NORMAL ANATOMY 1 AND EMBRYOLOGY the gallbladder. Accordingly, it is a pathologic NORMAL ANATOMY and not an anatomic entity (). 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 liver, 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 cancer, 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 bile 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 pylorus, duodenum, and hepatic flexure of pancreas, 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 histology 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). ) a mucosa composed of columnar epithelium 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- -). The gallbladder lacks a muscularis mucosae duct bile from the bile canaliculi to the bile ducts and submucosa. 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 common hepatic duct, cystic its lumen expands. During contraction, these duct, gallbladder, and common bile duct com- folds come together and increase in height prise the extrahepatic biliary system. (5). 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 organ, the gallbladder membrane. The cells have ovoid basal nuclei is normally found under the right lobe 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 cystic duct, (36,2). 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. -2, duct. Originally considered a fourth part of the left) (0). These cells are considered modified gallbladder, the pouch is now thought to result columnar cells, although their nature and func- from chronic inflammation. It often contains tion are unknown. Because of their enzymatic gallstones 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 (4). 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 connective tissue, 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 lymphocytes. 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. -2, right). elongated or ovoid nuclei whose long axis is Usually, a few intramucosal plasma cells are seen parallel with the basement membrane. These in normal gallbladders. 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. -3). Goblet cells have been columnar cells and should not be confused with described in the normal fetal gallbladder as well 2 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 lymphocyte 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 glands, 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. -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 (2). scattered isolated paraganglia (figs. -5, -6). Lamina Propria. The lamina propria con- When multiple, the paraganglia may coalesce or sists of a thin layer of loose connective tissue fuse, and form larger endocrine structures that lacking a muscularis mucosae; it contains few may simulate a paraganglioma (fig. -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 3 Tumors of the Gallbladder, Extrahepatic Bile Ducts, and Vaterian System Figure 1-3 FETAL NORMAL GALLBLADDER A gallbladder from a 5-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). 4 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. 5 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-00 epithelium. They are found in less than 0 percent protein (fig. -8). of gallbladders, although figures from 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- (4). 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