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Home , Common bile duct, Common hepatic duct, Duct (anatomy), Lamina propria

NORMAL 1 AND EMBRYOLOGY

the . Accordingly, it is a pathologic NORMAL ANATOMY and not an anatomic entity (111). For reasons of anatomy alone, physicians are The superior surface of the gallbladder is often challenged by tumors arising in the ex- adherent to the , while its inferior surface trahepatic biliary system. The separation of be- is covered with peritoneum which is continu- nign from malignant conditions, the treatment ous with the liver. The interface between the of , and the morphologic variations of gallbladder and liver contains connective tis- malignant tumors require an understanding of sue, blood vessels, lymphatic channels, and anatomic relationships and common variants. occasionally, small accessory ducts that do For the surgeon, knowledge of the anatomy is not always communicate with the gallbladder. essential to avoid operative complications and The inferior surface of the gallbladder lies near injury to the patient. In contrast to the liver and the , , and hepatic flexure of , which are also foregut derivatives, the the colon. The gallbladder usually contains 40 extrahepatic biliary tree is primarily a system of to 70 mL of bile. ducts. The anatomy and are therefore Less complex than the intestine, the gallblad- emphasized in order to underscore the connec- der wall has four defined layers histologically: tion between structure and pathology (28). 1) a mucosa composed of columnar Anatomically, the biliary tree originates in and underlying lamina propria; 2) a smooth the liver and extends from the canals of Hering, muscle layer; 3) a layer of perimuscular connec- located at the margins of the most peripheral tive tissue; and 4) a serosa that does not extend portal tracts, to the pancreaticobiliary ampulla between the gallbladder and liver interface (fig. (formally the ampulla of Vater). The canals con- 1-1). The gallbladder lacks a bile from the bile canaliculi to the bile ducts and . in the portal tracts of the liver, which eventually Mucosa. The mucosa forms multiple irregu- coalesce to form the right and left hepatic ducts. lar folds that flatten as the gallbladder fills and These ducts and the , cystic its lumen expands. During contraction, these duct, gallbladder, and common com- folds come together and increase in height prise the extrahepatic biliary system. (15). The epithelium consists of a single layer of tall, uniform, columnar cells aligned along Gallbladder a periodic acid–Schiff (PAS)-positive basement A pear-shaped saccular , the gallbladder membrane. The cells have ovoid basal nuclei is normally found under the right of the and pale cytoplasm that may contain vacuoles. liver near the quadrate lobe. Traditionally, it Functionally, the cells secrete mucoproteins, has been divided into three parts: fundus, body, some of which are related to colonic mucins and neck. The neck tapers into the , (36,112). MUC5B is the most abundant mucin which opens into the common hepatic duct. A in the gallbladder (112). Interspersed among the small diverticulum, Hartmann pouch, is often columnar cells are narrow, dark-staining cells located at the junction of the neck and cystic that have been described as penciloid (fig. 1-2, duct. Originally considered a fourth part of the left) (110). These cells are considered modified gallbladder, the pouch is now thought to result columnar cells, although their nature and func- from chronic . It often contains tion are unknown. Because of their enzymatic and is usually associated with adhe- activity, it is unlikely that these cells are effete sions between the cystic duct and the neck of or represent artifacts of fixation (114).

 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

Figure 1-1 NORMAL GALLBLADDER Top: The section includes the mucosa, lamina propria, muscle layer, and perimuscular , including adipose tissue and serosa. The mucosal folds are of different height and width. The lamina propria consists of a very thin layer of connective tissue. The muscle layer is discontinuous. The perimuscular connective tissue includes normal adipose tissue. Bottom: The mucosal folds are lined by a single layer of tall colum­ nar cells.

