bromochloroacetic-acid and Cholangiocarcinoma

Cholangiocarcinomas (CC) are tumors that arise from the epithelial cell of the biliary tract. They represent the second most frequent primitive liver malignancy after hepatocellular carcinoma. Recent epidemiological data show an increase incidence of CC independently of the increased incidence of cirrhosis. According to their location in the biliary tract, we distinguish intrahepatic, hilar (Klastkin tumors) and extrahepatic CC. In literature, confusion exists around hilar CC that are included, according series, to intrahepatic or extrahepatic CC. However, hilar CC share common clinical, morphological and therapeutic features with extrahepatic CC. So, OMS classification of digestive tumors defined two groups of CC: intrahepatic or peripheral CC which develop from small intrahepatic biliary duct beyond the second segmentation, and extrahepatic CC comprising hilar CC and tumors from common hepatic bile duct. In this chapter, we will describe the different gross features and histological characteristic of CC and will detail the major histopronostic criteria of these tumors.

Topics: Bile Duct Diseases; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Biopsy; Cholangiocarcinoma; Humans; Incidence; Keratins; Liver; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasm Staging; Precancerous Conditions; Prognosis

Topics: alpha-Fetoproteins; Antigens, Tumor-Associated, Carbohydrate; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Cholangiocarcinoma; Humans; Immunohistochemistry; Keratins; Oligosaccharides; Prognosis; Sialyl Lewis X Antigen

A case is reported herein of intrahepatic cholangiocarcinoma (ICC) with multicystic, mucinous appearance and oncocytic change. Because of liver dysfunction, a 73-year-old woman was hospitalized in early October 2003. She was diagnosed as having ICC of the right hepatic lobe with occlusion of the hilar and perihilar bile ducts by imaging examination. Extended right lobectomy was performed but the patient died of liver failure on the next day. In surgically resected specimens, the tumor (3 x 3 cm) was mainly located in the right lobe, and tumors infiltrated along the biliary tree as well as invading into the adjacent hepatic parenchyma. The tumor mass had a sponge or honeycomb appearance. Microscopically, these tumors were composed of multiple microcysts filled by abundant mucin and lined by micropapillary adenocarcinoma cells. Their cytoplasm was acidophilic, appearing as an oncocyte, and carcinoma cells were positive for mitochondrial antigen in addition to biliary cytokeratins. There were no ovarian-like stromas around these cystic tumors, and communication of the biliary lumen with these carcinomatous cysts was not evident, thus different from biliary mucinous cystadenocarcinoma and intraductal papillary neoplasm of the liver. This is the third case of multicystic mucinous ICC and the present case might have been derived from intrahepatic peribiliary glands.

Topics: Adenocarcinoma, Mucinous; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Cysts; Female; Humans; Immunohistochemistry; Keratin-7; Keratins

A 59-year-old woman presented with epigastric pain and weight loss. Ultrasound, computed tomography, and magnetic resonance imaging scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. The tumor was subsequently resected, and histopathology showed a poorly differentiated adenocarcinoma immunoreactive for CA 19-9 and cytokeratin 19. In the absence of any other clinically detectable primary tumor, the lesion was diagnosed as a peripheral intrahepatic cholangiocarcinoma. In addition, multiple bile duct hamartomas were found in the surrounding parenchyma. The tumor was unrelated to Caroli disease, primary sclerosing cholangitis, ulcerative colitis, or nonbiliary cirrhosis, as demonstrated by further clinical and histopathologic investigations, but probably was associated with the presence of multiple bile duct hamartomas. To our knowledge, this is the eighth reported case of a cholangiocarcinoma associated with multiple bile duct hamartomas.

Topics: Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; CA-19-9 Antigen; Cholangiocarcinoma; Female; Hamartoma; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Middle Aged

Spontaneous hepatic neoplasms were identified in two adolescent (<5 years of age) male cynomolgus monkeys (Macaca fascicularis). Monkey No. 1 had a solitary hepatocellular carcinoma (HCC). Monkey No. 2 had multiple discrete tumors consisting of several poorly circumscribed HCCs and a mixed hepatocholangiocellular carcinoma (MHC). Metastases were not evident in either monkey. Histochemical and immunohistochemical stains were used to assess phenotypic alterations in the tumors. Many or most neoplastic hepatocytes (NHs) of both monkeys stained positive for low-molecular-weight cytokeratin (LMWCK), cytokeratin (CK) 8, and CK 18. In monkey No. 1, small aggregates of NHs were positive for carcinoembryonic antigen (CEA), glutathione S-transferase-pi (GST), and alpha-fetoprotein (AFP), but NHs were uniformly negative for CK 7. NHs in monkey No. 2 were negative for CEA and AFP but were multifocally positive for GST and CK 7. Broad-spectrum cytokeratin (BSCK), high-molecular-weight cytokeratin (HMWCK), and CK 19 did not react with NHs of either animal. Neoplastic cells forming ductlike structures in the MHC of monkey No. 2 stained with LMWCK, CK 7, CK8, CK 18, BSCK, and GST but not with HMWCK or CK 19. Tumors in both monkeys had enhanced pericellular fibronectin staining. Nonneoplastic parenchyma of both monkeys contained multiple discrete foci of cellular alteration and scattered aggregates of hepatocytes with strong cytoplasmic staining for fibronectin. Staining patterns of these tumors demonstrate immunophenotypic heterogeneity of the neoplastic cells within individual tumors and variability among tumors. This information may serve as a useful reference for others encountering similar lesions in primates.

Topics: alpha-Fetoproteins; Animals; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Glutathione Transferase; Immunohistochemistry; Keratins; Liver Neoplasms; Macaca fascicularis; Male; Monkey Diseases

Proliferation of preexisting bile ducts, ductular metaplasia of hepatocytes and proliferation and differentiation of liver stem cells are discussed in the pathogenesis of neoductular structures in the liver. Under the condition of experimental bile duct obstruction and in extrahepatic bile duct stenosis neoductular structures are first the result of proliferation and sprouting of preexisting ducts and cholangioles. Especially in later stages of cholestasis but also in other chronic progredient liver diseases such as chronic alcoholic liver disease and chronic active hepatitis periportal hepatocytes may show a phenotypic shift towards ductular epithelia. In postnatal liver diseases hepatocytes first express keratin 7 and later keratin 19 during ductular transdifferentiation. This is in contrast to embryonal cholangiogenesis. In alpha-1-antitrypsin-deficiency, hemochromatosis, Wilson's disease, and chronic active hepatitis B cellular deposites typically located in hepatocytes such as alpha-1-AT, siderin, copper, HBs-Ag, and HBc-Ag can also be found in neoductular cells close to hepatocytes. These deposites seem to be retained during the ductular transdifferentiation of hepatocytes. Expression of bile duct-type integrin subtypes and TGF beta 1 in neoductular cells are involved in the changing parenchymal/mesenchymal interplay during neoductogenesis, resulting in periductular basal membrane and periductular fibrosis. In FNH the ductular transdifferentiation of hepatocytes is integrated in the histogenesis of micronodules and portal tract equivalents of these tumor-like lesions. Ductular structures in hepatoblastomas and especially in combined hepatocellular and cholangiocarcinomas (CHCC) may reflect the common embryologic derivation of hepatocytes and biliary epithelia. Non-neoplastic liver tissue in resection specimens of our CHCC showed a lower rate of cirrhosis, and a significantly higher Ki 67-LI of neoductular cells compared to liver tissue in resection specimens of HCC and liver metastases. 3 of 10 CHCC had developed in alpha-1-AT-deficiency, in which this protease-inhibitor was predominantly retained in periportal hepatocytes. These findings in non-neoplastic tumor-bearing liver tissue suggest that CHCC include a special histogenic type of primary liver carcinoma which in analogy to some experimental liver tumors might develop from periportal parenchymal cells.

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Animals; Bile Ducts; Bile Ducts, Extrahepatic; Carcinoma, Hepatocellular; Cell Differentiation; Cell Division; Cholangiocarcinoma; Cholestasis; Copper; Hepatitis B Core Antigens; Hepatitis B Surface Antigens; Hepatoblastoma; Humans; Hyperplasia; Keratins; Liver; Liver Diseases; Liver Neoplasms; Metaplasia

The WHO classification describes that combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell subtype (CHC-INT) is composed of tumour cells with features intermediate between hepatocytes and cholangiocytes. However, we previously reported that CHC-INT showed a high positive rate of biliary markers, but the expression of hepatocyte paraffin (HepPar)-1 was low. In this study, we examined the expression of other hepatocyte markers, such as arginase-1 (Arg-1), keratin (K) 8 and K18 in CHC-INT in order to examine the utility of pathological diagnosis in CHC-INT.. We performed immunohistochemistry (IHC) of Arg-1, K8 and K18 using 32 previously diagnosed as CHC-INT. Immunoreactivity was evaluated with grading from 0 to 4 according to the distribution area of positive cells. The obtained findings of Arg-1, K8 and K18 were compared with those of K7, K19 and HepPar-1.. Out of the 32 cases, 22 (68.8%) cases were positive for Arg-1. Twenty-five (78.1%) were positive for K8. The IHC scores of Arg-1 and K8 were significantly higher than those of HepPar-1, but significantly lower than those of K7 and K19. The K18 expression was widely observed in all cases (100%). The IHC score of Arg-1 and K8 in CHC-INT was intermediate between hepatocellular carcinoma and cholangiocarcinoma.. Arg-1 and K8 were good markers to identify intermediate cells between hepatocytes and cholangiocytes. These can be useful markers for pathological diagnosis of CHC-INT, which usually has wide histological diversities, in combination with other hepatocytic and/or cholangiocytic markers.

