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1.
Histopathology ; 80(5): 859-868, 2022 Apr.
Article in English | MEDLINE | ID: mdl-35076959

ABSTRACT

BACKGROUND AND AIMS: The type IV intermediate filament, nestin, may be a candidate diagnostic marker for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). Therefore, the significance of nestin as a diagnostic marker for cHCC-CCA categorized by the World Health Organization (WHO) 2019 classification and its relationship with clinicopathological features were examined in the present study. METHODS AND RESULTS: Nestin expression was immunohistochemically assessed in the liver sections from 75 patients with cHCC-CCA, 22 with small duct-type intrahepatic cholangiocarcinoma (iCCA), 20 with large duct-type iCCA and 35 with hepatocellular carcinoma (HCC). Nestin expression and its relationship with clinicopathological features and genetic alterations were investigated in cHCC-CCA. Nestin expression was detected in significantly more patients with cHCC-CCA (66.7%) than in those with large duct-type iCCA (5%) (P < 0.01), HCC (2.9%) (P < 0.01) and small duct-type iCCA (40.9%) (P < 0.05). Nestin expression was partly associated with neural cell adhesion molecule (NCAM) and vimentin expression. Nestin expression was also observed in significantly more patients with small duct-type iCCA than in those with large duct-type iCCA and HCC (P < 0.01). Nestin-positive cHCC-CCA was characterized by a smaller tumour size, the more frequent presence of cholangiolocellular carcinoma (CLC) components, a higher rate of p53 overexpression and a higher rate of multiple genetic alterations (P < 0.05). Furthermore, p53 overexpression was associated with a higher histological grade and multiple genetic alterations (P < 0.05) in nestin-positive cHCC-CCA. CONCLUSION: Nestin may be a useful diagnostic marker for a specific subgroup of cHCC-CCA and small duct-type iCCA associated with CLC components, p53 mutations and multiple genetic alterations, which are related to stemness and multipotent differentiation.


Subject(s)
Bile Duct Neoplasms/diagnosis , Biomarkers, Tumor/analysis , Carcinoma, Hepatocellular/diagnosis , Cholangiocarcinoma/diagnosis , Liver Neoplasms/diagnosis , Nestin/analysis , Adult , Aged , Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/pathology , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/genetics , Cholangiocarcinoma/pathology , Female , Genes, p53/genetics , Humans , Immunohistochemistry , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Male , Middle Aged , Mutation , Neoplasm Grading , Nestin/genetics
2.
Am J Transplant ; 16(6): 1653-80, 2016 06.
Article in English | MEDLINE | ID: mdl-26848550

ABSTRACT

The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.


Subject(s)
Immunity, Cellular/immunology , Liver Transplantation , Allografts , Animals , Humans
3.
Transplant Proc ; 46(10): 3523-35, 2014 Dec.
Article in English | MEDLINE | ID: mdl-25498084

ABSTRACT

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) occurring after liver transplantation is a relatively rare complication but it often takes a life-threatening course. However, the detailed etiology and mechanism of VOD/SOS after liver transplantation (LT) remains unclear. We report two cases with rapidly progressive VOD/SOS after ABO-identical LT resistant to various therapies. In case 1, in which the patient underwent deceased-donor LT, the first episode of acute allograft rejection was triggered VOD/SOS, and the presence of donor non-specific anti-HLA antibodies was confirmed. The recipient died with graft failure on day 46 after transplantation. Case 2, in which the patient underwent living-donor LT from the mother, had neither rejection nor mechanical venous obstruction, but condition of the patient rapidly worsened and he died on day 13 after transplantation. This recipient's direct cross-match test for the donor's B lymphocyte was strongly positive, but that for T lymphocyte was negative. In both cases, neither stenosis of hepatic vein outflow tract nor C4d deposition in post-transplantation liver biopsy specimens and autopsy specimen was found. On the other hand, in both cases, the patient was transfusion unresponsive thrombocytopenia and hyperbilirubinemia persisted postoperatively, and glycoprotein Ⅰ bα was strongly stained in the neighboring centrilobular area (zone 3), especially in the space of Disse, and platelet phagocytosis was observed in Kupffer cells and hepatocytes around zone 3 such as clinical xenotransplantation of the liver in post-transplantation liver biopsy specimens. From the viewpoint of graft injury, VOD/SOS was considered that sustained sinusoidal endothelial cells injury resulted in bleeding in the space of Disse and led to around centrilobular hemorrhagic necrosis, and the fundamental cause was damage around centrilobular area including sinusoid by acute cellular rejection, antibody-mediated rejection or ischemic reperfusion injury. The extrasinusoidal platelet activation, aggregation, and phagocytosis of platelets were some of the main reasons for VOD/SOS and transfusion-resistant thrombocytopenia.