Basal cells, which are smaller than columnar the more common intraepithelial . cells, are located immediately above the base- As in the intestine, T lymphocytes are found ment membrane. They are usually round, with among the columnar lining cells (fig.1 -2, right). elongated or ovoid nuclei whose long axis is Usually, a few intramucosal plasma cells are seen parallel with the . These in normal . cells, which are not common, are randomly Fetal gallbladders usually have penciloid distributed along the epithelium. Basal cells are cells and short smooth muscle bundles that are always separated from the lumen by the taller discontinuous (fig.1 -3). Goblet cells have been columnar cells and should not be confused with described in the normal fetal gallbladder as well

 Normal Anatomy and Embryology

Figure 1-2 NORMAL GALLBLADDER EPITHELIUM Left: Penciloid thin cells are mixed with columnar cells and rest on a basement membrane. Right: A small intraepithelial is present. as in gallbladders of children under 6 years of flammatory conditions as well as in adenomas age with a wide variety of liver diseases (54,117). and intramucosal carcinomas. These goblet cells are not present in normal Smooth Muscle. The muscle layer, which is adult gallbladders (117). Mucin-secreting , most prominent near the neck of the gallblad- which differ morphologically and histochemi- der, is thinner than the muscle layer of the small cally from pyloric-type glands, are normally and large intestines. The gallbladder lacks a mus- seen in the neck. Goblet cells are immunoreac- cularis mucosae and a submucosa. The muscle tive for cytokeratin (CK)7, CK20, MUC2, and layer is composed of compact, discontinuous, CDX2 (117). In abnormal gallbladders showing parallel aligned bundles of smooth muscle cells. intestinal metaplasia, endocrine cells, including Gaps exist between the ends of these bundles, EC cells, are usually found among the columnar and it is through these gaps that the Rokitansky- and goblet cells (4,58). Also, foveolar epithelium Aschoff sinuses invaginate (fig. 1-4). is seen in some cases of intestinal metaplasia. Perimuscular Connective Tissue and Serosa. Melanocytes, which presumably are the origin The perimuscular connective tissue contains of melanomas, have been observed in the nor- nerves, blood vessels, lymphatic channels, and mal human gallbladder (12). scattered isolated paraganglia (figs. 1-5, 1-6). Lamina Propria. The lamina propria con- When multiple, the paraganglia may coalesce or sists of a thin layer of fuse, and form larger endocrine structures that lacking a muscularis mucosae; it contains few may simulate a paraganglioma (fig. 1-7). The lymphatic and small blood vessels. Expansion endocrine cells of paraganglia show immuno- of the lamina propria occurs in a variety of in- reactivity for chromogranin and synaptophysin

 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

Figure 1-3 FETAL NORMAL GALLBLADDER A gallbladder from a 15-week gestational age fetus. There are no mucosal folds and few penciloid cells are seen admixed with the cuboidal biliary cells. The smooth muscle cells do not form bundles.

Figure 1-4 NORMAL GALLBLADDER The muscle layer is discontinuous. Muscle gaps are clearly shown.

Figure 1-5 PARAGANGLION A small paraganglion is located in the perimuscular connective tissue of the gallbladder (arrow).

 Normal Anatomy and Embryology

Figure 1-6 PARAGANGLION A: A paraganglion with a well-defined lobular pattern. B: The chief cells contain round hyperchromatic nuclei. C: This paraganglion is surrounded by numerous lymphocytes. D: The chief cells have clear cytoplasm.

 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

Figure 1-7 Figure 1-8 MULTIPLE PARAGANGLIA PARAGANGLION: IMMUNOHISTOCHEMISTRY Confluent paraganglia simulate a small paragan­ The immunostain for synaptophysin shows greater glioma. reactivity at the periphery of the paraganglion. while the sustentacular cells label with S-100 epithelium. They are found in less than 10 percent protein (fig. 1-8). of gallbladders, although figures from 1 to 50 The physiologic role of the paraganglia of the percent have been reported (52). They have also gallbladder is unknown. These paraganglia are been found in human fetuses (53). The ducts are usually found near nerve fibers and ganglion easy to recognize microscopically since they are cells. Ganglion cells are occasionally found in the usually surrounded by compressed fibrous connec- lamina propria, among smooth muscle bundles, tive tissue (45). They often consist, however, of and in the perimuscular connective tissue; they a meshwork of multiple tiny ductules. Luschka are most numerous in the neck of the gallbladder ducts represent a variation on the normal anat- (14). Along the hepatic surface, no serosa exists, omy of the biliary tree. These ducts do not open and the perimuscular connective tissue is continu- into the gallbladder and their lumens usually ter- ous with the interlobular connective tissue of the minate blindly. Of particular clinical significance liver. This continuity facilitates the extension of is that leakage of bile from these ducts following malignant tumors directly into the liver. may lead to biliary Small aberrant supravesicular or accessory (78,100). Leakage is more likely to occur when the bile ducts (Luschka ducts), which are remnants gallbladder is removed laparoscopically. of the embryonic primordium of the liver, are Immunohistochemistry. The normal colum- occasionally seen in the perimuscular connective nar cells of the gallbladder express several types tissue adjacent to the liver. Usually less than 2 of cytokeratins such as AE1/AE3, CK7, CK19, mm in diameter, these ducts are lined by biliary and CAM5.2 (fig. 1-9). In contrast, they are

