Current update on gallbladder carcinoma.

Objective: To describe the differential diagnosis and treatment options for xanthogranulomatous cholecystitis (XGC), the presentations and management of 68 patients were described. Subjects and Methods: Demographical and clinical data from 68 cases of XGC treated between January 2004 and January 2010 were analyzed. Clinical characteristics, radiological and surgical findings, histopathological features and postoperative recoveries were recorded. Clinical features of laparoscopic cholecystectomy versus open surgery and XGC versus gallbladder (GB) cancer were compared. Results: The CA19-9 levels of XGC and coexisting GB cancer were significantly different (p = 0.0034). In radiological findings, focal thickening of the GB wall was more frequent in coexisting GB cancer, early enhancement of the GB was observed more often in coexisting GB cancer, and lymph node enlargement was seen more often in coexisting GB cancer (p < 0.05). There were also significant differences between laparoscopic and open surgery for CA19-9, intramural hypoattenuated nodule, pericholecystic invasion, lymph node enlargement and maximum thickness, focal thickening, heterogeneous enhancement and early enhancement of the GB wall (p < 0.05). These findings were confirmed by multivariate analysis. Conclusions: Ultrasound, computed tomography scan and intraoperative frozen section were the helpful modalities for XGC diagnosis. CA19-9 (>37 kU/l), pericholecystic invasion, lymph node enlargement (>10 mm), and focal thickening and early enhancement of the GB wall were the criteria for open surgery. In some selected cases, laparoscopic cholecystectomy was preferable.

INTRODUCTION: Gallbladder (GB) cancer (GBC) accounted for 3960 deaths in the US in 2019. With only 1 in 5 GBCs diagnosed at early stage, the overall 5-year survival rate is a meager 19%. Given the low 5-year survival, the best treatment is prevention. Risk factors for GBC include age, ethnicity, GB polyps >1 cm, primary sclerosing cholangitis, anomalous pancreaticobiliary junction, toxins, and GB stones. There remains controversy as to whether size of GB stones increases the risk of GBC. The aim of this systematic review and meta-analysis was to determine if risk of GBC increases with increasing size of GB stones. METHODS: A systematic search was conducted using the terms “gallbladder cancer,” “cholelithiasis,” “gallstones,” and “gallstone size” with all permutations of pubmed/medline, google scholar, embase, and cochrane. Papers were translated, if necessary. A recursive search of bibliographies of included articles was also performed. GB stone size was primarily determined post-cholecystectomy. The relevant data was inputted into RevMan 5.4 in order to generate odds ratios and Forest plots. RESULTS: The search yielded 357 total articles, of which 8 met our final inclusion criteria with GB stone measurement and prevalence of GBC in each study population. The data was then divided into 3 groups, based on size of GB stones, greater or lesser than 3 cm, 2 cm, or 1 cm. We found that the OR of developing GBC was 1.93 [1.29–2.90], 1.42 [1.06–1.90], and 1.62 [1.24–2.11] for stones greater than 3 cm, 2 cm, and 1 cm, respectively. CONCLUSION: Patients with GB stones >1 cm had increased odds of developing GBC, however we did not observe a linear relationship between GBC and increasing stone size. Our meta-analysis found an OR of 1.93 for stones >3 cm which is significantly less than the 9.1 previously reported. The association between GB stone size and GBC is likely related to the chronicity of GB stones rather than absolute size. Jain et al. proposed that chronic inflammation could subsequently lead to loss of heterozygosity of tumor suppressor genes. In summary, we found the risk of GBC is similar regardless of size of stones >1 cm. Therefore while we usually observe asymptomatic GB stones, clinicians should be aware that GB stones >1 cm may have increased risk of GBC in symptomatic individuals. Further studies are needed in asymptomatic individuals to define the optimal GB stone size cutoff to perform cholecystectomy to reduce GBC risk.Figure 1.: Odds of developing gallbladder cancer with increasing size of gallstones. (Events = # of cases of gallbladder cancer; Total = # of cases of patients with gallstones > or < the specified size).

