Immunoglobulin deposits in the biliary remnants of extrahepatic biliary atresia: a study by immunoperoxidase staining in 128 infants

Bile duct remnants taken from 128 infants during surgery for extrahepatic biliary atresia were paraffin embedded prior to immunoperoxidase staining. Immunoglobulin deposits were found in 44 remnants. They were made up of IgM alone in 25 cases and of IgM and IgG in 19. Deposits were observed along the basement membranes of glandular structures. These findings suggest that extrahepatic bilary atresia might be an acquired and evolving disease.     

Primary umbilical adenocarcinoma. A case report and review of literature.

A case of primary adenocarcinoma of the umbilicus is reported along with a review of the literature and discussion of possible origins of glandular tissue within this area. Multiple connections are present within the umbilicus (vascular, lymphatic, and embryologic) that may give this area access to metastatic lesions. The primary tumors may originate within the usual umbilical tissue (skin and soft tissue). Glands that are not normally present in the region of the umbilicus rarely develop malignant neoplasms. As postulated, glandular tissue may arise either as metaplasia from squamous epithelium or from glandular embryologic rests including omphalomesenteric duct remnants and urachal remnants.     

Immunohistochemical analysis of biliary tract lesions.

The distinction among inflammatory, benign, and malignant lesions of the biliary tract can at times be difficult. Several methods have been used, including immunohistochemistry (IHC), with variable success. We evaluated a panel of IHC stains to determine their utility in discriminating between bile duct lesions. Formalin-fixed, paraffin-embedded 4-microm sections from 12 inflammatory lesions, 10 bile duct adenomas, and 13 bile duct carcinomas were immunostained using a modified avidin-biotin-complex technique after epitope enhancement using antibodies for p53, Ki-67, and bcl-2. For p53 and bcl-2, greater than 1% of cells staining positive was interpreted as positive. The proliferation index was calculated by determining the number of Ki-67-positive cells in a 1000 cell count. In the inflammatory group, 0 of 12 reacted with anti-p53, 2 of 12 were positive with anti-bcl-2, and the proliferation index with was 22.9% +/- 3.9%. Two of 10 bile duct adenomas showed reactivity with anti-bcl-2, and none were decorated with anti-p53 or Ki-67. In the carcinoma group, 6 of 13 were positive with anti-p53, 9 of 12 were positive with anti-bcl-2, and the proliferation index was 35.3% +/- 5.5%. The proliferation rates differed significantly between groups (P < 0.05). The presence of bcl-2 and p53 immunoreactivity coupled with a high proliferative rate in a biliary tract lesion suggests a malignant process. A panel using these antibodies may be useful in difficult cases.     

聚丙交酯/乙交酯胆道支架生物降解及与宿主的相容性

背景：胆道支架广泛应用于不同的胆道疾病的外科治疗中,但目前使用的胆道支架存在一定的缺陷。 目的：探讨聚丙交酯/乙交酯胆道支架的生物降解性和相容性。 方法：制备聚丙交酯/乙交酯胆道支架,浸入胆汁中,浸泡后1,2,3,4,5周,分别取8个实验支架干燥处理后置于扫描电镜下进行观察。于无菌条件下将实验支架植入大鼠皮下,分别于植入后1,2,3,4,5周,处死2只,将实验支架取出,观察支架外观及实验动物周围肌肉组织情况。观察不同时间的支架大体外观和电镜扫描情况,计算降解率,并了解实验动物肌肉埋植情况和支架情况。 结果与结论：植入后1周支架外形基本保持完整,但质地变软,之后逐渐出现表面粗糙并存在裂痕,支架管壁出现塌陷,植入后5周支架被完全降解。降解前,实验支架经扫描电镜观察呈现出清晰的三维立体网状结构,随着实验时间的不断延长,支架表面和截面腐蚀现象不断加重。经凝胶渗透色谱仪检测发现,植入后1周,支架相对分子质量出现迅速的下降现象,之后渐保持平缓下降状态。植入后2周检测,相对分子质量下降为15 000;植入后4周,支架质量损失约40%;所有实验动物均成活,未出现中毒和过敏以及热源反应等,手术伤口均良好愈合,未发生感染。经组织学观察,植入后5周,支架被完全降解,降解率为100%,周围肌肉组织恢复至正常状态。结果表明,聚丙交酯/乙交酯胆道支架具有良好的体外降解性以及生物相容性。 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