Topics: Aged; Arginase; Bile Duct Neoplasms; Biomarkers; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Gene Expression Regulation, Neoplastic; Hepatocytes; Humans; Immunohistochemistry; Immunophenotyping; Keratin-18; Keratin-8; Keratins; Liver; Liver Neoplasms; Male; Middle Aged

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

Topics: Aniline Compounds; Animals; Anisoles; Antineoplastic Agents; Benzeneacetamides; beta Catenin; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cholangiocarcinoma; Clodronic Acid; Heterocyclic Compounds, 2-Ring; Humans; Keratins; Liposomes; Macrophages; Male; Mice, Nude; Pyridines; Pyrimidines; Pyrimidinones; Rats, Sprague-Dawley; Tamoxifen; Wnt Signaling Pathway; Xenograft Model Antitumor Assays

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Chromosomal Proteins, Non-Histone; Diagnosis, Differential; DNA-Binding Proteins; Humans; Keratins; Liver Neoplasms; Magnetic Resonance Imaging; Male; Middle Aged; Rhabdoid Tumor; SMARCB1 Protein; Transcription Factors; Tumor Suppressor Proteins; Vimentin

Our purpose was to assess the clinicopathological features and surgical outcomes of combined hepatocellular-cholangiocarcinoma (HCC-CC) in an Asian center.. Between 1998 and 2009, 27 patients were diagnosed with combined HCC-CC at our hospital. Their medical records were reviewed and clinicopathological data retrospectively analyzed.. The 27 patients included 24 (88.9%) males and 3 (11.1%) females with a mean age of 58.26 ± 11.18 years. Cirrhosis was present in 10 patients (37.0%), and 12 patients had hepatitis C or hepatitis B virus infection. Serum alpha fetoprotein was >20 ng/ml in 7 of the 19 patients in whom it was measured (36.8%). Twenty-five patients underwent hepatic resections and 2 received liver transplantations. Five (18.5%) patients had separate HCC and CC within the same liver (type I), 21 (77.8%) had tumors with mixed components (type II), and 1 patient had a type III tumor (3.7%). Of 22 patients with immunohistochemical data, 19 (86.4%) were cytokeratin (CK) 7-positive, 20 (90.9%) were CK19-positive, and 4 (18.2%) were CK20-positive. Mean follow-up was 25.8 months. The 1- and 2-year survival rates were 72.5 and 49.4%, respectively. The 1- and 2-year disease-free survival rates were 54.2 and 41.3%, respectively. Symptoms at the time of diagnosis, and regional lymph node metastases, were associated with higher mortality and recurrence.. Lymph node metastasis and positive resection margins are important factors affecting HCC-CC surgical outcomes.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Keratins; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasms, Multiple Primary; Prognosis; Retrospective Studies

Presentation of the Case A 37-year-old woman presented at 35 weeks of gestation with her third child with failure to adequately gain weight and was noted by her obstetrician to have delay in the growth of her baby. Ultrasound of the abdomen incidentally revealed the presence of a liver lesion. After additional evaluation, she ultimately delivered her daughter at 36 weeks uneventfully. She subsequently underwent additional evaluation. Liver magnetic resonance imaging (MRI) revealed a 5-cm solitary solid mass in segment 4A of the liver, concerning for malignancy. Serum α-fetoprotein, carcinoembryonic antigen, cancer antigen (CA)19-9, CA15-3, and CA125 were all normal. Liver biopsy was positive for adenocarcinoma. The tumor cells demonstrated a phenotype suggesting a possible breast primary, although the immunohistochemistry did not support that diagnosis and the tumor was negative for mammaglobin, gross cystic disease fluid protein (GCDFP)-15, estrogen receptor (ER), and progesterone receptor (PR) (Table 1). The tumor was also CDX2 and cardiotrophin-1 negative, but cytokeratin (CK) 19 positive. Her endoscopic retrograde cholangiopancreatography, upper endoscopy, colonoscopy, breast mammogram, and breast MRI were completely normal. A positron emission tomography-computed tomography scan showed a fluorodeoxyglucose-avid 5.8-cm × 6.0-cm hypoattenuating lesion with peripheral enhancement involving segment 4 and segment 8 at the dome. In addition, central necrosis within the lesion was noted. The left main portal vein was mildly attenuated by the mass. She eventually underwent a left hepatectomy en bloc with caudate resection, portal lymphadenectomy, cholecystectomy, and omental pedicle flap. On exploration of the abdomen, no additional disease was noted. The final pathology revealed a 9.4-cm moderately to poorly differentiated adenocarcinoma of the intrahepatic bile ducts. Venous invasion was present. Perineural invasion was absent. The margins were negative. Thirteen lymph nodes were obtained, all of which were negative, consistent with a stage T2, N0, MX intrahepatic cholangiocarcinoma. The tumor was positive for CK7, CK19, and CA19-9 and negative for CK20, CDX2, CA125, ER, PR, GCDFP-15, synaptophysin, and chromogranin (Table 1). The uninvolved liver was unremarkable and a trichrome stain showed no fibrosis. Following an uneventful postoperative recovery, she was referred for consideration of adjuvant therapy.

Topics: Adenocarcinoma; Adult; alpha-Fetoproteins; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers; Biopsy; CA-125 Antigen; Capecitabine; Carcinoembryonic Antigen; Carrier Proteins; CDX2 Transcription Factor; Chemotherapy, Adjuvant; Cholangiocarcinoma; Cholangiopancreatography, Endoscopic Retrograde; Cytokines; Deoxycytidine; Female; Fluorodeoxyglucose F18; Fluorouracil; Gemcitabine; Glycoproteins; Hepatectomy; Homeodomain Proteins; Humans; Immunohistochemistry; Keratin-20; Keratins; Liver; Liver Neoplasms; Lymph Node Excision; Magnetic Resonance Imaging; Membrane Transport Proteins; Phenotype; Portal Vein; Pregnancy; Receptors, Estrogen; Receptors, Progesterone

Fibrolamellar hepatocellular carcinoma is a subtype of hepatocellular carcinoma occurring in non-cirrhotic liver at a younger age. The tumor expresses both hepatocellular and cholangiocellular markers. Previously, our group described overexpression of tight junction protein claudin 4 in cholangiocellular carcinoma in contrast to hepatocellular carcinoma. In the present study, tight junction protein expressions were studied to possibly clarify bipotential lineage of fibrolamellar hepatocellular carcinoma. Eleven fibrolamellar hepatocellular carcinomas were compared with seven "conventional" hepatocellular carcinomas, seven cholangiocellular carcinomas, and five normal liver samples. By immunohistochemistry, all fibrolamellar hepatocellular carcinomas were positive for HepPar1 and cytokeratins 7, 8, and 18, but negative for cytokeratin 19. Glypican-3 gave weak staining in two cases. Expression of claudin 1 was lower, while that of claudin 2 was higher in fibrolamellar hepatocellular carcinomas than in other tumors. Claudins 3, 4, and 7 were not detectable in fibrolamellar hepatocellular carcinomas as in the majority of "conventional" hepatocellular carcinomas, contrary to high expression observed in cholangiocellular carcinomas. Focal or diffuse claudin 5 expression was detected in nine of 11 fibrolamellar hepatocellular carcinomas contrary to other tumors. Tricellulin was significantly downregulated in all tumors compared with normal liver. Our findings showed claudins to exhibit specific expression patterns in fibrolamellar hepatocellular carcinomas not observed in other primary liver tumors, with unique claudin 5 expression and pattern features similar to common hepatocellular carcinoma, but different from cholangiocellular carcinoma. This is the first report describing the loss of tricellulin expression in human hepatic tumors.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Child; Cholangiocarcinoma; Claudins; Female; Glypicans; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; MARVEL Domain Containing 2 Protein; Membrane Proteins; Middle Aged; Retrospective Studies; Young Adult

The presence of para-aortic lymph node metastasis in biliary cancer negatively impacts prognosis. The present study aims to immunohistochemically identify and evaluate the clinical significance of para-aortic lymph node micrometastases in 66 patients who had undergone curative resection of biliary cancer.. We used an antibody against cytokeratins 7 and 8 (CAM5.2) to immunostain 529 para-aortic lymph nodes that were negative according to conventional analysis from 66 patients with biliary cancer.. We detected CAM5.2-positive occult carcinoma cells in para-aortic lymph nodes from 3 (5%) of the 66 patients and in 3 (0.6%) of the 529 para-aortic lymph nodes. One of the 3 patients also had micrometastasis in the regional lymph nodes. All 3 patients with para-aortic lymph node micrometastasis are alive at 45, 48 and 90 months after surgery despite having locally advanced cancer.. Occult cancer cells were identified in para-aortic lymph nodes from 5% of patients with node-negative biliary cancer, yet these patients have survived over the long term. The presence of para-aortic nodal micrometastasis might not have an influence on survival. However, further studies using a greater number of patients are required to support this notion.

Topics: Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers; Carcinoma; Cholangiocarcinoma; Female; Gallbladder Neoplasms; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Keratins; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Prognosis; Retrospective Studies

Intrahepatic clear cell cholangiocarcinoma is very rare - only 8 cases have been reported. A 56-year-old Japanese man with chronic hepatitis B infection was diagnosed with a 2.2 cm hepatocellular carcinoma on imaging, and hepatic segmentectomy was performed. Histopathologically, the tumor cells had copious clear cytoplasm and formed glandular structures or solid nests. These pathological findings suggested the tumor was a clear cell variant of intrahepatic cholangiocarcinoma. Particular stains and radiological images suggested that the cause of the clear cell change had been glycogen, not mucin nor lipid. On immunohistochemical staining, cytokeratin (CK) 7 and CK19 were positive, whereas CK20 was negative. Vimentin was detected on the cell membranes, and CD56 was focally positive. The patient was given adjuvant chemotherapy and is currently free from the tumor 7 mo postoperatively. Careful follow-up with adequate postoperative supplementary chemotherapy is necessary because the characteristics of this type of tumor are unknown.

Topics: Adenocarcinoma, Clear Cell; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Humans; Keratins; Male; Middle Aged; Vimentin

Topics: Actins; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Female; Giant Cells; Humans; Keratins; Liver Neoplasms; Osteoclasts; Vimentin

In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis.. A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review.. The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p<0.001).. The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.

Topics: Adolescent; Adult; Aged; Antibodies; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Child; Cholangiocarcinoma; Cluster Analysis; Diagnosis, Differential; Female; Hepatocytes; Humans; Immunohistochemistry; Keratin-19; Keratin-7; Keratins; Liver Neoplasms; Male; Medical Oncology; Middle Aged; Reproducibility of Results; Young Adult

To compare the immunoprofiles of intrahepatic cholangiocarcinoma and metastatic colorectal adenocarcinoma for mucin glycoproteins (including MUC1, MUC2, MUC5AC and MUC6) and cytokeratins (including CK7, CK19 and CK20), and to assess their diagnostic value.. One hundred cases of intrahepatic cholangiocarcinoma and 21 cases of metastatic colorectal adenocarcinoma were enrolled into the study. Immunohistochemical study for MUC1, MUC2, MUC5AC, MUC6, CK7, CK19 and CK20 was carried out in all cases by EnVision method.. In intrahepatic cholangiocarcinoma, the expression rates of MUC1, MUC2, MUC5AC and MUC6 were 61.0%, 2.0%, 22.0% and 8.0% respectively, as compared to 57.1%, 47.6%, 19.0% and 23.8% respectively in metastatic colorectal adenocarcinoma. On the other hand, the expression rates of CK7, CK19 and CK20 in intrahepatic cholangiocarcinoma were 73.0%, 53.0% and 15.0% respectively, in contrast to 14.3%, 90.5% and 85.7% respectively in metastatic colorectal adenocarcinoma. The difference in expressions of MUC2, MUC6, CK7 and CK20 carried statistical significance.. The immunoprofile for mucin glycoproteins and cytokeratins provides important clues in distinguishing between intrahepatic cholangiocarcinoma and metastatic colorectal adenocarcinoma to liver. The immunophenotype of MUC2-/MUC6-/CK7+/CK20- indicates the diagnosis of intrahepatic cholangiocarcinoma, while MUC2+/MUC6+/CK7-/CK20+ suggests the possibility of metastatic colorectal adenocarcinoma.

