Anatomy, Histology, Embryology, and Developmental

Anomalies of the Pancreas

Dr Jagveer singh
DM Resident
Dept of Gastroenterology
Osmania General Hospital
 Headigns

1. Anatomy
2. Histology and ultrastructure
3. Development of pacreas
4. Developmental anomalies
 Anatomy of pancreas
The head of the pancreas is
on the right, lying within
the curvature of the
duodenum

The anterior surface of the

head of the pancreas is
adjacent to the pylorus,
the first part of the
duodenum, and the
transverse colon.

Posterior to the neck of the

pancreas lies the confluence of
the portal vein with the
The posterior surface abuts
superior mesenteric and splenic
the hilum and medial border
veins.
of the right kidney, the
inferior vena cava and the
Anteriorly it is covered in part
right renal vessels, the right
by the pylorus and peritoneum
gonadal vein, and the right
of the lesser sac.
crus of the diaphragm.

The uncinate process lies anterior to the

aorta and inferior vena cava and is
covered superiorly by the superior
mesenteric vessels that emerge below the
neck of the pancreas.
The tip of the tail is intraperitoneal lying between layers
of the splenorenal ligament.

The tail is relatively mobile, with its tip usually reaching

the hilum of the spleen.

It is retroperitoneal and held against the aorta by the

peritoneum of the lesser sac.

The anterior surface of the body is covered by peritoneum

of the omental bursa, which separates the stomach from
the pancreas.

Posterior to the body of the pancreas are the aorta, the

origin of the superior mesenteric artery, the left crus of the
diaphragm, the left kidney, the left adrenal gland, and the
splenic vein.

The midline part of the body overlies the lumbar spine,

which makes this area of the pancreas most vulnerable to
abdominal trauma.
  Approximately 70% of the general
population has a patent accessory duct (of
Santorini), which is also known as the minor
Duct.

 The accessory duct lies anterior to the

bile duct and drains into the minor papilla,
which lies proximal to the major papilla.

The main pancreatic duct (of Wirsung) begins

near the tail of the pancreas.

It courses left to right and is enlarged by

additional ducts.

At the level of the major papilla, the duct turns

horizontally to join in most cases with the bile
duct.

The duct of Wirsung and the common bile duct

empty into the duodenum obliquely via the
major papilla.

Upper limits of normal for the pancreatic duct

diameter in the head (5 mm), body (4 mm), and
The length of the common channel (when present) tail (3 mm) are generally accepted.
averages 4.5 mm, with a range of 1 to 12 mm.
Arterial supply
Venous drainage
Lymphatic drainage
Innervation
 Histology
Exocrine portion - Acinus (composed of acinar cells) and
- Pancreatic ductal system (composed of duct cells)

Endocrine portion - Consists of the islets of Langerhans

1. Acinar cells

 By light microscopy, acinar cells are tall pyramidal or columnar epithelial cells, with their
broad bases on a basal lamina and their apices converging on a central lumen.

 In the resting state, numerous eosinophilic zymogen granules fill the apical portion of the
cell.

 The most prominent feature of the acinar cell is the dense zymogen granules that are
concentrated in the apical pole.

 Tight junctions form a belt-like band around the apical end of the cell and are produced
by the apposition of the external membrane leaflets of neighboring cells. These junctions
prevent the reflux of secreted substances from the duct into the intercellular space.

 Gap junctions, which allow intercellular flow of small molecules, are distributed on the
lateral cellular membranes and are formed by the apposition of larger, disk-shaped
membrane plaques.
2. Duct cells-
 The duct cells have electron-lucent cytoplasm containing few cytoplasmic
organelles ( typically contain free ribosomes that are abundant in small, round
mitochondria).

 The prevalence of mitochondria is necessary for allowing the duct cells to carry out
their primary function of active ion transport.

 Acinar cells secrete small amounts of sodium chloride–rich fluid, the duct cells absorb
the chloride and actively secrete bicarbonate and water to provide the bulk of
pancreatic juice.

 Several enzymes and a multitude of ion channels within the duct cells orchestrate this
net bicarbonate and water secretion. They include carbonic anhydrase and the CFTR.

 Severe defects in CFTR cause pancreatic duct plugging during pancreatic development
and intrauterine destruction of the exocrine pancreas, with formation of cysts and
fibrosis; hence the name coined for the disorder is “cystic fibrosis”.
3. Pancreatic stellate cell (PSC)-

The collagen fibers and other extracellular matrix proteins are secreted by a less
common resident cell type, the pancreatic stellate cell (PSC).

 In the quiescent state, the PSC has baseline functions of maintaining the pancreatic
microarchitecture and even facilitating acinar cell secretion.

