Primary Gallbladder Carcinoma Research Articles

Potential Therapeutic Targets for the Primary Gallbladder Carcinoma: Estrogen Receptors

Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, ERα, ERβ and ERγ. ERα and ERβ appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma.

Gallbladder carcinoma in a pregnant patient with Crohn's disease complicated with gallbladder involvement

Primary gallbladder (GB) carcinoma and Crohn's disease (CD) of the GB are individually rare. We present a case of a pregnant woman with CD found to have GB involvement and primary GB carcinoma. A 34-year-old female at 6 wk gestation with a 21 year history of CD of uncertain extent presented with 3 mo of diarrhea, urgency and abdominal pain. During work-up, she was found to have elevated transaminases and an abnormal alkaline phosphatase. Imaging revealed two gallbladder polyps both greater than 1 cm in size. Resection and histological evaluation was consistent with Crohn's involvement of the GB, poorly differentiated adenocarcinoma of the GB with invasion through the muscularis propria and matted lymph nodes in the porta hepatis positive for metastatic carcinoma (stage pT2N1). Six cases of CD involving the GB, two cases of primary GB carcinoma in CD, and ten cases of cholangiocarcinoma in pregnancy have been published. This is the only case that describes all three factors. Common features in CD of the GB include acute cholecystitis, ileal involvement, and presence independent of active intestinal disease. Common features in CD patients with GB malignancy include younger age of detection, a long history of CD, extensive colonic and ileal involvement of disease, the absence of cholelithiasis, and pre-existing gallbladder disease (primary sclerosing cholangitis and gallbladder polyps). Pregnancy is specific to this case. The role of CD in the development of GB malignancy is not well understood nor is the contribution of pregnancy to the spread of disease. Chronic inflammation and immunosuppression compounded by hormonal influence is implicated.

Expression of Multidrug Resistance-Associated Protein 2 in Human Gallbladder Carcinoma

Gallbladder carcinoma (GBCA) is one of the most aggressive malignancies. It is usually diagnosed at an advanced stage, and prognosis remains poor despite advances in imaging techniques and aggressive surgical treatment. Overexpression of multidrug resistance-associated proteins (MRPs) in tumor cells is a major cause of the intrinsic multidrug resistance phenotype. Despite the documented importance of MRP expression in many carcinomas, the prognostic significance of MRP2 expression in primary GBCA is not known. Immunostaining for MRP2 was performed on tissue samples obtained from 143 patients with GBCA. We examined the association between MRP expression and clinicopathological characteristics and outcome of patients with GBCA. GBCA demonstrated MRP2 immunoreactivity in the apicolateral membranes of epithelial cells. MRP2 expression was positive in 53.1% (76/143) of GBCA samples. Positive MRP2 expression was significantly associated with the presence of local recurrence (P = 0.038), lymphatic invasion (P = 0.038), vascular invasion (P = 0.023), and perineural invasion (P = 0.006). In addition, the median survival time of patients with MRP2-positive GBCA (15 months) was significantly shorter than that of patients with MRP2-negative GBCA (85 months, P = 0.011). We found that the expression of MRP2 in GBCA contributed to aggressive tumor behavior and poor prognosis, suggesting that MRP2 expression can be used as a potential prognostic biomarker of GBCA.

Overexpression of Histone Deacetylase 2 Predicts Unfavorable Prognosis in Human Gallbladder Carcinoma

As important regulators of chromatin, histone deacetylases (HDACs) are involved in silencing tumor suppressor genes. HDAC2, a member of HDACs, has been demonstrated to be implicated in the development and progression of various human malignancies; however, its expression and role in human primary gallbladder carcinoma (PGC) are not fully understood. Therefore, we conducted this study to address this problem. The subjects were 136 patients underwent resection for PGC. Immunostainings for HDAC2 were performed on these archival tissues. The correlation of HDAC2 expression with clinicopathological characteristics including survival was analyzed. HDAC2 was positively expressed in the nucleus of tumor cells in 86.0% (117/136) of PGC but not in the normal epithelium of the gallbladder. Additionally, there was a significant difference in the incidence of positive nodal metastasis between high and low HDAC2 expression groups (P = 0.001). The incidences of advanced clinical stage (P = 0.005) and pathologic T stage (P < 0.001), and higher histologic grade (P < 0.001) were respectively higher in the high HDAC2 expression group than in the low group. Moreover, univariate and multivariate analyses revealed the high HDAC2 expression to be an independent prognostic factor for both overall and disease-free survival of patients with PGC. High HDAC2 expression was correlated with a high incidence of lymph node metastasis and aggressive tumor progression of PGC. It also was an independent prognostic factor for poorer overall and disease-free survival in patients. Therefore, detection of HDAC2 expression may help us screen patients at increased risk of malignant behavior for PGC.

