Cholangiocarcinomas Arising in Cystic Lesions of the Hepatobiliary Tract and in Pancreaticobiliary Maljunction
There is a well-known association between cholangiocarcinomas and several types of cystic lesions of the hepatobiliary tract and pancreaticobiliary maljunction. Specifically, biliary tract cysts and inflammatory changes occurring in them result in significant risk for cholangiocarcinogenesis. These cysts include cystic dilatation of the common bile duct, diverticulum of the extrahepatic duct, choledochocele, multiple extrahepatic biliary cysts, and Caroli’s disease. Among complications of choledochal cysts, malignant transformation is in fact the most concerning. Carcinomas develop either in the cyst wall itself or in undilated parts of intrahepatic or extrahepatic ducts. Histologically, cyst-associated cancers are mostly classical cholangiocarcinomas, but squamous cell carcinomas and other malignancies may also occur. A second group of biliary tract conditions that are associated with increased carcinoma risk are various forms of pancreaticobiliary maljunction.
KeywordsBile Duct Common Bile Duct Autosomal Dominant Polycystic Kidney Disease Choledochal Cyst Gallbladder Carcinoma
Cancers Arising in Choledochal Cysts
Choledochal cysts are uncommon congenital or acquired cystic dilatations of the extrahepatic or intrahepatic bile ducts. These distinct lesions were first described by Vater and Ezler in 1723. In 1852, Douglas described the clinical features of choledochal cyst based on a jaundiced female adolescent patient who showed a palpable abdominal mass (reviews: Yamaguchi 1980; Lipsett et al. 1994; Gigot et al. 1996; Soreide et al. 2004; Visser et al. 2004; Wiseman et al. 2005).
Todani classification of biliary tree cysts (modified)
Cystic dilatation of the common bile duct
I A: saccular, involving the entire extrahepatic bile duct
I B: saccular, involving a limited segment of the extrahepatic duct
I C: fusiform, involving all or most of the extrahepatic duct
True diverticulum of the extrahepatic bile duct
Choledochocele (cystic change limited to the intraduodenal portion of the distal common bile duct)
Multiple extrahepatic biliary cysts
IV A: associated intrahepatic cysts
IV B: extrahepatic cysts only
Type I cysts are the most common (80–90 %) and are characterized by saccular or fusiform dilatation of the entire common bile duct and common hepatic duct or of parts/segments of each. As seen in the Table, the cyst morphology and the extent of involvement are used to subdivide type I cysts into three subtypes. Type II cysts present as mostly isolated protrusions projecting from the common duct wall. The diverticular morphology ranges from rather flat or sessile to pedunculated lesions showing a stalk. In Type IV A, the most common configuration is that of a large extrahepatic solitary cyst associated with multiple smaller cysts of the intrahepatic bile ducts. Type IV B show multiple dilatations involving exclusively the extrahepatic bile duct system. Type V, identical to Caroli’s disease, shows dilatations of the intrahepatic biliary radicles that mostly involve both liver lobes. Unilobar/monolobar disease may also occur and usually involves the left liver lobe.
Among complications of choledochal cysts, malignant transformation is the most concerning. This is an age-related phenomenon occurring in 10–14 % of adults with choledochal cysts. All studies have shown that cholangiocarcinoma and other carcinomas complicating choledochal cysts occur more often in adults than in children.
