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ABSTRACT: BACKGROUND AND AIM: Cholangiocarcinoma arising in the large bile ducts undergoes a multistep carcinogenesis process in chronic biliary diseases, and biliary intraepithelial neoplasia is known as a precursor lesion. This study examined the expression of S100 proteins in the multistep cholangiocarcinogenesis to clarify their clinicopathological significance. METHODS: Immunohistochemical analysis was performed for the expression of S100A2, S100A4, S100A6, and S100P. Bile concentrations of S100P were measured using enzyme-linked immunosorbent assay. RESULTS: The immunohistochemical expression of the S100 proteins was increased in biliary intraepithelial neoplasia as well as invasive adenocarcinoma of perihilar cholangiocarcinoma. Among the proteins, S100P expression was most drastically increased during the multistep carcinogenesis process. In cases with perihilar and extrahepatic cholangiocarcinoma, the immunohistochemical expression of S100A2 in cholangiocarcinoma cells significantly correlated with the histological grade, lymph node metastasis, clinical stage, and a poor survival rate of the patients. The bile levels of S100P were increased significantly in patients with cholangiocarcinoma compared to those in patients with lithiasis. Receiver operating characteristic curve analysis showed that S100P bile concentration was an indicator of cholangiocarcinoma with a sensitivity of 93% and a specificity of 70%. CONCLUSIONS: These results suggest that S100P may be useful for the detection of cholangiocarcinoma as tissue and bile biomarkers, and the immunohistochemical expression of S100A2 is a potential prognostic marker in cholangiocarcinoma patients.
Journal of Gastroenterology and Hepatology 04/2013; · 2.87 Impact Factor
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ABSTRACT: The increasing grades of biliary intraepithelial neoplasia (BilIN) reflect multistep carcinogenesis of cholangiocarcinoma, BilIN-3 representing the carcinoma in situ stage. A different form of in situ growth form of cancer cells is the intraepithelial spreading of cholangiocarcinoma cells. We examined the histological characteristics of carcinoma in situ in the biliary tract on 64 partial hepatectomy specimens with a diagnosis of hepatolithiasis. We distinguished two forms of carcinoma in situ: BilIN-3 and intraepithelial spread of carcinoma (IES). BilIN-3 is defined by epithelial atypia gradually decreasing towards the transition to adjacent normal biliary epithelium. In IES, the lesion shows an abrupt transition to normal biliary epithelium, in which the intraepithelial carcinoma then tends to spread. BilIN-3 and IES were observed in 17 (94 %) and seven (39 %), respectively, in cases of invasive cholangiocarcinoma (n = 18), and neither of them was observed in cases without invasive cholangiocarcinoma (n = 46). Most lesions of BilIN-3 and IES microscopically showed a flat or pseudopapillary pattern. The less frequent micropapillary configuration was noted more often in BilIN-3. BilIN-3 was not observed in septal and small intrahepatic bile ducts, while IES was regularly observed in such bile ducts. Immunohistochemical analysis showed p53 to be expressed significantly more frequently in IES (29 %) than in BilIN-3 (8 %). In conclusion, carcinoma in situ in the biliary tract is morphologically heterogeneous, and it is important to distinguish BilIN-3 and intraepithelial carcinoma spreading as distinct lesions, to better understand their biology.
Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 02/2013; · 2.49 Impact Factor
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Yuji Hodo,
Masao Honda,
Akihiro Tanaka,
Yoshimoto Nomura,
Kuniaki Arai,
Taro Yamashita,
Yoshio Sakai,
Tatsuya Yamashita,
Eishiro Mizukoshi,
Akito Sakai, Motoko Sasaki,
Yasuni Nakanuma,
Mitsuhiko Moriyama,
Shuichi Kaneko
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ABSTRACT: PURPOSE: Several single nucleotide polymorphisms (SNPs) in the interleukin 28B (IL28B) locus have recently been shown to be associated with antiviral treatment efficacy for chronic hepatitis C (CH-C). However, such an association with hepatocellular carcinoma (HCC) is unknown. Here, we investigated the association between the IL28B genotype and the biology and clinical outcome of HCC patients receiving curative treatment. EXPERIMENTAL DESIGN: Genotyping of 183 HCC patients with CH-C who were treated with hepatic resection or radiofrequency ablation (RFA) was carried out, and the results were analyzed to determine the association between the IL28B genotype (rs8099917) and clinical outcome. Gene expression profiles of 20 HCC patients and another series of 91 CH-C patients were analyzed using microarray analysis and gene set enrichment analysis. Histological and immunohistochemical analyses were also performed. RESULTS: The TT, TG and GG proportions of the rs8099917 genotype were 67.8% (124/183), 30.6% (56/183) and 1.6% (3/183), respectively. Multivariate Cox proportional hazard analysis demonstrated that the IL28B TT genotype was significantly associated with HCC recurrence (p = 0.007; hazard ratio, 2.674; 95% CI, 1.16-2.63). Microarray analysis showed high expression levels of interferon-stimulated genes in background liver samples and immune-related genes in tumor tissues of the IL28B TG/GG genotype. Histological findings showed that more lymphocytes infiltrated into tumor tissues in the TG/GG genotype. CONCLUSIONS: The IL28B genotype is associated with HCC recurrence, gene expression and histological findings in patients with CH-C.
Clinical Cancer Research 02/2013; · 7.74 Impact Factor
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ABSTRACT: BACKGROUND: Similar to the pancreatic intraepithelial neoplasia (PanIN)-pancreatic carcinoma sequence model, intrahepatic cholangiocarcinoma (ICC) also reportedly follows a stepwise carcinogenesis process through the a precursor lesion: biliary intraepithelial neoplasia (BilIN). For this study, the authors investigated the status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) mutations and tumor protein 53 (p53) overexpression in the stepwise process of cholangiocarcinogenesis. METHODS: Thirty patients with hepatolithiasis were surveyed, and their lesions were categorized as follows: non-neoplastic large bile duct (LBD) (n = 12), peribiliary gland (PBG) (n = 9), BilIN-1 (low-grade dysplasia; n = 12), BilIN-2 (high-grade dysplasia; n = 16), and BilIN-3 (noninvasive or in situ carcinoma; n = 10). KRAS mutation at codons 12 and 13 and GNAS mutations at codons 601 and 602 were analyzed using genomic DNA extracted from isolated lesions by laser capture microdissection. Immunohistochemical expression of p53 also was evaluated in BilIN lesions, ICCs, and extrahepatic cholangiocarcinomas (ExCCs). RESULTS: A prevalence of KRAS mutations was identified in patients with ICC (31.5%), BilIN-3 (30%), and BilIN-2 (43.8%) compared with BilIN-1 (25%). Furthermore, KRAS mutations were detected in LBD lesions (41.7%) and PBG lesions (44.4%), and these mutations were observed with greater frequency in patients who had BilIN with KRAS mutations. GNAS mutations were not identified in any of the ICCs or other lesions examined. The overexpression of p53 was not identified in BilIN lesions and was less frequent in ICCs (18.2%) compared with ExCCs (38.1%) and gallbladder carcinomas (61.5%). CONCLUSIONS: KRAS mutations, which were present in approximately 33% of BilIN lesions, occurred as an early molecular event during the progression of BilIN to ICC, whereas p53 overexpression was identified as a late molecular event. Furthermore, the current results indicted that BilIN also may arise from LBD and PBG lesions in patients who have hepatolithiasis with KRAS mutations. Cancer 2013. © 2013 American Cancer Society.
