OBJECTIVETo study the clinicopathologic features of combined hepatocellular-cholangiocarcinoma (cholangiolocellular type, CLC type) with stem cell features and its relationship to hepatic progenitor cells (HPCs).

METHODSClinical and histologic features of 26 cases of combined hepatocellular-cholangiocarcinoma (CLC type) were reviewed. Histochemistry was performed to confirm the type of mucin and immunohistochemical study was carried out for hepatocytic markers (Hep Par-1 and AFP) and biliary/HPCs markers (CK7, CK9, EMA, EpCAM, NCAM, CKIT).

RESULTSThe age of patients ranged from 51 to 82 years (mean 64 years). All 26 cases contained CLC and hepatocellular carcinoma components. CLC area was composed of mixtures of small monotonous glands with abundant fibrous stroma and lymphocytic infiltrate. Tumor cells were cuboidal, smaller in size than normal hepatocytes, with basophilic cytoplasm and round nuclei. All cases, especially at the tumor boundary, showed HCC-like trabecular areas characterized by mildly atypical tumor cells with abundant eosinophilic cytoplasm and little stroma. Out of 26 cases, 21 showed definite glandular formation with mucin production, representing intrahepatic cholangiocarcinoma areas. The three distinct areas showed transitional zones merging with each other. The surrounding liver tissue showed cirrhosis and chronic hepatitis with varying degrees of fibrosis and periportal ductular reaction. Immunohistochemistry showed that biliary/HPC markers (CK7, CK9, EMA, EpCAM, NCAM and CKIT) were strongly positive in CLC area in almost all cases, similar to the staining pattern of ductular reaction. In HCC-like areas, CK7 and CK19 were positive in all cases and the expression rates of EMA, EpCAM, NCAM, CKIT, AFP, Hep Par-1 were 80.8% (21/26), 88.5% (23/26), 84.6% (22/26), 88.5% (23/26), 46.2% (12/26) and 53.8% (14/26) respectively, similar to the staining pattern of intermediate hepatocytes. In ICC areas, CK7, CK9, EMA and EpCAM were positive in all cases without the expression of NCAM and CKIT.

CONCLUSIONThe clinicopathologic findings and immunohistochemical results in this study highly suggest a hepatic progenitor cell origin of combined hepatocellular-cholangiocarcinoma (CLC type).

Bile Duct Neoplasms ; pathology ; Biomarkers ; metabolism ; Carcinoma, Hepatocellular ; pathology ; Cholangiocarcinoma ; pathology ; Hepatocytes ; cytology ; Humans ; Immunohistochemistry ; Liver Cirrhosis ; pathology ; Liver Neoplasms ; pathology ; Mucins ; metabolism ; Stem Cells ; cytology

A 51-year-old male patient with chronic hepatitis B was referred to our hospital due to a 1-cm liver nodule on ultrasonography. Alpha-fetoprotein (AFP) was slightly elevated. The nodule showed prolonged enhancement on dynamic liver magnetic resonance imaging and appeared as a hyperintensity on both diffusion-weighted and T2-weighted imaging. The nodule was followed up because it was small and typical findings of hepatocellular carcinoma (HCC) were not observed in the dynamic imaging investigations. However, liver contrast-enhanced ultrasonography performed 1 month later showed enhancement during the arterial phase and definite washout during the delayed phase. Also, AFP had increased to over 200 ng/mL even though AST and ALT were decreased after administering an antiviral agent. He was presumptively diagnosed as HCC and underwent liver segmentectomy. Microscopy findings of the specimen indicated bile duct adenoma. After resection, the follow-up AFP had decreased to within the normal range. This patient represents a case of bile duct adenoma with AFP elevation mimicking HCC on contrast-enhanced ultrasonography.
Bile Duct Neoplasms/*complications/*diagnosis/pathology ; *Bile Ducts, Intrahepatic ; Hepatitis B, Chronic/*complications/*diagnosis/pathology ; Humans ; Liver/pathology/ultrasonography ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Tomography, X-Ray Computed ; alpha-Fetoproteins/*metabolism