The response of human endometriotic implants to the anti-progesterone steroid R 2323: a histologic and ultrastructural study

The histology and ultrastructure of small endometriotic lesions were studied in 19 patients before and after hormonal therapy with the anti-progesterone steroid R 2323 (Gestrinone). Histologic results demonstrate that treatment of endometriosis with this steroid does not result in complete elimination of the endometriotic foci, although glandular proliferation and secretion are arrested in most implants. The ultrastructural results indicate that this inhibition of proliferation and secretion is related to an enhanced activity of the lysosomal system in the epithelial cells of some endometriotic foci. In other implants, or even in other cells of the same foci, epithelial cells with only a small amount of supranuclear cytoplasm but lacking lysosomes may be found. The morphologic data demonstrate that the cellular involutionary response to the antiprogesterone drug Gestrinone involves an activation of the lysosomal system, an abortive apocrine secretion of cell remnants and finally, in some implants, an extrusion of individual epithelial cells. Since this involutionary process of endometriotic cells mimics the pre-menstrual lysosomal degradation in the endometrium, it is suggested that the competitive binding of the antiprogesterone Gestrinone to the progesterone receptors of endometriotic epithelium may cause a cellular progesterone withdrawal effect.     

Oncocytic biliary cystadenocarcinoma is a form of intraductal oncocytic papillary neoplasm of the liver.

Biliary cystadenocarcinoma with oncocytic differentiation was first reported in 1992. This is a report of a second case. The patient (a 71-year-old man) was admitted to our hospital complaining of abdominal fullness. Multicystic lesions were identified in the left hepatic lobe radiologically. The patient died of peritoneal dissemination of carcinoma 20 months later. At autopsy, the tumor of the left hepatic lobe was found to be composed of adjoining multiple cystic lesions and a solid lesion with infiltration of the hepatic hilus and peritoneal dissemination. Histologically, the multicystic lesions were covered by papillary neoplastic epithelial cells with an eosinophilic granular cytoplasm resembling that of oncocytes and a fine fibrovascular core. The cyst wall was fibrous, but there was no mesenchymal stroma. In the solid lesion and infiltrated areas, acidophilic and granular carcinoma cells formed small glandular or solid cord patterns with much mucin secretion (mucinous carcinoma). Immunohistochemically, carcinoma cells of both components were found to contain many mitochondria and showed the phenotypes of hepatocytes and cholangiocytes. Interestingly, the intrahepatic biliary tree also was invaded by carcinoma cells. This may be a case of intraductal oncocytic papillary neoplasm of the left hepatic lobe followed by secondary cystic dilatation of the affected bile duct.     

Ischemic type biliary lesions in histidine-tryptophan-ketoglutarate (HTK) preserved liver grafts

Ischemic type biliary lesions lead to considerable morbidity following orthotopic liver transplantation. The exact pathogenesis is unknown. One major hypothesis is that insufficient perfusion of the arterial vessels of the biliary tree, especially under perfusion with the high viscous University of Wisconsin solution, might be responsible for ischemic type biliary lesions. Due to low viscosity, HTK solution is reported to have a lower incidence of biliary complications. However, there is no data concerning ischemic type biliary lesions in HTK preserved livers. In this paper we report our results after orthotopic liver transplantation with special regard to ischemic type biliary lesions in liver grafts preserved with HTK solution. Between 09/1997 and 01/2005 300 liver transplantations were performed in our center. Thirty-two (10.7%) liver grafts were preserved with HTK solution, 268 (89.3%) were preserved with UW solution. Six and 43 grafts showed ischemic type biliary lesions after orthotopic liver transplantation in HTK- (18.8%) and UW- (16.0%) groups, respectively (p=0.696). There was no statistical significant difference between the two groups. Donor related factors, recipient age, indication for transplantation, transplantation technique, immunosuppression and ischemia time were comparable in both groups. Ischemic type biliary lesions occurred with the same frequency in HTK preserved livers compared to UW preserved organs. We suggest that low viscosity of the preservation fluid by itself does not guarantee reliable perfusion of the small arteries of a liver graft and a pressure perfusion might be beneficial even in HTK solution.     

