Precancerous lesions of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC), also known as cholangiocellular carcinoma or peripheral bile duct carcinoma, is an intrahepatic malignant tumor that consists of cells resembling the biliary epithelium. The proportion of ICC among primary hepatic malignancies is approximately 10% worldwide. Although the etiology and pathogenesis remain unclear in a great majority of cases, preceding pathologic conditions or etiologies in the development of ICC are known or suspected in a proportion of these patients. Some forms of ICC, such as those associated with hepatolithiasis or liver fluke infestation, are endemic in parts of the world, particularly in East Asia. ICC is reportedly a late complication of primary sclerosing cholangitis. Most of these preceding pathologic conditions are forms of chronic cholangitis, and longstanding inflammation, chronic injury, and regenerative hyperplasia of the biliary epithelium may be causally related to malignant transformation. Biliary epithelial dysplasia is encountered in the intrahepatic bile ducts both near and remote from ICC foci in the liver and near and remote from the chronically inflamed biliary tree. This lesion could be a precancerous lesion, and it shows telomerase activity and increased proliferative activities. Furthermore, congenital and developmental disorders of the biliary system, such as Caroli's disease, congenital hepatic fibrosis, and pancreatico-biliary malformation are occasionally associated with ICC. Benign biliary tumors, such as biliary papillomatosis, may eventually undergo malignant transformation. These lesions could be regarded as precancerous or borderline lesions. Some ICCs may also develop in nonbiliary viral cirrhosis. In the majority of cases of ICC, however, the etiology, pathogenesis, and developmental processes and precancerous lesions of the ICC remain unclear.     

Pathology and pathogenesis of intrahepatic bile duct loss

In recent years, the pathology and pathogenesis of bile duct loss have been extensively studied, and a num‐ber of hepatobiliary diseases have been added to the list of ductopenic diseases. In addition, the biology of biliary epithelial cells is now being studied with respect to bile duct loss, as well as biliary epithelial neoplasia. In this review, recent advances in pathogenetic and pathological studies of intrahepatic bile duct loss are described, with an emphasis on immune‐mediated cholangiopathies. The bile duct loss, an acquired and pathologic process that occurs in the biliary tree, is recognizable as an absence of bile duct in an individual portad tract, and also as such absence in the vicinity of parallel running hepatic arterial branches that constitute the portal triad. Immunostaining with biliary cytokeratin and other carbohydrate materials is useful for the identification of biliary elements in the inflamed portal tracts or fibrous septa. The underlying processes responsible for bile duct loss include immunological, ischemic, infectious, metabolic, and toxic processes. Bile duct loss in primary biliary cirrhosis and primary sclerosing cholangitis is immune‐mediated, that in interventional radiology using hepatic arterial branches is related to biliary ischemia, while that in hepatic allograft rejection is related to both immunological and ischemic insults. Bacterial and viral cholangitis with bile duct loss is an example of infectious cholangitis. The biliary tree maintains its homeostasis by renewal and dropout, and bile duct loss occurs mainly via biliary apoptosis. In some patients with bile duct loss, such as occurs in drug‐induced injuries, the bile ducts regenerate and finally redistribute in the liver, while in other types of bile duct loss, the loss is progressive and is followed by vanishing bile duct syndrome, leading to biliary cirrhosis or liver transplantation. More analysis of the biology of biliary epithelial cells is mandatory for the evaluation of the pathobiology of bile duct loss, as well as for the effective restoration of biliary epithelial cells, in ductopenic liver diseases.     

