Intraductal papillary neoplasm of the bile duct (IPNB) is a papillary neoplasm that can be recognized macroscopically residing inside bile duct. Microscopically, the neoplasm is composed of papillae with thin fibrovascular cores occasionally with tubular components, which shows various grades of atypia that is classified into low-grade, high-grade, and invasive. Invasive components show either tubular adenocarcinoma or mucinous carcinoma. Neoplastic papillae can be classified by morphological characteristics into four subtypes including gastric, intestinal, pancreatobiliary, and oncocytic, which corresponds to variations in intraductal papillary mucinous neoplasms of the pancreas. The Japan-Korea classification of IPNBs into type 1 and type 2 enabled to evaluate classic/typical IPNBs and atypical IPNBs, which is well associated with distinctive clinicopathological features including molecular aberrations and patients' prognosis.

To avoid bile duct injury during laparoscopic cholecystectomy, we propose visualizing both the Rouvière sulcus and the right edge of the baseline of the quadrate lobe (S4) for orienting the gallbladder, then exposing the inner layer of the subserosal layer or perimuscular connective tissue (SS-inner) by bluntly dissecting the surrounding fat tissue. These steps are indispensable but inadequate because the definition of the baseline of the S4 remains ambiguous and the surface of the SS-inner resembles that of the fibromuscular layer of the extrahepatic bile duct. Although standardization ensures safety, it cannot prevent every error caused by carelessness or preconception. Thus, in addition to procedural standardization, preliminary recognition of various pitfalls can help achieve zero surgical morbidity.

Evidences reported after Tokyo Guidelines 2018 was published are introduced. A study using the data of national clinical database (NCD) in 2018 revealed that 90-day mortality after cholecystectomy was 0.6%. A population-based propensity score analysis performed in Canada comparing operative outcomes between early and delayed cholecystectomy for acute cholecystitis was published. Early cholecystectomy was associated with a lower risk of major bile duct injury. There was not a high level of evidence regarding PTGBD. Randomized controlled trial performed in the Netherlands demonstrated that there had not been significant difference in mortality rates between the PTGBD group and the laparoscopic cholecystectomy group although recurrent biliary disease and major complications occurred more often in the PTGBD group. It is to be desired that a physician selects the therapeutic strategy for acute cholecystitis according to a patient's status and a condition of each institution.

Assessment of longitudinal extent of distal bile duct cancer, especially at hepatic site, is essential to determine the resectability, extent of resection, and surgical methods. The extension patterns of the tumors are divided into mucosal and intramural extension. The macroscopic appearances of the tumors are categorized into papillary type, nodular type, and flat type, and each type is divided into filling type and invasive type. The papillary type and nodular filling type (so called localized type) mainly present mucosal extension, and the nodular type and flat type (so called invasive type) mainly present intramural extension. On the image findings, intramucosal extension is expressed by the thickening and rigidity of the bile duct wall and luminal stenosis. These finding are evaluated by MDCT, MRI/MRCP, EUS, ERCP, and IDUS. On the other hand, it has been difficult to assess the mucosal extension because it shows flat extension. However, recently, several reports suggested the usefulness of POCS with mapping biopsy, and it is becoming popular.

Bile acids are not only a driving force for bile secretion, but have also being attracting attention in recent years as a signal molecule to maintain homeostasis in living organisms, including glucose metabolism and lipid metabolism. Bile acids produced from cholesterol in the liver are excreted to the intestinal tract via bile ducts, where they suppress the growth of gut microbiome. Bile acids return to the liver through the portal vein (enterohepatic circulation), after receiving deconjugation and dehydration reactions by gut microbiome. Namely, bile acids are a molecule that transmits the intestinal environment containing gut microbiome to the liver. In addition to detailed molecular mechanisms involved in bile acid metabolism, this review will outline recent findings on congenital or acquired cholestasis, and therapies targeting bile acid related molecules.

Incidental gallbladder cancer is increasing with technological advances in laparoscopic cholecystectomy. The principles of resection for T1b or greater gallbladder cancer are radical cholecystectomy including gallbladder bed and lymphadenectomy and extended hepatic or biliary resection as necessary to obtain a negative margin. For incidental gallbladder cancer over T1b, therefore, additional resection is recommended. In our 3, 061 cholecystectomies on benign disease, we experienced 48 cases (1.6%) with incidental gallbladder cancer. Recurrence was observed in 19 (40%) cases. Additional resection was 11 (23%), and 3 cases suffered from recurrence. In conclusion, grately careful attention concerning with cancer is significant for preoperative diagnosis for cholecystectomy. If highly suspected gallbladder cancer, whole layer cholecystectomy is recommended to avoid spilling bile as this can result in peritoneal dissemination. Moreover, additional resection should be considered for T1b or greater cancer on postoperative pathologic review.

