The biliary tract originates from embryonic foregut, simultaneously with liver, at fourth week. The initial phase starts from a diverticulum, arisen from the ventral surface of the foregut, that later will become the duodenum. The liver develops from mesenchymal cells of septum transversum and from the endodermal evagination of the foregut. After the development of liver parenchyma, the cells located between the liver and the foregut generate the bile ducts precursors. The extrahepatic biliary tract and the gallbladder originate from the caudal portion of the liver diverticulum, while the intrahepatic biliary system, together with the hilum, originates from the upper portion of the diverticulum. The well-known similarity between the intrahepatic pattern of portal vein branches and ductal biliary system is given by the growth of ductal cells, which follows the connective tissue of the portal veins system. The formation of the main duct completes later, when the cells of the initial occluding epithelium begin to vacuolate and a continuous epithelial-lined lumen is formed; the same process occurs for the cystic duct and the gallbladder. The main duct originates from the dorsal mesentery of the second portion of the duodenum, as pancreatic duct, thus explaining the fact that some biliary and pancreatic lesions have the same pathological behavior. The development of the sphincter of Oddi and of the papilla of Vater is the last phase of biliary tract growth [4, 5].

Jaundice is the most frequent manifestation of benign biliary neoplasms, and the onset of symptoms may be acute or chronic. Pain, when noticed, has the typical characteristics of hepatic and biliary area: it focalizes in epigastrium and in upper right quadrant with diffusion to the right shoulder and to the back. Weight loss is not as frequent as for pancreatic and biliary tract cancers but can be important in clinical setting, especially because there are not specific typical signs of benign biliary and gallbladder lesions. It is important to remark that sometimes these tumors are slow-growing neoplasms, and therefore symptoms may be intermittent.

Other physical findings are not typical such as gallbladder distension and liver enlargement.

The first diagnosis of a biliary or gallbladder lesion is usually given by the use of US, which has high variability on specificity and sensibility due to tumor size and to the presence of biliary dilatation.

The progress of modern radiology has allowed to avoid an extensive use of invasive exams (that are used mostly to relieve symptoms and rarely to clarify the site and extension of the stenosis), such as endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) which were extensively used in the past. The introduction of modern high-quality computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) resulted in a significant improvement in the diagnosis of these lesions, although the differential diagnosis with malignant lesions remains difficult (this is clearly confirmed by the high incidence of intraoperative or postmortem findings). The role of modern radiology in the diagnosis of liver lesions is treated in part II of this book. The use of biliary brushing during ERCP or PTC has high positive-predictive value but only very low negative-predictive value, and this is its great limit for clinical usefulness.

The 2010 WHO classification of digestive system tumors divides epithelial biliary tumors in benign or premalignant lesions (Table 15.2) [7].

Bile duct adenoma is treated in part III, Chap. 13, of this book. Here we examine specifically the intraductal and the mucinous cystic neoplasia that only in recent years have been considered as autonomous entities.

Intraductal papillary neoplasm of the bile duct (IPNB) is a special form of biliary neoplasm [8] that is associated with better outcome compared with conventional bile duct carcinoma and may represent an alternative carcinogenesis pathway in the biliary tract (flat biliary dysplasia vs. exophytic proliferation of biliary epithelium) [9].

Only recently WHO recognized IPNB as a distinct pathologic entity [6], and therefore IPNB can now be defined as “tumor showing papillary proliferation of neoplastic biliary epithelial cells with delicate fibrovascular stalks within the bile ducts, microscopic or macroscopic presence of mucin, and variable dilatation or multilocular cystic changes in the affected bile ducts” [8].

IPNBs can be separated from mucinous cystic neoplasms of the liver by their origin, their luminal communication with the bile duct, and the absence of ovarian-like stroma in the cyst wall; some authors affirm that they may be a biliary counterpart to IPMN.

Hepatolithiasis, liver flukes, and alcohol intake have been associated with these tumors, while smoking has been not [8, 9].

The most common presenting symptoms are those related to cholangitis such as abdominal pain, jaundice, fever, and mucobilia, but some patients may remain asymptomatic [8, 9]. Symptoms and abnormal laboratory findings (elevation in liver function test, e.g., AST, γGT, and CRP) may be caused by bile duct obstruction due to the tumor itself or to mucin production [8], and they are not significantly different between invasive and noninvasive lesions [8, 9].

These tumors can be histologically classified as low-, intermediate- or high-grade intraepithelial neoplasia (carcinoma in situ) and can have an associated invasive carcinoma [6, 8–10].

Also the neoplastic cells are classifiable cytologically into four phenotypes (pancreatobiliary (PT), intestinal (IT), gastric (GT), and oncocytic type (OT)) that are closely associated with the grade of malignancy (PT and IT with adenocarcinoma, while GT with adenoma or borderline tumor) and with the prognosis (a better outcome after resection for OT and GT and a poorer outcome for PT and IT) [8, 9].

The degree of invasion is highly correlated with outcome, and the tumors showing mucin secretion are associated with decreased invasion and better survival. Instead, the primary site of the lesion does not affect the course of the disease, its prognosis, and the survival [9].