Embryology :Development of the

PancreasPratap Sagar Tiwari, Resident, NAMS, Department of Hepatology

Overview• The pancreas, named from the Greek

words pan (all) and kreas (flesh), is a 12-15–cm long J-shaped (like a hockey stick), soft, lobulated, retroperitoneal organ. It lies transversely, although a bit obliquely, on the posterior abdominal wall behind the stomach, across the lumbar (L1-2) spine.(1,2,3)• The adult gland weighs between 70

and 110 g.

1.Agur AMR, Lee MJ, Grant JCB. Grant’s Atlas of Anatomy. 10th ed. London, UK: Lippincott Williams and Wilkins; 1999.2.Romanes GJ. Cunningham's Manual of Practical Anatomy. 15th ed. New York, NY: Oxford Medical Publications, Oxford University Press; 1986. Vol II: Thorax and Abdomen:3.Grant JCB, Basmajian JV, Slonecker CE. Grant's Method of Anatomy: A Clinical Problem-Solving Approach. 11th ed. London, UK: Williams and Wilkins; 1989.

History of Pancreas• The first description of the pancreas was made by the Greek physician Herophilos

at around 300 bc. • In the late first century ad, Greek physician, Rufus of Ephesus, named the organ

the “pancreas.” The term literally means “all flesh .• “Kalikreas,” meaning “beautiful flesh,” given by Galen.• In 1642, Wirsung characterized the pancreatic ducts of humans. • In 1664, de Graaf discovered pancreatic secretions from the pancreatic fistula of

dogs.• The histologic structure of the pancreas was first described in 1869 by Langerhans.• In 1923:Canadians Banting,Charles Best and Macleod were awarded the Prize for

successfully purifying insulin .

Development of Pancreas

Source: Gorelick F, Pandol, SJ, Topazian M. Pancreatic physiology, pathophysiology, acute and chronic pancreatitis. Gastrointestinal Teaching Project, American Gastroenterologic Association. 2003.

The pancreas develops from the two budsVentral bud: Arises from the hepatic diverticulum and gives the lower part of the head and uncinated process.Dorsal bud: Arises from the dorsal aspect of the duodenum and gives the upper part of the head ,neck , body & tail.

Initially the dorsal pancreas grows on the dorsal side of the duodenum into the mesoduodenum. Somewhat later the ventral pancreas appears as an evagination of the bile duct. Source: http://www.embryology.ch(universities of Fribourg, Lausanne and Bern)

4 to 7 weeks : reference Sleisenger 10th ed.

Development of pancreatic ducts• The main pancreatic duct(duct of wirsung): from the duct of ventral

pancreas (proximally), distal part of the duct of dorsal pancreas (distally).• The accessory pancreatic duct(duct of Santorini): from the proximal

part of the duct of the dorsal pancreas.

Development of pancreatic acini and isletsSide branches extend from the ducts to the surrounding mesoderm.Some of them become canalized pancreatic acini.Others separate & not canalized Islets of Langerhans.The pancreatic connective tissue stroma and interlobar septa: from the splanchnic mesoderm.

Signalling pathways : Pancreas• The signaling pathways underlying the development process include the Hedgehog

system, the homeobox gene :Pdx1 and Notch signaling [1,2]. • Inhibition of Hedgehog signaling leads to ectopic budding of pancreatic structures in

the stomach and the duodenum [3]. • Pdx1 expression in the duodenum during development marks the location of

pancreatic bud development [2]. • Notch signaling inhibits endocrine cell differentiation and promotes exocrine cell

differentiation [4]. (Inhibition of Notch signaling results in marked endocrine cell expansion with blockade of exocrine cell development.)Neurogenin-3 ,a protein is expressed in endocrine progenitor cells and is required for endocrine cell development in the pancreas.1. Habener, J.F., Kemp, D.M., and, M.K. Thomas, Minireview: transcriptional regulation in pancreatic development. Endocrinology, 2005. 146(3): pp. 1025–34.2. Kim, S.K., and MacDonald, R.J., Signaling and transcriptional control of pancreatic organogenesis. Curr Opin Genet Dev, 2002. 12(5): pp. 540–7. 3. Parkin, C.A., and Ingham, P.W., The adventures of Sonic Hedgehog in development and repair. I. Hedgehog signaling in gastrointestinal development and disease. Am J Physiol Gastrointest Liver Physiol, 2008. 294(2): p. G363–7.4. Kim, W., et al., Notch signaling in pancreatic endocrine cell and diabetes. Biochem Biophys Res Commun, 2010. 392(3): pp. 247–51