 Normal Anatomy and Embryology

Figure 1-9 NORMAL GALLBLADDER EPITHELIUM All the columnar cells lining the mucosal folds are positive for cytokeratin (CK) 7.

usually negative for CK20. As indicated above, of on smooth muscle via cho- MUC5B, also synthesized by the columnar cells, lecystokinin-A receptors on their surface (113). labels mucoproteins related to colonic mucins It is unknown whether these cells contribute to (112). Although malignant epithelial cells are stone formation or cause abnormal gallbladder diffusely reactive for carcinoembryonic antigen motility. An increased number of interstitial cells (CEA), normal columnar cells are reactive only of Cajal was described in the gallbladder adjacent along the apical cytoplasmic border, especially to a gastrointestinal stromal tumor (81). with a polyclonal antibody (5). The reactivity in The intraepithelial lymphocytes stain for normal cells is now attributed to cross-reacting leukocyte common antigen. They are also im- CEA-related antigens (65). munoreactive for T-cell markers, such as the The gallbladder epithelium is immunoreactive monoclonal antibodies CD3 and CD45RO for MUC1, a mucoprotein expressed in the api- (fig. 1-11), in paraffin-embedded material. cal cytoplasm of the epithelial cells that line the Intramucosal plasma cells usually contain im- mucosal surfaces of many organs including the munoglobulin (Ig) A, while those found in the gallbladder, extrahepatic bile ducts, and pancreas muscle layer contain IgM (34). (116). Since the normal human gallbladder does Ultrastructure. The normal epithelium is not contain endocrine cells, immunostains for composed of three types of cells: ordinary light peptide are uniformly negative. columnar cells, dark penciloid cells, and basal Interstitial cells of Cajal, similar to those cells (24). The light columnar cells comprise found in the , were first 98 percent of the total. Both the columnar and described in the gallbladder in 2000 (81). They penciloid cells are covered with microvilli and are distributed along the border of the muscle rest on a similar to that found un- layer and in the lamina propria (40,81,66). der all epithelia (figs.1 -12–1-16). The basal cells These cells are immunoreactive with antibodies are confined to the region of the basal lamina against CD117/c-kit and CD34 (fig.1 -10). They and do not reach the lumen. are intimately associated with smooth muscle Adjacent columnar cells are connected by cells and most likely responsible for their rhyth- junctional complexes located at the apical ends mic contractions. Studies in animals suggest that of the lateral walls. These walls have complex the interstitial cells of Cajal mediate the effects membrane interdigitations and are separated by

 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

Figure 1-10 NORMAL GALLBLADDER: INTERSTITIAL CELLS OF CAJAL A: The CD117-positive dendritic cells are seen at the periphery of the muscle bundles. B: A neuron-like interstitial cell of Cajal is in the center. (A,B: Figs. 4A and B from Ortiz-Hidalgo C, de Leon Bojorge B, Albores-Saavedra J. Stromal tumor of the gallbladder with phenotype of interstitial cells of Cajal: a previously unrecognized neoplasm. Am J Surg Pathol 2000;24:1420-3.) C: An elongated interstitial cell of Cajal is present between the smooth muscle cells.

 Normal Anatomy and Embryology

Figure 1-11 NORMAL GALLBLADDER EPITHELIUM: INTRAEPITELIAL LYMPHOCYTES Several intraepithelial CD3- positive T lymphocytes are pre­ sent between the columnar epithelial cells. Adjacent colum­ nar cells are unreactive.

Figure 1-12 Figure 1-13 NORMAL COLUMNAR CELLS: ULTRASTRUCTURE NORMAL COLUMNAR CELLS: ULTRASTRUCTURE Several columnar cells are covered by microvilli and Portions of three columnar cells showing microvilli with contain mucin droplets, mitochondria, and large electron- filamentous glycocalyx. The apical cytoplasm contains large dense bodies. Most cytoplasmic organelles are located above electron-dense granules which probably represent mucin. the nucleus. A junctional complex is also visible.

