Please see the discussion for question 4

Please see the discussion for question 4

Please see the discussion for question 4

Pancreatic development is a complex process in which primitive endodermal cells give rise to highly differentiated ductal, endocrine, and exocrine tissues.

Human pancreatic development starts on the 26th day of gestation, with the formation of the dorsal pancreatic bud, arising from the dorsal foregut. Six days after, the ventral pancreatic bud develops from a more caudal position in the foregut. Once formed, the ventral bud rotates approximately 180° in clockwise direction to fuse with the dorsal bud. Remnants of this migration give rise to annular pancreas. In the fully developed pancreas, the dorsal bud contribution consists of the superior and anterior portion of the pancreatic head, the neck, body, and tail of the pancreas. The ventral bud contributes to the inferior and posterior part of the pancreatic head as well as the uncinate process. As noted above, it is interesting that the dorsal anlage gives rise to anterior elements, while the opposite holds true for [1] the ventral anlage (Fig. 18.1).

Annular pancreas is often associated with other congenital malformations such as Down’s syndrome, intestinal malrotation, duodenal and esophageal atresia, and tracheoesophageal fistulas. This condition becomes symptomatic by causing duodenal obstruction. While presentation is most common in early life, there have been cases reported in adults. Treatment involves surgical bypass of the obstruction. Division of the constricting annulus is not advised due to the frequent presence of pancreatic ductal structures [2] (Fig. 18.2).

Originally, the dorsal bud is drained by its own duct (Santorini) which opens into the more cephalad minor pancreatic papilla in the duodenum. In similar fashion, the ventral bud is drained by the duct of Wirsung into the ampulla of Vater. However, as both pancreatic buds fuse, their ductal systems are rearranged. The distal part of the duct of Santorini (draining the body and tail) fuses with the duct of Wirsung, giving rise to a main pancreatic duct that runs along the entire length of the gland. Meanwhile, the proximal part of the duct of Santorini may regress completely or drain the upper portion of the pancreatic head independently.

Failure of this ductal fusion results in pancreas divisum, an entity in which the original ductal systems for the ventral and dorsal buds are maintained. This anomaly is found in up to 10 % of the population. It is thought that the minor pancreatic papilla is too small to accommodate the exocrine output of the upper head, body, and tail of the pancreas, giving rise to increased ductal pressure and recurrent pancreatitis. Over time, the elements derived from the dorsal bud atrophy, giving a typical non-enhancing appearance on CT scanning and ultrasound, in contrast with the normal texture of the ventral anlage. ERCP and MRCP are the main diagnostic modalities. Treatment involves enlarging the minor papilla to facilitate flow. While surgical sphincterotomy and sphincteroplasty were performed in the past, endoscopic sphincterotomy and stenting are currently more widely practiced [3, 4].

It has been well established that the endocrine pancreas is also derived from the foregut endoderm. The first pancreatic endocrine cells to appear are glucagon positive. These cells are integrated among the exocrine pancreas and in contact with the ductal lumen. There is a period of “secondary transition” in which the endocrine cells of the pancreas undergo exponential expansion and the β cells become the dominant type. Around this period, the endocrine cells of the pancreas detach themselves from the ductal margins and group in cords along the blood vessels to form the islets of Langerhans. Differentiation yields specialized glucagon-producing α-cells, insulin-producing β-cells, somatostatin-producing δ-cells, ghrelin-producing ε-cells, and pancreatic polypeptide-producing PP cells. While the islets of Langerhans are distributed throughout the pancreas, there are regional variations within the predominant cell type within the islets [5–9].

Please see the discussion for question 6

Islet cell tumors, also known as neuroendocrine tumors, are rare malignancies that arise from the endodermal cells that give rise to the islets of Langerhans. They were previously classified as APUD tumors, based on their ability to uptake and decarboxylate amine precursors. Their incidence is 1–1.5 cases per 100,000. They account for 1–2 % of all pancreatic malignancies.

As a group, they are recognizable by the presence of neurosecretory granules as well as markers such as chromogranin, synaptophysin, and neuron-specific enolase. Clinically, they can be divided into functioning and nonfunctioning, based on hormone production and associated endocrine derangements. Nonfunctioning tumors are the most frequent type. Due to their uncommon presentations, these tumors are often diagnosed in late stages. Even though gastrinomas are relatively more malignant than other pancreatic endocrine tumors, their prognosis is far more benign than that of pancreatic adenocarcinoma. Approximately half of pancreatic neuroendocrine tumors have endocrine activity and are classified by the hormone they produce, although it must be kept in mind that many produce more than one hormone.

Neuroendocrine tumors express a high concentration of somatostatin receptors. This allows diagnosis via scintigraphy with indium-labeled octreotide (a somatostatin analogue). This trait may also allow palliative treatment with somatostatin analogues, which may reduce hormone production and the clinical manifestations thereof.

Intraoperative ultrasound is the most sensitive diagnostic modality for localization as well as for the diagnosis of lesions that might have escaped noninvasive imaging modalities. Endoscopic ultrasound has also proven to be an excellent modality especially in the tumors of the head and body of the pancreas. The tail of the pancreas is out of the range of this technique [10, 11].

Among the functional tumors, insulinomas are the most common type. They present in older females. The main manifestations are associated with hypoglycemia, made worse with fasting. Common symptoms include fatigue, weakness, tremors, and hunger. Whipple described the triad of symptoms of hypoglycemia, measured low blood glucose levels (less than 50 mg/dl), and relief of symptoms with administration of glucose. Most insulinomas are benign, 1–2 cm in size, solitary, and equally distributed through the pancreas. Specific diagnostic tests include measurements of serum insulin, proinsulin, and C-peptide levels. Enucleation is the preferred form of surgical treatment for lesions that do not involve major ductal structures (i.e., small tumors or those close to the edge of the pancreas). Pancreatic resection is reserved for cases in which enucleation is not possible.

