Hepatobiliary Imaging Clinical Observations

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1 CT of Cholangiocarcinoma with Pyogenic Cholangitis Hepatobiliary Imaging Clinical Observations C D E M N E U T R Y L I M C I G O F I N G Jung Hoon Kim 1 Tae Kyoung Kim 2 Hyo Won Eun 3 Jae Young yun 4 Moon-Gyu Lee 5 Hyun Kwon Ha 5 Yong Ho uh 6 Kim JH, Kim TK, Eun HW, et al. Keywords: biliary system, cancer, cholangiocarcinoma, CT, liver disease, pyogenic cholangitis DOI: /JR Received March 19, 2005; accepted after revision June 13, Department of Radiology, Soonchunhyang University Hospital, 657 Hannam-Dong, Youngsan-Ku, Seoul, South Korea ddress correspondence to J. H. Kim (junghkim@hosp.sch.ac.kr). 2 Medical Imaging, Toronto General Hospital, University Health Network, Toronto, ON, Canada. 3 Department of Diagnostic Radiology, College of Medicine, Ewha Womans University, Seoul, South Korea. 4 Department of Diagnostic Radiology, Kangnam St. Mary s Hospital College of Medicine, The Catholic University of Korea, Seoul, South Korea. 5 Department of Diagnostic Radiology, san Medical Center, Seoul, South Korea. 6 Department of Radiology, Cornell University Weill Medical College, New York, NY. JR 2006; 187: X/06/ merican Roentgen Ray Society CT Findings of Cholangiocarcinoma ssociated with Recurrent Pyogenic Cholangitis OJECTIVE. The purpose of our study was to determine the characteristic CT findings of cholangiocarcinoma cholangitis. CONCLUSION. CT findings of cholangiocarcinoma cholangitis are important in order to improve early diagnosis and proper treatment. Cholangiocarcinoma cholangitis is predominantly located in the atrophic hepatic lobes and in the hepatic lobes of biliary calculi and is associated with the narrowing or obliteration of the portal vein. ecurrent pyogenic cholangitis is R characterized clinically by recurrent attacks of fever, chills, abdominal pain, and jaundice caused by intrahepatic ductal strictures and pigment stones. This disease is endemic to Southeast sian countries, but it is being increasingly encountered in the West as a result of growing sian immigration. The cause of recurrent pyogenic cholangitis is repeated bouts of cholangitis from enteric organisms such as Escherichia coli or endemic parasites such as Opisthorchis sinensis and scaris lumbricoides. Pathogenic factors that can contribute to disease progression include malnutrition, parasitic infection, and portal bacteremia [1 4]. In general, recurrent pyogenic cholangitis is a well-known risk factor for cholangiocarcinoma. The pathogenesis is incompletely understood. Some investigators report that chronic bacterial infection, bile stasis, and mechanical irritation from biliary calculi can lead to the development of mucosal adenomatous hyperplia and chronic proliferative cholangitis, which can undergo a progressive change to atypical epithelial hyperplasia and, ultimately, to cholangiocarcinoma [5 7]. There are many clinical reports about recurrent pyogenic cholangitis associated with cholangiocarcinoma. The incidence of cholangiocarcinoma associated with recurrent pyogenic cholangitis is reported to be % of patients with recurrent pyogenic cholangitis [5, 6, 8 21]. Cholangiocarcinoma associated with recurrent pyogenic cholangitis has a poor prognosis as a consequence of delayed diagnosis, a low diagnosis rate, and few curative resections [11 14]. It is difficult to accurately diagnosis cholangiocarcinoma associated with recurrent pyogenic cholangitis before treatment. The CT features of recurrent pyogenic cholangitis include bile duct dilation, bile duct stricture, biliary calculi, hepatic atrophy, portal vein obliteration, hepatic abscess, and biloma. These findings may lead to delayed diagnosis of cholangiocarcinoma cholangitis because they may obscure the underlying cholangiocarcinoma [3, 4]. lthough there are some reports of CT findings for cholangiocarcinoma associated with recurrent pyogenic cholangitis in a small number of patients [22], to our knowledge there has not been a report of a large series addressing the use of CT when these two pathologies are coincident. Thus, this study assesses the CT features of cholangiocarcinoma associated with recurrent pyogenic cholangitis in 82 patients. Materials and Methods Patients This study was approved by our institutional review board for human investigation, and informed consent was obtained from patients or their relatives. computerized search of the medical records of two institutions from January 1998 to ugust 2002, revealed 1,344 patients with recurrent pyogenic cholangitis. Of these patients, 82 patients with pathologically proven cholangiocarcinoma associated with recurrent pyogenic cholangitis constituted the basis of this study. JR:187, December

