Cholangiocarcinoma: Diagnosis, management, and prognosis

Introduction

Cholangiocarcinoma is an epithelial carcinoma of the bile ducts, which can be divided anatomically into intra- and extrahepatic. Intrahepatic and extrahepatic cholangiocarcinoma are distinct entities that have different considerations with regard to diagnosis, staging, and treatment. Intrahepatic cholangiocarcinoma (ICC) arises directly from the hepatic ducts within the liver, whereas extrahepatic cholangiocarcinoma (ECC) can include both hilar and distal bile duct cancers. We herein review the management of ICC and extrahepatic hilar cholangiocarcinomas, also known as Klatskin tumors.

Epidemiology and risk factors

Cholangiocarcinomas are relatively rare in the United States. Cholangiocarcinoma is, however, the second most common primary hepatobiliary malignancy after hepatocellular carcinoma. ^, Around 25% of cases involve the common/hepatic bile duct, and the remaining are intrahepatic, nonperihilar tumors. ^, Cholangiocarcinoma is the ninth most common gastrointestinal cancer and it accounts for approximately 13% of cancer-related deaths worldwide (3% in the United States).

The incidence of cholangiocarcinoma varies widely with geography. The reported incidence is highest in Southeast Asia (96 per 100,000) and lowest in Australia (0.1 per 100,000). In the United States, the incidence is approximately 1 per 100,000 for both ICC and ECC. ^, The incidence of ICC has been increasing over the past 30 years worldwide, ^{, ,} and this increase does not seem to be solely attributable to improvements in diagnostic modalities or better pathologic characterization of the disease. ^, In the United States, age-adjusted incidence of ICC increased from 0.32 in 1975 to 0.85 per 100,000 in 2000, and has not yet reached a plateau. At the same time, incidence of ECC has declined.

The prevalence of cholangiocarcinoma is approximately equal between the two genders, with a slightly higher prevalence in males. ^, Almost all patients are older than 50 years at the time of diagnosis, with most patients in the United States diagnosed in their sixth decade of life. Asian Americans and Hispanics have a 2.5 times and 1.8 times, respectively, increased incidence of cholangiocarcinoma compared with non-Latino whites in the United States.

Cholangiocarcinoma is associated with conditions that result in chronic biliary inflammation and cholestasis. For example, the risk of cholangiocarcinoma has been associated with primary sclerosing cholangitis and inflammatory bowel disease, biliary fluke infestations, hepatitis (due to hepatitis B and C virus or alcoholic steatohepatitis), and cirrhosis. In addition, biliary malformations, hepatolithiasis, carcinogens (i.e., thorotrast), as well as chronic conditions like diabetes mellitus or HIV infection have also been reported to be associated with a higher risk of cholangiocarcinoma. ^{, , ,}

In the United States, one of the most common risk factors for cholangiocarcinoma is primary sclerosing cholangitis (PSC). PSC can cause fibrosis and stricture formation. Patients with PSC often present with cholangiocarcinoma at a younger age—often up to two decades earlier than non-PSC patients. On average, the diagnosis of cholangiocarcinoma usually occurs 2.5 years after the diagnosis of PSC. ^, In contrast, the increased incidence of cholangiocarcinoma in Southeast Asia is associated with increased infection rates with Clonorchis sinensis or Opisthorchis viverrini . The World Health Organization has labeled both of these organisms as grade 1 carcinogens. Humans can become infected by both types of flukes through ingestion of raw or undercooked seafood. ^,

Patients with malformations such as choledochal cysts or Caroli disease are also at increased risk of cholangiocarcinoma. Choledochal cysts are cystic dilations of the biliary tract, and Caroli disease is associated with multiple intrahepatic cysts. Both are associated with an approximately 10%–15% lifetime risk of cholangiocarcinoma. ^, Hepatolithiasis is another well-recognized risk factor for cholangiocarcinoma. In these cases, the stones are usually found in proximity to the tumor site. Some authors have reported a 10% lifetime risk of cholangiocarcinoma with hepatolithiasis. ^, Thorotrast, a past radiocontrast agent, and dioxins also increase the risk of cholangiocarcinoma. Both hepatitis B and hepatitis C are considered potential risk factors for ICC but not ECC.