Intrahepatic biliary cystic lesions

Intrahepatic biliary cysts encompass a large lesional spectrum including hereditary diseases as polycystic liver disease or Caroli's syndrome, malformative lesions as non hereditary Caroli's disease or simple biliary cyst and true neoplastic lesions as cystadenoma or cystadenocarcinoma. The diagnostic approach of these lesions relies firstly on imaging. Nevertheless, the pathologist not exceptionally receives surgical specimens from cystic fenestration or liver specimen resection with one or several cystic lesions. The clues for pathological diagnosis of these lesions have to be known by pathologists. As regards neoplastic cystic lesions, true non-communicating cystic tumors and cystic variants of intraductal biliary tumors have to be distinguished; in both cases, the classification is now identical to the one of pancreatic cystic tumors.     

Expression of cell cycle-related molecules in biliary premalignant lesions: biliary intraepithelial neoplasia and biliary intraductal papillary neoplasm

Cholangiocarcinoma of intrahepatic and extrahepatic bile ducts has a multistep carcinogenesis. Two premalignant lesions have been suggested for invasive cholangiocarcinoma: biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. How the carcinogenetic process differs between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct is not clear. In this study, we performed a pathological study to reveal the expression of key molecules related to the cell cycle during 2 carcinogenetic lineages. We immunohistochemically examined the expression of p21, p53, cyclin D1, and Dpc4 in a total of 89 cases: nonneoplastic biliary epithelium, biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and invasive cholangiocarcinoma. The expression of p21, p53, and cyclin D1 was up-regulated with histological progression in both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct, whereas Dpc4 expression was down-regulated in these 2 lineages. In biliary intraepithelial neoplasia, p21 expression was significantly up-regulated early on. In contrast, levels of all molecules changed gradually in intraductal papillary neoplasm of the bile duct. Changes in p53 expression during histological progression differed significantly between biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was dramatically up-regulated at the invasive stage of biliary intraepithelial neoplasia, whereas it was quite low in noninvasive biliary intraepithelial neoplasia. In contrast, p53 expression was already up-regulated in low-grade intraductal papillary neoplasm and reached a plateau in high-grade intraductal papillary neoplasm and invasive cholangiocarcinoma. This study suggested p21, p53, cyclin D1, and Dpc4 to be involved in the carcinogenesis of both biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. p53 expression was regulated differently in biliary intraepithelial neoplasia compared with intraductal papillary neoplasm of the bile duct.     

Multicystic biliary hamartoma: a hitherto undescribed lesion

In this report, we presented 3 cases of unusual hamartomatous nodules of the liver. These nodules were located around hepatic capsule of the left hepatic lobe and characteristically protruded from the liver. Histologically, these nodular lesions consisted of ductal structures, periductal glands, and fibrous connective tissues containing blood vessels. Smooth muscle bundles focally surrounded ductal structures. Bile-like materials were observed within some ducts. Two cases were associated with xanthogranulomatous inflammation around bile-like materials, and this inflammatory process extended from ductal lumens to periductal connective tissues. In contrast, the remaining case, which was not associated with inflammation, showed a honeycomb appearance. Ductal epithelium and periductal glands resembled biliary epithelium and peribiliary glands, respectively, and they also expressed biliary-type cytokeratins such as cytokeratins 7 and 19. These nodules shared pathologic characteristics of ciliated hepatic foregut cysts, such as their location (around the falciform ligament) and periductal smooth muscle bundles, but did not fulfill the diagnostic criteria (no ciliated cells and multilocular lesions). These hamartomatous nodules of the liver did not fit into any of the described categories of hepatic nodular lesions. At present, we speculate that these lesions might be related to developmental abnormalities of the biliary tract or embryonal foregut.     

