Primary neuroendocrine tumors originating from the extrahepatic bile duct are rare. Among these tumors, large cell neuroendocrine carcinomas (NECs) are extremely rare. A 59-year-old man was admitted to Sanggye Paik Hospital with jaundice that started 10 days previously. He had a history of laparoscopic cholecystectomy, which he had undergone 12 years previously due to chronic calculous cholecystitis. Laboratory data showed abnormally elevated levels of total bilirubin 15.3 mg/dL (normal 0.2–1.2 mg/dL), AST 200 IU (normal 0–40 IU), ALT 390 IU (normal 0–40 IU), and gamma-glutamyl transferase 1,288 U/L (normal 0–60 U/L). Serum CEA was normal, but CA 19-9 was elevated 5,863 U/mL (normal 0–37 U/mL). Abdominal CT revealed a 4.5 cm sized mass involving the common bile duct and liver hilum and dilatation of both intrahepatic ducts. Percutaneous transhepatic drainage in the left hepatic duct was performed for preoperative biliary drainage. The patient underwent radical common bile duct and Roux-en-Y hepaticojejunostomy for histopathological diagnosis and surgical excision. On histopathological examination, the tumor exhibited large cell NEC (mitotic index >20/10 high-power field, Ki-67 index >20%, CD56 [+], synaptophysin [+], chromogranin [+]). Adjuvant concurrent chemotherapy and radiotherapy were started because the tumor had invaded the proximal resection margin. No recurrence was detected at 10 months by follow-up CT.
Bile Duct Neoplasms ; Bile Ducts, Extrahepatic* ; Bilirubin ; Carcinoma, Neuroendocrine* ; Cholecystectomy, Laparoscopic ; Cholecystitis ; Common Bile Duct ; Diagnosis ; Dilatation ; Drainage ; Drug Therapy ; Follow-Up Studies ; Hepatic Duct, Common ; Humans ; Jaundice ; Liver ; Middle Aged ; Neuroendocrine Tumors ; Radiotherapy ; Recurrence ; Synaptophysin ; Tomography, X-Ray Computed ; Transferases

A 54-year-old female with postprandial dyspepsia and abdominal pain was diagnosed as locally advanced unresectable intrahepatic cholangiocarcinoma by radiologic imaging studies resulting in invasion to bilateral main bile duct and right portal vein. The patient underwent extended right hepatectomy and portal vein resection after gemcitabine and cisplatin combined chemotherapy for a total of 40 cycles after the diagnosis. Final pathology showed, followed by pathological complete remission, without any residual cancer cell. The patient has survived for over 6 years without any evidence of recurrence. This case suggests that locally advanced intrahepatic cholangiocarcinoma, which can't be resected, was also proved to be capable of pathological complete remission with active chemotherapy, and long-term survival could be achieved. Therefore, active multidisciplinary approach and patient-oriented treatments using various methods should be considered for locally advanced unresectable intrahepatic cholangiocarcinoma.
Abdominal Pain ; Bile Duct Neoplasms ; Bile Ducts ; Cholangiocarcinoma* ; Cisplatin ; Diagnosis ; Drug Therapy* ; Dyspepsia ; Female ; Hepatectomy ; Humans ; Middle Aged ; Neoplasm, Residual ; Pathology ; Portal Vein ; Recurrence

In the palliative setting, the necessity of biliary drainage of both liver lobes for malignant hilar biliary obstruction remains controversial. However, bilateral biliary drainage is a reasonable option to prevent cholangitis of the undrained lobe and to preserve liver function during the course of chemotherapy. Bilateral biliary drainage can be accomplished by the percutaneous or endoscopic placement of multiple self-expandable metallic stents (SEMS). Although SEMS placement via bilateral (multiple) percutaneous routes is technically simple, multiple percutaneous transhepatic biliary drainage (PTBD) may lead to additional morbidity. SEMS placement via a single percutaneous route is a useful method; however, negotiation of a guidewire into the contralateral bile duct is occasionally impossible if the hilar angle between the right hepatic duct and left hepatic duct is acute. Percutaneous dual SEMS placement is generally performed using the stent-in-stent technique (T configuration or Y configuration) or the side-by-side technique. In addition, the crisscross technique has been reported as being a useful method for trisegmental drainage. The side-to-end technique is also useful for multiple SEMS placement. In the future, the combination of percutaneous intervention and endoscopic ultrasonography-guided procedures may be effective in the management of malignant hilar biliary obstruction.
Bile Ducts ; Biliary Tract Neoplasms ; Cholangitis ; Drainage ; Drug Therapy ; Hepatic Duct, Common ; Liver ; Methods ; Negotiating ; Stents*