Ferraris et al. 1944; Irwin and Morison 1944; Armanino 1946; Wilson et al. 1956; Dexter 1957; Fischer 1958; McKenzie et al. 1958; George and Maingot 1962; Nakajima et al. 1963; Ashby 1964; Kelly and Schlueter 1964; Fukuuchi 1967; Hizawa et al. 1967; Macfarlane and Glenn 1967; Thistlethwaite and Horwitz 1967; Schiewe et al. 1968; Tanaka et al. 1968, 1969; Jones and Shreeve 1970; Lorenzo et al. 1971; Nasu et al. 1971; Weber et al. 1971; Gallagher et al. 1972; Spitz 1972; Uchimura et al. 1972; Yoshimura et al. 1972; Shimomura et al. 1974; Fukushima 1975; Iinuma 1975; Shinagawa et al. 1975; Aikawa et al. 1976; Fujiwara et al. 1976; Keminger et al. 1976; Komi et al. 1976; Tsurimi et al. 1976; Yamamura et al. 1976; Flanigan 1977; Todani et al. 1977; Tsuchiya et al. 1977; Kagawa et al. 1978; Chaudhuri et al. 1982; Bova et al. 1983; Voyles et al. 1983; Bourdin et al. 1984; Nagorney et al. 1984; Samshima et al. 1986; Yeoh et al. 1986; Baumann et al. 1987; Rossi et al. 1987; Valabrega et al. 1987; Binstock et al. 1988; Leong et al. 1988; Okayama et al. 1991; Pisano et al. 1991; Holzinger et al. 1996; Han and Choi 1996; Stalder et al. 1996; Todani and Toki 1996; Ishibashi et al. 1997; Kale and Kuzu 1997; Lenriot et al. 1998; Yoshikane et al. 1998; Okamura et al. 2000; Patel et al. 2001; de Vries et al. 2002; Jan et al. 2002; Atkinson et al. 2003; Tseng et al. 2003; Tsuchida et al. 2003b; Zheng et al. 2004.
Carcinomas and other malignancies develop either in the cyst wall itself or in remnant tissues or undilated parts of the intrahepatic or extrahepatic bile duct system. The tumors are either detected at primary operations or secondary operations (review: Kagawa et al. 1978), but several cases were found at autopsy only, without previous operation (Armanino 1946; Dexter 1957; George and Maingot 1962; Jones and Shreeve 1970; Nasu et al. 1971; Gallagher et al. 1972).
Gallbladder carcinoma or cholangiocarcinoma was noted in 9.7 % of 42 patients (Lipsett et al. 1994). Among 42 patients with various types of choledochal cysts, cholangiocarcinoma was found in six patients, four of whom had previously undergone internal drainage procedures (de Vries et al. 2002). In a follow-up study of 72 adult patients who presented with choledochal cysts, the incidence of cholangiocarcinoma with non-cyst excision or non-operated congenital choledochal cysts was 10.8 % (Zheng et al. 2004). Intrahepatic cholangiocarcinoma can develop in patients subsequent to choledochal cyst resection, sometimes after a period exceeding 30 years (Fukuuchi 1967; Gallagher et al. 1972; Shields 1977; Chaudhuri et al. 1982; Yoshikawa et al. 1986; Scudamore et al. 1994; Kobayashi et al. 1999; Watanabe et al. 1999; Goto et al. 2001; Suzuki et al. 2004; Ono et al. 2008; Shimamura et al. 2009). In a review of nine cases of cholangiocarcinoma developing subsequent to resection of a choledochal cyst, the time period between cyst resection and diagnosis of carcinoma ranged from 2 to 34 years, in five cases exceeding 10 years and in four cases exceeding 20 years (Shimamura et al. 2009). Cholangiocarcinoma has been found in an adult patient aged 26 years after an infantile choledochal cyst resected at the age of 5 months (Ono et al. 2008).