Cancer 01/2013; · 4.77 Impact Factor
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Yuko Kakuda,
Kenichi Harada,
Seiko Sawada-Kitamura,
Hiroko Ikeda,
Yasunori Sato, Motoko Sasaki,
Hirofumi Okafuji,
Eishiro Mizukoshi,
Shuichi Terasaki,
Hajime Ohta,
Satomi Kasashima,
Atsuhiro Kawashima,
Yasuharu Kaizaki,
Shuichi Kaneko,
Yasuni Nakanuma
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ABSTRACT: Recently, our research team proposed a new histologic staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histologic heterogeneity. The present study aimed to confirm the usefulness of the new evaluation system. A total of 152 liver biopsy specimens and clinical data (including outcomes in patients with PBC before treatment with ursodeoxycholic acid) were analyzed with respect to the new system. Staging was evaluated on the basis of 3 histologic components (fibrosis, bile duct loss, and deposition of orcein-positive granules), and grading was assessed on the basis of chronic cholangitis activity and hepatitis activity. Concurrently, the classical systems, that is, the Scheuer and Ludwig staging systems, were also assessed and compared with our new system. PBC cases showed different distributions in each stage of the 3 systems. The new staging and grading system reflected liver dysfunctions before specific treatment. This was on a par with the results obtained using the classical systems. Development of cirrhosis-related conditions correlated well with the new staging system compared with the 2 classical staging systems, and in particular, the amount of deposition of orcein-positive granules could reflect development of cirrhosis-related conditions (scores 0-1 versus scores 2-3 groups, P < .0001). In conclusion, the new PBC staging system was demonstrated to reflect clinicolaboratory features, and its progression was associated with the development of cirrhosis-related conditions.
Human pathology 01/2013; · 3.03 Impact Factor
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ABSTRACT: BACKGROUND/AIMS: We have reported the involvement of deregulated autophagy and subsequent cellular senescence in biliary epithelial lesions in primary biliary cirrhosis (PBC). Given that mitochondria are a major target of autophagy, we hypothesized that deregulated autophagy of mitochondria may be involved in autoimmune pathogenesis in PBC. METHODS: We examined immunohistochemically the expression of pyruvate dehydrogenase complex-E2 component (PDC-E2) and cytochrome c oxidase, subunit I (CCO), in livers taken from patients with PBC (n = 42) and control livers (n = 76). The colocalization of mitochondrial antigens with an autophagy marker microtubule-associated protein-light chain 3β (LC3), a deregulated autophagy marker p62/sequestosome-1 (p62) and a lysosomal marker LAMP-1 was examined by double immunofluorescence. We examined the colocalization of mitochondrial antigens with LC3, p62 and LAMP-1 and the cell-surface expression of PDC-E2 in cultured biliary epithelial cells (BECs) treated with various stresses. RESULTS: Intense granular expression of PDC-E2 and CCO was seen in the damaged small bile ducts (SBDs) in PBC and the expression was significantly more frequent in PBC than in control livers (P < 0.01). The granular expression of mitochondrial antigens was colocalized with LC3 in damaged SBDs in PBC. The accumulation of LC3-expressing punctae colocalized with PDC-E2 and CCO was significantly more increased in cultured BECs treated with various stresses. The cell-surface expression of PDC-E2 was induced by various stresses in BECs. CONCLUSION: Deregulated autophagy may contribute to the abnormal expression of mitochondrial antigens and may be involved in the autoimmune pathogenesis of bile duct lesions in PBC.