Primary Gallbladder Carcinoma in a Pregnant Patient with Crohnʼs Disease Complicated with Gallbladder Involvement

Purpose: Primary gallbladder (GB) carcinoma and Crohn's disease (CD) of the GB are individually rare. We present a case of a pregnant woman with CD found to have GB involvement and primary GB carcinoma. Case: A 34-year-old female at 6 weeks gestation with a 21 year history of CD of uncertain extent presented with 3 months of diarrhea, urgency, and abdominal pain. Her disease had been indolent for the majority of her life. She was adherent to her medications, mesalamine and mercaptopurine, as needed at times of symptoms. Sigmoidoscopy showed mild patchy colitis of the descending and sigmoid colon with rectal sparing. Pathology showed moderately active chronic colitis with crypt distortion and cryptitis without granuloma. She was started on oral and topical mesalamine. Initial labs included abnormal alkaline phosphatase 515 U/L, AST 96 U/L, and ALT 181 U/L. Further labs included a negative anti-mitochondrial antibody (AB), anti-smooth muscle AB, celiac and viral hepatitis serologies and anti-nuclear AB. A non-contrast MRCP was obtained revealing two hypointense smooth margined masses with small stalks in the neck and fundus of the GB, 1.4 × 1.8 cm and 1.4 × 2.3 cm, respectively. No GB wall thickening, cholilithiasis, ductal dilation, strictures, or liver parenchymal abnormalities were present. Laparoscopic cholecystecomy was performed at 18 wks gestation. Histology revealed a poorly differentiated adenocarcinoma of the GB with invasion through the muscularis propria and an adjacent tubulovillous adenoma with highgrade dysplasia without nodal involvement (stage pT2N0). Additionally, there was widespread epithelial dysplasia in the gallbladder with acute superficial inflammation, transmural chronic inflammation with numerous plasma cells and one granuloma consistent with CD. Muscularis propria invasion prompted partial liver resection and portal lymphadenectomy, revealing matted lymph nodes in the porta hepatis positive for metastatic carcinoma (stage pT2N1). Liver tissue was negative for primary sclerosing cholangitis. Conclusion: Seven cases of CD involving the GB and 3 cases of primary GB carcinoma in CD have been published. This is the only case that describes both. Common features in CD of the GB include acute cholecystitis, ileal involvement, and presence independent of active intestinal disease. Common features in CD patients with GB malignancy include younger age of detection, a long history of CD, extensive colonic and ileal involvement, and absence of cholelithiasis. Adnomatous GB polyps and pregnancy is specific to this case. The role of CD in the development of GB malignancy is not well understood; however, longstanding immunosuppression is implicated.

Primary Gallbladder Carcinoma in a Patient with Ulcerative Colitis and Primary Sclerosing Cholangitis (PSC)

Case: 46-year-old male with history of ulcerative colitis (UC) diagnosed 28 years ago presented to clinic with three days of abdominal pain, diffuse pruritis and found to have mild jaundice on exam. Initial blood work demonstrated abnormal liver function tests in a mixed cholestatic/hepatotoxic pattern prompting hospital admission. Magnetic resonance cholangiopancreatography showed abrupt narrowing of proximal common bile duct (CBD) with severe dilatation of intra-hepatic bile ducts, suggestive of primary sclerosing cholangitis (PSC). Endoscopic retrograde cholangiopancreatography showed a dominant biliary stricture in the CBD as well as dilatation of proximal CBD and left and right main hepatic ducts. The stricture was treated with dilation and stent placement. CBD brush biopsy results were positive for adenocarcinoma. The patient then underwent a resection of CBD, gallbladder as well as liver biopsy and reconstruction of hepatic ducts. Final pathology revealed poorly differentiated primary gallbladder adenocarcinoma with local tumor extension as well as portal inflammation and fibrosis, consistent with PSC. The patient completed four cycles of chemotherapy and radiation with subsequent re-staging imaging showing no recurrence of disease with normal tumor markers one year after diagnosis. Discussion: PSC is a chronic cholestatic disorder of unclear etiology involving both the intra- and extra-hepatic bile ducts with histology most prominently showing fibrotic and inflammatory changes. Up to 90% of PSC cases are associated with inflammatory bowel disease (IBD), of these 87% have UC. The majority of PSC patients have extensive intestinal and hepatobiliary inflammation that may promote carcinogenesis and are at a high risk for developing hepatobiliary and intestinal neoplasms, mainly cholangiocarcinoma, whereas gallbladder carcinoma (GBC) is rarely reported. The present case demonstrates that prompt recognition of alarming symptoms and aggressive workup led to cancer-free survival despite the diagnosis of GBC, which typically has a very poor prognosis. Therefore, high level of suspicion and attention should be applied to IBD and PSC patients who present with acute signs of possible hepatobiliary pathology as it could represent early signs of hepatobiliary carcinoma.Figure: MRCP showing narrowing of proximal CBD with dilatation of intra-hepatic bile ducts.