肝内胆管细胞癌的临床病理学观察

常见肝内胆管恶性肿瘤有肝内胆管癌（ICC）、细胆管细胞癌（CLC）及混合细胞型肝癌（CHC）中的胆管癌成分。ICC是肝脏第二常见恶性肿瘤,根据我院手术切除的3．3万余例肝脏恶性肿瘤的病理资料统计,肝细胞癌（HCC）和ICC分别占85．6％和7．7％,ICC的发病呈逐年上升趋势,具有易转移复发的生物学特性;CLC少见,因起源于肝脏双向分化的前体细胞而具有侵袭性强的特点;CHC的病理检出率有增多趋势,预后较HCC和ICC更差。准确的病理分型对于临床诊治和预后评估具有实际意义。     

Epidemiology, risk factors, and pathogenesis of cholangiocarcinoma

Cholangiocarcinoma (CCA) is a fatal cancer of the biliary epithelium, arising either within the liver (intrahepatic, ICC) or in the extrahepatic bile ducts (extrahepatic ECC). Globally, CCA is the second most common primary hepatic malignancy. Several recent epidemiological studies have shown that the incidence and mortality rates of ICC are increasing. This review of the literature on the international epidemiological rates of CCA, both intra- and extrahepatic, explores possible explanations for the trends found. The possible role of epidemiological artifact in the findings is discussed and the known risk factors for CCA are summarized. These include primary sclerosing cholangitis, liver fluke infestation, congenital fibropolycystic liver, bile duct adenomas, and biliary papillomatosis, hepatolithiasis, chemical carcinogens such as nitrosamines, Thorotrast, chronic viral hepatitis, cirrhosis, chronic non-alcoholic liver disease and obesity. Potential pathways involved in the molecular pathogenesis of CCA are also summarized.     

Successful treatment of complex cholangiolithiasis following orthotopic liver transplantation with interventional radiology

Bile duct stones are a serious and the third most common complication of the biliary system that can occur following liver transplantation.The incidence rate of bile duct stones after liver transplantation is1.8%-18%.The management of biliary stones is usually performed with endoscopic techniques;however,the technique may prove to be challenging in the treatment of the intrahepatic bile duct stones.We herein reporta case of a 40-year-old man with rare,complex bile duct stones that were successfully eliminated with percutaneous interventional techniques.The complex bile duct stones were defined as a large number of bile stones filling the intra-and extrahepatic bile tracts,resulting in a cast formation within the biliary tree.Common complications such as hemobilia and acute pancreatitis were not present during the perioperative period.The follow-up period was 20 mo long.During the postoperative period,the patient maintained normal temperature,and normal total bilirubin and direct bilirubin levels.The patient is now living a high quality life.This case report highlights the safety and efficacy of the percutaneous interventional approach in the removal of complex bile duct stones following liver transplantation.     

Intraductal papillary neoplasm of the bile duct extending superficially from the intrahepatic to extrahepatic bile duct

Intraductal papillary neoplasm of the bile duct (IPNB) or liver is a recently noted rare disease, and its pathogenesis remains unclear. Here we present a case of IPNB with an interesting morphology, which was treated by resection of the right hemiliver and extrahepatic bile duct. A 79-year-old woman was found to have a high alkaline phosphatase level and slight dilatation of the right intrahepatic bile duct on imaging studies. The right intrahepatic bile duct became dilated over a 2-year period; however, no solid mass could be detected, and tumor markers were not elevated. Hepatic resection was scheduled because a mucin-producing bile duct carcinoma of the liver was suspected. A right hemihepatectomy was conducted, and the extrahepatic bile duct was also resected after malignant cells were found in the surgical stump of the right bile duct and in the bile itself. Macroscopically, diffuse dilatation of the intrahepatic bile duct was noted, but no solid component or mucin within the duct was found. Histopathological findings revealed carcinoma in situ, IPNB, in the majority of intrahepatic bile ducts, with no lymph node metastasis, and it extended continuously to the epithelium of the common bile duct. No tumor recurrence or biliary dilatation was observed at follow-up 2 years after surgery. It is important to consider malignancy in the presence of a dilated bile duct and in the absence of any cause of occlusion. Complete resection of IPNB results in a good prognosis and no recurrence.     

