22 - Esophagus | Histology for Pathologists

Editors: Mills, Stacey E.

Title: Histology for Pathologists, 3rd Edition

> Table of Contents > VII - Alimentary Tract > 29 - Gallbladder and Extrahepatic Biliary System

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Gallbladder and Extrahepatic Biliary System

Edward B. Stelow

Seung-Mo Hong

Henry F. Frierson Jr.

Introduction

The gallbladder is one of the most common surgical pathology specimens. It is most often resected because of stones or inflammatory disease and is only rarely resected because of neoplasia. Somewhat uncommonly, grossly and microscopically normal gallbladders are removed incidentally during surgery for other reasons (e.g., liver transplantation). At most institutions, these specimens are rarely seen. The situation is quite different with the extrahepatic bile ducts and ampullae of Vater. These sites are infrequently sampled by biopsy only when neoplasia is suspected, especially cholangiocarcinoma or ampullary adenocarcinoma. The distal common bile duct and ampulla can be studied in the occasional pancreatoduodenectomy specimen but will often be abnormal due to the effects of an ampullary or periampullary neoplasm. The remaining extrahepatic bile duct is rarely resected. The complete biliary system and ampulla can be only studied with autopsy material; however, due in some part to the toxicity of bile, significant autolysis is usually present in these specimens.

This chapter discusses the gross anatomy, physiology, histology, immunohistochemistry, and ultrastructure of the normal gallbladder, extrahepatic bile ducts, ampulla of Vater, and minor papilla.

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Gallbladder

Gross Anatomy

The gallbladder is a piriform bladder that is attached to the extrahepatic biliary system via the cystic duct and rests in a shallow depression located on the inferior surface of the posterior right lobe of the liver. It measures up to 10 cm long and 3 to 4 cm wide in normal adults, and its wall is approximately 1 to 2 mm thick, varying due to the degree of muscular contraction. The serosal surface of the liver extends to cover the gallbladder, while interlobular connective tissue of the liver merges with the subserosal connective tissue of the gallbladder. The gallbladder is anatomically divided into a blindly ending fundus, a large central body, and a narrow neck that joins the cystic duct. The tapered area of the body that joins the neck is considered the infundibulum. It is here that a peritoneal fold, the cholecystoduodenal ligament, attaches the gallbladder to the first portion of the duodenum. Hartmann's pouch, a small bulge at the infundibulum, is probably not normal and may result from chronic inflammation or stone impaction (1). The neck is somewhat serpentine, measures 5 to 7 mm long, and narrows as it connects with the cystic duct (2).

Physiology

The gallbladder concentrates, stores, and releases bile. Approximately 800 to 1000 mL of bile flow daily into the gallbladder from the liver (3). Its filling results from complex neural and hormonal stimulations that result in its relaxation and the contraction and closing of the sphincter of Oddi. When the sphincter is closed, the intraluminal pressure of the bile ducts will increase as bile is continuously produced by the liver; bile will then flow into the gallbladder. When relaxed the gallbladder can store only 40 to 70 mL of bile and retains a constant intraluminal pressure (3). A much larger volume, however, is handled as the gallbladder concentrates bile via a sodium-coupled transport of chloride, mediated by sodium potassium-ATPase (NaK-ATPase) (4). The active transport of electrolyte into the lateral intercellular space creates an osmotic gradient, and water ultimately flows through the basement membrane into the capillaries of the lamina propria. The gallbladder also has a secretory role, liberating mucosubstances from the surface epithelial cells and neck mucous glands.

Contraction of the gallbladder is also mediated by complex neural and humoral mechanisms and occurs both after and between meals (5). Cholecystokinin, released from the mucosa of the proximal duodenum after fatty meals, is the most important hormone that promotes gallbladder contraction (6). Motilin aids in interdigestive gallbladder contraction, which occurs in tandem with giant migratory complexes of the intestines every two hours or so (5,7). Other peptides including pancreatic polypeptide and somatostatin may affect gallbladder motility (5,7,8,9). The vagal system may also play a role both directly and indirectly in gallbladder contraction (10). The complicated balance of humoral and neural mechanisms involved in the working of the gallbladder is sometimes disrupted and many disease states have been implicated in the development of gallbladder dysmotility. Dysmotility may, in turn, result in gallbladder pathology (11).

Blood Supply and Lymphatic Drainage

The arterial supply of the gallbladder varies both in its anatomy and in its relationship to the extrahepatic biliary system. The cystic artery supplies the gallbladder and usually arises from the proximal portion of the right hepatic artery. Indeed, 72% of all cystic arteries in a study by Moosman and Collier (12) arose from the right hepatic artery, whereas 13% arose from the superior mesenteric artery; the remainder originated from the common hepatic artery, left hepatic artery, gastroduodenal artery, celiac artery, or aorta. Most commonly, the artery is located superior to the cystic duct (Figure 29.1). In Moosman and Collier's study, 70% of all cystic arteries coursed to the right of the common hepatic duct, and 17% traveled anterior to the common hepatic duct; the remainder of the cystic arteries passed posterior to

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the common hepatic duct, anterior or posterior to the common bile duct, to the right and inferior to the cystic duct, or posterior to both hepatic ducts. The cystic artery branches to form superficial channels that lie over the gallbladder serosa and deep channels that lie between the gallbladder and its hepatic bed (2). One of the more common anatomic variations noted is the double cystic artery. In their study of the extrahepatic biliary tree in 250 cadavers, Moosman and Collier noted a double cystic artery in 14% of their cases. Michels found double cystic arteries in one-quarter of 200 cadavers (13).

Figure 29.1 Although variations are common, this diagram depicts the usual relationships of the extrahepatic bile ducts, portal vein, and branches of the common hepatic artery. (PV, portal vein; GA, gastroduodenal artery; CHA, common hepatic artery; LHA, left hepatic artery; LHD, left hepatic duct; RHD, right hepatic duct; RHA, right hepatic artery; GB, gallbladder; CA, cystic artery; CD, cystic duct; CBD, common bile duct)

A single large cystic vein does not exist (2). The venous drainage consists, in part, of small venous channels on the hepatic side of the gallbladder that lead directly into the liver. Other small veins flow toward the cystic duct and merge with channels from the common bile duct before terminating in the portal venous system.