BACKGROUND/AIMS: Biliary drainage is performed in many patients with cholangiocarcinoma (CCA) to relieve obstructive jaundice. For those who have undergone biliary drainage, bile cytology can be easily performed since the access is already achieved. This study aims to determine the clinical usefulness of bile cytology for the diagnosis of CCA and to evaluate factors affecting its diagnostic yield. METHODS: A total of 766 consecutive patients with CCA underwent bile cytology via endoscopic nasobiliary drainage or percutaneous transhepatic biliary drainage from January 2000 to June 2012. Data were collected by retrospectively reviewing the medical records. We evaluated the diagnostic yield of bile cytology with/without other sampling methods including brush cytology and endobiliary forcep biopsy, and the optimal number of repeated bile sampling. Several factors affecting diagnostic yield were then analyzed. RESULTS: The sensitivity of bile cytology, endobiliary forceps biopsy, and a combination of both sampling methods were 24.7% (189/766), 74.4% (259/348), and 77.9% (271/348), respectively. The cumulative positive rate of bile sampling increased from 40.7% (77/189) at first sampling to 93.1% (176/189) at third sampling. On multivariate analysis, factors associated with positive bile cytology were perihilar tumor location, intraductal growing tumor type, tumor extent > or =20 mm, poorly differentiated grade tumor, and three or more samplings. CONCLUSIONS: Although bile cytology itself has a low sensitivity in diagnosing CCA, it has an additive role when combined with endobiliary forceps biopsy. Due to the relative ease and low cost, bile cytology can be considered a reasonable complementary diagnostic tool for diagnosing CCA.
Aged ; Bile/*cytology ; Bile Duct Neoplasms/*diagnosis/pathology/radiography ; CA-19-9 Antigen/metabolism ; Cholangiocarcinoma/*diagnosis/pathology/radiography ; Drainage ; Female ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Neoplasm Staging ; Retrospective Studies

BACKGROUND/AIMS: To evaluate the expression of CXC motif chemokine receptor 4 (CXCR4) in the tissues of patients with hilar cholangiocarcinoma (hilar-CCA) and to investigate the cell proliferation and frequency of neural invasion (NI) influenced by RNAi-mediated CXCR4 silencing. METHODS: An immunohistochemical technique was used to detect the expression of CXCR4 in 41 clinical tissues, including hilar-CCA, cholangitis, and normal bile duct tissues. The effects of small interference RNA (siRNA)-mediated CXCR4 silencing were detected in the hilar-CCA cell line QBC939. Cell proliferation was determined by MTT. Expression of CXCR4 was monitored by quantitative real time polymerase chain reaction and Western blot analysis. The NI ability of hilar-CCA cells was evaluated using a perineural cell and hilar-CCA cell coculture migration assay. RESULTS: The expression of CXCR4 was significantly induced in clinical hilar-CCA tissue. There was a positive correlation between the expression of CXCR4 and lymph node metastasis/NI in hilar-CCA patients (p<0.05). Silencing of CXCR4 in tumor cell lines by siRNA led to significantly decreased NI (p<0.05) and slightly decreased cell proliferation. CONCLUSIONS: CXCR4 is likely correlated with clinical recurrence of hilar-CCA. CXCR4 is involved in the invasion and proliferation of human hilar-CCA cell line QBC939, indicating that CXCR4 could be a promising therapeutic target for hilar-CCA.
Aged ; Bile Duct Neoplasms/metabolism/*pathology ; Bile Ducts, Intrahepatic/metabolism/*pathology ; Case-Control Studies ; Cell Line, Tumor ; Cell Proliferation ; Cholangiocarcinoma/metabolism/*pathology ; Female ; Humans ; Immunohistochemistry ; Male ; Middle Aged ; Neoplasm Invasiveness ; Neoplasm Recurrence, Local/metabolism/pathology ; RNA Interference/*physiology ; RNA, Small Interfering/metabolism ; Receptors, CXCR4/antagonists & inhibitors/*metabolism ; Tumor Cells, Cultured

No abstract available.
Aged ; Bile Duct Neoplasms/metabolism/*pathology ; Bile Ducts, Intrahepatic/metabolism/*pathology ; Cholangiocarcinoma/metabolism/*pathology ; Humans ; Immunohistochemistry ; Keratin-19/metabolism ; Male ; Positron-Emission Tomography ; Tomography, X-Ray Computed

OBJECTIVETo study the correlation between clinicopathological features and serum carbohydrate antigen 19-9 (CA19-9)/carcinoembryonic antigen (CEA) in patients with extrahepatic cholangiocarcinoma (ECC).

METHODSThe clinicopathological data of 126 cases of extrahepatic cholangiocarcinoma treated in our department from Jan. 1999 to Dec. 2012 were collected and analyzed in this study. The correlation between clinicopathological features and sensitivity of CA19-9/CEA was analyzed by chi-square test. The correlation of clinicopathological features and value of serum CA19-9/CEA was analyzed by t test and F test.