Topics: Adenocarcinoma; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Colorectal Neoplasms; Female; Glycoproteins; Humans; Keratins; Male; Middle Aged; Mucins; Neoplasm Staging

A high serum cytokeratin 19 fragment (CYFRA21-1) concentration in patients with various cancers is associated with poor prognosis. This study aimed to establish the clinical significance of preoperative serum CYFRA21-1 in patients with intrahepatic cholangiocarcinoma.. CYFRA21-1, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 concentrations were measured in sera from 71 patients with intrahepatic cholangiocarcinoma. The prognostic significance of serum CYFRA21-1 levels was assessed by univariate and multivariate analyses.. Analysis of the areas under the receiver operator characteristic (ROC) curves clearly showed better discrimination between intrahepatic cholangiocarcinoma and benign liver diseases for CYFRA 21-1 than for CEA or CA 19-9. Based on the maximization of the Youden's index, the optimal cut-off value was 2.7 ng ml(-1) for CYFRA 21-1 (sensitivity, 74.7%; specificity, 92.2%). The serum CYFRA21-1 concentration was related to tumor stage, since the CYFRA21-1 concentrations varied according to tumor size, vascular invasion, and number of tumors. The 3-year recurrence-free survival rates for patients with high and low concentrations of CYFRA21-1 were 25.0% and 76.2%, respectively (log-rank test, p < 0.01). The 3-year overall survival rates for patients with high and low concentrations of CYFRA21-1 were 39.4% and 63.6%, respectively (p = 0.01). On multivariate analysis, a high concentration of CYFRA21-1, nodal metastases, and a microscopic resection margin involvement were independent prognostic factors associated with both tumor recurrence and postoperative death.. A high serum CYFRA21-1 concentration is associated with tumor progression and poor postoperative outcomes in patients with intrahepatic cholangiocarcinoma.

Topics: Aged; Antigens, Neoplasm; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Cholangiocarcinoma; Disease-Free Survival; Female; Humans; Keratin-19; Keratins; Lymphatic Metastasis; Male; Multivariate Analysis; Neoplasm Invasiveness; Prognosis; ROC Curve; Sensitivity and Specificity

We describe the histopathologic features of 2 cases of biliary neoplasia with extensive intraductal spread arising in liver cirrhosis. The prevalence of this type of biliary neoplasia may be 0.4% from the review of 468 cases of cirrhotic liver. Histologic analysis revealed that the micropapillary proliferation of the atypical biliary epithelium composed of columnar cells with enlarged nuclei diffusely extended superficially from the septal intrahepatic bile duct to the reactive ductules associated with liver cirrhosis. Both cases exhibited prominent fibrous or sclerotic stroma near the biliary lesion. Immunohistochemical analysis revealed a characteristic cytokeratin and mucin expression pattern (CK7++, CK19++, CK20+, MUC1+/-, MUC2-, MUC5AC+, MUC6-). The tumor cytoplasm was focally positive for laminin gamma2 together with linear staining of the basement membrane. Proliferative activity confirmed by Ki67 staining was relatively high. Both patients were disease-free for 3 years after the operation. We believe that the possibility of biliary neoplasia with extensive intraductal spread should be considered to be a variant of biliary intraepithelial neoplasia.

Topics: Bile Ducts, Intrahepatic; Biliary Tract Neoplasms; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Count; Cell Proliferation; Cholangiocarcinoma; Hepatitis C, Chronic; Humans; Immunoenzyme Techniques; Keratins; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Mucins; Neoplasms, Multiple Primary; Treatment Outcome

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).. 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.. 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.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Autopsy; Bile Duct Neoplasms; Bile Ducts; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; CD56 Antigen; Cholangiocarcinoma; Colorectal Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Male; Middle Aged; Neural Cell Adhesion Molecules; Organ Size; Vimentin

Two types of neoplastic lesions preceding invasive intrahepatic cholangiocarcinoma (ICC) are identified: a flat-type neoplastic lesion called 'biliary intraepithelial neoplasia (BilIN)' and an intraductal papillary neoplasm of the bile duct (IPN-B). Multi-step carcinogenesis has been suggested in both lesions, although phenotypic changes during this process remain unclarified.. We immunohistochemically examined expression patterns of MUC1, MUC2, MUC5AC, cytokeratin 7 (CK7), and CK20 in BilIN, IPN-B, and ICC in 110 cases of hepatolithiasis.. Thirty-seven cases of ICC in hepatolithiasis were divided into 18 tubular adenocarcinomas with BilIN, 10 tubular adenocarcinomas with IPN-B and nine colloid carcinomas with IPN-B. Carcinogenesis via BilIN was characterized by MUC2-/CK7+/CK20-with increasing MUC1 expression. IPN-B was characterized by the intestinal phenotype (MUC2+/CK20+), and carcinogenesis leading to tubular adenocarcinoma was associated with increasing MUC1 expression and that to colloid carcinoma with MUC1-negativity. Pathological stages of tubular adenocarcinoma of ICC with BilIN or IPN-B were more advanced than those of colloid carcinoma with IPN-B.. Immunophenotypes of MUCs and cytokeratins might characterize three cholangiocarcinogenetic pathways in hepatolithiasis. Increased expression of MUC1 in BilIN and also IPN-B is associated with tubular adenocarcinoma, while colloid carcinoma in IPN-B is characterized by MUC1-negativity and less advanced pathologic stages.

Topics: Adenocarcinoma, Papillary; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Cholelithiasis; Diagnosis, Differential; Disease Progression; Humans; Immunohistochemistry; Keratins; Mucins; Neoplasm Staging; Precancerous Conditions

In general, intrahepatic cholangiocarcinoma (ICC) is not related to liver cirrhosis. However, a few cases have been reported in which ICC was accompanied by severe liver fibrosis. Some researchers have proposed that hepatocellular and cholangiocellular (HC-CC) carcinoma, an intermediate mixed phenotype possibly arising in cirrhotic liver, might originate from hepatic precursor cells. In the liver, hepatocytes and cholangiocytes form the epithelial element, but stromal and mesenchymal elements may be produced by hepatic stem cells. Based on these aspects, not only HC-CC, but also other combinations of cellular phenotypes, would cover all the cancers with stem cell features. In this study, which aimed at determining the characteristics of the ICC phenotype, we used immunohistochemistry to examine the expression of basal/stem-cell markers, i.e., p63 in ICC with and without liver cirrhosis, as well as the expressions of cytokeratin (CK) 34 beta E12, specific for the basal-cell marker, and c-kit, specific for the stem-cell marker. Aberrant p63 was frequently expressed in ICC arising in cirrhotic liver. This result suggests that ICC cancer cells originate from hepatic precursor cells with a hidden multi-differentiation potential.

Topics: Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers; Cell Differentiation; Cholangiocarcinoma; DNA-Binding Proteins; Female; Genes, Tumor Suppressor; Hepatocytes; Humans; Keratin-7; Keratins; Liver Cirrhosis; Male; Middle Aged; Phenotype; Phosphoproteins; Proto-Oncogene Proteins c-kit; Stem Cells; Trans-Activators; Transcription Factors; Tumor Suppressor Proteins

The cytoplasmic staining of thyroid transcription factor (TTF)-1 was analyzed in 86 liver resection specimens, including 40 hepatocellular carcinoma (HCC), 4 metastatic HCC, 20 cholangiocarcinoma, 2 combined hepatocellular-cholangiocarcinoma (CHC), and 20 metastatic carcinoma (MC) specimens with immunohistochemical stains to TTF-1, cytokeratin (CK)19, hepatocyte paraffin 1, alpha-fetoprotein, polyclonal carcinoembryonic antigen, CK7, and CK20. TTF-1 cytoplasmic staining was identified in 93% of HCCs (37/40), 100% of metastatic HCCs (4/4), 10% of cholangiocarcinomas (2/20), and 5% of MCs (1/20). CK19 was positive in all cholangiocarcinomas and MCs but only in 5% of HCCs (2/40) and none of the metastatic HCCs (0/4). TTF-1 cytoplasmic staining positively correlates with differentiation and the trabecular growth pattern of HCC. The results suggest TTF-1 cytoplasmic staining, together with CK19, might serve as a useful marker for the diagnosis of primary and metastatic HCC and for the differential diagnosis of HCC from cholangiocarcinoma and MC. The mechanism of TTF-1 cytoplasmic staining is explored.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cytoplasm; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Middle Aged; Nuclear Proteins; Thyroid Nuclear Factor 1; Transcription Factors

To study the differences between the hepatocellular carcinoma (HCC) and peripheral type of cholangiocarcinoma (CHC) using cytokeratin (CK) and carcinoembryonic antigen (CEA) expressions and assessing their accuracy on paraffin sections in the differential diagnosis.. The following antibodies were analyzed: AB1 complex (anti CK9-CK20), AB2 complex (anti CK1-CK8), pCEA, and the monoclonal antibodies against cytokeratins CK7, CK8/18, CK17 and CK19. In the mmunohistochemical studies, 15 selected surgically resected liver tumors, 10 HCCs and 5 CHCs, with well established diagnosis (by morphological criteria) were included. Other markers, such as AFP si CA 19-9, were not available.. No CHC, but 50% of HCCs were positive for CEA, presenting a canalicular staining pattern. For CK 7, all but one (which was focally positive), meaning 80% of CHCs were diffusely positive, whereas only two HCCs were positive. For CK 19, 80% of CHCs were diffusely positive, while all but two HCCs (a moderately and a poorly differentiated tumor) were negative. For CK 8/18, 70% of HCCs were diffusely positive, whereas only 20% of CHCs were positive. For CK 17, 60% of CHCs were positive, while all HCCs were negative. 80% of CHCs were positive for AB1 anti-CKs complex, whereas only 50% of HCCs were positive, and relating to AB2 anti-CKs complex, 50% of HCCs were diffusely positive and only 20% of CHCs.. The immunohistochemical expression of CKs and CEA might be considered helpful in addition to other diagnostic criteria for the differential diagnosis of primary carcinomas of the liver, especially in difficult cases.

Topics: Adolescent; Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Middle Aged; Retrospective Studies

Pancreatobiliary and ampulla of Vater adenocarcinomas frequently metastasize to regional lymph nodes, liver, or lung and are difficult to diagnose because they lack specific immunohistochemical markers. We studied the expression of cytokeratin 7 (CK7), cytokeratin 17 (CK17), cytokeratin 20 (CK20), CDX2, mucin 1 (MUC1), mucin 2 (MUC2), and mucin 5AC (MUC5AC) in 46 cases of pancreatic ductal carcinoma, 18 ampulla of Vater adenocarcinomas, and 24 intrahepatic cholangiocarcinomas. The expression of MUC1 and CK17 was restricted to pancreatic ductal carcinoma (41 of 46, 89%; 38 of 46, 83%, respectively), the ampullary carcinoma of pancreatobiliary origin (6 of 6, 100%; 5 of 6, 83%, respectively), and intrahepatic cholangiocarcinoma (20 of 24, 83%; 17 of 24, 71%, respectively). More than 50% of cases of pancreatobiliary adenocarcinomas showed diffuse cytoplasmic CK17 positivity. In contrast, less than 5% cases (8 of 184) of extra-pancreatobiliary nonmucinous adenocarcinomas expressed CK17, and only 3 of them showed diffuse CK17 positivity. The expression of MUC2 and CDX2 was restricted to the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin (9 of 11, 82%; 11 of 11, 100%, respectively). MUC2 was rarely expressed in pancreatic ductal carcinoma (1 of 46, 2%) and was negative in the ampullary carcinoma of pancreatobiliary origin and in intrahepatic cholangiocarcinoma. A heterogeneous CDX2 staining pattern was seen in 1 of 6 cases of the ampullary carcinoma of pancreatobiliary origin (17%), 5 of 24 intrahepatic cholangiocarcinomas (21%), and 10 of 46 (22%) pancreatic ductal carcinomas. In contrast, all 11 cases of the intestinal, mucinous, and signet-ring cell-type adenocarcinomas of duodenal papillary origin showed homogeneous CDX2 nuclear positivity. We concluded that CK17 is a useful marker in separating pancreatobiliary adenocarcinomas from extra-pancreatobiliary nonmucinous adenocarcinomas, including adenocarcinomas from the colon, breast, gynecologic organs, stomach, lung, prostate, thyroid, kidney, and adrenal gland, and malignant mesothelioma. MUC1+/CK17+ can be used as positive markers for pancreatic ductal carcinomas, the ampullary carcinoma of pancreatobiliary origin, and cholangiocarcinomas with positive predictive values of 76%, 83%, and 58%, respectively. MUC2+/CDX2+ can be used as positive markers for the intestinal-type adenocarcinoma of duodenal papillary origin with a positive predictive value of 82%.