Choledochal Cyst-Associated Adenocarcinoma
The types of cancer that have been reported in these lesions or the draining intrahepatic bile ducts mainly comprised classical cholangiocarcinoma and less commonly squamous cell carcinoma. In one of the first reports, from 1944, the tumor arising in a stone-containing choledochal cyst itself was squamous carcinoma (Irwin and Morison 1944). In a study reviewing 40 cases, adenocarcinoma was found in 31 cases, undifferentiated carcinoma in seven cases, and squamous cell carcinoma in two cases (Kagawa et al. 1978). Carcinoma can develop at the anastomotic site of hepaticojejunostomy (Yamamoto et al. 1996). It is known that late bile duct cancer is a complication of biliary-enteric anastomosis as such, i.e., not only after resection of choledochal cyst (Strong 1999). Among 204 patients with adult choledochal cyst disease in whom cysts were resected, de novo malignancy at the cyst remnant occurred in two patients (1 %; Cho et al. 2011). A part of congenital choledochal cysts are associated with pancreaticobiliary maljunction. In a study of 1433 Japanese patients with choledochal cysts, 151 patients had maljunction (Yamaguchi 1980). There is evidence that maljunction increases the risk of biliary tract carcinogenesis in choledochal cyst disease (Kobayashi et al. 1999; Song et al. 1999; Sugiyama et al. 1999; Matsumoto et al. 2003; Tashiro et al. 2003). Extrahepatic cholangiocarcinoma has been found in patients having choledochal cyst associated with pancreaticobiliary maljunction (Baumann et al. 1987; Sameshima et al. 1987; Okamura et al. 2000). Among 52 patients with choledochal cyst, pancreaticobiliary maljunction was associated with choledochal cyst in 64 % of the cases, but maljunction was only found in Todani types I and IV. Carcinoma developed only in the maljunction group (32 %; Song et al. 1999).
Early Choledochal Cyst-Associated Carcinoma
Early carcinoma c an sometimes be detected in choledochal cysts. In one case, a resected cyst showed a white plain area of thickness 3 and 8 mm in diameter, histologically characterized by well-differentiated tubular adenocarcinoma (Kraus et al. 2003). There are few published observations referring to precursor lesions of cholangiocarcinoma found in choledochal cysts. Adenomatous hyperplasia was detected in a simple excision specimen of cysts, followed by cholangiocarcinoma 2 years later (Coyle and Bradley 1992). Development of cholangiocarcinoma from an adenoma in choledochal cyst has also been described. In one patient, the resected cyst was lined with a shaggy papillary pink mucosa histologically representing a predominantly villous adenoma, at one place with a transition to cholangiocarcinoma (Franko et al. 2006). In rarer situations, early cancer or invasive adenocarcinoma has been observed in the dilated intrahepatic ducts associated with choledochal cysts (Tajiri et al. 1997; Kawamoto et al. 1998). It is currently thought that chronic inflammatory damage of epithelium and erosion/ulceration followed by persistent regeneration is the main pathogenic pathway for cancerogenesis in these cysts. Cholangiocarcinoma may also develop after surgical treatment of choledochal cysts (Tsuchida et al. 2003b), possibly caused by ascending cholangitis. In one patient with treated Todani type Ia congenital biliary dilatation, intrahepatic cholangiocarcinoma developed 10 years after Roux-en-Y hepaticoduodenostomy (Goto et al. 2001).
Choledochal Cyst-Associated Squamous Cell Carcinoma
Few cases of squamous cell carcinoma have been reported (Todani et al. 1977; Harris et al. 2002; Jan et al. 2002; Price et al. 2008). These carcinomas may develop from squamous metaplasia within cysts. Metaplasia can undergo dysplasia, thus initiating a dysplasia-carcinoma sequence.
Biliary Papillomatosis/Intraductal Papillary Neoplasms
Choledochal cyst can be complicated by the development of biliary papillomatosis followed by adenocarcinoma (Negi et al. 2009). A patient with congenital choledochal cyst associated with intrahepatic gallstones developed biliary papillomatosis with point mutation of the K-ras gene (Ohita et al. 1993).
Very rarely, choledochal cysts are complicated by development of sarcomas , e.g., pleomorphic rhabdomyosarcoma (Tufail et al. 2006). On the other hand, embryonal rhabdomyosarcoma of the common bile duct may radiologically mimic choledochal cyst in childhood (Tireli et al. 2005).