The lymphatic system of the gallbladder has been investigated by anatomic and physiologic studies and by studies of gallbladder malignancy (14,15). The lymphatics of the gallbladder drain first into lymph nodes at the gallbladder neck or cystic duct. Following this, drainage may proceed to retropancreatic, celiac, or mesenteric lymph nodes. These pathways appear to all converge at abdominal aortic lymph nodes located at the superior mesenteric artery (14). In a study in which dye was injected directly into lymphatic vessels of the gallbladder, the dye flowed initially into the cystic node and pericholedochal nodes, then into lymph nodes posterior to the pancreas, portal vein, and common hepatic artery, and finally into interaortocaval nodes near the left renal vein (15). Ascending lymph flow to the hepatic hilum does not usually occur; however, retrograde flow to the hepatic hilum may occur when there is blockage of lymphatic channels by cancer, inflammation, or surgical ligation (15).

Nerve Supply

Nerve branches from the left trunk of the vagus join the hepatic plexus. The hepatic plexus then supplies the gallbladder with sympathetic, parasympathetic, and possibly afferent nerve fibers (2). Vagal stimulation, both directly and indirectly, may then stimulate interdigestive periodic contractions of gallbladder smooth muscle (10). Neuropeptide Y nerve fibers, which may also participate in gallbladder smooth muscle contraction, are found in all layers of the gallbladder. They form a particularly dense network in the lamina propria, running near the epithelium and paralleling the muscle bundles (16).

Histology

The layers of the gallbladder include the mucosa (surface epithelium and lamina propria), smooth muscle, perimuscular subserosal connective tissue, and serosa. A muscularis mucosae and submucosa are not present. The luminal folds are lined by a single layer of columnar epithelium and have cores of lamina propria. The height and width of the folds are variable, and branching is characteristic (Figure 29.2). The columnar epithelial cells have lightly eosinophilic cytoplasm with occasional small apical vacuoles (Figure 29.3). Nuclei are aligned at the cell base or slightly more centrally. They are oval and uniform and have fine chromatin and smooth membranes. Nucleoli are absent or very small and inconspicuous. Occasional columnar cells are

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narrow with dark eosinophilic cytoplasm (1). These cells, dignified with the appellation pencil-like cells, appear to be little more than contracted columnar cells, although they reportedly have a few ultrastructural and enzymatic properties that differ from those of the usual columnar cells. Basal cells are inconspicuous and have nuclei that lie just above and parallel to the basement membrane.

Figure 29.2 The luminal folds of the gallbladder vary in height and contain a delicate core of lamina propria above the bundles of smooth muscle.

Figure 29.3 The gallbladder is lined by a single layer of tall columnar cells with basally oriented nuclei.

Figure 29.4 Mucous glands are present only in the neck of the normal gallbladder.

Tubuloalveolar mucous glands are located only in the neck of the gallbladder (17). They have cuboid or low columnar cells with abundant clear to lightly basophilic cytoplasm and round, basally oriented nuclei (Figure 29.4). Their lectin-binding profile is dissimilar to that of the surface epithelial cells (18). The neck mucous glands also differ morphologically and histochemically from the antral-type metaplastic glands found in the fundus, body, or neck of chronically inflamed gallbladders or those that contain gallstones (17). Rare endocrine cells can be found here but are otherwise absent in the normal gallbladder (19,20). Gastric metaplasia (foveolar-type epithelium or antral-type glands) and intestinal metaplasia (absorptive cells with prominent brush borders, endocrine cells, goblet cells, and Paneth's cells) are not observed in the normal gallbladder but commonly occur in chronic cholecystitis and cholelithiasis (1,17,21,22,23,24,25). Squamous metaplasia, rarely found in diseased gallbladders, is also absent in normal gallbladders (1). Melanocytes are not found in the normal epithelial lining. However, a few small lymphocytes often are seen between the surface columnar cells.

Gallbladder epithelial cells contain chiefly sulfated acid mucin with very small quantities of nonsulfated acid mucin (17). In contrast, metaplastic cells (goblet cells, superficial gastric-type cells, antral-type glands) contain nonsulfated acid mucin and neutral mucin but little sulfated acid mucin. By immunohistochemistry, the epithelial cells express MUC5AC and MUC6, akin to gastric epithelium; however, pepsinogens I and II, present in pyloric gland metaplasia, are not seen in normal gallbladder epithelium (24,26). Lysozyme is also absent in the normal columnar cells but may be found in metaplastic glands (27). Alpha-1-antitrypsin and 1-antichymotrypsin are present in both normal and metaplastic epithelia (27).

Immunohistochemical staining for carcinoembryonic antigen (CEA) (polyclonal; unabsorbed) of normal gallbladders shows focal weak staining along the apices of some lining cells (28). In contrast to the results using monoclonal antibodies to CEA, inflamed epithelium usually shows immunostaining with polyclonal antisera (29). Absorption of at least one polyclonal antibody with human liver powder abolishes the immunoreactivity because there is removal of the CEA-related glycoproteins nonspecific cross-reacting antigen (NCA) and biliary glycoprotein (BGP) (29). The surface epithelium and neck mucous glands are strongly immunoreactive for epithelial membrane antigen and low-molecular weight keratin (CAM 5.2 antibody). The CAM 5.2 antibody also stains some smooth muscle fibers in the gallbladder wall. Normal gallbladder epithelium also reacts with antibody directed against cytokeratin (CK)7 and does not react with antibody directed against CK20 (Figure 29.5) (30). Because endocrine cells are not found in the normal epithelium of the fundus or body, immunohistochemical staining for neuron-specific enolase and chromogranin A is absent (19). A few argentaffin (enterochromaffin) cells are present in the mucous glands of the neck; these cells are readily detected by an antibody to chromogranin A (19). Normal gallbladder mucosa lacks immunoreactivity for estrogen receptor, whereas in 6 of 31 cases of cholelithiasis, a few immunoreactive cells were observed chiefly in metaplastic mucous glands (pseudopyloric glands) (31). Adhesion molecules expressed by normal gallbladder epithelial cells include -catenin, -catenin, -catenin, CD44, CD99, and E-cadherin (32).

The lamina propria contains loose connective tissue, elastic fibers, nerve fibers, small blood vessels, and lymphatic

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channels. Mast cells and macrophages may be seen in small numbers, and it has been noted that these cells are more numerous in normal or minimally inflamed gallbladders than in those with overt chronic cholecystitis (Figure 29.6) (33). Polymorphonuclear leukocytes normally are not present in the lamina propria, but small numbers of lymphocytes and plasma cells are usual. Plasma cells that contain immunoglobulin (Ig)A occur chiefly in the lamina propria, whereas IgM-containing cells are more frequent in the smooth muscle layer (34). A few IgG-containing plasma cells also may be present.