Primary gallbladder carcinoma presenting as advanced-stage ovarian cancer

Primary gallbladder carcinomas are rare and the prognosisis very poor. The incidence is 1e2% of all gastro-intestinal(GI) tract cancers [1]. Information on ovarian metastasis ofprimary gallbladder cancer is limited [2e13], partly becauseprimary gallbladder cancers are rare, and partly becausemetastases from primary gallbladder cancer are mediatedthrough either lymphatic or hematogenous routes. Sinceprimary gallbladder cancers are mucinous tumors, there areproblems with the differential diagnosis if mucinous ovariancarcinomas are found. Furthermore, primary or secondaryovarian mucinous tumors may present similar clinical symp-toms, for example, non-specific GI symptoms or signs, andsimilar findings on imaging studies or tumor marker surveys.Before and during an operation, an accurate diagnosis some-times cannot be made [14]. Herein, we present a case ofsecondary ovarian mucinous cancer emanating from primarygallbladder mucinous carcinoma.An 84-year-old woman was sent to the emergency roombecause of diffuse abdominal pain and poor appetite. Clinicalexamination showed an acutely ill-looking woman withapparent peritoneal signs (diffuse tenderness and reboundingpain) associated with a lower abdominal mass. Ultrasoundshowed a 15-cm complex cystic mass in the right adnexa, butthe uterus and the left ovary were normal. Computed tomog-raphy further identified this 15-cm ill-defined right adnexalheterogeneous mass with diffuse peritoneal seeding andcarcinomatosis. Serum tumor markers, including CA 125, CA153, CA 199, and CEA were 327.3 U/mL, 29.0 U/mL, 218.0U/mL, and 85.8 ng/mL, respectively. The other hematologicaland biochemical tests were normal. Upper and lower gastro-intestinal tract evaluations were negative.Under the diagnosis of ovarian cancer, an exploratorylaparotomy was done. A complex cystic right ovarian masswith a mucinous component was found, as well as diffusecarcinomatosis involving the entire lower and upper abdom-inal cavity, including the omentum, in which the inflamedgallbladder was embedded. Frozen section of the removedovarian tumor favored the diagnosis of primary ovariancarcinoma, mucinous type. The patient underwent a subop-timal debulking surgery, including total hysterectomy, bilateralsalpingo-oophorectomy, omentectomy, and retroperitoneallymph node sampling, and multiple biopsies. The finalpathology was primary gallbladder mucinous carcinoma.Microscopic features showed hyperchromatic dysplasia ofthe mucinous glandular cells of the gallbladder; the mucinoustumor occupied the entire cavity of the gallbladder. The tumorhad invaded whole layers of the gallbladder, and penetrated tothe outside serosa and the attachment of the omentum. Othersections of the right ovary, appendix, omentum, abdominalwall, mesentery, and right pelvic lymph nodes all showedtumor metastases with floating mucinous tumor cells within anextensive mucin pool.Using the American Joint Committee on Cancer (AJCC)staging for gallbladder cancer, the final diagnosis was gall-bladder cancer stage IVB (pT4NxM1). However the patientdied of disease 48 days after the operation.This case report raised the following interesting issues.First, since 15% of ovarian cancers are secondary and 7e15%

