1 THE NORMAL PANCREAS EMBRYOLOGY are also a variety of endocrine lineage–restricted The embryonic pancreas first appears in the transcription factors such as Ngn3, NeuroD/Beta2, 5th week of gestation as dorsal and ventral evagi- Nkx2.2, and Nkx6.1 (14,28,32,37). nations of foregut endoderm (21). As suggested In contrast to the relative abundance of in- by Edlund (12), there are three components of formation regarding the transcription factors the complex events required for normal pan- required for islet development, a paucity of infor- creatic development. First, foregut endoderm mation exists regarding similar factors required becomes patterned to form dorsal and ventral for exocrine differentiation. The p48 component pancreatic buds; second, cells undergo lineage of the heterotrimeric PTF1 transcription factor commitment to either endocrine or exocrine cell complex is required for normal exocrine differ- fates; and third, pancreatic morphogenesis oc- entiation (23). Although initially presumed to be curs by way of extensive growth and branching. an “exocrine-specific” transcription factor, Pdx1 While recent studies suggest that distinct signal- is now believed to play a far more expansive role ing pathways may control these events, tissue in pancreatic specification (28). specification, lineage commitment, and growth In addition to intrinsic transcription fac- are highly interdependent and are characterized tors, the pancreas is also responsive to cell by considerable spatial and temporal overlap. fate determining signals from developmental Several transcription factors are now known patterning pathways, such as the Notch and to be required for pancreas specification. Prior to Hedgehog signaling pathways. For example, and during budding, the organ primordium ex- Notch signals are required for epithelial branch- presses the homeodomain protein pancreatic and ing and normal exocrine lineage commitment duodenal homeobox gene 1 (Pdx1) (also known as (29). Notch signaling appears to maintain the insulin promoter factor 1 [IPF1]) (12); all three dif- undifferentiated state of the putative pool of ferentiated pan creatic cell types, islet cells, aci- pancreatic stem cells. These stem cells mediate nar cells, and pancreatic duct cells, are derived cellular turnover and repair, and may expand in from Pdx1-positive progenitors. Deletion of the face of neoplastic transformation. Indeed, the Pdx1 gene allows successful specification of widespread upregulation of Notch transcripts is pancreatic mesenchyme and initial pancreatic common in ductal adenocarcinoma of the pan- bud formation, but results in severely aborted creas as well its precursor lesions, reinforcing the morphogenesis and failure to generate differen- commonality of signaling pathways involved in tiated islet, acinar, and ductal cell types (2). The development and cancer genesis (26). early embryonic ductal epithelium expresses The Hedgehog gene was first discovered in Pdx1 uniformly, but later, Pdx1 expression is studies of Drosophila (33). In mammals, three primarily restricted to the islets of Langerhans, Hedgehog genes are essential for embryogen- with only low levels detectable in some acinar esis: Sonic Hedgehog (Shh), Indian Hedgehog cells. Under certain conditions, Pdx1 expres- (Ihh), and Desert Hedgehog (Dhh). Ihh and Dhh sion again becomes detectable in individual are detected during development as well as in pancreatic ductal epithelial cells, suggesting the mature pancreatic tissue, consistent with the persistence of multipotential stem cells within hypothesis that the hedgehog pathway is active mature pancreatic epithelium (40). during certain specific phases of pancreas forma- Additional transcriptional factors involved in tion (15). In midgestational embryos, the Shh pancreatic morphogenesis include, but are by no ligand is expressed in nearly all epithelial cells means limited to, Sox17, HLXB9, and PTF1, which lining the alimentary canal, and its function is appear to be required in early specification. There critical for proper foregut and gastrointestinal 1 Tumors of the Pancreas development. In contrast, Shh is excluded from the developing pancreas, but remains expressed in the surrounding gastric and duo- denal epithelium. Notochord-derived inhibitory signaling via activin and fibroblast growth factor 2 (FGF2) represses Shh and permits appropriate transcriptional activation of pancreatic gene ex- pression (16). Thus, Shh expression establishes a sharp molecular boundary, which allows for the proper patterning of the duodenal and pancreatic epithelium. If Shh expression in areas adjacent to pancreatic tissue is responsible for restricting pancreas growth, loss of Shh should increase pancreatic mass. Indeed, chemical inhibition of the Shh signaling pathway in experimental models leads to ectopic formation of pancreas buds and an increase in endocrine cell number. Conversely, overexpression of Shh within the de- veloping pancreas of transgenic Pdx1-Shh mice leads to attenuation of the pancreatic phenotype and induction of an intestinal