Subject(s)
Graft Rejection/complications , Hepatic Veno-Occlusive Disease/etiology , Liver Transplantation/adverse effects , Tissue Donors , Adult , Biopsy , Female , Graft Rejection/diagnosis , Hepatic Veno-Occlusive Disease/diagnosis , Humans , Male , Severity of Illness Index , Transplantation, Homologous
4.
Clin Exp Immunol ; 173(2): 268-75, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23607494

ABSTRACT

Biliary atresia (BA) is thought to be associated with infections by viruses such as Reoviridae and is characterized histologically by fibrosclerosing cholangitis with proinflammatory cytokine-mediated inflammation. Interleukin (IL)-32 affects the continuous inflammation by increasing the production of proinflammatory cytokines. In this study, the role of IL-32 in the cholangitis of BA was examined. Immunohistochemistry for IL-32 and caspase 1 was performed using 21 samples of extrahepatic bile ducts resected from BA patients. Moreover, using cultured human biliary epithelial cells (BECs), the expression of IL-32 and its induction on stimulation with a Toll-like receptor [(TLR)-3 ligand (poly(I:C)] and proinflammatory cytokines was examined. BECs composing extrahepatic bile ducts showing cholangitis expressed IL-32 in BA, but not in controls. Caspase 1 was expressed constantly on BECs of both BA and control subjects. Furthermore, poly(I:C) and proinflammatory cytokines [(IL-1ß, interferon (IFN)-γ and tumour necrosis factor (TNF)-α] induced IL-32 expression strongly in cultured BECs, accompanying the constant expression of TLR-3 and caspase 1. Our results imply that the expression of IL-32 in BECs was found in the damaged bile ducts of BA and induced by biliary innate immunity via TLR-3 and proinflammatory cytokines. These findings suggest that IL-32 is involved initially in the pathogenic mechanisms of cholangitis in BA and also plays an important role in the amplification and continuance of periductal inflammatory reactions. It is therefore tempting to speculate that inhibitors of IL-32 could be useful for attenuating cholangitis in BA.


Subject(s)
Bile Ducts/immunology , Biliary Atresia/immunology , Cholangitis/immunology , Epithelial Cells/immunology , Interleukins/metabolism , Bile Ducts/pathology , Caspase 1/genetics , Caspase 1/metabolism , Cells, Cultured , Female , Humans , Immunity, Innate , Immunohistochemistry , Infant , Infant, Newborn , Inflammation Mediators/metabolism , Interleukins/genetics , Male , Poly I-C/immunology , Toll-Like Receptor 3/genetics , Toll-Like Receptor 3/metabolism , Up-Regulation
5.
Clin Exp Immunol ; 168(3): 279-84, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22519590

ABSTRACT

One of the major obstacles in dissecting the mechanism of pathology in human primary biliary cirrhosis (PBC) has been the absence of animal models. Our laboratory has focused on a model in which mice, following immunization with a xenobiotic chemical mimic of the immunodominant autoepitope of the E2 component of pyruvate dehydrogenase complex (PDC-E2), develop autoimmune cholangitis. In particular, following immunization with 2-octynoic acid (a synthetic chemical mimic of lipoic acid-lysine located within the inner domain of PDC-E2) coupled to bovine serum albumin (BSA), several strains of mice develop typical anti-mitochondrial autoantibodies and portal inflammation. The role of innate immune effector cells, such as natural killer (NK) cells and that NK T cells, was studied in this model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. We report herein that, following in-vivo depletion of NK and NK T cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK and NK T cells in initiating the breakdown of tolerance. However, the data suggest that adaptive autoimmune effector mechanisms are required for the progression of clinical disease.