RESULTSThe average value of CA19-9 before surgery in the 126 patients was 595.3 U/ml. The values of CA19-9 in 91 patients were abnormal and the sensitivity of CA19-9 was 72.2%. The average value of CEA before surgery was 12.6 U/ml. The value of CEA in 26 patients were abnormal and the sensitivity of CEA was 20.6%. The values of combined detection of serum CA19-9 and CEA before surgery were abnormal in a total of 97 cases with a sensitivity of 77.0%. There was no significant correlation between clinicopathological features and sensitivity of CA19-9 (P > 0.05). The location of tumor was significantly correlated to the diagnostic sensitivity of CEA. The sensitivity of CEA to distal ECC was only 15.4%. The value of CA19-9 was relatively high in patients >60-year old or with neural invasion, while CEA was higher when tumor was located in the middle of bile duct (P < 0.05). There was no significant difference of serum CA19-9 before and after jaundice reduction (P > 0.05).

CONCLUSIONSThe diagnostic sensitivity of CA19-9 is not affected by gender, age, blood type, tumor location, degree of differentiation, tumor size, T stage, vascular tumor thrombus, lymph node metastasis, perineural invasion, and preoperative jaundice. However, the diagnostic sensitivity of CEA is affected by tumor location. The value of CA19-9 is correlated with tumor invasion and is relatively high in patients above 60 years old.

Bile Duct Neoplasms ; metabolism ; pathology ; Bile Ducts, Intrahepatic ; metabolism ; pathology ; Biomarkers, Tumor ; metabolism ; CA-19-9 Antigen ; metabolism ; Carcinoembryonic Antigen ; metabolism ; Cholangiocarcinoma ; metabolism ; pathology ; Humans ; Lymphatic Metastasis

OBJECTIVETo investigate the expressions of the active form of glycogen synthase kinase-3(GSK-3)-pGSK-3α/β (Tyr279/216) and its downstream moleculor X-linked inhibitor of apoptosis protein (XIAP) in cholangiocarcinoma and to analyze their correlation with clinicopathological and survival significance.

METHODSImmunohistoehemistry was used to detect the expressions of the active form of GSK-3- pGSK-3α/β (Tyr279/216) and its downstream moleculor XIAP proteins in 50 cholangiocarcinoma tissues and 20 normal bile duct tissues.

RESULTSThe positive rates of pGSK-3α/β (Tyr279/216) and XIAP were 62.0% and 68.0% in cholangiocarcinoma, and 10.0% and 25.0% in normal bile duct tissues, respectively. The intensity of pGSK-3α/β (Tyr279/216) and XIAP expressions in cholangiocarcinoma were significantly higher than that in the normal bile duct tissues (P < 0.001), and there was a significant correlation between pGSK-3α/β (Tyr279/216) and XIAP expressions (r = 0.544, P < 0.001). The expression of pGSK-3α/β(Tyr279/216) protein in cholangiocarcinoma was associated with TNM stage (P = 0.042), histological grade (P = 0.031), whereas the expression of XIAP protein in cholangiocarcinoma was correlated with CEA level (P = 0.006). Patients with positive expression of pGSK-3α/β (Tyr279/216) and XIAP demonstrate a significantly worse prognosis than that of patients with negative expression of pGSK-3α/β (Tyr279/216) and XIAP for overall survival (P = 0.002, P = 0.018). Multivariate survival analysis revealed that positive pGSK-3α/β (Tyr279/216) expression provided significant independent prognostic value for overall survival (P = 0.002).

CONCLUSIONSThe expressions of pGSK-3α/β(Tyr279/216) and XIAP proteins were significantly associated with the development and progression of cholangiocarcinoma. pGSK-3α/β(Tyr279/216) may be an important prognostic factor for survival of patients with cholangiocarcinoma.

Bile Duct Neoplasms ; metabolism ; pathology ; surgery ; Bile Ducts, Intrahepatic ; Carcinoembryonic Antigen ; blood ; Cholangiocarcinoma ; metabolism ; pathology ; surgery ; Female ; Follow-Up Studies ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Neoplasm Staging ; Prognosis ; Survival Rate ; X-Linked Inhibitor of Apoptosis Protein ; metabolism

No abstract available.
Aged ; Antigens, CD20/metabolism ; Antigens, CD3/metabolism ; Bile Duct Neoplasms/ultrasonography ; Female ; Humans ; Immunohistochemistry ; Liver Diseases/*pathology/radiography ; Pseudolymphoma/*pathology/radiography ; Tomography, X-Ray Computed