Figure 29.5 The epithelial lining of the gallbladder reacts strongly with antibodies directed against cytokeratin 7 (immunoperoxidase technique).

Figure 29.6 Occasional mast cells are identified within the gallbladder by kit-immunostaining. No interstitial cells of Cajal were identified (immunoperoxidase technique).

The smooth muscle consists of loosely arranged bundles of circular, longitudinal, and oblique fibers that do not form well-developed layers like they do in the luminal gut. Fibrovascular connective tissue focally separates the muscle bundles. The muscle fibers sometimes extend high into the lamina propria to just beneath the epithelial basement membrane. The thickness of the muscle layer is quite variable, which may simply reflect variable contractile states of the specimen. Ganglion cells are found in the lamina propria, between smooth muscle bundles, and in the subserosal connective tissue (Figure 29.7). We have been unable to identify interstitial cells of Cajal, although they have been rarely noted by other authors, and rare gastrointestinal stromal tumors of the gallbladder have been reported (1,35).

Figure 29.7 Ganglion cells are readily seen in the connective tissue layers of the gallbladder.

Figure 29.8 Paraganglia are located in the subserosal connective tissue of the normal gallbladder.

The subserosal tissue contains loose collagen fibers, fibroblasts, elastic fibers, adipocytes, blood vessels, nerves, and lymphatics. Small aggregates of lymphocytes may occur around vessels. Uncommonly, a lymph node is found in the subserosal connective tissue (36). Paraganglia, infrequently seen in routine sections, are found adjacent to blood vessels and small nerves (Figure 29.8). Examining serial blocks and subserial sections of gallbladders, the investigators of one study found one to five paraganglia in the subserosal tissue of nine of ten cholecystectomy specimens (37).

Rokitansky-Aschoff sinuses represent herniations of epithelium into the lamina propria, smooth muscle, or subserosal connective tissue (Figure 29.9). Although these

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are commonly considered a feature of chronic cholecystitis, they are often present in histologically normal gallbladders, albeit more superficially. In a series of 125 cholecystectomy specimens that were inflamed or contained gallstones, 86% had Rokitansky-Aschoff sinuses, almost 90% of which penetrated into or through the smooth muscle (38). The sinuses were also observed in 42% of 112 normal gallbladders examined at autopsy (39). When present in normal gallbladders, they were generally confined to the lamina propria, with infrequent penetration of the smooth muscle. The sinuses are not found in gallbladders from fetuses, but a few superficial outpouchings may be observed in organs from infants (40). The diameters of the sinuses are variable, and flask-shaped formations are usual. Although the exact mechanism for their formation is unknown, herniation of the epithelium may result from overdistension (with increased intraluminal pressure) and extreme contractions of the gallbladder, with subsequent weakening of its wall (40).

Figure 29.9 Rokitansky-Aschoff sinuses occur in the normal gallbladder but uncommonly penetrate through the smooth muscle bundles.

Figure 29.10 Luschka's ducts consist of groups of small ducts having lumina of various caliber. They are surrounded by condensed connective tissue.

Luschka's ducts are small, usually microscopic, bile ducts that lie in the subserosal connective tissue, most commonly on the hepatic side of the gallbladder (Figure 29.10). Occasionally, a few ducts are present in the subserosal connective tissue on the peritoneal side. The ducts have been found in 10 to 12% of routine sections from cholecystectomy specimens, occurring in both normal and diseased organs (39,40). They have been observed in gallbladders from infants, adolescents, and adults and may represent embryonic remnants. Reports of their drainage site are varied. Most have argued that they communicate with intrahepatic bile ducts; however, some have argued that those beneath the serosa possibly drain into the peritoneal cavity, and others, rarely, have suggested that they may drain into the gallbladder lumen, especially within its neck (38,40,41).

The ducts are solitary or multiple but are usually present in small groups surrounded by a distinctive ring of connective tissue and may be adjacent to blood vessels. In serial sections, they sometimes are seen as a system of anastomosing channels. The diameters of their lumina vary from several microns up to a few millimeters. The ducts are lined by cells similar to those of the intrahepatic bile ducts. In some instances, small foci of hepatic parenchyma are located adjacent to the ducts (40). Luschka's ducts are distinct from Rokitansky-Aschoff sinuses, and the two should not communicate. It should be noted that the term Luschka's duct has been used somewhat indiscriminately and has been used to refer to entities ranging from Rokitansky-Aschoff sinuses to true accessory ducts.

At surgery and by cholangiography, larger accessory ducts (up to several millimeters long) sometimes are seen in the gallbladder bed. They may be mistaken grossly for small veins or thin strands of fibrous tissue (42). If these ducts are not ligated during surgery, a bile leak may develop, which typically ceases spontaneously. In one study, 9% of 204 patients with randomly selected cholecystectomies had bile leaks from the drain tube; some of these were considered to be due to a divided subvesical duct (43). Although these ducts lie in the gallbladder wall, they usually do not drain into the lumen of the fundus but communicate with the cystic or hepatic ducts (44,45). In a study of 20 autopsy dissections from patients without biliary disease, six subvesical ducts were found, five of which were placed centrally in the gallbladder bed and one in the lateral peritoneal reflection (43). Five led to the right hepatic duct, and one entered the common hepatic duct.

Ectopic hepatic, pancreatic, adrenal, gastric, and thyroid tissues have been reported in the gallbladder (46,47,48,49). Ectopic hepatic and adrenal tissues are typically incidental findings, whereas ectopic pancreatic or gastric tissues may lead to symptoms related to their secretions (46).

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Ultrastructure

The surface columnar cells measure 15 to 25 m in height and 2.5 to 7.0 m in width and rest on a basement membrane (50). These cells have numerous apical microvilli with filamentous glycocalyx and core rootlets (Figure 29.11). The microvilli are shorter and more variable in size and density than those of the intestinal epithelium. Pinocytotic vesicles are formed from the intervillous portions of the cell membrane. The lateral cell membranes are straight at the apex and connected by junctional complexes. Below this boundary, the cell membranes have complex interdigitations that surround lateral intercellular spaces (Figure 29.11). The diameter of the intercellular space varies, depending on the state of fluid transport (51). It is collapsed when there is no water transport but is distended during influx of electrolytes and water. The nuclei are oval, have prominent euchromatin, and occasional small nucleoli. The cytoplasm contains rough endoplasmic reticulum, mitochondria, glycogen, filaments, Golgi apparatus, mucous granules, vesicles, and lysosomes.