Subject(s)
Dihydrolipoyllysine-Residue Acetyltransferase/immunology , Immune Tolerance , Killer Cells, Natural/metabolism , Liver Cirrhosis, Biliary/immunology , Mitochondria/immunology , Mitochondrial Proteins/immunology , Natural Killer T-Cells/metabolism , Animals , Autoantibodies/blood , Autoantigens/immunology , Biomimetic Materials/chemistry , Cattle , Cells, Cultured , Cytokines/blood , Dihydrolipoyllysine-Residue Acetyltransferase/chemistry , Dihydrolipoyllysine-Residue Acetyltransferase/metabolism , Disease Models, Animal , Humans , Immunization , Immunodominant Epitopes/chemistry , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Lymphocyte Depletion , Mice , Mice, Inbred C57BL , Mitochondria/metabolism , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/metabolism , Natural Killer T-Cells/immunology , Natural Killer T-Cells/pathology , Peptide Fragments/administration & dosage , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Serum Albumin, Bovine/administration & dosage , Serum Albumin, Bovine/chemistry , Thioctic Acid/administration & dosage , Thioctic Acid/chemistry , Thioctic Acid/metabolism
6.
Clin Exp Immunol ; 167(3): 532-42, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22288597

ABSTRACT

Hepatoportal sclerosis accompanied by dense elastic fibre deposition is generally regarded as the primary lesion in the development of idiopathic portal hypertension (IPH). This study was performed to clarify the mechanism of elastic fibre deposition in the peripheral portal tracts of IPH liver in relation to serum anti-endothelial cell antibodies (AECA). In-vitro experiments were performed using human dermal microvascular endothelial cells (HMVEC) and patients' sera. The presence of serum AECA was assayed by a cell-based enzyme-linked immunosorbent assay (ELISA) using HMVEC. Immunohistochemical analysis of elastin was performed using liver tissue sections of IPH patients. IPH sera contained one or more AECA that could bind to the vascular endothelial cells of the peripheral portal tracts of the liver. When the value of AECA greater than the mean ± 2 standard deviations of healthy controls was regarded as positive, the positive detection rate of either immunoglobulin (Ig)G, IgA or IgM AECA in IPH sera was 30% (10 of 33 cases). IPH sera induced the expression of elastin in HMVEC, which appeared to be associated with the presence of AECA. Apoptosis was also induced in HMVEC by the stimulation with IPH sera. In vivo, elastin expression was observed in the endothelial cells of the peripheral portal tracts of IPH livers in a proportion of cases. The disease pathogenesis of IPH seems to be heterogeneous, and this study elucidated a possible contribution of the induction of elastin expression in the portal vessels to hepatoportal sclerosis of IPH, which might be linked to serum AECA as a causative factor.


Subject(s)
Autoantibodies/blood , Elastin/biosynthesis , Endothelial Cells/immunology , Endothelial Cells/metabolism , Hypertension, Portal/etiology , Liver Cirrhosis/etiology , Pancytopenia/etiology , Portal Vein/pathology , Splenomegaly/etiology , Apoptosis , Base Sequence , Case-Control Studies , Cells, Cultured , DNA Primers/genetics , Elastin/genetics , Humans , Hypertension, Portal/immunology , Hypertension, Portal/metabolism , Hypertension, Portal/pathology , Immunohistochemistry , In Vitro Techniques , Liver Cirrhosis/immunology , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Pancytopenia/immunology , Pancytopenia/metabolism , Pancytopenia/pathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sclerosis , Splenomegaly/immunology , Splenomegaly/metabolism , Splenomegaly/pathology , Idiopathic Noncirrhotic Portal Hypertension
8.
Clin Res Hepatol Gastroenterol ; 35(5): 347-52, 2011 May.
Article in English | MEDLINE | ID: mdl-21474418