Insemination of bile duct carcinoma to the liver after insertion of percutaneous biliary endoprosthesis

Percutaneous transhepatic biliary drainage is widely used to relieve bile duct obstruction which can be caused by bile duct or pancreas carcinomas. Although the incidence is low, insemination of carcinoma along the transhepatic catheter tract is considered to be a serious complication of percutaneous transhepatic biliary drainage. The authors present a case of intrahepatic insemination of bile duct carcinoma along the catheter that subsequently underwent a curative resection consisting of pancreaticoduodenectomy and right hepatic lobectomy. It is suggested that a percutaneous biliary endoprosthesis through the tumor should be avoided in patients in whom a possible curative resection can be considered. External biliary drainage should only be performed in order to minimize the manipuIation of the tumor in such patients.     

Pathological classification of intrahepatic cholangiocarcinoma based on a new concept

Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic differentiation. To date, ICC was largely classified into adenocarcinoma and rare variants. Herein, we propose to subclassify the former, based on recent progress in the study of ICC including the gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is, ICC is classifiable into the conventional (bile duct) type, the bile ductular type, the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic parenchyma. Hepatic progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites, IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB, particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma, mucinous/signet ring cell carcinoma, clear cell type, undifferentiated type, neuroendocrine carcinoma and so on. This classification of ICC may open up a new field of research of ICC and contribute to the clinical approach to ICC.     

先天性胆管扩张症合并肝内胆管扩张的手术治疗对策

目的探讨先天性胆管扩张症合并肝内胆管扩张的手术治疗对策,以提高手术的远期疗效。方法第1组不管是否提示合并肝内胆管扩张,均单纯行扩张胆总管、胆囊切除,肝总管空肠Roux—en—Y吻合。第2组在第1组手术术式基础上,对胆管狭窄者行胆管成形术和冲洗处理胰胆管共同通道。采用时序分组进行对比分析研究。结果第1组13例,6例合并肝内胆管扩张,4例为囊样扩张。第2组共46例,18例有肝内胆管扩张,其中11例为囊样扩张,同时存在胆管狭窄。第2组术后腹痛、胆道感染的发生率明显低于第1组。讨论在标准根治术(囊肿切除胆道重建)的基础上对近端肝内胆管狭窄矫治、可能存在的复杂胆道畸形的处理及远端胰胆管共同通道冲洗,可有效降低术后胆道胰管并发症的发生,提高手术远期疗效。     

Epithelial cell proliferation activity of the biliary ductal system with congenital biliary malformations

Congenital biliary malformations such as anomalous arrangement of the pancreaticobiliary ductal system (AAPB), congenital cystic dilatation of the common bile duct (CCDB), and congenital biliary strictures at the hepatic hilum (CBSH) are newly designated disease entities and are frequently found in adult patients with biliary malignancy such as gallbladder carcinoma, common bile duct carcinoma, and intrahepatic bile duct carcinoma. In the present study, the relationship of these malformations and biliary malignancy was investigated. We studied 61 gallbladders of patients with AAPB and 56 gallbladders of patients without AAPB; 16 common bile ducts of patients with CCDB (12 with AAPB and 4 without AAPB) and 11 gallbladders of patients without CCDB; and 17 intrahepatic bile ducts of patients with CBSH and 6 intrahepatic bile ducts of patients without CBSH. Tissue sections from the mucosa of the gallbladder, common bile duct, and intrahepatic bile duct were stained for proliferating cell nuclear antigen (PCNA). The PCNA labeling indexes of patients with these malformations were significantly higher than those of patients without these malformations (P < 0.05). Cell proliferation of the epithelia in the biliary ductal system in patients with these congenital biliary malformations was accelerated. Consequently, these congenital malformations appear to be an important risk factor for the occurrence of biliary malignancy.     