Tumor markers and molecular pathogenesis

The biomarkers carbohydrate antigen 19-9 (CA 19-9), carcinoembryonic antigen (CEA), and carbohydrate antigen 125 (CA 125) are often used during the diagnostic workup for cholangiocarcinoma. These markers are, however, not specific for cholangiocarcinoma and may be elevated in other conditions, including cholangitis, hepatolithiasis, or other malignancies such as colorectal cancer. The sensitivities of CA 19-9, CEA, and CA 125 have been reported to be less than 70%. The sensitivity and specificity of CA 19-9 is higher among patients with PSC at 78.6% and 98.5%, respectively. However, even in PSC, CA 19-9 does not prove to be an effective screening tool. In areas with high incidences of liver fluke infestations, serum or stool tests, as well as urinary 8- oxo -7,8-dihydro-2′-deoxyguanosine levels may be potential screening tests.

Biliary fluke infestation and hepatolithiasis have aided in the study of the molecular pathogenesis of cholangiocarcinoma. Specifically, biliary flukes can cause mechanical and toxic damage to bile ducts, causing chronic inflammation of the biliary epithelia leading to carcinogenesis. Similarly, hepatolithiasis can also cause biliary inflammation and bile stasis, leading to increased exposure of carcinogenic bile acids. Biliary injury and inflammation leads to the release of cytokines, which increases the production of nitric oxide (NO) and reactive nitrogen oxide species (RNOS) through the expression of inducible nitric oxide synthase in epithelial cells. NO and RNOS can cause DNA mutations and inactivate DNA repair proteins. Through a multistep process, normal biliary epithelium can be transformed into hyperplastic, dysplastic, and eventually malignant epithelium. Notably, two distinct precursors have been identified for cholangiocarcinoma: biliary intraepithelial neoplasia and intraductal papillary mucinous neoplasia of the liver. ^, Several growth factors or cytokines have been found to increase biliary proliferation. These factors include hepatocyte growth factor, transforming growth factor α (TGF-α), endothelial growth factor, leukocyte inhibitory factor, and interleukin 6 (IL-6).

Pathologic and morphologic classification

There have been many classification systems proposed to describe the pathologic and gross appearance of ICC and ECC. For ICC, the Liver Cancer Study Group of Japan’s (LCSGJ’s) classification scheme proposed dividing cholangiocarcinoma into three morphologies: mass forming, periductal infiltrating, and intraductal growth types ( Figure 10-1 ). ^, In the mass-forming type, a nodular, gray-white lesion or mass is typically found in the hepatic parenchyma ( Figure 10-2 , A ). The mass is generally solid and well defined, with significant variations in size. The center of the mass can often be necrotic or fibrotic, with rare calcifications. The periductal infiltrating type grows along the bile duct wall and appears as a concentric thickening that is ill defined and frequently not recognized ( Figure 10-2 , B ). The bile ducts may appear to be strictured, narrowed, or obstructed, resulting in stasis of bile. The liver often appears green and enlarged. Both the intra- and extrahepatic bile ducts are often involved in the periductal-infiltrating type. Intraductal-growing cholangiocarcinoma is characterized by intraluminal papillary tumors of the bile ducts that partially obstruct and dilate the ducts. The projections form sessile or polypoid masses covered with columnar epithelial cells. The papillary tumors produce mucin that is often retained within the tumor or may leak out into the bile duct, leading to obstructive jaundice in excessive cases. Traditionally, ECC has been described as nodular, sclerosing, and papillary, corresponding to mass-forming, periductal infiltrating, and intraductal-growing types of intrahepatic cholangiocarcinoma, respectively.

In contrast, hilar cholangiocarcinomas are typically classified anatomically based on the location within the biliary tree using the Bismuth-Corlette classification, types I-IV (see Figure 11-2 ). ^, Type I cholangiocarcinoma begin distal to the confluence of the right and left hepatic ducts, involving the common hepatic duct. Type II cholangiocarcinoma affect the confluence of the right and left hepatic ducts. Type IIIa cholangiocarcinoma involve the junction of the right and left hepatic ducts along with part of the right hepatic duct, and type IIIb also involves the junction and part of the left hepatic duct. Type IV cholangiocarcinoma include tumors that are multifocal or affect the union of the right and left hepatic ducts along with both the right and left hepatic ducts.

Overview: Intrahepatic cholangiocarcinoma