Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations.

BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.

[Pilot study of the relationship between clinical classification of gallbladder cancer and prognosis: a retrospective multicenter clinical study].

Objectives: To propose a novel clinical classification system of gallbladder cancer, and to investigate the differences of clinicopathological characteristics and prognosis based on patients who underwent radical resection with different types of gallbladder cancer. Methods: The clinical data of 1 059 patients with gallbladder cancer underwent radical resection in 12 institutions in China from January 2013 to December 2017 were retrospectively collected and analyzed.There were 389 males and 670 females, aged (62.0±10.5)years(range:22-88 years).According to the location of tumor and the mode of invasion,the tumors were divided into peritoneal type, hepatic type, hepatic hilum type and mixed type, the surgical procedures were divided into regional radical resection and extended radical resection.The correlation between different types and T stage, N stage, vascular invasion, neural invasion, median survival time and surgical procedures were analyzed.Rates were compared by χ(2) test, survival analysis was carried by Kaplan-Meier and Log-rank test. Results: Regional radical resection was performed in 940 cases,including 81 cases in T1 stage,859 cases in T2-T4 stage,119 cases underwent extended radical resection;R0 resection was achieved in 990 cases(93.5%).The overall median survival time was 28 months.There were 81 patients in Tis-T1 stage and 978 patients in T2-T4 stage.The classification of gallbladder cancer in patients with T2-T4 stage: 345 cases(35.3%)of peritoneal type, 331 cases(33.8%) of hepatic type, 122 cases(12.5%) of hepatic hilum type and 180 cases(18.4%) of mixed type.T stage(χ(2)=288.60,P<0.01),N stage(χ(2)=68.10, P<0.01), vascular invasion(χ(2)=128.70, P<0.01)and neural invasion(χ(2)=54.30, P<0.01)were significantly correlated with the classification.The median survival time of peritoneal type,hepatic type,hepatic hilum type and mixed type was 48 months,21 months,16 months and 11 months,respectively(χ(2)=80.60,P<0.01).There was no significant difference in median survival time between regional radical resection and extended radical resection in the peritoneal type,hepatic type,hepatic hilum type and mixed type(all P>0.05). Conclusion: With application of new clinical classification, different types of gallbladder cancer are proved to be correlated with TNM stage, malignant biological behavior and prognosis, which will facilitate us in preoperative evaluation,surgical planning and prognosis evaluation.

[The survival prediction model of advanced gallbladder cancer based on Bayesian network: a multi-institutional study].

Objective: To investigate the clinical value of Bayesian network in predicting survival of patients with advanced gallbladder cancer(GBC)who underwent curative intent surgery. Methods: The clinical data of patients with advanced GBC who underwent curative intent surgery in 9 institutions from January 2010 to December 2015 were analyzed retrospectively.A median survival time model based on a tree augmented naïve Bayes algorithm was established by Bayesia Lab software.The survival time, number of metastatic lymph nodes(NMLN), T stage, pathological grade, margin, jaundice, liver invasion, age, sex and tumor morphology were included in this model.Confusion matrix, the receiver operating characteristic curve and area under the curve were used to evaluate the accuracy of the model.A priori statistical analysis of these 10 variables and a posterior analysis(survival time as the target variable, the remaining factors as the attribute variables)was performed.The importance rankings of each variable was calculated with the polymorphic Birnbaum importance calculation based on the posterior analysis results.The survival probability forecast table was constructed based on the top 4 prognosis factors. The survival curve was drawn by the Kaplan-Meier method, and differences in survival curves were compared using the Log-rank test. Results: A total of 316 patients were enrolled, including 109 males and 207 females.The ratio of male to female was 1.0∶1.9, the age was (62.0±10.8)years.There was 298 cases(94.3%) R0 resection and 18 cases(5.7%) R1 resection.T staging: 287 cases(90.8%) T3 and 29 cases(9.2%) T4.The median survival time(MST) was 23.77 months, and the 1, 3, 5-year survival rates were 67.4%, 40.8%, 32.0%, respectively.For the Bayesian model, the number of correctly predicted cases was 121(≤23.77 months) and 115(>23.77 months) respectively, leading to a 74.86% accuracy of this model.The prior probability of survival time was 0.503 2(≤23.77 months) and 0.496 8(>23.77 months), the importance ranking showed that NMLN(0.366 6), margin(0.350 1), T stage(0.319 2) and pathological grade(0.258 9) were the top 4 prognosis factors influencing the postoperative MST.These four factors were taken as observation variables to get the probability of patients in different survival periods.Basing on these results, a survival prediction score system including NMLN, margin, T stage and pathological grade was designed, the median survival time(month) of 4-9 points were 66.8, 42.4, 26.0, 9.0, 7.5 and 2.3, respectively, there was a statistically significant difference in the different points(P<0.01). Conclusions: The survival prediction model of GBC based on Bayesian network has high accuracy.NMLN, margin, T staging and pathological grade are the top 4 risk factors affecting the survival of patients with advanced GBC who underwent curative resection.The survival prediction score system based on these four factors could be used to predict the survival and to guide the decision making of patients with advanced GBC.

