Biliary Malignancy Research Articles

Update on Surgical Management of Gallbladder Cancer

Gallbladder cancer is the most common biliary tract malignancy and has poor 5-year survival. Incidental gallbladder cancers have good survival after cholecystectomy because most are diagnosed at an early stage. The latest The American Joint Committee on Cancer guideline (8th edition, 2017) has changes in the criteria for T and N staging, leading to new surgical approaches for gallbladder cancer. In the new guideline, negative resection margins with adequate clearance for regional lymph nodes is the main principle of curative treatment.

Hyperthermic intraperitoneal chemotherapy for management of gastrointestinal and biliary tract malignancies: a systematic review and meta-analysis of randomized trials.

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) promised to transform the management of peritoneal carcinomatosis (PC). Forty years since the introduction of the technique, published data from randomized controlled trials (RCTs) remain scarce. We assessed the cumulative comprehensive available evidence on the use of HIPEC in gastrointestinal (GI) and biliary tract malignancies and established the current benchmark for GI HIPEC research in both the prevention and treatment of peritoneal metastases. RCTs were identified through a systematic search of Medline, Cochrane and Embase databases. Overall survival and progression-free survival were the outcomes of interest. The search resulted in 13 RCTs for gastric cancer (10 on prophylactic and 3 on therapeutic HIPEC), 4 for colorectal cancer (2 on prophylactic and 2 on therapeutic HIPEC), and 1 for pancreatic cancer. No RCTs were identified that included other types of GI or biliary tract cancers. Current randomized evidence does not support any overall survival benefit from the use of HIPEC in the adjuvant setting for gastric cancer or for colorectal cancer in any setting. Despite the survival benefit noticed in the treatment of PC from gastric cancer (risk ratio 0.85, 95% confidence interval 0.77-0.93; P<0.001), the results were derived from only 190 patients. The current evidence from RCTs does not support the use of HIPEC in the treatment/prevention of PC in GI and biliary tract malignancies. HIPEC should continue to be considered experimental until level 1 evidence from properly designed international multicenter studies becomes available.

A combination therapy of bortezomib, CXCR4 inhibitor, and checkpoint inhibitor is effective in cholangiocarcinoma in vivo

Cholangiocarcinoma (CCA) is a biliary tree malignancy with a dismal prognosis. Tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) has been shown to be involved in drug resistance. To model the interactions between cancer cells and the TME, we established CCA complex patient-derived organoids (cPDOs) to include epithelial PDO (ePDOs) and matched CAFs. While ePDOs were sensitive to bortezomib, we found the matched cPDOs were relatively resistant. Mechanistically, this resistance was correlated with over-expression of CXCR4 in the CAF component of cPDOs. In accord with the role of CXCR4 in the resistance to bortezomib, we found that a CXCR4 inhibitor can reverse the resistance to bortezomib invivo. Furthermore, we found that the inhibition of CXCR4 allowed bortezomib to sensitize CCA to anti-PD1 treatment, with a significant reduction of tumor burden and long-term overall survival. This novel cancer/stroma/immune triple treatment holds great promise for the treatment of CCA.

Role of radiofrequency ablation in advanced malignant hilar biliary obstruction.

Malignant hilar biliary obstruction (MHO), an aggressive perihilar biliary obstruction caused by cholangiocarcinoma, gallbladder cancer, or other metastatic malignancies, has a poor prognosis. Surgical resection is the only curative treatment for biliary malignancies. However, the majority of patients with MHO cannot undergo surgery on presentation because of an advanced inoperable state or a poor performance state due to old age or comorbid diseases. Therefore, palliative biliary drainage is mandatory to improve symptomatic jaundice and the quality of life. Among the drainage methods, endoscopic biliary drainage is the current standard for palliation of unresectable advanced MHO. In addition, combined with endoscopic drainage, additional local ablation therapies, such as photodynamic therapy or radiofrequency ablation (RFA), have been introduced to prolong stent patency and survival. Currently, RFA is commonly used as palliative therapy, even for advanced MHO. This literature review summarizes recent studies on RFA for advanced MHO.