Expression of HLA-DR antigens on interlobular bile ducts in primary biliary cirrhosis and other hepatobiliary diseases: an immunohistochemical study

Using a monoclonal antibody to alpha chains of HLA-DR antigens, we found that damaged biliary epithelial cells in primary biliary cirrhosis (PBC) and, to a lesser degree and frequency, in other hepatobiliary diseases expressed HLA-DR antigens, while normal bile ducts did not. There was no correlation between biliary epithelial expression of HLA-DR antigens and intraepithelial migration of HLA-DR-positive cells. In PBC, HLA-DR antigens were strongly expressed on the damaged bile ducts surrounded by no or mild inflammatory cell infiltration (nonflorid duct lesion) and on those surrounded by intense lymphoid cells (florid duct lesion). Immunoelectron microscopy confirmed the presence of HLA-DR antigens on the cellular membranes of damaged biliary epithelial cells. Although expression of HLA-DR antigens on bile ducts may itself be a nonspecific epiphenomenon of damaged bile ducts, it seems possible in PBC that biliary epithelial cells are at first damaged in some way and express HLA-DR antigens (and probably self-antigens), and then fall victim to an autoimmune reaction characterized by marked lymphoid cell infiltration (florid duct lesions). The agent causing nonflorid duct lesions is unknown. The reasons why such expression does not lead to immunologic reactions in other hepatobiliary diseases are only speculative.     

Marked diffuse dilations of the biliary tree associated with intrahepatic calculi,biliary sludges and a mucinous cyst of the pancreatic head in a 99-year-old woman

A 99-year-old woman was admitted to Shizuoka Shimizu Municipal Hospital because of fever and anasarca. Imaging and laboratory tests showed pneumonia, urinary tract infection, and cardiac failure. The patient died 20 days after admission. An autopsy revealed marked diffuse dilations of the biliary tree ranging from the lower common bile duct to intrahepatic bile ducts. Intrahepatic calcium bilirubinate stones and biliary sludges were recognized within the dilated bile ducts. A unilocular cyst (2 cm in diameter) was present in the pancreatic head adjacent to the lower common bile duct, and it appeared to compress the common bile duct. Histologically, the walls of the dilated biliary tree showed proliferation of peribiliary glands, fibrosis, and infiltration of lymphocytes and neutrophils (cholangitis). The lumens of the dilated biliary ducts contained neutral and acidic mucins, fibrinous materials, bacteria, neutrophils, and Aspergillus fungi, in addition to the calculi and sludges. The background liver showed atrophy (400 g). The pancreatic unilocular cyst was composed of mucous columnar cells with a few infoldings, and the pancreas also showed foci of mucinous duct hyperplasia and ectasia; the pathological diagnosis of the cyst was cystic dilations of a pancreatic duct branch (mucinous ductal ectasia or mucinous cyst). Other lesions included aspiration pneumonia, emaciation, atrophy of systemic organs, gastric leiomyoma, serous cystadenoma of the right ovary, and arteriosclerotic nephrosclerosis. The present case suggests that a mucinous cyst of the pancreas may compress the biliary tree and lead to marked diffuse dilations of the biliary tree. Alternatively, the dilations of the bile ducts may be associated with aging or may be of congenital origin. The dilated bile ducts may, in turn, give rise to bacterial and fungal cholangitis and formation of biliary sludges and intrahepatic calcium bilirubinate stones.     

Biliary reabsorption of cholate sodium,glycocholate sodium,and taurocholate sodium from the rat biliary tree after retrograde intrabiliary injection

Summary The results demonstrate the biliary reabsorption of¹⁴C-cholate,¹⁴C-glycocholate, and¹⁴C-taurocholate from the rat biliary tree after retrograde intrabiliary injection. It could be shown that retrograde injection of these bile salts (20 nmol) in a total volume of 40 µl leads to significantly increased biliary reabsorption in contrast to the administration in a retrograde volume of only 20 µl. These differences in reabsorption may be explained by greater reabsorption at a more proximal site in the biliary tree. Furthermore¹⁴C-glycocholate and¹⁴C-taurocholate are reabsorbed to a lesser extent in contrast to¹⁴C-cholate when bile flow was restarted at once after retrograde injection in a volume of 40 µl. It is speculated that conjugation of cholate to glycine and taurine has some effect on the extent of biliary reabsorption of this bile acid. Following the results presented in this paper one might hypothize that biliary reabsorption has an important influence on bile composition i.e. the biliary excretion of bile salts.     