Topics: Adenocarcinoma; Ampulla of Vater; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Pancreatic Ductal; CDX2 Transcription Factor; Cholangiocarcinoma; Common Bile Duct Neoplasms; Female; Homeodomain Proteins; Humans; Immunohistochemistry; Keratins; Male; Mucins; Neoplasm Proteins; Pancreatic Neoplasms

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biopsy, Fine-Needle; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cholangiocarcinoma; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Lymphoma; Male; Middle Aged; Mucin-1; Review Literature as Topic; S100 Proteins; Vimentin

A 62-year-old man had been followed because of an elevated serum level of carcinoembryonic antigen without the detection of any cancer lesions. However, there was a sudden increase in the serum level of carcinoembryonic antigen, and abdominal imagings showed a hepatic tumor with peripheral intrahepatic bile duct dilatation, and a submucosal tumor at the sigmoid colon with intact mucosa. Histopathological findings showed that the hepatic tumor had perineural invasion, suggesting an intrahepatic cholangiocarcinoma, and that the colon tumor infiltrated the submucosa, while its mucosa was intact. Both tumors showed similar pathological features and were positive for cytokeratin 20 and 7. These findings suggested intrahepatic cholangiocarcinoma with metastatic sigmoid colon cancer.

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoembryonic Antigen; Cholangiocarcinoma; Colonic Neoplasms; Humans; Immunohistochemistry; Keratin-20; Keratin-7; Keratins; Male; Middle Aged; Sigmoid Neoplasms

The diagnostic utility of aquaporin (AQP)-1 in liver tumors was tested and compared with other well-established markers. In 30 cholangiocarcinomas (CCs), 20 hepatocellular carcinomas (HCCs), and 10 metastatic colorectal carcinomas (MCCs) of the liver, expression of AQP-1, CD10, cytokeratin (CK) 7, CK20, and polyclonal carcinoembryonic antigen (pCEA) was tested. In addition, staining patterns of CD10 and pCEA were analyzed. To compare the selectivity of AQP-1 and CK7 as possible markers for differentiated cholangiocytes, liver biopsies of cholestatic disease were also analyzed. Aquaporin-1 expression was found in 93% of all CCs compared with 0% of HCC (P < .000001) and with 30% of MCC (P < .01). CD10 was positive in 16.7% of CC compared with 40% of HCC (P < .04) and to 20% of MCC (not significant). Cytokeratin 7 was positive in 90% of CC compared with 10% of HCC (P < .00001) and with 20% of MCC (P < .0001). Cytokeratin 20 was positive in 90% of MCC compared with 16.7% of CC (P < .0001) and with 20% of HCC (P < .00001). Canalicular staining patterns of CD10 and pCEA were observed in HCC (100% and 89.5%, respectively) but typically not in CC (0% and 6.7%, respectively) and never in MCC. In cholestatic disease, AQP-1 was expressed in differentiated epithelial cells of the bile ducts, whereas CK7-positive hepatocytes of Rappaport zone 1 did not show any AQP-1 reactivity. Therefore, AQP-1 seems to be a highly selective marker for differentiated cholangiocytes and can be very helpful in the differential diagnosis of liver tumors.

Topics: Adult; Aged; Aged, 80 and over; Aquaporin 1; Biomarkers, Tumor; Capillaries; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Cholestasis; Colorectal Neoplasms; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratin-7; Keratins; Liver Neoplasms; Male; Middle Aged; Neprilysin

Scirrhous hepatocellular carcinoma (SHCC) is a rare variation of HCC, for which characteristics of tumor cells and the fibrotic stroma have not been clarified in detail. The present study was therefore carried out to elucidate cytological features of tumor and stromal cells and components of the stromal extracellular matrix in 15 SHCC patients undergoing hepatectomy without preoperative transarterial embolization. Diagnosis was on the basis of a scirrhous histological pattern exceeding 50% of the tumor area. Expression of cytoplasmic and extracellular matrix proteins was compared among SHCC, HCC and intrahepatic cholangiocarcinoma (ICC) cases with immunohistochemical staining. The lesions could be histologically divided into radiating and sinusoidal types. Common stromal components of SHCC and ICC were collagen types I and III. There was no expression of laminin-5 in the stroma of SHCC, but it was present in almost all ICC cases. Tenascin-C expression was significantly lower in the SHCC cases and its distribution differed between SHCC and ICC. Matrix metalloproteinase-7 (MMP-7) expression was significantly higher in SHCC compared with HCC. Almost all stromal cells were alpha-smooth muscle actin-positive both in SHCC and ICC, whereas glial fibrillary acid protein (GFAP)-positive stromal cells were significantly more increased in ICC than in SHCC. SHCC clearly differed from HCC with respect to collagen types I, III and MMP-7 expression, and from ICC with regard to stromal components including laminin-5, tenascin-C and GFAP(+) stromal cells.

Topics: Adenocarcinoma, Scirrhous; Aged; Apoptosis; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cell Proliferation; Cholangiocarcinoma; Collagen Type I; Collagen Type III; Female; Fibroblast Growth Factor 2; Humans; Keratins; Laminin; Liver Neoplasms; Male; Matrix Metalloproteinase 7; Middle Aged; Tenascin

To investigate the sensitivity, specificity, and spatial distribution of the product of p28 gene (p28(GANK) protein) in human hepatocellular carcinoma (HCC) and nonhepatocellular carcinomas in relation to immunostaining with Cytokeratin 18 (CK18), alpha-fetoprotein (AFP), and Hepatocyte paraffin 1 (HepPar1).. In this retrospective study, formalin-fixed paraffin-embedded tissues from 24 HCCs, five intrahepatic cholangiocarcinomas (ICC), five combined hepatocellular cholangiocarcinomas (C-HCC-CC) and mine metastatic hepatic carcinomas (MHC) were immunostained for p28(GANK) as well as CK18, AFP and HepPar1. Only cases with more intensified staining in carcinoma contrast to the adjacent liver tissues were accepted as positive.. In HCC, p28(GANK) was expressed restrictively in hepatocytes of both para-lesion and carcinoma liver tissues, while absent in the bile duct epithelial cells, Kupffer cells, and other interstitial cells. The positive staining of p28(GANK) was noted in 16 (66.7%) specimens of HCC and three (60.0%) specimens of C-HCC-CC, and no specific lesion staining was found in all tested specimens of ICC and MHC. Sensitivity and specificity for hepatocyte-originated carcinoma were, respectively, 65.5% and 100% for p28(GANK), 79.3% and 85.2% for CK18, 20.7% and 100% for AFP, 79.3% and 92.0% for HepPar1.. The hepatocytic staining for p28(GANK) is clearly useful in differentiating hepatocyte-originated carcinoma from non-HCC. p28(GANK) may be used as an ancillary marker for the diagnosis of HCC.

Topics: alpha-Fetoproteins; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Hepatocytes; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Oncogene Proteins; Paraffin; Proteasome Endopeptidase Complex; Proto-Oncogene Proteins; Sensitivity and Specificity

To investigate whether immunohistochemically demonstrated lymph node micrometastasis has prognostic significance in patients with histologically node-negative (pN0) hilar cholangiocarcinoma.. The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, no reports have addressed this issue with regard to hilar cholangiocarcinoma.. A total of 954 lymph nodes from surgical specimens of 45 patients with histologically node-negative hilar cholangiocarcinoma who underwent macroscopically curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were examined for relationships with clinical and pathologic features and with patient survival.. Lymph node micrometastases were detected immunohistochemically in 11 (24.4%) of the 45 patients, being found in 13 (1.4%) of 954 lymph nodes examined. Of the 13 nodal micrometastases, 11 (84.6%) were found in the N2 regional lymph node group rather than N1. Clinicopathologic features showed no associations with lymph node micrometastases. Survival curves were essentially similar between patients with and without micrometastasis. In addition, the grade of micrometastasis showed no effect on survival. The Cox proportional hazard model identified microscopic venous invasion, microscopic resection margin status, and histologic differentiation as significant prognostic factors in patients with pN0 disease.. Lymph node micrometastasis has no survival impact in patients with otherwise node-negative hilar cholangiocarcinoma. The authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostic evaluation.

Topics: Adult; Aged; Antibodies, Monoclonal; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Female; Humans; Immunohistochemistry; Keratins; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Prognosis; Proportional Hazards Models; Survival Analysis

We report a surgical case of liver tumor, 40 x 35 mm in size, with squamous cell carcinoma (SCC) and hepatocellular carcinoma (HCC) components in a 60-year-old Japanese man with steatohepatitis. Most of the SCC component showed typical intercellular bridge and keratinization, while most of the HCC components showed a thick trabecular pattern with mild to moderate nuclear atypia. Both components transit each other without undifferentiated foci; however, a small foci showing glandular structure was intermediated. No cyst formation was found in the liver. The primary site of the squamous cell carcinoma was not detected in general clinical and radiological examination. Immunohistochemical analysis revealed that part of the HCC components neighboring the SCC showed patchy and weak expression of cytokeratin 7. There are several possibilities for the origin of squamous cell carcinoma in this case: marked squamous metaplastic change of cholangiocarcinoma and/or HCC, and carcinoma originating from pleuripotential stem cells. Irregular fatty changes, scattered giant mitochondria and acellular fibrosis with bridging were seen in the liver; however, this patient had no episode of hepatitis-associated viral infection. This is an interesting case of combined hepatocellular and cholangiocarcinoma with marked SCC components arising in a non-cirrhotic fibrotic liver.

