˜Jâ€™ shaped. Situation :
It is situated in the anterior part of the digastric triangle. It is roughly â€˜Jâ€™-shaped being indented by the posterior border of mylohyoid which divides it into large part superficial to the muscle, and a small part lying deep to muscle. Superficial part : This part extends upwards deep to the mandible upto the mylohyoid line. It has a) Inferior b) Lateral c) Medial surfaces. The gland is partially enclosed between two layers of deep cervical fascia. The superficial layer of fascia covers the inferior surface of the gland and is attached to the base of the mandible. The deep layer covers the medial surface of the gland and is attached to mylohyoid line of the mandible. Relations : A) Inferior surface : Inferior surface is covered by a) Skin. b) Platysma c) Cervical branch of facial nerve d) Deep fascia e) Facial vein f) Sub-mandibular lymph nodes. B) Lateral surface : Is related to a) Sub mandibular fossa on the mandible b) Insertion of medial pterygoid c) Facial artery
C) Medial surface : This surface is divided into 3 parts. a) Anterior part b) Middles part c) Posterior part a) Anterior part : Is related to ii)
b) Middle part : Is related to i)
Sub mandibular ganglion
c) Posterior part : Is related to i)
Wall of pharynx
And inferiorly it overlaps stylohyoid and the posterior belly of digastric. Deep part : This part is small in size. It lies deep to mylohyoid and superficial to the hyoglossus and the styloglossus. Posteriorly it continues with superficial part round the posterior border of mylohyoid. Anteriorly it extends upto the posterior end of sub lingual gland. Sub mandibular duct : It is thin walled and is about 5 cm long. It emerges at the anterior end of the deep part of the gland. 23
↓ Runs between the lingual and hypoglossal nerves. ↓ At the anterior border of hyoglossus the duct is crossed by lingual nerve. ↓ It opens on the floor of the mouth on the summit of the sub lingual papilla at the side of the francium of the torque. Blood supply : It is supplied by the facial artery. The veins drain into the common facial or lingual vein. Lymphatic drainage : Lymph passes to sub mandibular lymph nodes. Nerve supply : Supplied by the branches of submandibular ganglion. These branches convey a) Secretomotor fibres. b) Sensory fibres fromlingual nerve c) Vasomotor sympathetic fibres from the plexus of facial artery. Secretomotor pathway begins in superior salivarynuclers ↓ Preganglionic fibres pass through the sensory root of facial – nerve, ↓ Geniculate ganglion, ↓ Farial nerve, ↓ Chorda tympani and lingual nerve to reach sub-mandibular ganglion Then port ganglionic fibres enter the sub mandibular gland. 24
3) Sub-lingual salivary gland : This is the smallest of the three major salivary glands. It is almond shaped and weighs about 3-4gm. Situation : It lies-above mylohyoid, below mucoso of the floor. Behind is deep art of sub mandibular gland. Medial to the sub lingual fossa of mandible and lateral to the genioglosses. About 15 ducts emerge from the gland. Most of these ducts (ducts of Rinivus). Open directly into the floor of the mouth on the summit of the sub-lingual fold. A few of them join sub mandibular duct. Blood supply : Blood supply is from lingual and sub mental arteries. Nerve supply : It is similar to sub mandibular gland. II) MINOR SALIVARY GLANDS : Labial glands : A large percentage of substance of the lips is glandular tissue. Here multiple small glands lie between the mucosa of the lip and orbicularies muscle. They open directly by many small ducts directly onto lip mucosa. Buccal glands : In a similar, diffuse fashion, to that labial glands, the buccal glands are located in the cheek, between the mucosa and the buccinator muscle. Palatine glands : The posterior one third of the hard palate is covered with palatine glands. These glands are sparsely found anterior to the bicuspid region of the plate. They are also found in the soft palate. They are quite numerous here.