A clinical analysis on 23 patients with advanced gallbladder carcinoma

Objective To summarize the clinical features and surgical treatment experience of primary galildadder carcinoma,and to explore the effects of different procedures on the prognosis and analyze the prognostic factors.Methods The clinical data on 23 patients with gallbladder carcinoma who had been treated in our hospital from June 2006 to June 2010 were reviewed.The association of prognosis with tumor stages and surgical procedures was analyzed.Results 21 patients were followed up.The 6-month survival rate,1 -year survival rate,and 3-year survival rate were 80.95 ％,52.38％,and 28.57％.The three different survival rates were markedly increased in the radical treatment group ( 100.00％,71.48％,and 42.85％ ),as compared with the non-radical group ( P＜ 0.05 ).Conclusions Standard radical surgery for advanced gallbladder carcinoma can significantly improve survival rate. Key words: Primary gallbladder carcinoma; Diagnosis; Treatment

Decreased expression of chromodomain helicase DNA-binding protein 5 is an unfavorable prognostic marker in patients with primary gallbladder carcinoma

Chromodomain helicase DNA-binding protein 5 (CHD5) plays a role in normal neural development and in tumorigenesis of various human cancers. However, its role in primary gallbladder carcinoma (PGC) is still unclear. The aim of this study was to investigate CHD5 expression in PGC and its clinical significance. CHD5 mRNA and protein expression in 120 PGC and 20 normal gallbladder specimens was determined by quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and Western blotting analysis, respectively. The expression levels of CHD5 mRNA and protein in PGC tissues were both significantly lower than those in the normal epithelium of the gallbladder (mRNA: P = 0.006; protein: P = 0.01). CHD5 mRNA expression was closely correlated with its protein expression (r = 0.8; P < 0.001). Additionally, the low expression of CHD5 protein was significantly associated with high pathologic T stage (P = 0.01) and clinical stage (P = 0.008), and advanced histologic grade (P = 0.009). The expression levels of CHD5 protein in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Survival analysis showed that low CHD5 expression was associated with shorter disease-free (P = 0.01) and overall survival (P = 0.008) compared to those with high CHD5 expression in PGC patients. Furthermore, multivariate analyses showed that the decreased expression of CHD5 was an independent prognostic marker for both unfavorable disease-free (P = 0.01) and overall survival (P = 0.006). CHD5 may be involved in carcinogenesis of PGC and its down-regulation may be significantly correlated with unfavorable clinicopathologic features including poor overall and disease-free survival in patients.

Expression differences of Cathepsin B and Cathepsin D in primary gallbladder cancer, gallbladder adenomatous polyps and chronic cholecystitis

Objective To investigate the expression of cathepsin B (CatB) and cathepsin D (CatD) in primary gallbladder carcinoma,adenomatoid polyp without malignant transformation,and chronic cholecystitis tissues and to assess their mutual correlation ships as well as the relationships between their expressions and clinical pathological features.Methods Detected the expressions of CatB and CatD in gallbladder tissues including 32 specimens of primary gallbladder carcinoma,10 specimens of adenomatoid polyp without malignant transformation and 10 specimens of chronic cholecystitis by immunohistochemical method.The expressions were assessed by semi-quantitative analysis.Results The positive rate of CatB,CatD and CCL20 in primary gallbladder carcinoma was 93.75％ (30/32) and 90.63％ (29/32) respectively,being significantly higher than those in adenomatoid polyp without malignant transformation (60％and 60％,P ＜0.05) and chronic cholecystitis groups (60％ and 50％ P ＜0.05).The expression levels of CatB and CatD were not significantly related to the clinical features including age and gender,or pathological features including grades of cell differentiation,pathological types and Nevin stages ( P ＞ 0.05 ).CatB and CatD had significantly positive correlations ( r =0.434,P ＜ 0.05 ).Conclusion ( 1 ) CatB and CatD CCL20 might serve as the histological marker of primary gallbladder carcinoma.(2) The expression levels of CatB and CatD in primary gallbladder carcinoma are not related to the clinical or pathological features.(3) There is positive correlation between the expression levels of CatB and CatD in primary gallbladder carcinoma. Key words: Primary gallbladder carcinoma; Cathepsin B; Cathepsin D; Immunohistochemistry