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cholangiocarcinoma; Humans; Immunohistochemistry; Keratin-7; Keratins; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary; Stem Cells

Topics: Adenocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Biopsy, Needle; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Sarcoma; Vimentin

Using an electrochemiluminescence immunoassay, CYFRA 21-1 concentrations were measured in sera from 187 patients with primary liver cancer (164 with hepatocellular carcinoma (HCC) and 23 with intrahepatic cholangiocarcinoma (ICC)) and 87 patients with benign liver diseases. Concentrations of CYFRA 21-1 were significantly higher in patients with ICC (5.0; interquartile range 3.1-10.7 ng ml(-1)) than in those with benign liver disease (1.4; 1.0-1.9; Mann-Whitney U-test, P<0.0001) or HCC (1.7; 1.1-2.7; Mann-Whitney U-test, P<0.0001). Using cutoff values selected for 95% specificity in the benign group (3.0 ng ml(-1)), CYFRA 21-1 showed higher sensitivity for ICC (87.0%) than three commonly used markers including alpha-fetoprotein (17.4%), carcinoembryonic antigen (34.8%), and carbohydrate antigen 19-9 (60.9%). Serum CYFRA 21-1 increased in ICC from stages I/II to IV (Kruskal-Wallis test, P=0.0102). CYFRA 21-1 concentration increased with extent of local invasion, but not nodal status. Serum CYFRA 21-1 represents a useful diagnostic test for ICC that offers high sensitivity. CYFRA 21-1 reflected differences in tumour burden, suggesting applicability to staging and follow-up.

Topics: Adult; Aged; alpha-Fetoproteins; Antigens, Neoplasm; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Humans; Keratin-19; Keratins; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Sensitivity and Specificity

Quantitative immunohistochemistry of ERBB-2 and MET receptor proteins and of cyclooxygenase 2 (COX-2) was undertaken to determine if there is a positive correlation between overexpression of either ERBB-2 or MET and up-regulation of COX-2 in human cholangiocarcinogenesis. ERBB-2, MET, and COX-2 immunoreactivities were measured in cancerous parenchyma of 71 archival cases of human cholangiocarcinoma (ChC) compared with hyperplastic small biliary ducts in surrounding nonneoplastic liver and with bile ducts of normal adult human liver. ERBB-2, MET, and COX-2 immunoreactivities were also assessed in both large and small hyperplastic biliary ducts (HBDs) in 27 archival cases of hepatolithiasis and 20 archival cases of primary sclerosing cholangitis (PSC), both of which are risk conditions for human cholangiocarcinogenesis. There was a strong positive correlation between increased ERBB-2, but not MET, and COX-2 immunoreactivity measured in the tumors and risk conditions. Enhanced immunoreactivity for ERBB-2 and COX-2 also correlated directly with tumor differentiation and was highest in well-differentiated tumors. Interestingly, some but not all cases of hepatolithiasis and most cases of PSC showed increased ERBB-2 and COX-2 immunostaining in the large but not small HBDs, whereas strong MET immunostaining was detected in both the large and small ducts. In conclusion, overexpression of ERBB-2 and COX-2 may herald an early carcinogenic event in the human hepatic biliary tract and one that is consistent with a frequent anatomic site of origin of the tumors. The results also suggest ERBB-2 and COX-2 as potentially important targets relevant to chemoprevention or adjunct therapy of ChC.

Topics: Adult; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Cholangitis, Sclerosing; Cyclooxygenase 2; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Isoenzymes; Keratins; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Risk Factors; Up-Regulation

The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80% of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.

Topics: Aged; Autopsy; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Hepatocellular; Child, Preschool; Cholangiocarcinoma; Female; Fetus; Humans; Immunohistochemistry; Infant; Infant, Newborn; Keratins; Liver; Liver Neoplasms; Male; Middle Aged; Prognosis; Survival Analysis

Distinguishing hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC) and metastatic adenocarcinoma (MA) involving the liver can be problematic, often requiring the use of immunohistochemistry to facilitate diagnosis. Hep Par 1, a monoclonal antibody with expression confined primarily to benign and malignant hepatocytes, has recently become commercially available. We evaluated Hep Par 1 along with other immunohistochemical markers used to differentiate HCC, CC, and MA, including AE1/AE3, CAM 5.2, B72.3, monoclonal carcinoembryonic antigen (mCEA), polyclonal CEA (pCEA), alpha-fetoprotein (AFP), factor XIIIa, inhibin, CD10, villin, MOC-31, cytokeratin (CK) 7, CK 19, and CK 20, to determine the markers most useful in differentiating these entities. Forty-two cases of HCC, 9 cases of CC, and 56 cases of MA (24 colon, 15 pancreas, 8 ovary, 5 breast, and 4 stomach) were studied. Hep Par 1 was sensitive and specific for HCC, with 38 of 42 (90%) cases staining positively, whereas reactivity was observed in only 8 of 56 (14%) MAs and 0 of 9 CCs. Though limited somewhat by poor sensitivity, a bile canalicular pattern of staining with pCEA, CD10, and villin was specific for HCC and was not observed in the other tumors. Lack of mCEA and MOC-31 immunoreactivity was also characteristic of HCCs. CK 19 positivity favored CC over HCC, but was not useful in differentiating CC from MA. Expression of AFP, although observed in only about one third of the cases, favored HCC over CC and MA. CK 7 and CK 20 were also useful in this differential diagnosis, particularly when dealing with MA of colonic origin. AE1/AE3, CAM 5.2, B72.3, inhibin, and factor XIIIa were noncontributory in differentiating these entities.

Topics: Adenocarcinoma; alpha-Fetoproteins; Antibodies, Monoclonal; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Carrier Proteins; Cholangiocarcinoma; Diagnosis, Differential; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Microfilament Proteins; Neprilysin; Sensitivity and Specificity

It has been reported that the cytokeratin 19 (CK19) fragment, CYFRA 21-1, is increased in sera of some hepatocellular carcinoma patients. We hypothesized that CYFRA 21-1 might be released directly from hepatocellular carcinoma. To investigate this mechanism, we evaluated expression of CK19 in 8 human cell lines by immunoradiometric assay, Western blotting, immunohistochemistry, and reverse transcriptase-polymerase chain reaction in Chang liver cells, 2 cholangiocarcinoma cell lines, and 5 hepatocellular carcinoma cell lines. Three of 5 hepatocellular carcinoma cell lines released CYFRA 21-1, synthesized CK19 protein and expressed mRNA for CK19, as observed in 2 cholangiocarcinoma cell lines. In contrast, there was no expression of CK19 in Chang liver cells or 2 of 5 hepatocellular carcinoma cell lines. Analysis of genomic DNA for CK19 demonstrated that exon 1 was not amplified in the 3 cell lines not expressing CK19. However, there were no point mutations within exon 1 and the promoter region of CK19 in hepatocellular carcinoma cell lines. Our present study demonstrates that: i) the expression of CK19 was evident in some human hepatocellular carcinoma cell lines, and ii) the expression of mRNA for CK19 was related to the release of CYFRA 21-1. These results partially clarify the mechanism by which some hepatocellular carcinoma cell lines produce CK19 and others do not.

Topics: Antigens, Neoplasm; Base Sequence; Bile Duct Neoplasms; Blotting, Western; Carcinoma, Hepatocellular; Cholangiocarcinoma; DNA Primers; DNA, Neoplasm; Gene Expression; Humans; Immunoenzyme Techniques; Immunoradiometric Assay; Keratin-19; Keratins; Liver Neoplasms; Molecular Sequence Data; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Cells, Cultured

Intraductal papillary neoplasia of the liver (IPN-L) was recently proposed as the name for intraductal papillary proliferation of neoplastic biliary epithelium with a fine fibrovascular stalk resembling intraductal papillary mucinous neoplasm of the pancreas. We histochemically and immunohistochemically examined IPN-L alone or associated with hepatolithiasis, with an emphasis on the gastrointestinal metaplasia, nuclear p53 expression, and histologic progression. A total of 66 cases of IPN-L were divided into 4 groups: group 1, IPN-L with low-grade dysplasia (13 cases); group 2, IPN-L with high-grade dysplasia (20 cases); group 3, IPN-L lined with carcinoma in situ and no or microinvasion (19 cases); and group 4, group 3 with distinct invasive carcinoma (14 cases). It is suggested that IPN-L progresses from group 1 to group 4. As controls, 20 cases of nonneoplastic intrahepatic large bile ducts and 17 cases of nonpapillary invasive intrahepatic cholangiocarcinoma (ICC) were used. Biliary epithelial hypersecretion of sialomucin rather than sulfomucin was prevalent in IPN-L, and this was associated with the progression of INP-L. Immunohistochemically, cytokeratin (CK) 20 and MUC2, a gastrointestinal marker, were expressed more frequently in IPN-L than in nonneoplastic bile ducts and nonpapillary ICC (P <0.01), and their incidence were significantly increased in parallel with the progression of IPN-L (P < 0.01). In contrast, expression of CK 7, a biliary marker, was decreased in IPN-L compared with nonpapillary ICC. Nuclear p53 immunostaining was detected in 30% of IPN-L as a whole and increased in tandem with the progression of IPN-L (P < 0.01). It is suggested that IPN-L forms a spectrum of biliary epithelial neoplasia with frequent gastrointestinal metaplasia, different from the usual nonpapillary ICC, and shows stepwise progression from the perspective of mucin profile, gastrointestinal metaplasia, and p53 nuclear expression.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Nucleus; Cholangiocarcinoma; Disease Progression; Female; Humans; Immunoenzyme Techniques; Keratin-7; Keratins; Lithiasis; Liver Diseases; Male; Metaplasia; Middle Aged; Mucins; Phenotype; Precancerous Conditions; Tumor Suppressor Protein p53

Epstein-Barr virus (EBV) has been linked to carcinomas of several body sites, especially of the nasopharynx, salivary gland, lung, and stomach. We present five cases of lymphoepithelioma-like cholangiocarcinoma, including one that had been previously reported. Two patients were men and three were women. Their ages ranged from 42 to 66 years. Histologically, all five tumors were composed of variable proportions of undifferentiated epithelial cells and glandular components in a lymphocyte-rich stroma. EBV was detected in all five tumors by in situ hybridization for EBER-1 in both lymphoepithelioma-like carcinoma (LELC) and glandular parts, but not in 36 cases of cholangiocarcinoma without the LELC component. Taken together, these observations indicate that lymphoepithelioma-like cholangiocarcinoma is strongly linked to EBV. The LELC type of cholangiocarcinoma, like LELC of other body sites, may be more common in areas with endemic EBV infection.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Squamous Cell; Cholangiocarcinoma; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunoenzyme Techniques; In Situ Hybridization; Keratins; Male; Middle Aged; RNA, Viral

The regulatory mechanism of cell-specific gene expression in cholangiocytes has not been sufficiently evaluated. In this study, we characterized the 5'-flanking region of the cytokeratin 19 gene expressed specifically in cholangiocytes.. We cloned a 2952-bp fragment in the 5'-flanking region of cytokeratin 19 and evaluated the regulatory mechanism of gene expression in this region by assaying transient expression of reporter gene and DNA footprinting.. This segment of the 5'-flanking region of the human cytokeratin 19 gene shows an intense transcriptional activity in the cholangioma cell line KMBC, which was about 10 times its activity in the osteosarcoma cell line Saos-2, which does not express cytokeratin 19. From the results of reporter assays, important transcription regulatory elements are considered to be located in the segments from -2249 to -2050 bp and from -732 bp to the first ATG, and six protein-binding sites were detected in the segment from -732 bp to the first ATG by the DNA footprinting technique.. Sp1 site, CCAAT box, and TATA box were present in the segment from -374 to the first ATG, and they are considered to constitute a cholangiocyte-specific promoter.