Lingual glands : There are two groups of lingual glands. Anteriorly, on the ventral surface of the tongue, is anterior lingual gland (of Blandin and Nuhn). On the dorsal surface of tongue are the glands surrounding the trough of the circumvallate papillae. Also, on the dorsal surface are glands around the lingual crypts at the base of the tongue. HISTOLOGY OF SALIVARY GLANDS Serous cells : The parotid gland is the largest of the salivary glands. The acine of the gland are serous although mucous cells have occasionally been reported. The cells have characteristic granular appearance with rouine haemotoxylin and eosin staining. Connective tissue septa can be seen sub dividing the secretory parenchyma into lobes and lobules. The connective tissue contain blood vessels, nerves and collecting ducts. The lumina of acini are very hallow, unless distended by the accumulation of secretions. The prominent nuclei are round and located in the basal third of the cell which is basophilic (due to presence of ro7ugh endoplasmic reticulum). In the ultra structural appearance of serous acini, the cells have wedge shaped outline and surround the central lumen The basal part of each serous cell is delineated from the surrounding connective tissue by a basal lamina. This region of cell contains the nucleus and
approximations to this surface. The leminal part of the cell contain dense round symogen granules. Many narrow canaliculi run between the cells and join the lumen. Both the canaliculi and lumen are lined by short microvilli. Adjacent cells membranes contact at desmosomes, gap junctions and tight junctions.
Mucous cells : In routine microscopy the collections of mucous acini are readily distinguished in the resting gland because the mucous acini are paler since their mucinous content does not readily take up routine stains or is lost during preparation. The nucli are compressed into the basal part of the cell. small crescent shaped collections of serous cells may be found in routine sections at the most distal ends of the mucous acini. These are referred to as serous demilunes. Mucous acini can be specifically differentiated from serous cells by staining with alcian blue (or) PAS (periodoe acid â€“ schiff). The distentions caused by mucous granules with in each cell results in a flattering and displacement of the nucleus into the basal cyto plasm. In the early stages of synthesis of its secretory products, large amounts of rough endoplasmic reticulum and few mucous droplets are present. Compared with serous cells, the mucous cells have more golgo apparatus. As â†‘ carbohydrates at the later stage of its secretion round pale granules are exhibited. Myoepithelial cells : Myoepithelial cells lie between the basal lamina and the basal membranes of the acinar secretory cells and intercalated duct cells. Myoepithelial cells around acini are dendritic cells consisting of a stellate â€“ shaped body containing the nucleus and a number of tapering processes radiating from it. Myoepithelial cells in the intercalated ducts are elongated, run longitudinally along the duct and have few short processes. Around the acini, the processes lie in gathers on the surface of the secretory cells, so the out line of the acinus remains smooth. Around the intercalated ducts, the cells lie more superficially and produce a bulge in the out line of the duct. Myoepithelial cells contract as a result of activity of both parasympathetic 27
and sympathetic stimulations. Ultrastructurally, the nucleus tends to be flattened and intra cellular organelles associated with protein synthesis are not abundant. Cell contains numerous contractile actin microfilaments 4 -8Âľm in diameter. Myo epithelial cells have desmoromal attachment with under lying parenchymal cells, gap junctions and remidesmoromal attachment with the basal lamina. Myoepithelial cells contain cytokeratin inter mediate filament 14 and contractile acine filaments. The presence of cyto keratin confirms the epithelial origin of myoepithelial cell. pincytotic vesicles and dense attachment areas are associated with that part of plasma membrance of the myoepithelial cell covered by basal lamina. Functional role of myoepithelial cells in salivary secretions. 1) Accelerate the initial out flow of saliva. 2) Reduce leminal volume 3) Contribute to the secretory pressure. 4) Support the underlying parenchyma and reduce back permeation of fluid. 5) Help salivary flow to overcome increases in peripheral resisitance â€“ but of this is excessive of may lead to sialectatic damage of striated ducts, thereby increasing over all permeability. And also include assistance for some parenchymal cells to expel their contents. HISTOLOGY OF THE SALIVARY DUCTS Duct : The duct differs in each of major salivary glands. The duct system has 2 main structural parts: Intra lobular and the interlobular portions. Intra lobular ducts are of two types : 1) Inter calated ducts 2) Striated ducts. 28
