Cyclins are the regulatory subunits of cyclin-dependent kinase and play an important role in cell proliferation. Many tumors, such as colon, breast and gastric carcinomas are known to be involved in the deregulation or amplification of cyclins, especially cyclin E, which involves the restriction point of G1-S transition. We investigated the expression of cyclin E in benign and malignant epithelial tumors of the gallbladder and compared the results with the activity of cell proliferation by the Ki67 antigen using immunohistochemical staining. Cyclin E was expressed in the adenocarcinoma tissue in 33.3% of patients (4 out of 12 cases), whereas only one out of 8 cases of adenoma expressed cyclin E (12.5%). There was a correlation between cyclin E expression and the Ki67 labeling index. These results suggest that the high expression of cyclin E in adenocarcinoma of the gallbladder is related to a high rate of cell proliferation.
Adenocarcinoma/pathology ; Adenocarcinoma/metabolism* ; Adenoma/pathology ; Adenoma/metabolism* ; Adult ; Aged ; Cyclin E/metabolism* ; Female ; Gallbladder Neoplasms/pathology ; Gallbladder Neoplasms/metabolism* ; Human ; Immunohistochemistry ; Male ; Middle Age

Adenocarcinoma ; metabolism ; pathology ; surgery ; Aged ; Cholecystectomy ; Chondrosarcoma ; metabolism ; pathology ; surgery ; Female ; Gallbladder ; chemistry ; pathology ; surgery ; Gallbladder Neoplasms ; metabolism ; pathology ; surgery ; Humans ; Immunohistochemistry ; Keratin-3 ; metabolism ; S100 Proteins ; metabolism

OBJECTIVETo study the expression of ephrin-A7 (EphA7) and metadherin (MTDH) and their clinicopathological significances in the benign and malignant lesions of gallbladder.

METHODSEnVisiom immunohistochemical methods was used for determining the expressions of EphA7 and MTDH in routinely paraffin-embedded sections of surgically-resected specimens from 108 cases with gallbladder adenocarcinoma, 15 cases with adenomatous polyp and 35 cases with chronic cholecystitis treated from June 1996 to June 2006. And 46 cases of peritumoral tissues were also harvested as controls (n = 35).

RESULTSThe positive expression rates of EphA7 and MTDH were significantly higher in gallbladder adenocarcinoma than those in peritumoral tissues (χ(2)(EphA7) = 12.65, χ(2)(MTDH) = 13.00; P < 0.01), adenomatous polyp (χ(2)(EphA7) = 8.21, χ(2)(MTDH) = 9.39; P < 0.01) and chronic cholecystitis (χ(2)(EphA7) = 21.21, χ(2)(MTDH) = 23.68; P < 0.01); Moderately-or severely-atypical hyperplasia of gallbladder epithelium was found in the benign lesions with positive expression of EphA7 and/or MTDH. The positive rates of EphA7 and MTDH were significantly lower in the cases of well-differentiated adenocarcinoma, maximal diameter of tumor < 2 cm, no-metastasis of lymph node, and tumor with no-invasiveness of regional tissues than those in the poorly-differentiated adenocarcinoma (χ(2)(EphA7) = 12.34, χ(2)(MTDH) = 12.80; P < 0.01), maximal diameter of tumor ≥ 2 cm (χ(2)(EphA7) = 5.22, χ(2)(MTDH) = 5.00; P < 0.05), cases with metastasis of lymph node (χ(2)(EphA7) = 5.15, χ(2)(MTDH) = 5.86; P < 0.05) and cases with invasiveness of regional tissues (χ(2)(EphA7) = 7.06, P < 0.01; χ(2)(MTDH) = 4.13; P < 0.05) in gallbladder adenocarcinoma (P < 0.05). The high consistency was found between the expressive levels of EphA7 and MTDH in gallbladder adenocarcinoma (χ(2) = 13.11, P < 0.01). The univariate Kaplan-Meier analysis showed that the increased expression of EphA7 (P = 0.023) and MTDH (P = 0.034) was negatively associated with the overall survival. The multivariate Cox regression analysis showed that increased expression of EphA7 and/or MTDH (P(EphA2) = 0.023, P(MTDH) = 0.034) was an independent poor-prognostic predictor for gallbladder adenocarcinoma.