 In its activated state during pancreatic injury and inflammation, however, it transforms
into myofibroblast-like cells that help replenish the matrix necessary for recovery or it
may even serve as a facultative progenitor cell.

 The PSC also participates in providing an abundant stromal environment around

a pancreatic adenocarcinoma, which can limit the effect of cancer therapies.

 Finally, PSCs can also accompany cancer cells to metastatic sites to facilitate cancer
progression.
4. Islets of Langerhans-

Each islet is about 0.2 mm in diameter, much larger than an acinus, and separated
from the surrounding exocrine tissue by fine connective tissue fibers that are continuous
with those of the exocrine gland.

Each islet is penetrated by a rich network of capillaries lined by a fenestrated

endothelium.

 The capillaries are arranged in a portal system that conveys blood from the islets to
the acinar cells.

This islet-acinar portal axis consists of afferent

arterioles that enter the islet, form a capillary
glomerulus, and leave the islet as efferent capillaries
passing into the exocrine tissue this portal system
permits the local action of islet hormones, especially
insulin, on the exocrine pancreas.
 DEVELOPMENT OF THE PANCREAS
Embryonic and Fetal Development

 The pancreas arises from posterior foregut endoderm.

At about 4 weeks of gestation, At about 6 weeks the ventral By about 7 weeks, fusion of the dorsal At birth, the pancreas is a single
dorsal and ventral buds are pancreas extends toward the larger and ventral pancreas has occurred and organ, and ductular
formed from the foregut. dorsal pancreas. ductular anastomosis is beginning. anastomosis is complete.
Dorsal pancreas forms-
- the tail, body, and superior portion of the pancreatic head
- the distal portion of the main pancreatic duct of Wirsung (dorsal duct)
- the entire minor accessory duct (of Santorini).

Ventral pancreas forms-

- the uncinate process and the inferior part of the head.
- the proximal portion of the main pancreatic duct of Wirsung (ventral duct)

Notably, all 3 functionally distinct parenchymal cell types—acinar, duct, and islet
cells—differentiate from a common pancreatic progenitor lineage.

Classic studies by Rutter and colleagues have divided pancreatic differentiation into 2
distinct phases.

1. Primary transition - Defined as the conversion of predifferentiated cells to a protodifferentiated

state in which low levels of pancreas-specific proteins are present.
2. Secondary transition - Marked by a dramatic rise in pancreatic cell number and pancreas-specific
protein synthesis, as well as an acceleration in both exocrine and endocrine
differentiation.
Although the dorsal pancreas arises before the ventral, both appear to
exhibit simultaneous exocrine differentiation according to the 2 phases.

In the ontogeny of endocrine cells, glucagon-positive alpha cells initially

predominate. After the secondary transition, however, insulin-positive beta
cells outnumber all other endocrine cell types.

Transcription Factors and Extrinsic Signals

1. Pancreatic and duodenal homeobox 1 (Pdx1)-

[insulin promoter factor 1 (Ipf1) or islet/duodenum homeobox 1 (Idx1)]

 Pdx1 is the earliest pancreas-specific transcription factor, detected at 5

weeks of development, before bud formation.Thus Pdx1 is used as a marker of
early pancreatic progenitors.

Deletion of Pdx1 in mice and humans leads to pancreatic agenesis.

During adulthood, Pdx1 expression becomes largely confined to the beta cells,
where it maintains beta cell identity and binds to and activates the insulin
promoter.

Thus Pdx1 is required for proper pancreas development as well as beta cell
function.

2. Pancreas-specific transcription factor 1 (Ptf1)-

The alpha subunit of pancreas-specific transcription factor 1 (Ptf1α) (also

known as p48) functions as part of a trimeric protein complex in the regulation
of exocrine gene expression.

 It is initially coexpressed with Pdx1 and supports the specification of all 3

pancreatic cell type precursors, but later becomes confined to acinar cells.

In a human pedigree, a truncating single nucleotide mutation in Ptf1α led to

pancreatic and cerebellar agenesis.
3. Human homeobox gene 9 (Hlxb9)-
Motor neuron and pancreas homeobox 1 (Mnx1)

 Expressed as early as the eighth somite stage in the notochord and pancreatic
endoderm.

Hlxb9-deficient mice have complete agenesis of the dorsal pancreas, but only minimal
defects of the ventral portion.

Post development, Hlxb9 expression within the pancreas is maintained only in beta cells.

4. Neurogenin3 (Ngn3)-

 Ngn3 expression is down regulated after endocrine differentiation initiates.

Mice completely deficient in Ngn3 lack pancreatic endocrine cells.