Carcinoma Arising in Caroli’s Disease
Caroli’s disease is a congenital disorder of the hepatobiliary tract characterized by usually nonobstructive fusiform or saccular dilatations of larger intrahepatic bile ducts (review: Yonem and Bayraktar 2007). Probably owing to progressive damage and regeneration of epithelia, there is an increased risk of cholangiocarcinoma (Leroy et al. 1980; Balsells et al. 1993; Falco et al. 1993; Abdalla et al. 1999; Totkas and Hohenberger 2000; Wang 2002; Vlachogiannakos et al. 2004; Kasper et al. 2006). Cholangiocarcinoma was observed in a female patient with Caroli’s disease accompanied by hepatolithiasis and choledochlithiasis (Takei et al. 1991). Carcinoma in situ of dilated bile duct segments was detected in Caroli’s disease (Joly et al. 1990).
Carcinoma Arising in Ciliated Foregut Cyst
Ciliated foregut cyst is a rare congenital cystic lesion of the liver derived from the embryonic foregut. The term was coined in 1984 to describe an hepatic cyst sharing common histologic features with both esophageal and bronchial/bronchogenic cysts (Wheeler and Edmondosn 1984). The cysts are thought to originate from evagination of a foregut component into the liver anlage. This type of cyst is usually located in the left liver lobe, with a strong predilection for segment IV, but it has also been observed in the right liver lobe, the gallbladder, the pancreas, and the retroperitoneal space. The cyst is lined by a single layer of ciliated cuboidal to prismatic cells. A little more than 100 cases have been reported, with less than 20 cases diagnosed in children (review: Fujita et al. 2011). Carcinomas can develop in ciliated foregut cysts. Almost all cases were squamous cell carcinomas (Vick et al. 1999; de Lajarte-Thirouard et al. 2002; Furlanetto and De Tos 2002; Zhang et al. 2009). This type of carcinoma may develop on the basis of squamous metaplasia known to occur in foregut cysts of the liver. In most instances, metaplasia was found in cysts that also had squamous cell carcinoma (Vick et al. 1999; de Lajarte-Thirouard et al. 2002; Furlanetto and Dei Tos 2002). In one case without associated carcinoma, the cyst was lined mainly by a regular squamous epithelium without keratinization. The squamous epithelial cells expressed cytokeratin 5/6 and cytokeratin 19, while the superficial squamous cells expressed cytokeratin 7. Focally, a ciliated pseudostratified columnar epithelium with some goblet cells was found. This ciliated epithelium expressed cytokeratins 7 and 19 (Ben Mena et al. 2006).
Cancer Arising in Nonparasitic Simple Liver Cysts
Cholangiocarcinoma can develop in simple developmental liver cysts (Ackerholm et al. 1981). Typically, the involved cysts show hemorrhage and/or inflammatory changes and have been found to be filled with chocolate-colored fluid. Squamous cell carcinoma was also demonstrated in simple nonparasitic cysts (Richmond 1956; Greenwood and Orr 1972; Bloustein and Silverberg 1976; Bloustein 1977; Lynch et al. 1988; Nieweg et al. 1992; Pliskin et al. 1992; Banbury et al. 1994; Weimann et al. 1996; Monteagudo et al. 1998; Hsieh et al. 2005). Symptoms and signs described in this type of tumor include pain and loss of weight. Jaundice and a palpable mass in the epigastrium have sometimes been found. At least a part of the tumors described in the literature were large lesions within remnants of a cyst. The carcinoma often grows into the tissue encircling the cyst, making resection difficult. The tumor tends to metastasize to the locoregional lymph nodes, while remote metastases have less often been found. Large squamous cell carcinoma tends to undergo necrosis and form central cysts, but the presence of innocuous epithelium in the cystic parts of the mass excludes the possibility that the cyst had arisen from necrosis of a preexistent primary or metastatic solid tumor. Biliary carcinosarcoma was also found in a simple liver cyst (Terada et al. 1994).
