Cholangiocarcinoma: modern advances in understanding a deadly old disease

Abstract

Cholangiocarcinomas are tumors that arise anywhere in the biliary tract, presumably of cholangiocyte origin. The global incidence of this rare disease is on the rise. Several known risk factors exist, and link chronic biliary inflammation to the pathogenesis of cholangiocarcinoma. Among these, amplification of the epidermal growth factor receptor, the interleukin-6 signaling pathway, inducible nitric oxide, erb-2, and cyclooxygenase-2 are well defined. Most patients present late, with a median survival of months. Although, imaging studies and clinical context often indicate cholangiocarcinoma, pathologic and cytologic diagnosis is difficult to obtain. Advanced cytologic tests with fluorescence in situ hybridization or digital image analysis can increase diagnostic sensitivity. Surgical resection is the current therapy of choice for both intrahepatic and ductal cholangiocarcinomas. However, the 5-year survival is poor, with 60 to greater than 90% recurrence rates. In a single center experience, liver transplantation with neoadjuvant chemoirradiation, for highly selected patients, has a 5-year disease free survival of greater than 80%. Future targeted therapies will depend on a better understanding of the cellular and molecular biology of cholangiocarcinomas.

Fig. 1

Classification of cholangiocarcinoma. Cholangiocarcinomas are broadly classified into intrahepatic (also known as peripheral) or extrahepatic tumors. Each is morphologically classified further into mass-forming, periductal-infiltrating or intraductal-growing. This classification also corresponds to the depiction of extrahepatic tumors as nodular, sclerosing or papillary.

Fig. 2

Bismuth-Corlette classification of hilar cholangiocarcinoma. Type I hilar cholangiocarcinoma involves only the common hepatic duct, distal to the confluence of the left and right hepatic ducts (biliary confluence). Type II involves the biliary confluence. Type IIIa affects the right hepatic duct in addition to the biliary confluence and Type IIIb involves the left hepatic duct in addition to the biliary confluence. Type IV tumors either involve both the right and left hepatic ducts in addition to the biliary confluence or are multifocal.

Fig. 3

Molecular features of cholangiocarcinogenesis. Epithelial changes driven by chronic inflammation that promote tumor formation are depicted here. Autonomous proliferation is promoted by the following: interleukin 6(IL6), its receptor glycoprotein (gp130), epidermal growth factor receptor (EGFR), Her-2 (neu) gene product (c-erb-2), inducible nitric oxide synthetase (iNOS), cyclooxygenase-2 (COX-2), and the oncoprotein K-ras. Evasion of apoptosis is promoted by: myeloid cell leukemia 1 (Mcl-1), Bcl-XL, Bcl-2, nitric oxide (NO) and cellular FLICE inhibitory protein (cFLIP). Escape from senescence is promoted by: p16INK4a, p53, p21, Mdm-2 and telomerase. Lastly, invasion and metastases are promoted by alterations of: E-cadherin, β-catenin, α-catenin, matrix metalloproteinase (MMP), vascular endothelial growth factor (VEGF) and aspartyl β-hydroxylase.

Fig 4

Magnetic resonance imaging of a hilar cholangiocarcinoma. Representative MRI imaging with gadolinium enhancement with Feridex and with MRCP are shown. (A) A 4 cm mass is seen centrally with abrupt cutoff of the left hepatic ducts. The mass and thickening also extend along the right posterior ductal system. Intrahepatic bile ducts are dilated. (B) MRCP shows bilateral intrahepatic biliary dilatation with abrupt cutoff corresponding to the 4 cm mass shown in A.

Fig 4

Magnetic resonance imaging of a hilar cholangiocarcinoma. Representative MRI imaging with gadolinium enhancement with Feridex and with MRCP are shown. (A) A 4 cm mass is seen centrally with abrupt cutoff of the left hepatic ducts. The mass and thickening also extend along the right posterior ductal system. Intrahepatic bile ducts are dilated. (B) MRCP shows bilateral intrahepatic biliary dilatation with abrupt cutoff corresponding to the 4 cm mass shown in A.

Fig. 5

Fluorescence in situ hybridization of biliary brushing. A representative fluorescence photomicrograph of biliary brushings from a patient with cholangiocarcinoma is shown here. Each colored spot represents one chromosome, therefore, 2 spots per color are indicative of the normal diploid state. In this example, >2 spots are seen for more than 1 color (indicating more than 1 chromosome pair is abnormal), leading to a diagnosis of polysomy.

Fig. 6

T-stage modification of the Memorial Sloan Kettering criteria for resectability of extrahepatic cholangiocarcinoma. T-1 tumors do not involve vascular structures. They are limited to the hilum with unilateral involvement up to secondary biliary radicles. T-2 tumors involve the biliary confluence and additionally unilateral portal vein branch or secondary biliary radicles or ipsilateral lobar atrophy, all indicative to hilar disease with unilateral biliary or vascular involvement. T-3 tumors have evidence of bilateral biliary or vascular involvement in addition to a tumor at the biliary confluence. In some T-3 tumors the main portal vein alone is involved, in this case resection with portal vein reconstruction may be a possibility.

Fig. 7

Survival following transplantation for unresectable cholangiocarcinoma. A total of 94 patients underwent staging surgery from 1993-2006. Survival rate since time of diagnosis for patients who received liver transplantation (solid line) and those that were not transplanted (dotted line) because of the presence of extrahepatic disease on staging is shown.