Despite advances in diagnostic imaging, it remains difficult to distinguish Xanthogranulomatous cholecystisis (XGC) from gallbladder cancer. However, this distinction is important to avoid over-surgery for XGC, which is a benign disease. We examined 15 cases of XGC in our department to identify factors associated with diagnosis and therapy. Findings that are strong indicators of XGC include: a history of moderate or severe cholecystitis attacks; an area of low absorption in the thickened gallbladder wall on contrast-enhanced CT; uniform imaging of the lumen surface; and a change in the image over a short period of time. These factors can be examined before surgery in cases in which it is difficult to distinguish XGC from gallbladder cancer. During surgery, it is important to make full use of pathological diagnosis to avoid overly invasive surgery.

In the biliary tract, inflammation and carcinogenesis are closely associated with each other. Gallstones provoke inflammation in the bile duct, which can cause development of carcinoma. The relative risk of hepatolithiasis and choledochal stones for development of carcinoma is 17.64. Pancreaticobiliary maljunction causes reflux of pancreatic juice and chronic inflammation with or without dilatation in the bile duct. Carcinoma can be found in 20% of the dilated type and 40% of the non-dilated type of pancreaticobiliary maljunction. Primary sclerosing cholangitis is associated with carcinoma in 7% of patients. Liver fluke causes chronic inflammation and carcinoma. Biliary intraepithelial neoplasia and intraductal papillary neoplasm, precursor lesions in the bile duct, are found frequently in the bile duct with inflammation. In genome analyses of bile duct carcinomas, the mutation signature indicates inflammation-associated APOBEC activation as an etiology. Peribiliary glands harbor stem cells that can become a source for regeneration of bile duct epithelium. Inflammation is supposed to accelerate regeneration of biliary epithelia, which may increase a risk for development of carcinoma.

Surgical resection is the curative treatment for biliary tract cancer. Biliary tract cancer is classified into hilar cholangiocarcinoma, distal cholangiocarcinoma, duodenal papilla cancer, gallbladder cancer, etc., but hilar cholangiocarcinoma is the most difficult to operate. There are many technique-dependent and highly invasive surgeries such as resection and reconstruction with vascular (hepatic artery/portal vein) resection and reconstruction and hepatopancreatoduodenectomy, but the results have improved in recent years. The progress of drug therapy for biliary tract cancer is also remarkable. Development of new therapies combined with chemotherapy, such as conversion surgery for patients who responded to chemotherapy for unresectable biliary tract cancer and preoperative chemotherapy for resectable biliary tract cancer, is also expected. This paper clarifies the current status of surgical treatment for biliary tract cancer, especially hilar cholangiocarcinoma, and also describes future prospects.

We could observe the growth process of a gallbladder adenosquamous carcinoma from occurrence to resection. Two years ago, we encountered a 79-year-old woman having a gallbladder polyp with 3.9mm diameter. We found growth of the polyp to the diameter of 24mm during about two years, which gave us the tumor volume doubling time of 111 days. Under the presumptive diagnosis of gallbladder cancer, she underwent surgery, and the pathology of the tumor was adenosquamous carcinoma. Among gallbladder cancers, adenosquamous carcinoma is associated with extremely poor prognosis due to its rapid growth. However, the growth was rather retarded in this case suggesting that the growth might be dependent on the proportion of squamous component in the tumor. What this means is that some cases of adenosquamous carcinoma might not show rapid growth. Therefore, the complete resection of the gallbladder might be suffice for such adenosquamous carcinoma just as adenocarcinoma.

We report a case of repeated needle-shaped intrahepatic stones after pancreaticoduodenectomy. The patient was a man in his 60s. He underwent pancreaticoduodenectomy for intraductal papillary mucinous neoplasm. Two years after the operation, CT revealed a linear hyper-attenuated structure reaching from the left intrahepatic bile duct to the hepaticojejunostomy. Four years after the operation, he developed acute cholangitis and underwent balloon enteroscopy. The aperture of the hepaticojejunostomy was filled with a bundle of black-brown needle-shaped objects with muddy stones. We removed them using grasping forceps. The patient was stable after treatment, but cholangitis developed two years after the endoscopic treatment and CT revealed similar linear hyper-attenuated structures. Enteroscopy was performed and needle-shaped stones were again found in the anastomotic site. We removed them endoscopically. Subsequent CT confirmed the disappearance of the needle-shaped objects; however, they were visualized again one year after second retreatment. The main component of the endoscopically removed objects was bilirubin calcium.

Systemic chemotherapy has been developed and applied not only to the treatment of unresectable disease, but also as postoperative adjuvant therapy in patients with biliary tract cancer (BTC). Gemcitabine plus cisplatin (GC) has been used globally as the standard chemotherapy for unresectable BTC. In Japan, gemcitabine plus S-1 and GC plus S-1 have also been demonstrated to yield survival benefit in phase III studies, and they are recommended as alternative treatments for unresectable BTC.

Based on the results of a phase III trial conducted in the UK, capecitabine has begun to be used as adjuvant therapy after surgery. In Japan, S-1 is currently under investigation in a phase III trial as postoperative adjuvant therapy.

Immune checkpoint inhibitors and various compounds based on genomic profiling, such as IDH and FGFR2, have also been investigated. Improvements in the survivals of patients with advanced BTC would be expected with the developments of these treatments in the future.