Primary Gallbladder Carcinoma Research Articles

Multiple brain metastases from primary gall bladder carcinoma treated by sequential surgery, radiotherapy and chemotherapy

Abstract Gallbladder carcinoma tends to be an aggressive tumour that spreads early and leads to rapid death after diagnosis as compared to other gastrointestinal carcinomas. Brain metastasis in such patients further cuts short their

NDRG2 down-regulation and CD24 up-regulation promote tumor aggravation and poor survival in patients with gallbladder carcinoma

Recent studies have demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) may reduce the metastatic potential of breast cancer and hepatocellular carcinoma cells by regulating the expression of CD24, which is expressed in a large variety of solid tumors. The aim of this study was to clarify the clinical value of NDRG2 and CD24 expression in primary gallbladder carcinoma (GBC). One hundred and thirty GBC tissues were evaluated by immunohistochemistry for NDRG2 and CD24 expression. The associations of NDRG2 and CD24 expression with the clinicopathological characteristics and the overall survival of patients with GBC were analyzed. NDRG2 and CD24 were positively expressed in 49/130 (37.69%) and 107/130 (82.31%) of GBC tissues, respectively. In addition, the tumors with the down-regulation of NDRG2 and the up-regulation of CD24 more frequently had lymph node metastasis and lymphovascular invasion. Moreover, the tumors with the down-regulation of NDRG2 and the up-regulation of CD24 tended to show deeper invasion depth and higher TNM stage. There was a negative correlation between NDRG2 expression and CD24 expression in GBC tissues (r = -0.86, P < 0.001). The patients with NDRG2 negative expression correlated with poor prognosis of GBC (P = 0.01), as opposed to CD24 (P = 0.01). The survival rate of the patients with NDRG2-/CD24+ expression was the lowest (P < 0.001), and conjoined expression of NDRG2-/CD24+ was an independent prognostic indicator of GBC (P = 0.003). Our data suggest that NDRG2 down-regulation or CD24 up-regulation is an important feature of GBC. A combined detection of NDRG2/CD24 co-expression may benefit us in prediction of the prognosis in GBC.

Significance and expression of p-STAT3 and survivin in primary gallbladder carcinoma

Objective To detect the expression of p-STAT3 and survivin in primary gallbladder carcinoma (PGC) and explore its significance for the genesis and development of PGC.Methods The expression of p-STAT3 and survivin were determined with immunohistochemistry in samples from 45 PGC tissues and 20 chronic cholecystitis.The relationship between the expression of these proteins and various clinicopathological factors was evaluated.Results The expression rate of p-STAT3 and survivin in 45 PGC tissues was 55.6％ ( 25/45 ) and 64.4％ ( 25/45 ),respectively,which was significantly higher than those in 20chronic cholecystitis tissues 5.0％ ( 1/20),10％ ( 2/20 ) ( P ＜ 0.01 ).pSTAT3 expression was correlated with survivin ( r =0.830,P ＜0.01 ).p-STAT3 and survivin protein expression were significantly associated with histopathological grading,lymph node metastatis,nevin staging and 3-year survival rate.Conclusions p-STAT3 and survivin might play a vital role in the development of PGC.The expression of p-STAT3 or survivin was an independent prognostic factor in PGC. Key words: Gallbladder neoplasms/ME; STAT3 transcription factor/ME; Microtubule-associated proteins/ME

