Factor For Gallbladder Carcinoma Research Articles

New trends in diagnosis and management of gallbladder carcinoma.

Gallbladder (GB) carcinoma, although relatively rare, is the most common biliary tree cholangiocarcinoma with aggressiveness and poor prognosis. It is closely associated with cholelithiasis and long-standing large (> 3 cm) gallstones in up to 90% of cases. The other main predisposing factors for GB carcinoma include molecular factors such as mutated genes, GB wall calcification (porcelain) or mainly mucosal microcalcifications, and GB polyps ≥ 1 cm in size. Diagnosis is made by ultrasound, computed tomography (CT), and, more precisely, magnetic resonance imaging (MRI). Preoperative staging is of great importance in decision-making regarding therapeutic management. Preoperative staging is based on MRI findings, the leading technique for liver metastasis imaging, enhanced three-phase CT angiography, or magnetic resonance angiography for major vessel assessment. It is also necessary to use positron emission tomography (PET)-CT or 18F-FDG PET-MRI to more accurately detect metastases and any other occult deposits with active metabolic uptake. Staging laparoscopy may detect dissemination not otherwise found in 20%-28.6% of cases. Multimodality treatment is needed, including surgical resection, targeted therapy by biological agents according to molecular testing gene mapping, chemotherapy, radiation therapy, and immunotherapy. It is of great importance to understand the updated guidelines and current treatment options. The extent of surgical intervention depends on the disease stage, ranging from simple cholecystectomy (T1a) to extended resections and including extended cholecystectomy (T1b), with wide lymph node resection in every case or IV-V segmentectomy (T2), hepatic trisegmentectomy or major hepatectomy accompanied by hepaticojejunostomy Roux-Y, and adjacent organ resection if necessary (T3). Laparoscopic or robotic surgery shows fewer postoperative complications and equivalent oncological outcomes when compared to open surgery, but much attention must be paid to avoiding injuries. In addition to surgery, novel targeted treatment along with immunotherapy and recent improvements in radiotherapy and chemotherapy (neoadjuvant-adjuvant capecitabine, cisplatin, gemcitabine) have yielded promising results even in inoperable cases calling for palliation (T4). Thus, individualized treatment must be applied.

Aldehyde oxidase 1 promotes gallbladder carcinogenesis through ROS-mediated activation of the Wnt/β-catenin pathway

BackgroundAldehyde oxidase 1 (AOX1) is associated with various pathophysiological processes, including cancer. Specifically, AOX1 has been demonstrated to have a close relationship with the progression of certain cancers. However, the expression, function, and mechanisms of action of AOX1 in gallbladder cancer (GBC) remain unclear. MethodsUtilizing immunohistochemistry, the study quantified the prevalence of AOX1 within tissues of gallbladder carcinoma and those of the surrounding non-cancerous regions. In vitro assays using gallbladder carcinoma cell lines with modulated AOX1 expression levels were performed to assess the protein's role in cell proliferation, migration, and invasion. Furthermore, flow cytometry techniques were harnessed to determine the influence of AOX1 on the content of reactive oxygen species (ROS) in these cells. Additionally, the expression of epithelial-mesenchymal transition (EMT) markers and the Wnt/β-catenin signaling pathway markersin cells with varied AOX1 expression, detected through Western blot analyses. An in vivo xenograft model involving athymic mice was implemented to explore the influence of AOX1 on gallbladder tumor growth, with Western blot analysis applied to measure EMT marker expression in the resulting tumours. ResultsElevated AOX1 protein levels have been observed in gallbladder carcinoma tissues, with such upregulation linked to a negative prognostic outlook for patients. In vitro analyses demonstrate that enhanced AOX1 expression facilitates gallbladder carcinoma cell proliferation, migration, and invasion, while AOX1 suppression yields an inhibitory effect on these cellular behaviors. Western blot results reveal an inverse relationship between AOX1 and E-cadherin levels, yet was positively correlation with N-cadherin, Vimentin, and Snail within both gallbladder cancer cells and in vivo xenograft tumours. Further mechanistic investigation indicates that AOX1 elevation augments reactive oxygen species (ROS) production and initiates the Wnt/β-catenin signaling pathway in these cells. The application of N-acetylcysteine (NAC) and/or KY1797K attenuates the proliferative, migratory, and invasive enhancements imparted by AOX1 overexpression and reinforces these effects when AOX1 is silenced—achieved through ROS mitigation and the obstruction of the Wnt/β-catenin pathway. In vivo studies corroborate these findings, showing AOX1 overexpression to amplify xenograft tumor growth and mesenchymal marker expression, whereas AOX1 interference did the opposite. ConclusionsThe study indicates that AOX1 functions as a carcinogenic factor in gallbladder carcinoma, enhancing cell proliferation, migration, invasion, and the EMT. These effects are driven by the activation of the Wnt/β-catenin pathway mediated by reactive oxygen species (ROS). Therefore,AOX1 presents potential as a valuable prognostic and diagnostic marker as well as a target for therapeutic intervention in the gallbladder cancer.

