CYSTIC DISEASES OF LIVER AND BILIARY TRACT (Part Two)

Cystic diseases of the biliary tract

Bile duct cysts may occur as solitary or multiple cystic dilatations throughout the entire biliary tree. Originally, these abnormalities were termed choledochal cysts, based on the frequent occurrence of cysts in the common bile duct.

• However, cystic dilatations may occur throughout the entire biliary tree and “bile duct cysts” or “cystic diseases of the biliary tract” are considered as more appropriate terms for this condition.
  
• When confined to the intrahepatic bile ducts, the term Caroli’s disease is generally used, whereas the term choledochal cyst is still frequently used for dilatations limited to the extrahepatic bile duct.
  
• In addition to these types of bile duct cysts, a rarer condition, characterized by multiple periductal cysts, has been identified.

Multiple periductal cysts

• Small cystic lesions of 1 to 2 mm are incidentally found within Glisson’s capsule along the large intra- or extrahepatic bile ducts.
  
• These rare cystic lesions have been referred to as mucinous hamartoma or periductal cysts.
  
• They usually occur in chronically diseased livers, but isolated presentations in otherwise normal livers have been reported as well.
  
• Occasionally, they are found in transplanted livers and are a cause of obstructive jaundice after liver transplantation.
  
• The cysts contain watery or mucoid material and have been considered as retention cysts, resulting from obstructed periductal glands.
  
• The inner lining consists of a mucinous epithelial lining and cysts are surrounded by a mild chronic inflammatory reaction.
  
• Although they are most frequently found in patients with severe chronic liver disease and portal hypertension, periductal cysts are usually asymptomatic and an incidental finding at autopsy
  
• When they occur in an otherwise normal liver and cause biliary obstruction, differentiation from a malignancy can be difficult and resection of the affected part of the liver can be indicated.

Caroli’s disease and Caroli’s syndrome

• Caroli’s disease is a developmental anomaly characterized by segmental dilatations of the large intrahepatic ducts, without an obstructive cause.
  
• Typical for this disease are localized and saccular dilatations of the large bile ducts, resembling a picture of multiple cyst-like structures of varying size.
  
• Two types of abnormalities have been described:
  

1. a type with bile duct abnormalities alone, and
   
2. a type with bile duct abnormalities in combination with periportal fibrosis, similar to congenital hepatic fibrosis.
   

• This combined type is also known as Caroli’s syndrome and has been reported more frequently than the pure type, or Caroli’s disease.

In Caroli’s disease, saccular dilatations of the large bile ducts are more frequently seen on the left side of the liver.

• In 30 to 40% of the cases, abnormalities are confined to one segment or sector of one side of the liver.
  
• Bilateral abnormalities are more frequently seen in the second type, or Caroli’s syndrome.
  
• The abnormal bile ducts are in continuity with the remaining normal bile tree, and therefore contain bile.
  
• Biliary stasis, leading to stone formation, is commonly seen in the dilated ducts and predisposes to the development of recurrent cholangitis and septicemia.

Other complications include amyloidosis and cholangiocarcinoma, the latter of which is found in 7 to 10% of the patients.

Caroli’s syndrome is associated with renal disorders: nephrospongiosis and renal cysts in 30 to 40% of the patients.

• Patients with Caroli’s disease donot have a higher incidence of renal disorders.
  
• Choledochal cysts, however, have been described in combination with both types.
  The disorder usually becomes symptomatic during childhood or early adult life, although initial symptoms may also be delayed until later ages.
• Males are slightly more affected than females.
  
• Typically, the clinical features are related to cholangitis and/or portal hypertension (in case of Caroli’s syndrome), and may include recurrent episodes of abdominal pain, chills, and fever.
  
• Jaundice may develop secondary to obstruction of the extrahepatic bile ducts by stones, which have migrated from the intrahepatic ducts.
  
• In the combination with congenital hepatic fibrosis (Caroli’s syndrome), symptoms from portal hypertension, such as hematemesis from bleeding esophageal varices, usually occur at an earlier age than cholangitis.
  • In this situation hepatomegaly and splenomegaly can be found during physical examination, whereas usually no abnormalities are found on physical examination in patients with Caroli’s disease.