Clinical value of Tiam1–Rac1 signaling in primary gallbladder carcinoma

Tiam1-Rac1 signaling plays an important role in the migration, invasion and metastasis of tumor cells. The aim of the present study was to clarify the clinical value of Tiam1 and Rac1 expression in primary gallbladder carcinoma (PGC). Eighty-six PGC tissues were evaluated by immunohistochemistry for Tiam1 and Rac1 expression. The association of Tiam1 and Rac1 expression with clinicopathological characteristics and the univariate survival analysis for the influence of Tiam1 and Rac1 expression on the overall survival were analyzed. Tiam1 and Rac1 immunoreactivities were observed in 72 (83.7%) and 68 (79.1%) of the 86 PGC cases, but not in the non-neoplastic gallbladder tissues, respectively. The tumors with the positive expression of Tiam1 and Rac1 more frequently showed lymph node metastasis (P = 0.01 and 0.008), lymphovascular invasion (P = 0.009 and 0.01) and recurrence (both P = 0.01), respectively. In addition, the tumors with the positive expression of Tiam1 and Rac1 significantly tended to show deeper invasion depth (P = 0.007 and 0.005) and higher TNM stage (both P = 0.005). The Kaplan-Meier survival curves demonstrated that patients with the positive expression of Tiam1 and Rac1 had a significantly shorter survival time than those patients with their negative expression (both P = 0.01). Multivariate analysis revealed that the positive expression of Tiam1 (P = 0.02) and Rac1 (P = 0.02), as well as TNM stage (P = 0.04), to be independently associated with a poor prognosis of patients with PGC. The data from this study suggest for the first time that Tiam1 and Rac1 are frequently expressed in PGC and are associated with decreased survival of the patients. Therefore, Tiam1 and Rac1 expressions may be independent predictors for the poor prognosis in patients with PGC.

Correlation Between MMP1-PAR1 Axis and Clinical Outcome of Primary Gallbladder Carcinoma

Matrix metalloprotease-1 and protease-activated receptor-1 axis plays an important role in many cancers, with activation often associated with poor survival. The aim of the present study was to determine whether the immunohistochemical detection of matrix metalloprotease-1 and protease-activated receptor-1 could provide useful information as novel therapeutic or prognostic factors in primary gallbladder carcinoma. Eighty-six gallbladder carcinoma tissues were evaluated by immunohistochemistry for matrix metalloprotease-1 and protease-activated receptor-1 expressions. The association of matrix metalloprotease-1 and protease-activated receptor-1 expressions with clinicopathological characteristics and the univariate survival analysis for the influence of matrix metalloprotease-1 and protease-activated receptor-1 expressions on the overall survival were analyzed. Matrix metalloprotease-1 and protease-activated receptor-1 immunoreactivities were observed in 62 (72.1%) and 59 (68.6%) of the 86 gallbladder carcinoma cases, respectively. The tumors with the positive expressions of matrix metalloprotease-1 (P= 0.007) and protease-activated receptor-1 (P= 0.01) more frequently showed lymph node metastasis, respectively. In addition, the tumors with the positive expressions of matrix metalloprotease-1 and protease-activated receptor-1 tended to show a deeper invasion depth (P= 0.006 and 0.008, respectively) and more frequent lymphovascular invasion (both P= 0.01). The Kaplan-Meier survival curves demonstrated that patients with the positive expressions of matrix metalloprotease-1 and protease-activated receptor-1 had a significantly shorter survival time than those patients with their negative expression (both P= 0.02). A subset of gallbladder carcinoma cases revealed the overexpression of matrix metalloprotease-1 and protease-activated receptor-1, which was associated with a progressive pathological feature and an aggressive clinical course. Therefore, matrix metalloprotease-1 and protease-activated receptor-1 expressions may be predictors for a poor prognosis in patients with gallbladder carcinoma. This is the first report describing about the involvement of matrix metalloprotease-1 and protease-activated receptor-1 axis in gallbladder carcinoma.

Gallbladder carcinoma: clinicopathological study of 24 cases

INTRODUCTION: Despite preoperative procedures, gallbladder carcinoma is commonly detected intraoperatively or on anatomopathologic examination after cholecystectomy. OBJECTIVE: To study the clinical-morphological aspects and evolution of patients with primary gallbladder carcinoma. METHODS: We reviewed medical records and pathologic material of all patients diagnosed with gallbladder carcinoma at our institution from 1997 to 2008. RESULTS: Twenty-four cases with primary carcinoma were studied, predominantly among female patients, mean age of 61.1 years. The most common clinical symptom was upper right hypochondriac pain. Five patients were diagnosed in early stages and 19 were in advanced stages. Only seven patients were diagnosed with carcinoma preoperatively, all of them in advanced stages. As to macroscopic examination, three early cases were identified as type IIa, two type IIb and 13 advanced cases were flat and infiltrating. Histologically, there were 23 adenocarcinomas and one adenosquamous carcinoma. Simple cholecystectomy was performed in seven patients, extended cholecystectomy in four patients, cholecystectomy and omentectomy in one patient, and tumor biopsy in only two patients. The median survival rate for patients in early stages was 59 months, and for pT2, pT3 and pT4 stages were 22 months, nine months and three days, respectively. CONCLUSION: There was a prevalence of advanced neoplasias diagnosed through anatomopathological examinations with poor prognosis. Furthermore, earlier detection contributed to higher survival rate. Investigation of anatomopathologic features, specially the macroscopic patterns of gallbladder carcinoma, is essential to improve diagnostic accuracy and to provide a definite treatment.