Objective To investigate the expressions of Yes-associated protein-1 (YAP1) in gallbladder mucosal epithelium of normal persons, in patients with simple/calculous cholecystitis, and in patients with gallbladder carcinoma; and to study the mechanism of YAP1 in gallbladder carcinoma development. Methods Immunohistochemistry was used to detect the expression and distribution of YAP1 protein in 50 persons with normal gallbladder, 101 patients with simple cholecystitis/calculous cholecystitis and 100 patients with gallbladder carcinoma. RT-PCR and western-blot were used to detect the mRNA and protein levels of YAP1 in normal and malignant gallbladder mucosal epithelium cells. siRNA was used to shut down the expression of YAP1 in SGC996 cells. MTT was used to test cell vitality. Flow cytometry was used to measure cell cycle. Results Immunohistochemistry revealed the expression rates of YAP1 in the gallbladder carcinoma group, the cholecystitis/gallstone group and the control group to be 87.0% (87/100), 56.4% (57/101) and 5.0% (1/20), respectively (P<0.01). The YAP1 protein levels were higher in gallbladder carcinoma tissues and cells when compared to normal tissues and cells. RT-PCR showed the mRNA levels of gallbladder carcinoma cells to be 12.5±1.2 times of normal gallbladder mucosal epithelial cells (P<0.05). After using siRNA to shut down the YAP1 expression, EMT associated proteins were down-regulated, cell vitality was decreased, and cell cycle was arrested in the S-phase. Conclusions YAP1 is closely related to cell proliferation and metastasis of gallbladder carcinoma. It may promote tumor progression through epithelial-mesenchymal transition. Key words: Primary gallbladder carcinoma; Yes-associated protein 1; Epithelial-mesenchymal transition; Tumor progress

Elevated bile amylase level in patients with pancreaticobiliary maljunction (PBM) or high confluence of pancreaticobiliary ducts (HCPBD) is well known as a risk factor for gallbladder carcinoma (GBC) development. However, the effects of occult pancreaticobiliary reflux (OPR), a condition characterized by high bile amylase level in the presence of an anatomically normal pancreaticobiliary junction, on GBC development remain unclear. The aim of this study was to assess the relationship between OPR and GBC. Clinicopathological data of 52 patients who were preoperatively diagnosed with gallbladder (GB) tumor (22 malignant, 30 benign) were retrospectively reviewed. All of the patients underwent preoperative endoscopic retrograde cholangiopancreatography to evaluate pancreaticobiliary junction morphology and bile amylase level. The relationship between the histological diagnosis of GB lesions, and pancreaticobiliary junction morphology and bile amylase level were investigated. Pancreaticobiliary maljunction, HCPBD, and normal pancreaticobiliary junction (NPJ) were identified in 12, nine, and 31 patients, respectively. The rates of GBC in patients with PBM, HCPBD, and NPJ were 58% (7/12), 67% (6/9), and 29% (9/31), respectively. Of the 31 patients with NPJ, 22 had OPR and nine of these had GBC. None of the patients with NPJ and normal bile amylase level had GBC. Additionally, among patients with NPJ, bile amylase level was significantly higher in patients with GBC than in patients with benign tumors. Occult pancreaticobiliary reflux, like PBM and HCPBD, is a risk factor for GBC development.

Extracellular vesicles (EVs), which are heterogeneous membrane-based vesicles with bilayer cell membrane structures, could be versatile biomarkers for the identification of diverse diseases including cancers. With this potential, this study has attempted the Raman spectroscopic identification of gall bladder (GB) cancer by directly measuring the EV solution extracted from human bile without further sample drying. For this purpose, bile samples were obtained from four normal individuals and 21 GB polyp, eight hepatocellular carcinoma (HCC), and five GB cancer patients, and EVs were extracted from each of the bile samples. The Raman peak shapes of the EVs extracted from the GB cancer samples, especially the relative intensities of peaks in the 1560-1340 cm-1 range, were dissimilar to those of the samples from the normal, GB polyp, and HCC groups. The intensity ratios of peaks at 1537 and 1453 cm-1 and at 1395 and 1359 cm-1 of the GB cancer samples were lower and higher, respectively, than those of the samples of the remaining three groups. The differences of peak intensity ratios were statistically significant based on the Mann-Whitney U test. DNA/RNA bases, amino acids, and bile salts contributed to the spectra of EVs, and their relative abundances seemed to vary according to the occurrence of GB cancer. The varied metabolite compositions and/or structures of EVs were successfully demonstrated by the dissimilar peak intensity ratios in the Raman spectra, thereby enabling the discrimination of GB cancer.

Screening of gall bladder cancer through infrared analysis of bile and examination of varied bile constituent composition by the disease

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. 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. 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). 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.