Tumefactive Sludge Mimicking Gallbladder Neoplasm: A Case Report and Review of the Literature.

Biliary sludge (or very thick bile) is mainly comprised of calcium bilirubinate granules and lesser amounts of cholesterol crystals, and it can produce a layer of low amplitude of echoes in the most dependent part of the gallbladder (GB). In tumefactive biliary sludge, low-amplitude echoes do not form a fluid-fluid level but instead tend to give the appearance of a polypoid mass that is bounded by a smooth margin, round, and lobulated. Differential diagnoses for an echogenic mass in the GB lumen include GB carcinoma, tumefactive sludge, and gangrenous cholecystitis. In this case report, we describe a rare case in which biliary sludge did not form a fluid-fluid level but tended to accumulate and appear as a polypoid mass within the lumen of the GB. The lesion was finally identified as being tumefactive sludge mimicking neoplasm of the GB.

Establishment and characterization of a novel highly aggressive gallbladder cancer cell line, TJ-GBC2.

BACKGROUND: Human gallbladder cancer (GBC) is an aggressive malignant neoplasm with a poor prognosis. The development of ideal tools for example tumor cell lines for investigating biological behavior, metastatic mechanism and potential treatment in GBCs is essential. In present study, we established and characterized a GBC cell line derived from primary tumor. METHODS: Primary culture method was used to establish this cell line from a primary GBC. Light and electron microscopes, flow cytometry, chromosome analysis, heterotransplantation and immunohistochemistry were used to characterize the epidemic tumor characteristics and phenotypes of this cell line. RESULTS: A novel GBC cell line, named TJ-GBC2, was successfully established from primary GBC. This cell line had characteristic epithelial tumor morphology and phenotypes in consistent with primary GBC, such as polygon and irregular cell shape, increased CA19-9 and AFP levels, and positive expression of CK7, CK8, CK19 and E-cadherin with negative vimentin. Moreover, about 25% of the cells were in the S-G2/M phase; abnormity in structure and number of chromosome with a peak number of 90-105 and 80% hypertetraploid were observed. Furthermore, this cell line had higher invasion and highest migration abilities compared to other GBC cell lines; and metastatic-related marker MMP9 and nm23 were positively expressed. CONCLUSIONS: A novel highly aggressive GBC cell line TJ-GBC2 was successfully established from primary GBC. TJ-GBC2 cell line may be efficient tool for further investigating the biological behaviors, metastatic mechanism and potential targeted therapy of human GBC.

Xanthogranulomatous cholecystitis: diagnostic performance of US, CT, and MRI for differentiation from gallbladder carcinoma.