CONCLUSIONSThe expression of EphA7 and/or MTDH might be closely related to the carcinogenesis, progression, clinical biological behaviors and prognosis of gallbladder adenocarcinoma. The positive expression of EphA7 and/or MTDH may predict bad-prognosis in gallbladder adenocarcinoma.

Adult ; Aged ; Cell Adhesion Molecules ; metabolism ; Cholecystitis ; metabolism ; pathology ; Female ; Follow-Up Studies ; Gallbladder ; metabolism ; pathology ; Gallbladder Diseases ; metabolism ; pathology ; Gallbladder Neoplasms ; metabolism ; pathology ; Humans ; Male ; Middle Aged ; Polyps ; metabolism ; pathology ; Prognosis ; Receptor, EphA7 ; metabolism

Carcinoma ; metabolism ; Cell Differentiation ; genetics ; Gallbladder Neoplasms ; genetics ; metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Kangai-1 Protein ; genetics ; metabolism ; NM23 Nucleoside Diphosphate Kinases ; genetics ; metabolism

Gastrointestinal stromal tumors (GISTs) of the gallbladder are representative of an extremely rare group of tumors. We have encountered a patient with a malignant GIST of the gallbladder and presented it with a review of some articles. A 72-yr-old woman initially presented with right upper quadrant abdominal pain, fever and chills. Emergency cholecystectomy was performed under the impression of gallbladder empyema. Liver metastasis was found at 7 months postoperatively and the patient expired 9 months after the surgery. At the time of cholecystectomy, the gallbladder showed a necrotic serosal surface with an irregular thickened wall. A mass, 6 cm in length and 3 cm in width, encircled the whole wall of the neck and upper body of the gallbladder. Microscopic findings revealed frequent mitotic figures (more than 20/50 HPF) and tumor necrosis. Hyperchromatic, pleomorphic and spindle shaped neoplastic cells that were arranged in a pattern of short fascicles infiltrated the entire layer of the gallbladder. The tumor cells were immunoreactive for CD117 antigen (c-kit protein) and vimentin. They were negative for desmin, smooth muscle actin and S-100 protein. Mutations of the c-kit proto-oncogene were not found in this case. These findings were sufficient to provide enough clinical, histopathological and immunohistochemicalevidence in diagnosing our case as a malignant GIST.
Aged ; Female ; Gallbladder Neoplasms/genetics/metabolism/*pathology ; Gastrointestinal Stromal Tumors/genetics/metabolism/*pathology ; Humans ; Proto-Oncogene Protein c-kit/genetics/metabolism

BACKGROUNDCurrently, all frequently used staging systems in gallbladder cancer (GBC) are based on postoperative pathological examinations. In patients undergoing curative operation, there is no effective method to predict survival preoperatively. In this study, we explored whether a combined utilization of two tumor biomarkers, namely carbohydrate antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), could give a preoperative prediction of survival in resectable GBC.

METHODSSeventy-three patients who underwent radical resection for GBC were included in this study. A retrospective analysis of clinical-pathological data was conducted.

RESULTSBy multivariate analysis, CA 19-9 elevation (P < 0.05) and CEA elevation (P < 0.001) were discovered as two individual factors for postoperative survival. By a combined utilization, patients were divided into three groups: patients with elevation of CEA (group I), patients with elevation of CA 19-9 but without CEA (group II), and patients with nonelevations of either CA 19-9 or CEA (group III). The cumulative 5-year survival rates in groups I, II, and III were 0, 14.0%, and 42.8%, respectively (P < 0.05).

