Introduction

The pancreas is a retroperitoneal gland that facilitates digestion and metabolism. The pancreatic head and uncinate process adjoin the duodenal curvature; its neck positioned posterior to the pylorus and anterior to the portal venous confluence. The pancreatic body lies posterior to the stomach; the tail enters the peritoneum near the splenic hilum. Unique for a foregut organ, the pancreas receives blood supply from branches of both the celiac trunk and superior mesenteric artery. Autonomic nerves forming the pancreatic plexus arise from the celiac ganglia, which coordinate sympathetic and parasympathetic synapses from the greater splanchnic and vagus nerves, respectively. Pancreatic tissue is largely composed of acini which secrete digestive proenzymes into a system of ducts that coalesce to form the main and accessory pancreatic ducts. Most exocrine secretions drain into the second part of the duodenum at the level of the major duodenal papilla where they aid in digestion through proteolysis and lipolysis.

There is dispersed endocrine tissue throughout the pancreatic parenchyma in functional units known as islets of Langerhans. These conglomerates secrete a host of hormones directly into the circulation, notably insulin, glucagon, and somatostatin. Derived from the foregut, the pancreas has endodermal origins and undergoes nuanced development in utero to become an organ with dual endocrine and exocrine functions. This embryologic review focuses on human pancreatic morphogenesis, physiologic maturation, and relevant congenital malformations in a clinical context.[1][2]

Development

Two endodermal buds give rise to primitive pancreatic tissue during the fifth embryonic week. A small ventral bud projects from the hepatic diverticulum and becomes the pancreatic head and uncinate process. A larger dorsal bud originates from foregut endoderm and becomes the pancreatic neck, body, and tail. In the sixth week, the dorsal bud grows laterally left until it enters the dorsal mesentery where the pancreatic tail is intraperitoneal. Developmental forces in the embryonic gut reposition the ventral bud and allow for union with the dorsal bud by the seventh week in utero. As the hepatic diverticulum and foregut tube grow, the ventral bud and common bile duct are pulled counter-clockwise around the primitive duodenum into a dorsal position. There, the pancreatic buds unite as one organ and integrate with the common bile duct and duodenum. By approximately gestational day 33, the dorsal bud develops a microscopic luminal network that becomes the acinar, ductal system responsible for handling exocrine secretions. Although the dorsal pancreas forms the bulk of the organ, its associated duct becomes the accessory pancreatic duct of Santorini. Conversely, the duct from the smaller ventral pancreas becomes the main pancreatic duct of Wirsung. Both ducts fuse in the seventh intrauterine week. After birth, exocrine juices preferentially flow through the main pancreatic duct because the portion of the accessory duct distal to its union with the main duct becomes stenotic or obliterates in most humans.[3][4]

During embryogenesis, the nascent pancreatic endoderm is pluripotent. All pancreatic cells, endocrine and exocrine, are derived from the endodermal buds. Insulin secreted from fetal islets is detectable during the first trimester, but the majority of fetal glucose regulation occurs through active transport of maternal glucose at the placenta. Nonetheless, transplantation studies in murine models have demonstrated that an eight-week embryonic pancreas is capable of full differentiation and produces functioning beta cells capable of controlling hyperglycemia. By the tenth week post-conception, the primitive islets become vascularized. By the thirteenth week post-conception, a full complement of alpha, beta, and delta cells are present in the islets.[5]

A host of genetic and molecular factors drive the morphologic development in the pancreas. Comprehensive discussions appear in Jennings et al. and Larson et al. where they present detailed, up-to-date evidence.[6][7] The pancreatic buds are positive for SRY-box transcription factors SOX-9, PDX1, and GATA4, all of which facilitate parenchymal growth. Expression of transcription factor neurogenin 3 (Neurog3) surges at the end of the first trimester and serves as the trigger for pancreatic progenitor cells to undergo endocrine differentiation.[8] Another hallmark of foregut development is the inhibition of sonic hedgehog gene products (SHH).[9]

Testing

An international committee known as the INSPPIRE group published updated clinical practice guidelines in 2017 for the diagnostic evaluation of children with recurrent acute pancreatitis and chronic pancreatitis.[10] This population has a higher likelihood for harboring embryologic malformations and therefore merits advanced imaging, endoscopic techniques, and specialized molecular assays.

