Monolobar Caroli's Disease and Cholangiocarcinoma

Caroli's Disease (CD) is a rare congenital disorder characterized by cystic dilatation of the intrahepatic bile ducts. This report describes a patient with cholangiocarcinoma arising in the setting of monolobar CD. In spite of detailed investigations including biliary enteric bypass and endoscopic retrograde cholangiography, the diagnosis of mucinous cholangiocarcinoma (CCA) was not made for almost one year. The presentation, diagnosis and treatment of monolobar CD and the association between monolobar CD and biliary tract cancer are discussed. Hepatic resection is the treatment of choice for monolobar CD.


INTRODUCTION
Caroli's Disease(CD) is a rare congenital condition characterized by diffuse or focal cystic dilatation of the intrahepatic bile ducts [1]. Two forms are described, a simple type in which bile ducts are dilated and cystic, without hepatic fibrosis or its sequelae. The second type is assoc-iated with peri-portal fibrosis and leads to portal hypertension, esophageal varices and sometimes liver failure. Both types are characterized by recurrent episodes of intrahepatic biliary lithiasis and cholangitis as well as increased risk for development of biliary tract cancer. In some patients, the disease is confined within one hepatic lobe, with less than 150 cases of monolobar CD reported in the literature [2,3].
The etiology of CD is unclear, but it has been postulated that prenatal vascular accident leads to stricture and dilatation of bile ducts [1]. Liver resection, biliary bypass, endoscopic or percutaneous drainage, alone or in combination, have all been used to treat CD [4][5][6]. This report describes a patient with CD confined to the left liver, who developed recurrent cholangitis after biliary enteric bypass and required left lobectomy. At the time of lobectomy, the patient was found to have metastatic, low-grade nucinous cholangiocarcinoma. The presentation, diagnosis and treatment of mono-*Corresponding author. Surgical exploration revealed a normal appearing liver with a remnant of the gallbladder infundibulum and long cystic duct with an inflammatory node obstructing the common bile duct. There was no hepatic mass palpable or identified by intraoperative ultrasound. Intraoperative choledochoscopy showed mild ductal inflammation and a single left intrahepatic stone, which was extracted. Frozen and permanent sections of the common hepatic duct and liver parenchyma revealed no tumor or cirrhosis. Endto-side hepaticoduodenostomy was performed to provide adequate drainage and retain endoscopic access to the biliary tree. The patient was discharged after five days.
The patient returned within one year with recurrent cholangitis. Biliary scan revealed normal excretion of the right lobe of the liver with delayed excretion of the left liver. Computed tomography scan demonstrated persistent multifocal dilatation confined to the left bile duct system without mass (Fig. 1). Endoscopic retrograde cholangiography showed cystic dilatation of the left bile duct system without evidence of obstruction and a normal right biliary tree. The choledochoduodenostomy was patent. Brushing FIGURE CT scan of the abdomen reveals dilated left biliary system, normal right biliary system and no evidence of a mass or tumor. cytology was negative. Magnetic resonance cholangiography confirmed patent intra-and extrahepatic bile ducts with ductal dilatation confined to the left liver. Given the persistent cholangitis and that disease was confined to a single hepatic lobe, left lobectomy was indicated.
At operation, sheets of mucinous tumor were found, though restricted to the dome of the liver and right hemidiaphragm. Frozen section revealed low-grade adenocarcinoma. There was no other implant or lymphadenopathy found upon further exploration of the abdomen. A palliative left hepatic lobectomy was performed. Given the low-grade nature of the neoplasm, the peritoneum of the right diaphragm and the hepatic capsular implants were resected to debulk all gross disease. The post-operative course was unremarkable but for a mild pneumonia which had resolved at discharge on the ninth post-operative day.
On examination of the resected specimen, the hepatic capsule was unremarkable while coronal sections revealed gross ectasia of the left bile duct system without definite obstruction by stone or tumor mass. The ducts were filled with mucin and their walls were thickened. The surrounding hepatic parenchyma was grossly unremarkable. Histopathology revealed diffuse involvement of the bile duct by a well-differentiated papillary mucinous cholangiocarcinoma (Fig. 2). The neoplastic epithelium displayed increased nuclear/ cytoplasmic ratio, nuclear hyperchromasia and cigar shaped, tightly packed nuclei. The cytoplasm was filled with mucin and architecturally ranged from flat to papillary. In spite of exhaustive sampling of the specimen, no infiltrative neoplasm was identified. The peritoneal implants were composed of small strips of lowgrade epithelium in large pools of mucin.

