Cases Of Chronic Cholecystitis Research Articles

Ultrasonographic evaluation of hepatobiliary diseases

Background and Objectives: The science of Diagnostic ultrasound is perhaps the most promising of the imaging modalities currently available. The main objective of this study is to establish the efficacy of ultrasonography to detect various hepatobiliary lesions and provide necessary information, aiding in their appropriate management. Methods: This study, carried over a period of two years, included 150 patients with various hepatobiliary lesions. There were patients of both sexes and their ages were above 5 years and below 85 years. After the routine blood and urine investigations and liver function tests, the patients were subjected to ultrasound examination. Results: One fifty cases, aged between 5 and 85 years, with various hepatobiliary lesions were studied with real time ultrasonography. The most frequently encountered Gall bladder lesion was Gallstones (44) with associated chronic cholecystits in 32 cases, acute cholecystitis in 10 cases, Gall bladder carcinoma in 2 cases. There were 3 cases of GB polyp, 2 case of chronic cholecystitis, 1 case of CA Gallbladder which were not associated with gall stones. Among the CBD lesions there were 2 cases of choledocholithiasis, 2 cases of cholangiocarcinoma and 1 case of choledochal cyst. The most frequently encountered focal liver lesion in this study was amoebic liver abscess which was found in 20 cases. The second most commonly encountered focal liver lesion was hepatocellular carcinoma which was found in 12 cases. 10 cases with hepatic metastasis were found. 4 cases with ultrasound features highly suggestive of haemangioma and 2 cases with hepatic hydatid disease were found. One case each of an intrahepatic haematoma and a simple liver cyst was found. Among the diffuse liver diseases, the most commonly encountered was fatty liver which was seen in 16 cases. The second most common diffuse liver disease was cirrhosis which was seen in 12 cases. 10 cases of acute hepatitis, 4 cases of chronic hepatitis and 3 cases of congestive liver was found. Conclusion: Ultrasound proved to be a sensitive, easily available and safe imaging modality for the diagnosis and follow-up of various hepatobiliary lesions and should therefore be the first line of investigation in suspected cases.

Microarray based gene expression profiling of advanced gall bladder cancer.

Gall bladder cancer (GBC) is an aggressive cancer with specific predilection like female gender and specific geographical areas, however the molecular mechanisms and factors contributing to the clinical or biological behavior are not understood. The aim of this study was to perform a comprehensive analysis of differentially expressed genes in advanced GBC and chronic cholecystitis(CC) cases. Microarray was planned on fresh specimens of advanced GBC and CC cases using single color cRNA based microarray technique (8X60K format; Agilent Technologies, USA). Twelve advanced GBC and four CC patients were included in the study. Of the total of 1307differentially expressed genes, 535genes were significantly upregulated, while 772genes were significantly downregulated in advanced GBC vs CC samples. Differentially expressed genes were associated with biological processes (55.03%), cellular components (31.48%), and molecular functions (13.49%) respectively. The important pathways or key processes affected were cell cycle, DNA replication, oxidative stress, gastric cancer pathway. Using in silico analysis tools, three differentially expressed genes i.e. TPX2, Cdc45and MCM4were selected (for their significant role in DNA replication and microtubule function) and were further validated in 20advanced GBC cohort by immunohistochemistry. Significant positive association of Cdc45and MCM4proteins was found in advanced GBC cases (p=0.043), suggesting the probable oncogenic role of Cdc45and MCM4proteins in advanced GBC. Our data demonstrate the potential regulation of Cdc45-MCM4axis in advanced GBC tumors. Additionally, our study also revealed a range of differentially expressed genes (e.g. TPX2, AKURA etc.) between GBC and CC, and further validation of these genes might provide a potential diagnostic or therapeutic target in future.