CONCLUSIONSBy a combined utilization of CA 19-9 and CEA, individualized prediction of survival is available in resectable GBC before operation. Extended radical operation brings the most prognostic benefits in patients with nonelevations of either CA 19-9 or CEA. However, if operation would be in a larger-scale destructive manner, careful consideration of surgical decisions should be made in patients with elevation of tumor biomarkers, especially CEA.

Adult ; Aged ; Aged, 80 and over ; CA-19-9 Antigen ; metabolism ; Carcinoembryonic Antigen ; metabolism ; Female ; Gallbladder Neoplasms ; metabolism ; mortality ; Humans ; Male ; Middle Aged ; Multivariate Analysis ; Retrospective Studies

OBJECTIVETo study the expression levels of ANXA1 and ANXA2 and elucidate their clinicopathological significance in adenocarcinoma, peritumoral tissues, adenomatous polyp and chronic cholecystitis of gallbladder.

METHODSEnVision(TM) immunohistochemical staining was used to detect the expression of ANXA1 and ANXA2 in paraffin-embedded tissue sections from resected specimens of adenocarcinoma (n = 108), peritumoral tissue (n = 46), adenomatous polyp (n = 15) and chronic cholecystitis (n = 35).

RESULTSThe positive rates and scores of ANXA1 and ANXA2 were significantly higher in adenocarcinoma (59.3%, 56.5%; 3.2 ± 0.9, 3.4 ± 0.8) than those in peritumoral tissues (34.8%, 1.1 ± 0.8, P < 0.01; 30.4%, 1.0 ± 0.8, P < 0.01), adenomatous polyp (26.7%, 0.9 ± 0.7, P < 0.05 or P < 0.01; 26.7%, 0.9 ± 0.8, P < 0.05 or P < 0.01) and chronic cholecystitis (17.1%, 0.7 ± 0.9, P < 0.01; 20.0%, 0.8 ± 0.8, P < 0.01). The benign lesions with positive ANXA1 and/or ANXA2 expression showed mild to severe atypical hyperplasia of the gallbladder epithelium. The positive rates of ANXA1 and/or ANXA2 were significantly lower in the well-differentiated adenocarcinoma, in a maximal diameter of < 2 cm, with no metastasis to lymph nodes and no invasion to surrounding tissues than those in the moderately or poorly-differentiated adenocarcinoma, in a maximal diameter of ≥ 2 cm, with metastasis to lymph nodes and invasion in surrounding tissues (P < 0.05 or P < 0.01). A high consistence was found between the expression levels of ANXA1 and ANXA2 (χ(2) = 67.84, P < 0.01), and a close positive correlation between the scores of ANXA1 and ANXA2 (r = 0.78, P < 0.01) in gallbladder adenocarcinoma. Kaplan-Meier analysis and multivariate Cox regression analysis showed that ANXA1 or ANXA2 was not an independent prognostic predictor in gallbladder adenocarcinoma.

CONCLUSIONThe expression levels of ANXA1 and/or ANXA2 may be important biological markers in the carcinogenesis, progression and biological behaviors of gallbladder adenocarcinoma.

Adenocarcinoma ; metabolism ; pathology ; surgery ; Adenocarcinoma, Mucinous ; metabolism ; pathology ; surgery ; Adenomatous Polyps ; metabolism ; pathology ; Adult ; Aged ; Annexin A1 ; metabolism ; Annexin A2 ; metabolism ; Cholecystectomy ; methods ; Cholecystitis ; metabolism ; pathology ; Female ; Gallbladder ; metabolism ; pathology ; Gallbladder Neoplasms ; metabolism ; pathology ; surgery ; Humans ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Invasiveness ; Proportional Hazards Models ; Survival Rate