Background and Aim: Gallbladder (GB) cancer has poor prognosis as it progresses very fast. Etiology or pathogenesis of GB cancer is still obscure and very little is known about it. A better understanding of risk factors that lead to its development could help improve the management options. Presence of stones in GB generates varied mucosal reaction which results in different types of histopathological changes. Our aim was to correlate the various types of mucosal response like inflammation, hyperplasia, metaplasia, and carcinoma to different gall stones characteristics (like number and morphology type). Materials and Methods: A retrospective study of 346 cases of removed GB was done which was based on the histological changes. A total of 313 (90%) were associated with gallstones and the rest 33 cases (10%) were of acalculous cholecystitis. The changes in mucosa of calculous GB (313 cases) were studied and correlation between the mucosal changes and the number and type of stones was evaluated. Varied parameters of gall stones like number and morphological type were studied. Tissue section for histopathological studies was taken from fundus, body, neck, and from abnormal looking areas while doing grossing. Results: Gender study revealed a higher incidence of inflammatory changes in males, while GB hyperplasia, intestinal metaplasia, and cancer were only found in females. A progressive increase in the average age was noticed fromintestinal metaplasia to carcinoma, suggesting that the metaplasia-carcinoma succession may occur in GB cancer. Conclusion: Correlation of mucosal changes with size and morphological type of stones has suggested that there could be an association between some histological alterations of GB and cancer.

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

BackgroundAdenomyomatosis of gallbladder is an acquired hyperplastic lesion, characterized by focal or diffuse thickening of the gallbladder with intramural cysts or echogenic areas with comet tail on ultrasonography. But in some cases, especially in the localized fundal type of adenomyomatosis, the intramural anechoic cystic spaces are uncertainty which causes difficult to differential adenomyomatosis from GB cancer. The purpose of this study was to determine the accuracy of real-time contrast-enhanced ultrasonography(CEUS) in the diagnosis of the fundal localized type of gallbladder adenomyomatosis.MethodsWe performed a retrospective study of 21 patients with pathologically proven fundal localized type of gallbladder (GB) adenomyomatosis. All patients underwent preoperative grayscale ultrasound (US) and real-time CEUS examination. The study’s reviewers made the diagnosis of adenomyomatosis according to the presence of the focal thickening of the fundal gallbladder wall with intramural cyst or intramural echogenic foci on grayscale US or CEUS. The diagnostic accuracy of US and CEUS was compared. The enhanced pattern and degree of intactness of the GB wall were also recorded.ResultsThe fundal portion of the GB wall showed localized thickness in all 21 patients. Small anechoic spaces or intramural echogenic foci were detected in 14 (66.7 %) and 21 (100 %) of cases respectively, and the intactness of the GB wall’s outer hyper-echoic layer was demonstrated in 17 (81 %) and 20 (95 %) on grayscale US and CEUS, respectively. The accuracy rate of the above two examination modalities was significantly different (p < 0.05). In the arterial phase of the CEUS, areas of focal thickened GB wall were iso-enhanced in 18 cases and hyper-enhanced in 3 cases. All 21 cases appeared to show heterogeneous enhancement with small non-enhancement spaces. The mucosal and serosal layers of the GB wall surrounding the lesions were enhanced, which presented as two “hyper-echoic lines” in the arterial phase of CEUS. In the venous phase of the CEUS, 19 lesions were iso-enhanced and 2 lesions were hypo-enhanced. The small non-enhancement spaces were more clearly during the venous phase.ConclusionThe small non-enhancement space is a characteristic finding of the fundal localized type of gallbladder adenomyomatosis on CEUS. CEUS could increase the degree of visualization of Rokitansky-Aschoff sinuses (RAS) and intactness of the GB wall, which play an important role in differential diagnosis.

To analyze the clinical features of patients with gallbladder cancer from 17 hospitals in 5 Northwestern provinces (autonomous region) of China from 2009 to 2013. A total of 2 379 cases with gallbladder cancer in 17 tertiary hospitals from 5 Northwestern provinces of China from January 2009 to December 2013 were reviewed retrospectively. The clinical data was collected by standardized "Questionnaire for Clinical Survey of Gallbladder Cancer in Northwestern Area of China". χ² test was used to analyze the data. (1) Gallbladder cancer from 17 hospitals accounted for 1.6%-6.8% of all bile tract diseases from 2009 to 2013 in Northwestern China, average was 2.7%. Gallbladder cancer accounted for 0.4%-0.9% of abdominal surgery, average was 0.7%. (2) The incidence of gallbladder cancer was higher in the aged females, the ration of female to male was 1.0 to 2.1. The average age of gallbladder cancer was (64 ± 11) years. The occupation of patients was mainly farmers (χ² = 147.10, P < 0.01). (3) 57.2% of the gallbladder cancers were associated with gallstones. (4) The main pathological patterns of gallbladder cancer were moderate and poor differentiated adenocarcinoma, showing an aggressive malignancy. TNM stage IV accounted for 55.1% of all cases, which was associated with the poor prognosis. (5) The curative resection rate was 30.4%. Gallbladder cancer is common in the aged females and mainly at advanced stage. The screening and follow-up of high-risk groups with ultrasound and other methods regularly could increase the early diagnosis rate of gallbladder cancer, aggressive surgical resection combined with other comprehensive treatment could improve the prognosis of patients.