Topics: Base Sequence; Cholangiocarcinoma; Cloning, Molecular; DNA; DNA Footprinting; Humans; Keratins; Molecular Sequence Data; Osteosarcoma; Peptide Fragments; Promoter Regions, Genetic; Tumor Cells, Cultured

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Squamous Cell; Cholangiocarcinoma; Diagnosis, Differential; Epstein-Barr Virus Infections; Germinoma; Herpesvirus 4, Human; Humans; Immunohistochemistry; Keratins; Lymphoma; Male; Melanoma; Middle Aged; Mucin-1; Skin Neoplasms

Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3. These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.

Topics: Adenoma, Bile Duct; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cholangiocarcinoma; Hemochromatosis; Homozygote; Humans; Immunoenzyme Techniques; Keratins; Liver Neoplasms; Male; Middle Aged; Mucin-1; Mutation

Differentiating chronic aseptic meningitis from leptomeningeal carcinomatosis or gliomatosis can be difficult, particularly when the differentiation is based solely on routine cytologic examination. The diagnosis of cerebrospinal fluid tumor dissemination in at-risk patients requires cytologic examination of cerebrospinal fluid and radiography of the leptomeninges. Routine cytologic examination alone has proven less than desirable, in most instances providing confirmation in as little as 50% of cases in the first lumbar puncture. This percentage increases to 85% to 90% after multiple lumbar punctures. We retrospectively reviewed 2 cases of leptomeningeal dissemination (one gliomatosis, the other carcinomatosis) with initial false-negative test results. However, after further examination of the cerebrospinal fluid by selected battery of immunocytochemical stains, both cases were identified as positive for malignancy (ie, false negatives). Immunocytochemistry can be useful in distinguishing chronic aseptic meningitis from leptomeningeal carcinomatosis or gliomatosis in patients at risk or when abnormal cells are seen on routine cerebrospinal fluid cytologic examination.

Topics: Adult; Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Brain Edema; Calcinosis; Cerebrospinal Fluid; Cholangiocarcinoma; Chronic Disease; Diagnosis, Differential; Fatal Outcome; Female; Glial Fibrillary Acidic Protein; Humans; Immunohistochemistry; Keratins; Male; Meningeal Neoplasms; Meningitis, Aseptic; Mucin-1; Neoplasms, Neuroepithelial; Retrospective Studies

In the liver, the immunostaining of cytokeratins (CK) 7 and 20 has been used to distinguish usual peripheral cholangiocarcinomas (CC) and colorectal carcinoma metastasis (CRM). However, other subtypes of CC are not infrequent and may be particularly difficult to distinguish from CRM by histology and even immunohistochemistry. Therefore, 48 CC from different locations, either peripheral (n = 19), or nonperipheral, that is, from the large intrahepatic bile ducts, the hilum, and the extrahepatic bile ducts (n = 29), and with different cytoarchitectural patterns were tested for CK7 and CK20 and compared with 31 CRM. CC were positive for CK7 and CK20 in 96% and 70%, respectively, whatever the architecture and differentiation of the tumor. The labeling index (LI) of CK7 in CC was always high, whereas it was low or moderate for CK20. CK20-positive phenotype was significantly more frequent in nonperipheral than in peripheral CC (82% vs 47%; p = 0.007). CRM were all positive for CK20 with a high LI, and mostly negative (81%) for CK7. In conclusion, (1) the CK immunoprofile of CC varies according to the location of the tumor in the biliary tract, peripheral CC being more often CK7+/CK20-, and nonperipheral ones CK7+/CK20+; and (2) a decision tree based on CK20 LI and CK7 positivity allows the distinction of CRM and CC, even for the nonperipheral type.

Topics: Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Colorectal Neoplasms; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Male; Middle Aged; Predictive Value of Tests; Prognosis; Sensitivity and Specificity; Staining and Labeling

We evaluated the cytokeratin profile of intrahepatic cholangiocarcinoma with respect to its histological classification and intrahepatic location (peripheral vs. hilar), and compared its profile with that of a variety of metastatic adenocarcinomas in liver.. Expression of cytokeratins 7, 8, 18, 19 and 20 was immunohistochemically examined in intrahepatic cholangiocarcinoma (n = 77) and metastatic adenocarcinoma in liver (21 colorectal, 14 gastric, three gallbladder and three pancreatic cancers). Materials were autopsy or surgical specimens. Cytokeratins 7, 8, 18 and 19 were expressed in 75 (97%), 75 (97%), 59 (77%) and 71 (92%) cases of intrahepatic cholangiocarcinoma, respectively. Moderate and extensive expression of cytokeratin 18 was more frequent in the peripheral than in the hilar type. Moderate and extensive expression of cytokeratin 19 was seen in almost all cases of well-differentiated intrahepatic cholangiocarcinomas, while expression was decreased relatively in the moderately and decreased more in the poorly differentiated cases. While cytokeratin 20 was not found in non-neoplastic biliary epithelia or in well-differentiated intrahepatic cholangiocarcinomas, this cytokeratin was occasionally detectable in moderately and poorly differentiated intrahepatic cholangiocarcinomas and its expression was more frequent in the hilar type. Cytokeratin 20 expression was observed in 17 (81%) of metastatic adenocarcinomas in liver from colorectal regions, to a lesser degree in those from gastric regions, and was rare in those from gallbladder and pancreatic regions; cytokeratin 7 showed a reverse expression pattern in these metastatic adenocarcinomas in liver. The profile of cytokeratins 7 and 20 of metastatic colorectal and gastric carcinomas differed from that for intrahepatic cholangiocarcinomas, while that of metastatic gallbladder and pancreatic carcinoma was similar to that for intrahepatic cholangiocarcinomas. Moreover, cytokeratin 18 and 19 expression was significantly infrequent in metastatic gastric carcinomas than in intrahepatic cholangiocarcinomas and metastatic colorectal carcinomas.. The combined immunostaining of cytokeratins 7, 18, 19 and 20 is useful for the characterization of intrahepatic cholangiocarcinomas with respect to histological subtypes and intrahepatic location. It helps to differentiate intrahepatic cholangiocarcinoma from metastatic adenocarcinomas in liver and from colorectal and gastric regions; it also indicates the primary focus metastatic adenocarcinomas in livers.

Topics: Adenocarcinoma; Biomarkers; Cholangiocarcinoma; Colorectal Neoplasms; Gallbladder Neoplasms; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms

This study was designed to identify a difference in immunostaining that might help to distinguish between primary and metastatic liver neoplasms.. We examined immunohistochemical expression of cytokeratins (CKs) 7, 8, 19, and 20 in 12 intrahepatic cholangiocarcinomas (ICCs; 9 of the mass-forming and 3 of the infiltrating type), 25 metastatic colorectal carcinomas (MCCs), and 7 metastatic gastric carcinomas (MGCs) of the liver.. CKs 7 and 19 were expressed in all ICCs of infiltrating type, while each was seen in 7/9 (77.8%) of mass-forming type. CK 7-positive/CK 20-negative was seen in 9/12 (75.0%) of ICCs and in none of the 25 MCCs, while CK 7-negative/CK 20-positive was seen in 1/12 (8.3%) of ICCs and 20/25 (80.0%) of MCCs. No differences were observed between MGCs and ICCs.. These results suggest that immunohistochemical staining for both CKs 7 and 20 is useful for the differential diagnosis of ICCs and MCCs, whereas phenotypic expression of CKs appears to be different between mass-forming and infiltrating types of ICCs.

Topics: Adenocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Staining and Labeling

Malignant tumors of the liver with intrabiliary growth are rare, except for some cholangiocarcinomas. Metastases with intrabiliary growth, whatever their origin, are rare. Moreover, colorectal metastasis can be particularly difficult to distinguish morphologically from some cholangiocarcinomas. We report 3 cases of late colorectal metastasis with intrabiliary growth, presenting as cholangiocarcinomas of the large ducts. Immunostaining with cytokeratins 7 and 20 attested the diagnostic and pointed out the spreading pattern of colorectal metastasis within biliary ducts. This study illustrates the capacity, probably underestimated, for colorectal metastasis to develop in the lumen of bile ducts and emphasizes the relevance of cytokeratin 7 and 20 immunostainings in such cases.

Topics: Aged; Bile Duct Neoplasms; Biomarkers, Tumor; Cholangiocarcinoma; Colorectal Neoplasms; Diagnosis, Differential; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratin-7; Keratins; Liver Neoplasms; Male; Middle Aged

Eight hepatic atypical adenomatous hyperplasias (AH), 30 hepatocellular carcinomas (HCC) consisting of 11 well-, 13 moderately and six poorly differentiated HCC, and 10 intrahepatic cholangiocarcinomas (CC) were investigated immunohistochemically with anti-alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), CA19-9, epithelial membrane antigen (EMA), and cytokeratins (CK) 18 and 19 antibodies. Immunostaining was regarded as positive when more than 5% of cells were stained. Alpha-fetoprotein was positive, although focally, in five (17%) of 30 HCC but negative in all AH and CC. Carcinoembryonic antigen (polyclonal antibody) did not stain the cytoplasm of all AH and HCC, but stained two (25%) of eight AH and 10 (33%) of 30 HCC in a bile canalicular staining manner. Carcinoembryonic antigen showed intracytoplasmic or luminal border staining in six (60%) of 10 CC. CA19-9 was negative in all AH and HCC, while six (60%) of 10 CC were positive for CA19-9. Epithelial membrane antigen was positive in one (13%) of eight AH, seven (23%) of 30 HCC and in all 10 cases of CC. Cytokeratin 18 was positive in all AH, HCC and CC. Cytokeratin 19 was negative in both AH and HCC, whereas it stained the cytoplasm of tumor cells in all CC diffusely and intensely. These results suggest that immunostaining of AFP, CEA, CA19-9, EMA, CK18 and CK19 are not useful in the differential diagnosis between AH and well-differentiated HCC, and that CK19 is the most suitable reagent for the differential diagnosis between HCC and CC.

Topics: Adenoma; alpha-Fetoproteins; Biomarkers, Tumor; CA-19-9 Antigen; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Humans; Hyperplasia; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Mucin-1; Precancerous Conditions; Predictive Value of Tests; Prognosis

Immunocytochemistry has indicated that, in the liver, the bcl-2 gene is generally expressed in bile duct cells and tumors of biliary origin. Both in situ hybridization and immunocytochemistry were used to analyze the expression of bcl-2 messenger RNA (mRNA) and its protein product (Bcl-2) in the tissue of 50 pure primary liver tumor (PLT) specimens including 40 hepatocellular carcinoma (HCC) specimens and 10 cholangiocellular carcinoma (CC) specimens. The phenotype of the tumors expressing bcl-2 was confirmed by immunocytochemical assessment of the cytokeratin (CK) profile (CK8, CK18, CK7, and CK19). Whereas positive immunoreaction with the anti-Bcl-2 MoAb was revealed in only 8 (20%) of 40 HCC specimens and 1 (10%) of 10 CC specimens, high contents of bcl-2 mRNA were found in 26 (65%) of 40 HCC specimens and 9 (90%) of 10 CC specimens. Regarding the CK profile, only 25 (62%) of 40 HCC specimens showed pure hepatocytic lineage (CKs 8-18), whereas among the remaining 15 HCC specimens, positivity for either CK7 (12 specimens) or CK19 (5 specimens) was observed. All 10 CC specimens stained with CKs 8-18-19, and 8 of 10 stained with CK 7 as well. These results indicate that PLTs display a greater expression of bcl-2 mRNA than of the Bcl-2 protein. Furthermore, CK profile assessment confirmed that bcl-2 expression is not confined to liver tumors of biliary origin. In the absence of a well-demonstrated post-transcriptional control of the gene, the authors propose the detection of bcl-2 mRNA by in situ hybridization as a possible alternative method for assessing the expression of bcl-2 mRNA in PLT.

