Extrahepatic Biliary Carcinoma Research Articles

Computed Tomography Evaluation of Gall Bladder Mass with Histopathological Correlation

Background: In extrahepatic biliary carcinoma patients, unresectable disease is frequently discovered during exploration despite thorough preoperative assessment, leading to unnecessary laparotomy. Gallbladder carcinoma ranks fifth among gastrointestinal malignancies, following colorectal, pancreatic, gastric, and esophageal carcinomas. Aim of the study: The aim of the study was to establish the diagnostic usefulness of computed tomography (CT) in the diagnosis of gallbladder mass. Methods: This case-control study was conducted at the Department of Radiology and Imaging, Rajshahi Medical College Hospital, Rajshahi, Bangladesh from March 2018 to August 2018. The study included 65 patients diagnosed with a gallbladder mass, selected through purposive sampling. SPSS version 23.0 was utilized for data analysis. Results: CT scans accurately predicted various features of gallbladder mass, showing high sensitivity, specificity, and accuracy, with positive and negative predictive values of ≥95% for adenocarcinoma, squamous carcinoma, cholecystitis, metastases, GB polyp, and adenoma. Chronic cholecystitis sensitivity was over 83%. Overall, CT diagnosis performed at least 88.9% across all features. The histopathological assessment also detected nearly similar features of gallbladder mass. Conclusion: Computed tomography (CT) serves as a valuable diagnostic tool for distinguishing gallbladder neoplasms preoperatively. It is worth noting that CT scans aid in the rational management approach for patients with gallbladder neoplasms.

Particle Beam Therapy for Intrahepatic and Extrahepatic Biliary Duct Carcinoma: A Multi-Institutional Retrospective Data Analysis.

To examine the efficacy and toxicity of particle beam therapy (PT) for biliary duct carcinoma (BDC) and compare the outcomes between extrahepatic BDC (eBDC) and intrahepatic BDC (iBDC). We analyzed multi-institutional data from May 2009 to December 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS) and toxicity. We included 150 patients with unresectable BDC treated with PT using a median prescribed dose of 70.2 GyRBE (range, 44-77 GyRBE) in 25 fractions (range, 10-38 fractions). With a median follow-up of 13.0 months, median survival time (MST) was 21 months, and 2-year OS was 44.8%. For eBDC and iBDC, the MSTs were 20 and 23 months, respectively. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Vascular invasion, prescribed dose and serum tumor marker level (carcinoembryonic antigen: CEA) were identified as poor prognostic factors for OS. A higher radiation dose EQD2 ≥ 67 Gy showed superior OS, with a hazard ratio of 0.341. The radiation dose of PT is an important predisposing factor for overall survival. The MST for patients with eBDC given a higher radiation dose was 25 months, compared to 15 months for those given the lower dose and 23 months for patients with iBDC (all iBDC given higher doses). iBDC and eBDC duct carcinomas showed equivalent outcomes with PT, especially when treated with a high radiation dose. In detailed analysis, baseline CEA level in iBDC, and radiation dose and GTV in eBDC were statistically significant predicators for OS. Acute and late toxicity grade ≥3 occurred in 2.2% and 2.7% of patients, respectively, including two late grade-5 toxicities. In conclusion, PT showed good efficacy for BDC, both eBDC and iBDC, with a low incidence of severe toxicity.

Surgery for Recurrent Biliary Carcinoma: Results for 5 Recurrent Cases

Introduction: Typically chemotherapy has been used as standard treatment and surgeries were rarely performed for recurrent extrahepatic biliary carcinoma (RBC). Thus whether surgery for RBC is feasible has remained unclear. Methods: From 2013 to 2019, 5 patients underwent radical resection for RBC at our institution. We retrospectively reviewed the medical data. Results: Recurrence sites were liver metastasis in 3 patients (LM group) and local or bile duct recurrence in 2 patients (BD group). In the LM group, the underlying pathology was distal bile duct carcinoma, gallbladder carcinoma and ampullary carcinoma. Limited resections of the liver were performed for all 3 patients in the LM group. There was no morbidity nor mortality. 1 patient with liver metastasis of gallbladder carcinoma survived 6 years after surgery for RBC. The other 2 patients had recurrence at 9 and 14 months after surgery. In the BD group, the underlying pathology was distal bile duct carcinoma and proximal bile duct carcinoma. 1 patient underwent pancreaticoduodenectomy in the primary surgery and extended right hemihepatectomy for RBC. The other underwent central bisegmentectomy of the liver in the primary surgery and right lateral sectionectomy of the liver for RBC. There was morbidity in 1 patient but no mortality. Both patients could achieve curative resection and survive without recurrence for 9 and 2 months after surgery for RBC. Conclusion: Surgery for RBC is technically demanding procedure but appears feasible and have a possibility of offering longer survival for selected patients but we should be cautious of indication.

