Chapter Outline
Structural Development of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas
Structural and Developmental Anomalies of the Gallbladder
Structural and Developmental Anomalies of the Extrahepatic Biliary Tract
Structural and Developmental Anomalies of the Pancreas
Complete and Partial Pancreatic Agenesis
Congenital Cyst of the Pancreas
Congenital Pancreatic Exocrine Deficiencies
Neonatal Islet Cell Hypertrophy and Hyperplasia
Introduction
Developmental, congenital, hereditary, and structural disorders that can affect the gallbladder, extrahepatic biliary tract, and pancreas are listed in Box 36.1 . This chapter focuses primarily on the few disorders that are encountered peripherally or directly in surgical pathology. Hereditary pancreatitis is discussed in Chapter 39 .
Gallbladder
Agenesis
Hypoplasia
Duplication or multiple gallbladders
Septation
Phrygian cap
Diverticulum
Anomalous location
Heterotopias
Extrahepatic biliary tract
Choledochal cysts
Biliary atresia
Pancreas
Agenesis
Duct abnormalities
Pancreas divisum
Annular pancreas
Heterotopic pancreas
Congenital cysts
Cystic fibrosis
Pancreatic exocrine deficiencies
Shwachman-Diamond syndrome
Johanson-Blizzard syndrome
Sideroblastic anemia and exocrine pancreatic insufficiency
Enzymatic deficiencies
Diabetes mellitus
Hereditary pancreatitis *
* See Chapter 34 .
Neonatal islet cell hypertrophy and hyperplasia
Maternal diabetes
Beckwith-Wiedemann syndrome
Persistent hyperinsulinemic hypoglycemia of infancy (i.e., nesidioblastosis)
Structural Development of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas
Some disorders of the gallbladder, extrahepatic biliary tract, and pancreas are easier to conceptualize if the embryologic development of these structures is understood. The liver, gallbladder, biliary tract, and pancreas bud from the endodermal epithelium of the foregut (i.e., duodenum) at approximately the third week of gestation. A small caudal portion of the liver bud (i.e., caudal foregut diverticulum) expands to form the gallbladder. While the diverticulum enlarges, its connection with the intestine narrows to form the biliary tree. Early in this process, these structures form hollow cylinders that become solid cords because of epithelial cell proliferation. They subsequently develop a lumen by a process known as cellular vacuolization at approximately the seventh week of gestation.
The pancreas arises from the dorsal and ventral diverticula, which first appear at approximately the fourth week of gestation. The dorsal bud elongates to form part of the head, body, and tail of the pancreas. The ventral bud develops at the base of the hepatic diverticulum. The left segment of this structure atrophies, and the right rotates posteriorly with the rotation of the duodenum to fuse with the dorsal bud. Portions of the pancreas derived from either diverticulum are histologically indistinguishable. Because of the direct association of the development of the common bile duct with the ventral portion of the pancreas, they share a common outflow tract, the ampulla of Vater. Although the length of this common channel varies from person to person, it is less than 3 mm in most people, and in some, the two ducts do not converge but drain into the duodenum through two adjacent but separate orifices.
When the two pancreatic buds merge at the sixth to seventh week, their duct systems also coalesce to form the main pancreatic duct of Wirsung. A remnant of the dorsal bud duct persists as the accessory duct of Santorini in approximately 40% of people, with its opening in the minor papilla of the duodenum ( Fig. 36.1 ).
Structural and Developmental Anomalies of the Gallbladder
Congenital abnormalities of the gallbladder are rare. They are traditionally classified according to their number, form, and location.
Agenesis
Gallbladder agenesis was originally described in 1701. It occurs in less than 0.1% of the population. Autopsy series report an equal sex distribution. Some patients have a variety of disparate congenital anomalies and syndromes. Rare familial associations have also been described. As with many structural anomalies of embryogenesis, the cause of gallbladder agenesis is unknown. It may result from a complete lack of bud formation or lack of recanalization of the bud during its growth. A compensatory secondary dilation of the right hepatic bile duct that takes on a bile storage function develops in some patients. Patients with gallbladder agenesis who are symptomatic are likely to be women in their fourth or fifth decade who have right upper quadrant symptoms. Possible mechanisms responsible for symptoms include abnormalities of the biliary tree, primary duct stones, biliary dyskinesia, and nonbiliary disorders.
Hypoplasia
Hypoplasia of the gallbladder is classically associated with biliary atresia and cystic fibrosis. Some cases of gallbladder hypoplasia presumably have a cause similar to that of gallbladder agenesis. Gallbladder hypoplasia is associated with rare genetic syndromes and structural anomalies. This entity likely is underdiagnosed because the main differential diagnosis of gallbladder hypoplasia is fibrotic retraction caused by chronic cholecystitis.
