Bile acids are most abundant organic compounds in the bile, and are biosynthesized from cholesterol. Bile acids play an important role on bile formation as well as the solubilization of cholesterol in the bile. Recent studies elucidated the mechanism of metabolism and transport of bile acids and its regulatory system. As the mechanism of the action of UDCA, the theory of biliary bicarbonate umbrella has recently been postulated. Itching observed in cholestasis has been reported to be caused by lysophosphatidic acid produced from lysophsphatidylcholine, not by bile acids or opioids. FXR is a nuclear receptor with bile acids as ligands, and TGR5 is a membrane receptor with bile acids as ligands. Recently, bile acids have been reported to play an important role in the metabolism of sugars, lipids and energy through these receptors, and the development of new drugs for various diseases have been conducted with these bile acid receptors as targets.

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Recently, ERCP and associated procedures are widely used for the management of pancreatobiliary disorders, because of the increasing needs for minimal invasive procedures. Deep cannulation of the desired duct is a prerequisite for successful therapy at ERCP. Achieving deep biliary cannulation can be challenging at times for experts and novices alike. Endoscopists should not repeat the same approach. They should try to use alternative techniques which are tailored to the individual papillary and ductal anatomy of each patient. Endoscopic sphincterotomy (EST) is not only the first line of treatment for bile duct stones but also the first step for many therapeutic or diagnostic procedures. ERCP and associated procedures are much less invasive and involve much less manpower, preparation, and procedure time. However, procedure-related complications occur occationary. It is necessary to be aware of the fundamental knowledge and techniques of these procedures in order to avoid unexpected results.

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We described the tips of bile duct stenting and gallbladder stenting. For the master of biliary endoscopists, we should know the characteristics of many kinds of metal stents in patients with distal bile duct obstructions. In particular, whether the stent belongs to the braided type and laser cut type metal stent affects the stenting. We should know the key factors of metal stent as follows: shortening rate, axial force and radial force. Based on the detail of stent characteristics, we should place the stent across the strictures. In terms of gallbladder stenting, it is very important for successful procedure to find the bifurcation of cystic duct. After finding it, the guidewire is advanced into the gallbladder using several techniques, e.g. twist, rotation, and back and forth of guidewire.

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Single port surgery (SPS) is an attempt to reduce damage to the abdominal wall by introducing the scope and instruments in a relatively small area. Less invasiveness of this approach comparing to the standard one is yet to be proven. Cosmetic superiority is obvious and the operative scar is almost invisible 2 weeks after SPS surgery. Another approach to reduce damage to the body wall is needlescopic surgery where the diameter of instruments is less than 3 mm. Researchers have noticed that pros and cons that SPS and needlescopic surgery pose are complimentary and mixed use of these technique ease the technical difficulty while keeping the excellent cosmetic outcome. This hybrid approach is collectively named reduced port surgery. NOTES device and surgical robot (DaVinci) has reportedly been used in reduced port surgery. Combined use of these tools with minimal damage to the body wall would be the future of minimally invasive surgery.

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After the three-dimensionally angiography by computed tomography (3DCT), radical operation was performed in 67 cases of hilar-cholangiocarcinoma or gallbladder cancer. Based on deformation and constriction seen mainly through the maximum intensity projection (MIP) of 3DCT, tumor infiltration of the hepatic artery and portal vein was determined for a pre-operative diagnosis and compared with the histopathological presentation of vascular infiltration to evaluate the efficacy of 3DCT in such a pathological state. The overall accuracy, sensitivity and specificity were 79.1%. 91.7% and 76.4% for arterial infiltration and 76.1%, 80.0% and 74.5% for portal vein infiltration, respectively. All indicated a high degree of concordance with the histopathological diagnosis. The findings of the present study indicated that a diagnosis based mainly on the MIP images of 3DCT makes a significant contribution to the diagnosis of vascular invasion by hilar- cholangiocarcinoma and by gallbladder cancer.