Initial laboratory testing should include hepatic function screens with aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total bilirubin, fasting lipid profile, and serum calcium. The transaminases help diagnose obstructive and chronic metabolic hepatobiliary processes. Hypertriglyceridemia (greater than 1000 mg/dL) is classically associated with pancreatitis. Hypercalcemia can trigger pancreatitis as well and should undergo an evaluation to rule out primary hyperparathyroidism.

The index presentation merits advanced imaging in children. The INSPPIRE group advocates for magnetic resonance cholangiopancreatography (MRCP) over computed tomography (CT) imaging. MCRP poses no risk of radiation exposure to the child, provides a finer spatial definition, and can digitally reconstruct the pancreaticobiliary ductal system. Some institutions can conduct secretin-enhanced MRCP, which can help evaluate the acinar ducts. Endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound (EUS) are useful imaging modalities but should be secondary to MRCP for initial diagnosis. The techniques for ERCP and EUS are technically more invasive. ERCP also utilizes fluoroscopy which uses ionizing radiation with X-ray.[11]

Ruling out cystic fibrosis (CF) and other genetic causes is crucial in the workup of recurrent pediatric pancreatitis.[12] Even with negative newborn CF screening, this population requires more definitive evaluation with a chloride sweat test. Formal genetic testing for a broader spectrum of known CF mutations not included in routine newborn screening is possible. Other hereditary causes of pancreatitis in children have been identified with PRSS1 (serine protease 1, trypsinogen), SPINK1 (serine peptidase inhibitor, Kazal type 1), and CTRC (chymotrypsin C) genes. Molecular assays are available to test for mutations in these genes and correlate with the clinical picture.[13]

Pathophysiology

Developmental anomalies of the pancreas can cause obstructive jaundice, pancreatitis, bilious emesis, failure to thrive, and more. The physiologic underpinnings of these clinical presentations will be explored here. While more than one mechanism can cause these presentations, the pathophysiology described in this section is relevant for patients with embryologic malformations of the pancreas. These concepts are broad; specific diagnoses will be discussed in the following section.

Anatomical misconfigurations can impinge the common bile duct, leading to biliary tree obstruction and stasis. Increased intraluminal pressure eventually overwhelms biliary canaliculi in the liver. Intercellular junctions between hepatocytes leak, allowing bile to infiltrate the hepatocyte cords. Bile fills the perisinusoidal space of Disse and subsequently diffuses into the hepatic sinusoid system. From there, it drains into hepatic veins, the inferior vena cava, and circulates systemically. Biliary compounds deposit and accumulate in capillary beds of the skin and mucosa, causing the yellow skin tone known as jaundice. Another complication of prolonged bile duct stasis is microbial growth and ascending cholangitis, generally with gram-negative enteric flora.[14]

Similar to the biliary tree, the pancreatic duct system can also become obstructed. Abnormal ductal architecture or insufficient sphincter function at the level of the duodenum can cause stasis of exocrine secretions. Increasing intraluminal pressure then promotes the activation of digestive proenzymes within the pancreatic ductal system. Parenchymal inflammation ensues, triggering positive-feedback cytokine cascades that further exacerbate pancreatitis. Exocrine enzymes, notably alpha-amylase and lipase, spill over into the circulation. Lipase itself is a sensitive and specific serum marker for diagnosing pancreatitis.[15]

Pancreatic tissue can anomalously encircle or ectopically implant along the alimentary canal. In these cases, encroaching tissue can cause varying degrees of sticture or, in rare scenarios, small bowel obstruction. Owing to its regional proximity, the duodenum is the most commonly affected site with the highest potential for symptomatic stricture development. Bile entering into the second part of the duodenum encounters resistance distally at the site of stricture or obstruction. Proximal backflow through the pylorus causes bilious emesis, a hallmark of duodenal (or jejunal) obstruction. While other causes of bilious emesis are far more common than pancreatic etiologies, the pathophysiology behind the clinical presentation is similar.[16]