Developmental anomalies• Variations of the Pancreatic Duct• Developmental Anomalies of the Pancreas

Pancreatic divisum• Itis the most common congenital anomaly of the pancreas. • PD results from a failure of the dorsal and ventral pancreatic ducts to

fuse during embryogenesis .(1)• Thus, the bulk of pancreatic exocrine secretions must drain through

the relatively small dorsal duct of Santorini and minor papilla rather than the ventral duct of Wirsung and the major papilla. • It has been detected in 5% to 10% of the population in autopsy

studies and in a similar percentage of patients undergoing ERCP.(2,3,4)

1. F. P. Agha and K. D. Williams, “Pancreas divisum: incidence, detection, and clinical significance,” American Journal of Gastroenterology, vol. 82, no. 4, pp. 315–320, 1987.2. Kleitsch W. Anatomy of the pancreas: A study with special reference to the duct system. AMA Arch Surg 1955; 71:795-802.3. Dawson W, Langman V. An anatomical-radiological study of the pancreatic duct pattern in man. Anat Rec 1961; 139:59-68.4. Smanio T. Proposed nomenclature and classification of the human pancreatic ducts and duodenal papillae: Study based on 200 postmortems. Int Surg 1969; 52:125-41.

Pancreatic divisum• ERCP :most definitive and reliable diagnostic method for revealing

pancreas divisum. Magnetic resonance cholangiopancreatography is a non invasive and accurate method in the diagnosis of pancreas divisum. The clinical relevance of pancreas divisum remains controversial.• Most patients with pancreas divisum are asymptomatic [1]. A relative

obstruction to pancreatic exocrine secretory flow through the duct of Santorini and minor papilla could result in pancreatitis in a small number of patients with pancreas divisum [2].• Endoscopic stenting and sphincterotomy of the minor papilla might be

effective in some patients with pancreas divisum [3]. 1. J. A. Soto, B. C. Lucey, and J. W. Stuhlfaut, “Pancreas divisum: depiction with multi-detector row CT,” Radiology, vol. 235, no. 2, pp. 503–508, 2005. 2. P. B. Cotton, “Congenital anomaly of pancreas divisum as cause of obstructive pain and pancreatitis,” Gut, vol. 21, no. 2, pp. 105–114, 1980.3. S. A. Cohen, F. D. Rutkovsky, J. H. Siegel, and F. E. Kasmin, “Endoscopic stenting and sphincterotomy of the minor papilla in symptomatic pancreas divisum: results and complications,” Diagnostic and Therapeutic Endoscopy, vol. 1, no. 3, pp. 131–

139, 1995.

Annular Pancreas• It is a rare congenital anomaly in which a ring of pancreatic tissue surrounds the duodenum. • It is estimated that it occur in 1 of every 12,000–15,000 live births [1]. • The annular pancreatic tissue forms a complete (25%) or partial (75%)

ring around the descending duodenum [2,3].• It is frequently associated with other congenital abnormalities such as

esophageal atresia, imperforate anus, congenital heart disease, malrotation of the midgut, and Down syndrome.

1. N. Lainakis, S. Antypas, A. Panagidis et al., “Annular pancreas in two consecutive siblings: an extremely rare case,” European Journal of Pediatric Surgery, vol. 15, no. 5, pp. 364–368, 2005.2. F. Gress, A. Yiengpruksawan, S. Sherman et al., “Diagnosis of annular pancreas by endoscopic ultrasound,” Gastrointestinal Endoscopy, vol. 44, no. 4, pp. 485–489, 1996.3. K. Sandrasegaran, A. Patel, E. L. Fogel, N. J. Zyromski, and H. A. Pitt, “Annular pancreas in adults,” American Journal of Roentgenology, vol. 193, no. 2, pp. 455–460, 2009.