differentiation pro- gram (4). The latter phenomenon acquires great significance in the context of human pancreatic neoplasia, where the early precursor lesions of pancreatic adenocarcinoma demonstrate similar histopathologic features as observed in the Pdx1- Shh mice, and also harbor a transcriptional profile that is more akin to foregut epithelium than to Figure 1-1 native pancreatic ducts (46). During the development of the pancreas, ANATOMY OF THE DEVELOPING PANCREAS evaginations (buds) of cuboidal epithelium Top: The dorsal pancreatic bud appears first as a bud from the foregut grow to produce a complex caudal to the stomach. The smaller ventral pancreatic bud arises from the base of the hepatic diverticulum. Neither branching epithelial tree (25). The larger dorsal bud expresses the Sonic Hedgehog (shh) gene whereas the pancreatic bud appears first, caudal to the stom- adjacent foregut does. ach, and grows rapidly in the dorsal mesentery. Bottom: Rotation of the duodenum to the right carries The smaller ventral pancreatic bud arises from the ventral bud to a position posterior to the dorsal bud. The two primitive buds then fuse to form the pancreas. The the base of the hepatic diverticulum attached to dorsal bud gives rise to the cephalad portion of the head, as the entry of the bile duct into the duodenum, well as the body and tail, whereas the ventral bud gives rise and grows between the layers of the ventral to the caudal portion of the head and the uncinate process. mesentery. Initially, the ventral bud is com- The main pancreatic duct (duct of Wirsung) is formed by the union of the distal portion of the dorsal pancreatic duct posed of two parts, right and left, but the left and the ventral pancreatic duct. The proximal portion of the bud atrophies early and the right bud, adjacent dorsal pancreatic duct forms the accessory duct of Santorini. to the primitive bile duct, persists (fig. 1-1, top). (Artwork by Jennifer Parsons Brumbaugh.) Around the 7th week of gestation, following rotation of the primitive intestine and its deriva- uncinate process (fig. 1-1, bottom). The main tives to the right, a move that gives the duode- pancreatic duct (duct of Wirsung) is formed by num its C shape, the two pancreatic primordia the union of the distal part of the dorsal pancre- fuse to form a single organ. The dorsal bud gives atic duct and the smaller ventral pancreatic duct rise to the tail, body, and the cephalad portion during the 7th week of gestation. As a result, of the pancreatic head; the ventral bud forms the main duct empties into the major duodenal the caudal half of the pancreatic head and the papilla (the ampulla of Vater). The proximal 2 The Normal Pancreas Figure 1-2 ANATOMIC VARIATIONS IN THE PANCREATIC AND COMMON BILE DUCT SYSTEM A: The proximal portion of the dorsal pancreatic duct regresses completely. B: The proximal portion of the dorsal pancreatic duct remains patent as the accessory duct of Santorini and drains into the minor papilla. C: The entire dorsal pancreatic duct drains into the minor papilla and the smaller ventral pancreatic duct joins the com- mon bile duct at the major papilla (pancreas divisum). D: The ventral pancreatic duct fuses with the dorsal pan creatic duct and drains the gland through the minor papilla leav- ing the common bile duct to drain into the major papilla. (Artwork by Jennifer Parsons Brumbaugh.) part of the dorsal pancreatic duct may persist creas; the neck; the body; and the tail. The main as the accessory duct of Santorini. When pres- pancreatic duct (of Wirsung) averages 3 mm in ent, the accessory duct of Santorini drains into diameter (range, 1.8 to 9.0 mm), curves inferiorly the minor papilla located 2 cm cephalad to the at the head, and drains the majority of the gland ampulla of Vater or it may become a tributary into the duodenum via the major papilla (ampulla to the duct of Wirsung (fig. 1-1, bottom). of Vater). Here the diameter of the duct increases to about 4.5 mm. Main ducts greater than 10 mm GROSS ANATOMY are considered pathologically dilated. The mature pancreas is a uniformly lobulated There are a number of variations in the anatomy organ, 14 to 20 cm in length and weighing, on of the pancreatic ductal system and in the rela- average, 100 g in the adult, with the pancreata tionship of the pancreatic ductal system to the of men slightly heavier than those of women. common bile duct (fig. 1-2). The usual arrange- The newborn pancreas weighs only 5 g and the ment is for the main pancreatic duct to drain the pancreata of the elderly weigh less than those bulk of the gland into the duodenum at the major of younger adults. papilla along with the common bile duct (fig. The four anatomic areas of the pancreas are 1-2A). Another arrangement is for the accessory the head, which comprises the bulk of the pan- duct of Santorini to be patent and drain through 3 Tumors of the Pancreas Figure 1-3 ANATOMIC VARIATIONS IN THE UNION OF THE COMMON BILE DUCT AND THE MAIN PANCREATIC DUCT AT THE MAJOR PAPILLA A: Early fusion with a long common channel of 3 mm or more.