Incidental precancerous and cancerous neoplasms in routine cholecystectomy specimens – A fascinating series of cases in a tertiary care center

Laparoscopic cholecystectomy is one of the most commonly performed surgeries for benign gall bladder pathologies. Pre-cancerous and malignant gall bladder neoplasms often have overlapping non-specific clinical manifestation in their early stages. Radiological findings are also non-specific in the early stages with the presence of cholelithiasis in a significant proportion of cases. Cholelithiasis is said to be one of the important comorbid risk factors for gall bladder carcinoma (GBC) as a source of constant irritation to biliary mucosa. In such cases, cholecystectomy done for benign indications may lead to a histopathological diagnosis of incidental gall bladder carcinomas. Pancreaticobiliary type of adenocarcinoma is the most common subtype of GBC with two described cases in this series. Invasive foci need to be ruled out in. All cases of high-grade biliary intraepithelial neoplasia as were seen in the third case. Intracholecystic papillary neoplasm is a recently described entity with one reported case in this series that was associated with invasive adenocarcinoma. Signet ring adenocarcinoma is a rarely encountered adenocarcinoma in gall bladder with worse outcome. One such case has been described here where the patient has succumbed to death within 3 months of surgery and during the course of adjuvant therapy.

Prognostic impact of postoperative infection after resection of biliary malignancy: A multicenter retrospective cohort study

BackgroundThe aim of this study was to investigate the prognostic impact of postoperative infections in patients who underwent resection for biliary malignancy, including intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, gallbladder carcinoma, and carcinoma of the ampulla of Vater. MethodsThis study was conducted in an 11-center retrospective cohort study. Patients with biliary tract cancer who underwent curative resection between April 2013 and March 2015 at 11 institutions in Japan were enrolled. We analyzed the prevalence of postoperative infection, infection-related factors, and prognostic factors. ResultsOf the total 290 cases, 33 were intrahepatic cholangiocarcinoma, 60 were perihilar cholangiocarcinoma, 120 were distal cholangiocarcinoma, 55 were gallbladder carcinoma, and 22 were carcinoma of the ampulla of Vater. Postoperative infectious complications, including remote infection, were observed in 146 patients (50.3%), and Clavien–Dindo ≥III in 115 patients (39.7%). Postoperative infections occurred more commonly in the patients who received pancreaticoduodenectomy and bile duct resection. Patients with infectious complications had a significantly poorer prognosis than those without (median overall survival 38 months vs 62 months, P = .046). In a diagnosis-specific analysis, although there was no correlation between infectious complications and overall survival in intrahepatic cholangiocarcinoma, perihilar cholangiocarcinoma, distal cholangiocarcinoma, and carcinoma of the ampulla of Vater, infectious complications were a significantly poor prognostic factor in gallbladder carcinoma (P = .031). ConclusionPostoperative infection after surgery for biliary tract cancer commonly occurred, especially in patients who underwent pancreaticoduodenectomy and bile duct resection. Postoperative infection is relatively associated with the prognosis of patients with biliary malignancy, especially gallbladder carcinoma.

Stepwise correlation of TP53 mutations from pancreaticobiliary maljunction to gallbladder carcinoma: a retrospective study

BackgroundThe genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS).MethodsWe retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status.ResultsThe most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p < 0.01).ConclusionsTP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

The Spectrum of Gallbladder Histopathology at a Tertiary Hospital in a Developing Country: A Retrospective Study.