Liver international: official journal of the International Association for the Study of the Liver 11/2012; · 3.82 Impact Factor
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ABSTRACT: Embryologically, intrahepatic small bile ducts arise from hepatic progenitor cells via ductal plates, whereas the pancreato-extrahepatic biliary progenitor cells expressing the transcription factors PDX1 and HES1 are reportedly involved in the development of the extrahepatic biliary tract and ventral pancreas. The expression of cellular markers characteristic of the different anatomical levels of the biliary tree and pancreas, as well as PDX1 and HES1, was examined in cholangiocarcinoma components of combined hepatocellular cholangiocarcinoma (12 cases), intrahepatic cholangiocarcinoma (21 cases), hilar cholangiocarcinoma (25 cases), and pancreatic ductal adenocarcinoma (18 cases). Anterior gradient protein-2 and S100P were frequently expressed in hilar cholangiocarcinoma and pancreatic ductal adenocarcinoma, whereas neural cell adhesion molecule and luminal expression of epithelial membrane antigen were common in cholangiocarcinoma components of combined hepatocellular cholangiocarcinoma. PDX1 and HES1 were frequently and markedly expressed in pancreatic ductal adenocarcinoma and, to a lesser degree, in hilar cholangiocarcinoma, although their expression was rare and mild in cholangiocarcinoma components in combined hepatocellular cholangiocarcinoma. The expression patterns of these molecules in intrahepatic cholangiocarcinoma were intermediate between those in hilar cholangiocarcinoma and cholangiocarcinoma components of combined hepatocellular cholangiocarcinoma. Pancreatic ductal adenocarcinoma and hilar cholangiocarcinoma had a similar expression of mucin, immunophenotypes, as well as transcription factors. Pancreatic ductal adenocarcinoma and hilar cholangiocarcinoma showed similar postoperative prognosis. In conclusion, the similar expression of phenotypes related to pancreatobiliary anatomy and embryology may in part explain why these 2 types of carcinoma present similar clinicopathologic features. Further studies on the carcinogenesis of these carcinomas based on their similarities are warranted.
Human pathology 11/2012; · 3.03 Impact Factor
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ABSTRACT: We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14 cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.
Japanese journal of radiology 08/2012; · 0.65 Impact Factor
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ABSTRACT: Sasaki M, Matsubara T, Yoneda N, Nomoto K, Tsuneyama K, Sato Y & Nakanuma Y (2012) Histopathology Overexpression of enhancer of zeste homolog 2 and MUC1 may be related to malignant behaviour in intraductal papillary neoplasm of the bile duct Aims: Intraductal papillary neoplasm of the bile duct (IPNB) usually has a favourable prognosis, but occasionally is associated with invasive carcinoma. Overexpression of the polycomb group protein enhancer of zeste homolog 2 (EZH2) is involved in the progression of malignant tumours. In this study, we examined the significance of EZH2 expression in IPNB and its association with clinicopathological features and the expression of p16(INK4a) , p53 and mucin core proteins. Methods and results: We examined immunohistochemically the expression of EZH2, p16(INK4a) , MUC mucin core proteins and p53 in 15 patients with IPNB without invasion, including the cystic variant [male/female ratio (M/F) = 9/6], and in 19 with IPNB associated with invasive carcinoma (M/F = 13/6). The expression levels of EZH2, p53 and MUC1 were significantly lower (P < 0.01), and of MUC6 were significantly higher (P < 0.05), in IPNB without invasion than in IPNB with invasion. Expression of EZH2 was significantly correlated with expression of MUC1 (P < 0.01) and inversely correlated with expression of MUC6 (P < 0.05). In cholangiocarcinoma cells (HuCTT-1 and TFK-1), knockdown of EZH2 and MUC1 by small interfering RNA decreased invasion and proliferation, whereas knockdown of MUC6 increased invasion. Conclusions: Overexpression of EZH2 may be associated with malignant behaviour in IPNB in parallel with up-regulated MUC1 expression and down-regulated MUC6 expression.