Annular pancreas……………..continue• There are two main hypotheses to explain pathogenesis of annular pancreas. One is

that the tip of the right ventral bud adheres to the duodenal wall and stretches to form a ring during normal rotation, as proposed by Lecco [1].

• The other hypothesis is that the left ventral bud persists, which develops to complete a circle of pancreatic tissue around the duodenum, as proposed by Baldwin [2].

• Some pathologists support Lecco’s hypothesis, because annular pancreatic tissue is composed of PP-rich islets, which is believed to be derived from the right ventral anlage [3].

• Adults present with abdominal pain, pancreatitis, or with nausea, vomiting, and bloating.• Duodenoduodenostomy appears to be an effective surgical treatment for bowel obstruction.• The risk of pancreaticobiliary neoplasia is significantly increased in adults with annular

pancreas(4) and an association with duodenal carcinoma has been reported as well.(5)

1. T. M. Lecco, “Zur morphologie des pankreas annulare,” Sitzungsberichte der Heidelberger Akademie der Wissenschaften, vol. 119, pp. 391–406, 1910. 2. W. A. Baldwin, “A specimen of annular pancreas,” The Anatomical Record, vol. 4, no. 8, pp. 299–304, 1910. 3. K. Suda, “Immunohistochemical and gross dissection studies of annular pancreas,” Acta Pathologica Japonica, vol. 40, no. 7, pp. 505–508, 1990. 4. Zyromski N, Sandoval J, Pitt H, et al. Annular pancreas: Dramatic differences between children and adults. J Am Coll Surg 2008; 206:1019-25; discussion 1025-7.5. Bronnimann E, Potthast S, Vlajnic T, et al. Annular pancreas associated with duodenal carcinoma. World J Gastroenterol 2010; 16:3206-10.

Choledochal Cysts• CC are a well-known anomaly that appears as dilatation of extra- or

intrabiliary trees. • CC have been classified into five subtypes radiologically by Todani et

al. [1], which is a modification of the Alonso-Lej classification [2]. • CC, which are rare and more common in F than M, occur in approx 1 : 

100,000–150,000 live births in Western countries [3]. • CC are much more prevalent in Asia than in Western countries.

Approximately 33%–50% of reported cases come from Japan, where the frequency in some studies has approached one case per 1000 population [4].

1. T. Todani, Y. Watanabe, M. Narusue, et al., “Congenital bile duct cysts: classification, operative procedures, and review of thirty-seven cases including cancer arising from choledochal cyst,” American Journal of Surgery, vol. 134, no. 2, pp. 263–269, 1977.

2. F. Alonso-Lej, W. B. Rever Jr., and D. J. Pessagno, “Congenital choledochal cyst, with a report of 2, and an analysis of 94, cases,” International Abstract of Surgery, vol. 108, no. 1, pp. 1–30, 1959. 3. M. Yamaguchi, “Congenital choledochal cyst. Analysis of 1,433 patients in the Japanese literature,” American Journal of Surgery, vol. 140, no. 5, pp. 653–657, 1980. 4. T. Miyano and A. Yamataka, “Choledochal cysts,” Current Opinion in Pediatrics, vol. 9, no. 3, pp. 283–288, 1997.

Todani classification of Choledochal cysts

Todani T, Watanabe Y, Toki A, et al. Classification of congenital biliary cystic disease: special reference to type Ic and IVA cysts with primary ductal stricture. J Hepatobiliary Pancreat Surg 2003;10:340-4.

Todani Classification of Choledochal cysts

Type I and IV-A cysts are the mc types and account for nearly 90% of cases. APBJ is seen in >90% of patients with type I and IV-A choledochal cysts [35]. The pancreas with type I and IV-A choledochal cysts has been demonstrated as an anatomical anomaly of the pancreas .