BACKGROUND/AIMS: Statins act as antineoplastic agents through the inhibition of cell proliferation. This study sought to demonstrate the effects of statins on extrahepatic bile duct cancer cell apoptosis and to document the changes in protein expression involved in tumor growth and suppression. METHODS: Human extrahepatic bile duct cancer cells were cultured. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were performed to determine the effect of statins on cell proliferation. Apoptosis was measured by a cell death detection enzyme-linked immunosorbent assay and caspase-3 activity assay, and flow cytometry was used to determine the percentage of cells in each phase of the cell cycle. The protein expression of Bax, Bcl-2, insulin-like growth factor 1 (IGF-1) receptor, extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt was measured by Western blot analysis. RESULTS: Simvastatin suppressed cell proliferation by inducing G1 phase cell cycle arrest in bile duct cancer cells. Furthermore, it induced apoptosis via caspase-3 activation, downregulated the expression of the Bcl-2 protein, and enhanced the expression of the Bax protein. Moreover, simvastatin suppressed the expression of the IGF-1 receptor and IGF-1-induced ERK/Akt activation. CONCLUSIONS: Simvastatin induces apoptosis in bile duct cancer cells, which suggests that it could be an antineoplastic agent for bile duct cancer.
Antineoplastic Agents/pharmacology ; Apoptosis/*drug effects ; Bile Duct Neoplasms/*drug therapy ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Humans ; Hypolipidemic Agents/*pharmacology ; Receptor, IGF Type 1/*drug effects ; Simvastatin/*pharmacology

A 56-year-old man was diagnosed with cancer of the ascending colon along with retroperitoneal lymph node and peritoneal metastases. After six cycles of palliative chemotherapy, he presented with acute-onset jaundice. Imaging examinations did not show abnormal liver findings other than a periportal linear hypoattenuating area, and endoscopic retrograde cholangiography revealed a tight stricture of the proximal common bile duct. Total bilirubin continued to increase after endoscopic sphincterotomy and biliary stent insertion. Blind liver biopsy revealed tumor infiltration along liver lymphatics, but ruled out tumor involvement of hepatic parenchyma and sinusoids. Tumor cells were predominantly confined to within the lymphatic vessels and were not observed in the arteries or veins. Although one loading dose of cetuximab and two fractions of palliative radiotherapy were administered, the patient succumbed to acute liver injury 30 days after the development of jaundice.
Arteries ; Bilirubin ; Biopsy ; Cetuximab ; Cholangiography ; Colon* ; Colon, Ascending ; Colonic Neoplasms* ; Common Bile Duct ; Constriction, Pathologic ; Drug Therapy ; Humans ; Jaundice ; Liver* ; Lymph Nodes ; Lymphatic Metastasis ; Lymphatic Vessels ; Middle Aged ; Neoplasm Metastasis* ; Radiotherapy ; Sphincterotomy, Endoscopic ; Stents ; Veins