Abnormal laboratory studies of liver function are usually not found, but will be compatible with obstructive cholestasis in patients with stones in the extrahepatic bile ducts.

The diagnosis is usually made by radiologic studies, such as ultrasonography or computed tomography, or by cholangiography during endoscopic retrograde cholangiopancreaticography (ERCP).

• Typical findings are saccular or cystically dilated intrahepatic ducts up to 5 cm in diameter, filled with stone material or sludge.
  
• Differential diagnosis includes
  
• • primary sclerosing cholangitis,
    
  • dilatations secondary to obstruction, and
  • Oriental cholangitis.
• Primary sclerosing cholangitis can usually be differentiated by the concomitant multiple strictures of the intra- and extrahepatic bile ducts in this disorder.
  
• In biliary obstruction due to a malignant tumor along the bile duct, the entire biliary tree proximal to the mass is dilated, including the small peripheral intrahepatic ducts.
  
• In the Asian population, differential diagnosis with recurrent pyogenic cholangitis or Oriental cholangitis can be difficult.

Oriental cholangitis usually occurs at an older age and is associated with a straightening and rigidity of the dilated large ducts, with acute peripheral tapering.

In uncomplicated cases, without signs of cholangitis or obstruction, conservative therapy with observation is indicated.

Medical treatment of complicated cases should focus on

• drainage of the obstructed or infected ducts and treatment of the bacterial cholangitis.
  
• In these cases surgical interventions are usually required in order to reduce the risk of
  • recurrent cholangitis and
    
  • formation of secondary biliary cirrhosis or
    
  • cholangiocarcinoma.

Surgical procedures may vary from

• drainage of the hepatic bifurcation via a hepaticojejunostomy, to a
  
• partial liver resection, with or without hepaticojejunostomy.
  
• Liver transplantation should be considered in selected patients with generalized disease or with concomitant liver fibrosis and portal hypertension(Caroli’s syndrome).

Choledochal cysts

• Choledochal cysts are relatively rare disorders, characterized by cystic dilatation of main bile ducts.
  
• The first classification, as proposed by Alonso-Lej in 1959, included three types, located in the extrahepatic bile duct.
  
• This classification was modified by Todani et al. In 1977, who identified two more types and included intrahepatic cystic dilatations of the large bile ducts, as found in Caroli’s disease.

Type I, a segmental or diffuse dilatation of the common bile duct, is most frequently found, accounting for 75 to 95% of all cases.

Type II represents a diverticulum of the common bile duct.

Type III has been identified as a choledochocele, which term represents a herniation of the distal end of the common bile duct into the duodenum, resulting in a cystic mass in continuity with the common bile duct.

Type IV has been recognized as a combination of cysts, either extrahepatic alone (type IVb) or as a combination of extra- and intrahepatic (Caroli-like) cysts (type IVa).

Multiple cysts of the large intrahepatic ducts (Caroli’s disease) were identified as type V.

Although there is no uniform definition of what size of the bile duct should be considered a cystic dilatation, a diameter above 1.5 to 2 cm is generally regarded as abnormal.

However, it should be realized that some widening of the common bile duct occurs with aging and is considered to be physiologic.

• The cyst wall is thickened and fibrotic, and the mucosa severely inflamed or even absent and replaced by granulation tissue.
  
• The classical classification scheme has recently been challenged and some investigators believe that type II (diverticula) and type III (choledochocele) are unrelated to the other types of cystic dilatation of the bile duct and should, therefore, not be considered as a subtype of choledochal cysts.

About 75% of the choledochal cysts occur in women and lesions are far more common in the Far East than in Western countries. The estimated prevalences vary from 1 : 1000 in Japan, to 1 : 13,000 live births in the US.

The etiology of choledochal cysts is unknown but several possible mechanisms have been proposed.

• One theory is based on the increased incidence of an anomalous pancreaticobiliary junction, which is seen in up to 85% of the patients with a choledochal cyst.
  
• This anomaly, which is also known as the “long common channel,” may represent failure of the embryological ducts to migrate fully into the duodenum.
  