ABSTRACT

Pathological features of primary biliary cirrhosis (PBC) are reviewed. Immune-mediated, non-suppurative cholangitis is the initial lesion and is followed by the gradual and extensive destruction of bile ducts and development of chronic cholestasis. Simultaneously, necro-inflammatory activities of the hepatic parenchyma and limiting plates of milder form develop not infrequently. Eventually, liver fibrosis and cirrhosis develop. A new system applicable to needle liver biopsies in which staging is evaluated using a combination of three factors (fibrosis, cholestasis, and bile duct loss) and necro-inflammatory activities of the bile duct and hepatic parenchyma are graded, is proposed. The clinical and therapeutic evaluation of PBC using this system is warranted.


Subject(s)
Liver Cirrhosis, Biliary/classification , Liver Cirrhosis, Biliary/pathology , Pathology, Clinical , Disease Progression , Humans , Physician's Role , Severity of Illness Index
9.
Am J Transplant ; 11(3): 518-27, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21219581

ABSTRACT

The outcomes of primary sclerosing cholangitis (PSC) after living donor liver transplantation (LDLT) in a large series have not been reported. We aimed to determine long-term patient and graft survival, risk factors for PSC recurrence, and the significance of recurrence after LDLT in a Japanese registry. Questionnaires concerning patient characteristics, treatments, and clinical courses were used. Data of 114 patients undergoing primary LDLT for PSC from July 1996 to December 2008 in 29 institutions were evaluated. For strict diagnoses of recurrence, patients with hepatic artery thrombosis (n = 8), ABO-blood-type-incompatible transplantation (n = 8), and established ductopenic rejection (n = 2) were excluded and 96 patients were analyzed for risk factors. Recurrence was diagnosed in 26 patients (27%) at 8 to 79 months after transplantation. Patient, graft, and recurrence-free survivals were 78, 74 and 57% at 5 years after LDLT, respectively. The graft loss rate was 69 versus 23% in patients with versus without recurrence, respectively. Multivariate analysis revealed that high MELD scores, first-degree-relative donors, postoperative CMV infection, and early biliary anastomotic complications were significant risk factors for recurrence. PSC recurrence was a significant risk factor of graft loss but not patient death. PSC recurrence was frequent and had significant impacts on outcomes after LDLT.


Subject(s)
Liver Transplantation/adverse effects , Living Donors , Postoperative Complications , Adolescent , Adult , Aged , Asian People , Child , Child, Preschool , Cholangitis, Sclerosing/etiology , Female , Graft Rejection , Humans , Infant , Male , Middle Aged , Recurrence , Registries , Retrospective Studies , Risk Factors , Treatment Outcome , Young Adult
10.
Clin Exp Immunol ; 157(2): 261-70, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19604266

ABSTRACT

An innate immune response to bacterial components is speculated to be involved in the pathogenesis of primary biliary cirrhosis (PBC). Recently, CD4-positive T helper type 17 (Th17) cells, characterized by the secretion of interleukin (IL)-17, have been implicated in the pathogenesis of autoimmune diseases. Human Th17 cells are generated from Th0 cells by IL-6 and IL-1 beta and maintained by IL-23. In this study, the role of IL-17 in PBC and its association with biliary innate immunity were examined. Using cultured human biliary epithelial cells (BECs), the expression of Th17-related cytokines and chemokines and changes therein on treatment with pathogen-associated molecular patterns (PAMPs) and IL-17 were examined. Immunohistochemistry for IL-17 and Th17-related cytokines was performed using tissue samples of human liver. Consequently, the expression of IL-6, IL-1 beta, IL-23p19 and IL-23/IL-12p40 mRNAs, and their up-regulation by PAMPs, were found in BECs. Moreover, BECs possessed IL-17-receptors and stimulation with IL-17 induced production of IL-6, IL-1 beta, IL-23p19 and chemokines. Several IL-17-positive cells had infiltrated damaged bile ducts and the expression of IL-6 and IL-1 beta was enhanced in the bile ducts of PBC patients. In conclusion, IL-17-positive cells are associated with the chronic inflammation of bile ducts in PBC which is associated causally with the biliary innate immune responses to PAMPs.