Histopathology 08/2012; · 3.08 Impact Factor
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ABSTRACT: Hepatocellular adenoma usually arises in the absence of significant fibrosis. Herein, we report seven patients with serum amyloid A-positive hepatocellular neoplasm, which shares features with inflammatory hepatocellular adenoma arising in alcoholic cirrhosis. Seven patients (two women and five men, age range 41-67 years) with hypervascular hepatocellular nodules associated with alcoholic cirrhosis were retrieved from our pathological files (1997-2011). The hepatocellular nodules were multiple (>3) in all patients and 17 nodules were histologically examined. We surveyed the immunoreactivity for serum amyloid A, glutamine synthetase, and glypican-3 in the hepatocellular nodules and control lesions, including 5 focal nodular hyperplasia, 18 dysplastic nodules, and 54 hepatocellular carcinomas in various background diseases. In all, 15 of 17 nodules showed strong and distinct immunoreactivity for serum amyloid A, sharing features with inflammatory hepatocellular adenoma. The serum amyloid A-positive hepatocellular neoplasms showed increased cellular density, inflammatory infiltrate, sinusoidal dilatation, and ductular reaction to various degrees. Although about a half of dysplastic nodules and hepatocellular carcinomas showed focal immunoreactivity for serum amyloid A, the extent of serum amyloid A expression was significantly higher in serum amyloid A-positive hepatocellular neoplasms, than in control nodules. The serum amyloid A-positive hepatocellular neoplasms did not show the overexpression of glutamine synthetase or immunoreactivity for glypican-3. In contrast, most hepatocellular carcinomas showed the overexpression of glutamine synthetase and immunoreactivity for glypican-3, irrespective of background diseases. In conclusion, this study highlights a characteristic group of hepatocellular neoplasms arising in alcoholic cirrhosis, which share features with inflammatory hepatocellular adenomas. These serum amyloid A-positive hepatocellular neoplasms may be a new type of inflammatory hepatocellular tumors in alcoholic patients.Modern Pathology advance online publication, 6 July 2012; doi:10.1038/modpathol.2012.114.
Modern Pathology 07/2012; · 4.79 Impact Factor
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ABSTRACT: The recent World Health Organization classification for tumors of the digestive system defined grossly and histologically hepatic mucinous cystic neoplasms and intraductal papillary neoplasms of the bile duct separately. In this study, the immunohistochemical features of intraductal papillary neoplasm of the bile duct (19 cases) and hepatic mucinous cystic neoplasm (5 cases) were characterized and compared with those of similar pancreatic lesions, intraductal papillary mucinous neoplasm of the pancreas (12 cases), and pancreatic mucinous cystic neoplasm (6 cases) and with those of other biliary cystic lesions, peribiliary cysts (10 cases). Intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas frequently expressed cytokeratin 7; mucin core proteins 1, 2, 5AC, and 6; trypsin; and amylase. Hepatic and pancreatic mucinous cystic neoplasms frequently expressed cytokeratin 7, mucin core proteins 1 and 5AC, estrogen receptor, progesterone receptor, trypsin, and amylase. Estrogen and progesterone receptors were expressed in the subepithelial stromal cells. The groups with intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas were different from the groups with hepatic and pancreatic mucinous cystic neoplasm with respect to several phenotypes reflecting gastric and intestinal metaplasia and also the lack of expression of estrogen and progesterone receptors. The Ki-67 and p53 labeling indexes increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. The p16 labeling index decreased and EZH2 labeling index increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. In conclusion, intraductal papillary neoplasm of the bile duct and hepatic mucinous cystic neoplasm might be regarded as biliary counterparts of intraductal papillary mucinous neoplasm of the pancreas and pancreatic mucinous cystic neoplasm, respectively, and the mucinous cystic neoplasm and intraductal papillary neoplasm groups differed from each other. Labeling indexes of Ki-67, p53, p16, and EZH2 were comparable in intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas along with their malignant progression, suggesting a common carcinogenic process of the tumors.
Human pathology 06/2012; · 3.03 Impact Factor
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ABSTRACT: Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that is crucial in embryogenic development and differentiation of pancreas, and its overexpression is reportedly involved in the progression of many malignancies, including pancreatic carcinoma. In this study, the role of Pdx1 was examined in cholangiocarcinogenesis.
Forty-three cases of human cholangiocarcinoma (CC) and 66 cases of hepatolithiasis or primary sclerosing cholangitis (PSC) with biliary intraepithelial neoplasia (BilIN) lesions and also eight fetal and 20 adult normal livers were examined immunohistochemically. Pdx1 was constantly expressed in the nuclei of fetal bile ducts, but was virtually absent in the large bile ducts of adults. By contrast, Hairy and enhancer of split 1 (Hes1), which represses pancreatic exocrine and endocrine differentiation, was expressed frequently in the adult bile ducts. Pdx1 was expressed in 67% of invasive CCs. In large bile ducts, expression of Pdx1 increased while that of Hes1 decreased during the progression of BilIN lesions to CC. Expression of Pdx1 correlated with proliferative activities in CCs. In an in vitro study, all three CC cell lines expressed Pdx1 mRNA and protein.