BACKGROUND/AIMS: Ampullary adenomyoma is a benign lesion whose malignant potential has yet to be confirmed. Despite its benign nature, adenomyoma is frequently misdiagnosed as a carcinoma or adenoma and is overtreated by extensive surgery. This study was performed to analyze the clinical, pathological, and immunohistochemical features of adenomyomas in the ampulla of Vater. METHODS: Nine cases of adenomyoma in the ampulla of Vater, diagnosed in Chungbuk National University Hospital between 2008 and 2011, were enrolled in this study. We reviewed the clinical data on the symptoms, laboratory data, and radiologic findings of the abdominal computed tomography and endoscopic retrograde cholangiopancreatography. For pathological analysis, all the slides were reviewed by one pathologist, and immunohistochemical stainings with antibodies against cytokeratin 7 (CK7), cytokeratin 20 (CK20), alpha-smooth muscle actin (alpha-SMA), and Ki-67 antigen were performed. RESULTS: All the cases were CK7 positive and CK20 negative. A strong cytoplasmic expression of alpha-SMA was confirmed in all cases. The Ki-67 index was less than 1% in eight cases and 5% in one case. Four cases underwent endoscopic papillectomy, and one case received surgical ampullectomy during colorectal cancer surgery. Five cases that underwent endoscopic or surgical treatment remained symptom-free for three years. Four cases that were closely observed with repeated endoscopic examinations exhibited no interval changes in the papillary lesions. CONCLUSIONS: Endoscopic biopsy and immunohistochemistry can aid in the diagnosis of ampullary adenomyomas. Endoscopic papillectomy or surgical ampullectomy is adequate for the treatment of symptomatic ampullary adenomyomas.
Actins/metabolism ; Adenomyoma/*pathology/surgery ; Aged ; Ampulla of Vater/*pathology ; Cholangiopancreatography, Endoscopic Retrograde ; Common Bile Duct Neoplasms/*pathology/surgery ; Female ; Humans ; Immunohistochemistry ; Keratin-20/metabolism ; Keratin-7/metabolism ; Ki-67 Antigen/metabolism ; Male ; Middle Aged ; Retrospective Studies ; Tomography, X-Ray Computed ; Treatment Outcome

OBJECTIVETo explore the molecular mechanism of γ-aminobutyric acid (GABA) inhibitory on the growth of cholangiocarcinoma cell line (QBC939).

METHODSQBC939 cells were cultured in different groups and treated with GABA, GABA + bicuculine (A receptor antagonist), GABA + phaclofen (B receptor antagonist) for 48 hours. MTT assay was used to determine the proliferation of QBC939 cells. Annexin V-FITC/PI binding assay was used to detect apoptosis in the QBC939 cells. Western blot was applied to check the expression of signal transducer and activator of transcription 3 (STAT3) and phosphorylation-STAT3 (p-STAT3) proteins in different groups of QBC939 cells. Animal models of cholangiocarcinoma bearing nude mice were established by subcutaneous injection of QBC939 cells and randomized into 2 groups: control and GABA-treated groups. The effect of GABA was evaluated after 5 weeks, including the body weight and tumor volume. The expression of p-STAT3 was detected by immunohistochemistry and Western blot in xenograft tumors.

RESULTSMTT and FCM assays both showed that the effect of GABA inhibitory on the proliferation (15.30% ± 0.80% vs. 2.66% ± 0.74%, t = 23.15, P = 0.00) and induced apoptosis (23.15% ± 0.21% vs. 4.30% ± 0.69%, t = 52.40, P = 0.00) of QBC939 cells could be antagonized by phaclofen, but not bicuculine. The expression of STAT3 and p-STAT3 proteins were all observed in the QBC939 cells and GABA significantly down-regulated p-STAT3 protein expression (0.77 ± 0.00 vs. 0.45 ± 0.01, t = 63.14, P = 0.00), this action was also antagonized by phaclofen (0.45 ± 0.01 vs. 0.76 ± 0.01, t = 56.25, P = 0.00). Xenograft tumor volume ((0.62 ± 0.03) cm³ vs. (0.34 ± 0.03) cm³, t = 13.45, P = 0.00) and the expression of p-STAT3 protein were significantly decreased in GABA-treated group as compared with control group.

CONCLUSIONSGABA may inhibit the growth of cholangiocarcinoma cells QBC939 through GABA(B) receptor, and down-regulation of the p-STAT3 expression perhaps is one of its anti-tumor mechanisms.

Animals ; Apoptosis ; drug effects ; Bile Duct Neoplasms ; pathology ; Bile Ducts, Intrahepatic ; pathology ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cholangiocarcinoma ; pathology ; Humans ; Mice ; Mice, Nude ; STAT3 Transcription Factor ; metabolism ; Tumor Burden ; gamma-Aminobutyric Acid ; pharmacology