OBJECTIVES: The purpose of this study is to evaluate the diagnostic performance of HRUS, CT, and MRI for differentiating xanthogranulomatous cholecystitis (XGC) from gallbladder (GB) cancer. MATERIALS AND METHODS: Patients with surgically proven XGC (n = 40) and GB cancer (n = 44), who had undergone at least one HRUS (n = 43), CT (n = 82), or MRI (n = 34) examination between 2000 and 2012, were included. Two radiologists retrospectively graded the likelihood of XGC or GB cancer using a 5-point confidence scale; they also assessed the imaging features. Statistical analyses were performed using ROC, ANOVA, and Fisher's exact test. RESULTS: Diagnostic performance of MRI was better than HRUS for differentiating XGC from GB cancer (AUCs = 0.867 and 0.911 vs. AUCs = 0.818 and 0.86). However, HRUS showed a better performance than CT (AUCs = 0.818 and 0.86 vs. AUCs = 0.806 and 0.84) with moderate to excellent agreement (κ = 0.48-0.83). Statistically common findings for XGC included non-focal thickening, smooth GB wall, presence of intramural nodules, type I enhancement of wall, transient hepatic attenuation difference, and continuity of mucosa (p < 0.05). Co-existence of gallstones (OR = 16.5), non-focal thickening (OR = 14.7), and collapsed lumen (OR = 13.0) on HRUS, and type I enhancement on CT (OR = 3.52) were independently associated with XGC (p < 0.05). CONCLUSION: Although MRI showed a better performance than both HRUS and CT, HRUS showed a better performance than CT. The co-existence of gallstones, non-focal thickening, and collapsed lumen on HRUS was independently associated with XGC.

Ability of FDG-PET/CT in the detection of gallbladder cancer.

PURPOSE: To assess the value of FDG-PET/CT in the evaluation of gallbladder carcinomas (GBC). METHODS: A prospective cohort of patients with suspicion of or confirmed GBC was studied with FDG-PET/CT. Diagnostic accuracy parameters were calculated in comparison with pathology and/or the clinical course of patients. Clinical impact of PET/CT imaging was estimated. RESULTS: Forty-nine patients were enrolled (34 malignant tumors, 15 benign lesions; 37 staging, 12 restaging). Overall diagnostic accuracy was 95.9% for the diagnosis of the primary lesion, 85.7% for lymph node involvement and 95.9% for metastatic disease. Mean SUVmax in malignant gallbladder lesions was 7.92 ± 6.25 Analysis of ROC curves showed a SUVmax cut-off value of 3.62 for malignancy (S: 78.1%; Sp: 88.2%). Diagnostic accuracy in the restaging group reached 100%. FDG-PET/CT changed the management of 22.4% of the population. COMMENTS: Diagnosis of malignancy or benignity of suspicious gallbladder lesions is accurately made with FDG PET/CT, allowing a precise staging of GBC due to its ability to identify unsuspected metastatic disease. SUVmax has a complementary role in addition to visual analysis.

FDG Avid Intracholecystic Papillary Neoplasm Mimicking Hepatic Metastasis in a Patient with Head-and-neck Cancer.

A 75-year-old male with head-and-neck squamous cell cancer received a staging f-18-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) scan which showed additional focal abnormal uptake in the right hepatic lobe. The patient was treated for probable metastatic disease. Restaging FDG PET/CT scan revealed resolution of uptake in the head-and-neck and persistent focal uptake in the presumed liver metastasis. An abdominal CT with intravenous contrast revealed an enhancing mass in the gallbladder, without extension into the liver. Cholecystectomy revealed an intracholecystic papillary neoplasm of the gallbladder. The initial appearance of hepatic metastasis was due to a misregistration artifact.

Risk score for malignancy in patients with suspicious gallbladder lesions: Retrospective analysis of 175 cases.