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Gene Expression Regulation, Neoplastic; Humans; Immunoenzyme Techniques; In Situ Hybridization; Keratins; Liver Neoplasms; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger

Cholangiocarcinomas may be extrahepatic or intrahepatic; the latter are further divided into hilar and peripheral types. Peripheral cholangiocarcinomas often resemble adenocarcinomas arising in other organs. Although clear cell changes may occur in hepatocellular carcinoma and extrahepatic cholangiocarcinoma, peripheral cholangiocarcinomas with clear cell change are rare. In such cases, an extrahepatic primary carcinoma must be excluded. We present a patient with a large, clear cell papillary carcinoma in the liver. Extensive workup of the patient for other possible primary sites including kidneys, adrenals, thyroid, prostate, or urinary bladder failed to indicate any other neoplasm. The patient is alive without evidence of disease 30 months after complete resection. The histological, immunohistochemical, and electron microscopic results were most consistent with a neoplasm in the cholangiocarcinoma family. To the best of our knowledge, a clear cell papillary peripheral cholangio carcinoma has not been described previously. This neoplasm may be related to the recently described clear cell carcinomas of the gallbladder and extrahepatic bile ducts.

Topics: Adenocarcinoma, Clear Cell; Aged; Antibodies; Biomarkers, Tumor; Carcinoma, Papillary; Cholangiocarcinoma; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Periodic Acid-Schiff Reaction

CYFRA 21-1 is a fragment of cytokeratin 19 (CK 19). Four patients with large intrahepatic (or peripheral) cholangiocarcinoma (CC) and high serum levels of CYFRA 21-1 (normal, < or = 2 ng/ml) are reported. CYFRA 21-1 levels exceeded 9 ng/ml in all 4 patients. Carcinoembryonic antigen (CEA), was high in 1 (CEA; normal range, < or = 5.0 ng/ml) and carbohydrate antigen 19-9 (CA 19-9) was high in 3 (CA19-9; normal range, < or = 36 U/ml). We also measured serum levels of CYFRA 21-1 in 13 patients with hepatocellular carcinoma (HCC) more than 5 cm in diameter. Levels of CYFRA 21-1 exceeded 2 ng/ml in 9 of the HCC patients and were higher than 9 ng/ml in 2 of the HCC patients. Levels of alpha fetoprotein (AFP) and/or protein induced by vitamin K absence or antagonist II (PIVKA II) were elevated in all HCC patients (AFP, PIVKA II, respectively; normal range, < or = 10.0 ng/ml and < or = 0.1 AU/ml) CYFRA 21-1 levels were measured twice or three times during the clinical course in 2 CC patients and in 6 HCC patients, and increased gradually with tumor growth in the 2 CC patients and in 3 of the 6 HCC patients. Marked increases in serum CYFRA 21-1 levels in patients with large liver cancers, particularly in those with normal levels of AFP and PIVKA II, would suggest the existence of intrahepatic CC rather than HCC.

Topics: alpha-Fetoproteins; Antigens, Neoplasm; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cholangiocarcinoma; Diagnosis, Differential; Female; Humans; Keratin-19; Keratins; Liver Neoplasms; Male; Middle Aged; Protein Precursors; Prothrombin; Tomography, X-Ray Computed

To examine the usefulness of Hep Par 1 together with selected antibodies in the separation of hepatocellular carcinoma (HCC) from cholangiocarcinoma (CC), combined tumours (HCC-CC) and metastatic carcinoma.. Antibodies to Hep Par 1, CK19, CK20 and factor XIIIa were applied to 32 HCCs, 27 CCs, five HCC-CCs and 19 metastatic carcinomas from a variety of sites. Hep Par 1 produced distinctive granular staining of all benign hepatocytes and stained 30 HCCs in a heterogeneous manner, irrespective of the degree of differentiation. While labelling all cases of combined HCC-CC, the antibody also stained the mucus-secreting cells of four cases of pure CC. Anti-CK19 produced distinctive staining of bile ducts and CC but also decorated four HCCs and 10 metastatic tumours. Factor XIIIa was not found in normal, reactive or neoplastic hepatocytes. CK20 was found in some cases of HCC and CC and in all cases of metastatic carcinomas from the colon.. Hep Par 1 was a sensitive marker of hepatocytes but its variable staining in HCC may produce false negative results in small biopsies and it was occasionally found in CC. The highest diagnostic yield was obtained when anti-Hep Par 1, CK19 and CK20 were used in a panel. Factor XIIIa staining has no role in the diagnosis of liver cancers.

Topics: Antibodies; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Differentiation; Cholangiocarcinoma; Diagnosis, Differential; Humans; Immunohistochemistry; Intermediate Filament Proteins; Keratin-20; Keratins; Liver Neoplasms; Neoplasms, Multiple Primary; Transglutaminases

To assess the utility of cytokeratin (CK) profile and albumin mRNA detection (as revealed by in situ hybridization) in the differential diagnosis of primary liver carcinomas (PLCs) we evaluated a series of surgically resected PLCs, comprising 20 "pure" hepatocellular carcinomas (HCCs) (10 well-differentiated, 10 poorly differentiated), 15 cholangiocarcinomas (CCs) (6 peripheral, 5 hilar, and 4 major duct ones) and 10 hepatocholangio-carcinomas (HCC-CCs). 11 of 20 (55%) of the pure HCCs expressed CKs of pure hepatocytic lineage (CK 8 and CK 18); 2 of 10 (20%) of the HCC-CCs displayed only hepatocytic profile, whereas 12 of 15 (80%) of the CCs evidenced mature bile duct cell phenotype (CK 8, CK 18, CK 7, CK 19). All HCCs expressed varying distributions of albumin mRNA, whereas 4 of 6 (67%) peripheral CCs showed cells with focal positivity for albumin mRNA. This suggests that the phenotypic expression of PLC cells are often not fixed, and in particular: (1) peripheral CCs have a different phenotype from hilar and large duct ones; (2) the CK profile and albumin mRNA expression in peripheral CCs show many similarities with those of some HCCs. Furthermore, the results show that a mixed biological phenotype (ie, CK 8, CK 18 and CK 7 and/or CK 19) can be found both among morphologically pure HCCs and peripheral CCs, suggesting that these two forms could share a common histogenesis. We think that special attention should be given to cases in which CK profile and albumin mRNA reveal mixed phenotype, as these tumors could have different biological behavior and respond differently to therapy.

Topics: Aged; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Humans; Immunohistochemistry; In Situ Hybridization; Keratins; Liver Neoplasms; Male; Middle Aged; RNA, Messenger; Serum Albumin

A case of a combined hepatocellular-cholangiocarcinoma (HCC-CC) is presented showing mucin production in both the HCC and the CC component. Immunohistochemical staining for cytokeratins 7 and 19 was performed and it is concluded that immunoreactivity for cytokeratin 7 and 19 is an additional criterion to the detection of mucin in making the diagnosis of a combined HCC-CC of the transitional type.

Topics: Carcinoma, Hepatocellular; Cell Differentiation; Cholangiocarcinoma; Female; Humans; Keratins; Liver Neoplasms; Middle Aged; Mucins; Neoplasms, Multiple Primary

We clinicopathologically studied 23 surgically resected cases of combined hepatocellular and cholangiocarcinoma (HCC-CC). The frequency of this cancer in our subjects, who had primary liver cancer and who underwent hepatectomy, was 6.3%. The mean age of patients was 64.0 years old and the male: female ratio was 1.9:1. Serum alpha-fetoprotein was positive in 70% of cases and its levels were relatively low (< or = 1000 ng/mL) in most cases. The positive rate of serum carcinoembryonic antigen was 18% and its levels were also low. In regard to hepatitis virus markers, 17% of the 20 combined HCC-CC cases were positive to HBs antigen and 70% were positive to the HCV antibody. Of the 23 combined HCC-CC cases, 9 cases (39%) were associated with liver cirrhosis. Tumours were classified macroscopically into a separated type (HCC and CC are clearly separated 17%), a HCC-predominant type (resembles HCC 49%), and a CC-predominant type (resembles CC 34%). The separated and HCC-predominant types were associated with liver cirrhosis in 50 and 55% of cases, respectively. These cases with liver cirrhosis presented the features of HCC more apparently, while those without liver cirrhosis presented the features of CC. Histologically, all cases were classified into either Type I (HCC and CC were clearly distinguished; 17%), Type II (HCC and CC were contiguous and shared transitional features; 66%), and Type III (cancer cells were able to be evaluated as either HCC or CC and were considered to be an intermediate type; 17%). Immunohistological stains for cytokeratin were useful to distinguish HCC and CC. Specifically, CC was positive to cytokeratin 7 and 19. The tumour, in which HCC and CC were almost indistinguishable, such as Type III), indicates the presence of intermediate tumour cells that can differentiate either to HCC or CC.

Topics: Aged; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Middle Aged; Neoplasms, Multiple Primary

We performed immunohistochemical studies on 90 surgically resected liver tumors, including 30 tumors each from hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), and metastatic colorectal adenocarcinoma (MCA), using monoclonal antibodies against cytokeratin (CK) 7, CK 19, and CK 20 to examine the differences in the CK expressions in primary and metastatic carcinomas of the liver. We also investigated the usefulness of such expression in the differential diagnosis in addition to existing markers such as alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen 19-9. For CK 7, all except for one (97%) of the CCs were diffusely positive, whereas only two (7%) HCCs and one (3%) MCAs were diffusely positive. For CK 19, 23 (77%) CCs and 19 (64%) MCAs were diffusely positive, whereas no HCCs were positive. For CK 20, 22 (74%) MCAs were diffusely positive, whereas no HCC and three (10%) CCs were diffusely positive. The findings concerning the expression of immunohistochemical CK are therefore considered to be useful in addition to the diagnostic criteria when making a differential diagnosis of primary and metastatic carcinomas of the liver.