Detection of helicobacter species related genes in mucosa and bile in the primary carcinoma of the gallbladder

Objective To investigate the relationship between helicobacter pylor (Hp) and primary carcinoma of the gallbladder (PCG), providing a theoretical basis for the treatment of PCG.Methods Mucosa and bile of gallbladder samples were collected from 18 patients with PCG (PCG group), 40 patients with chronic cholecystitis or cholelithiasis (CC group), and 20 patients with no PCG and CC (control group). 16S rDNA-based polymerase chain reaction (PCR) followed by DNA sequence analysis of the obtained PCR fragments was performed. A developed search for Hp was also carried out by PCR. Five genes specific for Hp were amplified. Results In the PCG group, 81% samples of mucosa and bile were positive for Helicobacter-specific 16S rRNA gene. The positive rate in PCG group was significantly higher than those of the CC group (50%) and the control group (20%).Of the 16S rDNA sequence of Helicobacter pylori positive samples of mucosa and bile, 52% of samples were positive in cagA, 86% were positive in 26 KDa, 48% were positive in ureA separately. The vacA and rps4 genes were never detected in any of the samples of mucosa and bile. At least one gene was positive in 93% of samples of musca and bile. The sequencing showed more than 99% homology of Helicobacter 16S rRNA in PCG and Hp groups. Conclusion A higher infection rate is present in bile and gallbladder mucosa from patients with PCG. Hp in the biliary system may be one of the risk factors for occurrence of PCG. Key words: Helicobacter pylor; Primary carcinoma of the gallbladder; Polymerase chain reaction

Relationship of CDX-2 with intestinal metaplasia and biliary tract tumor

Caudal-related homeobox transcription factor (CDX-2) is selectively localized in the fetal and adult mu-cosal epithelial nuclei of normal small and large intestines.CDX2 plays an important role in the regulation of cell proliferation and differentiation of the intestinal epithelium. Ec-topic expression of CDX-2 in the stomach, esophagus and other hollow organs might be a cause of intestinal metaplasia and adenocarcinoma. CDX-2 is expressed in both cultured and primary gallbladder carcinoma cells, and dysplasia.CDX2 is not detected in normal gallbladder and biliary tract mucosa. Ectopic CDX2 expression is an early event in gallbladder carcinogenesis. The frequency of CDX-2 expression is significantly higher in well-differentiated type than in the moderately and poorly differentiated tumors. The present study clearly showed that MUC2 expression in intestinal differentiation was dependent on the nuclear expression of CDX-2 in intraductal papillary neoplasia of the liver (IPNL)and mucinous intrahepatic cholangiocarcinoma (ICC) in the same manner as in the gastric mucosa and Barrett s esophagus. CDX-2 may also be a key factor in gallbladder carcinogenesis with intestinal differentiation and is a useful immuno-histochemical marker of intestinal differentiation in intestinal metaplasia of the gallbladder. CDX2-dependent regulation of cell proliferation may be an important factor in defining prognosis of patients with BTC. Key words: Gallbladder; Biliary tract; Intestinal metaplasia; Turner; CDX-2

Astrocyte elevated gene-1 overexpression in human primary gallbladder carcinomas: An unfavorable and independent prognostic factor

Astrocyte elevated gene-1 (AEG-1), as an HIV-1 or TNF-α-inducible transcript, is correlated with various aspects of tumor malignancy. However, the status of AEG-1 expression and its clinical significance in human gallbladder carcinoma (GBC) remains unknown. In the present study, we investigated AEG-1 expression in two GBC cell lines (GBC-SD and SGC-996) and GBC tissues by immunohistochemical, Western blot and real-time PCR analysis. We found that AEG-1 was highly expressed in GBC samples (63.4%, 26 of 41) compared with normal gallbladder mucosa (p=0.0003) and highly invasive GBC-SD cell lines at both the protein (p=0.0043) and mRNA levels (p=0.0001), and strongly correlated with differentiation degree (p=0.006), Nevin stage (p=0.0344), Ki-67 expression (p=0.0024) and liver infiltration (p=0.0332) in these patients. Multivariate analysis indicated that AEG-1 overexpression was an independent prognostic marker for GBC patients. Moreover, patients with high AEG-1 levels had shorter survival time (p=0.008). Our results suggest that the AEG-1 protein is a valuable marker of GBC progression and could be a potential therapeutic target.