Distortion in TGFβ1 peptide immunolocalization in biliary atresia: Comparison with the normal pattern in the developing human intrahepatic bile duct system

Biliary atresia is an important cause of neonatal obstructive jaundice in which there is inflammation, sclerosis and eventual obliteration of the bile duct system. Its onset may be antenatal, affecting the normal development of the biliary system. The intrahepatic biliary system is derived from the ductal plate, a sheath of cuboidal epithelium that appears at the hepatocyte-mesenchymal junction around the portal vein branches at 6 weeks gestation. This epithelial structure is moulded into a network of tubular bile ducts by the proliferating mesenchyme. Certain portions of the ductal plate are selected to become definitive bile ducts, while redundant biliary epithelium is deleted. The molecular dynamics controlling the intra-uterine development of the biliary system in humans are not yet clearly understood. Transforming growth factor-β1 is a cytokine that stimulates mes-enchymal proliferation and inhibits epithelial growth, and has been shown to be important in organogenesis. In the present study, the pattern of TGFβ1 peptide immunolocalization was investigated with the aid of computerized image analysis, in normal human bile duct development and in biliary atresia. TGFβ1 peptide was detected within hepata-cytes and ductal plate epithelium from 7 weeks gestation; increased TGFβ1 immunoreactivity was present within the epithelium of developing bile ducts at 13 weeks gestation, and apical polarization of the cytokine was observed from 16 weeks gestation. In biliary atresia, the TGFβ1 immunoreactivity pattern within the bile duct structures at the porta hepatis and within intrahepatic portal tracts resembled that of the primitive ductal plate, and there was no significant apical polarization. This may indicate a developmental arrest in the normal ductal plate remodelling process in biliary atresia, and suggests an underlying epithelial-mesenchymal interactive disorder.     

Microsatellite instability in intraductal papillary neoplasms of the biliary tract.

Intraductal papillary neoplasms of the biliary tree are unusual lesions characterized by solitary or diffuse growth along the intra- and/or extrahepatic biliary tract. Biliary papillary neoplasms bear some clinicopathologic similarity to intraductal papillary mucinous neoplasms of the pancreas. Like intraductal papillary mucinous neoplasms of the pancreas, biliary papillary neoplasms can be purely intraductal lesions or can give rise to invasive adenocarcinomas. We recently studied the genetic alterations present in a series of biliary papillary neoplasms and noted the presence of allelic shifts in some biliary tumors during allelic loss assays on chromosomes 5q and 18q. This suggested that microsatellite instability might play a role in the molecular pathogenesis of biliary papillary neoplasms. Genomic DNA was extracted from 17 intraductal papillary neoplasms, 6 associated invasive cholangiocarcinomas, and corresponding normal tissues, and microsatellite instability testing was performed using the 5 microsatellite loci recommended by the 1997 National Cancer Institute-sponsored consensus conference (D2S123, D5S346, D17S250, Bat-25, and Bat-26). High-level microsatellite instability was considered to be present when at least two of five microsatellite loci showed allelic shifts, and low-level microsatellite instability, when only one locus was shifted, as per the National Cancer Institute criteria. We also determined the methylation status of the DNA mismatch repair gene hMLH1 by bisulfite treatment of genomic DNA, followed by methylation-specific PCR. High-level microsatellite instability was present in 2 of 17 (11.8%) biliary papillary neoplasms, including 1 case of purely intraductal tumor and 1 case with both intraductal and invasive cholangiocarcinoma components. In both cases there was extensive microsatellite instability, with allelic shifts in five of five and four of five microsatellite markers, respectively. Low-level microsatellite instability was present in 6 of 17 (35.3%) biliary papillary neoplasms, including 2 cases of purely intraductal tumor and 4 cases with both intraductal and invasive cholangiocarcinoma components. Interestingly, the pattern of allelic shifts was frequently not identical between the intraductal and invasive cholangiocarcinoma components; although the same microsatellite markers were shifted, alleles of differing lengths were generated in the intraductal and invasive components of the neoplasms with high-level microsatellite instability and of two neoplasms with low-level microsatellite instability. None of the biliary papillary neoplasms (0 of 10 cases with adequate DNA for evaluation) showed methylation of hMLH1. These results indicate that microsatellite instability is a relatively frequent event in papillary neoplasms of the biliary tree but is not associated with hMLH1 promoter hypermethylation. The finding that alleles of differing lengths were frequently generated between the intraductal and invasive components of those tumors with microsatellite instability suggests that there is significant genetic heterogeneity within these neoplasms.     