BACKGROUND: Among cancers, carcinoma gallbladder has one of the most dismal prognosis. Early lesions are difficult to biopsy because of proximity to luminal structures and risk of biliary peritonitis. However, early surgery offers the only chance of a complete cure. Utilizing a risk score would allow characterization of the risk of malignancy and early referral to an oncology centre thereby resulting in better outcomes for patients with carcinoma gallbladder. METHODS: The aim of this study was to develop a risk score for carcinoma in patients with suspicious gallbladder lesions based on clinical presentation and imaging. All patients with suspicious gallbladder lesions on radiological imaging who underwent surgery were analyzed. Patients were considered for scoring if the ultrasound showed the gallbladder wall thickening (more than 4 mm) and computed tomography scan showed operable disease. Statistical analysis was done to derive a score for malignancy. RESULTS: Total 175 patients underwent an operation for suspicious gallbladder lesions from January 2005 to December 2014. The factors analyzed were clinical biochemical and imaging findings. Of these, 71 were benign on the final histopathology and 104 were malignant. The score was constructed with the following variables: female sex, high total bilirubin (≥ 1 mg/dL), presence of a mass, focal location of the lesion, presence of gallbladder stones and nodal involvement in the hepatoduodenal region on imaging. A model score and modified score were obtained. In this modified score, score of more than 8 out of 20 predicted malignancy with a sensitivity of 78% and specificity of 70.4%. Receiver operating characteristic (ROC) curve constructed with these variables had an area under curve of 0.828. There was no statistically significant difference between the model score and the modified score. CONCLUSIONS: A pre-operative risk score was obtained for carcinoma gallbladder, which needs to be validated prospectively in future.

Papillary Neoplasms of the Gallbladder and Extrahepatic Bile Ducts: A Report of Two Cases With Associated Invasive Carcinoma.

Intracholecystic papillary neoplasm (ICPN) of the gallbladder is a macroscopically visible premalignant lesion protruding into the gallbladder lumen, with infrequent association with invasive adenocarcinoma. Intraductal papillary neoplasm of the bile ducts (IPNB) is a non-invasive lesion characterized by intraductal papillary or villous architecture. Both ICPN and IPNB are rare findings in the gallbladder and biliary tract pathology. Diagnosis relies on clinical manifestations, imaging techniques, and comprehensive histological examination. Here, we present two cases: a 63-year-old male with mild abdominal pain found to have a gallbladder mass, diagnosed histologically as ICPN with associated invasive carcinoma; and a 65-year-old female with chronic jaundice and a large tumor mass in the common bile duct, histologically diagnosed as IPNB with associated invasive carcinoma. These cases highlight the importance of a careful and thorough microscopic examination to rule out differential diagnoses and to reveal any potential invasive carcinoma associated with these uncommon lesions.

Benefit of adjuvant radiotherapy for gallbladder cancer: a comparability-based meta-analysis.

BACKGROUND AND PURPOSE: The benefits of adjuvant radiotherapy (ART) in gallbladder cancer (GBC) treatment remain inconclusive owing to the rarity of GBC and lack of randomized studies. METHODS: PubMed, Medline, Embase, and Cochrane Library were systematically searched until March 2021. The primary endpoint was overall survival (OS). Comparative clinical studies that reported survival outcomes in GBC patients treated with or without ART were included. The comparability of each study was assessed by considering all possible clinical indicators (group 2: ART arm with poor clinical profile; group 1: ART arm with statistically similar profile or no evidence of having inferior clinical factors compared to non-ART arm). RESULTS: Twenty-one studies involving 6876 GBC patients were reviewed. In pooled analyses of OS, the odds ratio (OR) was 1.26 (p = 0.111) neither favoring ART or non-ART arms. In subgroup analyses considering comparability, the OR significantly favored the ART arm (1.92, p = 0.008) among comparability group 1 studies, whereas it was 1.03 (p = 0.865) in comparability group 2 studies. The pooled rate of 5-year OS in the ART vs. non-ART arms was 44.9% vs. 20.9% in group 1 and 34.1% vs. 40.0% in group 2. With ART, significant reduction in locoregional recurrence (OR 0.21, p = 0.001) but not in distant metastasis (OR 1.32, p = 0.332) was noted. CONCLUSION: ART not only showed benefits in patients with a similar clinical profile to those treated without ART but also yielded comparable survival in patients with an inferior clinical profile. Our results suggest the more active application of ART in GBC treatment. PROTOCOL REGISTRATION: This study is registered in PROSPERO (CRD42021240624, available at: https://www.crd.york.ac.uk/ ).

Long-term results and prognostic factors after surgical treatment for gallbladder cancer.