Inter lobular portion ducts are termed the excretory ducts. Intercaled ducts : Intercaled ducts are lined by low cuboidal epithelium and drain secretory end pieces. They contain few secretory granules, rough endo plasmic reticulum, mitochondria, round / oval centrally placed nucleus. Striated ducts : Are next largest ducts located between the excretory and intercalated ducts. They carry ion-transport functions that occur along the route of the saliva from the acinar lumen to the oral cavity. They are lined by tall columnar epithelial cells, with distinct eosnophillic cytoplasm, special, centrally or ecentrally placed nuclei. The term striated refers to light microscopic appearance of the basal cytoplasm that has well developed striations perpendicular to the base of the cells. Striated duct cells are present around lumen. Sodium reabsorption and potassium excretion occur within these cells and effect the change of level of adrenal cortical steroid hormone mainly aldosterone. Sodium reabsorption changes saliva from an isotonic to a hypotonic osmolarity. Excretory ducts : These excretory ducts empty the secretions into the oral cavity. As the excretory ducts become larger the epithelium lining of these ducts change from simple columnar to psuedo stratified or stratified columnar epithelium. At or near the entrance of oral cvity these ducts become lined with stratified squamous epithelium continued with buccal epithelium. CONGENITAL ANOMALIES Salivary gland Heterotopia : Presence of salivary gland tissue outside the major salivary glands and the upper aerodigestive tract is called as hypertopia. Etiology : Embryonic migration of salivary gland. It is congenital anomaly due to developmental defect. 29
It may be intalymphatic / extralymphatic. Intra lymphatic hype : In lymph nodes Most lymph nodes was to parotid than S.M. (or) upper cervical nodes. Consist â€“ Inter collated, interlobular ducts, acini. Extra lymphatic i)
High form â€“ limited to parotid
- Neoplastic transformation is rare. Developmental abnormalities / disturbance of salivary glands 2) Aplasia / Agenesis 3) Hyper plasia of palatal glands 4) Atresia 5) Aberrancy 6) Anterior lingual depression. 1) Aplasia / Agenesis : Aplasia is congenital absence of any of the major salivary gland. Any of the gland may be missing unilaterally or bilaterally. Etiology : Etiology is unknown and is not necessarily associated with othe rectodermal dysplasias. May be familial (or) hereditary. Two such cases, accruing in father and son have been reported by smith. Clinical features : i)
Xerostomia / dry mouth.
Oral mucosa becomes dry and smooth.
Accumulation of debris over oral mucosa is seen.
Cracking of lips
Fissuring at corners of mouth
Rarupant caries 30
Treatment : - Oral hygienes maintenance - Flouride treatment 2) Hyperplasia of palatal glands : - It appears as small localized swelling in palatal mucosa has been described by Giansanti and associates. - They are 1 cm (or) more in size. - These are of normal in colour. Causes : Cause is unknown. The following may result in salivary gland enlargement. Aging
syndrome Wald enstrom’s
macroglobulinemia Uveo parotid fever
disease Benign lympho
Clinical features : - It presents a small localized swelling, measuring from several mm to 1 cm in diameter, usually on hard palate or at the junction of the hard and soft palates. - The lesion has intact surface and is firm, sessile and normal in colour. - It is usually asymptomatic and patient may be un aware of the lesion. Histological features :
Mass appears microscopically as closely packed collections of normal appearing mucous acini with the usual intermingling of normal ducts. There is no inflammation, no spillage of mucous, no florosis. Treatment : They should be excised as these cannot be differentiated from neoplasm at palatal mucosa. (because malignant palatal neoplasms also don’t ulcerate). And no further treatment is necessary and the condition is not reported to recur. 3) Atresia : Congenital occlusion (or) absence of one (or) more of the major salivary ducts in termed as atresia. As the salivary duct is absent it may lead to the retention cyst and xerostomia. Such a case has been reported by forotich and his associates. 4) Aberancy : The situations at which the salivary glands found other than there usual locations. Eg. Static Bone Cyst / Stafne’s cyst It is well circumscribed lesion. Causes : It is formed due to developmental inclusion of salivary gland tissues within (or) adjacent to the site, where it is formed. Radiographic features : - Ovoid area of radiolucency between mandibular canal and inferior border of jaw (below mandibular canal). Differential diagnosis : - Haemorrhagic bone cyst. - Traumatic bone cyst. 5) Anterior lingual depression : - It is poorly circumscribed depression on the anterior part of lingual aspect of mandible. - It is present between central incisor and 1st premolar area. This anterior radiolucency also represents a cavity (or) depression on lingual surface of the mandible. 32