A Case of Chronic Cholecystitis with Peri-hilar Bile Duct Stenosis that was Difficult to Differentiate

A Case of Chronic Cholecystitis with Peri-hilar Bile Duct Stenosis that was Difficult to Differentiate

Study of histopathological findings in gallbladder diseases

Introduction: Cholecystectomy is one of the most frequently performed emergency abdominal operation as the gallstones are one of the major causes of morbidity and mortality all over the world affecting 10% of adult population. According to consolidated report of population based registries of India 2009-2011 (by National centre for disease informatics and research), India has shown high incidence of gall bladder cancer in female population of Kamrup (Assam) district, which is highest among the world. Clinical diagnosis of the cholecystitis is made, based on history and physical examination along with laboratory and radiological findings. However, histopathological study is the gold standard for the diagnosis of cholecystitis. Histopathological examination many time reveals an unusual diagnosis bearing significant implications on the treatment, prognosis and outcome of the patient. Aim and Objectives: To study various lesions encountered in cholecystectomy specimens on histopathology. Observations and Results: The most common histopathological diagnosis was chronic cholecystitis seen in 112 out of 130 cases (86.3%), followed by acute cholecystitis 12 cases (9.2%). There were 4 (3.0%) cases of adenocarcinoma of gallbladder. Total 92.5% chronic cholecystitis cases were calculous while 66.6 % of acute cholecystitis and 25 % (one out of four) of gall bladder carcinoma were associated with gall stones. Out of total 113 (86.9%) gallstones – 4 (3.5%) were pure cholesterol stones, 14(12.4%) pigmented stones and 95 (84.1%) were mixed stones. In the present study all 4 cases (100%) of malignancy were adenocarcinoma; out of which 1 case was (25%) papillary adenocarcinoma, 1 case (25%) was poorly differentiated and 2 cases (50%) were moderately differentiated adenocarcinoma. Amongst the four cases of adenocarcinoma, 3 (75 %) cases showed serosal infiltration and liver infiltration. Conclusions: Clinical presentation of diseases of gall bladder is vague. Even malignancy of gall

Hyalinizing Cholecystitis: A Rare Subtype of Chronic Cholecystitis

Hyalinising cholecystitis is rare form of chronic cholecystitis. It comprises about 1.6% of the cholecystectomy specimens. Hyalinising cholecystitis is said to be associated with risk of gallbladder cancer. We hereby present a case of a 54-year-old woman who came with chief complain of pain in right upper abdomen. She was diagnosed as a case of chronic cholecystitis on ultrasonography. For this the patient underwent cholecystectomy during which the gallbladder was removed. The final diagnosis of hyalinising cholecystitis was given on histopathology.

Prognostic significance of AgNOR Proliferative Index in gallbladder carcinoma - A potential alternative to frozen section analysis

Introduction: Number of Argyrophillic Nucleolar Organizer Regions (AgNORs) is a good indicator of cellular proliferation activity and is useful diagnostic tool to estimate the malignant potential of tumors. Methods: Tissue sections from 40 cases of gall bladder disease, including 27 cases of gallbladder carcinoma and 13 cases of chronic cholecystitis, were studied for AgNORs count. The correlation of the AgNOR was carried out with various clinco-pathological parameters. Results: Mean AgNOR counts in gallbladder cancer (11.354 ± 1.7866) were significantly higher than chronic cholecystitis (2.0815 ± 0.3731). Amongst patients with gallbladder carcinoma, well-differentiated (9.5867 ± 1.8928), moderately-differentiated (11.1971 ± 1.3181) and poorly-differentiated adenocarcinoma (13.1829 ± 0.9779) showed statistically significant difference in AgNOR counts. On inter stage comparison, study revealed progressive and statistically significant increase in AgNOR count from Tis to T4 stage. Mean AgNOR count for GBCs without metastasis was lower (10.5186 ± 1.6911) than metastatic GBC (12.2538 ± 1.4581), difference being statistically significant (p=0.009). Discussion and conclusions: Our results demonstrate that AgNOR parameters are useful indicators to evaluate malignant behavior of gallbladder carcinoma and its combination with conventional cytology may increase the diagnostic accuracy. AgNOR index can be used as a rapid, inexpensive and easily performed diagnostic tool to aid in early confirmation of a suspicious case of malignant gallbladder disease.

Abstract 3907: Expression of vascular endothelial growth factor a (VEGF-A) in advanced gallbladder cancer.