Up-regulation of Pdx1 is a feature of cholangiocarcinogenesis associated with chronic cholangitis. Furthermore, expression of Pdx1 in CC is related to increased proliferative activity in CCs.
Histopathology 05/2012; 61(2):266-76. · 3.08 Impact Factor
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ABSTRACT: α-Fetoprotein is expressed in hepatocellular carcinoma, yolk sac tumor, and some gastric carcinomas. The α-fetoprotein-producing gastric carcinoma composed of hepatoid and common adenocarcinoma shows morphological similarities to combined hepatocellular and cholangiocarcinoma. In this study, the expression of putative hepatic stem/progenitor markers (EpCAM, OV-6, DLK-1, and NCAM/CD56), hepatocyte markers (HepParI, α-fetoprotein, glypican 3), and the germ cell marker SALL4 was examined in α-fetoprotein-producing gastric carcinoma (20 cases) and combined hepatocellular and cholangiocarcinoma (20 cases) for evaluation of pathologic differentiation and also the histogenesis of both tumors. The SALL4 protein was expressed in 95% of α-fetoprotein-producing gastric carcinoma, including the hepatoid component (hepatoid gastric carcinoma), but was absent in combined hepatocellular and cholangiocarcinoma. Glypican 3 and α-fetoprotein were detected in all hepatoid-type α-fetoprotein-producing gastric carcinoma but variably in combined hepatocellular and cholangiocarcinoma. NCAM/CD56 was expressed focally in combined hepatocellular and cholangiocarcinoma but was rare in hepatoid gastric carcinoma. EpCAM, DLK-1, and OV6 were variably expressed in hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma. SALL4 was a useful differential marker for combined hepatocellular and cholangiocarcinoma and hepatoid gastric carcinoma. The histogenesis of hepatoid gastric carcinoma expressing SALL4 seems to reflect fetal gut differentiation or involve the germ cell lineage and may be different from that of combined hepatocellular and cholangiocarcinoma involving the hepatic stem cell or progenitor cell lineages. In conclusion, hepatoid gastric carcinoma and combined hepatocellular and cholangiocarcinoma shared morphologies, whereas the distinction of hepatoid gastric carcinoma from combined hepatocellular and cholangiocarcinoma is possible by immunostaining for SALL4. These 2 tumors seem to differ in their histogenesis with respect to SALL4 expression.1.
Human pathology 04/2012; 43(11):1955-63. · 3.03 Impact Factor
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Jing Xu,
Saya Igarashi, Motoko Sasaki,
Takashi Matsubara,
Norihide Yoneda,
Kazuto Kozaka,
Hiroko Ikeda,
Jihun Kim,
Eunsil Yu,
Osamu Matsui,
Yasuni Nakanuma
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ABSTRACT: Intrahepatic cholangiocarcinomas (ICCs) are usually adenocarcinomas with fibrotic and hypovascular stroma. Intrahepatic cholangiocarcinomas in cirrhosis and precirrhotic liver (ICC-cirrhosis) are increasingly being diagnosed, and can display hypervascular enhancement resembling a hepatocellular carcinoma on dynamic imaging.
In this study using ICC-cirrhosis (71 cases), ICC with non-specific reactive changes (ICC-reactive) (72 cases) and the cholangiocarcinoma component of combined hepatocellular cholangiocarcinoma (HCC-ICC) (30 cases), we tried to compare the tumour vasculature.
