CCA can occur along any area of the bile duct , and can be divided anatomically into intrahepatic (IH-CCA), and extrahepatic lesions (EH-CCA), occurring at the hilum, perihilar (p-CCA), and distal bile ducts (d-CCA) [12]. Perihilar cancers involving the left and right hepatic duct junction are referred to commonly as Klatskin tumors [13]. CCA possesses histological and molecular characteristics of adenocarcinoma in 90 % of cases. A recent study suggested that pluripotent hepatic stem cells are the progenitor cell line [14]. CCAs are thought to transform in a similar fashion to other adenocarcinomas; from early hyperplasia and metaplasia, to dysplasia and onto carcinoma [15]. Histologically, CCA can range from well differentiated to undifferentiated, with surrounding tissue displaying fibrotic and desmoplastic traits. Chronic inflammation and bile duct obstruction are considered to be major contributors to the development of CCA, making cirrhotic liver tissue an ideal media for oncogenesis [16].

Two pathologically and biologically different IH-CCA have been reported; a peripheral mass-forming lesion, and a central periductal infiltrating tumor [17]. The central periductal IH-CCA tend to present more commonly with portal pedicle and bile duct infiltration, with associated jaundice. Peripheral mass-forming IH-CCA has been linked to chronic hepatitis [18]. The mass-forming lesion typically has less local recurrence (76.1 % compared to 92.9 %) and a significantly higher median survival (32 months compared to 22 months) than periductal infiltrating tumors [19].

In rare cases, tumors can contain elements of both CCA and HCC. Referred to as mixed tumors, they are diagnosed by positive cytokeratin 19 and cytokeratin 7 immunohistochemistry tissue staining [12]. Liver biopsy is indicated for atypical radiographic findings prior to liver transplantation (LT) . One retrospective review of patients with mixed tumors following LT failed to identify useful pre-LT serum characteristics for their diagnosis [20]. Retrospective radiographic review of such patients after LT demonstrated progressive contrast enhancement throughout the arterial and portal venous phases without the classic washout seen in pure HCC [21]. Unifocal mixed tumors smaller than 2 cm appear to have similar 1, 3, and 5-year post-LT survival compared to LT for HCC inside accepted criteria [22]. Overall, however, mixed tumors are associated with poorer outcomes following LT than pure HCC, with cumulative 5-year recurrence rates of 65 % [21, 23].

Clinical signs and symptoms of CCA at presentation can be difficult to distinguish from decompensated cirrhosis. Abnormal liver function tests, abdominal pain, jaundice, weight loss, and pruritus can occur. IH-CCA more commonly presents with pain than with jaundice, as displaced hepatic parenchyma presses on the liver capsule [24]. Many patients, however, are asymptomatic, and their tumors are only detected incidentally on imaging studies. The diagnosis of IH-CCA requires microscopic tissue examination, as no other serum or imaging test is sufficiently sensitive and specific for disease confirmation (Fig. 23.2). The histological appearance of IH-CCA is similar to metastatic nonhepatic primary tumors and can be difficult to distinguish. Florescence in situ hybridization (FISH) analysis of tissue cells, which uses fluorescently labeled DNA probes to detect chromosomal abnormalities, can increase the specificity of the diagnosis when added to standard cytology [25]. FISH analysis involves scanning for cytologically atypical cells by determining the number of identified peri-centromeric signals on certain chromosomes, along with assessment for nuclear enlargement or irregular nuclear contour. High numbers of specific chromosomal abnormalities detected by FISH can aid in diagnosis. Serum carcinoembryonic antigen (CEA) and CA 19-9 may be elevated in 85 and 40 % of patients, respectively [26], thus facilitating a presumptive diagnosis or assisting in monitoring for recurrence after surgery. However, values must be interpreted with caution, as CA 19-9 elevation can be related to underlying cholangitis or biliary obstruction.

Radiographic differentiation of IH-CCA from HCC can be difficult. Magnetic resonance imaging (MRI) appears to offer an advantage over ultrasound and computer tomography (CT) scans. MRI with intravenous contrast can demonstrate progressive contrast uptake throughout different phases, as opposed to contrast washout in delayed phases as seen with HCC [27]. On MRI, IH-CCA typically appears hypointense on T1-weighted images and hyperintense on T2-weighted images (Fig. 23.3). MRI with cholangiopancreatography (MRI/MRCP) can be helpful in visualizing the ductal system and in determining the anatomic extent of the tumor. A previous study found that CT was limited in detecting the extent of CCA extent, specifically with periductal infiltrating tumors [28]. On CT scan imaging, the typical appearance is of a hypodense mass in the noncontrast phase with generally irregular margins and peripheral rim enhancement in the arterial phase, and then progressive hyperattenuation on venous delayed phase. This is in contrast to HCC, which is characterized by a rapid enhancement during the arterial phase and a washout in the delayed venous phases. This being said, the two lesions can be very difficult to distinguish on imaging. Endoscopic ultrasound (EUS) is useful in assessing and sampling suspicious lymph nodes and can be used for biopsy of the primary lesion. If, however, the lesion is perihilar in nature and LT is being considered, EUS-guided biopsy of the lesion will exclude the patient from LT because of concerns for tumor seeding. Fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning can provide diagnostic utility because of the high glucose uptake of the bile duct epithelium, but is less helpful in smaller or periductal infiltrative tumors [29]. The sensitivity of PET–CT is higher for IH-CCA (90 %) than for EH-CCA (60 %), with a distant metastatic detection rate reported to be 100 % [30]. Despite all attempts at preoperative staging with imaging studies, final determination of resectability occurs at the time of surgery [31]. Tumor size may or may not provide prognostic information for resection. Poor outcomes are associated with positive lymph nodes, positive margins, multiple nodules, and vascular invasion. Lymph node metastases are found in up to 30 % of surgically assessed IH-CCAs [32].