Abstract Gallbladder cancer (GBC) is a highly fatal disease with poor prognosis and few therapeutic alternatives. Molecular mechanisms involved in GBC pathogenesis remain poorly understood. The Vascular Endothelial Growth Factor A (VEGF) is a potent proangiogenic agent involved in the carcinogenesis of many human tumors and it is an attractive target for cancer therapy. The aim of this study was characterize VEGF expression in advanced gallbladder cancer and determine it's relationships with clinicopathologic features and utility as a prognostic factor. VEGF expression was examined by immunohistochemistry (IHC) in tissue microarrays containing 224 advanced gallbladder carcinomas and 39 cases of chronic cholecystitis (CC). The advanced GBC were classified as low or high expression to evaluate the association of VEGF expression level with clinical variables. Statistical analysis was performed using univariate analyses with a significance level of P<0.05; survival analysis was performed by the Kaplan- Meier method with the log-rank test. High expression of VEGF was observed in 183 of 224 (81%) tumors and 2 of 39 (5.1%) of chronic cholecystitis (P<0.0001). The VEGF expression had a significant relationship with clinical or pathological features included histological grade and TNM stage (P<0.05). Moreover, 5-year survival analysis indicated that high expression of VEGF is associated with a poor prognosis in patients with advanced gallbladder cancer (P = 0.0116). Our results indicate that VEGF is highly expressed in gallbladder cancer and correlates with poor prognostic, suggesting that VEGF expression could be used as a biomarker for predicting malignant behavior and to identify a subset of patients who may benefit from anti-VEGF therapies. Citation Format: Pablo Letelier, Kurt Buchegger, Carmen Ili, Patricia Garcia, Priscilla Brevi, Alejandra Sandoval, Pamela Leal, Ismael Riquelme, Juan Carlos Roa. Expression of vascular endothelial growth factor a (VEGF-A) in advanced gallbladder cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3907. doi:10.1158/1538-7445.AM2013-3907

The Correlation between Ultrasonography and Histopathology in the Management of Gall Bladder Polyps

Introduction : The diagnosis of gall bladder polyps has increased greatly due to widespread implementation of abdominal ultrasound.Patients and methods : Between February 2005 and February 2010 a total of 39 laparoscopic cholecystectomies were performed for suspected gall bladder polyps. We retrospectively analysed these patients pre-operative ultrasound and histopathology report.Results : The study comprised 10 male and 29 female symptomatic patients with a mean age of 51.4 years. Histo-pathology demonstrated seven true polyps and 23 pseudopolyps. There were no cases of malignant specimens and nine cases of chronic cholecystitis. The positive predictive value (PPV) of ultrasonography for gall bladder polyps was 0.77 and the PPV for true polyps 0.18.Conclusion : PPV for the identification of true gallbladder polyps using ultrasound remains very low at 0.18. We suggest that more advanced imaging modalities are required to improve this figure and enhance patient management.

PERINEURAL LYMPHOID INFILTRATION IN CHRONIC PANCREATITIS, PANCREATIC ADENOCARCINOMA AND CHRONIC CHOLECYSTITIS

Objective: to study the quantitative and qualitative composition of perineural lymphoid infiltration in chronic pancreatitis and pancreatic cancer. Methods. The histological specimens of 28 patients with chronic pancreatitis, 12 patients with pancreatic cancer and 1 patient with chronic cholecystitis who had undergone the surgery of the head of pancreas were studied. Immunohistochemical expression of CD-45, CD-20, CD-5, CD-3 and CD-79 was studied in 14 cases (10 cases of chronic pancreatitis, 3 cases of pancreatic adenocarcinoma in chronic pancreatitis background disease and 1 case of chronic cholecystitis). Results. Hyperplasia and hypertrophy of nerve trunks in the pancreas and parapancreatic adipose tissue were detected in 26 of 28 cases of chronic pancreatitis, in 9 of 12 cases of pancreatic cancer and in 1 case of chronic cholecystitis. The perineural lymphoid infiltration was revealed in more than a half of the revealed cases. The considerable variability of qualitative and quantitative cell composition of perineural infiltrate was determined in chronic pancreatitis. Conclusion. The reparative hyperplasia and hypertrophy of nervous tissue is the consequence of primary enzymatic damage of myelin sheaths of nerves in pancreas during acute conditions of chronic pancreatitis. These changes of nerve trunks are accompanied by the development of an autoimmune response which is probably the cause of pancreatic pain in the period between exacerbations of chronic pancreatitis. The ratio of T-cells and B-cells in perineural infiltrate is probably caused by different duration of pathological process.