Failure to thrive predominantly occurs in neonates and children with metabolic and malabsorptive conditions. Congenital pancreatic disease is among the most critical causes of malabsorptive etiology. Pancreatic peptidases, lipases, and amylases catabolize large nutrients into small peptides, fatty acids, and oligosaccharides that are readily absorbable. Children with obstructive pathology or exocrine insufficiency cannot catabolize nutrients to forms that are suitable for handling by the intestinal brush border. While patients may have an appropriate nutritional intake, they become malnourished by this mechanism.[17]

Clinical Significance

Disorders of pancreatic embryology can remain clinically silent or manifest with obstructive pancreaticobiliary symptomatology outlined in the previous section. Although initial presentation can occur at any age, recurrent or chronic pancreatitis during early childhood merits diagnostic workup to search for anatomical anomalies. Guidelines from the INSPPIRE group provided a framework diagnosing underlying causes of pancreatitis in children. Advanced imaging with MRCP, ERCP, and EUS can reveal embryologic etiologies. Depending on the clinical severity, management strategies can be conservative or employ interventional or operative therapy. The majority of acute pancreatitis cases in children resolve with intravenous hydration using isotonic crystalloids followed by dextrose-containing maintenance fluids. Fasting was traditionally believed to rest the pancreas, but newer studies have demonstrated outcome benefits with dietary advancement as early as tolerated.[18] In severe cases, nutrition remains an important goal that can be met with enteral tube feeds. Readmissions for pancreatitis should raise the index of suspicion for underlying embryologic defects. In addition to imaging studies and endoscopy, there are genetic panels and laboratory assays available (see ‘Testing’ section above) to screen for inheritable causes of pancreatitis and failure to thrive in children. The clinical conditions presented here are the most relevant to classic pancreatic embryogenesis. Nonetheless, many cases remain idiopathic and do not fit into one of the following entities.

Pancreas divisum (PD) is the most commonly occurring congenital malformation of the pancreas, with an estimated prevalence of roughly 10 percent in humans. The widespread occurrence of PD has led many clinicians to consider it a normal anatomical variation. The popular textbook Current Surgical Therapy, edited by pancreatic surgeon John Cameron, draws the interesting comparison that PD is roughly as common as left-handedness. Divisum occurs when the primitive ducts of the ventral and dorsal pancreas do not fuse.[19] As a result, the larger dorsal pancreas drains through the accessory pancreatic duct of Santorini into the second part of the duodenum at the minor duodenal papilla. Most humans have a nonfunctional or absent accessory duct or sphincter of Helly at the minor papilla, but those with divisum rely on this anatomy for primary drainage of exocrine secretions. Drainage of bile and some pancreatic secretions from the head and uncinate process through the major duodenal papilla continues because the common bile duct shares origins with the ventral pancreas.

Most people with PD are asymptomatic, but those who come to clinical attention often present with acute recurrent pancreatitis or chronic pancreatitis. This disease may be a reflection of intraductal stasis of pancreatic secretions secondary to poor sphincter functionality at the minor duodenal papilla. Some patients develop an identifiable “Santorinicele” on ERCP or MRCP caused by increased accessory duct pressure.[20] These patients are often amenable to minor papillotomy that may undergo reinforcement with ductal stenting.

