Diagnosis and Treatment of Cholangiocarcinoma Kirsten Muri Boberg, MD, PhD and Erik Schrumpf, MD, PhD
Address Medical Department, Rikshospitalet, 0027 Oslo, Norway. E-mail:
[email protected] Current Gastroenterology Reports 2004, 6:52–59 Current Science Inc. ISSN 1522-8037 Copyright © 2004 by Current Science Inc.
Epidemiologic studies have demonstrated increasing mortality rates from intrahepatic cholangiocarcinoma during the past decades. Primary sclerosing cholangitis is the most important predisposing condition to the development of cholangiocarcinoma. Improvements in noninvasive diagnostic techniques have led to decreased use of invasive procedures. Magnetic resonance imaging (MRI) has the potential to depict parenchymal, ductal, and vascular tumor involvement. However, diagnosis can be difficult, and often ultrasonography, MRI, CT, and invasive cholangiography are complementary investigations. Genetic aberrations in brush cytology specimens should be explored further in prospective studies. Endoscopic ultrasonography, intraductal ultrasonography, and positron emission tomography are interesting techniques that are under evaluation. Radical surgery with negative histologic margins is the only curative option in cholangiocarcinoma. With more aggressive surgical approaches, including partial hepatectomy, 3-year survival rates of 35% to 50% can be achieved. Liver transplantation for unresectable cholangiocarcinoma was shown to be feasible in pilot studies of highly selected patients.
from England and Wales showed that more deaths had been recorded annually from cholangiocarcinoma than from hepatocellular carcinoma since 1993 [4]. Patients with cholangiocarcinoma typically present with advanced-stage tumor. Moreover, the diagnosis is often difficult to confirm. Representative biopsies can be difficult to obtain, even if cholangiocarcinoma is suspected. Primary sclerosing cholangitis (PSC) is complicated with cholangiocarcinoma in 6% to 20% of patients [5]. In this condition in particular, it can be difficult to differentiate between benign regenerative bile duct reactions and malignant growth [1]. Treatment results in cholangiocarcinoma are poor, with only 5% to 10% rates of overall 5-year survival. Untreated patients usually die within a few months to a year after diagnosis. The British Association for the Study of the Liver recently published a consensus document with guidelines for the diagnosis and treatment of cholangiocarcinoma [6••]. The guidelines are based on a thorough search of the literature, and we refer to this report for a comprehensive review of current recommendations. Efforts are continuously being made to improve the sensitivity and specificity of diagnostic procedures in cholangiocarcinoma, and promising techniques are under evaluation. To improve survival in patients with cholangiocarcinoma, more aggressive therapeutic strategies have recently been attempted, and new treatment modalities have been proposed. In the following review we discuss selected diagnostic and therapeutic approaches to this malignancy.
Introduction
Diagnosis
About two thirds of cholangiocarcinomas are localized to the perihilar region, one quarter arise from the distal extrahepatic duct, and the remainder are found in the intrahepatic ducts [1,2]. Epidemiologic studies have revealed increasing mortality rates from intrahepatic cholangiocarcinomas [3,4]. In the United States, the age-adjusted mortality rate from this tumor increased from 0.07 per 100,000 in 1973 to 0.69 per 100,000 in 1997 [3]. However, mortality rates from extrahepatic biliary tract tumors decreased over the same time period [3,4]. The reasons for the increased incidence and lower mortality rates of intrahepatic cholangiocarcinoma are unknown. Worldwide, cholangiocarcinoma accounts for 15% to 20% of primary liver cancers. However, incidence varies geographically. A study
Clinical presentation Patients with perihilar or extrahepatic cholangiocarcinoma commonly present with symptoms of biliary obstruction, including jaundice, pale stools, dark urine, and pruritus [1,2,6••]. Often signs of advanced disease, such as pain, malaise, and weight loss, are present, particularly in more peripheral intrahepatic tumors. Results of blood tests show cholestasis, and no specific diagnostic tests exist for cholangiocarcinoma. Imaging techniques Several imaging techniques can be used in the diagnosis of cholangiocarcinoma, as summarized in the following sections and in Table 1.
Diagnosis and Treatment of Cholangiocarcinoma • Boberg and Schrumpf
Table 1. Imaging techniques available for diagnosis of cholangiocarcinoma Commonly available methods
Specialized or experimental methods
Ultrasonography Computed tomography Magnetic resonance imaging (including MRC and MR angiography) Endoscopic retrograde cholangiography Percutaneous transhepatic cholangiography
Endoscopic ultrasonography Intraductal ultrasonography Positron emission tomography
MRC—magnetic resonance cholangiography.
Ultrasonography Ultrasonography is usually the first imaging procedure performed when biliary obstruction is suspected [2]. This investigation most commonly excludes the presence of gallstones. Intrahepatic cholangiocarcinomas appear as homogenously hyperechoic mass lesions, although sensitivity is low [7]. Perihilar, extrahepatic, and periampullary tumors can also be difficult to detect. Ultrasonography can reveal dilated bile duct segments peripheral to the tumor as an indirect sign. Color Doppler imaging can visualize vascular tumor involvement, including compression, encasement, thrombosis, or occlusion of the portal vein or hepatic artery [1,6••]. Computed tomography The next imaging step in the diagnosis of cholangiocarcinoma is CT scanning and/or magnetic resonance imaging (MRI) [1,6••,7]. The helical CT technique has significantly improved visualization of anatomic details and allows multiphasic imaging after intravenous contrast injection. Specific findings depend upon tumor localization. Intrahepatic tumors appear as hypoattenuating rounded masses with irregular margins and various degrees of segmental intrahepatic bile duct dilation [7]. Delayed phase contrast enhancem e n t w i t h in t h e l e s i on c a n b e in di c a t ive o f cholangiocarcinoma [7]. Perihilar cholangiocarcinoma usually presents as a mass at the liver hilum with peripheral bile duct dilation. Distal extrahepatic tumors typically cause dilated extra- and intrahepatic bile ducts and distention of the gallbladder. However, in perihilar or distal cholangiocarcinoma, a tumor mass can be difficult to visualize. CT scans have the potential to depict vascular or extrahepatic invasion and lymphadenopathy [6••], and can, to some extent, predict the resectability of cholangiocarcinoma. In a preoperative study of 21 patients with Klatskin tumor, the positive predictive value of CT was 100% in determination of unresectable disease [8]. However, among 12 patients with tumors thought to be resectable, only six had resectable lesions at surgery. The ability of CT to define the ductal extension of cholangiocarcinomas accurately is also limited [6••,8].
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Magnetic resonance imaging Magnetic resonance imaging combines investigation of the liver parenchyma with that of the bile ducts and vessels when MR cholangiography (MRC) and MR angiography are included. MRI has become an important tool in the diagnosis and preoperative assessment of tumors of the biliary tract [1,6••,9,10•,11•] and is recommended as the optimal initial investigation for suspected cholangiocarcinoma [6••]. In a comparison of the efficacy of MRC and endoscopic retrograde cholangiopancreatography (ERCP) in delineating the anatomic extent of hilar cholangiocarcinoma, Yeh et al. [9] found that MRC had better performance than ERCP. The anatomic extent was correctly determined in 21 of 26 patients with MRC versus 14 of 24 with ERCP (P