Insulinomas may be associated with MEN-1 syndrome, in which case they tend to be multiple, and appear during the third decade of life. Of note, the most common type of neuroendocrine pancreatic tumor in MEN-1 is nonfunctional tumor, followed by gastrinomas and insulinomas [12].

Gastrinomas are the second most common type of neuroendocrine tumor of the pancreas. They are different from the others in that G cells are not normally present in the islets of Langerhans. Ectopic G cells can be found outside their normal location in the antrum and duodenum, in an area that has been termed gastrinoma triangle. This is defined as the space between the junction of the neck and body of the pancreas, the cystic to common bile duct junction and the duodenum. Gastrinomas are present in 0.1 % of patients with peptic ulcer disease and in 2 % of those with recurrent ulcer disease. Gastrinomas exhibit a paradoxical response to secretin administration. While this hormone normally abolishes gastrin production, gastrinomas respond to it by an increase in production. This trait is useful in establishing the diagnosis [13].

Gastrinomas are the cause of Zollinger–Ellison syndrome, characterized by hypergastrinemia and multiple peptic ulcers in classic and atypical locations (e.g., postbulbar duodenum, esophagogastric junction, and proximal small bowel). Surgical exploration for gastrinoma should always include duodenotomy, as the duodenum is the most common site for this tumor. In 5 % of cases, it is not possible to locate the tumor. Under this circumstance, antrectomy with vagotomy is advised. Finally, when gastrinomas are associated with primary hyperparathyroidism as part of MEN-1 syndrome, it is advisable to perform a parathyroidectomy before resection of the gastrinoma. This recommendation is based on the fact that calcium is a potent gastric secretagogue by itself [14].

VIPomas are the cause of Verner–Morrison syndrome also known as pancreatic cholera. Hypersecretion of vasoactive intestinal peptide induces secretory diarrhea (rich in bicarbonate), hypokalemia, and achlorhydria. Stool output is as high as 5–10 l per day. Most VIPomas are located in the tail of the pancreas. VIP-induced diarrhea responds dramatically to octreotide administration. This drug is very useful as an adjunct during preoperative fluid resuscitation [15].

Glucagonomas are very rare tumors that cause the four “Ds” of diabetes mellitus type 2, DVT, depression, and dermatitis (necrolytic migratory erythema). Due to their nonspecific presentation, diagnosis is usually delayed, and tumors are large (>5 cm) at the time of presentation. Like with VIPomas, these tumors are more commonly found in the tail of the pancreas.

Somatostatinomas produce steatorrhea, cholelithiasis, diabetes mellitus type 2, and hypochlorhydria. Most tumors are malignant and located within the head of the pancreas, making pancreaticoduodenectomy necessary. Fortunately, these tumors follow a rather indolent course, with 100 % 5-year survival after R0 resection and 60 % survival in the presence of metastatic disease.

Ghrelin is a relatively newly discovered hormone whose main role appears to be the induction of hunger. However, multiple functions of this hormone have been identified. It induces gastric secretion and contractility. Interestingly, it also seems to play a role in neurological development, learning, memory, and depression. While its main site of production is the stomach, it is also produced in the pancreas. A case of pancreatic ghrelinoma and another of gastric ghrelinoma are reported in the literature. In both cases, no particular clinical syndrome was identified [16].

As would be expected from the portal drainage of pancreatic venous blood, the liver is the primary site of metastasis for neuroendocrine tumors of the pancreas. When feasible, anatomic liver resection with curative intent should be attempted. More limited resections or angiographic hepatic embolization are useful palliative techniques.

Carcinoid tumors, while not particular to the pancreas, are presumed neuroendocrine tumors, being diagnosed with increasing frequency in the wall of the duodenum as well as pancreas.

Please see the discussion for question 8

The vascular anatomy of the head of the pancreas is classically based on four vessels: the celiac trunk derived anterior superior pancreaticoduodenal artery (ASPDA) and posterior superior pancreaticoduodenal artery (PSPDA) and the superior mesenteric artery derived anterior inferior pancreaticoduodenal artery (AIPDA) and posterior inferior pancreaticoduodenal artery (PIPDA). Anteriorly and posteriorly the superior and inferior PDA’s anastomose forming two vascular arcades (anterior and posterior), which supply the head of the pancreas and C-loop of the duodenum. These four arteries are described as having matching veins [17, 18].

However, the abovementioned pattern is subject to multiple variations, the more frequent being absence of an arcade, presence of vessels communicating and interrupting the anterior and posterior arcades, and missing veins [19].

While it was originally thought that due to their common blood supply the duodenum and pancreatic head were indivisible, it has been shown that it is possible to separate both structures through careful dissection and ligation of the branches supplying the pancreas while preserving the vascular arcades and branches to the duodenum. In this process, the area of greatest difficulty is in the vicinity of the papillae [20]. It must be noted that this procedure is indicated only for benign pathology [21–23].

Branches of the splenic artery supply the body and tail of the pancreas. The splenic artery gives rise to the pancreatica magna artery near the junction of the body and tail. The importance of recognizing this artery lies in that ligation of the splenic artery proximal to its emergence may lead to pancreatitis and necrosis of the pancreatic tail. This concept must also be applied when performing angiographic splenic embolization.