It was found that ICC-cirrhosis and the cholangiocarcinoma component of HCC-ICC showed a higher density of arteries and microvessels (1.59 ± 0.58/mm(2) (mean ± SD) and 140 ± 43/mm(2) in ICC-cirrhosis and 1.74 ± 0.67/mm(2) and 131 ± 46/mm(2) in the cholangiocarcinoma component of HCC-ICC) than in ICC-reactive (1.26 ± 0.61/mm(2) and 103 ± 45/mm(2) ). Dynamic computed tomography (CT) and magnetic resonance imaging (MRI) showed that a majority of ICC-cirrhosis displayed strong hypervascular enhancement, whereas one-third of ICC-reactive each showed strong, weak and no or minimal enhancement respectively. The increased vascular density was positively correlated with enhanced arterial phase of dynamic CT and MRI.
The density of arteries and microvessels of ICC-cirrhosis was higher than that in ICC-reactive and comparable to that in the cholangiocarcinoma component of HCC-ICC, and the higher density of arteries and microvessels in ICC may be responsible for the hypervascular enhancement of ICC-cirrhosis.
Liver international: official journal of the International Association for the Study of the Liver 03/2012; 32(7):1156-64. · 3.82 Impact Factor
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ABSTRACT: Recent studies disclosed that autophagy facilitates the process of senescence. Given that cellular senescence is involved in the pathophysiology of ductular reaction (DR) in primary biliary cirrhosis (PBC), we examined an involvement of autophagy in DRs in PBC and control livers.
We examined immunohistochemically the expression of microtubule-associated proteins light chain 3β (LC3) as autophagy marker, p62/sequestosome-1 (p62) as autophagy-related marker in bile ductular cells in livers taken from the patients with PBC (n = 42), and control livers (n = 100). The expression of senescent markers (p16(INK4a) and p21(WAF1/Cip1)) in bile ductular cells and their correlation with autophagy was also evaluated.
The expression of LC3 was seen in coarse vesicles in the cytoplasm of bile ductular cells and significantly more frequently in PBC of both early and advanced stages when compared to control livers (p < 0.01). The expression of p62 was seen as intracytoplasmic aggregates and significantly more frequently in PBC when compared to control livers (p < 0.05). The expression of LC3 and p62 significantly correlated with each other (p < 0.01). The expression of LC3 and p62 significantly correlated with the expression of p16(INK4a), p21(WAF1/Cip1) (p < 0.05).
Autophagy is frequently seen in bile ductular cells in DRs in PBC. Since cellular senescence of bile ductular cells is rather frequent in the advanced stage of PBC, autophagy may precede cellular senescence of bile ductular cells in DRs in PBC.
Digestive Diseases and Sciences 03/2012; 57(3):660-6. · 2.12 Impact Factor
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ABSTRACT: Hepatocellular adenoma (HCA) is generally a benign hepatocellular tumor arising in a nonfibrotic/cirrhotic liver, and recently four major subgroups were identified based on genotype and phenotype classification from Europe. HCA is rare in Asian countries including Japan, and there have been few studies regarding the subgroups of HCA in Japan. We surveyed subgroups of HCA in 13 patients (7 women) in Japan, based on the phenotypic classification. As results, we identified 2 hepatocyte nuclear factor (HNF) 1α-inactivated HCAs (15%), two β-catenin-activated HCAs (15%), 5 inflammatory HCAs (39%), and 4 unclassified HCAs (29%). The use of oral contraceptives was found only in 2 unclassified HCAs (29%). Rather low percentage of female patients and use of oral contraceptives appear to be common clinicopathological features in Japan and also East Asian countries. Furthermore, a group of possible inflammatory HCAs characterized by strong immunoreactivity for serum amyloid A (SAA) was found in patients with alcoholic cirrhosis. The inflammatory HCA/SAA-positive hepatocellular neoplasm in alcoholic cirrhosis may be a new entity of HCA, which may have potential of malignant transformation. Further studies are needed to clarify genetic changes, monoclonality, and pathogenesis of this new type of hepatocellular neoplasm.
International journal of hepatology. 01/2012; 2012:648131.