Hafezi et al. published a systematic review in 2017 on the management of pancreas divisum and examined endoscopic minor papillotomy alongside operative intervention.[21] With success rates approaching 90%, there is no question that ERCP-guided minor papillotomy (with or without stenting) is the initial treatment of choice for symptomatic patients. Even so, several patients fail to improve and require re-intervention. At this juncture, it is acceptable to consider operative intervention. Discussion on surgical approaches sparked another paper by Ferri et al. that grouped the available operations by whether they are decompressive or demolitive and then discussed the merits and disadvantages of each.[22]

Before endoscopy, the surgical mainstay for symptomatic PD and chronic pancreatitis was transduodenal sphincteroplasty. The procedure was originally described in a 1952 five-patient case series of relapsing-remitting pancreatitis where sphincteroplasty resolved pain and promoted weight restoration.[23] While the procedure remained popular through most of the late twentieth century, the literature now offers little discussion on sphincteroplasty except in a few case series of patients with soft pancreas who failed to improve from multiple endoscopic procedures.[24][25]

Additional operations were developed and modified to drain the pancreas in severe cases of chronic pancreatitis. The Puestow procedure effectively relieves ductal obstruction or dilatation by creating a longitudinal side-to-side pancreaticojejunostomy.[26] Over half of pediatric patients experience lasting improvements, and there are reported 90% success rates for chronic pancreatitis secondary to PD.[27] The most common reason for failure to improve postoperatively is inadequate pancreatic head drainage. Frey devised an operation in 1987 that combined pancreaticojejunostomy (Puestow procedure) with circumscribed pancreatic head resection (a modified Beger procedure), effectively decompressing the entire pancreatic ductal system while still preserving the duodenum.[28] A 2013 case series included six patients with symptomatic PD who benefitted from the Frey procedure.[29] The authors also noted a decreased use or cessation of opioids postoperatively in previously opioid-dependent patients. Another modification underwent development at the University of Bern where they performed the technique for duodenum-sparing pancreatic head resection with anastomosis to a Roux-en-Y jejunal loop rather than a longitudinal pancreaticojejunostomy (as in the Frey procedure).[30] Lastly, for patients with chronic pancreatitis complicated by fibrosis, there is some consensus that pylorus-preserving pancreaticoduodenectomy (“mini-Whipple”) may be appropriate.

Anomalous pancreaticobiliary junction (APBJ) is a rare ductal anomaly in which the main pancreatic duct and common bile duct converge in the head of the pancreas before entering the duodenum. Normally the ducts join and form the hepatopancreatic ampulla of Vater within the duodenal wall. Without this support, the muscularis externa that normally forms the sphincter of Oddi cannot prevent reflux into the pancreas and biliary tree. In fact, patients with APBJ often have malformed sphincter of Oddi muscles wrapped around the common channel within the pancreatic head. Diagnosis can be made with ERCP demonstrating the two ducts uniting in the pancreatic head more than 15 millimeters from the duodenal papilla. Choledochal cysts frequently occur in association with APBJ.[31]

Japanese investigators assembled the first clinical practice guidelines for patients with pancreaticobiliary maljunction in 2012.[32] As the first committee to address this condition, they defined it as an anomalous union occurring outside the duodenal wall, leading to reflux and accumulation of bile and pancreatic secretions. They distinguished between patients who develop common bile duct dilation and those who do not. The pathogenesis of this condition remains unclear, but they agreed on a hypothesis where the ventral pancreatic bud becomes dysplastic during embryogenesis. The mechanism for common bile duct dilatation is likely related to dysregulation between development in the duodenum and biliary tree. Normal duodenal development involves luminal obliteration and subsequent recanalization before birth. The biliary tree in patients with APBJ likely continues to receive growth signals during the period before the duodenum recanalizes.

The reflux seen in APBJ can be pancreaticobiliary or biliopancreatic. Pancreaticobiliary reflux is far more common because pressures in the common bile duct are generally lower than the pancreatic duct, creating a pressure gradient which allows pancreatic enzymes to enter the bile. Reflux can cause gallbladder and biliary amylase levels to rise over 100000 IU/L, driving inflammation that is believed to convey higher risk for biliary tree malignancies, notably gallbladder carcinoma and cholangiocarcinoma.[33] Interestingly, the Japanese committee noted higher rates of biliary cancers in APBJ patients without bile duct dilatation than those with dilatation (42.4% vs. 21.6%).