 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

Figure 1-14 Figure 1-15 NORMAL COLUMNAR CELLS: ULTRASTRUCTURE NORMAL MUCOSA The basal cytoplasm of two cells rests on the basal Scanning electron micrograph of the gallbladder mucosa lamina. The complex interdigitations of the lateral cell shows a surface composed of small, rolling folds covered membranes are seen. Many glycogen particles, some by uniform epithelial cells. (Fig. 3 from Schaff Z, Lapis K, mitochondria, lysosomes, and some rough endoplasmic Csikos A. Scanning electron microscopy study of human reticulum are also present. The lamina propria contains gallbladder mucosa in cholelithiasis. Acta Morphol Acad many collagen fibers and a capillary. Sci Hung 1979;27:110.)

Figure 1-16 NORMAL MUCOSAL CELLS Scanning electron micrograph shows normal epithelial cells. The cells, which are separated by deep intercellular clefts, have rounded tips and are nearly identical in size and shape.

10 Normal Anatomy and Embryology

intercellular spaces. Fluid transport occurs through the junctional complexes and lateral spaces. Most cytoplasmic organelles are located in the supranuclear region and consist of mi- tochondria, rough endoplasmic reticulum, a prominent Golgi apparatus, lysosomes, and a variety of vesicles and secretory granules (56, 57). The secretory granules, which are released into the lumen by exocytosis, contain mucinous sulfated glycoproteins. Mitochondria are most numerous in the supranuclear area and may be partially surrounded by rough endoplasmic reticulum. In the human, mucus production is not prominent, but becomes excessive in some pathologic conditions such as chronic (26), benign epithelial tumors, and adenocarcinomas. The penciloid cells are characterized by a nar- row dark profile and a well-developed rough en- doplasmic reticulum located above the nucleus. Comprising about 1 percent of all columnar cells, they are recognized by light microscopy Figure 1-17 (38). These cells are dispersed singly along the epithelium, although they often increase in NORMAL BILE DUCT chronic cholecystitis. Found in many species, Diagrammatic representation of the shows folds in the lining epithelium, the openings of the penciloid cells have also been described as peg sacculi of Beale, and a cross section through the wall. Smooth or dark cells. muscle is most pronounced along the intrapancreatic The basal cells are randomly distributed segment of the common bile duct. It is usually sparse along the epithelium. They tend to be ovoid or proximal to the intrapancreatic segment of the common duct. (Modified from fig.1 from Burden VG. Observation on elongated and have some mitochondria, which the histology and pathologic anatomy of the hepatic cystic usually surround the nucleus, and minimal and common bile ducts. Ann Surg 1925;82:585.) endoplasmic reticulum. The cytoplasm forms complex interdigitations with adjacent colum- nar cells. They are similar to the basal cells seen Extrahepatic Bile Ducts in other sites. The intraepithelial lymphocytes contain the Of greater physiologic significance than the round, lobulated or cerebriform nuclei char- gallbladder are the extrahepatic bile ducts (fig. acteristic of T lymphocytes. They are located 1-17), which serve as a conduit for bile from adjacent to the basal lamina and the basolateral the liver to the . Emerging from aspect of the columnar cells. Under the scan- the liver, the left and right hepatic ducts join to ning electron microscope, the mucosal surface form the common hepatic duct, which descends appears as rolling, branching folds lined with on the lateral aspect of the hepatoduodenal uniform epithelial cells (fig. 1-15) (57,96). The ligament. Connecting the gallbladder to the cells have regular, polygonal, or hexagonal common hepatic duct is the cystic duct. Their boundaries and a slightly convex surface cov- union forms the common bile duct, which passes ered with microvilli (fig. 1-16). This structural behind the first part of the duodenum, traverses arrangement corresponds in many respects to the head of the pancreas, and opens into the sec- the surface architecture of the and ond part of the duodenum through the greater small intestine. Mucosal changes, as seen by duodenal papilla (formally known as the papilla scanning electron microscopy, have been pub- of Vater), which is a small polypoid prominence lished for some pathologic conditions (74,96). often obscured by duodenal folds.