2 TLE 1: CT Findings in 82 Patients with Cholangiocarcinoma ssociated with Recurrent Pyogenic Cholangitis CT Findings No. κ Peripheral cholangiocarcinoma 66 Contrast enhancement pattern Thin and lobulated enhancement at periphery Thick and lobulated enhancement at periphery Ill-defined homogeneous enhancement Intratumoral appearance Marked hypoattenuation Slight hyperattenuation Septum-like linear structure Morphologic change of the liver Segmental atrophy Narrowing or obliteration of portal vein iliary calculi Hilar and extrahepatic cholangiocarcinoma 16 Ill-defined hypoattenuating mass in hilum Enhancing intraductal mass Enhancing focally thickened biliary ductal wall Narrowing or obliteration of bile duct Cholangiocarcinoma is classified into three types on the basis of anatomic location. Peripheral cholangiocarcinoma is defined as carcinoma arising from second-order or more distal branches of the intrahepatic ducts. Hilar cholangiocarcinoma is defined as carcinoma arising from one of the hepatic ducts or the bifurcation of the common hepatic duct. Extrahepatic cholangiocarcinoma is defined as carcinoma arising from an extrahepatic bile duct distal to the hilum. There were 66 patients with peripheral cholangiocarcinoma, nine patients with hilar cholangiocarcinoma, and seven patients with extrahepatic cholangiocarcinoma. ll 82 patients had acute cholangitis with abdominal pain, fever, or jaundice at the time of admission. ll patients had been symptomatic from 4 to 30 years (mean, 9.5 years) and had had recurrent attacks of the disease on more than three occasions. Leukocytosis and hyperbilirubinemia were also present in 63 and 42 patients, respectively. Thirtyfive of the 82 patients had a history of Opisthorchis sinensis infestation and five of the 82 patients had a history of Escherichia coli in bile cultures. Thirty-six patients had previously undergone cholecystectomy because of gallbladder stone. Of these 82 patients, 53 underwent dual-phase CT and 29 underwent single-phase CT. There were 50 men and 32 women. Patient ages ranged from 30 to 72 years (mean, 56 years). The pathologic diagnoses were confirmed by surgical resection (n = 25), exploratory laparotomy (n = 7), percutaneous liver biopsy (n = 40), and percutaneous transhepatic choledochoscopy guided biopsy (n = 10). Surgical procedures included right lobectomy (n =5), left lobectomy (n = 14), and segmentectomy (n =6). Serum for tumor markers, including carcinoembryonic antigen (CE) and cancer antigen (C) 19-9, were available for 53 patients. The normal value for CE was less than 4 ng/ml; for C19-9, it was less than 37 U/mL. CE was elevated in 18 (34%) patients and C19-9 was elevated in 29 (55%) patients. CE values ranged from 6.51 to 83.1 ng/ml (mean, 41.5 ng/ml); C 19-9 values ranged from 45 to 3,500 U/mL (mean, 655 U/mL). Imaging CT was performed with a 9800 Quick System (GE Healthcare), a HiLight dvantage (GE Healthcare), or a Somatom Plus-S (Siemens Medical Solutions) scanner. Each patient received 120 ml of contrast medium ([iopamidol] Iopamiro 300, racco; or [iopromide] Ultravist, Schering) by bolus injection in a forearm vein at a rate of 3 ml/s. ll patients ingested 1,000 ml of water before scanning. Helical CT parameters included 8-mm collimation, table feed of 10 mm, and reconstruction increments of 8 mm. Unenhanced CT scans were obtained in all patients; and dual-phase CT scans, including hepatic arterial and portal venous phases, were then obtained 35 and 70 seconds, respectively, after initiation of the infusion. Single-phase CT scans were obtained 70 seconds after initiation of the infusion. nalysis CT findings were retrospectively analyzed independently by two board-certified radiologists. We used a hard-copy system. When the reviewers interpretations differed, a third opinion was obtained. The radiologists experience with abdominal CT ranged from 5 to 15 years. In cases of peripheral cholangiocarcinoma, the following imaging variables were analyzed: tumor size, number of lesions, contrast-enhancement patterns, intratumoral appearance, narrowing or obliteration of the portal vein, segmental atrophy, coincident biliary calculi, and other ancillary findings such as the presence of biloma or abscess. In hilar cholangiocarcinoma and extrahepatic cholangiocarcinoma, imaging variables included the presence or absence of an ill-defined hypoattenuating mass in the hilum, enhancing intraductal mass, enhancing focally thickened biliary ductal wall, and narrowing or obliteration of the bile duct (Table 1). If a patient had multiple lesions, the largest mass was analyzed. In contrast-enhancement patterns, thick, lobulated contrast enhancement at the tumor periphery was diagnosed when the thickness was greater than 3 mm with a well-defined line at the margin of the mass. Ill-defined homogeneous