Langalis and his co-workers examined 12 dried mandibles and revealed that either anatomic variants related to the digastric (or) sublingual fossa or developmental anomalies caused by impingement of the sublingual gland. Cause : It is formed due to inclusion or impingment of salivary gland tissues. Complications : A complications occasionally reported is the development of true central salivary gland neoplasm from the included salivary gland tissue, but this is rare. Clinical considerations 1) Hyper function Salivary secretion is increased : Etiology : - Mentally retarted children - Underlying neurological disease like cerebral palsy - Side effect of the neuroleptic drugs like fluphenaz Triflupro mazine - Ill-fitting dentures - Optics ulcers - Rabies - Heavy metal poisoning Clinical features â€“ Patient present with hyper salivation noticed clinically. - Drooling of saliva in mentally retarted children - Cerebral palsy - Mental retardations - Macerated sores around mouth - Constant soling of cloths and beds Idiopathic paroxysmal sialorrhea : 33
- 2 – 5 Minutes - Cause is unknown - Episodes of nausea / epigastria pain is noticed. Treatment : - If mild treatment is not method - Increased saliva with gastro esophageal reflux,1st that reflux should be corrected and saliva decreased. - Anticholinergic medications – Scopolamine - Excision of sub mandibular and ligations of parotid duct - Sectioning of chordac tympanic. Sometimes relocations of parotid / sub mandibular duct positioned posteriorly to tonsillarfossa. 2) Hyposalivation : Decrease in the salivary flow Etiology : (i)
Iatrogenic – Medicaments
Neurological – Bells palsy
Metabolic disease- Mental depression,malnutrition, Vitamin deficiency dehydrations.
Hormonal diseases – Diabetes mellitus.
Infections – Bacterial Viral
Auto immune- Sjogren’s syndrome (non specific parotitis).
(vii) Local salivary disease – Sialolithiasis Tumors Carcinomas.
Medicaments : Diuretics : Ca+ blockers – Neifedepine
Verapmil Isosorbide dinitrate – Venal dialator ACE inhibitors Mixed dialators
Enalopril Captorpil Hydrochlorthiazide Frusemide
Antihypertensive drugs BETA-adrenergic blockers. Diuretics Ca+ channel blockers ACE inhibitors. α - blockers – phenotalanine B- Blockers – Atenolol Propronal Metaprolol Alpha beta blockers-labetolol
Antidepressant α-adrenergic blockers - Imipramine - Desipramine - Doxepin - Amoxapine Antiparkinsonisms (cholenergic) - Leuodopa - Carbidopa Antihistamines (cholenergic) - Promethazine - Chlorpheniramine
- Cimitidine - Ranitidine
- Famotidine - Thioperamide - Impromidine
Anticholinergic (cholinergic) - Atropone - Scopolamine Antipsychotics α-adrenergic - Chlorparazine - Thioridazine
Clinical features of hyposalivation / xerostomia : - ↑ Dental caries - Atrophy of mucosal surfaces - Increase chance for oral infections - Burning sensation of tongue - Difficulty in swallowing 36
- Altered taste perception Sjogrenâ€™s syndrome : Autoimmune disease involving salivary and lacrimal glands with lymphatic infiltration in the ducts. Etiology : - Autoimmune - At the time of viral / bacterial infection it may lead to expression of foreign molecular species at cell surface of salivary epithelial cells triggering an immune response. Treatment : - Glecerin - Lemon mouth wash - Artificial saliva Sailolithiasis (calculi / stones) Sialolioths calcified structures that develop within salivary ductal system. Araise from the deposition of Ca+ salts around nidus of debris within duct lesion. Debris may include - Bacteria - Foreign bodies - Ductal epi cells Clinical features : - Mostly sub-mandibular - Pain, swelling mostly in meal time - Seviority depends on obstruction / back pressure - If stone located at terminal portion of duct a hard mass may be palpated beneath the mucosa. 37
Diagnosis : - Not all stones are visible on standard radiographic examination. - Terminal portions of ducts – by occlusal radiograph - In panaromic / periapical x-rays – super imposed on mandible - Sailography - CT scan-computerized tomography - Ultrasound Treatment : - Massaging the gland – terminal ductal - Increase fluid intake - Sailogogues Surgical removal including gland - Salivary gland endoscopy – newer method i)
Introcorporeal lithotripsy to help fragment the stone.