Carcinoma in Autosomal Dominant Polycystic Disease
Intrahepatic cholangiocarcinoma rarely develops in autosomal dominant polycystic kidney disease (ADPKD) with liver involvement (Imamura et al. 1984; Kataoka et al. 1985; Carone et al. 1994; Sasaki et al. 2002; Matsuoka et al. 2005). In one autopsy case (Sasaki et al. 2002), a 69-year-old man with known ADPKD, the liver was mildly enlarged, and many cysts up to 3 cm in diameter were mainly distributed along the biliary tree at the liver hilus and to a lesser degree in the hepatic parenchyma. A yellowish-white firm tumor (6 cm) was present in the right hepatic hilus, extending into the right lobe of the liver and involving several of the cystic lesions. Histologically, the mass was composed of a well to moderately differentiated, desmoplastic tubular adenocarcinoma with vascular, lymphatic, and perineural invasion. In addition, there was well-differentiated papillary adenocarcinoma spreading in the lumen of several cysts embedded in and adjacent to the main carcinoma.
Cystadenocarcinoma Originating from Hepatic Cysts
Cholangiocarcinoma in Disorders of the Pancreaticobiliary Ductal Union
Anomalous pancreaticobiliary ductal union (APBDU ; synonym: pancreaticobiliary maljunction) is a congenital anomaly more commonly encountered in Asian than Western countries and significantly more common in females. The common feature of this condition is a pancreaticobiliary ductal union located proximal to the sphincter of Oddi, an anomaly first reported in 1969 (Babbitt 1969). APBDU is, therefore, characterized by union of the pancreatic and bile ducts located outside the duodenal wall, forming a very long common channel (usually >15 mm; average length in one study, 24.7 mm, Tanaka et al. 1998). Normally, the two ducts open into the duodenum either separately or via a common channel. The length of the common channel in normal subjects ranges from 1 to 12 mm, with a mean of 4.5 mm (Misra et al. 1989; Misra and Dwivedi 1990). The mode of union has been classified into two groups. The biliary-pancreatic (B-P) type junction has a common bile duct joining the main pancreatic duct; the pancreatic-biliary (P-B) type junction is the reverse of this (Kimura et al. 1985). APBDU may also be classified into dilated and non-dilated types in regard to the morphology of the common bile duct, the dilated type being more frequent. In a study of 1627 patients with APBDU enrolled and analyzed by the Japanese Study Group on Pancreaticobiliary Maljunction, 1239 patients had the dilated type, and 388 had the non-dilated type. Individuals with latter type were significantly older than those of the former (47 years vs. 24 years, respectively). APBDU is associated with various pancreaticobiliary diseases, including pancreatitis and biliary cancer (Kato et al 1983; Kamisawa et al. 2002, 2003, 2006, 2009b, 2010b; Matsumoto et al. 2002; Kimura et al. 2005; Miyazaki et al. 2008; Funabiki et al. 2009; Kimura 2009). The occurrence rate of cancer in the biliary tract was 10.6 % in the dilated type and 37.9 % in the non-dilated type (Tashiro et al. 2003).
APBDU is associated with a narrow portion of the terminal choledochus, and this narrow distal segment represents the functional region of the sphincter of Oddi (Kune 1964, 1970). Hence, the presence of APBDU is determined by two parameters, the length of the common channel and the length of the narrow segment (review: Nomura et al. 2002). Among patients with APBDU, biliary dilatation (>10 mm) was more frequent in those with the narrow choledochal portion (Nomura et al. 2005). A distinct entity is dilatation of the intrahepatic bile duct system associated with anomalous junction of the cystic duct, in the absence of APBDU (Ohama and Ishikawa 2006). APBDU is likely to be caused by disturbance in the morphogenesis of the connections of the pancreatic and biliary duct system that occurs very early during gestation when the common bile duct joins with the ventral pancreatic duct system (Matsumoto et al. 2001). Familial occurrence of APBDU has been described (Miyazaki et al. 1989). The long common channel causes two-way fluid regurgitation, with bile flowing into the pancreatic duct and pancreatic juice flowing into the bile duct, because the sphincter now cannot functionally affect the channel (Kamisawa and Okamoto 2006; Kamisawa et al. 2009a). There is a relation between pancreaticobiliary reflux and the length of the common channel. The minimum length of a common channel that could induce a markedly elevated amylase level in bile was determined as 5 mm. Based on this observation, high confluence of pancreaticobiliary ducts (HCPBD) was defined as cases with a common channel > or = 5 mm, in which the communication between the pancreatic and bile ducts was occluded with the sphincter contraction (Kamisawa et al. 2010a). In the majority of cases, APBDU is associated with a normal intrapancreatic duct morphology, but in a minority, there is dorsal pancreatic duct dominance. In this situation, most pancreatic juice in the upper dorsal pancreatic duct is drained into the duodenum through the minor duodenal papilla, and reflux of pancreatic juice to the biliary tract may be reduced, resulting in reduced damage (Kamisawa et al. 2005).