Effects of secretin on bile production in two kinds of cholestatic models by choledocho-caval fistula and bile duct ligation in rats

Secretin is known to stimulate bile flow from the bile duct epithelium. To investigate the effects of secretin in cholestasis, we studied the response of the bile flow and the excretion of biliary components to secretin using two cholestatic models with or without damage to the bile duct epithelium. The model without bile duct epithelial damage was a choledocho-caval (CC) fistula over a 24-hour period, and the model with bile duct damage was a bile duct ligation over a 48-hour period. Secretin was administered by intravenous infusion for 30 minutes and bile was collected for 120 minutes. Controls were given saline similarly. The bile flow and biliary bicarbonate excretion rate were significantly increased after secretin infusion in the CC fistula rats when compared with the control rats, but no stimulation by secretin was observed in the ligated rats. These data indicate that secretin-induced bile production was enhanced under cholestatic conditions with no bile duct epithelial disturbance.     

Anatomic and molecular pathology of intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is the second most common malignant tumor of the liver, and ICC is reportedly increasing recently. ICC is usually adenocarcinoma with variable desmoplastic reaction, although there are several special or unusual histological features. ICC may arise at the large intrahepatic bile duct near the hepatic hilus and also from the bile ductules at the border of the hepatic parenchyma. On the anatomical level, the pathology of ICC differs depending on the region from which the ICC arises. At the large intrahepatic bile duct, ICC presents papillary growth and periductal infiltration. Some cases show extensive papillary growth and intraluminal spread with marked gastroenteric metaplasia. Mucus core protein 1 is expressed in aggressive ICC. ICC arising from ductules shares phenotypes of hepatocellular carcinoma. ICC in chronic biliary diseases, particularly arising in hepatolithiasis, presents precancerous lesions that include biliary epithelial dysplasia, as well as in-situ carcinoma. Chronic advanced hepatitis C is one of the background diseases of ICC. Chronic inflammation, with the upregulation of cyclooxygenase-2 and growth factors, and the formation of reactive oxygen species are one of the causative factors in the DNA damage of biliary epithelial cells. K-ras mutation and aberrant expression of p53 are found in one-third of ICCs. The latter may be due to mdm-2 upregulation. Hepatocyte growth factor/met and interleukin 6 (IL6)/IL6 receptor are involved in cell proliferation/mitoinhibition and apoptosis in ICC. Fibrous stroma formation and invasion involve the proliferation of Α-smooth muscle antigen-positive stromal cells, and cell-to-cell and cell-to-matrix interactions involving E-cadherin/catenin and CD44 and matrix proteinases may be involved in the invasion of ICC. Evasion of immune surveillance involving the Fas/FasL system is important in the malignant progression of ICC. Further molecular and genetic studies are mandatory to evaluate the pathogenesis and progression of ICC.     

Protein expression of double‐stranded RNA‐activated protein kinase (PKR) in intrahepatic bile ducts in normal adult livers,fetal livers,primary biliary cirrhosis,hepatolithiasis and intrahepatic cholangiocarcinoma

Abstract: Background/Aim: The protein expression of double‐stranded RNA‐activated protein kinase (PKR) in intrahepatic bile ducts has not been investigated. Methods: Immunohistochemistry and a semiquantitative scoring method in normal liver and biliary diseases were used for the investigation. Results: In “normal” adult livers (n=10), intrahepatic bile ducts were negative for PKR. In normal fetal livers (n=25), primitive biliary epithelia were almost negative for PKR. In primary biliary cirrhosis (PBC) (n=30), damaged bile ducts were frequently positive for PKR, while uninvolved bile ducts were negative. In hepatolithiasis (n=27), proliferated bile ducts were positive for PKR, and the PKR score correlated with the degree of proliferation. In cholangiocarcinoma (CC) (n=44), PKR expression was frequently noted, and the PKR score correlated with good differentiation of CC, being highest in well‐differentiated CC and lowest in poorly‐differentiated CC. The PKR score decreased in the following order: CC (mean PKR score=3.96), hepatolithiasis (2.56), PBC (1.60), normal fetal liver (0.40), and normal adult livers (0.00). The PKR expression in hepatocytes was “baseline” in normal adult livers, while moderately increased in fetal livers, PBC, hepatolithiasis and CC. Conclusions: Although the significance of these data is unclear, they suggest (i) that PKR is absent in bile ducts in normal adult and fetal livers, (ii) that PKR in bile duct cells newly emerges or increases in PBC, hepatolithiasis, and CC, (iii) that PKR accumulates in damaged bile ducts in PBC, (iv) that PKR increases in parallel with biliary cell proliferation in hepatolithiasis, and (v) that PKR expression correlates with differentiation in CC. PKR expression in intrahepatic bile ducts seems to be associated with inflammation or cell proliferation of the bile duct cells.     