Gallbladder Duplication
Double or triple gallbladders are seldom encountered in clinical practice, although more than 200 cases have been reported. A female predominance is documented among symptomatic patients, whereas an equal sex distribution is seen for asymptomatic individuals.
Multiple gallbladders have been classified according to whether each of the gallbladders has a separate cystic duct insertion into the biliary tree (“H” configuration) ( Fig. 36.2 ) or a common cystic duct insertion (“Y” configuration). This distinction is of vital importance for intraoperative surgical management.
The spectrum of disease identified in patients with multiple gallbladders is similar to that found in patients with a single gallbladder. In the absence of symptoms, prophylactic cholecystectomy is not routinely advocated, although removal of all gallbladders is indicated if only one is found to be pathologic.
Septation
Septation of the gallbladder ( Fig. 36.3 ) is often diagnosed on preoperative ultrasonography. It most commonly results from cholelithiasis and inflammation, an association that is supported by prominent inflammation and fibrosis in most of the specimens. Congenital gallbladder septation also has been attributed to incomplete cavitation of the developing gallbladder bud.
Septations may be single or multiple. Rare multiseptate gallbladders occurring as part of a constellation of congenital abnormalities of the hepatobiliary-pancreatic tree offer the best evidence for septation as a congenital event, at least in some patients. They may occur in the pediatric population and commonly without gallstones. Each septation may contain a mucosal surface with interdigitating muscle fibers. Various amounts of chronic inflammation and secondary cholelithiasis have been described in these specimens.
The term hourglass gallbladder describes a transverse septum that divides the gallbladder into two compartments. This lesion may be congenital or acquired.
Phrygian Cap
The most exotically named congenital lesion of the gallbladder is the Phrygian cap. It occurs when the fundus of the gallbladder folds over its body. It is a common radiologic finding, occurring in approximately 4% of the general population ( Fig. 36.4 ). The term Phrygian cap refers to the shape of a soft, conical cap worn with the top curled forward by the inhabitants of the Bronze Age country of Phrygia, a region that is now known as Turkey. The lesion is important mainly from a radiologic perspective because it may lead to an erroneous diagnosis of cholelithiasis or pathologic septum.
Diverticulum
A congenital gallbladder diverticulum is identified in as many as 1% of cholecystectomies. They are distinguished from acquired lesions by mucosa and smooth muscle in the wall of the outpouching. This finding differentiates them from acquired Rokitansky-Aschoff sinuses. They may be single or multiple, and they rarely may cause symptoms.
Anomalous Location
Anatomic variations of position of the gallbladder may occur. Gallbladders occurring outside of the line of the middle hepatic vein on the visceral surface are referred to as aberrant gallbladders . These sites are classified as intrahepatic, left sided (i.e., an isolated finding or associated with situs inversus), transverse, and retrodisplaced. Rarely, they may be associated with anomalies of the liver. A gallbladder with little or no connection to the liver may wander or float in the peritoneal cavity. It may be completely surrounded by peritoneum or have abundant mesentery. Its mobility may allow twisting of the vascular supply and subsequent infarction of the gallbladder.
Heterotopias of the Gallbladder and Biliary Tree
Rarely, heterotopias consisting of pancreas, gastric or intestinal mucosa, liver, adrenal gland, and thyroid tissue have been described in the biliary tree and gallbladder. Of these, pancreatic heterotopia in the gallbladder is the most common. Most heterotopic lesions are found incidentally at the time of surgery. However, in some patients, classic biliary-type symptoms have been attributed to heterotopia.
Structural and Developmental Anomalies of the Extrahepatic Biliary Tract
With rare exceptions, anomalies of the extrahepatic biliary tract, apart from choledochal cysts, are usually diagnosed as incidental findings. These anomalies are relevant for clinical and radiologic diagnoses and for the prevention of surgical misadventures, such as injury to the extrahepatic biliary system.
Choledochal Cyst
Cystic dilation of the biliary tree was described as early as 1723. Not until the modern era was there significant improvement in understanding the pathophysiology of choledochal cysts. These cysts are uncommon, occurring in approximately 1 of 100,000 to 150,000 live births. Most patients are diagnosed in infancy and childhood; only 20% to 30% of patients are identified as adults. Table 36.1 summarizes the common presenting features.
| Feature | Pediatric Patients | Adult Patients |
|---|---|---|
| Overall occurrence | 75% | 25% |
| Male-to-female ratio | 1 : 4 | 1 : 4 |
| Median age at diagnosis | 2.2 yr | 37 yr |
| Symptoms | Obstructive jaundice Pain Abdominal mass | Abdominal pain Cholangitis Jaundice Fever Pancreatitis |
| Differential diagnosis | Infants Biliary atresia Prolonged neonatal jaundice Children Congenital hepatic fibrosis Congenital biliary stricture | Biliary stones Hepatitis Chronic pancreatitis |
| Most common type | I * | IV * |
* These types may represent a spectrum of the same disease, with intrahepatic disease resulting from biliary obstruction in older patients.