Subject(s)
Autoimmune Diseases/immunology , Biliary Tract/immunology , Interleukin-17/analysis , Liver Cirrhosis, Biliary/immunology , Bile Ducts, Intrahepatic/immunology , Case-Control Studies , Cells, Cultured , Epithelial Cells/immunology , Female , Follow-Up Studies , Humans , Immunity, Innate , Immunohistochemistry , Interleukin-17/genetics , Interleukin-17/pharmacology , Interleukins/genetics , Interleukins/immunology , Liver Cirrhosis, Biliary/pathology , Male , Middle Aged , RNA, Messenger/analysis
11.
Oncogene ; 28(32): 2910-8, 2009 Aug 13.
Article in English | MEDLINE | ID: mdl-19503097

ABSTRACT

The partition-defective 3 (PAR-3) protein is implicated in the formation of tight junctions at epithelial cell-cell contacts. We investigated DNA copy number aberrations in human esophageal squamous cell carcinoma (ESCC) cell lines using a high-density oligonucleotide microarray and found a homozygous deletion of PARD3 (the gene encoding PAR-3). Exogenous expression of PARD3 in ESCC cells lacking this gene enhanced the recruitment of zonula occludens 1 (ZO-1), a marker of tight junctions, to sites of cell-cell contact. Conversely, knockdown of PARD3 in ESCC cells expressing this gene caused a disruption of ZO-1 localization at cell-cell borders. A copy number loss of PARD3 was observed in 15% of primary ESCC cells. Expression of PARD3 was significantly reduced in primary ESCC tumors compared with their nontumorous counterparts, and this reduced expression was associated with positive lymph node metastasis and poor differentiation. Our results suggest that deletion and reduced expression of PARD3 may be a novel mechanism that drives the progression of ESCC.


Subject(s)
Carcinoma, Squamous Cell/genetics , Cell Cycle Proteins/genetics , Esophageal Neoplasms/genetics , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Membrane Proteins/genetics , Adaptor Proteins, Signal Transducing , Aged , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Movement , Esophageal Neoplasms/metabolism , Esophageal Neoplasms/pathology , Gene Deletion , Gene Dosage , Homozygote , Humans , Immunoblotting , Infant , Intercellular Junctions/metabolism , Male , Membrane Proteins/metabolism , Microscopy, Confocal , Microscopy, Fluorescence , Middle Aged , Oligonucleotide Array Sequence Analysis , Phosphoproteins/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Zonula Occludens-1 Protein
12.
J Pathol ; 215(2): 175-83, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18393368