Expression of N-myc downstream-regulated gene 1 in primary gallbladder carcinoma and its correlation with clinicopathological features and clinical outcome

N-myc downstream-regulated gene 1 (NDRG1), a member of the N-myc downstream-regulated gene family, is induced under a wide variety of stress and cell growth-regulatory conditions. In several cancers, recent studies have shown its association with inhibition of tumor metastasis and suggested it to be a tumor suppressor gene. However, its significance in primary gallbladder carcinoma (PGC) has not been studied. Therefore, the aim of this study was to investigate NDRG1 expression in PGC and its prognostic significance. We examined NDRG1 expression in tumor specimens from 138 patients with PGC by immunohistochemistry and analyzed the correlation between NDRG1 expression and clinicopathologic factors or survival. NDRG1 was expressed in 63.8% of PGC but not in the normal epithelium of the gallbladder, remarkably at the invasive front of the tumors. In addition, NDRG1 expression was significantly associated with high histologic grade, advanced pathologic T stage and clinical stage, positive nodal metastasis and venous/lymphatic invasion. Moreover, Kaplan-Meier curves showed that NDRG1 over-expression was significantly related to poor overall and disease-free survival (both P = 0.02). Furthermore, multivariate analyses showed that NDRG1 expression (hazard ratio, 3.338; P = 0.02) and clinical stage (hazard ratio, 3.128; P = 0.03) were independent risk factors for disease-free survival. Our data demonstrate for the first time that NDRG1 expression in PGC was significantly correlated with unfavorable clinicopathologic features and an independent poor prognostic factor for disease-free survival in patients. Taken together, our findings suggest that NDRG1 expression could be used as a novel prognostic factor for patient survival and might be a potential therapeutic target in PGC.

Synchronous primary gall bladder carcinoma and renal transitional cell carcinoma in the same patient: A rare case

Synchronous primary gall bladder carcinoma and renal transitional cell carcinoma in the same patient: A rare case

Profile of gallbladder diseases diagnosed at afyon kocatepe university: a retrospective study

Gallbladder is one of the most commonly encountered specimen in a pathology laboratory. A diverse spectrum of diseases affect the biliary system, often presenting with similar clinical signs and symptoms. We aimed to define the profile of gallbladder diseases in our region, and to determine potential correlations between histopathologic features we observed. We reviewed all cholecystectomies processed in Department of Pathology of Afyon Kocatepe University Hospital between January 2000 and March 2008. Gross and histopathologic features of the specimens were reevaluated. Among 1500 patients; 69.9% were women and 30.1% were men. We found out fourteen primary gallbladder carcinomas (0.93%) with adenocarcinomas being the most frequent type (78.57%). The rate of cholelithiasis was found as 89.9%. The most common type of gallstones was mixed cholesterol type gallstones with 67.5% followed by black pigment and brown pigment types as 23.83% and 5.89%, respectively. The association of metaplasia with dysplasia and also gallstones were statistically significant (p < 0.001, p < 0.005). The rate of the gallbladder polyps was 2.6% with the cholesterol polyps being the most common type (56.4%). Gallbladder diseases often present with similar clinical signs and symptoms and a surgical pathologist should be alert especially of precancerous lesions. With our results, we also conclude that elderly women with longstanding gallstone disease should undergo elective surgery even when no symptoms are present.