How frequent is APBDU? Among 680 individuals with clearly visualized pancreaticobiliary radiograms during ERCP, 8.7 % had APBDU (Wang et al. 1998). In a nationwide Korean cooperative prospective study of 10,243 patients undergoing ERCP, the frequency of APBDU and choledochal cyst was 4.1 % and 0.32 %, respectively (Kim et al. 2002). In a prospective study of 354 ERCP cases, a common channel was detected in 131 cases (37 %). Among these, 11 had APBDU and 13 a high confluence of pancreaticobiliary ducts (Kamisawa et al. 2007). A strong association of APBDU with congenital duct dilatation or choledochal cyst has been confirmed in several studies (Kimura et al. 1977; Ono et al. 1982; Todani et al. 1984; Okada et al. 1990), the incidence ranging from 64 % (Song et al. 1999) to 93.8 % (Wang et al. 1998). In one study, APBDU was found only in type I and type IV choledochal cysts according to Todani’s classification (Song et al. 1999). In congenital dilatation of the common bile duct associated with APBDU, epithelial hyperplasia accompanied by round cell infiltration and increased thickness of the duct wall with fibrosis was observed histologically in the resected bile duct in all patients (Oguchi et al. 1988).
Cholangiocarcinoma of the Extrahepatic Bile Ducts in APBDU
Cholangiocarcinoma involving the extrahepatic bile duct in APBDU is less often reported than gallbladder carcinoma, and the incidence varies considerably in the different reports (Kato et al. 1983; Suda et al. 1983; Strijk et al. 1984; Ohta et al. 1990; Tsai 2001; Nakamura et al. 2008; Saji et al. 2010). In an autopsy study of 72 cases of biliary tract carcinoma APBDU was found in 8/34 cases of common bile duct carcinoma and in 4/24 gallbladder carcinomas (Suda et al. 1983). Cholangiocarcinoma in APBDU associated with congenital biliary dilatation can already develop in childhood (Tanaka et al. 2006; Saikusa et al. 2009). In one study, 9/27 (33.3 %) patients with APBDU had common bile duct cancer, but only 1/47 (2.1 %) had hilar carcinoma (Wang et al. 1998). In another study, a long common channel was an infrequent finding in patients with cholangiocarcinoma. The mean length of the common channel in patients with cholangiocarcinoma was 6.43 mm, which was comparable to the length of the common channel in normal subjects (Sharma 1994). In a nationwide survey in Japan, a close relationship was shown between biliary tract carcinogenesis and APBDU, according to the type of maljunction (dilated vs. non-dilated types) and age distribution. APBDU patients with cystic dilatation of the bile duct had a high risk of bile duct cancer, even in those who were young (aged less than 20 years), and the incidence of gallbladder cancer increased markedly in patients older than 40 years. In contrast, the incidence of gallbladder carcinoma gradually increased in APBDU patients having the undilated type (Hasumi et al. 2000; Miyazaki et al. 2008). In a study of 38 patients with APBDU, the incidence of malignancy was 17.8 % in the dilated type (two patients with cholangiocarcinoma and three with gallbladder carcinoma) and 90 % in the non-dilated type (all with gallbladder carcinoma) (Tanaka et al. 1998). The predominance of gallbladder carcinomas over cholangiocarcinomas in non-dilated APBDU was shown in a previous study (Tanaka et al. 1993). The importance of the bile dilation status was confirmed in another study. Ninety-eight cases of APBDU were divided into five groups according to the maximum diameter of the extrahepatic bile duct. Gallbladder carcinoma developed in 55 % of patients whose maximum diameter of the extrahepatic duct was < or = 30 mm, but no gallbladder carcinoma occurred in patients with APBDU whose duct diameter was > or = 31 mm. Bile duct carcinoma occurred in 12 % of patients whose duct diameter was > or = 21 mm, but no bile duct carcinoma occurred in those with a duct diameter of < or = 20 mm (Kamisawa et al. 2006).