Gallbladder carcinoma in the elderly: a report of 48 patients

Objective To review the diagnosis and treatment of primary gallbladder carcinoma in patients older than 70 years.Method The clinical data of 48 patients older than 70 years with primary gallbladder carcinoma treated in our hospital from 2003 to 2010 were retrospectively analyzed.Results The preoperative diagnostic rate was 60.4％.Of 48 patients with primary gallbladder carcinoma,9 received cholecystectomy,18 radical resection,7 extended radical resection,8 palliative operation,while the remaining 6 received biopsy because of metastasis. The 3-year survival rate was 20.8％ and the 5-year survival rate was 8.3％.Conclusions Regular B-ultrasonography,CT-scan and MRI are suggested for elderly patients with chronic diseases of the gallbladder.Radical resection is recommended if clinically possible. Chinese traditional medicine given postoperatively improved the prognosis. Key words: Aged patients; Primary carcinoma of gallbladder; Diagnosis; Surgical treatment

Indoleamine 2,3-dioxygenase and forkhead boxP3 on immune tolerance of gallbladder carcinoma cells

Objective To investigate the expressions of indoleamine 2,3-dioxygenase (IDO) and transcription factor forkhead box P3(FOXP3)in gallbladder adenocarcinoma; and to evaluate the relationship between the expressions of IDO and FOXP3 protein,and clinicopathology and lymph node metastasis of gallbladder carcinoma.Methods The expressions of IDO and FOXP3 in 51 cases of primary gallbladder cancer,90 cases of chronic cholecystitis,and 20 cases of normal gallbladder tissues were studied by immunohistochemical staining. Results The positive expression rates of IDO and FOXP3 in gallbladder carcinoma were 72.5％ (37/51) and 60.8％ (31/51),in normal gallbladder mucosa were 5％ (1/20) and 20.0％ (4/20),in cholecystitis and gallstone were 11.1％ (10/90) and 32.2％ (29/90),respectively.There were significant differences among the three groups in IDO and FOXP3 expressions (P＜0.01).The positive expression rates of IDO and FOXP3 were 7.1％ and 14.3％ for simple hyperplasia,17.7％ and 35.3％ for atypical hyperplasia,40％ and 35％ for gallbladder carcinoma (stages Ⅰ-Ⅲ),and 77.4％ and 64.5％ for gallbladder carcinoma (stages Ⅳ-Ⅴ ).There were significant differences among the four groups in IDO and FOXP3 expressions (P＜0.01).There were significant differences among the Nevin stage groups,lymph node metastasis group and gallbladder stone in IDO and FOXP3 expressions.However,there were no significant differences among the sex groups and the age groups in IDO and FOXP3 expressions (P＞0.05).In gallbladder carcinoma,the expression of IDO had a positive correlation with FOXP3 expression in lymphocyte (γ=0.406,P=0.003).Conclusion In gallbladder cancer,a high-expression of IDO and an expression of FOXP3 in lymphocyte are closely related with immune tolerance of gallbladder carcinoma.The results provide a reference for clinical use of immunotherapy in gallbladder cancer. Key words: Primary gallbladder carcinoma; Indoleamine 2,3-dioxygenase; Forkhead box P3

Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma

AimSOX4, as a member of the SRY-related HMG-box (SOX) transcription factor family, has been demonstrated to be involved in tumorigenesis of many human malignancies; however, its role in primary gallbladder carcinoma (PGC) is still largely unknown. The aim of this study was to investigate SOX4 expression in PGC and its prognostic significance.MethodsFrom 1997 to 2006, 136 patients underwent resection for PGC. The median follow-up was 12.8 months. Immunostainings for SOX4 were performed on these archival tissues. The correlation of SOX4 expression with clinicopathological features including survival was analyzed.ResultsSOX4 was expressed in 75.0% (102/136) of PGC but not in the normal epithelium of the gallbladder. In addition, the over-expression of SOX4 was significantly associated with low histologic grade (P = 0.02), low pathologic T stage (P = 0.02), and early clinical stage (P = 0.03). The levels of SOX4 immunostainings in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01). Moreover, Kaplan-Meier curves showed that SOX4 over-expression was significantly related to better overall (P = 0.008) and disease-free survival (P = 0.01). Furthermore, multivariate analyses showed that SOX4 expression was an independent risk factor for both overall (P = 0.03, hazard ratio, 3.682) and disease-free survival (P = 0.04, hazard ratio, 2.215).ConclusionOur data indicate for the first time that the over-expression of SOX4 in PGC was significantly correlated with favorable clinicopathologic features and was an independent prognostic factor for better overall and disease-free survival in patients. Therefore, SOX4 might be an auxiliary parameter for predicting malignant behavior for PGC.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1534825818694957.

The impact of routine histopathological examination on cholecystectomy specimens from an Asian demographic.