Robotic portal lymphadenectomy: A standardized approach

Background: Portal lymphadenectomy is a mandatory component of oncologic surgery for gallbladder cancer and other biliary malignancies. Minimally invasive surgical approaches for oncologic hepatobiliary malignancies are becoming more common. Although there is a paucity of descriptions of standardized approaches for portal lymphadenectomy.

Robotic partial hepatectomy following immunotherapy for advanced intrahepatic cholangiocarcinoma

Background: Metastatic Intrahepatic cholangiocarcinoma (iCCA) carries a poor prognosis, with upfront hepatic resection of the primary tumor contraindicated. Response rates to systemic chemotherapy are low and confer only a modest survival benefit. Next generation sequencing (NGS) is useful for identifying potentially actionable mutations for therapeutic targets. For patients with a high tumor mutational burden, immunotherapy can produce a profound decrease in tumor size and distribution. Immunotherapy for iCCA is growing, and a dramatic response to immunotherapy may downstage previously unresectable iCCA, expanding the role for surgery in this complex biliary malignancy. There are a limited number of case reports describing successful hepatic resection of previously metastatic iCCA after immunotherapy. Herein, we report our experience performing a robotic partial hepatectomy for clearance of the only identifiable active disease 3 years after diagnosis and downstaging of metastatic iCCA with PD-1 blockage for microsatellite high instability (MSI High).

The Surgical Results of HPD for Widespread Biliary Malignancy, Especially for Pancreatic Fistula and Prognostic Impact of Lymph Nodal Metastasis State

The Surgical Results of HPD for Widespread Biliary Malignancy, Especially for Pancreatic Fistula and Prognostic Impact of Lymph Nodal Metastasis State

Endobiliary and Pancreatic Radiofrequency Ablations

AbstractRadio frequency ablation (RFA) involves use of thermal energy to perform ablation of tissues. It has a wide range of application in gastrointestinal tract. Over the last few years, several studies have reported successful and safe application in the biliary and pancreatic tissues. It is particularly beneficial in patients with biliary malignancies in whom it has shown to improve survival. Additionally, it can be applied in occluded metal stents secondary to tumor ingrowth to prolong the patency of stents. In pancreas, RFA can successfully ablate cystic lesions and neuroendocrine tumors. It has also been applied in unresectable pancreatic cancers. This review discusses the application of endobiliary and pancreatic RFAs.

Accurate Diagnosis After Multidisciplinary Tumor Board: A Case Report of Cholangiocarcinoma

Multidisciplinary tumor boards (MDTBs) provide a venue for discussion of diagnosis, staging, and treatment of patients with cancer. MDTBs have been shown to improve diagnostic accuracy and staging, exemplified in this patient with a hepatic flexure mass on colonoscopy and initial pathology suggestive of primary colonic adenocarcinoma with surface mucosal involvement. However, subsequent CT imaging revealed a biliary malignancy invading the colon. Discussion at a MDTB facilitated radiology-pathology correlation, with subsequent immunohistochemical stains compatible with a cholangiocarcinoma with transmural colonic invasion. Prompt and accurate diagnosis after the MDTB enabled the oncology team to offer the proper treatment approach.

Technical Feasibility, Short-Term Patency, Safety, and Efficacy of Percutaneously Delivered Double Pig-Tail Stent for Palliation of Unresectable Biliary Malignancies

Abstract Purpose The aim of this study was to evaluate the technical feasibility, complication rate, and efficacy of percutaneously delivered plastic biliary stent, compared with that of internal–external biliary drainage catheter. Methods Patients with unresectable malignant biliary obstruction were included who underwent percutaneous transhepatic biliary drainage and double pigtail plastic stenting (DPT-PS) or internal–external biliary drainage catheter in 15 months' duration. Results Seventy-seven patients were included in the study who underwent DPT-PS (n = 37) or internal external drainage catheter placement (n = 40). Overall, the technical success rate for percutaneous plastic stenting was 92.5% and technical success rate for primary stenting at the time of initial puncture was 62%. The incidence of fever and hemobilia was similar across the two groups, whereas bile leakage in the perihepatic space and through the skin at puncture site was higher in patients with internal–external drainage catheter. Both the techniques were effective in reducing the bilirubin levels of patients. Re-intervention was done in five patients in DPT-PS and six patients with ring biliary catheter. Conclusion DPT-PS may be used as a viable cost-efficient alternative for unresectable biliary malignancies with low post-procedure life expectancy