 In comparison, patients with a hypomorphic mutation in Ngn3 develop a

profound congenital diarrhea due to intestinal loss of Ngn3 causing absence of
enteroendocrine cells, but they do not succumb to neonatal diabetes.
4. Gata4 and Gata6-

Mutations in GATA4 or GATA6 will lead to pancreatic agenesis in humans.

More recent studies have demonstrated the role of Gata6 in functional beta cell
differentiation.

Early in embryonic development, the notochord is in direct contact with the dorsal
pancreas and controls its development.

 Removal of the notochord prevents expression of pancreatic exocrine and endocrine

markers from the dorsal bud, whereas co-culture of notochord with endoderm initiates and
maintains pancreatic gene expression.

 Signals from the notochord permit dorsal pancreas specification by suppressing the
expression of anti–pancreatic factor Shh, which enables the expression of PDX1.

In contrast, development of the ventral pancreas is dependent upon withdrawal

of FGF signaling from adjacent cardiac mesenchyme.

At a later period, endothelial tissue such as dorsal aorta and the vitelline veins, influence
pancreas development.
Growth factors secreted by pancreatic mesenchymal cells are also important
to development of the endodermal primordium.

FGF-10- shifts the growth state of pancreatic progenitors from differentiation

to proliferation.

Stromal components also influence the pancreas during development.

For example, neural crest cells that migrate into the pancreas influence beta
cell number.
Reemergence of Embryonic Factors During Pancreatic
Injury

1. During recovery from pancreatic injury (e.g., after a bout of acute pancreatitis),

Several embryonic transcription factors reemerge from within the remaining acinar cells to
form new ductular complexes called acinar-to-ductal metaplasia.

They precede the onset of recovery and regeneration of the pancreas.

2. Pancreatic ductal adenocarcinoma and its noninvasive precursor lesion( PIN)

Develop from a similar process of acinar-to-ductal metaplasia, by forcing the transcription of

embryonic genes such as Notch (in the setting of active pancreatic Kras mutations), or by
offsetting pathways such as β-catenin.
 DEVELOPMENTAL ANOMALIES
1. Annular Pancreas
 A portion of the pancreas forms a thin band around the preampullary portion of the
duodenum, leading to complete or partial bowel obstruction.

 Between 1 in 1000 and 3 in 20,000.

 Microduplication on chromosome 6q24.2 encompassing the utrophin gene (UTRN).

 More common in patients with other congenital anomalies such as trisomy 21, cardiac
defects, malrotation, duodenal atresia, genitourinary anomalies, and tracheoesophageal
fistula.

 Often diagnosed prenatally or during infancy,

(A second peak of detection occurs in the fourth through seventh decades of life)
Pediatric patients present with –

- Nonbilious emesis and

- Feeding intolerance.

Adults present with -

- Abdominal pain,
- Pancreatitis,
- Evidence of biliary obstruction,
- Nausea and vomiting
- Bloating.
Diagnosis -
In children - On abdominal radiographs, US, or upper GI series.
In adults - CT scan, MRCP, or ERCP

A film from a barium contrast upper GI series demonstrating a Pancreatic tissue that surrounds almost completely the
mid-duodenal stricture (arrow) with proximal dilatation, findings
compatible with an annular pancreas. second part of duodenum 
Duodenoduodenostomy appears to be an effective surgical treatment for bowel
obstruction in these cases and is considered the treatment of choice in children and in
some adult patients.

Following surgical repair, there appears to be an increased risk of acute and recurrent
pancreatitis into adulthood.

 The risk of pancreaticobiliary neoplasia is significantly increased in adults with annular

pancreas, and an association with duodenal carcinoma has been reported as well.
2. Pancreas Divisum
Pancreas Divisum results from a failure of the dorsal and ventral pancreatic ducts to fuse during
embryogenesis, resulting in the majority of exocrine secretions draining from the relatively
smaller dorsal duct of Santorini and minor papilla.

 Detected in 5% to 10% of the population in autopsy studies and in a similar percentage of

patients undergoing ERCP.

There are 3 types of pancreas divisum identified.

1. Classic or complete divisum, in which there is complete failure of fusion between the dorsal
duct (Santorini) and ventral duct (Wirsung), occurs in 71% of patients with PD.

2. Dominant type or dorsal duct pancreas divisum, in which there is absence of the ventral duct,
occurs in 6% of patients with divisum.

3. Incomplete pancreas divisum, in which there remains a small communication between the
ventral and dorsal ducts, occurs in 23% of patients.
Pancreas divisum can be diagnosed by ERCP, EUS, abdominal CT, or MRCP.

Although ERCP is considered the gold standard in diagnosing PD, secretin-enhanced

MRCP has emerged as a potential tool, with a recent study showing a sensitivity of
73.3% and a specificity of 96.8%.
3. Ectopic Pancreatic Tissue

 Ectopic (heterotopic) pancreatic tissue, often referred to as a pancreatic rest,

occurs in 0.6% to 13.7% of the population according to autopsy material.