CD133+gallbladder carcinoma cells exhibit self-renewal ability and tumorigenicity

To identify cancer stem cells (CSCs) in human gallbladder carcinomas (GBCs). Primary GBC cells were cultured under serum-free conditions to produce floating spheres. The stem-cell properties of the sphere-forming cells, including self-renewal, differentiation potential, chemoresistance and tumorigenicity, were determined in vitro or in vivo. Cell surface expression of CD133 was investigated in primary tumors and in spheroid cells using flow cytometry. The sphere-colony-formation ability and tumorigenicity of CD133(+) cells were assayed. In vitro culture experiments revealed that floating spheroids were generated from primary GBC cells, and these sphere-forming cells could generate new progeny spheroids in serum-free media. Spheroid cells were differentiated under serum-containing conditions with downregulation of the stem cell markers Oct-4, Nanog, and nestin (P < 0.05). The differentiated cells showed lower spheroid-colony-formation ability than the original spheroid cells (P < 0.05). Spheroid cells were more resistant to chemotherapeutic reagents than the congenetic adherent cells (P < 0.05). Flow cytometry showed enriched CD133(+) population in sphere-forming cells (P < 0.05). CD133(+) cells possessed high colony-formation ability than the CD133(-) population (P < 0.01). CD133(+) cells injected into nude mice revealed higher tumorigenicity than their antigen-negative counterparts (P < 0.05). CD133 may be a cell surface marker for CSCs in GBC.

CD44+CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma

Cancer stem cells (CSCs)/tumor-initiating cells have been defined as a subset of tumor cells responsible for initiating and sustaining tumor development. Emerging evidence strongly supports the existence of CSCs in various solid tumors, but they have not yet been identified in human gallbladder carcinomas (GBC). In this study, we identified CSCs in primary GBC and in the cell line GBC-SD using the cell surface markers CD44 and CD133. The percentages of CD44+CD133+ cells were 1.76-3.05% in primary tumors and 40.29% in GBC-SD cells. These cells showed stem cell properties, including self-renewal, differentiation potential, and high tumorigenicity. In vitro culture experiments revealed that CD44+CD133+ GBC cells possessed a higher spheroid-colony forming ability in serum-free media than other subpopulations. When injected into nonobese diabetic/severe combined immunodeficient mice, these cells formed new tumors and generated CD44+CD133+, CD44-, and CD133- progeny. CD44+CD133+ cells also showed a high degree of chemoresistance, possibly due to upregulation of the breast cancer resistance protein (ABCG2) and the transcription factor Gli1 in these highly tumorigenic cells. These results suggest that the CD44+CD133+ population exhibited CSC-like characteristics and may thus provide a novel approach to the diagnosis and treatment of GBC.

Advancement in researches of treatment of primary gallbladder carcinoma by DCs vaccines

Primary carcinoma of the gallbladder （PCG） is the common malignant tumor in the biliary system. Because there is no specific clinical manifestation, patients diagnosed with PCG are mostlyin intermediate or advanced stages. Therefore, they lose the chance of radical resection of gallbladder carcinoma and have a poor prognosis. Radiotherapy and chemotherapy are not effective palliative measures. Immunotherapy has become an alternative strategy be sides operation, chemotherapy and radiotherapy. Treatment with DCs vaccines, as a new method of immunotherapy, has become more and more important. Here we review treatment with DCs vaccines in primary carcinoma of gallbladder. Key words: Dendritic cells; Gallbladder neoplasms; Indoleamine 2,3-dioxygenase

Diagnosis of primary gallbladder carcinoma by CT

Objective To investigates the diagnostic value of CT of the gallbladder and accuracy.Methods Clinical data of 26 patients with pathologically confirmed gallhladder were retrospectively analyzed.Results 26 patients were diagnosed with CT.CT manifestations of primary gallbladder carcinoma:papillary intraluminal mass type,limited or diffuse gallbladder wall thickening,large cystic mass in full or swallowed type.Combined with the direct signs of pathology gallbladder cancer was divided into three types:infiltrative,nodular,tumor type;Enhance a performance of CT scan of gallbladder:artery of high density,such as density of the portal vein,followed by arterial and portal vein of both high-density,higher than normal latency of the gallbladder wall and liver,regression not significant,especially gallbladder junction local thickening of the gallbladder wall continued enhanced features.Conclusion The performance of primary gallbladder was complex,and CT examination was a key means of establishing diagnosis. Key words: Gallbladder neoplasms; Tomography,X-ray computed