Objectives: Gallbladder cancer is relatively rare and traditionally regarded as having poor prognosis. There is controversy about the effects of clinicopathological features and different surgical techniques on prognosis. The aim of this study was to investigate the effects of clinicopathological characteristics of the patients with surgically treated gallbladder cancer on long-term survival. Material and Methods: We retrospectively analyzed the database of gallbladder cancer patients treated at our clinic between January 2003 and March 2021. Results: Of 101 evaluated cases, 37 were inoperable. Twelve patients were determined unresectable based on surgical findings. Resection with curative intent was performed in 52 patients. The one-, three-, five-, and 10-year survival rates were 68.9%, 51.9%, 43.6%, and 43.6%, respectively. Median survival was 36.6 months. On univariate analysis, poor prognostic factors were determined as advanced age; high carbohydrate antigen 19-9 and carcinoembryonic antigen levels; non-incidental diagnosis; intraoperative incidental diagnosis; jaundice; adjacent organ/structure resection; grade 3 tumors; lymphovascular invasion; and high T, N1 or N2, M1, and high AJCC stages. Sex, IVb/V segmentectomy instead of wedge resection, perineural invasion, tumor location, number of resected lymph nodes, and extended lymphadenectomy did not significantly affect overall survival. On multivariate analysis, only high AJCC stages, grade 3 tumors, high carcinoembryonic antigen levels, and advanced age were independent predictors of poor prognosis. Conclusion: Treatment planning and clinical decision-making for gallbladder cancer requires individualized prognostic assessment along with standard anatomical staging and other confirmed prognostic factors.

Long-Term Oncologic Outcomes for T2 Gallbladder Cancer According to the Type of Surgery Performed and the Optimal Timing for Sequential Extended Cholecystectomy.

BACKGROUND: Sequential extended cholecystectomy (SEC) is currently recommended for T2 and higher gallbladder cancer (GBC) diagnosed after simple cholecystectomy (SC), but the value and timing of re-resection has not been fully studied. We evaluated the long-term oncologic outcomes of T2 GBC according to the type of surgery performed and investigated the optimal timing for SEC. METHODS: Patients diagnosed with T2 GBC who underwent SC, extended cholecystectomy (EC), or SEC between 2002 and 2017 were retrospectively reviewed. Those who underwent other surgical procedures or those with incomplete medical records were excluded. Overall survival (OS) and disease-free survival (DFS) according to the types of surgeries and prognostic factors for OS and DFS were analyzed. Survival analysis was done between groups that were divided according to the optimal cutoff time interval between SC and SEC based on DFS data. RESULTS: Of the 226 T2 GBC patients, 53, 173, and 44 underwent SC, EC, and SEC, respectively. The 5-year OS rate was 50.1%, 73.2%, and 78.7%, and the DFS rate was 46.8%, 66.3%, and 65.2% in the SC, EC, and SEC groups, respectively. EC (p = 0.001 and p = 0.001) and SEC (p = 0.007 and p = 0.065) groups had better 5-year OS and DFS rates than the SC group. Preoperative CA 19-9 level > 37 U/mL (HR 1.56; 95% CI 1.87-2.79; p < 0.001) and N1 stage (HR 2.88; 95% CI 1.76-4.71; p < 0.001) were associated with poorer prognosis. The optimal cutoff interval between SC and SEC was 28 days. Patients who underwent SEC ≤ 28 days after the initial cholecystectomy had better 5-year DFS rates than patients who underwent SEC after > 28 days (75.0% vs. 52.8%, p = 0.023). CONCLUSIONS: SEC is recommended for T2 GBC diagnosed after SC, because SEC provides better survival outcomes than SC alone. A time interval of less than 28 days to SEC is associated with an improved DFS.

Case Report: Idiopathic Traumatic Neuroma of the Gallbladder Without Previous Surgery.