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ABSTRACT: Primary biliary cirrhosis (PBC) is characterized by antimitochondrial autoantibodies (AMAs) in patients' sera and histologically by chronic nonsuppurative destructive cholangitis in small bile ducts, eventually followed by extensive bile duct loss and biliary cirrhosis. The autoimmune-mediated pathogenesis of bile duct lesions, including the significance of AMAs, triggers of the autoimmune process, and so on remain unclear. We have reported that cellular senescence in biliary epithelial cells (BECs) may be involved in bile duct lesions and that autophagy may precede the process of biliary epithelial senescence in PBC. Interestingly, BECs in damaged bile ducts show characteristicsof cellular senescence and autophagy in PBC. A suspected causative factor of biliary epithelial senescence is oxidative stress. Furthermore, senescent BECs may modulate the microenvironment around bile ducts by expressing various chemokines and cytokines called senescence-associated secretory phenotypes and contribute to the pathogenesis in PBC.
International journal of hepatology. 01/2012; 2012:452143.
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ABSTRACT: Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats.
American Journal Of Pathology 12/2011; 179(6):2845-54. · 4.89 Impact Factor
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ABSTRACT: Intrahepatic cholangiocarcinomas (ICCs) are known to arise in cases of non-biliary, chronic advanced liver disease (CALD), but their clinicopathological features remain unexplored. The aim of this study was to compare the histological and immunohistochemical ICCs arising inCALD with those arising in livers with non-specific reactive (NSR) changes.
Seventy-one cases of ICC arising in CALD were compared with ICCs arising in livers with NSR changes, including normal livers (72 cases) and the cholangiocarcinomatous (CC) component of hepatocellular cholangioncarcinomas (HC-CCs) (30 cases). The expression of mucin was higher in ICC with NSR changes, whereas it was relatively low in ICC with CALD and the CC component of HC-CC. The expression of biliary markers [cytokeratin (CK)7, CK19, epithelial membrane antigen, and epithelial cell adhesion molecule (EpCAM)] was lower in CC with CALD and in the CC component of HC-CC than in CC with NSR changes. The expression of hepatic progenitor cell markers [neural cell adhesion molecule (NCAM) and c-kit] was higher in ICC with CALD and the CC component of HC-CC than in ICC with NSR changes. EpCAM and CK19 were constantly expressed in cultured CC cells, whereas NCAM was infrequently expressed in cultured CC cells.
The carcinogenesis of ICC arising in CALD and the ICC component of HC-CC, each showing similar features, may involve hepatic progenitor cells.
Histopathology 12/2011; 59(6):1090-9. · 3.08 Impact Factor
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ABSTRACT: Cholangiocarcinoma often is diagnosed at an advanced stage. Thus, it is necessary to establish sensitive screening methods that would allow cholangiocarcinoma and preferably its precursor lesion [biliary intraepithelial neoplasia (BilIN)] to be detected. We sought to clarify the usefulness of heat shock protein (HSP) 27 and HSP70 as biomarkers of cholangiocarcinoma and have used immunohistochemical analyses of hepatolithiatic livers to characterize HSP27 and HSP70 expression during the multistep cholangiocarcinogenesis process. HSP27 and HSP70 were measured in serum and bile samples via enzyme-linked immunosorbent assay. In hepatolithiatic tissue, the expression of HSP27 and HSP70 was increased in BilIN as well as in invasive cholangiocarcinoma. The serum levels of HSP27 and HSP70 were not significantly different between the hepatolithiatic patients with and without cholangiocarcinoma. In contrast, the bile levels of HSP27 and HSP70 were increased significantly in the patients with cholangiocarcinoma compared with those in the patients with lithiasis. Combining the measurements of the bile levels of HSP27 and HSP70 increased their usefulness as biomarkers, and the sum (HSP27 + HSP70) yielded the best sensitivity (90%) and specificity (100%). These results suggest that HSP27 and HSP70 could be used as biliary biomarkers for the detection of cholangiocarcinoma including BilIN.
American Journal Of Pathology 10/2011; 180(1):123-30. · 4.89 Impact Factor