Pencil cells have slender outlines, narrow nuclei, and dense cytoplasm that is packed with organelles. At the base of the pencil cell, cytoplasmic extensions project into the basement membrane, unlike that for the typical columnar cell (52). However, microvilli and lateral membrane interdigitations are similar for the pencil cell.

The basal cell measures 10 to 15 m in diameter, has an irregular nucleus, and has cytoplasmic organelles that include rough and smooth endoplasmic reticulum, mitochondria, vacuoles, and ring-shaped osmiophilic inclusions (50,52). They have a cytoplasmic extension that runs parallel to the basement membrane, changes direction to run perpendicularly, and then branches toward the lumen (50). The branches are variable in length, delicate, and complex. Throughout the lining epithelium, there are intraepithelial nerve endings that originate from the nerve submucosal plexus and are associated with the small basal cells (50).

Figure 29.11 Ultrastructurally, the apical portion of the columnar cells of the gallbladder contains abundant microvilli with core rootlets, mitochondria, Golgi apparatus, mucous granules, lysosomes, and a few strands of rough endoplasmic reticulum. The lateral cell membranes form complex interdigitations (arrows).

Capillaries are found just below the epithelial basement membrane, and their lumina change in size according to the state of fluid transport. The epithelial cells of the glands in the gallbladder neck have a few short microvilli, relatively even lateral membranes, rare secretory granules, and round nuclei (53).

Cystic Duct

The cystic duct is located at the right free edge of the lesser omentum and usually joins the right lateral portion of the common hepatic duct approximately 2 cm distal to the union of the right and left hepatic ducts. In one study, the mean length of the cystic duct was 30 mm and ranged in size from 4 to 65 mm (12). The mean collapsed diameter was 4 mm. Connection and drainage into the common hepatic duct varies. Anatomic studies have found that most cystic ducts drain laterally at an acute angle into the common bile duct (12). In some cases, it may form an angular junction with either the anterior or posterior aspect of the common hepatic duct. A short cystic duct parallel to the common hepatic duct may be present, and a long cystic duct has been rarely noted. Rarely, the cystic duct may spiral and join the common hepatic duct anteriorly or posteriorly. In a cholangiographic study involving large numbers of patients, however, the cystic duct drained laterally at an acute angle into the common bile duct in only 17% of the cases, whereas in 35% it drained in a spiral form, in 41% posteriorly, and in 7% it first ran parallel to the common hepatic duct (54). In rare instances, the cystic duct may join the right and left hepatic ducts, forming a trifurcation. The cystic duct usually passes inferiorly to the cystic artery and to the right of the right hepatic artery.

The lining of the cystic duct is pleated, and in some areas there are short folds of varying width and height. The surface cells are identical microscopically and immunohistochemically to those of the gallbladder (55). Groups of mucous glands are embedded in the dense, collagenous lamina propria. Lectin-binding patterns of the lining cells are similar to those for the surface epithelial cells of the gallbladder body and neck, and the lectin-binding profiles for the mucous glands of the cystic duct are indistinguishable from those of the glands at the gallbladder neck (18). Enterochromaffin

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cells containing serotonin have been described in cystic ducts from patients with pancreaticobiliary disease (56). In this same group of patients, a few intramural gland cells have shown immunoreactivity for somatostatin.

Figure 29.12 The stroma of the spiral valve of Heister contains thin strands of smooth muscle fibers.

The connective tissue of the large, oblique folds, grossly visible in the cystic duct at the junction with the gallbladder neck, contains thin groups of smooth muscle fibers (spiral valve of Heister) (Figure 29.12). The smooth muscle is believed to prevent both overdistention and collapse of the cystic duct when it is subjected to changes in pressure (2). Abundant collagen and some elastic fibers, nerve fibers, and ganglion cells are intermixed with the smooth muscle. Nerve fibers showing immunoreactivity for vasoactive intestinal peptide (VIP) and other peptides have been described in the wall (9,56). The loose subserosal connective tissue contains adipose tissue, nerves with occasional ganglion cells, large blood vessels, and lymphatic channels. Lymphocytes and plasma cells are sparse or absent.

Right and Left Hepatic Ducts, Common Hepatic Duct, and Common Bile Duct

Gross Anatomy

The right and left hepatic ducts, common hepatic duct, and common bile duct are embedded between the serous layers of the hepatoduodenal ligament (the right free border of the lesser omentum). The hepatic ducts emerge from the liver and, in most instances, unite in the hilum approximately 1 cm from the liver to form the common hepatic duct. In 10 to 30% of cases, two large segmental ducts drain the right hepatic lobe and join separately with the left hepatic duct, common hepatic duct, or cystic duct; it is incorrect to label one of these ducts the right hepatic duct and the other as accessory (57). In a dissection of 100 autopsy specimens, the mean length of the right hepatic duct was 0.8 cm (range: 0.2 2.5 cm) and that of the left hepatic duct 1.0 cm (range: 0.2 3.5 cm) (58). The usual diameter of each hepatic duct was 3 to 4 mm, and the length of the common hepatic duct ranged from 0.8 to 5.2 cm (mean: 2.0 cm) (58). Its diameter ranged from 0.4 to 2.5 cm (59). The diameter of the common hepatic duct and its number of elastic fibers increase with age (59). The common bile duct, resulting from the union of the cystic duct and common hepatic duct, can be divided into supraduodenal, retroduodenal, pancreatic, and intraduodenal segments. It is usually about 1 mm thick and 5 cm long, but its length is quite variable (range: 1.5 9.0 cm) (58). The diameter at its midpoint ranges from 0.4 to 1.3 cm (mean: 0.66 cm), and its lumen narrows approximately 50% after entering the duodenal window (58,60). In an autopsy study of 100 selected subjects who ranged in age from 15 to 102 years, lacked a history of biliary tract disease, and had completely intact biliary tracts, the outer diameters of the upper portions of the common bile ducts ranged from 0.4 to 1.2 cm (mean: 0.74 cm) (61). The outer diameters increased with age but were not related to body weight or length (61). The pits in the surface epithelium (sacculi of Beale) are conspicuous in the extraduodenal portion of the common bile duct and the hepatic ducts. At approximately 2 mm from the duodenal wall, the wall of the common bile duct thickens (due to an increase in muscle), resulting in the abrupt narrowing of the duct's lumen.