Carcinoma of the Gallbladder in APBDU
APBDU confers a significant risk for gallbladder cancer. There is a clear predominance of female patients (Kamisawa et al. 2008). Even a long common channel (≥8 mm) in the absence of APBDU is associated with a higher frequency of gallbladder carcinoma (review: Misra and Dwivedi 1990). Among 106 Japanese patients with biliary tract cancer (58 patients with gallbladder carcinoma and 48 patients with cholangiocarcinoma), 10 patients (9.4 %) had APBDU (Sandoh et al. 1997). In a Chinese cohort of patients, the frequency of APBDU was significantly higher in patients with gallbladder carcinoma (Hu et al. 2003). Among 14 patients with APBDU, five patients developed gallbladder carcinoma, associated with a more frequent development of gallbladder mucosal metaplasia (Jung et al. 2004).
Kato et al. 1983; Kimura et al. 1985; Nagata et al. 1985; Yamauchi et al. 1987; Miyazaki et al. 1989; Sautereau et al. 1989; Ohta et al. 1990; Mori et al. 1993, 1999; Tanaka et al. 1993; Sandoh et al. 1997; Chang et al. 1998; Tanno et al. 1998a; Yoshida et al. 1999; Hasumi et al. 2000; Jung et al. 2004; Adham et al. 2005; Minami et al. 2008; Oshiro et al. 2008; Lahmar et al. 2010.
APBDU may be associated with hyperplastic polyp of the gallbladder (Okada et al. 2009), with adenomyomatosis of the gallbladder (more often in the presence of the undilated type of APBDU; Chang et al. 1998; Tanno et al. 1998b), and with multiseptate gallbladder (Yamamoto et al. 2005).
Pathogenesis of Cancer in APBDU
APBDU is associated with hyperplastic, metaplastic, and dysplastic alterations in the extrahepatic biliary tract and the gallbladder (review: Tsuchida and Itoi 2010). Children with APBSU showed epithelial hyperplasia of the gallbladder mucosa in up to 60 % (Tanno et al. 1999). In adults, 63 % of patients with APBDU has gallbladder epithelial hyperplasia, and this hyperplasia was significantly more frequent in the undilated type of APBDU. 2/9 high-grade hyperplasias revealed codon 12 K-Ras mutations (Tanno et al. 1998a). APBDU is associated with papillary epithelial hyperplasia in both the extrahepatic bile ducts and the gallbladder, which is a precursor lesion for cancer (Seki et al. 2005). In a study of 45 children with APBDU (median age: 2.9 years), the most common histological finding was villus-type mucosal hyperplasia (57.1 %) (Ono et al. 2010). Diffuse papillary hyperplasia of the gallbladder mucosa in APBDU exhibits senescent features such as expression of p16(INK4A) and low cell proliferative activity and is induced by lysolecithin, a lipid the level of which is elevated in gallbladder bile in APBDU (Yamaguchi et al. 2009). An effect of APBDU on carcinogenesis is shown in choledochal cysts, where carcinomas develop more frequently when the cysts are associated with APBDU (Song et al. 1999). Mutation of K-Ras (codon 12) seems to be involved in APBDU-associated biliary tract cancers (reviews: Matsubara et al. 1995; Matsumoto et al. 2003; Tsuchida et al. 2003a). In a series of 20 adult patients with APBDU, point mutations of K-Ras were detected in 80 % of the cancerous cases and 58 % of the hyperplastic and metaplastic lesions (Matsubara et al. 1996). Among 35 pediatric patients with APBDU, PCR analysis of cholangiocyte DNA revealed that K-Ras mutations were detected in five children, four of whom showed epithelial hyperplasia or metaplasia. In a 12-year-old girl, adenocarcinoma had developed in a choledochal cyst, and here both K-Ras and DPC-4 (Smad-4) mutations were found, suggesting a multistep cancerogenic process with K-Ras mutations occurring as an early event (Shimotake et al. 2003). Mutations of K-Ras and p53 genes were also found in noncancerous biliary epithelia of adult patients with APBDU (Matsubara et al. 2002). Even in the presence of a relatively long common channel (high confluence) alone without fulfilled criteria of APBDU, overexpression of p53 and K-Ras was found in epithelial of the gallbladder (Kamisawa et al. 2004). In gallbladder mucosal cells of patients with APBDU, Bcl-2 expression and activation of telomerase are early events involved in carcinogenesis (Ichikawa et al. 2004).