enhancement was diagnosed when the margin of the mass could not be outlined. In intratumoral appearance, marked hypoattenuation was defined as a decreased attenuation similar to that of water but less than that of back muscle. Presence of a slightly hyperattenuated area was defined as slightly hyperattenuated area within the hypoattenuated mass. Septumlike linear structure was defined as a linear-enhanced line within the mass. Narrowing of the portal vein was defined as a decreased diameter less than one third that of the main portal vein. Obliteration of the portal vein was defined as a vein being unapparent or unenhanced. Enhancing focally thickened biliary ductal wall was diagnosed when the thickness was greater than 5 mm. For the variable CT findings in each patient, the interobserver agreement was evaluated using the kappa statistic. kappa value less than 0.20 was considered poor; , fair; , moderate; , good; and excellent. The incidence of cholangiocarcinoma was compared between atrophic lobe and nonatrophic lobes, between lobes with narrowing or obliteration of the portal vein and lobes with normal portal veins, and between lobes having biliary calculi and lobes without biliary calculi, using Fisher s exact test, after adjusting for the effect of clustering according to literature references [23, 24] JR:187, December 2006

3 CT of Cholangiocarcinoma with Pyogenic Cholangitis Results Table 1 shows the CT findings in the 82 patients with cholangiocarcinoma associated with recurrent pyogenic cholangitis. Peripheral Cholangiocarcinoma Sixty-six patients had peripheral cholangiocarcinoma. The size of the masses as measured on CT was mm (mean, 51.5 mm) in the largest dimension. Five patients had multiple hepatic masses. The dominant mass was located in the left lobe (n = 36), right lobe (n = 25), or in both lobes (n =5). Thin and lobulated contrast enhancement at the tumor periphery was seen in 57 (86%) patients. The intratumoral appearance was marked hypoattenuation in 63 (95%) patients and slight hyperattenuation in 50 (75%) patients (Fig. 1). Segmental atrophy was seen in 41 (62%) patients. Segmental atrophy of the liver was seen in the lateral segment of the left lobe (n = 21), posterior segment of the right lobe (n = 11), left lobe (n = 5), and anterior segment of the right lobe (n = 4). mong these C 41 patients, 36 (88%) patients had a mass within the atrophic segment (Fig. 2). The incidence of cholangiocarcinoma was greater in the atrophic lobe (88%; 36 of 41 atrophic lobes) than in the nonatrophic lobe (33%; 30 of 91 nonatrophic lobes) (p < ). ll atrophic segments showed narrowing or obliteration of the portal vein. Radiographic changes of the portal vein, including luminal narrowing or obliteration, were seen in 60 (91%) patients. Narrowing or obliteration of the portal vein was seen in the right portal vein (n = 22) and the left portal vein (n = 38). mong these 60 patients, 50 (83%) had a mass within the lobe associated with narrowing or obliteration of the portal vein (Fig. 3). The incidence of cholangiocarcinoma was also greater in the lobe with narrowing or obliteration of the portal vein (83%; 50 of 60 lobes with narrowing or obliteration of the portal vein) than in the lobe with normal portal veins (22%; 16 of 72 lobes with a normal portal vein) (p < ). Fig. 1 Peripheral cholangiocarcinoma cholangitis in 69-year-old man who complained of abdominal pain, fever, and leukocytosis. He has history of recurrent attacks of cholangitis and had previously undergone cholecystectomy because of gallstone., Unenhanced CT scan shows hepatolithiasis in right intrahepatic duct (arrowheads) with severe atrophy in posterior segment of right lobe., Contrast-enhanced CT scan at same level shows luminal narrowing of right portal vein (arrowheads). C, Contrast-enhanced CT scan obtained 16 mm below during hepatic artery phase shows thick and lobulated enhancement at periphery of mass during arterial phase. This mass shows markedly hypoattenuated, septumlike linear structure and slightly hyperattenuated area. Diagnosis of cholangiocarcinoma was made at percutaneous liver biopsy. Intrahepatic biliary calculi were seen in 39 (59%) patients. Intrahepatic biliary calculi was seen in the right intrahepatic bile ducts (n = 14), the left intrahepatic bile duct (n =21), and both intrahepatic bile duct (n =4). mong the 39 patients with intrahepatic biliary calculi, 26 (67%) had a mass within the same lobe. The incidence of cholangiocarcinoma was also greater in lobes having biliary calculi (67%; 26 of 39 lobes having biliary calculi) than in lobes without biliary calculi (43%; 40 of 93 lobes without biliary calculi) (p < 0.02). iloma and abscess were seen in six and five patients, respectively. Three (50%) of six patients with biloma and two (40%) of five patients with abscess were correctly diagnosed. Hilar and Extrahepatic Cholangiocarcinoma Sixteen patients had hilar and extrahepatic cholangiocarcinoma. No patient had multiple hepatic masses. Hilar cholangiocarcinoma presented as an enhancing, focally thickened biliary duct in five (55%) patients, and as narrowing or obliteration of the bile duct in all JR:187, December