Expression of GRP78 in primary gallbladder carcinoma and its significance

近年来的研究发现,热休克蛋白(heat shock proteins,HSPs)在多种肿瘤组织中高表达,提示与肿瘤的发生、发展有关.本文用免疫组织化学方法检测胆囊癌组织中热休克蛋白(GRP78)的表达情况,旨在为胆囊癌的临床诊治和预后判断提供有价值的理论帮助。

Reduced expression of Raf-1 kinase inhibitory protein is a significant prognostic marker in patients with gallbladder carcinoma

Gallbladder carcinoma is one of the most aggressive malignancies. It is usually diagnosed at an advanced stage, and the prognosis remains poor despite advances in imaging techniques and aggressive surgical treatment. Because of the lack of reliable prognostic markers, the aim of this study was to investigate the prognostic significance of Raf-1 kinase inhibitory protein expression in gallbladder carcinomas. Immunostaining for Raf-1 kinase inhibitory protein was performed on chronic cholecystitis, adenoma, carcinoma in situ, and primary and nodal metastatic gallbladder carcinoma. Raf-1 kinase inhibitory protein expression was reduced in 68.8% (11/16) and 42.3% (44/104) of nodal metastatic and primary gallbladder carcinoma cases, respectively, but in no case of carcinoma in situ, adenoma, or chronic cholecystitis. The differences in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma versus nongallbladder carcinoma tissues (P < .001), and in nodal metastatic gallbladder carcinoma versus primary gallbladder carcinoma (P = .009), were statistically significant. Kaplan-Meier curves showed that patients with Raf-1 kinase inhibitory protein-negative or weakly positive gallbladder carcinoma had a significantly shorter overall survival than did patients with Raf-1 kinase inhibitory protein-positive gallbladder carcinoma (median, 14 versus 120 months; P = .011). Multivariate survival analysis showed that reduced Raf-1 kinase inhibitory protein expression was an independent prognostic predictor for overall survival (P = .020). Our results suggest that reduction in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma contributes to invasion and metastasis and is a significant prognostic marker in patients with gallbladder carcinoma.

Tumor-enhancing activity of Basigin expression in gallbladder carcinoma and its prognostic role

Basigin (EMMPRIN/CD147) is a multifunctional membrane glycoprotein that is overexpressed in many solid tumors and is involved in tumor invasion and angiogenesis. The main purpose of this study was to investigate the tumor-enhancing activity of Basigin in a gallbladder carcinoma (GC) cell line and in primary GC tissues. A system that blocks Basigin in the human primary GC cell line GBC-SD was developed using RNA interference. GBC-SD cells were transfected with the small interfering RNA that target Basigin, then the proliferative, invasive and migration activities of the cells were assayed in vitro. Additionally, tissue samples from 98 patients with GC and 26 patients with chronic cholecystitis were stained with anti-Basigin antibody for immunohistochemical analysis. Furthermore, the association of Basigin expression with the clinicopathological characteristics and prognosis of the patients was analyzed. siRNA-treated GBC-SD cells exhibited significantly decreased growth ability, invasion and migration capacities compared to control cells in vitro. Moreover, clinicopathological analysis demonstrated that the intensity of Basigin staining in cancerous tissue was significantly associated with the histological type (p=0.02), distant metastasis (p<0.01) and Nevin stage (p<0.01) of GC. A proportional hazards model revealed the survival rate of patients with stronger Basigin expression to be the lowest (p<0.01). These results suggest that Basigin is a prognostic marker and potential therapeutic target for patients with GC.

A case of hepatocellular carcinoma invading the gallbladder misdiagnosed as a primary gallbladder carcinoma

Extrahepatic metastasis of hepatocellular carcinoma (HCC) is occasionally seen in the lung, bone, adrenal gland, and lymph nodes. It is well known that HCC sometimes invades the biliary system. Since there is no peritoneum between the gallbladder and the liver fossa, a gallbladder cancer easily invades the liver; however, HCC seldom invades the gallbladder because it rarely destroys the muscle layer or the collagen fibers of the gallbladder wall. Routes of gallbladder metastasis of HCC include direct invasion, extension to the biliary system, and invasion of the adjacent hepatic vascular system. Some cases of gallbladder metastasis of HCC without direct invasion have been reported. We report here a case of HCC that directly invaded the gallbladder, and that resembled gallbladder carcinoma invading the liver.