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We present here six cases (five men and one woman, 72-89 years of age) of biliary tract cancer following EST. Initial EST was performed for removal of common bile duct stones in five patients and for postoperative bile leak in one case. Subsequent cholecystectomy was performed in three of five cases with gallstones. During the period of 26 to 78 months after EST, these six patients were diagnosed with biliary tract cancer, which included three patients with gallbladder cancer, two with bile duct cancer and one with multiple cancers (ampullary and bile duct cancers). Although surgical resection was performed in three cases, the remaining three were judged inoperable due to tumor extension and concomitant diseases. During the follow-up period, there was recurrence of bile duct stone in one patient, cholangitis without recurrent stone in three cases and obstruction of cystic duct in one patient. When cholangitis without recurrent stone occur after EST, special attention should be paid to the potential risk of biliary tract cancer and examinations should be performed more closely.

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Techniques of MDCT (multidetector row CT) and MRI have made great advances recently. Thin slice multiphase contrast enhanced dynamic CT can afford multi-directional reformatted images and 3D volume images which are useful for diagnosis of tumor extension. MRI includes not only MRCP (MR cholangiopancreatography) but also T1-weighted images, T2-weighted images, steady state images, and contrast enhanced dynamic images. MRI (MRCP) can offer detection of biliary carcinomas, degree of tumor extension, and secondary changes such as biliary cholestasis. Combination of MDCT and MRI can make more detailed imaging diagnosis of biliary carcinomas.

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IgG4-related sclerosing cholangitis (IgG4-SC) is a characteristic type of sclerosing cholangitis with unknown pathogenic mechanism. IgG4-SC patients show increased level of serum IgG4 and dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall. IgG4-SC is frequently associated with autoimmune pancreatitis, and occasionally with IgG4-related symmetrical dacryoadenitis/sialadenitis and IgG4-related retroperitoneal fibrosis. Various cholangiographic features of IgG4-SC are similar to those of primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma. Therefore, it is not easy to discriminate IgG4-SC from these progressive or malignant diseases on the basis of cholangiographic findings alone, and accurate diagnosis of IgG4-SC not associated with autoimmune pancreatitis is particularly difficult. The Research Committee in association with the Ministry of Health, Labor and Welfare Japan, and the Japan Biliary Association established the new clinical diagnostic criteria of IgG4-SC 2012. The criteria are believed to be practically useful for general physicians. Steroid therapy is very effective. Recently, immunosuppressive drugs have been introduced in the treatment of relapsed patients in the United States and Europe. Prognosis is generally good, however IgG4-SC cases showing liver atrophy have been reported.

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IPN of the bile ducts includes the previous categories of biliary papilloma and papillomatosis, and is characterized with a noninvasive papillary or villous biliary neoplasm covering delicate fibrovascular stalks. The patient was a woman in her 60s in whom multiple small liver cysts had been detected about 20 years earlier. The patient was referred to our hospital because a cyst with an internal high-echo bulge in hepatic segment 4 (S4) of the liver had been detected on abdominal ultrasonography conducted recently at a nearby clinic. Abdominal CT showed a gourd-shaped, unilocular cyst measuring 66 mm in diameter in S4 of the liver containing within it a papillary nodule measuring 36 mm in diameter. Endoscopic retrograde cholangiography (ERC) showed that the left intrahepatic bile duct was compressed and connected to the cyst. From these findings, intraductal papillary neoplasm of the bile duct (IPN-B) was diagnosed, and a left hepatic lobectomy was performed. In the resected specimen, a white granular nodule with a papillary growth were observed. Pathologically, the nodule was composed of atypical epithelium with clear round nuclei and an acidophilic cytoplasm. No submucosal invasion or ovarian-like stroma was observed. Multiple bile duct hamartomas were observed in the background liver, but no relationship between these tumors and IPN-B was found. At present, 2 years and 6 months after surgery, the patient remains alive without recurrence.