ABSTRACT

Polycomb group protein EZH2 and Bmi1 are reportedly involved in the progression of malignant tumours. We examined the participation of EZH2 in multi-step cholangiocarcinogenesis in hepatolithiasis with respect to tumour suppressor gene p16 INK4a. We examined 20 hepatolithiatic livers with intrahepatic cholangiocarcinoma (ICC) and 10 histologically normal livers. Neoplastic biliary lesions were classified into biliary intraepithelial neoplasm (BilIN-1, 2 and 3) and invasive carcinoma. We selected 15 foci of invasive carcinoma, 8 BilIN-3 (carcinoma in situ), 12 BilIN-2 (high-grade dysplasia), 32 BilIN-1 (low-grade dysplasia) and 37 non-neoplastic biliary epithelia from these livers. Expression of p16 INK4a, EZH2 and Bmi1 were surveyed in these foci. P16 INK4a promoter methylation was examined in microdissected tissues. Taking advantage of two cell lines of CC (HuCTT-1 and TFK-1) and small interfering RNA (siRNA), the effects of the knockdown of EZH2 on p16 INK4a methylation of CC cells were examined. Expression of p16 INK4a, which was frequent in BilIN1, was decreased in BilIN-2/3 and invasive carcinoma, while EZH2 expression showed step-wise increase from BilIN-1, -2 and -3 to invasive carcinoma (p < 0.01). P16 INK4a promoter hypermethylation was related to aberrant expression of EZH2. The knockdown of EZH2 in cultured CC cells decreased p16 INK4a methylation and decreased binding of EZH2 to the p16 INK4a gene promoter. The latter suggested that direct binding of EZH2 is involved in the regulation of the p16 INK4a gene. Our data suggest that over-expression of EZH2 may induce hypermethylation of p16 INK4a promoter followed by decreased expression of p16 INK4a in the multi-step cholangiocarcinogenesis through intraepithelial neoplasm in hepatolithiasis.


Subject(s)
Bile Duct Neoplasms/metabolism , Cholangiocarcinoma/metabolism , Cyclin-Dependent Kinase Inhibitor p16/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Transcription Factors/genetics , Bile Ducts, Intrahepatic/metabolism , Cell Line, Tumor , Cholelithiasis/metabolism , Cyclin-Dependent Kinase Inhibitor p16/analysis , DNA-Binding Proteins/analysis , Enhancer of Zeste Homolog 2 Protein , Gene Expression , Genes, Tumor Suppressor , Humans , Immunoblotting/methods , Immunohistochemistry , Nuclear Proteins/genetics , Polycomb Repressive Complex 1 , Polycomb Repressive Complex 2 , Proto-Oncogene Proteins/genetics , RNA Interference , RNA, Small Interfering/pharmacology , Repressor Proteins/genetics , Statistics, Nonparametric , Transcription Factors/analysis
13.
Histopathology ; 51(3): 390-400, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17553067

ABSTRACT

AIMS: The histogenesis and biological behaviour of peripheral intrahepatic cholangiocarcinoma (peripheral CC) remain unclarified. The aim of this study was to examine the growth pattern of peripheral CC (24 cases) in comparison with hepatocellular carcinoma (HCC, 27 cases) and metastatic colorectal adenocarcinoma (MCA, 24 cases). METHODS AND RESULTS: Tumour/surrounding liver borders were classified as: (i) fibrous encapsulation, (ii) compressive growth, and (iii) infiltrating replacement. Nineteen of 24 peripheral CCs showed (iii), whereas 23 of 27 HCCs showed (i) and 17 of 24 MCAs showed (ii). In (iii), carcinoma cells infiltrated the surrounding liver without compression, and hepatic supporting vascular structures such as portal tracts were secondarily incorporated into the tumour. In (i) and (ii), the surrounding liver was compressed and no or few portal tracts were incorporated within the tumour. Fifteen of 24 peripheral CCs were composed of carcinoma cells resembling reactive bile ductules and these cells were positive for neural cell adhesion molecule (NCAM), a marker of proliferating bile ductules. The remaining nine peripheral CCs were composed of ordinary adenocarcinoma and negative for NCAM. CONCLUSIONS: A subgroup of peripheral CCs with an infiltrating replacement growth pattern resembles reactive bile ductules and expresses NCAM. 'Bile ductular carcinoma' may be a better term for this subgroup.