Infectious cholecystitis due to enteric coccidian parasites

Background: Cholecystitis is one of the common surgical cases affecting human beings in many countries. A variety of microorganisms can be associated with acute and chronic cholecystitis especially in AIDS patients. Unfortunately, in as many as half of cases, no microorganism can be identified by pathological examination. Methods: Retrospective histopathologic review of 75 immunocompetent and immunocompromised patients with symptomatic cholecystitiswho underwent cholecystectomy fromMarch 2010 to December 2010 at some hospitals of Shiraz, southern Iran. Results: In all patients, no specific symptoms have been observed to be predictive of coccidian infection of the gall bladder, but have been significantly associated with an abnormal gall bladder ultrasound reported by radiologist. Pathologic investigation revealed an abnormal gall bladder with thick wall in all cases. Onmicroscopic examination of archived cholecystectomy samples using H&E stain, we found two cases of chronic cholecystitis without cholelithiasis due to infections with Sarcocystis sp. and Isospora belli in an AIDS female patient and amale patient respectively. Only the sexual stages of these coccidian parasites were detected in the gall bladder epithelium. Genus-specific PCR amplification was performed on archived paraffin-embedded sections. The microscopic and molecular characteristics of these microorganisms were consistent with Sarcocystis sp. and I. belli. Conclusion: To the best of authors’ knowledge, this is the first report of Sarcocystisand I. belli-associated chronic cholecystitis in patients from worldwide and Iran respectively. It is recommended that, the physicians should pay attention to the enteric coccidian parasites as possible causes of cholecystitis especially in immunocompromised patients.

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

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

Lessons Learned From Quality Assurance: Errors in the Diagnosis of Acute Cholecystitis on Ultrasound and CT

The purpose of this article is to study errors in the diagnosis of acute cholecystitis reported in the online departmental quality assurance (QA) database. The departmental QA database was searched from October 2005 to April 2010 for cases of acute cholecystitis. Errors were classified into overcalls and undercalls. We identified 14 cases of misdiagnosis involving acute cholecystitis. Three cases were classified as overcalls (21%) and eleven as undercalls (79%). Eight cases of misdiagnosis involved ultrasound studies (57%) and six cases involved CT studies (43%). Cases of overcall on ultrasound showed gallbladder wall edema, but none portrayed distention of the gallbladder. The final diagnosis in these cases included hepatitis, sepsis, and a case of chronic cholecystitis. All misinterpretations of CT cases were classified as undercalls. Contributing factors to misdiagnosis were lack of recognition of wall edema (n = 6), gallbladder distention (n = 4), absence of gallbladder wall edema (n = 1), lack of conclusion in the report (n = 2), and hospitalization in the ICU (n = 2). A possible case clustering was observed just after July almost every year. An important pitfall in the diagnosis of acute cholecystitis is lack of recognition of gallbladder wall edema on CT. A relaxed (nondistended) gallbladder provides important evidence against the diagnosis of acute cholecystitis. Intensive care patients with sepsis often have no specific signs for diagnosis of acute cholecystitis, making diagnosis especially challenging.