Arterial Supply, Venous Drainage, and Relationship to Bile Ducts

The common hepatic artery arises from the celiac trunk and divides into right and left hepatic branches (Figure 29.1). Variations in the origins of the right and left hepatic arteries and their relationships to the extrahepatic bile ducts are typical (62). In one study, almost 42% of 200 cadavers had aberrant hepatic arteries (13). Most often, the right hepatic artery is dorsal to the common hepatic duct and right hepatic duct. The common hepatic and left hepatic arteries lie to the left of the extrahepatic bile ducts and ventral to the portal vein. The gastroduodenal artery lies to the left of the common bile duct, and a branch, the superior pancreaticoduodenal, traverses the duct either dorsally or ventrally (2).

The extrahepatic bile ducts are supplied by numerous arteries. The major arteries that supply branches to the common hepatic duct and the common bile duct include the retroduodenal, right and left hepatic, posterior superior and anterior superior pancreaticoduodenal, common hepatic, cystic, gastroduodenal, and retroportal arteries (63). The most important branches travel along the lateral borders of the common bile duct (64).

The portal vein, formed by the union of the splenic and superior mesenteric veins, lies dorsal to the bile ducts (Figure 29.1).

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The mean length is 6.4 cm (range: 4.8 8.8 cm) and its mean diameter is 0.9 cm (range: 0.64 1.21 cm) (65). Venous channels that drain the superior portion of the common bile duct enter the liver directly, and those from the inferior portion lead to the portal vein.

Lymphatic Drainage

Lymphatic channels from the common bile duct drain into lymph nodes located along the hepatoduodenal ligament or within the posterior pancreaticoduodenal area. Drainage then proceeds to lymph nodes at the superior mesenteric artery, aorta, and common hepatic duct (66,67).

Nerve Supply

The nerve supply to the cystic and hepatic ducts derives from the anterior portion of the hepatic plexus, whereas nerves that supply the common bile duct arise from the posterior segment of the hepatic plexus. The nerve of the common bile duct, lying dorsally, is the right portion of the posterior hepatic plexus. Smaller branches from the posterior hepatic plexus travel inferiorly along the common bile duct and accompany the duct to the major duodenal papilla (2). Neuropeptide Y containing nerve fibers have the same pattern of distribution in the common bile duct as in the gallbladder (16).

Histology

The extrahepatic bile ducts, serving as conduits for the flow of bile, are lined by a single layer of tall columnar cells surrounded by a dense connective tissue layer (Figure 29.13). The surface of the epithelium is relatively flat or pleated. The columnar cells have basally oriented nuclei that are oval and uniform. Nucleoli are absent or very small. Goblet cells are absent in normal epithelium. The epithelium dips into the stroma to form shallow depressions or deeper pits the sacculi of Beale. In some sections, the deeper sacculi appear isolated from the surface epithelium, but deeper sections will often show their connections. Surrounding the sacculi are unevenly distributed lobules of glands that empty into the sacculi (Figure 29.14). These glands have been termed diverticula, crypts, parietal sacculi, deep glands, biliary glands, periductal glands, and extrahepatic peribiliary glands (68). When located in the more peripheral connective tissue, the glands are encircled by condensed stroma. The peribiliary tubular glands are branched or, occasionally, simple (68). Although they are found in all parts of the extrahepatic bile duct system, they are less frequent in the central portion of the common bile duct and in the intrapancreatic portion than around the bile duct at the ampulla. They are lined by low-columnar or cuboid cells, many of which are filled with mucin (Figure 29.14). With inflammation and fibrosis, the sacculi and glands may be distorted, mimicking well-differentiated

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adenocarcinoma with desmoplastic stroma. In small biopsy specimens and especially frozen sections, the distinction between adenocarcinoma and distorted benign glands may be impossible. The lack of a lobular arrangement and the presence of marked nuclear atypia and perineural invasion are diagnostic of adenocarcinoma (69). Hence, a haphazard growth pattern and cells whose nuclei vary in size and have irregular nuclear membranes are characteristic of adenocarcinoma. Benign glands of the extrahepatic bile ducts have not been reported to invade nerves.

Figure 29.13 Intrapancreatic segment of common bile duct. The extrahepatic bile ducts are lined by a single layer of tall columnar cells overlying dense, collagenous connective tissue. In segments of the common bile duct away from the duodenum, a few small groups of smooth muscle fibers are sometimes found in the outer half of the wall.

Figure 29.14 Glands embedded in the subepithelial collagenous stroma of the extrahepatic bile ducts typically contain cells with mucin-filled cytoplasm. (Inset: Alcian blue periodic acid-Schiff (PAS) stain from the same field).

The surface epithelial cells contain smaller quantities of mucin than the cells that line the gallbladder (70). The former also contain sulfated acid mucin, whereas metaplastic and dysplastic cells primarily contain nonsulfated acid mucin and smaller quantities of sulfated and neutral mucins. The normal lining epithelium stains similarly to that of the gallbladder for epithelial membrane antigen and low-molecular weight keratin (CAM 5.2 antibody). Cytokeratin 7 is consistently expressed in normal epithelium, while CK20 expression depends on the condition of the epithelial cells. In normal cells, expression of CK20 is usually absent; however, it may be expressed when metaplasia, hyperplasia, or carcinoma are present (30,71). Carcinoembryonic antigen immunoreactivity may be absent (using absorbed polyclonal antibody) or appear as focal weak staining along the apices of some cells (using unabsorbed polyclonal antibody) (72). Cytoplasmic staining using either polyclonal or monoclonal anti-CEA antibodies is typically absent (73). Immunoreactivity for lysozyme has been found in the cytoplasm of the cells in the glands, whereas staining of the surface epithelial cells is absent or very weak (72). In addition, cells of the peribiliary glands are usually immunoreactive for pancreatic and salivary -amylase, trypsin, and lipase (68). The surface epithelium of the common bile duct also shows immunoreactivity for these enzymes.

Gastric metaplasia and intestinal metaplasia are sometimes found in inflamed and fibrotic extrahepatic bile ducts that may also harbor carcinoma (23,70,74). Scattered endocrine cells, including cells immunoreactive for chromogranin and somatostatin, can be observed between mucin-containing cells in normal as well as diseased biliary epithelium (56,74,75,76).