Subject(s)
Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Bile Ducts/pathology , Cholangiocarcinoma/pathology , Adenocarcinoma/metabolism , Adenocarcinoma/secondary , Aged , Aged, 80 and over , Autopsy , Bile Duct Neoplasms/metabolism , Bile Ducts/metabolism , Bile Ducts, Intrahepatic/chemistry , CD56 Antigen/analysis , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/metabolism , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/secondary , Female , Humans , Immunohistochemistry , Keratins/analysis , Liver/chemistry , Liver/pathology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Male , Middle Aged , Neural Cell Adhesion Molecules/analysis , Organ Size , Vimentin/analysis
15.
Histopathology ; 49(5): 466-78, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17064292

ABSTRACT

AIMS: To define a new histological staging and grading system for primary biliary cirrhosis (PBC), to provide more information reflecting clinical laboratory data and the prognosis to hepatologists. METHODS AND RESULTS: First, 17 histological lesions of PBC were scored in 188 needle liver biopsy specimens. Factor analysis yielded three independent groups of factors: factor 1 (fibrosis, fibrous piecemeal necrosis, orcein-positive granules, bile plugs, Mallory bodies, feathery degeneration, bile duct loss and atypical ductular proliferation); factor 2 (portal inflammation, eosinophilic infiltration, lymphoid follicles, epithelioid granulomas, interface hepatitis and chronic cholangitis); and factor 3 (interface hepatitis, lobular hepatitis, acidophilic bodies and pigmented macrophages). The eight findings of factor 1, but not factors 2 and 3, were significantly correlated with clinical laboratory data and scores in the Mayo Clinic's prognostic model. Factor 1 lesions may reflect histological progression (staging), while factor 2 and 3 lesions may relate to necroinflammatory activity (grading). Then, we devised a staging and grading system using three lesions (bile duct loss, fibrosis and orcein-positive granules) from factor 1 and three from factors 2 and 3 (chronic cholangitis, interface hepatitis and lobular hepatitis). CONCLUSION: This new system might provide more pathological information on PBC patients for hepatologists.


Subject(s)
Liver Cirrhosis, Biliary/classification , Liver Cirrhosis, Biliary/pathology , Liver/pathology , Biopsy, Needle , Disease Progression , Humans , Liver Cirrhosis, Biliary/physiopathology , Prognosis
16.
J Clin Pathol ; 59(2): 184-90, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16443736

ABSTRACT

BACKGROUND: The Toll-like receptor (TLR) family recognises pathogen associated molecular patterns (PAMPs) and plays a pivotal role in the innate immune response. Biliary epithelial cells (BECs) lining the intrahepatic bile ducts are potentially exposed to bacterial components in bile, and murine BECs possess TLRs that recognise PAMPs, resulting in nuclear factor kappaB (NF-kappaB) activation. AIMS: To examine the presence of TLRs in human BECs and the influence of cytokines and PAMPs on TLR expression and NF-kappaB activation. METHODS: The expression of TLR2-5, MD-2, MyD88, and IRAK1 was examined in human liver tissue and cultured BECs by immunohistochemistry or reverse transcription polymerase chain reaction. The influence of PAMPs (peptidoglycan and lipopolysaccharide) in cultured cells preincubated with interferon gamma (IFNgamma) was evaluated by NF-kappaB activation. RESULTS: TLR2-5, MyD88, and IRAK-1 proteins were detectable in BECs of the intrahepatic biliary tree in human liver tissue. TLR2-5, MD-2, MyD88, and IRAK-1 mRNA was demonstrated in human cultured BECs. The expression of these TLRs was upregulated by IFNgamma, and TLR2 was upregulated by tumour necrosis factor alpha. Interleukins 4 and 6 failed to induce TLR upregulation. Interestingly, preincubation with IFNgamma synergistically increased the upregulation of NF-kappaB induced by PAMPs in cultured BECs. CONCLUSION: These results suggest that the TLR family is present in human biliary cells and participates in the innate immunity of the intrahepatic biliary tree. Disordered regulation of TLRs after intracellular signalling by cytokines and PAMPs may be involved in immune mediated biliary diseases.