Role of E-cadherin gene in gall bladder cancer and its precursor lesions

The aim was to investigate the genomic instability in the E-cadherin (CDH1) gene and to correlate it with its protein expression in gall bladder cancer (GBC) and in other gall bladder (GB) diseases viz. chronic cholecystitis (CC), xantho-granulomatous cholecystitis (XGC), and normal GB to explicate its role in GBC tumorigenesis. Microsatellite instability (MSI) and loss of heterozygosity (LOH) in CDH1 were studied using D16S421, D16S496, D16S503, D16S512, D16S2624, and D16S3021 microsatellite markers and D2S123 (2p16), D2S382 (2q24), D6S292 (6q21-23), D7S480 (7q31), and D17S796 (17p13.1-3) were used to investigate genomic instability at 2p, 2q, 6q, 7q, and 17p loci in 40 GBC, 50 CC, 34 XGC, and 15 normal GB cases. Immunohistochemistry was carried out to analyze the E-cadherin and p53 protein expression. Overall LOH in CDH1 and other markers was high in GBC and XGC as compared to CC; however, it did not correlate with its protein expression in GBC cases. Loss of E-cadherin expression was high in GBC (67%), while majority of the CC (94%) and XGC (91%) cases retained positive E-cadherin expression. Overexpression of p53 was high in GBC (43%) whereas CC, XGC, normal GB cases were negative for p53 overexpression. None of the normal GB cases showed genomic instability at any of the markers. High LOH in CDH1 and other chromosomal loci in GBC indicated that the genomic instability followed a GBC>XGC>CC trend during the process of neoplastic transformation in GB, highlighting the fact that CC might act as a precursor lesion of GBC.

Thirty Cases of Chronic Cholecystitis Treated by Acupuncture and Oral Adiministration of Da Chai Hu Tang

Thirty Cases of Chronic Cholecystitis Treated by Acupuncture and Oral Adiministration of Da Chai Hu Tang

Aberrant Promoter Hypermethylation of Multiple Genes in Gallbladder Carcinoma and Chronic Cholecystitis

Aberrant methylation of 5' gene promoter regions is an epigenetic phenomenon that is a major mechanism for silencing of tumor suppressor genes in many cancer types. There is limited information about the molecular changes involved in the pathogenesis of gallbladder carcinoma (GBC), including methylation status. We investigated the aberrant promoter methylation profile of 24 known or suspected tumor suppressor genes in 50 GBCs and compared those results with the findings in 25 chronic cholecystitis (CC) specimens without cancer. The methylation-specific polymerase chain reaction and combined restriction analysis methods were used to detect methylation, and the results were confirmed by sequencing of cloned polymerase chain reaction products. In GBC, gene methylation frequencies varied from 0% to 80%. Ten genes demonstrated relatively high frequencies of aberrant methylation: SHP1 (80%), 3-OST-2 (72%), CDH13 (44%), P15INK4B (44%), CDH1 (38%), RUNX3 (32%), APC (30%), RIZ1 (26%), P16INK4A (24%), and HPP1 (20%). Eight genes (P73, RARbeta2, SOCS-1, DAPK, DcR2, DcR1, HIN1, and CHFR) showed low frequencies (2-14%) of methylation, and no methylation of the remaining six genes (TIMP-3, P57, RASSF1A, CRBP1, SYK, and NORE1) was detected. In CC, methylation was detected for seven genes: SHP1 (88%), P15INK4B (28%), 3-OST-2 (12%), CDH1 (12%), CDH13 (8%), DcR2 (4%), and P16INK4A (4%). Significantly higher frequencies of methylation in GBC compared with CC were detected for eight genes (3-OST-2, CDH13, CDH1, RUNX3, APC, RIZ1, P16INK4A, and HPP1). Of those, four genes showed frequent methylation (>30%) in GBCs. The mean methylation index, an expression of the amount of methylated genes by case, was significantly higher in GBC (0.196 +/- 0.013) compared with CC (0.065 +/- 0.008; P < 0.001). Our study constitutes the most comprehensive methylation profile report available in GBC and demonstrates that this neoplasm has a distinct pattern of abnormal gene methylation. Whereas gallbladders from healthy individual were not available, our finding of methylation in CC cases without cancer suggests that this phenomenon represents an early event in the pathogenesis of GBC.

The clinical significance of gall-bladder non-visualization in cholescintigraphy of patients with choledochal cysts.