Traumatic neuroma mostly results from nerve injury caused by surgery or trauma. Traumatic neuroma of the gallbladder without prior abdominal surgery is extremely rare, and we termed it "idiopathic traumatic neuroma of the gallbladder." Due to its rarity and a lack of specific clinical and radiological features, it is most commonly misdiagnosed. In our case, the patient was admitted to our hospital for cholangiocarcinoma. Repeated abdominal contrast-enhanced computed tomography scans preoperatively indicated hilar cholangiocarcinoma. Due to insufficient future liver remnant, we planned preoperative percutaneous transhepatic cholangiodrainage and percutaneous transhepatic portal vein embolization based on multidisciplinary team consultation. The patient was then admitted 1 month later for surgery. We performed a laparoscopic cholecystectomy and an extensive laparoscopic right hepatectomy as gallbladder carcinoma was strongly suspected intraoperatively. However, the final diagnosis was traumatic neuroma of the gallbladder confirmed by pathological examination. Traumatic neuroma of the gallbladder is very rare, and we hope to provide some references for diagnosis by reporting our case and reviewing the literature on this topic so that extensive treatment can be avoided, thus improving patients' quality of life. To the best of our knowledge, this is the first reported case of traumatic neuroma without prior surgery in the English literature since 1996.

Rare Case of Gallbladder Neuroendocrine Carcinoma.

Neuroendocrine tumors (NET) are very uncommon, though when seen, they are typically found within the gastrointestinal tract. Rarely NETs can be seen within the lumen of the gallbladder. An 83-year-old woman presented to our hospital with vague abdominal pain and distention. She was found to have a mass within her gallbladder on imaging, and she was treated with surgical resection. Pathology revealed a gallbladder NET with lymphovascular involvement. NETs of the gallbladder remain a rare occurrence with a limited number of previous case reports.

Prognostic Value of Carcinoembryonic Antigen (CEA) and Carbohydrate Antigen 19-9 (CA 19-9) in Gallbladder Cancer; 65 IU/mL of CA 19-9 Is the New Cut-Off Value for Prognosis.

Due to the lack of appropriate tumor markers with optimal cut-off values to predict the prognosis of gallbladder cancer (GBC), this study aimed to demonstrate the relationship between prognosis and the levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), and to determine optimal thresholds. In total, 539 patients diagnosed with GBC were examined. The relationship between tumor marker levels and overall survival (OS) was analyzed. The C-tree method was used to suggest tumor marker thresholds, and multivariate analysis was conducted to identify prognostic factors for overall survival. The mean age of the patients was 65.3 years, and the 5-year overall survival rate in all patients was 68.9%. Following the C-tree method, the optimal cut-off value was set at 5 IU/mL for CEA and at 65 IU/mL for CA 19-9. Multivariate analysis revealed that age, CA 19-9 level, operative method, T stage, and N stage were significant prognostic factors for OS. Consequently, CA 19-9 had a stronger association with prognosis than CEA, and 65 IU/mL for CA 19-9 may be suggestive in evaluating the prognosis of GBC. Moreover, it could be an effective indicator for determining the surgical extent necessary and the need for adjuvant treatment.

The role of laparoscopic surgery in the surgical management of gallbladder carcinoma: A systematic review and meta-analysis.

Previous studies have explored the role of laparoscopic surgery (LS) in the surgical management of gallbladder carcinoma (GBC) and obtained satisfactory outcomes versus conventional open surgery. However, most of them either included a small number of patients or mainly focused on the early-staged lesions. Therefore, their results were less statistical powerful and a more comprehensive evaluation on the role of LS in GBC is warranted. A thorough database searching was performed in PubMed, EMBASE and Cochrane Library for comparative studies between the laparoscopic and open approach in the surgical management of GBC and 18 comparative studies were finally identified. RevMan 5.3 and Stata 13.0 software were used for statistical analyses. Pooled results revealed that patients in the laparoscopic group recovered faster with less intraoperative hemorrhage and less postoperative morbidity. Comparable operative time, overall recurrence rate, R0 resection rate, lymph node yield, intraoperative gallbladder violation rate and postoperative survival outcomes were also acquired. Regarding the debating issue of port-site recurrence, a significantly higher incidence of port-site recurrence was observed in laparoscopic group. However, having excluded studies on incidental gallbladder carcinoma, the subsequent pooled result showed no significant difference. Considering the inherent inconsistency of the surgical indication between laparoscopic and open surgeries and the deficiency of advanced lesions, we drew a conclusion that laparoscopic surgery seems to be only safe and feasible for early- or middle-staged lesions. Upcoming random controlled trials or comparative studies with equivalent surgical indication focused on advanced lesions are warranted for further evaluation.