Etiology
Choledochal cysts can be caused by a diverse set of abnormalities that predispose to reflux of pancreatic secretions into the common bile duct or obstruction of the distal common bile duct. Its predominance in pediatric populations, gender distribution, greater incidence among Asian populations, and rare association with other anomalies are consistent with a congenital origin. Most patients have an identifiable anomalous pancreaticobiliary junction between the common bile duct and the duct of Wirsung.
Although the mean length of the common channel increases with age, a common channel more than 6 mm long in adults is considered abnormal ( Figs. 36.5 and 36.6 ). The formation of this elongated common channel is thought to predispose to pancreaticobiliary reflux, with subsequent in utero dilation of portions of the extrahepatic biliary tract.
Possible mechanisms of distal common bile duct obstruction attributed to choledochal cyst formation include sphincter of Oddi dysfunction, autonomic innervation abnormalities, and other problems of embryogenesis. Different pathogenic mechanisms are probably responsible for different types of choledochal cysts. Even in adults, choledochal cysts are thought to be mostly congenital in origin. Uncommonly, adults have a dilated common bile duct after extrahepatic biliary tract surgery with normal results on initial intraoperative cholangiograms. These cases are probably derived in part from secondary stricture formation, although even in these patients, an anomalous pancreaticobiliary junction is common.
Classification
Todani and colleagues classified choledochal cysts into five major types according to their anatomic location ( Table 36.2 and Fig. 36.7 ). Ninety-two percent of choledochal cysts in children are classified as type I. This cyst has a fusiform or saccular dilation of the common bile duct ( Fig. 36.6 ). Infants commonly have a complete obstruction of the distal common bile duct. Type IV choledochal cysts are the most common type encountered in adults ( Fig. 36.8 ). In adults, the distal common bile duct is most commonly patent. Rarely, choledochal cysts may be entirely intraduodenal (i.e., choledochocele) or consist of multiple intrahepatic cysts (i.e., Caroli disease).
| Type | Description |
|---|---|
| I | Fusiform dilation of the extrahepatic duct |
| II | Focal saccular dilation or diverticulum of the extrahepatic duct |
| III | Cystic dilation of the bile duct confined to the duodenal wall (choledochocele) |
| IVa | Combined intrahepatic and extrahepatic dilation of the bile duct |
| IVb | Multiple dilations of the extrahepatic bile duct |
| V | Multiple intrahepatic biliary cysts (Caroli disease) |
Cystic malformations of the gallbladder probably share a common etiologic basis with choledochal cysts. Most patients are diagnosed with a variety of standard and invasive radiologic procedures.
The Todani classification has been criticized. Visser and colleagues made a strong case that the current nomenclature incorrectly groups four distinct diseases together as one entity and that types I and IV are artificially separated. They observed marked dissimilarities between Caroli disease and choledochocele and the remaining lesions classified by Todani as choledochal cysts.
Pathology
Grossly, a choledochal cyst may contain as much as 2 L of bile. The surface is typically coarsely granular. The wall is normally fibrotic, and distal narrowing is a common feature. Microscopic findings tend to vary with patient age. Intact surface columnar epithelium is characteristic of younger patients, and an increasing degree of chronic inflammation and adhesions to adjacent structures is characteristic of older patients ( Fig. 36.9 ). The cyst wall usually is composed of dense fibrous tissue with various amounts of smooth muscle.
Complications and Treatment
Delayed diagnosis may be associated with untoward complications such as pancreatitis, spontaneous perforation, cholelithiasis, cholangitis, secondary biliary cirrhosis, and portal hypertension. A significant risk of carcinoma is associated with choledochal cysts; this risk increases with age. The risk for children younger than 10 years of age is less than 1%, but the reported risk is as high as 30% to 43% for adults. Reflux of pancreatic enzymes into the common bile duct and abnormal bile composition may predispose to neoplastic change. For unknown reasons, the neoplasms have a predilection for the posterior wall of the cyst. Most commonly, the tumors are adenocarcinomas ( Fig. 36.10 ), although squamous cell carcinomas and anaplastic carcinomas also occur. Other types of neoplasms are rare. These patients also have an increased incidence of gallbladder carcinoma.