Topics: Adenocarcinoma; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Carcinoma, Hepatocellular; Cholangiocarcinoma; Colorectal Neoplasms; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Intermediate Filament Proteins; Keratin-20; Keratins; Liver Neoplasms

Because combined hepatocellular-cholangiocellular carcinoma is rare and its biological features and pathogenesis have not been well established, we investigated alterations of the p53, K-ras and Rb-1 genes, as well as expression patterns of carcinoembryonic antigen and keratin, in seven combined hepatocellular-cholangiocarcinomas out of 557 hepatocellular carcinomas autopsied at Tokyo University during 30 years. Mutations of the p53 gene were found in two cases, at codon 244 (GGC to TGC) in the cholangiocellular carcinoma component of case 1 (mixed type, showing an intimate intermingling of both elements) and at codon 234 (TAC to AAC) in both components of case 5 (combined type, consisting of contiguous but independent masses of both elements). Mutation of the K-ras gene (codon 12, GGT to GAT) was seen only in the cholangiocellular carcinoma component of clinically apparent double cancer, case 6. Allelic alteration of the Rb-1 gene was observed in two cases, deletion of both alleles in the hepatocellular carcinoma component of case 3 (combined type) and replication error of the same pattern in both components of case 4 (mixed type). Immunohistochemical analysis showed that the hepatocellular carcinoma components of five cases (cases 2, 3, 5, 6, 7) were immunoreactive for keratin, suggesting biliary epithelial transformation. In four of the five cases (cases 3 and 5 combined, case 7 mixed and case 6 double cancer), cholangiocellular carcinoma components were also positive for keratin. These results suggest that both components of combined hepatocellular-cholangiocarcinoma have the same genetic and phenotypic character and might have arisen from the same origin in some cases.

Topics: Aged; Alleles; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cholangiocarcinoma; DNA Mutational Analysis; Female; Gene Deletion; Genes, p53; Genes, ras; Genes, Retinoblastoma; Humans; Keratins; Liver Neoplasms; Male; Middle Aged; Neoplasm Proteins; Neoplasms, Multiple Primary

Thirteen cases of combined hepatocellular (HCC) and cholangiocellular carcinoma (CCC) were examined. In addition to routine pathology, immunoreactivities for carcinoembryonic antigen, alpha-fetoprotein (AFP), cytokeratin (Cam 5.2 and AE1), epithelial membrane antigen (EMA) and tumor-associated glycoprotein 72 (B72.3) were also examined. The average age of the 13 cases was 64.8 years, which lay between the average ages of pure HCC and CCC cases. They were categorized as separate type (2), collision type (6), and intermingled type (5). AE1 and EMA were the best markers to differentiate the CCC from the HCC area. B72.3 immunoreactivity was detected only in CCC (46%). There were no transitional features between HCC and CCC in two cases of the separate type and two cases of the collision type. However, focal transitional features from HCC to CCC were observed in all cases of the intermingled type and in four of six cases of the collision type. In one case of the intermingled type, many cancer cells contained both bile and mucus simultaneously, and revealed dual immunoreactivities. The conclusions are: 1) the combined type is generated from two sources; one is the intrahepatic double cancer (thoroughly separate type and a part of the collision type) and another is the stem cell origin with diverse phenotypes (intermingled type and a part of the collision tumor); and 2) AE1 was the most helpful marker to differentiate the CCC area from HCC, and other markers, e.g. AFP for HCC and EMA, CEA, and B72.3 for CCC, were also supportive but somewhat limited in the differential diagnosis.

Topics: Aged; alpha-Fetoproteins; Antigens, Neoplasm; Biomarkers, Tumor; Carcinoembryonic Antigen; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cholangiocarcinoma; Female; Glycoproteins; Humans; Keratins; Liver; Liver Neoplasms; Male; Membrane Glycoproteins; Middle Aged; Mucin-1; Mucins; Neoplasms, Multiple Primary; Neoplastic Stem Cells

We herein evaluated 36 cases of combined hepatocellular and cholangiocarcinoma (cHCC-CC) (including 29 surgically resected and seven autopsy cases) by the immunohistochemical methods of anticytokeratin antibodies 7 and 19, and then analyzed the clinicopathologic features by comparing cHCC-CC with ordinary hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The results indicated that even if mucin production could not be confirmed, nine cases with HCC areas that showed a histological resemblance to CC also showed immunohistological biliary differentiation. Therefore, we advocate that these HCC with biliary differentiation based on an immunohistochemical analysis should thus be included in the criteria of cHCC-CC in broad terms. Regardless of the extent of mucin production, the cHCC-CCs as indicated by an immunohistochemical analysis are considered to have a similar background to that of ordinary HCCs regarding such factors as the average age, male:female ratio, hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCVAb) positivity, alpha-fetoprotein level, and the presence of cirrhosis. However, cHCC-CCs tend to metastasize to many organs and the lymph nodes, and, as a result, have a poor prognosis.

Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Middle Aged; Prognosis; Staining and Labeling; Survival Analysis

It is well established that alterations in the expression of cell surface glycoproteins occur during the course of tumorigenesis and can be detected immunohistochemically. However, no consistent markers of malignancy in mouse hepatocellular tumors have yet been identified.. Lectin histochemistry, using three bile duct-specific lectins, Dolichos biflorus agglutinin (DBA), peanut agglutinin (PNA) and soybean agglutinin (SBA), and anti-epidermal keratin immunohistochemistry, was conducted on formalin-fixed, paraffin-embedded tissues of a spectrum of benign and malignant hepatocellular proliferative lesions of mice, including hepatocholangiocarcinomas. DBA- and PNA-binding glycoproteins in normal livers and in bile and liver tumors of mice were verified by SDS-PAGE and Western blot analysis.. Normal bile duct cells stained strongly with DBA but minimally to moderately with PNA and SBA. DBA-positive tumor cells were present in 96% of hepatocholangiocarcinomas, 89% of hepatocellular carcinomas, and 35% of hepatocellular adenomas. In comparison, 43% of hepatocholangiocarcinomas, 37% of hepatocellular carcinomas, and 24% of hepatocellular adenomas exhibited PNA staining. SBA did not specifically stain tumor cells. Normal hepatocytes and those in altered foci were consistently negative for these three lectins. Keratin-positive staining was found only in normal bile ductular cells and ductal elements in 70% of hepatocholangiocarcinomas. Electrophoresis and Western blot analysis demonstrated that, in normal livers, DBA and PNA bound to the 13- to 16-kDa and 27- to 30-kDa glycoproteins believed to be of bile duct cell origin and commonly present in hepatocellular adenomas, hepatocellular carcinomas, and hepatocholangiocarcinomas, with strongest expression in the last. In addition, hepatocholangiocarcinomas had the same high molecular mass glycoprotein (> 200 kDa) labeled with DBA as detected in bile.. Our results suggest that some malignant hepatocytes, especially in mouse hepatocholangiocarcinomas, have the potential of biliary differentiation. DBA is a sensitive marker for malignant hepatocytes in mice.

Topics: Adenoma; Animals; Bile Ducts; Carcinogenicity Tests; Carcinoma, Hepatocellular; Cholangiocarcinoma; Female; Immunohistochemistry; Keratins; Lectins; Liver Neoplasms; Male; Mice; Mice, Inbred Strains; Molecular Probes; Peanut Agglutinin; Plant Lectins; Precancerous Conditions; Retrospective Studies

The immunohistochemical expression of the oncofetal proteins alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), and the intermediate filament proteins keratin and vimentin was analysed in 18 canine liver carcinomas. All the tumours other than hepatocellular carcinomas, with the exception of one poorly differentiated carcinoma, were AFP negative, and only cholangiocarcinomas and mixed (hepatocellular and cholangiocellular) carcinomas were CEA positive. All the histological types of tumours expressed high and low molecular weight keratins, and keratin and vimentin were both expressed in three tumours (one moderately differentiated hepatocellular carcinoma, one mixed carcinoma and one poorly differentiated carcinoma). The findings demonstrate the use of immunohistochemical staining methods for analysing the expression of some tumour markers in routinely processed tissue samples of canine liver carcinomas, and suggest that some of the tumour markers are correlated with histological types of tumour.

Topics: alpha-Fetoproteins; Animals; Antibody Specificity; Carcinoembryonic Antigen; Carcinoma; Carcinoma, Hepatocellular; Cholangiocarcinoma; Dog Diseases; Dogs; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Sensitivity and Specificity; Vimentin

To determine if hyperplastic and neoplastic lesions from medaka showed similar immunoreactivity to intermediate filament antibodies as the tissues of origin, two week old medaka were exposed to 10 or 20 mg/L of methylazoxymethanol acetate for two hours and transferred to clean water for up to six months. Using a streptavidin peroxidase method, paraffin embedded Bouins fixed neoplasms were incubated with cytokeratin, vimentin, or neurofilament antibodies. Like their nonneoplastic cellular counterparts, hepatocellular carcinoma, pancreatic acinar carcinoma and mesenchymal neoplasms including hemangioma and hemangiopericytoma reacted negatively to cytokeratin antibodies. Cholangiocarcinoma, mesothelioma, and proliferative lesions containing biliary epithelial cells reacted positively to cytokeratin antibodies. All neoplasms and proliferative lesions were negative with vimentin and neurofilament antibodies. These data indicate that while some epithelial neoplasms showed cytokeratin reactivity similar to the parent tissues, additional markers are needed to identify mesenchymal tissues and neoplasms.

Topics: Adenoma, Liver Cell; Animals; Antibodies; Carcinogens; Carcinoma, Acinar Cell; Carcinoma, Hepatocellular; Cell Division; Cholangiocarcinoma; Hemangioma; Hemangiopericytoma; Hyperplasia; Immunohistochemistry; Intermediate Filaments; Keratins; Liver; Liver Neoplasms; Methylazoxymethanol Acetate; Neurofilament Proteins; Oryzias; Pancreas; Pancreatic Neoplasms; Vimentin

The present study was performed to evaluate the diagnostic reliability of antibodies to breast carcinoma-specific antigen and antibodies to cytokeratin catalogue in a metastatic hepatic lesion. Immunohistochemical examinations using antibodies to gross cystic disease fluid protein-15 (GCDFP-15), BCA-225 (a glycoprotein secreted by T47D breast carcinoma cell line) and BRST-5 (a glycoprotein identified in SK-BR-7 breast carcinoma cell line), anti-cytokeratin monoclonal antibodies of MA904, AE3, CAM5.2, PKK1 and cytokeratin 19, and polyclonal anti-keratin antibodies were done. These were on 15 cases of primary breast carcinoma, eight cases of metastatic breast carcinoma in the liver, five cases of cholangiocarcinoma, eight cases of hepatocellular carcinoma and 11 cases of metastatic adenocarcinoma of another primary tumor in the liver. Results showed that GCDFP-15 antigen was most reliable: it was 100% positive in both primary and metastatic breast carcinomas unrelated to histological subtypes, and 100% negative in primary or other metastatic carcinomas in the liver. BCA-225 antigen was detected in high amounts in breast carcinomas (100%, 23/23), but it was positive in cholangiocarcinomas (80%, 4/5) and another metastatic carcinoma in the liver (64%, 7/11). BRST-5 was specifically positive in breast carcinomas but the positivity was low (13%, 3/23). Cytokeratin 19 and keratin were useful to discriminate hepatocellular carcinomas (0%, 0/8) from breast carcinomas (87%, 20/23; 96%, 22/23), but they were also positive in cholangiocarcinomas (100%, 5/5) and other metastatic carcinomas in the liver (91%, 10/11).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Apolipoproteins; Apolipoproteins D; Breast Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Carrier Proteins; Cholangiocarcinoma; Female; Glycoproteins; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Membrane Transport Proteins; Middle Aged