Core Hippo pathway components act as a brake on Yap and Taz in the development and maintenance of the biliary network.

The development of the biliary system is a complex yet poorly understood process, with relevance to multiple diseases, including biliary atresia, choledochal cysts and gallbladder agenesis. We present here a crucial role for Hippo-Yap/Taz signaling in this context. Analysis of sav1 mutant zebrafish revealed dysplastic morphology and expansion of both intrahepatic and extrahepatic biliary cells, and ultimately larval lethality. Biliary dysgenesis, but not larval lethality, is driven primarily by Yap signaling. Re-expression of Sav1 protein in sav1-/- hepatocytes is able to overcome these initial deficits and allows sav1-/- fish to survive, suggesting cell non-autonomous signaling from hepatocytes. Examination of sav1-/- rescued adults reveals loss of gallbladder and formation of dysplastic cell masses expressing biliary markers, suggesting roles for Hippo signaling in extrahepatic biliary carcinomas. Deletion of stk3 revealed that the phenotypes observed in sav1 mutant fish function primarily through canonical Hippo signaling and supports a role for phosphatase PP2A, but also suggests Sav1 has functions in addition to facilitating Stk3 activity. Overall, this study defines a role for Hippo-Yap signaling in the maintenance of both intra- and extrahepatic biliary ducts.

Clinical study of S-1 single agent adjuvant chemotherapy in the radical resection of extrahepatic biliary carcinoma

Objective: To explore the clinical efficacy of S-1 single agent adjuvant chemotherapy for the patients undergoing radical resection of extrahepatic biliary carcinoma. Methods: The clinical data of 108 patients with extrahepatic biliary carcinoma receiving radical resection who were admitted from January 2014 to June 2017 were retrospectively analyzed. There were 62 males(57.4%)and 46 females(42.6%),with a median age of 59 years (range:26 to 79 years),10 cases(9.3%) in stage Ⅱ,85 cases(78.7%) in stage Ⅲ, and 13 cases (12.0%) in stage Ⅳ, 40 cases(37.0%) of hilar cholangiocarcinoma, 8 cases(7.4%) of middle cholangiocarcinoma, 25 cases (23.2%) of distal cholangiocarcinoma, 35 cases(32.4%) of gallbladder carcinoma.After radical resection of extrahepatic biliary carcinoma, 49 patients receiving S-1 single agent chemotherapy and 59 patients receiving non-special treatment were divided into the chemotherapy group and the operation group,respectively. All the dates of the patients were followed up and collected with the overall survival time,tumor-free survival time,1,2 and 3-year survival rate after operation,and the rate of major toxic reaction during chemotherapy of the chemotherapy group. Survival curve was drawn by the Kaplan-Meier method, and survival analysis was done using the Log-rank test. Results: There were no significant differences in the general date of two groups(sex, age, tumor size, tumor site, TNM stages, degree of differentiation). The median overall survival time and the median tumor-free survival time in the chemotherapy group were 27 months and 21 months,respectively,and in the operation group were 21 months and 17 months,respectively. There were differences between the two groups in the overall survival rates(χ(2)=3.967,P<0.05) and the 2 and 3-year survival rate(63.3%,36.6%;41.6%,20.4%;χ(2)=4.510,P<0.05;χ(2)=6.143,P<0.05),but the 1-year overall survival rate (83.4%,79.7%)was not statistically significant(χ(2)=0.286,P>0.05). There were no significant differences in the tumor-free survival time,1,2 and 3-year tumor-free survival rate(77.6%,41.4%,33.1%;62.7%,30.9%,21.2%)between the two groups(χ(2)=0.876,P>0.05;χ(2)=0.252,P>0.05;χ(2)=1.571,P>0.05;χ(2)=3.323,P>0.05,respectively). The main toxic reaction during chemotherapy were dyspepsia(28.6%, 14/49), anemia(26.5%, 13/49), and leukopenia(22.5%, 11/49), all of which were mild. Conclusion: S-1 single agent chemotherapy after radical reseetion of extrahepatic biliary carcinoma could effectly improve the survival of patients and all of the main toxic reaction during chemotherapy were mild.