A Case Report on Adenosquamous Carcinoma of Gallbladder: A Very Rare Malignancy.

Gallbladder (GB) carcinoma is a rare carcinoma with a poor prognosis. The prevalence is 0.7-21/100,000 worldwide and 1-2/100,000 in the United States. Adenosquamous cell carcinoma is composed of glandular and squamous components. The overall five-year survival rate is less than 5%, with a median survival of fewer than six months. We are presenting a case of adenosquamous carcinoma of the GB in a 76-year-old female who presented with right upper quadrant abdominal pain and was found to have an enlarged GB, with thickened irregular wall likely inflammatory or malignant and mildly dilated common bile duct on ultrasound imaging of the abdomen. Core needle biopsy of GB showed findings compatible with adenosquamous carcinoma and immunohistochemistry was positive for P40, CK5,6. She was diagnosed with stage T4 N0 M0. She was started on chemotherapy with cisplatin and gemcitabine (25 mg/m2 and 1000 mg/m2), respectively, every three weeks but her condition worsened after the fifth cycle of chemotherapy and she decided to move forward with hospice care given her bad prognosis. Unfortunately, she passed away one week after being discharged home.

Epstein-Barr Virus-associated Mixed Lymphoepithelioma-like Carcinoma and Adenocarcinoma of the Gall Bladder: An Unusual Entity.

Schmincke described lymphoepithelioma as an undifferentiated carcinoma with abundant lymphoid stroma in the nasopharynx. Tumors with a similar histomorphology in extrapharyngeal areas have been referred to as lymphoepithelioma-like carcinoma (LELC). The association of an Ebstein-Barr virus (EBV) infection with lymphoepithelioma is well established in the nasopharynx but not so well at the extrapharyngeal sites. Only four cases of LELC have been reported in the gall bladder, of which all were negative for the EBV. This paper reports the first case of an EBV-associated mixed gall bladder carcinoma exhibiting a distinct phenotype of LELC and adenocarcinoma with mucinous differentiation. The EBV was confirmed by the strong granular membranous and cytoplasmic expression of LMP-1 (latent membrane protein-1) on immunohistochemistry and nuclear EBER RNA on chromogen in-situ hybridization in the tumor. This is the first case of LELC positive for EBV in the gall bladder. LELC has a more favorable prognosis than conventional adenocarcinoma or squamous cell carcinoma, irrespective of the site. Although a higher T stage and nodal metastasis were exceptional in the present case in contrast to the previous cases, the EBV-associated lymphocytic response might limit the disease spread and confer better overall survival and prognosis in these patients. Nevertheless, more prospective studies with a larger cohort will be needed to understand the pathogenesis, biological behavior, and prognosis of this rare entity.

Inhibition of autophagy by chloroquine enhances the antitumor activity of gemcitabine for gallbladder cancer.

Gemcitabine (GEM), as an anti-metabolic nucleoside analog, has been shown to have anticancer effects in various tumors, but its chemotherapy resistance is still an important factor leading to poor prognosis of cancer patient. A large number of studies in recent years have shown that autophagy plays an important role in the chemotherapy sensitivity of many tumors, including pancreatic, non-small cell lung, and bladder cancer. However, whether GEM causes autophagy in gallbladder cancer (GBC) and whether it is related to chemotherapy resistance is unknown. In the present study, we demonstrated that GEM induced apoptosis and protective autophagy in GBC cells, which may be related to the AKT/mTOR signaling pathway, and GEM in combination with autophagy inhibitor chloroquine can strengthen the cytotoxic effect of GEM on GBC in vitro and in vivo. These findings showed that both autophagy and AKT/mTOR signals were engaged in GBC cell death evoked by GEM, GBC patients might benefit from this new treatment strategy, and molecular targeted treatment in combination with autophagy inhibitors shows promise as a treatment improvement.