Symptomatic and asymptomatic patients at least six-months-old are candidates for biliary diversion operations. For patients with ductal dilatation, high resection of the choledochal cyst near the convergence of the left and right hepatic ducts and subsequent hepaticojejunostomy with roux-en-Y anastomosis is a common approach. Hepaticoduodenostomy has fallen out of preference due to a concern of continued reflux of duodenal contents into the native pancreaticobiliary ducts.[34] For patients without ductal dilatation, the extent of biliary tree resection is debated. Nevertheless, high rates of gallbladder carcinoma make prophylactic cholecystectomy an essential priority for all APBJ patients.

Annular pancreas occurs when pancreatic tissue circumferentially covers the second part of the duodenum. During embryogenesis, growth of the hepatic bud normally lifts the ventral pancreas away from the developing foregut tube. If ventral bud tissue remains adherent to the growing duodenum, an annular pancreas can result.[19] Autopsy and radiologic imaging studies estimate the incidence of annular pancreas at 1 in 1000 to 1 in 6000. Roughly half of all patients with annular pancreas present with obstructive symptomatology as neonates. Imaging studies demonstrate the classic “double bubble” sign. Over two-thirds of neonates with annular pancreas have coexisting conditions such as tracheoesophageal fistulas and congenital heart defects, some of which occur in association with aneuploidies like Down syndrome.[35]

Gromski and colleagues from Indiana University recently published their experience of 46 patients with annular pancreas over a twenty-two year period.[36] Nearly half of patients in their series had coexisting pancreas divisum. Roughly one-third of their patients had findings of chronic pancreatitis. They made the diagnosis of annular pancreas when they could visualize a pancreatic duct wrapping around the duodenum on ERCP. The annular ductal branch originated from the ventral (main) pancreatic duct in 88% of those who received a formal pancreatogram. They also noted duodenal narrowing in 88% of cases, but only 5% had a duodenal stricture severe enough to restrict the flow of gastric chyme. Pancreaticobiliary neoplasms occur at higher rates in patients with an annular pancreas. Seven patients from this series were diagnosed with malignancies following biopsy on index ERCP. Nonetheless, causality between annular pancreas and neoplasm cannot be determined from these studies because many patients were sent to large referral centers once malignancy was suspected.

Circumportal pancreas is an annular variant that occurs when pancreatic tissue envelops the portal vein or its immediate tributaries, the superior mesenteric and splenic veins. This anomaly is believed to arise when the developing uncinate process (of the ventral bud) fuses with pancreatic body tissue (of the dorsal bud), thereby entrapping the portal venous confluence. The annular segment classification is by its relation to the splenic vein—suprasplenic, infrasplenic, or combined subtypes, with a further description describing whether the main pancreatic duct courses: anteportal or retroportal.[37][38][39]

Circumportal pancreas significantly increases the technical difficulty of pancreatic head resection. Moreover, this anatomic variant is often an intraoperative discovery not revealed by preoperative imaging. Resection of the retroportal annular segment requires intensive dissection and can complicate the creation of a pancreaticojejunal anastomosis. Postoperative pancreatic fistula is common with circumportal pancreas, approaching 70% in some studies, compared to 3 to 45% with the expected anatomy. Peritoneal drain amylase levels can be followed to monitor for fistula. Surgeons writing from Germany in 2017 described six cases of circumportal pancreas encountered intraoperatively. They advocated for wider resection—one-centimeter distally towards the tail—to decrease the incidence of pancreatic fistula.[40]

Congenital pancreatic hypoplasia is associated with some syndromes. Exocrine pancreatic insufficiency and severe pancreatitis starting in utero can present in Johanson-Blizzard syndrome, an autosomal recessive genetic disorder caused by inactivating mutations in UBR1 (E3 ubiquitin ligase).[41] The enzyme ubiquitin ligase is essential for tagging aged intracellular proteins so they can undergo degradation. Mutations in UBR1 greatly reduce enzymatic function, causing proteins to accumulate at toxic levels inside cells until they ultimately die through apoptosis.[42] Unfortunately, pancreatic acinar cells require some of the highest ubiquitin ligase levels in the body to maintain normal exocrine function. Hypoplasia and exocrine insufficiency may also present in some cases of Alagille syndrome, an autosomal dominant genetic disorder caused by anomalous Notch signaling.[43]