Most gallbladder carcinoma cases are suspected pre-operatively or intra-operatively. In Malaysia histopathological examination of cholecystectomy specimens has become routine practice. The aim of this study was to assess the impact of routine histological examinations on cholecystectomy specimens from an Asian demographic, which may differ from a Caucasian demographic. A retrospective study was performed of all histopathology reports for cholecystectomies (laparoscopic and open) undertaken over a period of 12 years (1997-2008) in a single teaching hospital. A total of 1,375 gallbladder specimens were sent for histopathological analysis, with 7 (0.5%) being reported as malignant while only three (0.2%) were found to contain primary gallbladder carcinoma. Other premalignant findings included two specimens with dysplastic changes of the mucosa and one tubulovillous adenoma with a dysplastic epithelium. From the ten malignant and premalignant specimens, seven were diagnosed pre-operatively, two were suspected intra-operatively and one was diagnosed with dysplastic changes on the histopathology report post-operatively. This study supports earlier research carried out in the UK and the demographic difference does not affect the impact of the histology examination on cholecystectomy specimens in diagnosing this disease. A selective policy is recommended in Malaysia.

Prognosis and Management for Gallbladder Cancer with Hepatic Invasion: Long-term Results of 139 Patients from a Single Center in China

To improve the diagnosis of primary gallbladder carcinoma (GBC) with/without hepatic metastases by analyzing our experience of different GBC treatment in our patients. A retrospective study was carried out to analyze the clinical data of the 139 patients with GBC who underwent hepatic resection in our unit from January 2003 to December 2007. Patients were divided into two groups according to whether they demonstrated hepatic invasion. Tumor presentation, surgical modes, and prognosis of each patient were retrospectively reviewed. Kaplan-Meier curves and log-rank tests were employed to compare the survival rates of those patients undergoing different surgical procedures. Of the 139 patients, 46 were men and 93 were women with the male to female ratio of 1:2.0. Their ages were ranged from 35 to 86 years with a mean age of 62.8±10.4 years. There were 73 patients complicated with hepatic invasion (group A), and no hepatic invasion occurred in the other 66 patients (group B). Compared with the group B, the patients with hepatic invasion suffered lower differentiation of tumor (p=0.000), more advanced Nevin staging (p=0.008) and poorer prognosis (p=0.013). Radical resection were more frequently performed in group B (75.76%) than in group A (45.20%) with better outcomes (p=0.000). GBC patients complicated with hepatic invasion had poorer prognosis than those without invasion in long-term follow-ups. Radical resection might result in a satisfied prognosis in patients without hepatic invasion, but appears less favorable than palliative resection in those who were complicated with hepatic invasion.

Overexpression of HIF-1α in primary gallbladder carcinoma and its relation to vasculogenic mimicry and unfavourable prognosis

As a novel mode of tumor neovascularization, vasculogenic mimicry (VM) has been reported to increase tumor-related mortality in many different solid tumors. In the present study, two established human gallbladder carcinoma (GBC) cell lines (highly aggressive GBC-SD and poorly aggressive SGC-996) cultured on a three-dimensional matrix were assessed for the ability of VM channel formation under normoxic or hypoxic conditions. In addition, the relationship between HIF-1α gene expression and VM channel formation of GBC cells in vitro was measured using the small interfering RNA (siRNA) technique, western blotting and real-time reverse transcription (RT)-PCR analysis. Furthermore, H&E and CD31/periodic acid-Schiff (PAS) staining were used to observe VM in GBC tissue samples. Additionally, all seventy-one specimens with VM and non-VM were stained for hypoxia inducible factor-1 α (HIF-1α) and its correlation with clinicopathological features and prognosis was analyzed simultaneously. We found that hypoxia could induce more VM channel formation and elevated HIF-1α expression in highly aggressive GBC-SD cells. HIF-1α siRNA efficiently knocked down HIF-1α expression and GBC VM networks under either normoxic or hypoxic conditions. VM was present in human primary GBC and overexpression of HIF-1α was significantly correlated with depth of invasion and perineural involvement in the non-VM group. Moreover, VM and HIF-1α were independent factors for the overall survival of GBC patients and correlated with decreased survival. In conclusion, VM was present in human GBC. As a critical mediator in VM formation, high expression of HIF-1α was associated with VM and tumor progression in GBC patients.