From August 1983 through March 1995, 204,099 people received ultrasonic mass survey of the abdomen for the first time. Among these examinees, 631 (0.31%) malignant neoplasm cases, such as 201 hepatocellular carcinoma (HCC), 81 gallbladder (GB) cancer, 57 pancreatic cancer, and 169 renal cell carcinoma (RCC), were detected. Three hundred seventy six out of 590 cases (64%), excluding chronic leukemia cases and metastatic liver cancer cases, were surgically resected. The resection rate of HCC, GB cancer, pancreatic cancer, and RCC were 25%, 88%, 49%, and 99%, respectively. The cumulative survival rate of the 376 resected cases was 79.5% at 10 years. The cumulative survival rates of resected cases of HCC, GB cancer, pancreatic cancer and cumulative survival rates of resected cases of HCC, GB cancer, pancreatic cancer and RCC were 34% at ten years, 83% at 10 years, 49% at 7 years, and 99% at 10 years, respectively. Ultrasonic mass survey is dramatically useful for early detection of various kinds of abdominal cancers, especially RCC and GB cancer. From now on, many earlier abdominal cancers will be found by establishing and promoting ultrasonic mass survey systems.

Objectives To investigate the role of contrast-enhanced ultrasound in the differentiation between gallbladder adenoma and carcinoma developing from gallbladder adenoma.Methods The data from 28 patients who received contrast-enhanced ultrasound (19 patients with gallbladder adenoma and 9 patients with gallbladder carcinoma developing from gallbladder adenoma) were retrospectively analyzed.We analyzed the contrast enhancement characteristics of the initial enhancement time,the enhancement level,enhanced morphology and the integrity of gallbladder wall adjacent to the lesions.All the lesions were confirmed by histopathology.Results The time to initial enhancement and the time to peak enhancement were significantly shorter in patients with gallbladder adenoma than in patients with gallbladder carcinoma developing from gallbladder adenoma [(13.11 + 3.63)s vs.(18.11-±-3.26)s,(17.36+3.95)s vs.(24.56-±-4.36)s,all P＜0.01].The time to iso-enhancement,however,showed no significant differences.The time to hypo-enhancement and enhancement time of the liver were significantly shorter in patients with gallbladder carcinoma developing from gallbladder adenoma than in patients with gallbladder adenoma [(55.56 ± 15.4) s vs.(91.00 ± 34.25) s,P＜0.01,(16.63+4.66)svs.(22.78+5.29)s,P＜0.05].Using ROC curve,the time to peak enhancement value greater than 20 s had a sensitivity of 89 ％ and a specificity of 85 ％ for detecting gallbladder carcinoma developing from gallbladder adenoma.The enhancement level showed no significant difference between the two groups.Inhomogeneous enhancement was found in 3 (33 ％) gallbladder cancer developing from gallbladder adenoma and none (0/19) in gallbladder adenoma (P＜0.01).Destruction of the integrity of gallbladder wall was found in 6 (66.7％) gallbladder carcinoma developing from gallbladder adenoma and none (0/19) in gallbladder adenoma (P＜0.01).Conclusions Contrast-enhanced ultrasound is useful in the identification of patients with gallbladder adenoma and gallbladder carcinoma developing from gallbladder adenoma.The time to peak enhancement,the enhancement morphology and the integrity of gallbladder wall adjacent to the lesions significantly improved the ability to differentiate between gallbladder adenoma and gallbladder carcinoma developing from gallbladder adenoma. Key words: Gallbladder neoplasms; Ultrasonography

Most carcinomas of the gall bladder are adenocarcinomas and adenosquamous cell carcinomas represent only about 5% of all gall bladder carcinomas. This paper describes a very rare case of adenocarcinoma and adenosquamous cell carcinoma coexsting in the gall bladder. An 87-year-old woman was seen at the hospital because of sudden right hypochondralgia. From clinical symptoms, findings, and various imaging methods, the patient was diagnosed as acute cholecystitis and cholecystectomy was performed. There were stones in the gall bladder, a lesser tubercle-like elevated lesion in the fundus of the gall bladder, and a papillary tumor in the cervical part of the organ. Histopathologically the lesion in the fundus was adenosquamous cell carcinoma in which adenocarcinoma partially accompanied by keratinization and a transition into squamous cell carcinoma. On the other hand, the lesion in the cervical part of the gall badder was adenocarcinoma. The both lesions were independent and no continuity between them was found. Multiple carcinoma of he gall bladder, coexisting of adenosquamous cell carcinoma and adenocarcinoma, has not been reported in Japan so far. A review of the relevant literature is also presented here.

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.