Intravenous radionuclide cholescintigraphy (IVRC) provides a very specific picture for choledochal cysts. However, the clinical significance of the non-visualization of the gall-bladder (GB) activity in these cases is unclear. In this study, we reviewed 27 patients with choledochal cysts who underwent IVRC within 7 days prior to operation and correlated the GB findings on IVRC with the histopathological results. In 18 of the 27 patients (66.7%), there was non-visualization of the GB at 4 h post injection. Among these, two had histopathological features of acute cholecystitis (AC), 11 had chronic cholecystitis (CC), and five had normal GBs. In the other nine patients with visualization of the GB, there were five cases of CC and four normal GBs. If we apply the finding of non-visualization of the GB at 4 h post injection as the criterion for the diagnosis of AC, the diagnostic accuracy was only 40.7% (11/27). We concluded that: (1) GB disease (AC and CC) was common (66.7%: 7.4% and 59.3% respectively) in choledochal cyst patients. (2) Non-visualization of the GB on IVRC did not necessarily indicate AC in choledochal cyst cases, and the diagnostic accuracy was low. (3) GB disease is not the only cause of GB non-visualization on IVRC. A huge choledochal cyst causing a mass or reservoir effect may be a cause of GB compression and result in non-visualization of the GB.

Differences in cell proliferation and prognostic significance of proliferating cell nuclear antigen and Ki-67 antigen immunoreactivity in in situ and invasive carcinomas of the extrahepatic biliary tract.

Cell proliferative activity is an important indicator of growth and behavior of various human tumors. Immunostaining of tissue sections with proliferating cell nuclear antigen (PCNA) and Ki-67 antibodies appears to be reliable in the assessment of tumor cell proliferation. This study examined differences in cell kinetics between neoplastic and nonneoplastic lesions of the gallbladder and biliary tract using an antibody against PCNA and Ki-67. There were a total of 27 cancer cases comprising patients with invasive carcinoma of the gallbladder (n = 13), common bile duct (n = 5) and ampulla of Vater (n = 8). Cases of chronic cholecystitis (n = 11) from the nonneoplastic group; carcinoma in situ (CIS) of the gallbladder (n = 4) and ampulla (n = 6) from the noninvasive group. Cell cycle activity was determined in sections of routinely formalin fixed, paraffin processed, biopsy material using immunohistochemical stains for the monoclonal PCNA, PC10, KI-67, and MIB-1. The expression of PCNA and MIB-1 in these conditions was determined by calculating the percentage of cell nuclei that stained positively to obtain the PCNA and MIB-1 indices, respectively. The PCNA and MIB-1 indices in chronic cholecystitis were significantly lower than those obtained in both moderately and poorly differentiated adenocarcinoma of the gallbladder (P < 0.001). Similarly, cases of ampullary and gallbladder CIS had significantly lower PCNA and MIB-1 indices than the invasive carcinoma cases (P < 0.001). There was a strong correlation between PCNA and MIB-1 expression (r = 0.828, r2 = 0.686; P = 0.001), although the PCNA index was generally higher than that of MIB-1. The poorly differentiated adenocarcinomas of the gallbladder had higher mean PCNA and MIB-1 indices but reduced patient survival when compared with the moderately differentiated carcinomas. In conclusion, gallbladder, ampulla, and common bile duct carcinomas have significantly higher PCNA and MIB-1 indices than CIS and nonneoplastic lesions. Because tumors with higher PCNA or MIB-1 indices are associated with a poorer prognosis, both PCNA and MIB-1 may be useful markers of tumor cell proliferative activity and biologic behavior in gallbladder, ampullary, and common bile duct carcinomas.