Hospitalization outcomes between intrahepatic bile duct carcinoma versus extrahepatic biliary cholangiocarcinoma

Background: Cholangiocarcinoma is an uncommon cancer with a very bad prognosis despite advances made in treatment. The location of the tumor (intrahepatic versus extrahepatic) determines surgical options. In our study, we examine variations in outcomes between patients admitted to the hospital with intrahepatic versus extrahepatic disease. Methods: Data from the NIS, a database developed for the healthcare Cost and Utilization project (HCUP) was used for our analysis. We identified patients who were 18 years and older with intrahepatic or extrahepatic biliary duct carcinoma who underwent a procedure (biliary stent, resection, bypass, pancreatic resection, liver resection and transplantation) during a hospitalization. Our primary aim was to describe outcomes in terms of inpatient mortality, length of stay and hospitalization cost based on tumor location. We used multivariable logistic regression to calculate adjusted odd ratios and mean differences for each cohort. We controlled for patient level characteristics (age, race, sex, comorbidity burden), hospital level characteristics (hospital region, size and teaching status), insurance type and procedure received during hospitalization using multivariable analysis. Results: We identified a total of 18,840 admissions in 2014 with a discharge diagnosis of cholangiocarcinoma (intrahepatic or extrahepatic). Of these, 13,930 (73.1%) were intrahepatic while 4,930 (26.1%) were extrahepatic. Inpatient mortality amongst patents with extrahepatic bile duct carcinoma was 5.5% while that for intrahepatic bile duct carcinoma was 7.69%. After controlling for confounders, including treatment received during hospitalization, patients with extrahepatic disease were 30% less likely (Adjusted Odds Ratio 0.70, 95 % CI 0.512-0.966) to die during hospitalization compared to patients admitted for intrahepatic bile duct carcinoma. Length of stay was similar between the two groups (Adjusted Mean Difference -0.10, 95 % CI -0.64 -0.44) as was average cost of hospitalization (Adjusted Mean Difference. -4126, 95% CI -1.0986.5 - 2733.16). Conclusion: The location of biliary duct carcinoma predicts inpatient mortality, even after controlling for treatment received. Intrahepatic cholangiocarcinoma has a worse prognosis than extrahepatic tumors, although length of stay and average cost of hospitalization are similar across the two cohorts. The two carcinomas have different histology, molecular characteristics, and associated genetic abnormalities. Intrahepatic cholangiocarcinoma is more likely to be associated with cirrhosis due to underlying viral hepatitis or non alcoholic fatty liver disease. It is unclear if these pathological characteristics or underlying chronic inflammation influence outcomes. We recommend prospective studies to better understand reasons for variation in hospitalization mortality seen in patients with intrahepatic cholangiocarcinoma.

Surgery for recurrent biliary carcinoma: results for 27 recurrent cases.

BackgroundVarious chemotherapies have been used as best practice to treat recurrent biliary malignancies. Conversely, relatively few surgeries have been described for recurrent extrahepatic biliary carcinoma (RExBC), so whether surgery for RExBC is feasible has remained unclear. This retrospective study was conducted to evaluate the feasibility of surgery for RExBC.MethodsFrom February 2000 to January 2014, a total of 27 patients, comprising 18 patients with extrahepatic cholangiocarcinoma and 9 patients with gallbladder carcinoma, met our criteria for radical resection of RExBC (resection group). Sites of recurrence consisted of liver metastases (ten patients), local/percutaneous transhepatic cholangio drainage (PTCD) fistula recurrence (eight patients), bile duct recurrence (six patients), and lymph node recurrence (one patient). To evaluate the survival impact of resection, we compared 123 RExBC patients (resection group) with patients who received palliative care (palliative group).ResultsMorbidity and mortality rates in the resection group were 6.6% and 0%, respectively. Overall cumulative 5-year survival rates were 23.5% in the resection group and 0% in the palliative group. Median survival time was 21.6 months in the resection group and 9.5 months in the palliative group, showing a significant difference (p < 0.01). No significant differences in cumulative survival were seen between extrahepatic cholangiocarcinoma and gallbladder carcinoma in the resection group. In addition, no significant differences were seen between liver metastases, bile duct recurrence, and local/percutaneous transhepatic biliary drainage (PTBD) fistula recurrence in the resection group.ConclusionsSurgery appears feasible for RExBC and offers longer survival for selected patients.

Three-Dimensional Fusion Images of Hepatic Vasculature and Bile Duct used for Preoperative Simulation before Hepatic Surgery

Recent developments in radiological technology allowed acquisition of images with high spatial resolution that facilitate effective 3-dimensional (3D) reconstruction of fusion images. Present study utilized 3D cholangiography and angiography with multi-detector-row computed tomography (MDCT) to acquire information regarding operative simulations. 3D-fusion images were evaluated in 39 patients with hepatobiliary malignancies who underwent surgical resections. An aberrant branch of segment 3 over the umbilical portal vein, a large hepatoma compressed the hilar vessels, an aberrant branch of the caudate lobe vasculature in case of metastatic liver tumor with a right-sided umbilical portal vein and transected biliary leakage were clearly observed by 3D imaging system. Four patients with intrahepatic cholangiocarcinoma underwent multiple biliary stent placements and adequate placement of biliary stents was possible. In 22 patients with extrahepatic biliary carcinomas, visualization of the extent of tumor invasion by 3D-fusion images was equivalent to conventional cholangiography. In 2 patients, adequate placement of multiple stents could be visualized with this system. In 2 patients who underwent hepatectomy, more extended cancer invasion was observed than was visualized by 3D-fusion images. 3D fusion images were very useful for preoperative simulations in order to understand relationships between tumors and adjacent vasculatures.