BackgroundAffections of the gallbladder remain exceedingly ubiquitous and often warrant surgical intervention. The histopathological patterns represent a spectrum, ranging from cholecystitis to gallbladder carcinoma. The present study aims to delineate the occurrence of various gallbladder histopathologies in a tertiary care hospital in Pakistan.MethodsA retrospective study was conducted at Maroof International Hospital, Islamabad, Pakistan. Histopathological records of 442 gallbladder specimens obtained from cholecystectomy were analysed. The prevalence of various histopathological outcomes was assessed. The data were eventually analysed using the SPSS 23.0 software (Armonk, NY: IBM Corp.). Thereafter, the distribution of various gallbladder histopathologies was tabulated across gender. ResultsOf the 442 patients included, 330 were females and 112 were males, with the mean age hovering at 45.77±14.65 years. The most common histopathological findings were chronic cholecystitis and cholesterolosis, observed in 78.6% and 32.8% of the patients, respectively. While only one case of gallbladder adenocarcinoma was observed, multiple specimens divulged premalignant lesions including reactive atypia and intestinal metaplasia.ConclusionsDiseases of the gallbladder often mandate prompt surgical intervention. Of these, chronic cholecystitis, which is an established risk factor for gallbladder carcinoma, is exceedingly common. The employment of histopathological techniques remains imperative in the detection of premalignant and malignant lesions that might otherwise evade macroscopic detection and thus progress to adenocarcinoma.

Tumor-infiltrating mast cells predict prognosis and gemcitabine-based adjuvant chemotherapeutic benefit in biliary tract cancer patients

BackgroundRecent studies have reported TIMs play an important role in tumors progression or regression, but the effect of TIMs in biliary tract cancer remains unclear. The aim of this study is to investigate the prognostic value of tumor infiltrating mast cells (TIMs) and its influence on gemcitabine-based adjuvant chemotherapy (ACT) benefits in biliary tract cancer patients after surgery.MethodsTIMs were evaluated by immunohistochemical staining of tryptase in 250 patients with resected gallbladder carcinoma (GBC) or extrahepatic bile duct carcinoma (EBDC) from Zhongshan Hospital. The relationships between TIMs and clinicopathological factors and postoperative prognosis were analyzed respectively.ResultsHigh TIMs infiltration was significantly correlated with prolonged overall survival (OS). Furthermore, multivariate analysis indicated TNM stage and TIMs as independent prognostic factors for OS. Patients with high TIMs infiltration appeared to significantly benefit from Gemcitabine-based ACT in the discovery and validation cohorts. Spearman analysis identified that TIMs infiltration were positively correlated with anti-tumor CD8+ T cells.ConclusionTIMs infiltration is an independent favorable prognostic factor in GBC and EBDC patients, which could better stratify patients with different prognosis and predict benefit from gemcitabine-based ACT.

The Geographical, Ethnic Variations and Risk factors of Gallbladder Carcinoma: A Worldwide View

Gallbladder carcinoma (GBC) is the most common malignant tumor of the biliary tract throughout the world with marked ethnic and geographical variations. GBC is the highly fatal disease with poor prognosis. GBC appears to develop dysplastic mucosa that progress to carcinoma in situ and then to invasive carcinoma. The incidence of GBC varies geographically with higher rates in certain areas of Latin America (Columbia, Peru and Ecuador), North America (Hispanic and American Indian populations) Eastern Europe (Poland, the Czech Republic, Slovakia, Hungary, and the former East Germany) and Japan. Mapuche Indians of Chile show the highest incidence and mortality of GBC. In India, GBC is more common in women in the North, North-East and East compared to the Southern part, The incidence of GBC is very high in the northern cities like Uttar Pradesh, Bihar, Orissa, West Bengal and Assam (e.g. in Delhi it is 4.5 per 100,000 for men and 10.1 per 100,000 for women) compared with the southern cities (in Chennai, Mumbai, Trivandrum, and Bangalore) incidence is 1.2 per 100,000 for men and 0.9 per 100,000 in women. Cholelithiasis/gallstones are found in 65-90% of patients with GBC. Apart from gallstones and gender biasness, a number of other risk factors favor the development of GBC like obesity, reproductive factors, genetic susceptibility, ethnicity, chronic infections and inflammations and environmental exposures to specific chemicals. Elucidating such risk factors not only provides insight into its pathogenesis accounting for its geographic and ethnic variances, but more importantly should yield strategies to prevent and treat this unusual malignancy.