Dorsal pancreatic agenesis (DPA) is an entity in which the bulk of the pancreas—wholly derived from the dorsal bud—is congenitally absent.[44] Fewer than sixty DPA cases have been reported in world literature since Heiberg’s first 1911 German description, Ein fall von fehlender cauda pancreatis (Case of the missing caudal pancreas).[45] In the modern molecular era, DPA has associations with three gene mutations. The first case report with molecular analysis appeared in 1997 in a neonate with a frameshift mutation in PDX1 (pancreatic and duodenal homeobox 1), one of the earliest markers expressed on pancreatic endodermal buds. Researchers have identified nonsense mutations in PTF1A (pancreas associated transcription factor 1a) in a few cases of concomitant pancreatic and cerebellar agenesis. Within the past decade, haploinsufficiency in GATA6 (GATA-binding protein 6), a conserved zinc-finger DNA-binding motif, is now believed to be the most common molecular cause of pancreatic agenesis and hypoplasia. Many neonates born with GATA6 mutations also have structural cardiac defects.[6]

Ectopic pancreas can be discovered intraoperatively or during the pathologic examination of excised surgical specimens. Although rare, this entity was first reported in 1727 by Shulz as aberrant pancreatic tissue located at the apex of a jejunal diverticulum. Today, there are four described subtypes based on histological examination. The deranged tissue can have normal parenchymal architecture (type 1), ductal structures only (type 2), glandular acini only (type 3), or endocrine islets only (type 4). Modern molecular studies have demonstrated that defective Notch signaling pathways and mutations in Neurog3 (neurogenin 3) are responsible for many cases. Most clinical literature takes form as case reports with heterotopic tissue documented in the stomach,[46] duodenum,[47] jejunum,[48] gallbladder,[49] mediastinum,[50] and more. In a larger nineteen-patient series of ectopic pancreas, roughly one-third had a history of generalized abdominal pain or gastrointestinal bleeding. They also noted unusually high rates of neoplastic potential in ectopic pancreas tissue. Specimens from three patients had concerning glandular atypia and one patient with ectopic pancreas was diagnosed with pancreatic adenocarcinoma.[51]

Congenital pancreatic cysts are benign fluid collections that result from anomalous development of the acinar ductal network or ductal obstruction.[52] These lesions generally have a lining of simple cuboidal epithelia that resemble the normal ducts. They are often sporadic and seen as incidental findings but can be viewed as hallmark components of genetic diseases like von Hippel-Lindau disease and autosomal-dominant polycystic kidney disease. Although exceedingly rare, solitary cysts seem to have a predilection for the pancreatic tail.[53] Cysts in the aforementioned inherited diseases are often numerous and consume the pancreatic architecture. The few documented cases of symptomatic cysts presented with abdominal pain, obstructive jaundice, pancreatitis, or esophageal varices secondary to splenic venous thrombosis. Transgastric cystostomy or resection with distal pancreatectomy have been used to manage cysts.[54]

Pancreatic organogenesis is a complicated process that requires growth coordination with the surrounding foregut tissues. Intricate molecular signaling guides the development of an organ with combined endocrine and exocrine functions. The clinical conditions discussed above range from common and largely asymptomatic to those that are rare and apparent at birth. Patients with congenital pancreatic malformations can present as neonates with vague abdominal symptomatology, jaundice, pancreatitis, intestinal obstruction, or failure to thrive. Conversely, congenital anomalies may present in adults throughout the lifespan. Advanced imaging with MRCP and ERCP can elucidate underlying pathology in most cases. Initial management can range from a conservative approach with medical therapy to minimally invasive intervention. For patients who do not improve, a number of surgical operations on the pancreas and biliary tree have proven successful.