4 (100%) patients (Fig. 4). Extrahepatic cholangiocarcinoma presented as an enhancing, focally thickened biliary duct in six (85%) patients, and narrowing or obliteration of the ductal lumen in all (100%) patients. Segmental atrophy and narrowing or obliteration of the portal vein was seen in three and five patients, respectively. Intrahepatic biliary calculi were seen in four patients. Discussion Many investigators confirm an association between cholangiocarcinoma and recurrent pyogenic cholangitis. The incidence of cholangiocarcinoma cholangitis is reported to be % of patients with recurrent pyogenic cholangitis C Fig. 2 Peripheral cholangiocarcinoma cholangitis in 65-year-old-man who complained of abdominal pain, fever, and leukocytosis. He has history of recurrent attacks of cholangitis and Opisthorchis sinensis infestation., Contrast-enhanced CT scan obtained during hepatic artery phase shows severe atrophy in left lobe of liver., Contrast-enhanced CT scan obtained during portal venous phase also shows severe atrophy in left lobe of liver. Masslike lesion within atrophic left lobe (arrows) has thin enhancement at periphery on both arterial phase () and portal phase. C, CT scan obtained 8 mm below shows obliteration of left portal vein (arrowheads). Diagnosis of cholangiocarcinoma was made at surgical resection. [5, 6, 8 21]. In our study, 6.1% of the cases of recurrent pyogenic cholangitis were associated with cholangiocarcinoma. Su et al. [6] report that cholangiocarcinoma cholangitis had a significantly worse survival rate than that of cholangiocarcinoma without recurrent pyogenic cholangitis. The 5-year survival rate was 42% in patients with cholangiocarcinoma without recurrent pyogenic cholangitis, which was significantly better than the 6% survival rate reported in those patients with cholangiocarcinoma associated with recurrent pyogenic cholangitis. These differences in survival rates may be attributed to delayed diagnosis, previous liver damage caused by long-standing cholangitis, the relatively fewer curative resections in cholangiocarcinoma associated with recurrent pyogenic cholangitis, and a lower diagnostic rate of radiologic studies. The diagnostic rate of radiologic studies is reported to range from 0 42% [6, 10 14]. Various reasons are postulated for the lower diagnostic rate, including limitations of the imaging studies such as difficulty differentiating cholangiocarcinoma associated with recurrent pyogenic cholangitis from abscess or biloma, or occurrence of an infiltrative tumor, usually in a stricture segment [6, 13]. ecause the radiologic findings for cholangiocarcinoma associated with recurrent pyogenic cholangitis are not well established, accurate preoperative diagnosis is usually difficult. In most patients, 1574 JR:187, December 2006

5 CT of Cholangiocarcinoma with Pyogenic Cholangitis the diagnosis is made during surgery. Consequently, identifying established CT findings of cholangiocarcinoma associated with recurrent pyogenic cholangitis is important to improve early diagnosis and proper treatment. Fig. 3 Peripheral cholangiocarcinoma cholangitis in 56-year-old-woman who complained of abdominal pain, fever, jaundice, leukocytosis, and hyperbilirubinemia. She has a history of recurrent attacks of cholangitis., Initial contrast-enhanced CT scan performed at another institution shows large, peripheral, enhanced, hypoattenuated mass in right lobe (arrows). spiration confirmed mass as abscess. trophied left lobe shows enhancement with intrahepatic duct dilatation but no definite mass., Five-month follow-up contrast-enhanced CT scan shows complete resolution of hepatic abscess in right lobe and newly developed hypoattenuated mass (arrowheads) and slightly hyperattenuated area in left lobe. Note severe atrophy of lateral segment of left lobe and concomitant narrowing of left portal vein (arrow). Diagnosis of cholangiocarcinoma was made at surgical resection. Fig. 4 Hilar cholangiocarcinoma cholangitis in 61-year-old-man who complained of abdominal pain, fever, jaundice, leukocytosis, and hyperbilirubinemia. He has history of recurrent attacks of cholangitis and Opisthorchis sinensis infestation., Contrast-enhanced CT scan of superior part of liver shows severe atrophy in lateral segment of left lobe of liver and obliteration of left portal vein (arrowheads)., CT scan 24 mm below shows narrowing and enhanced, focal, thickened wall of right main bile duct (arrows) with dilation of intrahepatic duct. Hilar cholangiocarcinoma was confirmed at percutaneous transhepatic choledochoscopy guided biopsy. In our study, cholangiocarcinoma associated with recurrent pyogenic cholangitis predominantly localizes in segments with atrophy and with narrowing or obliteration of the portal vein. Segmental atrophy was seen in 54% (44 of 82 patients), and narrowing or obliteration of the portal vein in 79% (65 of 82 patients). Segmental atrophy of the liver was predominantly located in the lateral segment of the left lobe (n = 21) and the posterior JR:187, December