 Lacks a physical connection to the pancreas and has an independent blood

supply

 Pancreatic rests are most commonly found in the stomach , duodenum,

proximal jejunum, and ileum.

 Less frequently, it can be found in a Meckel diverticula (6%), or even the

umbilicus, bile duct, gall bladder, splenic hilum, colon, or appendix.

 Although rarely clinically significant, ectopic pancreatic tissue has resulted in

pancreatitis, ulceration and bleeding, intussusception, and m alignancy.
On imaging, pancreatic rests appear as a smooth, broad-based submucosal mass
with about 45% having a classic central umbilication.

Endoscopic view of a pancreatic rest in the gastric antrumof an 8-year-old boy.

Note the central umbilication.
 EUS has been used for accurate preoperative differentiation between GISTs and
pancreatic rests, and typical features on EUS include antral location, mucosal
dimple, 3 to 4 layers, and lesional duct.

Treatment-
1. Endoscopic band ligation with snare polypectomy
2. Surgical resection is another option,
(whether to remove ectopic pancreatic tissue that is found incidentally remains
controversial rare malignant potential)
4. Pancreatic Agenesis

 Pancreatic agenesis is a rare condition that can be complete or Partial.

 Mutations in GATA6 , PDX1 and PTF1A have been reported in humans with pancreatic agenesis.

 Complete pancreatic agenesis is mostly fatal because infants are stricken with diabetes and
malabsorption, as well as intrauterine growth retardation due to lack of insulin, an important
intrauterine growth factor.

 Partial pancreatic agenesis, or agenesis of the dorsal pancreas, may be less significant clinically
owing to the presence of some functioning pancreatic tissue.

 Also known as congenital short pancreas, agenesis of the dorsal pancreas has been associated
with polysplenia and intestinal malrotation, renal anomalies, and heterotaxy.

 Pancreatic agenesis should be suspected based on clinical findings and can be confirmed with
MRI.
5. Congenital Cysts

 Rare and may be diagnosed at any age, even prenatally by routine US.

 Solitary or multiple,

 Distinguished from pancreatic fluid collections by the presence of an epithelial lining.

 They are thought to form due to anomalies in the development of the pancreatic ductal
system.

 Typically as permanent ducts develop, embryonic ducts regress; however, when the
embryonic ducts persist, they can become obstructed and fluid filled resulting in
congenital cysts.

 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
pancreatitis.
CT scan of the abdomen, with contrast, showing a bi-lobed soft tissue density lesion (arrows), inseparable
from the pancreas
• Solitary pancreatic cysts are often enteric duplications that may be located entirely within the
pancreatic parenchyma and may communicate with the pancreatic duct.

• Multiple pancreatic cysts tend to occur in patients with associated anomalies and may be
seen in systemic disorders such as von Hippel- Landau syndrome, Ivemark II syndrome, or
polycystic kidney.

• Disease most presented before the age of 2 years, and associated anomalies were found in
30% of cases.

• Congenital pancreatic cysts are more often located in the body and tail (62%) of the pancreas
than in the head (32%).

Treatment-

1. Surgical therapy consists of total excision when possible.

2. Cysts in the pancreatic head may be addressed using endoscopic or surgical drainage
procedures, when necessary.
6.Pancreaticobiliary Malunion(PBM)

 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.

 Billiary stasis, intermixed with refluxed pancreatic secretions, places affected

patients at increased risk for biliary neoplasms that manifest in adulthood.

 Biliary neoplasms are most frequently seen in the gallbladder.

 Biliary reflux into the pancreas increases risk for acute pancreatitis.
Classification for PBM
1. pb type :- The pancreatic duct appears to join the bile duct.
2. bp type:- The insertion of the bile duct is into the pancreatic duct.
3. Y type :- A long common channel measuring greater than 15 mm in
length.

 Approximately 15% of children with recurrent pancreatitis have this

disorder and choledochal cysts are almost universally associated with
PBM.

 Pancreaticobiliary malunion is diagnosed by traditional cholangiography

(ERCP, intraoperative cholangiography, or percutaneous cholangiography),
MRCP, or helical CT scan.

 Traditional cholangiography remains the gold standard.

Malunions were seen in 62.5% of adults with gallbladder cancer,in 50% of patients with
gallbladder adenomyomatosis, and in 33.3% of patients with bile duct cancer.

The incidence of biliary cancer is 15 to 20 years earlier in patients with PBM in

comparison to patients without PBM.

Given the cancer risk for the patient with this anomaly, consideration for
cholecystectomy, resection of the bile duct, and hepaticojejunostomy may be advised.
Thank you