C-erbB-2 Oncoprotein Immunoreactivity in Gallbladder and Biliary Tract Cancers

Overexpression of c-erbB-2 protein, a 185-kD transmembrane tyrosine kinase protein, is found in a number of human cancers. c-erbB-2 expression was examined, using immunohistochemistry with the polyclonal antibody NCL-PC 11 in carcinoma of the gallbladder (n = 13), biliary tract (n = 6), and ampulla of Vater (n = 9). These were compared with nonmalignant conditions such as chronic cholecystitis (n = 1 1), gallbladder dysplasia (n = 3), and adenoma (n = 1), and ampullary carcinoma in situ (n = 3) and adenoma (n = 1). Most gallbladder carcinomas (85%) and dysplasias (100%), common bile duct (83%) and ampullary (67%) carcinoma, and ampullary carcinoma in situ (67%) showed moderate to strong c-erbB-2 protein immunoreactivity. In contrast, the majority of cases of chronic cholecystitis (64%) had absent or weak c-erbB-2 protein immunostaining. However, immunohistologic detection of c-erbB-2 overexpression in the form of distinct cell membrane immunostaining was found in a minority of gallbladder carcinomas (23%) and not in any of the other preneoplastic or neoplastic lesions of the biliary tract or chronic cholecystitis. The patients who had carcinoma with c-erbB-2 overexpression had a shorter median survival period (3.1 months). However, there was no correlation between tumor stage and c-erbB-2 expression. This may be related to the small number of cases of gallbladder tumors available for this study, and further work with a larger series with adequate clinical follow-up time may be required to confirm the prognostic trend. The differences in c-erbB-2 expression between gallbladder, common bile duct, and ampullary carcinomas suggest that mutation of the gene may be a late event in the sequential development of gallbladder and biliary tract cancers.

Gallbladder Carcinoma: A Video Image Analysis of AgNOR Distribution and its Relation to Tumour Stage and Grade

The amount and distribution of interphase argyrophilic nucleolar organizer regions (AgNORs) was studied in 51 gallbladder surgical specimens including 32 primary carcinomas, 10 adenomas and 9 cases of chronic cholecystitis with calculi. The mean nuclear AgNOR area (NORA) and the AgNOR distribution score (NORDS), i.e. the percentage of cells carrying nucleolar aggregates with more than 6 distinct silver dots, were evaluated in 200 epithelial nuclei per specimen by means of automated image analysis and direct counting respectively. Statistical analysis (variance analysis and Student-Neuman-Keuls' test) performed on the pooled mean AgNOR values showed a significant difference (p < 0.001) between carcinomas and non-carcinomatous lesions. Both NORA and NORDS highly discriminated carcinomas with histopathological grade 4 versus cases with grade 1, 2 or 3 (p < 0.001); a less statistically significative p value (< 0.05) was encountered when NORDS values of well differentiated grade 1 carcinomas and adenomas were compared. The NORA parameter permitted the discrimination of stage IV versus stage I carcinomas (p < 0.001), while carcinomas in stage IV and those in stage II were distinguished with a p < 0.05; the NORDS parameter allowed also to distinguish stage IV from both stage I or II tumours (p < 0.001). Our results indicate that the above-mentioned AgNOR parameters may be utilized as additional, more objective quantitative criteria in the clinical-pathological assessment of the outcome of gallbladder carcinomas.

P53 protein immunoreactivity in cancers of the gallbladder, extrahepatic bile ducts and ampulla of Vater

Immunohistochemical expression of the p53 protein was investigated in carcinoma of the gallbladder (n = 13), common bile duct (n = 7) and ampulla of Vater (n = 9) using the polyclonal, CM1, and monoclonal, DO7, antibodies (Novocastra). This was compared with cases of chronic cholecystitis (n = 11) and preneoplastic lesions of the gallbladder (n = 4) and ampulla (n = 3). Nuclear immunostaining for p53 protein was found only in the poorly differentiated adenocarcinomas of the gallbladder (n = 9) and were associated with a shorter patient survival period (median: 18.6 mths). The moderately differentiated adenocarcinomas (n = 4) did not show p53 immunostaining and were associated with a longer median survival period (26 mths). The gallbladder dysplasias and adenoma also had no p53 protein immunoreactivity. The common bile duct carcinomas did not stain for p53. Focal p53 immunoreactivity was present in only one (11%) of the cases of ampullary carcinoma and in one (9%) of chronic cholecystitis. In summary, increased p53 immunostaining was associated with reduced patient survival and found more frequently in poorly differentiated adenocarcinoma of the gallbladder but not in the better differentiated carcinoma, chronic cholecystitis or preneoplastic lesions of the gallbladder. The differences in p53 immunohistological expression between gallbladder, common bile duct and ampullary carcinomas justify further investigation into the molecular mechanisms responsible for their development.