The patient was a 70-year-old male whose chief complaints were obstructive jaundice and weight loss. Abdominal imaging studies showed a 2.5 cm sized mass at the distal common bile duct, which was suggestive of bile duct cancer. Eccentric enhancing wall thickening in the transverse colon was also shown, suggesting concomitant colon cancer. A colonoscopy revealed a lumen-encircling ulcerofungating mass in the transverse colon, that was pathologically proven to be adenocarcinoma. The bile duct pathology was also adenocarcinoma. Pylorus-preserving pancreaticoduodenectomy and extended right hemicolectomy were performed under the diagnosis of double primary cancers. Postoperative histopathologic examination revealed moderately differentiated mucinous adenocarcinoma of transverse colon cancer, and mucinous adenocarcinoma of the distal common bile duct. Immunohistochemical staining studies showed that the bile duct cancer had metastasized from the colon cancer. The patient recovered uneventfully from surgery and will be undergoing chemotherapy for three months.
Adenocarcinoma ; Adenocarcinoma, Mucinous* ; Aged ; Bile Duct Neoplasms ; Bile Ducts ; Colon, Transverse* ; Colonic Neoplasms ; Colonoscopy ; Common Bile Duct Neoplasms ; Common Bile Duct* ; Diagnosis ; Drug Therapy ; Humans ; Jaundice, Obstructive* ; Male ; Mucins* ; Neoplasm Metastasis ; Pancreaticoduodenectomy ; Pathology ; Weight Loss

Ovarian metastases represent about 3-5% of all ovarian malignancies. Most of these tumors originate in the digestive tract and cholangiocarcinoma rarely involves the ovary. A 60-year-old woman was admitted for the investigation of abdominal distension that had lasted 1 week. One and a half years prior, the patient had undergone choledochal cyst excision, Roux-en Y hepaticojejunostomy and cholecystectomy. Computed tomography scans of the abdomen revealed a papillary mass in the remnant distal common bile duct and enlargement of both ovaries with a huge amount of ascites. An explorative laparotomy disclosed no peritoneal seeding with resectable cholangiocarcinoma and bilateral ovarian mass. Pylorus-preserving pancreatoduodenectomy and bilateral salphingo-oophorectomy with hysterectomy were performed. Histologically, it was a well-differentiated adenocarcinoma and all surgical margins were free of tumor. Both ovarian masses were consistent with metastatic adenocarcinoma from the common bile duct. The patient received six cycles of postoperative adjuvant systemic chemotherapy, dying after 10 months due to pulmonary embolism.
Abdomen ; Adenocarcinoma ; Ascites ; Cholangiocarcinoma ; Cholecystectomy ; Choledochal Cyst* ; Common Bile Duct* ; Drug Therapy ; Female ; Gastrointestinal Tract ; Humans ; Hysterectomy ; Laparotomy ; Middle Aged ; Neoplasm Metastasis* ; Ovarian Neoplasms ; Ovary ; Pancreaticoduodenectomy ; Pulmonary Embolism

OBJECTIVETo investigate the effect of photodynamic therapy (PDT) mediated by hematoporphyrin derivative (HPD) on apoptosis and invasion of cholangiocarcinoma QBC939 cell lines.

METHODSIn vitro cultured cholangiocarcinoma QBC939 cell line was exposed to 2, 4, 6, 8, 10, 12, and 14 μg/ml HPD with 5, 10, and 15 J/cm2 light intensity, respectively. The optical density at 450 nm of the QBC939 cells was measured by CCK8 assay and its growth inhibition ratio was calculated. Flow cytometry and transwell migration assay were applied to detect cell apoptosis and invasion respectively. RT-PCR and immunocytochemistry analyses were used to detect expressions of vascular endothelial growth factor-C (VEGF-C), cyclooxygenase-2 (COX-2), and proliferating cell nuclear antigen (PCNA). Enzyme-linked immunosorbent assay (ELISA) was carried out to examine the secretion of VEGF-C and COX-2 in QBC939 cells.

RESULTSExposure to HPD-PDT can significantly suppress the growth of QBC939 cells (all P<0.05). HPD-PDT can promote apoptosis of QBC939 cells at the early stage. When the concentration of HPD was 2 μg/ml and light irradiation was 5 J/cm2, HPD-PDT had no obvious inhibitory effect on QBC939 cell growth, but can obviously inhibit cell invasion, and significant difference was observed between the HPD-PDT and control groups (P<0.01). The HPD-PDT can reduce the mRNA and protein expressions of VEGF-C, COX-2, and PCNA, and decrease the secretion of VEGF-C and COX-2 in QBC939 cells.