• It has been suggested that this “long common channel” contributes to reflux of pancreatic secretions into the common bile duct, leading to damage of the wall and subsequent dilatation.

• Another theory proposes that choledochal cysts are part of the congenital fibropolycystic diseases, or ductal plate malformations.
  
• This theory is supported by the occasional finding of combinations of intrahepatic and extrahepatic bile disorders, with or without concomitant liver fibrosis.

Other factors that have been suggested to play a role in the pathogenesis of bile duct cysts are:

1. inadequate autonomic nerve innervation,
   
2. viral infections, and
   
3. abnormal function or dysmotility of the sphincter of Oddi.
   

• Probably, both congenital and acquired mechanisms can be involved in the pathogenesis of cystic dilatations of the bile ducts.

Most choledochal cysts become symptomatic during childhood.

• However, symptoms can be nonspecific, and the diagnosis can be missed until adolescence.
  
• The classic clinical triad of symptoms includes
  • intermittent upper abdominal pain,
    
  • jaundice, and a
    
  • palpable mass in the right upper quadrant of the abdomen.
• Occasionally, patients remain asymptomatic and the choledochal cyst is “incidentally” found during ERCP, computed tomography, or magnetic resonance cholangiopancreaticography (MRCP) performed for nonrelated symptoms.
  
• Secondary biliary cirrhosis is a rare complication in untreated patients in whom the diagnosis has been missed for several years.
  
• In infants, the disorder has to be differentiated from other diagnoses, which belong to the group of infantile obstructive cholangiopathies.
  
• In adults, differentiation between choledocholithiasis with secondary bile duct dilatation and a type I cyst in which stones have developed can usually not be made on the clinical symptoms alone.
  
• The definite diagnosis is usually made by radiologic imaging studies, similar to that discussed for Caroli’s disease above.

To treat or prevent complications, such as recurrent cholangitis and secondary cirrhosis, surgical treatment is generally indicated.

Another argument for surgical intervention is the risk of malignant degeneration, which has been reported in 2.5 to 30% of the patients in different series.

• Malignancies associated with choledochal cysts may arise within the cyst, but have also been described elsewhere within the liver or the biliary or pancreatic ducts.
  
• In fact, about one-third of the malignancies occur outside the bile duct cyst itself and they may even develop after cyst excision.

The current treatment of choice is a complete resection of the cyst and a hepaticojejunostomy, with a mucosa-to-mucosa anastomosis.

• If complete excision is not possible, partial cyst excision and a cystojejunostomy to an epithelial-lined portion of the cyst remnant is an acceptable second choice.

Endoscopic unroofing and sphincterotomy of the common bile duct has been successfully performed in patients with symptomatic small choledochoceles (type III choledochal cyst).

• The endoscopist, however, must be aware that an ampullary carcinoma may develop in a choledochocele, and complete surgical excision remains the treatment of choice in cases with large or “abnormal” looking choledochoceles.

A partial liver resection may be indicated in patients with cysts type IVa and type V (Caroli’s disease).

Liver transplantation should be considered in the more rare cases with concomitant diffuse intrahepatic abnormalities, such as congenital liver fibrosis or secondary biliary cirrhosis.

Simple drainage of the cyst alone, by a cyst-enterostomy, is generally regarded as an obsolete procedure, because of the high risk of late complications (anastomotic stricture formation, malignant degeneration).

• Especially in adults, how ever, the cyst wall is sometimes so adherent to the portal vein or the hepatic artery that a plane of dissection cannot be identified.
  
• In these cases, it has been recommended to enter the cyst and excise the entire mucosal lining, leaving the external wall attached to the adjacent structures.
  
• The mucosal lining of a choledochal cysts is currently considered as a precancerous condition, warranting complete excision.
  
• Although some investigators have found an increased risk for neoplasia to develop anywhere in the biliary tract, gallbladder, or pancreas in patients after resection of a choledochal cyst, others could not find malignant changes in the remnant proximal hepatic duct or terminal bile duct after a mean follow-up of 9.1 years.
  
• Prognosis in patients who have developed a cancer in the cyst is very poor, even after surgery.

Biliary cystadenoma and cystadenocarcinoma

Biliary cystadenomas are rare tumors, constituting about 2 to 5% of all intrahepatic tumors of biliary origin.