Subject(s)
Bile Ducts, Intrahepatic/immunology , Interferon-gamma/immunology , NF-kappa B/physiology , Toll-Like Receptors/metabolism , Aged , Cell Line , Cytokines/immunology , Epithelial Cells/immunology , Female , Gene Expression , Humans , Ligands , Lipopolysaccharides/immunology , Lymphocyte Antigen 96/metabolism , Male , Middle Aged , NF-kappa B/metabolism , Peptidoglycan/immunology , RNA, Messenger/genetics , Receptors, Cytokine/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Tumor Cells, Cultured
18.
Abdom Imaging ; 30(1): 71-6, 2005.
Article in English | MEDLINE | ID: mdl-15647874

ABSTRACT

Magnetic resonance imaging (MRI) findings of primary biliary cirrhosis (PBC; currently regarded as a vanishing bile duct syndrome) are not established. In this report, we describe our preliminary analysis of the relation between MRI findings and histopathologic staging of PBC and review clinical, morphologic, and MRI findings of PBC especially focusing on the staging of PBC.


Subject(s)
Liver Cirrhosis, Biliary/pathology , Magnetic Resonance Imaging , Diagnosis, Differential , Humans , Hypertension, Portal/etiology , Liver Cirrhosis, Biliary/complications , Lymphatic Diseases/diagnostic imaging , Neoplasm Staging , Radiography
20.
Histopathology ; 43(4): 340-6, 2003 Oct.
Article in English | MEDLINE | ID: mdl-14511252

ABSTRACT

AIMS: To investigate the participation of DMBT-1, a candidate tumour suppressor gene, in the development of intrahepatic cholangiocarcinoma via intraductal papillary neoplasm of the liver (IPN-L) arising in hepatolithiasis. DMBT-1 plays a role in mucosal immune defence. METHODS AND RESULTS: The expression of DMBT-1 was examined immunohistochemically in biliary epithelial cells in hepatolithiasis (n = 25), invasive and non-invasive cholangiocarcinoma associated with hepatolithiasis (n = 52), IPN-L with hepatolithiasis (n = 49), cholangiocarcinoma without hepatolithiasis (n = 32), and 10 normal control livers. DMBT-1 was expressed more frequently in the biliary epithelia of hepatolithiasis when compared with normal livers (P < 0.05). DMBT-1 expression was also frequent in IPN-L (57%) and non-invasive cholangiocarcinoma (79%). By contrast, DMBT-1 was decreased in invasive cholangiocarcinoma with and without hepatolithiasis (50% and 30%, respectively) (P < 0.05). The homozygous deletion of the DMBT-1 gene was recognized in four (20%) of 20 cholangiocarcinoma tissues and two (50%) of four cholangiocarcinoma cell lines, corresponding to the reduction of DMBT-1 expression. No deletion was detected in hepatolithiasis tissues. CONCLUSION: DMBT-1 expression is increased in IPN-L and non-invasive cholangiocarcinoma as well as in biliary epithelia in hepatolithiasis. Decreased expression of DMBT-1 and homozygous deletion of the DMBT-1 gene in invasive cholangiocarcinoma suggest that they occur in the late stage of cholangiocarcinogenesis.


Subject(s)
Agglutinins , Bile Duct Neoplasms/genetics , Brain Neoplasms/genetics , Cholangiocarcinoma/genetics , Gene Deletion , Gene Expression Regulation, Neoplastic/genetics , Receptors, Cell Surface/genetics , Bile Duct Neoplasms/metabolism , Bile Duct Neoplasms/pathology , Bile Ducts, Intrahepatic/pathology , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Calcium-Binding Proteins , Carcinoma, Papillary/genetics , Carcinoma, Papillary/metabolism , Carcinoma, Papillary/pathology , Cell Line, Tumor , Cholangiocarcinoma/metabolism , Cholangiocarcinoma/pathology , DNA-Binding Proteins , Humans , Immunoenzyme Techniques , In Situ Hybridization , Lithiasis/pathology , RNA, Messenger/metabolism , RNA, Neoplasm/analysis , Receptors, Cell Surface/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins
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