Demonstration of nucleolar organizer regions in intrahepatic bile duct carcinoma by the silver-staining technique

Abstract— A silver colloid technique to identify argyrophilic nucleolar organizer region associated protein (AgNOR) was applied to 43 cases of intrahepatic bile duct carcinoma (cholangiocarcinoma, CC), 2 with bile duct adenoma (BDA), 5 with focal duct epithelial hyperplasia (FEH) associated with hepatolithiasis, 15 with posthepatitic ductular proliferation (PHDP) associated with massive or submassive hepatic necrosis and 20 of normal liver. In the present study, only discrete, easily counted black dots within nuclei and silver-stained nucleolus were counted under a magnification of X 400 without oil-immersion objectives. The mean AgNOR count of CC was significantly higher than those of BDA, FEH, PHDP and normal controls (P>0.05, P>0.001, P>0.01, and P>0.001, respectively). Among CCs the mean AgNOR numbers of papillary adenocarcinoma (pap), moderately (tub2) and poorly differentiated (por) adenocarcinoma, and adeno-squamous carcinoma (as) were significantly higher than that of normal controls (P > 0.01, P > 0.001, P > 0.001 and P > 0.001, respectively), and those of tub2, por and as were also significantly higher than those of BDA, FEH and PHDP, whereas that of well differentiated tubular adenocarcinoma (tub 1) was not different from those of BDA, FEH, PHDP and normal controls, and that of pap was not different from those of BDA, FEH and PHDP. The mean numbers of AgNORs of BDA and FEH were not different from that of normal controls, whereas that of PHDP was significantly higher than that of normal controls (P > 0.01). Interestingly, the mean AgNOR counts of tubular adenocarcinoma were increased with histologic tumor grades. All cases with AgNOR counts of more than 2.24 had CC. Furthermore, not only quantitative but also striking qualitative abnormalities of AgNORs were seen in CCs. Large and/or irregularly shaped AgNORs without uniformity in size and density were characteristic for CCs, even in well differentiated adenocarcinoma, in contrast to the small, round, regular AgNORs seen in normal bile duct epithelium and rather large but regular AgNORs seen in benign bile duct lesions. These results indicate that the enumeration of AgNORs in various bile duct lesions is useful to identify moderate and high grade CCs and to evaluate tumor grade, but not useful to discriminate well differentiated adenocarcinoma from benign lesions. In case of normal or equivocal AgNOR counts, the presence of large and/or irregularly shaped AgNORs without uniformity in size and density would favor a diagnosis of carcinoma rather than benign counterparts.     