Hyperbilirubinemia has Predictive Potential for the Diagnosis of Appendiceal Perforation

Background: Acute appendicitis is an inflammation of the vermiform appendix. Usually, the diagnosis is made on clinical evaluation and elevated leukocyte count (TLC). But in cases when the clinical diagnosis is indeterminate, additional assessment needs imaging. Despite the increased use of modern diagnostic modalities such as Sonography, computed tomography (CT), and diagnostic laparoscopy, the frequency of misdiagnosis of appendicitis has remained constant (15%) as has the rate of appendiceal rupture. Presently, some serum markers such as C-reactive protein (CRP), lactate, and bilirubin have been proposed as a diagnostic tools for appendicitis. When compared CRP, TLC and lactate are found less explicit than bilirubin as predictive markers for acute appendicitis and its complications. Objective: To determine the diagnostic accuracy of hyperbilirubinemia in diagnosing perforated appendix by taking per-operative findings as the gold standard. Material &amp; methods: It is a cross-sectional survey conducted at the Surgery department at PAF Hospital Mushaf, Sargodha. The duration of the study was from 1st June 2018 to 1st December 2018. A total of 160 patients of both gender with acute appendicitis with Alvarado Score ≥ 7 were included. Patients with age less than 12 years, HBsAg &amp; anti-HCV positive, history of jaundice, history of liver disease (e.g.: Crigler-Najjar, Gilbert syndrome, cirrhosis, hepatitis), the patient is alcoholic, history of hemolytic disorders (e.g.: thalassemia, spherocytosis), history of the biliary disease (e.g.: biliary stones, worm infestation, atresia, etc), history of gastrointestinal&amp; hepato-pancreato biliary malignancy, patient with appendicular mass per-operatively and appendectomy performed incidentally or for other indications were excluded. All patients were tested by routine laboratory investigations including LFTs hyperbilirubinemia was recorded. All cases underwent appendectomy by the same surgical team&amp; peri-operative findings were recorded &amp; compared with pre-operative total bilirubin levels. Patients were categorized as true positive, true negative, false positive &amp; false negative. Results: The age range in this study was from 12 to 60 years with a mean age of 35.231± 8.63 years and mean Pre-Op Bilirubin Levels was 0.812±0.72 mg/dl. Laboratory Findings (Bilirubin levels ≥ 1mg/dl) diagnosed 44(27.5%) patients and Per Operative Findings diagnosed 60(37.5%) patients with Perforated Appendix. Laboratory Findings (Bilirubin levels ≥ 1mg/dl) have shown a sensitivity of 50%, specificity of 86%, the diagnostic accuracy of 73%, PPV 68.18%, NPV 74.4%, (p=0.000) in the diagnosis of Perforated Appendix. Conclusion: It is concluded that serum bilirubin level was higher in patients with appendiceal perforation, it s a definite predictive potential in these cases. Therefore, acquiring SB values upon admission can be used in combination with more recent diagnostic tests such as CT scans n, ultrasonography to help determine the presence of perforation and thus assist in timely clinical management. Keywords: Perforated appendix, Hyperbilirubinemia, Diagnostic accuracy

Sensitivity and Specificity of Cytology and Fluorescence in situ Hybridization for the Detection of Biliary Tract Malignancy

Sensitivity and Specificity of Cytology and Fluorescence in situ Hybridization for the Detection of Biliary Tract Malignancy

Single-cell dissection of remodeled inflammatory ecosystem in primary and metastatic gallbladder carcinoma