The etiology of biliary tract cancer is obscure, but there are evidences that bile acid plays a role in carcinogenesis. To find the association between biliary tract cancer and bile acid, this study compared the bile acid concentration and composition among patients with biliary cancer, biliary tract stones, and no biliary disease. Bile was compared among patients with biliary tract cancer (n = 26), biliary tract stones (n = 29), and disease free controls (n = 9). Samples were obtained by percutaneous transhepatic biliary drainage, endoscopic nasobiliary drainage, or gallbladder puncture, and analyzed for cholic, deoxycholic, chenodeoxycholic, lithocholic, and ursodeoxycholic acid composition. Total bile acid concentration was lower in the cancer group than the biliary stone and control groups; the proportions of deoxycholic (2.2% vs. 10.2% and 23.6%, p < 0.001 and p < 0.001, respectively) and lithocholic acid (0.3% vs. 0.6% and 1.0%, p = 0.065 and p < 0.001, respectively) were also lower. This result was similar when disease site was limited to bile duct or gallbladder. Analysis of cases with bilirubin < or = 2.0 mg/dL also showed lower total bile acid concentration and deoxycholic acid composition in the cancer group compared to controls (5.7% vs. 23.6%, p = 0.003). Although the presence of bile duct obstruction explains some of the difference in total concentration and composition of bile acid, there are other contributing mechanisms. We suspect the alteration of bile acid transport might decrease bile acid excretion and cause the accumulation of carcinogenic bile acid in bile duct epithelium.
Tumor Markers, Biological/analysis ; Middle Aged ; Male ; Humans ; Gallbladder Neoplasms/metabolism ; Female ; Cholic Acids/*analysis/metabolism ; Cholelithiasis/metabolism ; Biliary Tract Neoplasms/*chemistry/metabolism ; Aged, 80 and over ; Aged ; Adult ; Adolescent

The etiology of biliary tract cancer is obscure, but there are evidences that bile acid plays a role in carcinogenesis. To find the association between biliary tract cancer and bile acid, this study compared the bile acid concentration and composition among patients with biliary cancer, biliary tract stones, and no biliary disease. Bile was compared among patients with biliary tract cancer (n = 26), biliary tract stones (n = 29), and disease free controls (n = 9). Samples were obtained by percutaneous transhepatic biliary drainage, endoscopic nasobiliary drainage, or gallbladder puncture, and analyzed for cholic, deoxycholic, chenodeoxycholic, lithocholic, and ursodeoxycholic acid composition. Total bile acid concentration was lower in the cancer group than the biliary stone and control groups; the proportions of deoxycholic (2.2% vs. 10.2% and 23.6%, p < 0.001 and p < 0.001, respectively) and lithocholic acid (0.3% vs. 0.6% and 1.0%, p = 0.065 and p < 0.001, respectively) were also lower. This result was similar when disease site was limited to bile duct or gallbladder. Analysis of cases with bilirubin < or = 2.0 mg/dL also showed lower total bile acid concentration and deoxycholic acid composition in the cancer group compared to controls (5.7% vs. 23.6%, p = 0.003). Although the presence of bile duct obstruction explains some of the difference in total concentration and composition of bile acid, there are other contributing mechanisms. We suspect the alteration of bile acid transport might decrease bile acid excretion and cause the accumulation of carcinogenic bile acid in bile duct epithelium.
Tumor Markers, Biological/analysis ; Middle Aged ; Male ; Humans ; Gallbladder Neoplasms/metabolism ; Female ; Cholic Acids/*analysis/metabolism ; Cholelithiasis/metabolism ; Biliary Tract Neoplasms/*chemistry/metabolism ; Aged, 80 and over ; Aged ; Adult ; Adolescent

Antigens ; immunology ; Antigens, Neoplasm ; drug effects ; immunology ; metabolism ; Gallbladder Neoplasms ; immunology ; metabolism ; pathology ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Neoplastic Stem Cells ; immunology ; Octamer Transcription Factor-3 ; genetics ; metabolism ; Prostatic Neoplasms ; genetics ; metabolism ; pathology ; Tumor Cells, Cultured