A case of asymptomatic intraductal papillary neoplasm of the bile duct without hepatolithiasis

A 65-year-old woman was found to have dilatation of the intrahepatic bile duct in the right anterior segment during a general health. Laboratory data were within normal ranges and no solid mass was detected in her abdominal computer tomography （CT） or nuclear magnetic resonance imaging （MRI）. However, endoscopic retrograde cholangiopancreatography （ERCP） demonstrated an obstruction of the right bile duct. Intraoperative cholangiography showed stenosis of the intrahepatic bile duct in the anterior inferior segment （B5） and narrowness of the intrahepatic bile duct in the anterior superior segment （B8）, so that we strongly suspected intrahepatic cholangiocarcinoma （ICC）. Histologically, surgically resected liver specimens, without tumor mass by macroscopic observation, showed intraductal papillary proliferation with fibrovascular cores and intraductal spreading of carcinoma in situ throughout a considerable area, especially in bile ductules around the peripheral small portal area. Furthermore, the immunohistochemical profile of the tumor （MUC5AC＋/CK7＋） was compatible with an intraductal papillary neoplasm of the bile duct （IPN-B）. Consequently, this case was diagnosed as IPN-B with spreading CIS, stageⅠ（pT1, pN0, P0, H1, M0）. We report a case of IPN-B with interesting histopathologicalfindings and emphasize that cholangiography is especially helpful for the diagnosis of bile duct dilatation due to infiltration of carcinoma cells.     

A case of benign bile duct stricture causing difficulty in differential diagnosis from bile duct carcinoma

We report a patient with benign bile duct stricture causing difficulty in differential diagnosis from bile duct carcinoma. A 66-year-old woman consulted a local physician because of general fatigue. Blood biochemical tests showed increased levels of biliary tract enzymes. Abdominal ultrasonography (US) revealed tapering and blockage of the midportion of the bile duct and dilation of the intrahepatic bile ducts. Magnetic resonance cholangiopancreatography (MRCP) demonstrated obstruction of the midportion of the bile duct. Later, because a marked increase in biliary tract enzymes and jaundice appeared, percutaneous transhepatic biliary drainage (PTBD) was performed. Post-PTBD cytological examination of bile was negative for cancer. A third biopsy showed slight hyperplasia with no malignant findings. Recholangiography, performed through PTBD, suggested gradual improvement of bile duct stricture, but could not completely exclude the possibility of malignancy; thus, resection of the bile duct including the stricture site was performed, and the resected specimen was submitted for intraoperative frozen section examination. Histopathological diagnosis did not reveal malignant findings. After cholecystectomy and bile duct resection, hepaticojejunostomy (Roux-en-Y) was performed. Because only erosion and desquamation of the mucosal epithelium and mild submucosal inflammatory cell infiltration and fibrosis were observed, chronic cholangitis was diagnosed histopathologically. Surgical resection of the bile duct should be considered for potentially malignant stricture of the bile duct.     

Intrahepatic bile duct dilatation after percutaneous radiofrequency ablation for hepatocellular carcinoma: impact on patient's prognosis

Background: Percutaneous radiofrequency ablation (RFA) has been widely accepted as an alternative to surgery for small hepatocellular carcinoma (HCC). In RFA, a portion of liver tissue surrounding tumour is also ablated to achieve a safety margin. The intrahepatic bile duct may be injured and result in chronic bile duct dilatation upstream of the injured site. However, the impact of such an injury on the overall prognosis has been unclear. Methods: Patients who showed bile duct dilatation following RFA were identified by a retrospective review of imaging studies. Each dilatation was classified as mild (limited to one hepatic subsegment) or severe (affecting two or more subsegments). The relation between the incidence of intrahepatic bile duct dilatation and HCC recurrence or survival was analysed using proportional hazard models. Results: Among 589 consecutive HCC patients treated with RFA, 70 (11.9%) and 21 (3.6%) patients showed mild and severe bile duct dilatation respectively. Patients with severe dilatation, but not those with mild dilatation, had lower survival and higher HCC recurrence than patients without dilatation. Severe dilatation, but not mild dilatation, was significantly associated with death [hazard ratio (HR) 2.17, P=0.035] and recurrence (HR 2.89, P<0.001). Conclusion: Whereas mild bile duct dilatation after RFA is clinically negligible, bile duct dilatation affecting two or more subsegments should be regarded as a complication that may affect the prognosis and should be observed carefully.     