Presentation of gallbladder carcinoma and its surgical management

Objective:- To study the mode of presentation, age and sex distribution, socio-economic status and evaluation of various surgical methods adopted for treatment of localized and advanced gallbladder carcinoma. Design:- It was a prospective type of study. Place and duration of study: This study was conducted in the Department of Surgery Nishtar Hospital, Multan from January 2004 to June 2005. Patients and methods: Twenty five patients of all ages and both sex were taken from all surgical units. On the basis of history, examination and laboratory investigations they were suspected of having gallbladder cancer. All the patients were operated and were divided into three groups on the basis of operative findings and stage of disease. Results:- There were 4 males and 21 female with a male to female ratio of 1:5. Presenting feature in decreasing order of frequency were; pain in right hypochondrium in 88%, nausea and vomiting in 60%, weight loss in 40%, jaundice in 28%, anorexia in 28%, mass in right hypochondriu m in 24%, pruritis in 20%, fever in 12% and ascites in 4% patients. Preoperative diagnosis of carcinoma of gallbladder was possible in 12 (48%) patients with the help of ultrasound and CT scan but all were of advanced age of disease. Gall stone were the most important etiological factor in 20 (80%) patients, obesity was found in 7 (28%) and chronic typhoid infection in 2 (8%) patients. All patients were operated. Simple cholecystecytomy was done in 4 patients of stage I and II. Extended cholecystectomy done in 6 patients of stage III. Laparotomy and biopsy of the mass and/or palliative surgery for drainage of bile was done in 15 cases of stage IV and V disease. Adenocarcinoma was the most common histological type found in 22 (88%) cases. Conclusion:- Gallstone are the most important etiological factor in gall bladder carcinoma.

Neutrophil-lymphocyte ratio as a prognostic factor for gallbladder carcinoma after radical resection

Neutrophil-lymphocyte ratio as a prognostic factor for gallbladder carcinoma after radical resection

Impact of lymph node ratio as a valuable prognostic factor in gallbladder carcinoma, focusing on stage IIIB gallbladder carcinoma

PurposeIt is increasingly being recognized that the lymph node ratio (LNR) is an important prognostic factor for gallbladder carcinoma patients. The present study evaluated predictors of tumor recurrence and survival in a large, mono-institutional cohort of patients who underwent surgical resection for gallbladder carcinoma, focusing specifically on the prognostic value of lymph node (LN) status and of LNR in stage IIIB patients.MethodsBetween 2004 and 2011, 123 patients who underwent R0 radical resection for gallbladder carcinoma at the Chonnam National University Hwasun Hospital were reviewed retrospectively. Patients were staged according to the American Joint Committee on Cancer 7th edition, and prognostic factors affecting disease free survival, such as age, sex, comorbidity, body mass index, presence of preoperative symptoms, perioperative blood transfusion, postoperative complications, LN dissection, tumor size, differentiation, lymph-vascular invasion, perineural invasion, T stage, presence of LN involvement, N stage, numbers of positive LNs, LNR and implementation of adjuvant chemotherapy, were statistically analyzed.ResultsLN status was an important prognostic factor in patients undergoing curative resection for gallbladder carcinoma. The total number of LNs examined was implicated with prognosis, especially in N0 patients. LNR was a powerful predictor of disease free survival even after controlling for competing risk factors, in curative resected gallbladder cancer patients, and especially in stage IIIB patients.ConclusionLNR is confirmed as an independent prognostic factor in curative resected gallbladder cancer patients, especially in stage IIIB gallbladder carcinoma.