Radiotherapy and Chemotherapy as Therapeutic Strategies in Extrahepatic Biliary Duct Carcinoma

this report aims to provide an overview on radiotherapy and chemotherapy in extrahepatic biliary duct carcinoma (BDC). a PubMed research identified clinical trials in BDC through April 1, 2010 including randomised controlled trials, SEER analyses and retrospective trials. Additionally, publications on the technical progress of radiotherapy in or close to the liver were analysed. most patients with cholangiocarcinoma present with unresectable disease (80-90%), and more than half of the resected patients relapse within 1 year. Adjuvant and palliative treatment options need to be chosen carefully since 50% of the patients are older than 70 years at diagnosis. Adjuvant radiotherapy or chemotherapy after complete resection (R0) has not convincingly shown a prolongation of survival but radiotherapy did after R1 resection. However, data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy in patients with marginally resectable disease. For patients with unresectable biliary tract carcinoma (BTC), palliative stenting was previously the treatment of choice. But recent SEER analyses show that radiotherapy prolongs survival, relieves symptoms and contributes to biliary decompression and should be regarded as the new standard. Novel technical advances in radiotherapy may allow for dose-escalation and could significantly improve outcome for patients with cholangiocarcinoma. both the literature and recent technical progress corroborate the role of radiotherapy in BDC offering chances for novel clinical trials. Progress is less pronounced in chemotherapy.

Extrahepatic biliary carcinoma – a retrospective analysis

Die Mehrzahl der Patienten mit cholangiozellularem Karzinom befinden sich zum Zeitpunkt der Diagnosestellung bereits in fortgeschrittenen irresektablen Tumorstadien, und auch unter den primar operablen Patienten kommt es in den meisten Fallen zum Rezidiv innerhalb 1 Jahres. Wahrend die adjuvante Radio- bzw. Chemotherapie nach R0-Resektion keinen Uberlebensvorteil zeigt, existieren bei sorgfaltig selektierten Patientengruppen Daten zum Langzeituberleben nach neoadjuvanter Radiochemotherapie mit anschliesender Lebertransplantation. In der palliativen Situation ist derzeit die Einlage von Endoprothesen Methode der Wahl. Eine alleinige Radiotherapie fuhrt hier zwar zur Verbesserung der Lebensqualitat, eine Verlangerung des Gesamtuberlebens konnte jedoch bislang nicht sicher nachgewiesen werden. Durch Kombination von Strahlen- und Chemotherapie lies sich sowohl nach R1-Resektion als auch bei definitiver Behandlung die Uberlebenszeit verbessern, grosere Studien fehlen hier jedoch. Unter den derzeit verfugbaren Chemotherapeutika empfiehlt sich bei insgesamt masigen Ansprechraten Gemcitabin als Mittel der Wahl.

Oxaliplatin combined with leucovorin plus 5-FU (FOLFOX) in patients with advanced/metastatic biliary tract carcinoma

14093 Background: Biliary tract carcinoma is often diagnosed at advanced stage, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A phase II trial was conducted to study a FOLFOX regimen as first- or second- line therapy in biliary tract carcinoma. Methods: Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients were between 18 and 75 years of age and had histologically confirmed, measurable adenocarcinoma. Patients were stratified according to prior chemotherapy(6) and no prior chemotherapy(15). Treatment consisted of intravenous oxaliplatin (100mg/m2) as a 2 hours infusion on day 1 followed by leucovorin 100mg/m2 on day1 and 5-FU 1000∼1200mg/m2 as a 24 hours infusion on day 1,2. Treatment was repeated every 3 weeks for up to 6 cycles. Tumor response, survival and safety were determined Results: A total of 21 patients were evaluable;12 men and 9 women with a median age of 57(range 37–71). Tumor sites were: intrahepatic (n=7) and extrahepatic biliary duct (n=9); gallbladder (n=4); and ampulla (n=1). Total 115 cycles were administered (median 5 cycles, range 2∼12). According to RECIST criteria, partial response 3(14.3%), stable disease 10(47.7%) and disease progression.8(38%). The overall response rate with and without prior chemotherapy were 0%(0/6) and 20%(3/15), respectively. In patients without prior chemotherapy (15), median progression-free-survival and overall survival were 6.6(range, 1.2∼12.8) and 8.7(range, 3.7∼19.3) months. Grade 1–2 neurotoxicity, fatigue, diarrhea, anorexia, nausea were common. Grade 3 neutropenia and thrombocytopenia occurred in 23% and 4.7% of the patients respectively. There was no treatment related death. Conclusions: FOLFOX should be considered an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma. No significant financial relationships to disclose.