Quantitative assessment of the rat intrahepatic biliary system by three-dimensional reconstruction

The anatomical details of the biliary tree architecture of normal rats and rats in whom selective proliferation was induced by feeding alpha-naphthylisothiocyanate (ANIT) were reconstructed in three dimension using a microscopic-computed tomography scanner. The intrahepatic biliary tree was filled with a silicone polymer through the common bile duct and each liver lobe embedded in Bioplastic; specimens were then scanned by a microscopic-computed tomography scanner and modified Feldkamp cone beam backprojection algorithm applied to generate three-dimensional images. Quantitative analysis of bile duct geometry was performed using a customized software program. The diameter of the bile duct segments of normal and ANIT-fed rats progressively decreased with increasing length of the biliary tree. Diameter of bile ducts from ANIT-fed rats (range, 21 to 264 microm) was similar to that of normal rats (22 to 279 microm). In contrast, the number of bile duct segments along the major branch reproducibly doubled, the length of the bile duct segments decreased twofold, and the length of the biliary tree remained unchanged after ANIT feeding. Moreover, the total volume of the biliary tree of ANIT-fed rats was significantly greater (855 microl) than in normal rats (47 microl). Compared with normal rats, the total surface area of the biliary tree increased 26 times after ANIT-induced bile duct proliferation. Taken together, these observations quantitate the anatomical remodeling after selective cholangiocyte proliferation and strongly suggest that the proliferative process involves sprouting of new side branches. Our results may be relevant to the mechanisms by which ducts proliferate in response to hepatic injury and to the hypercholeresis that occurs after experimentally induced bile duct proliferation.     

Primary biliary cirrhosis and sclerosing cholangitis

Primary biliary disorders are often overlooked during routine assessment of liver biopsy specimens. Histological changes of large duct obstruction are now rarely observed as acute obstructive cholangiopathies are generally spotted on radiological imaging. Histopathologists are more likely to be confronted with chronic biliary disorders, in particular primary biliary cirrhosis (PBC) and ‘primary’ sclerosing cholangitis (PSC), where small and/or large segments of the bile ducts are injured and progressively destroyed. In this situation, the changes at the liver periphery may be misleading. Cholestasis is essentially absent in the early stages; the characteristic bile-duct lesions may not be sampled by biopsy needles, due to their uneven distribution and/or deep location within the liver; and portal and periportal biliary features may overlap with those of chronic hepatitis. The recognition of early biliary interface activity with subtle ductular reaction, cholate-stasis and copper-associated, orcein-positive granules, is critical to diagnose a cholangiopathy. This might confirm the clinical impression or provide valuable information to select additional investigations, such as autoantibody testing or performance of an ERCP. This article reviews the characteristic clinical, laboratory and radiological features, together with the morphological changes, which assist biopsy interpretation in both PBC and PSC. The main liver conditions in which bile ducts are prime targets of the injury, in particular those associated with a progressive loss of the intrahepatic bile ducts or ductopenia, are considered as they enter the differential diagnosis. The article ends with a brief note on idiopathic adulthood ductopenia, which remains a diagnosis of exclusion.     