The stroma directly beneath the surface epithelium is dense and contains abundant collagen and elastic fibers and some small vessels (Figure 29.13). Lymphocytes are sparse. Pancreatic acini and ducts may be seen in the wall of the intrapancreatic portion of the common bile duct (77). Small pancreatic ducts sometimes empty into this segment of the duct. The peripheral stroma of the common bile duct is less dense than the inner connective tissue and contains large blood vessels, lymphatics, nerves and ganglion cells, elastic fibers, and smooth muscle fibers. This stroma merges with the connective tissue of the hepatoduodenal ligament. The distribution of smooth muscle fibers varies throughout the bile duct. Scattered muscle fibers or no muscle fibers are present of the upper one-third of the bile duct, whereas a continuous or interrupted pattern of thick smooth muscle bundles is present throughout the lower one-third of the bile duct (Figure 29.15) (78). The muscle fibers are more frequently longitudinal and are intermixed with collagen and elastic fibers. Nerve fibers showing immunoreactivity for VIP are present beneath the epithelium and in muscle fibers (76).

Figure 29.15 Occasional strands of smooth muscle are demonstrated in the upper portion of the common bile duct reacting with antibodies directed against desmin (immunoperoxidase technique).

Vaterian System and Minor Papilla

Gross Anatomy

The Vaterian system is composed of the segments of the common bile duct and major pancreatic duct (occurring either separately or as a common channel) at the duodenum, major papilla, and the sphincteric musculature. It also includes the extraduodenal portion of the common bile duct and major pancreatic duct that join to form a common channel outside the duodenal wall (58). It is a complex structural unit composed of a highly developed mucosa, musculature, and nerve supply that regulates the flow of bile and pancreatic secretions. Its sphincteric function (sphincter of Oddi) is a part of the overall gastrointestinal motility system and is subject to regulation by myogenic, neural, and gastrointestinal hormonal elements (9,79).

The major pancreatic duct of Wirsung drains many small channels in its course from the tail of the pancreas to the duodenal ostium. It typically inserts into the duodenal window caudal or a little lateral to the common bile duct. Its lumen narrows at the duodenal wall. The minor duct of Santorini, usually present, joins the major pancreatic duct at

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a variety of angles and locations within the pancreas. Uncommonly, the duct of Wirsung is smaller than the duct of Santorini, and the latter may be the chief conduit for drainage of the pancreas (80). The duct of Santorini leads into the minor papilla but also may end blindly in 10 to 20% of cases (80,81). The luminal pressure of the major pancreatic duct is nearly always higher than that for the common bile duct except when the gallbladder empties (82).

The relationship of the common bile duct and duct of Wirsung at the papilla is complex and variable. The ducts may have separate openings into the duodenum, an interposed septum, or a common channel (sometimes forming an ampulla) (Figure 29.16). The ampulla, defined strictly, is a dilated, juglike conduit resulting from the union of the common bile duct and major pancreatic duct. In various studies of the pancreaticoduodenal junction, the frequency for separate openings into the duodenal lumen ranged from 12 to 54% and for a common channel from 46 to 88% (57,80,81,83,84,85,86,87). In most studies, more than two-thirds of the patients had a common channel. In a detailed gross and radiographic study, DiMagno et al. (83) examined 390 pancreaticoduodenal specimens at autopsy and found that 74% of the patients had a common channel, 19% had separate openings for the pancreatic duct and common bile duct, and 7% had an interposed septum. Twenty-five percent of their specimens had a well-defined ampulla, 18% had a long common channel (defined as a channel greater than 3 mm long in the absence of an ampulla), and 31% had a short common channel (defined as a channel less than 3 mm in length) (83). For those specimens with an interposed septum, the two ducts emptied together at the ostium of the papilla. For the ducts that opened separately into the duodenal lumen, their ostia were located from 1 mm to several centimeters apart. On occasion, the ducts will unite before the duodenal wall is breached, forming an extended common channel. In one study, the length of the extended common channel ranged from 0.9 to 3.3 cm (mean: 2.2 cm) (88). This lengthy common channel occurred in 13.8% of patients with carcinoma of the biliary tract (18 of 130 cases) and in those with congenital biliary dilatation (four of four cases) but was absent in a control group of 30 cases (88). This confluence of the pancreatic and bile ducts outside of the duodenal wall has been increasingly described in association with congenital dilatation of the bile duct, choledochal cyst, and cholangiocarcinoma (89,90).

Figure 29.16 Relationship of the common bile duct and duct of Wirsung at the major papilla. (A, ampulla; B, interposed septum; C, separate openings; D, short common channel; E, long common channel; F, extended common channel)

The major papilla, a cylindrical protuberance housing the terminations of the common bile duct and major pancreatic duct or a common channel, is situated medially at the midportion of the second part of the duodenum. It is usually completely or partially covered by a triangular fold of duodenal mucosa; a longitudinal mucosal fold projects from the caudal portion of its base, forming a frenulum, which was absent in about one-quarter of the cases in one study (91). In one series, the papilla had a mean length of 11.7 mm and a mean width of 5.2 mm (85). Rarely, the major papilla is located at or just below the level of the duodenal mucosa or is absent. Mucosal reduplications (valves of Santorini) at the ostium of the major papilla consist of columnar-shaped protrusions and traverse leaflike flaps of ductal mucosa (92,93). In one study, the columnar-shaped projections that arose from the terminal common bile duct numbered one to four per specimen and ranged from 1 to 5 mm in length (93). They were found in approximately one-third of adults but were not observed in fetuses. Leaflike flaps were present in the caudal wall of the common channel in over 90% of fetuses and adults and were separated by small cul-de-sacs of varying size and depth. The flaps sometimes extended into the major pancreatic duct. In cases in which a common channel was absent, the leaflike flaps were found only at the orifice of the duct of Wirsung. It was postulated by the authors that the flaps may flatten during the flow of pancreatic juice into the duodenum; when the cul-de-sacs are filled, the ostium is blocked and regurgitation is prevented (93).