Edible oil adulterants, argemone oil and butter yellow, as aetiological factors for gall bladder cancer

Carcinogenic potential of argemone oil (AO) and butter yellow (BY), the adulterants encountered in edible oil, in gall bladder of Swiss albino mice was undertaken to investigate the potential aetiological factors of gall bladder carcinoma (GBC) in the Indo-Gangetic basin. Twice weekly intraperitoneal (ip) administration of AO (5ml/kg body wt) and BY (25mg/kg body wt) to Swiss albino male and female mice for 30 and 60days indicated that females were more vulnerable to these adulterants in terms of responses to inflammatory markers. Subsequent experiments with dietary exposure of AO (1%) and BY (0.06%) for 6months in female mice showed symptoms related to cachexia, jaundice and anaemia. High levels of total cholesterol, low density lipoprotein (LDL), TG, bilirubin and low level of high density lipoprotein (HDL) as well as gallstone formation was shown by AO exposure only, leading to the development of adenocarcinoma. BY exposure resulted in adenoma and hyperplasia without stone formation. The cyclooxygenase (COX-2) overexpression was found to be related to prostaglandin E2 (PGE2) production in AO treated mice but not in BY exposed animals, thereby indicating a differential pathway specific carcinogenicity. PGE2 stimulates the secretion of secreted mucins (MUC5AC), which is involved in stone formation following AO exposure. Enhanced secretion of membrane bound mucins (MUC4) in BY and AO exposed mice resulted in the activation of ErbB2 and downstream signalling such as p-AKT, p-ERK and p-JNK, which ultimately affects the target proteins, p53 and p21 leading to adenoma and adenocarcinoma, respectively. The study suggests that AO and BY are responsible for producing GBC in mice along with stone formation in the AO exposed animals.

The expression and clinical significance of Twist, E-cadherin and N-cadherin in gallbladder carcinoma by tissue microarray

Objective To explore the expression and clinical significance of Twist. E-cadherin and N-cadherin in gallbladder carcinoma. Methods From 2000 to 2008, in Zhejiang Provincial People's Hospital, the expression of Twist, E-cadherin and N-cadherin protein were detected in 79 surgically removed gallbladder carcinoma tissue specimens in paraffin blocks and 20 normal gallbladder tissue specimens by tissue microarray technique and immunohistochemistry. Results Compared with normal gallbladder tissues, the expression of Twist and N-cadherin was up-regulated in gallbladder carcinoma tissues and the positive percentage was 68.3％ and 49.4％ respectively, while which both were 1/20 in normal gallbladder tissues. The percentage of high E-cadherin expression in gallbladder carcinoma tissues was only 27.8 ％, which was significantly lower than that in normal gallbladder tissues (20/20;X2 ＝29.31, P＜0. 05). The expression of Twist was correlated with T classification, lymph node metastasis, distant organ metastasis, hepatoduodenal ligament invasion, lymphatic invasion and UICC stage of gallbladder carcinoma (P＜0.05). The expression of E-cadherin was correlated with T classification, distant organ metastasis, hepatoduodenal ligament invasion, differentiation degree and UICC stage of gallbladder carcinoma (P＜0.05). The expression of N-cadherin was only correlated with lymphatic invasion of gallbladder carcinoma (P ＜0.05 ). There was significant negative correlation between Twist and E-cadherin expression (P＜0. 01). All the 79 gallbladder carcinoma patients were followed up after the surgery, the mean follow-up time was 30.6±14.3months. The 3-year survival rates of patients with low or high Twist expressions were 66％ and 7％ respectively,there was significant difference between the two groups(P＜0. 01). The 3-year survival rates of patients with low or high E-cadherin expressions were 25 ％ and 86 ％ respectively, the difference of two groups was significant(P＜0.01). The 3-year survival rates of patients with low or high Ncadherin expressions were 39％ and 41％ respectively, there was no significant difference between the two groups(P＞0.05). The multivariate analysis indicated that the Twist expression was one of independent prognostic factors of gallbladder carcinoma. Conclusion The abnormal expression of Twist and E-cadherin was correlated with the development and progression of gallbladder carcinoma,and Twist expression was one of the independent prognostic factors of gallbladder carcinoma. Key words: Gallbladder neoplasms; Twist transcription factor; Cadherins; Prognosis; Gnen expression

6512 POSTER Stromal Cell-derived Factor-1 Alpha is a Novel Independent Poor Prognostic Factor in Gallbladder Carcinoma

6512 POSTER Stromal Cell-derived Factor-1 Alpha is a Novel Independent Poor Prognostic Factor in Gallbladder Carcinoma

L1 cell adhesion molecule as a novel independent poor prognostic factor in gallbladder carcinoma