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An 81-year-old male was admitted to our hospital because of a gallbladder mass. Computed tomography (CT) revealed a protruding mass 18 mm in diameter in the fundus of the gallbladder, with wall thickening and enhancement suspicious of malignancy. Endoscopic ultrasonography (EUS) revealed a tear at the base of the lateral high echo layer. Given the possibility of gallbladder cancer with invasion of the liver bed, a S5/S4a liver resection and cholecystectomy with D2 lympadenectomy and biliary reconstruction was carried out. The postoperative course was uneventful and he was discharged after 12 days. The resected specimen showed a protruding tumor with a smooth mucosa and a white node from the gallbladder wall to the liver surface membrane in the sectioned surface. The pathological diagnosis was a suspected benign tuberculosis epithelioid granuloma and caseous necrosis with focal necrosis in the indurations. Although no tubercle bacilli were detected on Ziehl-Neelsen staining or PCR testing of the excised specimen, a gallbladder tuberculosis granuloma was diagnosed based on positive QuantiFERON testing. It is necessary to consider a gallbladder tuberculosis granuloma in the differential diagnosis of gallbladder masses with a history of tuberculosis.

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This report mentions a rare case of an adenoendocrine cell carcinoma in the papilla resected after neoadjuvant chemotherapy. A 68-year-old woman was admitted to our hospital with jaundice. Gastrointestinal endoscopy revealed a tumor at the papilla of the duodenum. The tumor biopsy showed neuroendocrine carcinoma. Pylorus preserving pancreaticoduodenectomy was performed, followed by two courses of CPT-11/CDDP. The response evaluation of chemotherapy was stable disease. The microscopically final diagnosis was adenoendocrine cell carcinoma. Immunohistochemically, the specimen showed positive staining for Chromogranin A and Synaptophysin. The patient, discharged uneventfully, has been doing well as an outpatient after 24 months of follow-up. Adenoendocrine cell carcinoma was characterized by poor prognosis, because of early metastasis for liver and lymph nodes. To the best of our knowledge, 11 cases of adenoendocrine cell carcinoma of the papilla were reported in Japan. We also hope that the treatments for adenoendocrine cell carcinoma in the papilla Vater will be further discussed.

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A female patient in her 60s presented at hospital with the principal complaint of nausea. Blood tests revealed jaundice and elevated hepatobiliary enzymes, and abdominal CT revealed an early stage tumor with strong contrast effect in the upper bile duct. ERCP showed stenosis in the upper to middle bile duct, with pronounced dilatation of the upstream bile duct. Re-examination of ERCP the following day showed a tumor shadow with a gentle slope, and a submucosal tumor was suspected. On oral cholangioscopy, most of the mass demonstrated the morphology of a submucosal tumor. Based on the above factors, the patient was pre-operatively diagnosed with submucosal invasion of cancer of the upper biliary tract, and an extrahepatic bile duct resection was performed. HE staining showed hyperplasia of small tumor cells with a high N/C ratio in a solid alveolar arrangement. Immunostaining findings were positive for chromogranin A and a diagnosis of neuroendocrine tumor (NET)-G2 was made based on the 2010 WHO classification.
Bile ducts are an extremely rare primary site for neuroendocrine tumors, and as there are no other case reports in which the patient has been observed preoperatively via oral cholangioscopy, this case was considered very valuable.

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Of all the treatment modalities for biliary tract cancer, only resection offers the opportunity for cure. However, because of metastases or of direct invasion of the tumor into the adjacent liver or hepatic artery, only a small minority of biliary tract cancer patients are suitable candidates for resection with curative intent. Chemotherapy is usually indicated for patients with unresectable, advanced biliary tract cancer or for those who develop relapse after operation; however, no standard treatments with solid evidence of a survival benefit have been established for such patients. Although gemcitabine therapy was regarded as the de facto standard treatment for advanced biliary cancer until recently, gemcitabine plus cisplatin has become established as the new global standard regimen based on the results of a phase III study conducted in UK and a randomized phase II study conducted in Japan. New therapeutic modalities such as molecular-targeted therapies have recently been evaluated for unresectable disease, and large-scale randomized controlled trials are under way to establish standard adjuvant chemotherapy for resectable disease.

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