Surgical treatment of choledochal cysts involves complete resection when possible, although specific surgical approaches are usually tailored to the findings in a patient. Resection has been reported to be safe, even in small infants. Until recently, Roux-en-Y cystojejunostomy was the surgical treatment of choice. However, long-term follow-up of patients treated in this manner identified a significant lifetime risk of anastomotic stricture formation and development of cholangiocarcinoma. Some published series identified patients previously treated by Roux-en-Y cystojejunostomy who underwent radical excision of their choledochal cysts in an attempt to decrease their risk of cancer. This approach was associated with low long-term morbidity and mortality rates. Rarely, adenocarcinoma may develop at the site of choledochal site excision. In most cases, the previous surgical excision was found to be incomplete.
Biliary Atresia
Biliary atresia is the most common neonatal hepatobiliary disorder and is the most frequent indication for liver transplantation in infants. Biliary atresia occurs in 1 of 8000 to 18,000 live births and typically manifests within the first 3 months of life with jaundice, acholic stools, and hepatomegaly in an otherwise apparently healthy infant. This progressive fibroinflammatory process results in complete obliteration of the lumens of the extrahepatic biliary tree, which leads to intrahepatic cholestatic injury and fibrosis of the intrahepatic bile ducts.
If diagnosed within 60 days of birth, hepatic portoenterostomy can restore bile flow, but 70% to 80% of patients ultimately require liver transplantation because of progressive biliary cirrhosis and its complications. The term extrahepatic biliary atresia is no longer used because the intrahepatic biliary lesion determines the overall prognosis and outcome of patients affected by this disease.
The two types of biliary atresia are the fetal (syndromic or prenatal) form and the acquired (perinatal) form. The fetal form accounts for as many as 20% of cases of biliary atresia and is associated with other congenital anomalies such as intestinal malrotation; asplenia or polysplenia; portal vein anomalies; situs inversus; congenital heart disease; annular pancreas; Kartagener syndrome; atresia of the duodenum, esophagus, or jejunum; polycystic kidneys; and cleft palate. This form manifests earlier in infancy with acholic stools and may be caused by a defect in morphogenesis of the biliary tree. Abnormal Notch pathway signaling, including mutations in the Jagged 1 ( JAG1 ) gene and in CFC1 , the gene that encodes the cryptic family 1 protein, is thought to play an etiologic role in biliary atresia.
The more common acquired form of biliary atresia usually manifests with cholestatic jaundice between 1 and 2 months of age and does not have coincident congenital anomalies. Several etiologic factors have been proposed, including infectious, vascular, toxic, and immune factors.
Structural and Developmental Anomalies of the Pancreas
Complete and Partial Pancreatic Agenesis
Complete and partial forms of pancreatic agenesis constitute a rare group of structural anomalies, many of which go undetected because they may not be associated with pancreatic insufficiency. Agenesis of the pancreas is a rare lethal anomaly that sometimes is associated with gallbladder agenesis. Partial agenesis, which may be familial in origin, is associated with complete absence of dorsal pancreatic parenchyma and has only rarely been reported. Patients may have pancreatitis of the remaining ventral pancreas. A linkage between two families demonstrating pancreatic and cerebellar agenesis and mutations in the PTF1A gene encoding pancreas transcription factor 1A has been described.
Duct Abnormalities
Because pancreatic development is complex, variations in duct anatomy are relatively common. A detailed autopsy study by Berman and associates, in which vinyl acetate casts of postmortem pancreas specimens were used, revealed the previously described pattern of duct arrangement in approximately 90% of specimens. Although several ductal anatomic patterns of development were seen, the most common aberrant finding was insertion of the main pancreatic duct into the common bile duct 5 to 15 mm proximal to the ampulla of Vater. This formation is known as the common channel or the anomalous pancreaticobiliary junction . In endoscopic retrograde cholangiopancreatography (ERCP) series, this variation in duct anatomy has been identified in 0.9% to 28% of patients (depending on patient selection) and is associated with an increase in pancreaticobiliary disease.
Pancreas Divisum
Pancreas divisum is the most common congenital anomaly of the pancreas, occurring in 5% to 10% of the population. Variations in the prevalence rate based on ethnicity have been reported. Since its identification in the 1970s with the introduction of ERCP, the significance of pancreas divisum has been intensively studied. Pancreas divisum has been identified in 12% to 26% of patients with idiopathic pancreatitis, and the pancreatitis was confined to the dorsal portions of the pancreas in some of these patients. Conversely, some studies have not shown a significant association between pancreas divisum and increased pancreatic disease.
The classic or complete type of pancreas divisum arises from a lack of fusion of the two embryologic portions of pancreas. As a result, the main portion of the pancreas is drained by a patent duct of Santorini into the minor duodenal papilla ( Fig. 36.11 ), and the inferior portion of the pancreatic head drains through the major papilla. An associated stenosis of the minor orifice in a subset of patients with pancreas divisum probably influences the predisposition to pancreatitis. A partial or incomplete type of divisum occurs when a small communication exists between the ventral and dorsal ducts. Several variants of this type have been elucidated.