Capecitabine combined with gemcitabine (CapGem) as first‐line treatment in patients with advanced/metastatic biliary tract carcinoma

Biliary tract carcinoma is an aggressive cancer, with median survival rarely exceeding 6 months. There is currently no established palliative standard of care. A Phase II trial was conducted to study a combination of oral capecitabine and gemcitabine (CapGem) as first-line therapy in patients with advanced and/or metastatic biliary carcinoma. Patients with unresectable or metastatic intrahepatic or extrahepatic biliary duct carcinoma and gallbladder carcinoma were enrolled. Eligible patients had histologically or cytologically confirmed, measurable adenocarcinoma and had not received prior therapy with capecitabine or gemcitabine. Treatment consisted of intravenous (i.v.) gemcitabine (1000 mg/m(2) on Days 1 and 8) plus oral capecitabine (650 mg/m(2) twice daily on Days 1-14) every 3 weeks for up to 6 cycles. Tumor response, survival, and safety were determined. A total of 44 patients were evaluable. Primary tumor sites were: intrahepatic (n = 14) and extrahepatic biliary duct (n = 16); gallbladder (n = 7); and ampulla (n = 7). Fourteen (32%) patients had a partial response and 15 (34%) patients had stable disease. Median time to disease progression and overall survival were 6.0 (range, 3.8-8.1) and 14 (range, 11.4-16.6) months, respectively. The 1-year survival rate was 58%. No Grade 4 adverse events were seen. Transient Grade 3 neutropenia/thrombocytopenia and manageable (almost invariably Grade 2) nausea, diarrhea, and hand-foot syndrome were the most common adverse events. CapGem is an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma that offers a convenient home-based therapy.

Expression of the Caudal-Type Homeodomain Transcription Factors CDX 1/2 and Outcome in Carcinomas of the Ampulla of Vater

Adenocarcinomas of the ampulla of Vater demonstrate a characteristic histology but vary significantly in outcome. As a consequence, prognostic factors for these cancers are poorly defined. The caudal-type homeodomain transcription factors 1 (CDX1) and 2 (CDX2) regulate axial development and intestinal differentiation. We assessed the expression of these putative intestinal epithelial-specific transcription factors and their influence on patient outcome. Fifty-three resected carcinomas of the ampulla of Vater, 31 pancreatic ductal adenocarcinomas, and 15 extrahepatic biliary carcinomas were analyzed for CDX1 and CDX2 expression using immunohistochemistry. Forty percent of carcinomas of the ampulla of Vater but less than 5% of pancreatic and biliary adenocarcinomas expressed CDX. Expression of CDX was associated with a better prognosis (P = .0009). Individually, both CDX1 (P = .02) and CDX2 (P = .02) expression were associated with a survival advantage on univariate analysis. Advanced T stage (P = .02), lymph node metastases (P = .004), and vascular space invasion (P = .0009) were associated with a poor prognosis. Multivariate analysis revealed vascular space invasion (P = .01) and CDX expression (P = .01) to be independent prognostic factors. Expression of CDX was an independent marker of outcome in patients with resected adenocarcinoma of the ampulla of Vater. Expression of CDX may distinguish good prognosis intestinal-like tumors, which potentially arise within intestinal epithelium, from poorer prognosis pancreatobiliary tumors, which arise in adjacent pancreatic and/or biliary ductal epithelium.

Chemoradiation May Prolong Survival of Patients with Non-Bulky Unresectable Extrahepatic Biliary Carcinoma

This study compared stenting and chemoradiation (CRT) and attempted to identify factors that are predictive of response to CRT. A retrospective analysis identified 98 patients treated. The primary tumor and lymphatics received 45 Gy of three-dimensional conformal radiotherapy. Tumors were boosted to a median total dose of 50.8 Gy. Simultaneous chemotherapy was 5-fluorouracil- (5-FU) and gemcitabine-based. RTOG/NCI-CTC toxicity criteria were applied. Median survival time was 11.8 months for all patients, 9.3 months for patients with stenting alone and 16.5 months with CRT (p = 0.22). Only tumor diameter was predictive of survival for treatment with CRT. A threshold of 40 mm at diagnosis distinguished two survival profiles (21.4 vs. 8.7 months; p = 0.01). Toxicity was lower for 5-FU-based CRT compared to gemcitabinebased CRT, but a safe schedule for gemcitabine-based CRT was identified. Two patients (2/25) with unresectable tumors at diagnosis had pathohistological complete response at resection after CRT. Inclusion criteria for future CRT trials should be based on tumor size at diagnosis: patients otherwise eligible for CRT should only be included with an inoperable tumor ≤ 40 mm, while patients with larger tumors may only benefit from palliation by stenting.

Expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia.

To compare the difference of expression of Bcl-2 and Bax in extrahepatic biliary tract carcinoma and dysplasia, and to analyze the role of Bcl-2 and Bax proteins in the progression from dysplasia to carcinoma and to evaluate the correlation of Bcl-2/Bax protein expression with the biological behaviors. Expressions of Bcl-2 and Bax were examined immunohistochemically in 27 cases of extrahepatic biliary tract carcinomas (bile duct carcinoma: n=21, carcinoma of ampulla of Vater: n=6), and 10 cases of atypical dysplasia. Five cases of normal biliary epithelial tissues were used as controls. A semiquantitative scoring system was used to assess the Bcl-2 and Bax reactivity. The expression of Bcl-2 was observed in 10 out of 27 (37.0%) invasive carcinomas, 1 out of 10 dysplasias, none out of 5 normal epithelial tissues. Bax expression rate was 74.1% (20/27) in invasive carcinoma, 30% (3/10) in dysplasia, and 40% (2/5) in normal biliary epithelium. Bcl-2 and Bax activities were more intense in carcinoma than in dysplasia, with no significant difference in Bcl-2 expression (P=0.110), and significant difference in Bax expression (P=0.038). Level of Bax expression was higher in invasive carcinoma than in dysplasia and normal tissue (P=0.012). Bcl-2 expression was correlated to Bax expression (P=0.0059). However, Bcl-2/Bax expression had no correlation with histological subtype, grade of differentiation, or level of invasion. Increased Bcl-2/Bax expression from dysplasia to invasive tumors supports the view that this is the usual route for the development of extrahepatic biliary tract carcinoma. Bcl-2/Bax may be involved, at least in part, in the apoptotic activity in extrahepatic biliary carcinoma.

Cholangiocarcinoma: the “other” liver cancer on the rise

The purpose of the study by Patel was to examine the secular trends in intrahepatic cholangiocarcinoma in the United States between 1973 and 1997. Incidence rates were calculated using data collected by the Surveillance, Epidemiology, and End Results program. Mortality rates were obtained from Vital Statistics data, collected by the National Center for Health Statistics. Cases included in this study were diagnosed with either a primary intrahepatic biliary tract cancer or extrahepatic biliary tract cancer (gallbladder, primary extrahepatic biliary tract, other specified extrahepatic biliary tract). The age-adjusted incidence rates of intrahepatic cholangiocarcinoma significantly increased from 0.13 per 100,000 in 1973 to 0.67 per 100,000 in 1997, with an overall annual percent change of 9%. For the same cancer, the age-adjusted mortality rates significantly increased from 0.07 per 100,000 in 1973 to 0.69 per 100,000 in 1997. There were no significant differences between men and women. In contrast, deaths from extrahepatic biliary tract cancers progressively decreased during the same time period. The second article by Taylor-Robinson et al. examined mortality statistics collected in England and Wales to explore time trends in liver cancer deaths using data from the Office for National Statistics in London for the years 1968 through 1996. The total number of deaths caused by malignant liver tumors increased steadily from 967 in 1968 to 1,822 in 1996. The age-adjusted mortality rate related to liver cancer increased from 1.29 per 100,000 to 1.93 per 100,000 in women, and from 2.56 per 100,000 to 3.70 per 100,000 in men. Of all liver cancer types, the most significant rise in mortality was attributed to intrahepatic cholangiocarcinoma. The total number of intrahepatic cholangiocarcinoma increased from 38 in 1968 to 736 in 1996 and was similar for men and women. Conversely, a decrease was observed in the total number of deaths and age-adjusted mortality rates for gallbladder, extrahepatic biliary, and pancreatic carcinomas. Based on these findings, the authors concluded that the observed increase in liver cancer deaths occurring in England and Wales was caused by a steady increase in intrahepatic cholangiocarcinoma.

