Biliary tract cancer comprises a variety of invasive adenocarcinomas, including extrahepatic and intrahepatic cholangiocarcinoma (CCA), gallbladder carcinoma, and ampullary carcinoma [1]. Although CCA is a rare type of cancer, it is the second-most frequent primary tumor of the liver and the most frequent biliary malignancy, accounting for about 3% of all gastro-intestinal neoplasia [2]. CCAs are associated with a 10–40% 5-year survival rate and show a high recurrence after surgery [3].

2. Pathology

Depending on their localization, CCAs are classified into intrahepatic, perihilar, and distal [4]. Intrahepatic CCAs are located in the segmental and smaller bile ducts of the liver and account for 20% of all cholangiocarcinomas ^[5][6][7][5,6,7]. Perihilar CCAs or Klatskin tumors account for 50–60% of all cholangiocarcinomas and occur between the segmental bile ducts and at the junction between the cystic and the main hepatic duct ^[8][9][8,9]. Distal CCAs account for 20–30% of cases and involve the common bile duct [10]. Macroscopically, intrahepatic CCA exhibits different growth patterns; the most frequent one is mass-formation (65%), followed by periductal infiltration and intraductal growth ^[11][12][13][11,12,13]. Perihilar and distal CCAs occur most frequently as nodular plus periductal infiltrating patterns (>80%) ^[11][14][15][11,14,15]. While periductal infiltration has a longitudinally growth pattern leading to biliary strictures, intraductal tumors tend to grow towards the duct lumina ^[14][16][14,16]. Microscopically, the vast majority of perihilar and distal CCA are mucinous adenocarcinomas (conventional type) or papillary tumors ^[10][16][17][10,16,17], originating from the columnar mucous cholangiocytes and peribiliary glands ^{[14][17][18][19][20][21]}[14,17,18,19,20,21]. Precancerous lesions include the following:

• Biliary epithelial neoplasia presents as flat or micropapillary lesions with dysplasia [22], sometimes associated with CCA [23]; it may occur in chronic liver disease, particularly in chronic HCV infection or alcoholic hepatitis [24]. The lesions are usually asymptomatic.

EUS may be helpful in the setting of bile duct dilation if no mass is seen on CT or MRI [32], and unnecessary ERCP can be avoided in about one-third of the patients [33]. EUS evaluation of the biliary tree is performed from the level of the duodenal bulb and the distal part of the gastric antrum, for both biliary strictures and CCAs. Using EUS, they can be visualized either as a mass or as a biliary stricture.

The EUS aspect suggestive of CCA is a mass extending beyond the bile duct wall or periductal infiltration, with a wall thickness of more than 3 mm, or an intraductal mass-growing lesion ^[34][35][34,35] (Figure 1). In previous research, distal tumors which were closer to the EUS transducer were diagnosed in 100% of the cases, while tumors located further from the transducers were only diagnosed in 83% of the cases. Overall, EUS performed better in identifying tumors in comparison to CT or MRI (94, 30, 42%) [36]. Extrahepatic CCAs were diagnosed at an early stage when MRCP was followed by EUS (sensitivity 90% and specificity 98%) [37]. EUS is also useful when assessing common bile duct dilatation associated with normal hepatic tests and inconclusive imaging [38].

EUS proved a T staging accuracy of 60–81% (Table 1), while intraductal ultrasound (IDUS) can assess the T staging with 68% accuracy [39]. No comparative data exists for T staging between proximal or distal CCAs. The growth pattern of perihilar CCAs is an axial extension along and into the bile ducts, while distal CCAs also have an axial growth pattern, extending into the pancreatic parenchyma. Invasion into the liver parenchyma is isoechoic and can easily be missed on conventional B-mode ultrasound.

For this reason, the contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) can identify the tumor as grape-like clusters that invade the biliary ducts and expand into the liver and portal vein, features useful for assessing its resectability [45]. The suggestive contrast enhanced value of CCAs is that of a hyperenhanced lesion with rapid wash-out. In a single-center retrospective study, Otsuka et al. pointed out the importance of CH-EUS for T staging in patients with perihilar CCA and distal CCA compared to surgical assessment, with a better accuracy of CH-EUS for T staging compared to conventional EUS or contrast enhanced CT (73.7% vs. 60.5 vs. 39.5%) [46]. The detection of invasion into other organs did not differ significantly between the two EUS methods (e.g., for diagnosing invasion beyond the biliary wall, the accuracy was 92.1% for CH-EUS vs. 78.9% for EUS vs. 45.9% for contrast-enhanced CT, respectively) [46]. However, CH-EUS is not recommended by the authors to be used for N or M staging, since the contrast agent is washed out rapidly [46].

In recent studies, EUS had an accuracy of 100% for identifying major vascular invasion [46], while in studies performed 10 years ago, the sensitivity for detecting unresectable tumors was only 53% [36].

No data exist about elastography during EUS assessment in extrahepatic CCAs due to the fact that these are small tumors, surrounded by many vessels, and this impedes an appropriate elastographic examination.

The regional lymph nodes of the bile duct are located along the portal vein and the hepatic artery, anteriorly and posteriorly to the pancreatic head, and along the superior mesenteric artery [47]. The distant lymph nodes are located in the aortocaval, celiac, and periesophageal regions [48]. The most frequently affected lymph nodes are those in the periportal region, followed by the regional gastrohepatic sites and by the distant lymph nodes [48]. The presence of at least one malignant lymph node shortens the median survival from 1050 days to 353 [48].

The N staging accuracy varies between 66 and 81% (Table 1). It is important to keep in mind that a round, hypoechoic lesion more than 10 mm in diameter is not specific for malignancy [40]. EUS can identify nodal involvement with a higher accuracy than cross-sectional imaging (86 vs. 47%) [48]. The presence of malignant regional lymph nodes precludes curative oncological resection or liver transplant for CCA [49], and is associated with a four-fold higher risk of death [48].