• Malignant degeneration into a cystadenocarcinoma is even less frequently seen.
  
• The size of biliary cystadenomas varies between 0.5 and 30 cm, with an average diameter of 10 cm.
• Usually they have a multilocular and multilobular aspect, with papillary foldings.
  
• The tumors arise from the intrahepatic, and rarely from the extrahepatic, bile ducts or gallbladder.

Cystadenomas are most frequently found in middle-aged females, but a nearly equal sex distribution has been found for cystadenocarcinomas.

• The inner lining of the cysts is formed by columnar epithelium with or without a densely cellular (“ovarian-like”) stroma.
  
• Cystadenocarcinomas surrounded by an “ovarian-like” stroma are exclusively found in females, whereas the ones without a distinctive cellular stroma are seen in males.
  
• The presence of a true epithelial lining distinguishes these cysts from infectious lesions and “pseudocysts.”
• Another distinguishing feature is the mucinous content of these cysts, compared to the more serous fluid content of simple cysts.

The etiology of biliary cystadenomas is largely unknown.

• It has been suggested that they develop from ectopic remnants of primitive foregut sequestered within the liver.
  
• According to this theory cystadenoma is a congenital, rather than an acquired, disorder.
• Cystadenocarcinomas are considered to result from malignant degeneration of cystadenomas.
  • A transition zone between benign and malignant parts is often encountered on histological examination of cystadenocarcinomas, supporting this theory.

The clinical presentation and symptoms are usually mild and atypical.

• Cystadenomas are slowly growing tumors, which usually remain asymptomatic until the second or third decade of life.
  
• In more than 80% of the patients, the presenting symptoms include
  • upper abdominal pain or discomfort,
    
  • nausea,
    
  • jaundice, and
    
  • a palpable mass.
• Less than 20% are discovered coincidentally. Complications are also seen in about 20% and include
  • cholangitis or sepsis secondary to compression of bile ducts,
    
  • hypertension due to portal vein compression,
    
  • bleeding, and
    
  • ruptureLaboratory studies usually reveal normal liver function tests and normal serum levels of alpha-fetoprotein and CEA. CA19-9 levels, however, are elevated in most cases and measurement can be helpful in making the diagnosis.

On ultrasonography and computed tomography, cystadenomas are usually recognized as multilobular cysts with internal septation and/or small polyps.

Cystadenomas need to be differentiated from simple cysts, with or without malignant degeneration, hydatid cysts, metastatic cystadenocarcinomas, primary or metastatic neoplasms with central necrosis, and post-traumatic cysts.

• Cystadenocarcinomas should be highly suspected when large papillary or solid parts are found inside the cyst on imaging studies.

Preoperative differentiation between a congenital cyst with malignant degeneration and a cystadenocarcinoma can be very difficult, if not impossible.

• Percutaneous aspiration of the cystic fluid and needle biopsy have been propagated to facilitate the diagnosis.
  
• However, these techniques may cause seeding metastasis of the needle track and therefore this procedure should be avoided.

The treatment of choice is a complete excision of the mass.

• This can be done either as a (anatomical or extraanatomical) liver resection or enucleation, depending on the size and localization of the tumor.
  
• Partial excision of cystadenomas is associated with a recurrence rate of 90%.
  
• Even after complete excision, recurrences are seen in 5% of the patients and therefore patients should be given a long follow-up.
  In general, however, the prognosis is good in patients with cystadenomas, if the tumor can be completely resected with free margins of normal liver tissue.
  
• Patients with cystadenocarcinomas accompanied by an “ovarianlike” stroma, who have been treated with radical excision also have a relatively good prognosis.
  
• However, cystadenocarcinomas lacking a distinctive (“ovarian-like”) surrounding stroma usually follow a more aggressive course and are more likely to result in the patient’s death.
  
• In one series, median survival for male patients with cystadenocarcinomas was 3 years, whereas no deaths were seen during these years of follow-up in 30 female patient with cystadenocarcinomas which were surrounded by a mesenchymal stroma.
  
• Distant metastases are rarely seen, but can occur in the liver, lungs, and bones.