The sphincter of Oddi consists of the intrinsic circular and longitudinal musculature of the Vaterian system. It is embryologically and functionally distinct from the musculature of the duodenal wall. However, the muscle fibers from the duodenal wall aid in anchoring the Vaterian system in place in the duodenal window. In a study of the structure of the dense connective tissue around the major duodenal

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papilla, the papilla and duodenal wall were noted to form both a morphologic and a functional unit (94). Connective tissue fibers spread from the papilla orifice to the circular duodenal musculature and cross at different angles from the orifice to the distal common bile duct. The arrangement and amount of muscle bundles that form the sphincter are highly complex and variable. Important fibers are those around the intrapancreatic (near the duodenal wall) and intraduodenal portions of the common bile duct (sphincter choledochus) (95). In one study, accumulation of circular muscle fibers extended up the common bile duct to a mean distance of 13.6 mm from the pore of the papilla (91). Smooth muscle fibers are also present in the wall of the common channel, around the duct of Wirsung, and near the ostium of the papilla. It is controversial whether the smooth muscle bundles around the pancreatic duct above the common channel have important sphincteric function, but the finding of a sustained pancreatic duct high-pressure zone with phasic contractions after sphincterotomy may be evidence that the sphincter of Oddi extends above the common channel to include portions of the pancreatic duct (95,96,97). Muscle fibers have been found to extend up the pancreatic duct a mean of 7.3 mm from the papillary pore (91). The tunica muscularis of the duodenum may not have a primary role in managing the flow of bile and pancreatic juice at the choledochoduodenal junction.

The sphincter of Oddi serves to inhibit the flow of bile into the duodenum, pumps bile into the duodenum when necessary, and likely precludes the entry of duodenal contents into the common bile duct or major pancreatic duct (79). Manometric studies have shown that the control of the flow of bile during fasting results from the phasic contractions of the sphincter of Oddi (98). These contractions result in the liberation of small volumes of bile. The flow of pancreatic juice is also regulated. The contractions are in addition to the steady basal pressure of the sphincter of Oddi, which is several mm Hg higher than that for the common bile and pancreatic ducts (99). The high-pressure zone measures 4 to 6 mm long, and the phasic contractions may be antegrade, retrograde, or simultaneous (97). Cholecystokinin has been found to inhibit the phasic contractions of the sphincter and decrease the basal pressure, allowing the flow of large quantities of bile into the duodenum (98). Manometric and contractility studies of the effects of various hormones on the sphincter of Oddi in humans and animals have been summarized (79,97). Glucagon-like cholecystokinin decreases sphincteric pressure, whereas gastrin and secretin elevate basal pressure (97). The phasic contractions and basal tone of the sphincter can be increased or decreased by exogenous drugs. For instance, most narcotics increase sphincteric pressure, whereas atropine decreases it (97).

The minor papilla is nearly always present but may be difficult to locate grossly (81). Its size is variable. It is usually situated 2 cm proximal to the major papilla (81,100).

Vascular and Nerve Supply and Lymphatic Drainage

The intraduodenal portion of the common bile duct is supplied by vessels from the anterior and posterior superior pancreaticoduodenal arteries (2). Venous drainage occurs via small veins that lead to the portal vein. The fine venous architecture of the major papilla has been described in detail (101). Lymphatic drainage is variable, but generally lymphatics from the pancreaticoduodenal junction drain into the anterior and posterior pancreaticoduodenal lymph nodes and then to the nodes at the inferior pancreaticoduodenal artery (102). The Vaterian system is innervated extrinsically by parasympathetic nerve fibers in the vagal nerve and by sympathetic nerve fibers in the splanchnic nerves (9,79). Although little is known regarding the role of these nerve fibers in regulating the motility of the sphincter of Oddi, some evidence indicates that its motility is inhibited by vagal activation (79,103). Three separate ganglia cell groups provide intrinsic innervation. These are found at the base of the papilla in the duodenal wall, within the musculature of the papilla, and within the submucosa (79). This intrinsic innervation appears to provide tonic inhibition and is similar to that for other gastrointestinal sphincters, including the lower esophageal, pyloric, and internal anal sphincters.

Histology

The epithelial lining of the duct of Wirsung is identical to that of the common bile duct. The cytoplasm of the columnar cells also contains sulfated acid mucin (104). The epithelium may undergo hyperplastic, metaplastic, or dysplastic changes. Surrounding the normal epithelium is a dense fibrous layer with abundant collagen and elastic fibers. A few ganglion cells may be seen in the outer half of the fibrous wall. Small pancreatic ducts draining acini traverse the dense fibrous layer. At the orifice of the papilla, the epithelium of Wirsung's duct is thrown into folds (mucosal reduplications) that have cores of fibrovascular stroma. Goblet cells are found interspersed between the columnar lining cells within the papilla. Numerous small accessory pancreatic ducts drain into the ductal lumen near the ostium, and pancreatic acini are sometimes present just beneath the lining of the duct (Figure 29.17). A few lymphocytes may be seen within the ductal epithelium, and lymphocytes, plasma cells, and mast cells sparsely populate the fibrovascular cores. Circular smooth muscle bundles are present around the duct as it penetrates the duodenal wall (100).

The epithelium of the terminal portion of the common bile duct and common channel (if present) covers long, slender papillary fronds, or valvules, that in some respects resemble the fimbriae of the fallopian tube (Figure 29.18). They correspond to the mucosal reduplications seen

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grossly. These papillary formations are considerably larger than the duodenal villi, which are few or absent at the surface of the papilla. The valvules may branch and sometimes project beyond the ostium of the papilla, with shorter fronds at the periphery and longer ones centrally (60,105,106). The columnar lining cells have eosinophilic cytoplasm and basal nuclei. Interspersed goblet cells are more numerous near the ostium. The stroma forming the cores of the fronds contains a few lymphocytes, mast cells, and plasma cells. Muscle fibers, present at the base of the fronds, are occasionally found in the stroma of the fronds. The smooth muscle, forming the sphincter choledochus, becomes apparent in the wall of the duct several millimeters before the duct enters the duodenal window. About 5 mm from the duodenal wall, longitudinal muscle fibers are present around two-thirds of the common bile duct; at 2 mm from the duodenal musculature, circular muscle fibers increase and completely surround the duct (100). These intrinsic muscle fibers are separated from the muscularis propria of the duodenum by connective tissue and, at times, pancreatic tissue (100). Variable amounts of circular and longitudinal muscle fibers also surround the common channel. Before forming a common channel, the common bile duct is set apart from the pancreatic duct by a septum that eventually loses its muscle fibers, becoming a thin connective tissue membrane (100). Interspersed between areas of smooth muscle around the common bile duct or common channel are collagen, elastic fibers, small nerves, and ganglion cells. When the common bile duct and duct of Wirsung are separate within the papilla, they are distinguishable by light microscopy because the common bile duct is larger, has more prominent fronds, a greater amount of enveloping smooth muscle, and bile in its lumen.