Gallbladder carcinoma (GBC) is the most common biliary tract malignancy with the lowest survival rate, primarily arising from chronic inflammation. To better characterize the progression from inflammation to cancer to metastasis, we performed single-cell RNA sequencing across samples of 6 chronic cholecystitis, 12 treatment-naive GBCs, and 6 matched metastases. Benign epithelial cells from inflamed gallbladders displayed resting, immune-regulating, and gastrointestinal metaplastic phenotypes. A small amount of PLA2G2A+ epithelial cells with copy number variation were identified from a histologically benign sample. We validated significant overexpression of PLA2G2A across in situ GBCs, together with increased proliferation and cancer stemness in PLA2G2A-overexpressing GBC cells, indicating an important role for PLA2G2A during early carcinogenesis. Malignant epithelial cells displayed pervasive cancer hallmarks and cellular plasticity, differentiating into metaplastic, inflammatory, and mesenchymal subtypes with distinct transcriptomic, genomic, and prognostic patterns. Chronic cholecystitis led to an adapted microenvironment characterized by MDSC-like macrophages, CD8+ TRM cells, and CCL2+ immunity-regulating fibroblasts. By contrast, GBC instigated an aggressive and immunosuppressive microenvironment, featured by tumor-associated macrophages, Treg cells, CD8+ TEX cells, and STMN1+ tumor-promoting fibroblasts. Single-cell and bulk RNA-seq profiles consistently showed a more suppressive immune milieu for GBCs with inflammatory epithelial signatures, coupled with strengthened epithelial-immune crosstalk. We further pinpointed a subset of senescence-like fibroblasts (FN1+TGM2+) preferentially enriched in metastatic lesions, which promoted GBC migration and invasion via their secretory phenotype. Collectively, this study provides comprehensive insights into epithelial and microenvironmental reprogramming throughout cholecystitis-propelled carcinogenesis and metastasis, laying a new foundation for the precision therapy of GBC.

116P Expression of Her2/Neu and Ki-67 proliferation index in gall bladder carcinomas: Clinicopathological significance

Gall bladder carcinomas (GBC) are one of the most common and aggressive biliary tract malignancies causing significant mortality in South-East Asia and South America as a result of advanced stage at presentation, early metastases, and poor outcomes with standard chemotherapy. Overexpression of Her2/Neu is associated with poor prognosis in breast and gastric carcinomas, which is also being studied for GBC. Ki 67 proliferation index, a marker of replicative potential, is high in higher-grade and aggressive tumors.

S3439 Lemmel Syndrome Due to Periampullary Diverticular Food Impaction

Introduction: Lemmel Syndrome is a rare cause of mechanical biliary obstruction attributed to periampullary duodenal diverticula (PAD). It was first described in 1934 as obstructive jaundice in the absence of biliary stones or malignancy. The majority of PAD are asymptomatic, however, about 5% have symptomatic disease. We present a symptomatic case. Case Description/Methods: An 80-year-old woman with history of cholecystectomy, coronary artery disease, hypertension, and diabetes was transferred from a free-standing emergency room for acute pancreatitis. She had a one day history of postprandial epigastric pain with radiation to the back. Labs on presentation included lipase above 4000 U/L, BUN 27 mg/dL, AST 316 U/L, ALT 422 U/L, ALP 292 IU/L, total bilirubin 0.6 mg/dL. Abdominal ultrasound revealed 12mm common bile duct (CBD) with intrahepatic ductal dilatation. MRCP showed intra and extrahepatic biliary ductal dilatation with dilated pancreatic duct and a 3.6 cm fluid filled periampullary diverticulum. ERCP showed a large periampullary duodenal diverticulum with food impaction causing obstruction of the ampullary orifice which was removed with forceps. Cholangiogram revealed dilation of pancreatic, common bile, and intrahepatic ducts without any filling defects. Patient improved and was discharged home. (Figure) Discussion: The incidence of duodenal diverticula is approximately 17% with PAD being the most common type. PADs are pseudo-diverticula most commonly found in the second part of the duodenum and they pose a cannulation challenge during ERCP with an increased risk of complications. PAD in the setting of biliary obstruction is known as Lemmel Syndrome. It can cause biliary obstruction by sphincter of Oddi dysfunction, direct obstruction, or via external compression by fluid or material-filled PAD. In our case, there was biliary compression due to a food-filled PAD. Cross sectional imaging is critical for diagnosis, however, ERCP is the gold standard. Several therapeutic modalities including endoscopic extraction of entrapped food or stones, extracorporeal shock wave lithotripsy, and laparoscopic diverticulectomy have been used. Our case required endoscopic extraction of diverticular food debris and adds to the limited published cases to date. Lemmel Syndrome requires a high index of suspicion when a PAD is found in the setting of biliary obstruction.Figure 1.: A. MRCP image showing a large periampullary diverticulum packed with debris. B. ERCP image of food impacted inside periampullary diverticulum. C. MRCP image demonstrating a dilated common bile duct in absence of choledocholithiasis.