Cholangiocarcinoma: The “Other” Liver Cancer on the Rise

Abstract The purpose of the study by Patel was to examine the secular trends in intrahepatic cholangiocarcinoma in the United States between 1973 and 1997. Incidence rates were calculated using data collected by the Surveillance, Epidemiology, and End Results program. Mortality rates were obtained from Vital Statistics data, collected by the National Center for Health Statistics. Cases included in this study were diagnosed with either a primary intrahepatic biliary tract cancer or extrahepatic biliary tract cancer (gallbladder, primary extrahepatic biliary tract, other specified extrahepatic biliary tract). The age-adjusted incidence rates of intrahepatic cholangiocarcinoma significantly increased from 0.13 per 100,000 in 1973 to 0.67 per 100,000 in 1997, with an overall annual percent change of 9%. For the same cancer, the age-adjusted mortality rates significantly increased from 0.07 per 100,000 in 1973 to 0.69 per 100,000 in 1997. There were no significant differences between men and women. In contrast, deaths from extrahepatic biliary tract cancers progressively decreased during the same time period. The second article by Taylor-Robinson et al. examined mortality statistics collected in England and Wales to explore time trends in liver cancer deaths using data from the Office for National Statistics in London for the years 1968 through 1996. The total number of deaths caused by malignant liver tumors increased steadily from 967 in 1968 to 1,822 in 1996. The age-adjusted mortality rate related to liver cancer increased from 1.29 per 100,000 to 1.93 per 100,000 in women, and from 2.56 per 100,000 to 3.70 per 100,000 in men. Of all liver cancer types, the most significant rise in mortality was attributed to intrahepatic cholangiocarcinoma. The total number of intrahepatic cholangiocarcinoma increased from 38 in 1968 to 736 in 1996 and was similar for men and women. Conversely, a decrease was observed in the total number of deaths and age-adjusted mortality rates for gallbladder, extrahepatic biliary, and pancreatic carcinomas. Based on these findings, the authors concluded that the observed increase in liver cancer deaths occurring in England and Wales was caused by a steady increase in intrahepatic cholangiocarcinoma.

Intraductal EUS

Intraductal ultrasonography (IDUS) has been reported as a reliable method that can be used for more detailed evaluation of pancreatobiliary tumors, especially intraductal mucin-producing carcinomas of the pancreas 1 Furukawa T Tsukamoto Y Naitoh Y Hirooka Y Hayakawa T Differential diagnosis between benign and malignant localized stenosis of the main pancreatic duct by intraductal ultrasound of the pancreas. Am J Gastroenterol. 1994; 89: 2038-2041 PubMed Google Scholar , 2 Furukawa T Oohashi K Yamao K Naitoh Y Hirooka Y Taki T et al. Intraductal ultrasonography of the pancreas: development and clinical potential. Endoscopy. 1997; 29: 561-569 Crossref PubMed Scopus (76) Google Scholar , 3 Menzel J Foerster EC Ubrig B Keller R Kerber S Domschke W Ex vivo examination of the pancreas by intraductal ultrasonography (IDUS). Endoscopy. 1993; 25: 571-576 Crossref PubMed Scopus (26) Google Scholar , 4 Mukai H Yasuda K Nakajima M Differential diagnosis of mucin-producing of the pancreas by intraductal ultrasonography and peroral pancreatoscopy. Endoscopy. 1998; 30: A99-A102 PubMed Google Scholar or extrahepatic biliary carcinoma. 5 Tamada K Kanai N Ueno N Ichiyama M Tomiyama T Wada S et al. Limitations of intraductal ultrasonography in differentiating between bile duct cancer in stage T1 and stage T2: in-vitro and in-vivo studies. Endoscopy. 1997; 29: 721-725 Crossref PubMed Scopus (57) Google Scholar , 6 Kuroiwa M Goto H Hirooka Y Furukawa T Hayakawa T Naitoh Y Intraductal ultrasonography for the diagnosis of proximal invasion in extrahepatic bile duct cancer. J Gastroenterol Hepatol. 1998; 13: 715-719 Crossref PubMed Scopus (32) Google Scholar , 7 Fujita N Noda Y Kobayashi G Kimura K Yago A Staging of bile duct carcinoma by EUS and IDUS. Endoscopy. 1998; 30: A132-A134 Crossref PubMed Scopus (33) Google Scholar , 8 Tamada K Inui K Menzel J Intraductal ultrasonography of the bile duct system. Endoscopy. 2001; 33: 878-885 PubMed Google Scholar Accurate staging is the most significant role of IDUS. The procedures and usefulness of IDUS have been reported for biliary and pancreatic diseases. 9 Inui K Nakazawa S Yoshino J Wakabayashi T Okushima K Nakamura Y et al. Ultrasound probes for biliary lesions. Endoscopy. 1998; 30: A120-A123 PubMed Google Scholar , 10 Inui K Nakazawa S Yoshino J Yamachika H Kanemaki N Wakabayashi T et al. Mucin-producing tumor of the pancreas—intraluminal ultrasonography. Hepatogastroenterology. 1998; 45: 1996-2000 PubMed Google Scholar , 11 Inui K Nakazawa S Yoshino J Okushima Nakamura Y Endoluminal ultrasonography for pancreatic diseases. Gastroenterol Clin North Am. 1999; 28: 771-781 Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar On the other hand, a comprehensive image display has been required in US, similar to computed tomography and magnetic resonance imaging. Preliminary results have also been reported of 3-dimensional intraductal ultrasonography (3D-IDUS). 12 Kanemaki N Nakazawa S Inui K Yoshino J Yamao K Okushima K Three-dimensional intraductal ultrasonography: preliminary results of a new technique for the diagnosis of diseases of the pancreatobiliary system. Endoscopy. 1997; 29: 726-731 Crossref PubMed Scopus (82) Google Scholar 3D-IDUS with a high-frequency US probe is a new, exciting technique. This report demonstrates the usefulness and clinical application of IDUS and 3D-IDUS for diagnosis of biliary and pancreatic diseases.