11 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System

The common hepatic duct varies from 0.8 to into the duct lumen through small diverticula, 5.2 cm in length, while the common bile duct, the sacculi of Beale. Developmentally, these exclusive of the pancreaticobiliary duct, varies glands reach their maximum number within the from 1.5 to 9.0 cm. In general, the diameter first year of life. Thereafter, the number remains of the common bile duct increases with age fairly constant. In contrast, the lumen and wall of (67,89,109). The normal diameter is considered the common duct do not reach adult proportions less than 7 mm. The cystic duct varies from 0.4 until adult life (105). In small biopsy specimens to 6.5 cm in length (72). and frozen sections, these biliary glands may be The structure of the proximal cystic duct is mistaken for carcinoma, especially if they have similar to that of the gallbladder (90), although become hyperplastic and distorted by fibrosis as prominent mucosal folds, the valves of Heister, in primary sclerosing cholangitis (47). give the duct a spiral appearance. These spiral Because the walls of the extrahepatic bile ducts folds contain smooth muscle cells that respond are less than 1.5 mm in thickness and are well to hormonal, pharmacological, and neural innervated and vascularized, malignant tumors stimuli. The function of these valves is uncertain. can rapidly gain access to periductal tissues and Originally they were thought to regulate the flow thus invade small nerves and blood vessels. of bile in and out of the gallbladder, although Immunohistochemistry. The columnar cells newer studies suggest they only serve to main- of the extrahepatic bile ducts, sacculi of Beale, tain the patency of the duct (19). More than one and intramural glands are immunoreactive for left or right hepatic duct may be present. low molecular weight cytokeratins. Endocrine The common bile duct is divided into four cells, some containing immunoreactive soma- parts in relation to the duodenum and pan- tostatin, have been observed in the surface and creas: supraduodenal, the longest part; retro- glandular epithelia of the ampulla and bile duodenal; pancreatic; and intraduodenal. The ducts (18,106). These endocrine cells may be supraduodenal segment is the most accessible widely scattered or occur in clusters. It is often during laparotomy and the easiest to explore difficult, however, to determine whether such by the surgeon. endocrine cells are normally present or develop Histology. The hepatic, distal part of the in response to aging or pathologic processes. cystic duct and the common bile duct are es- As in the gallbladder, the lining epithelium sentially identical in structure (13). Lined by a contains lymphocytes, most of which are of the single layer of tall, uniform columnar cells, the suppressor/cytotoxic T-cell phenotype (17). mucosa of the bile ducts usually forms irregular Vaterian System pleats or small folds that run longitudinally. A dense underlying subepithelial layer is com- The pancreatobiliary ampulla and the greater posed of compact elastic and collagen fibers. duodenal papilla (papilla of Vater) comprise the Scattered small bundles of smooth muscle cells Vaterian system (7,22,68). Located 7 to 10 cm that react for desmin are found in the wall of from the pylorus, in the wall of the duodenum, the ducts. Usually aligned parallel with the lu- the Vaterian system resides at the confluence of men, they are generally absent or sparse in the the common bile duct and the major pancreatic upper segments of the bile ducts. The cystic duct, the duct of Wirsung, before opening into duct and the lower segment of the common bile the duodenum. In addition to the ducts, the duct often show an interrupted or continuous Vaterian system includes the greater duodenal muscle layer that is more prominent near the papilla, the pancreatobiliary ampulla (when (figs. 1-18, 1-19) (41). As in present), the sphincter muscle (sphincter of the gallbladder, interstitial cells of Cajal are also Oddi) that controls the flow of bile, and fibrous present in the muscle layer of the extrahepatic coverings (22). The ampulla is merely the dilated bile ducts. They are more densely aggregated in junction of the common bile duct and the major the bile ducts than in the gallbladder (3). . The ducts usually open into the The periductal layer consists of loose connec- second part of the duodenum through the tip tive tissue. Small intramural biliary glands that of the papilla, although occasionally they open increase in number toward the distal part open into the third part of the duodenum (84).

12 Normal Anatomy and Embryology

Figure 1-18 CYSTIC DUCT A: In cross section, the mucosal folds of the cystic duct are lined by columnar epithelium. Lobules of intramural biliary glands are seen in the lamina propria. The discontinuous smooth muscle layer and the periductal connective tissue are also present. B: Higher magnification shows a single layer of columnar epithelial cells, fibrous connective tissue, and smooth muscle bundles. C: A lobule of intramural biliary glands.

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