Ectopic Pancreas (pancreatic rests)• Ectopic (heterotopic) pancreas is described as a pancreatic tissue that lacks

anatomic or vascular continuity with the normal pancreas. • This incidence of this condition varies from 1% to 15%, depending on the

reported series. • Ectopic pancreas is mc(70%) located at the gastric antrum, proximal portion

of the duodenum or the jejunum. Rarely it can also be found in the ileum, colon, appendix, gallbladder or Meckel diverticulum. (1). • This anomaly is usually asymptomatic and occurs as an incidental finding on

gastroscopy, although complications such as ulceration, bleeding, intussusception and obstruction may develop. Rarely adenocarcinoma occuring in the ectopic pancreatic tissue may be seen (2).1. Yu J, Turner MA, Fulcher AS, Halvorsen RA. Congenital anomalies and normal variants of the pancreaticobiliary tract and the pancreas in adults: part 2, Pancreatic duct and pancreas. AJR Am J

Roentgenol. 2006;187:1544–1553. 2. Emerson L, Layfield LJ, Rohr LR, Dayton MT. Adenocarcinoma arising in association with gastric heterotopic pancreas: a case report and review of the literature. J Surg Oncol. 2004;87:53–57.

Ectopic Pancreas• At barium studies: A diagnostic feature is a central niche or

umbilication, representing the orifice of the rudimentary pancreatic duct, containing a small collection of barium, seen in up to 45% of cases (1).

• EUS has been used for accurate preoperative differentiation between GISTs and pancreatic rests,(2) and when necessary, endoscopic band ligation can safely resect the lesion(s) if symptoms are significant or histologic confirmation is needed.(3)

• Surgical resection is another option, but whether to remove ectopic pancreatic tissue that is found incidentally remains controversial.

1. Alexander LF. Congenital pancreatic anomalies, variants, and conditions. Radiol Clin North Am. 2012;50:487–498.2. Gheorghe C, Borca A, Gheorghe L. The role of EUS for accurate preoperative differential diagnosis between GIST and pancreatic rest. J Gastrointestin Liver Dis 2012; 21:442-3.3. Bain AJ, Owens DJ, Tang RS, et al. Pancreatic rest resection using band ligation snare polypectomy. Dig Dis Sci 2011; 56:1884-8.

Pancreatic Agenesis and Hypoplasia of the Dorsal Pancreas: congenital short pancreas• Total agenesis of the pancreas is extremely rare and is incompatible

with life. Hypoplasia (partial agenesis) results from the absence of the ventral or dorsal pancreatic anlage. • Mutations in PDX1 have been reported in humans with pancreatic

agenesis.(1)• Patients with dorsal pancreatic agenesis have an increased risk of DM

because most of the islet cells are located in the distal pancreas (2).

1. Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15:106-10.2. Lång K, Lasson A, Müller MF, Thorlacius H, Toth E, Olsson R. Dorsal agenesis of the pancreas - a rare cause of abdominal pain and insulin-dependent diabetes. Acta Radiol. 2012;53:2–4.

Congenital Cysts• Congenital cysts of the pancreas are rare and may be diagnosed at any age.• The cysts may be solitary or multiple, and are distinguished from pancreatic

pseudocysts by the presence of an epithelial lining. • The clinical presentation is variable, ranging from an incidental finding on an imaging

study to an abdominal mass, with or without vomiting, biliary obstruction, or acute paancreatitis.• Solitary pancreatic cysts are often located entirely within the pancreatic parenchyma

and may communicate with the pancreatic duct.(1) • Multiple pancreatic cysts :associated with anomalies and may be seen in systemic

disorders such as von Hippel-Landau syndrome, or PKD.(2)• Congenital pancreatic cysts are more often located in the body and tail of the

pancreas than in the head.1. Boulanger SC, Gosche JR. Congenital pancreatic cyst arising from occlusion of the pancreatic duct. Pediatr Surg Int 2007; 23:903-5.2. 131. Chahed J, Mekki M, Aloui S, et al. Congenital pancreatic cyst with Ivemark II syndrome: A rare case. J Pediatr Surg 2012; 47:e33-6.

Pancreaticobiliary Malunion• PBM is a congenital malformation in which a common channel for bile and pancreatic fluid is

formed owing to the absence of a septum between the ducts.• The abnormal union occurs outside the duodenal wall; thus,the influence of the sphincter of

Oddi is lost, allowing reflux of pancreatic exocrine secretions into the biliary system, and bile into the pancreatic duct.

• Affected patients at increased risk for pancreatitis, choledochal cysts, and neoplasms that manifest in adulthood.