S1772 Neurofibromatosis-Related Biliary Obstruction: Is There a Role in Screening for Biliary Malignancy?

S1772 Neurofibromatosis-Related Biliary Obstruction: Is There a Role in Screening for Biliary Malignancy?

S1712 Choledochal Cyst Mimicking the Gallbladder With a Surprising Twist

Introduction: Choledochal cysts are congenital rarities and often a pediatric diagnosis but 20% go undetected until adulthood. Etiology remains unclear but an obstructed common bile duct (CBD) has been identified as a pathogenic feature. We present a rare case of choledochal cyst initially mimicking the gallbladder in an elderly female. Case Description/Methods: A 90-year-old woman presented to the hospital for abdominal pain and unintentional weight loss. Past medical history was notable for breast cancer and colorectal cancer status post resection. Liver function tests and pancreatic markers were normal with mildly elevated alkaline phosphatase. CT abdomen and pelvis revealed a 2.8 cm dilated common bile duct (CBD), choledocholithiasis, pancreatic duct dilation and absent gallbladder. Patient however denied undergoing a cholecystectomy. Given the discrepancy of imaging and history, an abdominal ultrasound was performed demonstrating large gallstones in the gallbladder with normal CBD size. Endoscopic ultrasound (EUS) revealed a 28x26 mm mass in the ampulla (Figure). FNB was performed. The distal CBD measured 7 mm with a 35 mm proximal CBD consistent with a choledochal cyst full of large stones. Pancreatic duct measured up to 8 mm. Gallbladder was confirmed to be surgically absent. ERCP was performed which revealed an infiltrative 3-4 cm mass at the major papilla. Pancreatic and biliary sphincterotomies were performed and metal stents were placed in the ventral pancreatic duct and CBD. Biopsies taken revealed pancreatic adenocarcinoma. The following month, hepatobiliary surgery performed a Whipple procedure (pancreaticoduodenectomy). Pathology findings confirmed pancreatic adenocarcinoma with metastasis to one of twelve lymph nodes. Patient was arranged to follow up with outpatient oncology. Discussion: Choledochal cysts can be an elusive diagnosis in elderly adults given its rarity, prevalence in children, and common presentation of vague abdominal pain. Choledochal cyst should be part of the differential diagnosis regardless of patient age especially in cases of accompanying weight loss due to its increased risk of biliary malignancy. In our case, the patient was found to have choledochal cyst misrepresented as the gallbladder and incidentally found to have pancreatic adenocarcinoma. Additionally, patients may be unreliable historians leading to misinterpretation of imaging results. Further investigation is therefore warranted in these perplexing cases for an accurate diagnosis and appropriate management.Figure 1.: A. Ampullary mass B. Pancreatic duct dilation C. Choledochal cyst. D Post ERCP.