New development of biliary surgery in China

CHARACTERISTICS OF BILIARY CALCULOUS DISEASES IN CHINA: THE CHANGING SCOPE Diseases of the biliary tract in China is complicated with the prevalence of primary infection of the bile duct system. In the middle of the 20th century, biliary infection, biliary parasitic infestation, and biliary stones made up the three chief components of biliary diseases in China. As to the calculous diseases of the biliary tract, the relative incidence of primary bile duct stones accounted for 50% of the total cases. Therefore, calculous disease accounted for 60.1% among 228 surgical cases in the Chongqing Southwest Hospital, and 60 of the 80 common bile duct stones were primary bile duct origin ( including primary intrahepatic duct stones)[1,2].     

New clues for the developing human biliary system at the porta hepatis

The human biliary system is formed from the hepatic diverticulum, a structure which develops from the embryonic foregut in the fourth week of gestation. The cephalic portion of the hepatic diverticulum lies within the septum transversum, and gives rise to entodermal cells which become the primitive hepatocytes. The caudal part of the hepatic diverticulum is molded by mesenchyme to form the gallbladder, cystic duct, and extrahepatic bile duct. The gallbladder is initially tubular in shape, and undergoes morphological changes to become saccular during the 11th week of gestation. The extrahepatic bile duct elongates and widens as gestation progresses, and intramural mucus glands develop. There is no solid stage during the development of the extrahepatic bile duct. The extrahepatic bile duct is a well‐defined tubular structure by the 6th week of gestation, whereas the intrahepatic biliary system during this period of gestation is represented by the primitive ductal plate. The ductal plate undergoes structural changes from the 11th week of gestation, beginning at the porta hepatis and progressing through gestation to the periphery of the liver. This remodeling process shapes the ductal plate from a flat sheath of biliary epithelium surrounding the portal vein branches into a network of interconnecting tubular structures. Mesenchyme plays an important role in ductal plate remodeling. The intrahepatic biliary system is in luminal continuity with the extrahepatic bile duct throughout gestation at the porta hepatis. The major bile ducts at the porta hepatis are fully formed by the 16th week of gestation.     

Clinical aspects of congenital cystic dilatation of the common bile duct in adults

We reviewed the data for 155 patients with congenital cystic dilatation of the common bile duct (CCDB; Alonso-Lej Type I) treated at our institute in the past 12 years. Our definition of CCDB was segmental enlargement of the common bile duct or enlargement involving the proximal bile duct, visualized on cholangiograms. CCDB was subclassified as infant or adult type cyst, based on the extent of the enlargement and the clinicopathologic findings. The former is typically an enlargement of the common bile duct or an enlargement involving the common hepatic duct, while the latter is an enlargement of the entirety of the extrahepatic ducts or involves the intrahepatic bile ducts. Of the 155 patients, 5 (including 1 child) had infant type cysts and 150 (including 1 child) had adult type cysts; 125 patients had benign CCDB (3 with infant type cyst) and 30 exhibited CCDB biliary malignancy (2 with infant type). Anomalous arrangement of the pancreaticobiliary ductal system (AAPB) and congenital biliary stricture were frequently associated with CCDB and these features played an important role in the presenting symptoms of CCDB: AAPB was detected in 100 of the 155 patients, and stricture in 51. AAPB caused disturbance of the passage of bile from the terminal bile duct to the duodenum and cholestasis in the enlargement, with reciprocal regurgitation of bile into the pancreas and pancreatic juice into the bile duct, and the AAPB appeared to precede obstructive jaundice, acute pancreatitis, or biliary malignancies. Stricture was observed at one to all of six sites in the hepatic hilum. Intrahepatic stones were seen in 30 patients, and intrahepatic bile duct cancer was seen in 8 patients; in all these 8 patients, the cancer was associated with primary intrahepatic stones.