DISCUSSION
In 1958, Caroli [19]. Reports of CD in twin sisters and in families suggest that this disease is inherited [20]. When CD is associated with congenital hepatic fibrosis, it is transmitted as an autosomal recessive disorder [21]. Cholangitis, bile stasis and intrahepatic stone formation are common features of the disease as illustrated in the patient reported. Septicemia, intrahepatic and subphrenic abscess can follow. In the case presented, a single intrahepatic stone was extracted at the time of biliary bypass but cholangitis and bile duct dilatation persisted. The disease usually involves the entire liver but may be restricted to a single lobe or segment. In monolobar CD, the left liver is most commonly affected with a 3:1 left lobe predominance [5]. The reason for this predominant distribution is unknown. Symptoms occur after 5 to more than 60 years of life. The first episode of bacterial cholangitis is usually spontaneous, and the main (and often only) symptom is unexplained fever without pain or jaundice. If associated with congenital hepatic fibrosis, manifestations of portal hypertension may dominate the clinical presentation. Liver function tests are normal except for moderately elevated alkaline phosphatase and gamma glutamyltranspeptidase [5].
Ultrasound or computed tomography are often the first studies to demonstrate an abnormally dilated biliary system. Cholangiography (percutaneous or endoscopic) defines the biliary anatomy. Hepatobiliary scintigraphy evaluates function. In the patient presented it documented intact biliary excretion of the right lobe.
The most serious complication of CD is the development of biliary tract cancer. Dayton reported cancer in 10 of 142 patients with CD (7%) [6]. Similarly, Guntz,

years cholecystectomy
Hepaticoenter-Died at ostomy 13 months located on the left side and five on the right. All were cholangiocarcinomas except for one case of gallbladder carcinoma [21]. Similar to the case presented, the majority of the patients were men older than 50 suggesting longstanding subclinical disease before the onset of cancer.
The reason for this association remains unknown but bile stasis and chronic cholangitis are considered to be risk factors [26,33].
The diagnosis of cancer in the setting of CD is difficult. Endoscopic biopsy, with brushing and washing yields a diagnosis in less than half of cases of bile duct cancers. The overall sensitivity of preoperative cytology is 42% or less [34][35][36][37]. A mass is infrequently identified. Surgical explora-tion with frozen and permanent sections is frequently non-diagnostic [6].
The extent of intrahepatic disease and the presence of fibrosis or cirrhosis should guide the treatment of CD. When the disease is localized, resection is the mainstay of treatment [3,20,25,38]. Biliary bypass, whether by choledochoduodenostomy or Roux-en-Y choledochojejunostomy, cannot circumvent the development of hepatolithiasis, recurrent cholangitis, or the risk of cancer [25][26][27][28][29][38][39][40]. In the patient presented, the cholangiocarcinoma was a non-invasive, yet aggressive, mucinous tumor which implanted in the peritoneum of the right diaphragm and the capsule of the right lobe. This seeding outside of the biliary tract was likely due to the manipulation, including choledochoscopy, performed at the time of biliary enteric bypass.
Reports persist in the recent literature suggesting that localized disease might be treated palliatively, endoscopically or surgically with biliary enteric bypass, based on the premise that drainage procedures avert the risk of cancer associated with chronic infection and bile stasis [4]. This unfortunately ignores Todani's finding that 57% of 63 cases of carcinoma in patients with all types of biliary cystic disease had previously undergone drainage procedures, and that cancer was found from I to 32 years later [38].
Diffuse CD is a more difficult problem. Most recommend a combination of resection and internal bypass, endoscopic or percutaneous stents, or even in rare cases, hepatic transplantation. Antibiotics and litholytic agents are adjuncts [4,5]. Prognosis for extensive bilateral disease and CD associated with hepatic fibrosis is much worse than for limited disease.
In the patient presented, cholangiocarcinoma remained undiagnosed in spite of bile duct exploration and cytology, and was found 10 months following choledochoduodenostomy. The diagnosis of carcinoma is exceedingly difficult preoperatively and the prognosis is poor if the diagnosis is delayed. In monolobar CD, hepatic resection is the treatment of choice as it provides definitive treatment and may contribute to an early diagnosis of cancer. Non-surgical treatment is the mainstay of management of diffuse disease.  when the patient presented again with acute