Gallbladder carcinoma is a lethal malignancy and is hard to cure by current treatment. Thus, identification of molecular prognostic markers to predict gallbladder carcinoma as therapeutic targets is urgently needed. Recent studies have demonstrated that L1 cell adhesion molecule is associated with the prognosis of variable malignancy. Here, we investigated L1 cell adhesion molecule expression in gallbladder carcinoma and its prognostic significance. In this study, we examined L1 cell adhesion molecule expression in tumor specimens from 69 patients with gallbladder carcinoma by immunohistochemistry and analyzed the correlation between L1 cell adhesion molecule expression and clinicopathologic factors or survival. L1 cell adhesion molecule was not expressed in the normal epithelium of the gallbladder but in 63.8% of gallbladder carcinomas, remarkably at the invasive front of the tumors. In addition, L1 cell adhesion molecule expression was significantly associated with high histologic grade, advanced pathologic T stage and clinical stage, and positive venous/lymphatic invasion. Multivariate analyses showed that L1 cell adhesion molecule expression (hazard ratio, 3.503; P = .028) and clinical stage (hazard ratio, 3.091; P = .042) were independent risk factor for disease-free survival. L1 cell adhesion molecule expression in gallbladder carcinoma was significantly correlated with tumor progression and unfavorable clinicopathologic features. L1 cell adhesion molecule expression was an independent poor prognostic factor for disease-free survival in patients with gallbladder carcinoma. Taken together, our findings suggest that L1 cell adhesion molecule expression could be used as a novel prognostic factor for patient survival and might be a potential therapeutic target in gallbladder carcinomas.

Long-term results of surgical treatment in 181 cases of advanced stage gallbladder carcinoma

Objective To analyze the characteristics and prognostic factors of gallbladder carcinoma and investigate the measures of various modus operandi. Methods The clinicopathological data of 181 patients with advanced gallbladder carcinoma treated in our hospital from June 2002 to June 2008 were retrospectively analyzed. SPSS16. 0 software package was used for statistical analysis.Results The overall median survival rate of the 181 patients with gallbladder carcinoma was 6 months. The median survival rate after radical resection for gallbladder carcinoma was 19.5 months,which was remarkably higher than other R1 resection, R2 resection and palliative operation groups (P ＜0. 01) The RO resection rates were 95.5%, 62. 2%, 14.1% and 4.7%, respectively based on different pathological stages of Nevin( Ⅱ , Ⅲ, Ⅳ, and Ⅴ ). There were significant differences among all groups (P＜0.01). The Cox multivariate analysis revealed that pathological stages of Nevin, total bilirubin, CA-199 and therapeutic method had significantly higher risk ratios for gallbladder carcinoma.Conclusion Radical resection may help to improve the survival rate and prognosis of advanced gallbladder carcinoma. Key words: Gallbladder neoplasms; Radical resection

Expressions of Ep-CAM and cyclin D1 and their clinical significance in gallbladder carcinoma

To investigate the expressions of Ep-CAM and cyclin D1 and their correlation with the clinicopathological factors and prognosis in gallbladder carcinoma. Ep-CAM and cyclin D1 expressions were detected by PV6000 immunohistochemical staining in 60 gallbladder carcinoma and 15 para-cancerous mucosa specimens. Ep-CAM and cyclin D1 expressions were detected in 56.7% and 48.3% of the cancer tissues, respectively, significantly higher than those in the normal mucosa (P < 0.05). Ep-CAM expression was not correlated with clinicopathological data, however cyclin D1 expression was correlated with pathological differentiation and necrosis (P < 0.05). Survival analysis showed that patients with positive Ep-CAM or cyclin D1 expression had a shorter survival time than that in the patients without (P < 0.05). Moreover, Ep-CAM and cyclin D1 expressions were positively correlated with each other (r = 0.307, P = 0.017). Ep-CAM or cyclin D1 expression is a unfavorable prognostic factor in gallbladder carcinoma.