CONCLUSIONPDT could promote apoptosis and inhibit growth and invasion of cholangiocarcinoma cells QBC939 in vitro.

Apoptosis ; drug effects ; Bile Duct Neoplasms ; drug therapy ; pathology ; Bile Ducts, Intrahepatic ; Cell Line, Tumor ; Cell Movement ; drug effects ; Cholangiocarcinoma ; drug therapy ; pathology ; Humans ; Neoplasm Invasiveness ; Photochemotherapy ; Proliferating Cell Nuclear Antigen ; analysis

Biliary papillomatosis is rare, and its pathogenic mechanisms are not yet clear. Because of its high risk for malignancy transformation, surgical resection is regarded as a standard treatment. Photodynamic therapy (PDT) has been used by the intravenous administration of hematoporphyrin derivative followed by laser exposure. A photochemical process causes disturbance of the microvascular structure and degradation of membrane. Cholangitis is a major complication after PDT. A healthy 56-year-old man was diagnosed with biliary papillomatosis involving the common hepatic duct, both proximal intrahepatic bile ducts (IHD), and the right posterior IHD. After biliary decompression by endoscopic nasobiliary drainage, PDT was performed to avoid extensive liver resection and recurrence using endoscopic retrograde cholangiographic guidance. After portal vein embolization, the patient underwent extended right hemihepatectomy. Following administration of chemoradiation therapy with tegafur-uracil and 45 Gy due to local recurrence at postoperative 13 months, there was no local recurrence or distant metastases. This is the first case report on PDT for biliary papillomatosis in Korea. Preoperative PDT is beneficial for reducing the lesion in diffuse or multifocal biliary papillomatosis and may lead to curative and volume reserving surgery. Thus, PDT could improve the quality of life and prolong life expectation for biliary papillomatosis patients.
Antineoplastic Agents/therapeutic use ; Bile Duct Neoplasms/*diagnosis/drug therapy/surgery ; Bile Ducts, Intrahepatic/pathology ; Embolization, Therapeutic ; Gamma Rays ; Hepatectomy ; Hepatic Duct, Common/pathology ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local ; Papilloma/*diagnosis/drug therapy/surgery ; Photochemotherapy ; Tegafur/therapeutic use ; Uracil/therapeutic use

BACKGROUND/AIMS: Patients with cholangiocarcinoma usually present at an advanced stage, and more than 50% of cases are not resectable at the time of diagnosis. Recently, photodynamic therapy (PDT) has been proposed as a palliative and neoadjuvant modality. We evaluated whether combination of PDT and chemotherapy is more effective than PDT alone. METHODS: In total, 161 patients with cholangiocarcinoma diagnosed between February 1999 and September 2009 were evaluated. Sixteen patients were treated with PDT and chemotherapy (group A), and 58 were treated with PDT (group B). RESULTS: The median survival was 538 days (95% confidence interval [CI], 475.3 to 600.7) in group A and 334 days (95% CI, 252.5 to 415.5) in group B (p=0.05). Lymph node metastasis status, serum bilirubin of pretreatment, tumor node metastasis stage, treatment method (PDT with chemotherapy vs PDT alone), time to PDT and the number of PDT sessions were prognostic factors with statistical significance in the univariate analysis. A multivariate analysis showed that PDT with chemotherapy and more than two sessions of PDT were significant independent predictors of longer survival in advanced cholangiocarcinoma (hazard ratio [HR], 2.23; 95% CI, 1.18 to 4.20; p=0.013 vs HR, 1.79; 95% CI, 1.044 to 3.083; p=0.034). CONCLUSIONS: PDT with chemotherapy results in longer survival than PDT alone.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Bile Duct Neoplasms/*drug therapy ; *Bile Ducts, Intrahepatic ; Cholangiocarcinoma/*drug therapy/mortality ; Cholangiopancreatography, Endoscopic Retrograde ; Cisplatin/administration & dosage ; Combined Modality Therapy/mortality ; Deoxycytidine/administration & dosage/analogs & derivatives ; Female ; Fluorouracil/administration & dosage ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Photochemotherapy/*methods/mortality ; Treatment Outcome