Primary biliary cirrhosis of the liver

Primary biliary cirrhosis (PBC) of the liver is considered to be an autoimmune liver disease in which an immune aggression is directed against small biliary ducts--mitochondrial antigens of a biliary epithelium. The targets of an immune aggression in PBC may also be the histocompatibility antigens of the biliary ducts epithelium. This makes PBC resembling so-called disease "graft against host". The destruction of bile ducts in PBC is brought about through the mechanisms of an immune cytolysis and is manifested morphologically by the symptoms of the delayed hypersensitivity response. Cholangiole proliferation develops along the ductal destruction, sclerotic changes and cholestasis increase in their intensity. Small-nodular cirrhosis develops at the final stage of disease. Systemic manifestations of PBC are associated with a circulation of immune complexes containing hepatobiliary antigens. Cross-immune reactions are also of importance in the mechanisms of extrahepatic lesions.     

PTEN loss and KRAS activation cooperate in murine biliary tract malignancies

Carcinomas of the biliary tract are aggressive malignancies in humans. Loss of the tumour suppressor PTEN has previously been associated with cholangiocarcinoma development in a murine model. Activation of KRAS is reported in up to one‐third of human cholangiocarcinomas and 50% of gall bladder carcinomas. In this study we aimed to test the potential interaction between PTEN and KRAS mutation in biliary tract malignancy. We used an inducible Cre–LoxP‐based approach to coordinately delete PTEN and activate KRAS within the adult mouse biliary epithelium. We found that activation of KRAS alone has little effect upon biliary epithelium. Loss of PTEN alone results in the development of low‐grade neoplastic lesions, following long latency and at low incidence. Combination of both mutations causes rapid development of biliary epithelial proliferative lesions, which progress through dysplasia to invasive carcinoma. We conclude that activation of the PI3′K pathway following loss of PTEN is sufficient to drive slow development of low‐grade biliary lesions in mice. In contrast, mutational activation of KRAS does not result in a similar phenotype, despite a prediction that this should activate both the RAF–MEK–ERK and PI3′‐kinase pathways. However, mutation of both genes results in rapid tumourigenesis, arguing that PTEN normally functions as a ‘brake’ on the PI3′‐kinase pathway, limiting the influence of KRAS activation. Mutation of both genes creates a ‘permissive’ environment, allowing the full effects of both mutations to be manifested. These data reveal an in vivo synergy between these mutations and provides a new mouse model of biliary tract malignancy. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The developing human biliary system at the porta hepatis level between 11 and 25 weeks of gestation: A way to understanding biliary atresia. Part 2

In biliary atresia, inflammation and destruction of extra-hepatic and intrahepatic bile ducts with eventual fibrous obliteration occurs, causing neonatal obstructive jaundice. The onset of the disorder may start antenatally and progress after birth, and the porta hepatis is a constant site of involvement. To date, little is known about the intrauterine development of the bile ducts at the porta hepatis. The present work gives an account of the developmental pattern of bile ducts at the level of the porta hepatis in the normal human fetus from the 11th to the 25th weeks of gestation. It has been observed that the proximal portion of the hilar bile ducts derives from the intrahepatic biliary ductal plate. This occurs following a predictable remodeling sequence by which, from many ductal plate-derived ductules, those destined to become definitive bile ducts are enveloped in a concentric cuff of mesenchyma. Those which are not are deleted. The distal portions of the right and left main hepatic ducts develop from the extrahepatic bile duct. There was no gestational period in which the extrahepatic bile duct and the intrahepatic blliary system were separated. Furthermore, the developing intrahepatic bile ducts maintain lumina continuity with the common bile duct from the start of organogenesis. Biliary atresia may result from: (i) failure to establish a definitive type of bile duct; (ii) leakage of bile from primitive bile ducts resulting in an interstitial inflammatory reaction in the adjacent mesenchyma; and (iii) continuous proliferation of primitive bile ducts at the level of the porta hepatis beyond the 25th week of gestation, as a failed compensatory mechanism.