Protease-activating-receptor-2 is frequently expressed in papillary adenocarcinoma of the gallbladder

Gallbladder carcinoma is one of the most devastating malignant tumors in Japan. An important risk factor for gallbladder carcinoma is pancreaticobiliary maljunction (PBM), which allows reciprocal reflux of bile and pancreatic juice. Protease-activated-receptor-2 (PAR-2), which is activated by trypsin, may be a key molecule in the process of carcinogenesis in the gallbladder epithelium. We investigated the relation between the expression of PAR-2 and clinicopathological findings in gallbladder carcinoma. The study group comprised 58 patients with gallbladder carcinoma. PAR-2 expression was identified by immunohistochemical staining of all tumor specimens. PAR-2 was expressed in cancerous gallbladder epithelium in 37 of 58 patients (64%). PAR-2 expression occurred more frequently in papillary adenocarcinoma (15 of 16 patients, 94%) than in non-papillary types (20 of 42 patients, 48%, p=0.005). Neither lymphatic invasion (p=0.03) nor venous invasion (p=0.009) occurred more frequently in gallbladder carcinoma with PAR-2 than in that without PAR-2. PAR-2 expression was not directly related to PBM (p=0.46). Papillary adenocarcinoma was associated with polypoid growth (p=0.01), PBM (p=0.01), decreased invasion to lymphatic (p=0.007) and venous vessels (p=0.005), lower T-factor (p<0.001), and lower clinical stage (p=0.02). PAR-2 is frequently expressed in papillary adenocarcinoma of the gallbladder. Trypsin may play an important role for carcinogenesis of the gallbladder through PAR-2 signaling.

The role of lymph node dissection in the treatment of gallbladder carcinoma.

Lymph node involvement is an important prognostic factor in gallbladder carcinoma (GBC). The lymph node involvement pattern, extent, and indications for systematic lymph node dissection for patients with advanced GBC were investigated. Forty-one patients with GBC who underwent radical resection with systematic regional lymph node dissection over the past 11 years were analyzed. The lymph node metastasis rate was 63.4% overall, 0% in pT1 disease, 61.9% in pT2 disease, and 81.3% in pT3/pT4 disease. When reviewed according to site, the rate was 41.5% in pericholedochal lymph nodes, 22.0% in the lymph nodes around the common hepatic artery and the portal vein, 36.6% in the posterior pancreaticoduodenal lymph nodes, 28% (5/18) in the celiac lymph nodes, 19% (3/ 16) in the superior mesenteric artery (SMA) lymph nodes, and 26% (7/27) in the aortocaval paraaortic lymph nodes. Patients with severe hepatoduodenal ligament invasion had high rates of paraaortic lymph node involvement. The mortality rate was 2.4% (1 of 41 patients) and the 5-year survival rate was 33.1% overall, 100% in patients with pT1 disease, 49.8% in patients with pT2 disease, and 0% in patients with pT3/pT4 disease. The 5-year survival rate for pT2 disease according to lymph node involvement was 72.7% in patients with pN0+ pN1+ positive posterior pancreaticoduodenal lymph nodes and positive lymph nodes around the common hepatic artery in the N2 patients and 0% in the patients with positive celiac and SMA lymph nodes in the N2 patient group or the positive paraaortic lymph node group (P < 0.05). These results suggest that systemic dissection of N1 lymph nodes, posterior pancreaticoduodenal lymph nodes, and lymph nodes around the common hepatic artery and the portal vein in N2 patients is necessary to improve the prognosis of those patients with pT2 disease without moderate or severe hepatoduodenal ligament invasion.

K-ras gene mutation in gall bladder carcinomas and dysplasia.

Epithelial dysplasia of gall bladder is an important precancerous lesion of gall bladder carcinogenesis. To investigate the frequency of K-ras gene mutation in gall bladder carcinoma and dysplasia, K-ras codon 12 mutations were investigated by the polymerase chain reaction/restriction enzyme based method following direct sequencing. Mutation was detected in 59% (30 of 51) of gall bladder carcinomas, in 73% (8 of 11) of gall bladder dysplasia in gall stone cases, and in 0% of the normal gall bladder epithelium. There was, however, no correlation between K-ras mutation and clinicopathological factors of gall bladder carcinoma. K-ras gene mutation occurs even in gall bladder dysplasia at an incidence similar to that in carcinomas, suggesting that testing for K-ras gene mutation may prove useful as an adjunct to bile cytological or biopsy analysis.