Figure 29.17 The duct of Wirsung at the papilla of Vater is lined by a single layer of tall columnar cells with occasional interspersed goblet cells. Accessory pancreatic ducts and acini are also observed.

Figure 29.18 Near the ostium of the major papilla, the epithelium of the common bile duct lines prominent papillary fronds (valvules).

A bewildering assortment of glands and ducts of various caliber surround the common bile duct at the papilla. Frequently, it is only possible to distinguish mucous glands from the terminations of accessory pancreatic ducts by studying serial sections (77). Mucous glands drain into the shallow or deep recesses between the papillary fronds (Figure 29.19). The number of these glands and their distribution are variable. Glands near the surface of the papilla may be distended with mucus, and some may even represent dilated accessory pancreatic ducts (105). The number and distribution of accessory pancreatic ducts within the major papilla are also inconstant. These small accessory pancreatic channels, having been studied in serial sections and by camera lucida drawings, empty into the common bile duct (Figure 29.20), duct of Wirsung, common channel, surface of papilla, or through the duodenal mucosa near the papilla (77,107). They are sometimes numerous and may cause obstruction of the common bile duct, duct of Wirsung, or common channel. In such instances, a diagnosis of accessory duct hyperplasia may be

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appropriate (105). In an autopsy study, accessory pancreatic ducts were absent in only two of 100 major papillae (107). The ducts drain small lobules of pancreatic acini located within or, more often, near the papilla. In one study, pancreatic acini were found in 8% of 145 major papillae, whereas pancreatic islets were not seen in any of the major papillae (108). The ducts appear as packets of multiple lumens of small caliber encircled by a cellular fibrovascular stroma (Figure 29.21). Within a group of ducts, the larger central duct is surrounded by smaller branches. Groups of ducts are sometimes seen penetrating the duodenal smooth muscle. Small groups of heterotopic pancreatic acini and ducts also occur in the submucosa of the duodenum away from the major papilla (Figure 29.22).

Figure 29.19 Mucous glands are present around the common bile duct at the papilla and drain into recesses between the papillary fronds.

Figure 29.20 Accessory pancreatic ducts pierce the large smooth muscle bundles to empty into the lumen of the common bile duct.

Figure 29.21 Accessory pancreatic ducts that penetrate the smooth muscle bundles at the choledochoduodenal junction are surrounded by a fibrovascular stroma.

Immunohistochemically, the cells lining the common bile duct and the duct of Wirsung at the papilla are positive for low-molecular weight keratin (CAM 5.2 antibody), CK7, and epithelial membrane antigen (EMA). There may be linear apical staining for CEA (unabsorbed polyclonal antibody). The adjacent mucous glands and accessory pancreatic ducts have the same immunoreactivity for keratin and EMA. A few scattered cells lining the large ducts within the pancreas are positive for neuron-specific enolase, chromogranin A, insulin, and glucagon (109). Chromogranin-positive cells are sometimes located in the lining epithelium of the duct of Wirsung and common bile duct within the papilla. Mucous glands and accessory pancreatic ducts also contain scattered cells immunoreactive for neuron-specific enolase and chromogranin A (Figure 29.23). In patients with pancreaticobiliary disease, a few cells lining the lumen of the papilla and in adjacent mucous glands have been found to be immunoreactive for somatostatin (56). Although usually absent, endocrine cell micronests may be scattered singly or are grouped in the stroma adjacent to pancreatic ducts, ductules, or accessory

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glands but not around the common bile duct (108). They have been found in about 3% of major papillae. They consist of round, oval, trabecular, or ribbonlike groups of cells that immunohistochemically are distinct from those of pancreatic islets. They are typically scattered, rarely nodular, and immunohistochemically stain for somatostatin and pancreatic polypepide. It is unclear whether they are a normal finding or represent a metaplastic or hyperplastic condition. The functional role of these endocrine cells in the papilla of Vater is unknown.

Figure 29.22 Groups of heterotopic pancreatic ducts and acini may be seen in the submucosa of the duodenum away from the papilla of Vater.

Figure 29.23 Some of the small ducts around the duct of Wirsung at the major papilla contain a few cells that are immunoreactive for chromogranin A (immunoperoxidase technique).

At the minor papilla, the pancreatic duct of Santorini contains papillary fronds that are lined by simple columnar epithelium with some goblet cells (Figures 29.24,29.25). Small pancreatic ducts open into the lumen of the duct of Santorini at the minor papilla or separately into the duodenum (81). Small lobules of pancreatic acini may be present within the connective tissue of the minor papilla and were seen in 77% of 167 minor papillae in a study by Noda et al. (108), who noted that 14% of the papillae also contained well-formed pancreatic islets. Atrophic or poorly formed islets are present uncommonly. Smooth muscle bundles separated by collagen, small nerves, and ganglion cells surround the duct. The bundles of muscle occasionally are continuous with those of the muscularis mucosae of the duodenum, but in many instances continuity between the groups of muscle fibers is lacking (81). The lining epithelial cells and those of the small pancreatic ducts stain strongly for low-molecular weight keratin (CAM 5.2 antibody), CK7 and weakly for CEA (unabsorbed polyclonal antibody). A few cells within small ducts and some that line the lumen of the duct of Santorini are flask-shaped and immunoreactive for neuron-specific enolase and chromogranin A (Figure 29.26). Small groups of neuroendocrine cells may extend below the epithelial lining (Figure 29.27). In the above-mentioned study of 167 minor papillae, 16% contained endocrine micronests, which were

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predominantly scattered and rarely nodular (108). They were usually immunoreactive for somatostatin and pancreatic polypeptide and lacked staining for insulin and glucagon. It is possible that some of these micronests represent metaplasia/hyperplasia or neoplasia.

Figure 29.24 The duct of Santorini at the minor papilla contains papillary fronds and is surrounded by muscle bundles.

Figure 29.25 The duct of Santorini at the minor papilla is lined by tall columnar cells with interspersed goblet cells.

Figure 29.26 A few cells that line the duct of Santorini at the minor papilla are flask-shaped and immunoreactive for chromogranin A (immunoperoxidase technique).

Figure 29.27 A group of cells below the lining epithelium of the duct of Santorini at the minor papilla is immunoreactive for chromogranin A (immunoperoxidase technique).

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