Immunohistochemical evidence of the prognostic value of hedgehog pathway components in primary gallbladder carcinoma

The activation of hedgehog (Hh) pathways has been studied extensively in many malignant tumors to elucidate their clinical diagnostic and prognostic utilities. However, their roles in primary gallbladder carcinoma (GBC) remain poorly understood. This study was conducted to clarify the immunoreactivity and prognostic value of Hh pathway components in GBC. Levels of sonic hedgehog (Shh), its receptor, Patched (Ptch1), and its downstream transcription factor, Gli1 protein, were measured by immunohistochemistry in 93 specimens from patients with GBC. We analyzed the correlations between the expression of these factors and clinicopathological features, including prognosis. Among the 93 GBC specimens, 76 (81.7%), 70 (75.3%) and 66 (70.0%) were positive for Shh, Ptch1 and Gli1 expression, respectively. Expressions were significantly correlated with stage, lymph node metastasis, venous invasion, hepatic infiltration and lymphatic invasion (all P < 0.05). Patients with positive staining for Shh, Ptch1 and Gli1 had significantly lower survival rates than patients with negative staining. The expression patterns of Shh, Ptch1 and Gli1 were all associated with a malignant behavior risk category in GBC. To our knowledge, this is the first report to define the role of the Hh pathway in GBC. Shh, Ptch1 and Gli1 are frequently expressed in GBC and associated with poorer survival. Thus, high expressions of Shh, Ptch1 and Gli1 proteins could serve as auxiliary parameters for predicting the malignant behavior of GBC.

Sarcomatoid carcinoma of the gall bladder.

Primary gallbladder carcinoma is a malignant neoplasm with an incidence of 1.2 cases per 100 000 people each year. Its occurrence increases with age, particularly in women. It is the fifth most common cancer of the gastrointestinal tract, and the most common malignancy in the biliary tract. Adenocarcinoma is the most common type of gallbladder neoplasm whereas sarcomatoid carcinoma is rare with an incidence of less than one percent of all malignant gall bladder neoplasms. Sarcomatoid carcinomas are composed of malignant epithelial and sarcomatous components, sometimes with heterologous sarcomatous elements. In general, conservative treatments are thought to be unfavourable to the tumor. Prognosis is poor following curative resection for carcinosarcoma of the gall bladder because of recurrence as systemic metastasis of the liver and peritoneal dissemination.

Alpha-methylacyl coenzyme A racemase overexpression in gallbladder carcinoma confers an independent prognostic indicator

AimsIncreased β-oxidation of branched-chain fatty acids provides an additional metabolic advantage for cancer cells thereby enhancing tumour development and progression. Alpha-methylacyl coenzyme A racemase (AMACR) is an enzyme essential for...

Immunohistochemical Expression and Prognostic Value of CD97 and Its Ligand CD55 in Primary Gallbladder Carcinoma

Background. CD97 as a member of the EGF-TM7 family with adhesive properties plays an important role in tumor aggressiveness by binding its cellular ligand CD55, which is a complement regulatory protein expressed by cells to protect them from bystander complement attack. Previous studies have shown that CD97 and CD55 both play important roles in tumor dedifferentiation, migration, invasiveness, and metastasis. The aim of this study was to investigate CD97 and CD55 expression in primary gallbladder carcinoma (GBC) and their prognostic significance. Methods. Immunohistochemistry was used to investigate the expression of CD97 and CD55 proteins in 138 patients with GBC. Results. CD97 and CD55 were absent or only weakly expressed in the normal epithelium of the gallbladder but in 69.6% (96/138) and 65.2% (90/138) of GBC, respectively, remarkably at the invasive front of the tumors. In addition, CD97 and CD55 expressions were both significantly associated with high histologic grade (both P = 0.009), advanced pathologic T stage (P = 0.01 and 0.009, resp.) and clinical stage (both P = 0.009), and positive venous/lymphatic invasion (both P = 0.009). Multivariate analyses showed that CD97 (hazard ratio, 3.236; P = 0.02) and CD55 (hazard ratio, 3.209; P = 0.02) expressions and clinical stage (hazard ratio, 3.918; P = 0.01) were independent risk factor for overall survival. Conclusion. Our results provide convincing evidence for the first time that the expressions of CD97 and CD55 are both upregulated in human GBC. The expression levels of CD97 and CD55 in GBC were associated with the severity of the tumor. Furthermore, CD97 and CD55 expressions were independent poor prognostic factors for overall survival in patients with GBC.