There is evidence that the COX-2 pathway is involved in APBDU-induced carcinogenesis. Generally, COX-2 expression is strongly related to cancer progression or development by means of its anti-apoptotic effect, promotion of angiogenesis, and/or decrease of cell-to-cell adhesive activity. Bile from APBDU can significantly promote the proliferation of human cholangiocarcinoma cells. This response is associated with marked upregulation of COX-2 transcripts, and the proliferative reaction can be abolished by a COX-2 inhibitor (Wu et al. 2003). Immunohistochemically, overexpression of COX-2 in biliary tract tissues of patients with APBDU was found in 20 % of regenerative epithelium, 11.1 % of hyperplasia without atypia, 86.4 % of hyperplasia with mild atypia, and 75 % each of dysplasia and carcinoma. COX-2 expression was associated with expression of VEGF (Tsuchida et al. 2003c). In a second immunohistochemical study, COX-2 expression in noncancerous biliary tract tissue of patients with APBDU and biliary cancer was 20 % vs. 7.1 % in patients without APBDU (Watanabe et al. 2004).
The reflux phenomena associated with APBDU may cause bacterial colonization of the biliary tract. One microorganism considered to be a causative factor for biliary cancer is Helicobacter bilis. By the use of PCR analysis of bile juice and biliary tissue samples, it has been shown that Helicobacter bilis colonization of the biliary system is very common in patients with APBDU (Kosaka et al. 2010).
APBDU causes regurgitation of pancreatic juice into the biliary tract and into choledochal cysts. In choledochal cysts associated with APBDU, fatty acid calcium stones (Kaneko et al. 2008) and protein plugs develop. One component secreted by pancreatic acinar cells is lithostathine, which is an important component of protein plugs. Lithostathine is the major nonenzymatic protein of pancreatic secretions and has several synonyms, including pancreatic stone protein, protein-X, pancreatic thread protein, and P19, and is now termed Reg protein (review: De Reggi and Gharib 2001). The Reg I gene makes a part of the Reg protein gene family and encodes a 166-amino acid glycosylated protein with a 22-amino acid signal peptide (review: Okamoto 1999). The Reg I gene product has been identified as a regenerative/proliferative factor for pancreatic islet cells, but it is also active in other cell systems and in cancer cells and affects liver regeneration (Wang et al. 2009). It is upregulated in blood after trauma, and here it binds to and activates neutrophils (Keel et al. 2009).
In choledochal cysts associated with APBDU, protein plugs are an important or dominant cause of symptoms, and the plugs consist mostly of lithostathine. Activated trypsin from pancreatic juice is present together with lithostathine in bile of APBDU patients (Ochiai et al. 2004), and trypsin cleaves soluble lithostathine into insoluble forms that aggregate to form plugs (Kaneko et al. 2007). Lithostathine-containing protein plugs in choledochal cysts/APBDU are dissolved by acidic and basic solutions (Kaneko et al. 2009).
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