S372 Cystic Artery Pseudoaneurysm: A Rare Case of Upper Gastrointestinal Bleeding

Introduction: Cystic artery pseudoaneurysm (CAP) is a rare complication of acute cholecystitis and cholecystectomy. We present an unusual case of upper GI bleed due to CAP. Case Description/Methods: An elderly female presented with one month history of lethargy and unintentional weight loss. Clinical exam was unremarkable apart from pallor. Blood tests revealed severe iron deficiency anaemia and bland cholestasis. CT scan showed a common bile duct (CBD) mass and a gallbladder (GB) neck lesion with prominent regional lymph nodes, which was worrying for biliary malignancy. MRI scan showed a 3cm CBD stone with acute emphysematous cholecystitis and possible CAP at the GB neck. An urgent OGD and ERCP was done on the same day as she developed hematemesis and cholangitis. On endoscopy, there was active bleeding from possible enteric fistula at first part of duodenum (D1), this was treated with metal clips. During ERCP, haemobilia was noted on CBD cannulation. On cholangiogram, the endoclips were adjacent to distal CBD stone. A plastic stent was inserted into the CBD and she was referred to the surgeons. Cholecystectomy and CBD exploration was performed for definitive treatment. Intra-operatively, there was active bleeding into the GB from CAP. D1 was thinned out with adhesions to the GB. There was stale blood in the bile duct but no biliary-enteric fistula seen. CAP was sutured, adhesiolysis, subtotal cholecystectomy, omental patch repair of D1 and CBD stone was retrieved. Repeat OGD and ERCP with CBD stent removal done 2 months later showed healed D1 mucosa. Discussion: The clinical features of CAP include right upper quadrant pain, upper GI bleed due to haemobilia and abnormal liver enzymes. It is diagnosed on arterial phase of CT scan, angiography, MRI or during surgery. It is treated with surgery or angioembolization. This is a challenging case with delayed diagnosis of CAP as she lacks the typical presentation of CAP. A plain contrasted CT without arterial phase was done initially, which have mistaken the CAP as soft tissue lesion in GB. Endoscopic findings raises possibility of choledocho-duodenal fistula; this was excluded during surgery. The final diagnosis is acute calculous cholecystitis complicated by CAP with direct pressure on D1 leading to upper GI bleed. To our knowledge, this is the first case of CAP with such entity. In conclusion, CAP should be considered in patients with symptomatic gallstone disease and upper GI bleed in order to select appropriate imaging modality and guide therapy. Watch the video at https://tinyurl.com/ACGAbstractS372

Hepatic Abscess following Yttrium-90 Radioembolization in Patients with Surgical Bilioenteric Anastomosis or Compromised Sphincter of Oddi: A Tertiary Cancer Center Experience.

Purpose: We describe our experience with the development of hepatobiliary infection in patients with prior surgical, percutaneous, or endoscopic biliary interventions who are receiving transarterial radioembolization (TARE) with yttrium-90 (90Y) for primary or metastatic hepatobiliary lesions. Methods: Records of 15 patients with a history of prior biliary intervention and liver malignancy subsequently treated with TARE at the participating medical center from November 2009 to September 2015 were reviewed. The primary endpoint was the development of a hepatic abscess or cholangitis in a patient after radioembolization. Results: A total of 15 patients comprising 9 men and 6 women, with a median age of 49 years (range 30–73), underwent 17 TARE with 90Y procedures. Of the 15 patients, 2 (13.3%) of them developed a hepatobiliary infection. A single patient (6.6%) developed a hepatobiliary abscess. Conclusion: Our study shows a low incidence rate of hepatic abscess following TARE in patients with prior biliary intervention.

Extrahepatic bile duct malignancies.

Biliary tract malignancies belong to very aggressive malignancies of the gastrointestinal tract. The only radical treatment is surgical resection which is possible only in a limited number of cases due to late diagnosis. The aim of this report was to present the experience of our own department with the diagnosis and treatment of these tumours. In the years 2005-2021 radical (R0) resection was performed in 27 (28.4%) patients, the same number were managed only symptomatically and in 41 (43.2%) patients we used biliary stenting and external-internal drainage as the definitive procedure. Adjuvant oncological treatment was indicated in 16 (59.3%) of the radically operated and 49 (72.1%) of the non-operated patients. Median overall survival and median progression-free survival in the operated patients were 19.9 months and 15.7 months, respectively. Overall survival in the operated patients was significantly better (p.