Staging laparoscopy in patients with extrahepatic biliary carcinoma. Analysis of 100 patients.

To evaluate the benefit of staging laparoscopy in patients with gallbladder cancer and hilar cholangiocarcinoma. In patients with extrahepatic biliary carcinoma, unresectable disease is often found at the time of exploration despite extensive preoperative evaluation, thus resulting in unnecessary laparotomy. From October 1997 to May 2001, 100 patients with potentially resectable gallbladder cancer (n = 44) and hilar cholangiocarcinoma (n = 56) were prospectively evaluated. All patients underwent staging laparoscopy followed by laparotomy if the tumor appeared resectable. Surgical findings, resectability rate, length of stay, and operative time were analyzed. Patients underwent multiple preoperative imaging tests, including computed tomography scan, ultrasound, magnetic resonance cholangiopancreatography, and direct cholangiography. Laparoscopy identified unresectable disease in 35 of 100 patients. In the 65 patients undergoing open exploration, 34 were found to have unresectable disease. Therefore, the overall accuracy for detecting unresectable disease was 51%. There was no difference in the accuracy of laparoscopy between patients with gallbladder cancer and hilar cholangiocarcinoma. Laparoscopy detected the majority of patients with peritoneal or liver metastases but failed to detect all locally advanced tumors. In patients undergoing biopsy only, laparoscopic identification of unresectable disease significantly reduced operative time and length of stay compared with patients undergoing laparotomy. The yield of laparoscopy was 48% in patients with gallbladder cancer (56% in those who did not undergo previous cholecystectomy), but only 25% in patients with hilar cholangiocarcinoma. However, in patients with locally advanced but potentially resectable hilar cholangiocarcinoma, the yield of laparoscopy was greater, 36% (12/33, T2/T3 tumors) versus 9% (2/23, T1 tumors). Laparoscopy identifies the majority of patients with unresectable hilar cholangiocarcinoma or gallbladder carcinoma, thereby reducing both the incidence of unnecessary laparotomy and the length of stay. The yield of laparoscopy is lower for hilar cholangiocarcinoma but can be improved by targeting patients at higher risk of occult unresectable disease. All patients with potentially resectable primary gallbladder cancer and patients with T2/T3 hilar cholangiocarcinoma should undergo staging laparoscopy before surgical exploration.

Down-regulated p16 expression predicts poor prognosis in patients with extrahepatic biliary tract carcinomas.

The prognosis of extrahepatic biliary tract cancer (EBT) patients is generally accepted to be poor. We immunohistochemically evaluated expression of p16, a cyclin-depend kinase inhibitor, in tumor specimens surgically removed from 99 EBT patients. We also examined whether there was any relationship between expression of p16 and biological malignancy of the tumor by comparing its clinicopathological factors. Consequently, we found that there were three types of p16 expression in the tumor cells; diffuse, heterogeneous and negative types, the percentages of which were 19, 41 and 39%, respectively. Heterogeneous and negative types, whose expression of p16 was considered to be down-regulated, showed scirrhous (p=0.022) and infiltrating growth (p=0.002). In addition, we found that the proportion of down-regulated expression of p16 was different, depending on the location of the tumor. We also observed that the down-regulated p16 expression was the highest in a proportion of patients with the extrahepatic bile duct carcinoma. In contrast, the proportion of down-regulated p16 expression was the least among the patients in the region of the ampulla of Vater with better prognosis, and we showed that the prognosis of patients with down-regulated expression of p16 was the poorest in terms of the cancer location where it is limited to the region of ampulla of Vater. These findings suggest that down-regulated p16 expression is evaluated as a factor of poorer prognosis and also that immunohistochemical pattern of p16 expression becomes a marker reflecting the biological malignancy of EBT patients.