• Bile duct dilation may or may not be present in cases of PBM. • A classification for PBM has been proposed by dividing it into 3 types:

1. a pb type, in which the pancreatic duct appears to join the bile duct;

2. a bp type, in which the insertion of the bile duct is into the pancreatic duct;

3. a Y type, in which there is a long common channel measuring greater than 15 mm in length.(1)

• Approximately 15% of children with recurrent pancreatitis have this disorder,(2)and choledochal cysts are almost universally associated with PBM (94% and 100% in 2 series).(3)

1. Guelrud M, Carr-Locke D, Fox V. ERCP in Pediatric Practice: Diagnosis and Treatment. Oxford: St. Louis, MO: Isis Medical Media, 1997.2. Guelrud M, Morera C, Rodriguez M, et al. Normal and anomalous pancreaticobiliary union in children and adolescents. Gastrointest Endosc 1999; 50:189-93.3. Wang H, Wu M, Lin C, et al. Pancreaticobiliary diseases associated with anomalous pancreaticobiliary ductal union. Gastrointest Endosc 1998; 48:184-9.

Accessory Pancreatic Lobe• The accessory pancreatic lobe, an extremely rare anomaly, is defined

as an accessory lobe of pancreatic tissue originating from the main pancreatic gland and containing an aberrant duct (1). • Recurrent acute pancreatitis is the most common (66%) clinical

manifestation of this anomaly. 1. Oeda S, Otsuka T, Akiyama T, Ario K, Masuda M, Taguchi S, et al. Recurrent acute pancreatitis caused by a gastric duplication cyst communicating with an aberrant pancreatic duct. Intern Med.

2010;49:1371–1375.

Variations of Pancreatic Contours• The head and neck portions of the pancreas may have lobulated

contours, mimicking a pancreatic tumor, peripancreatic metastatic tumor deposit or lymphadenopathy • The attenuation or signal intensity of the lobular pancreas is the same

as the normal pancreatic tissue in all phases, including unenhanced, arterial, pancreatic parenchymal and portal phases. This is the key point that helps to differentiate this condition from a pancreatic neoplasm (1).

1. Yu J, Turner MA, Fulcher AS, Halvorsen RA. Congenital anomalies and normal variants of the pancreaticobiliary tract and the pancreas in adults: part 2, Pancreatic duct and pancreas. AJR Am J Roentgenol. 2006;187:1544–1553.

Meandering main pancreatic duct(MMPD)• Meandering main pancreatic duct (MMPD) comprises of a reverse Z-

type and loop-type of pancreatic ducts.• These ductal variants are found in ERCP and MRCP studies..

1. Gonoi W, Akai H, Hagiwara K et-al. Meandering main pancreatic duct as a relevant factor to the onset of idiopathic recurrent acute pancreatitis. PLoS ONE. 2012;7 (5): e37652.

Increased incidence of MMPD has been reported in patients with idiopathic recurrent acute pancreatitis (40%) compared with in subjects from community population (2.2%) 1.

The thick line indicates the CBD, and the thin line indicates the main PD. MMPD is classified : normal type (A), examples of loop type (B1–2), and examples of reverse-Z type (C1–3).

Ansa pancreatica• It is a rare type of anatomical variation of the pancreatic duct. It is a

communication between the main pancreatic duct (of Wirsung) and the accessory pancreatic duct (of Santorini). • The ansa pancreatica has been considered as a predisposing factor in

patients with idiopathic acute pancreatitis .(1)• The ansa pancreatica arises as a branch duct from the main

pancreatic duct. It descends down initially, it then ascends upward forming a loop and finally it terminates at the minor papilla.

1. Mortelé KJ, Rocha TC, Streeter JL et-al. Multimodality imaging of pancreatic and biliary congenital anomalies. Radiographics. 2006;26 (3): 715-31.

Summary: Development of PancreasTwo outpouchings of the endodermal

lining of the duodenum

Dorsal Bud

• lower part of the head• uncinated process

• upper part of the head • neck • body & tail

• Week 7 to 20 - pancreatic hormones secretion increases, small amount maternal insulin• Week 10 - glucagon (alpha) differentiate first, somatostatin (delta), insulin (beta) cells differentiate, insulin

secretion begins• Week 15 - glucagon detectable in fetal plasma

Ventral Bud

End of slides