Extracorporeal shock wake lithotripsy have been used successfully in Europe and Japan
Treatment of xerostomia : - Artificial saliva - Continuous water through out the day - Sugar less candy – stimulate salivary flow - Biotene o Lactoferrin o Lactoperoxidase o Lysozyme - Dicontinuation of the medications - Sailogogue – pilocarpone – parasymptomatic against pilocarpine 510mg – thrice / four times a day. 38
- Cerimeline hydrochloride (acetyl chloride derivative) (recently approved in USA) - cevimelius, pilocorpine – avoided in glaucoma. - Fluoride applications - Mouth rinses - Bethanechol 75-200mg /day - Amifostine – IV before radiotherapy
REFERENCES : 1)
Pediatric developmental pathol 2004 May-June 7 (3) 262-267 INTRATHYROIDAL BRANCHIAL CLEFT LIKE CYST WITH HETEROTOPIC SALIVARY GLAND-TYPE TISSUE The patient was a 7yr old girl with growing mass in the left lateral neck. The ultrasonography revealed a cystic lesion in left thyroid. Histologically, the cyst was lined by squamous / respiratory type epi. The cyst was intimately associated with hypertropic tissues including lobules of well differentiated seromucinous salivary glands, mature fat tissue, and islands of the cartilage.
O.S.O.M.O.P.O. Radio Endod 2004 Dec 98 (6) 712-714. UNILATERAL AGENESIS OF THE PAROTID GLAND. They reported a case of unilateral agenesis of parotid gland without involvement of other major glands together with a compensatory hypertrophy of the contralateral parotid gland.
British jour Oral maxillo Fac Surg 2002 Oct 40 (5) : 455. CONGENITAL ATRESIA OF THE ORIFICE OF THE SATMANDIBULAR DUCT.
2 infants presented with unilateral cystic swelling in the floor of the mouth as a result of imperforate sub-mandibular ducts. This is thought to result from a congenital failure of canalization of the terminal end of the duct. Both cases responded to simple incision and decompression of the fluid-filled duct. Early treatment is important to avoid feeding difficulties and to prevent later complications such as ranula or sialadenitis. 4)
J Oral Pathol Med. 2004 Nov ; 33(10): 634-6. APLASIA OF SUBMANDIBULAR SALIVARY GLANDS ASSOCIATED WITH ECTODERMAL DYSPLASIA
CONCLUSION : The harshness of the process of chewing is mellowed down by the secretions of salivary glands i.e. and saliva. To put in a nut-shell, all salivary glands are a collection of secretory acini which empty their secretion into intercalated ducts. The secretion from several intercalated ducts converges into larger ducts and the process of convergence continues until finally the secretion is poured into the mouth. Thus, the salivary glands and saliva acts as a foundation for the garden of the oral cavity to maintain the natural form of soft and hard components.
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