6 segment of the right lobe (n = 11), where intrahepatic ductal calculi usually occurred. This may be related to the more acute angulation of these ducts, resulting in less efficient drainage on this side of the biliary system. ll atrophic segments showed narrowing or obliteration of the portal vein. The pathogenesis of cholangiocarcinoma cholangitis is incompletely understood. Some investigators report that chronic proliferative cholangitis in the presence of biliary calculi can undergo progressive changes to atypical epithelial hyperplasia, which may progress to cholangiocarcinoma [5 9]. In our study, the coincident rate of peripheral cholangiocarcinoma in hepatic atrophy was 88% (36 of 41 cases), and that of peripheral cholangiocarcinoma in portal vein narrowing or obliteration was 83% (50 of 60 cases). Kubo et al. report [11] that portography might be useful for diagnosing cholangiocarcinoma cholangitis. In their report, the portal vein in the hepatic lobe with cholangiocarcinoma could not be seen in any of the five patients with cholangiocarcinoma associated with recurrent pyogenic cholangitis. Therefore, they insist that portal vein obstruction indicates deterioration of the hepatic tissue and strongly suggests the existence of cholangiocarcinoma. lthough we do not have a pathologic correlation, portal vein obliteration and subsequent parenchymal atrophy can be a result of involvement of the portal vein by the tumor instead of occurring before the development of the tumor. In any event, there is high frequency of coexistence of the two events cholangiocarcinoma and portal vein or parenchymal change and one should look for the tumor carefully in the hepatic segment or lobe with portal vein obliteration and parenchymal atrophy. In our study, intrahepatic biliary calculi were seen in 52% (43 of 82) of patients. Twenty-six (32%) patients had a mass within the same lobe. Su et al. [6] report that tumor and biliary calculi were closely related in 26 (96%) of 27 patients with cholangiocarcinoma associated with recurrent pyogenic cholangitis. In previous reports, biliary calculi were present in approximately 75 80% of cases of recurrent pyogenic cholangitis; in the remaining cases, the biliary tree was recurrently infected in the absence of calculi [1 4]. Complications of hepatolithiasis include abscess and biloma. It is also often difficult to differentiate between these benign lesions and cholangiocarcinoma [11, 13]. Kubo et al. [11] report that 50% (five of 10) of their patients with cholangiocarcinoma associated with hepatolithiasis were initially diagnosed as having hepatolithiasis with liver abscess or cholangitis. These findings may lead to delayed diagnosis of cholangiocarcinoma associated with hepatolithiasis. In our study, 50% (three of six) patients with biloma and 40% (two of five) patients with abscess were correctly diagnosed. ecause of the difficulty differentiating between these benign lesions and cholangiocarcinoma, further prospective study is required to establish the differences between these lesions. Our study has some limitations. First, the study was performed retrospectively without a control group. We did not evaluate the sensitivity and specificity of the observed CT findings to establish the diagnosis of cholangiocarcinoma cholangitis. Second, surgical correlation of recurrent pyogenic cholangitis with cholangiocarcinoma was not available for all patients. prospective study with pathologic correlation is required to elucidate the pathogenesis of cholangiocarcinoma from recurrent pyogenic cholangitis. Third, we used thick collimation by using helical CT; if we had used thinner collimation by using MDCT, we would have increased the number of good results. Despite these limitations, our study suggests several unique CT findings of cholangiocarcinoma cholangitis. We analyzed the relationship of cholangiocarcinoma, hepatic atrophy, and portal vein obliteration. The interrelationship of hepatic atrophy, portal vein obliteration, and cholangiocarcinoma in patients with recurrent pyogenic cholangitis, as evaluated by CT, is unknown. This significant correlation of cholangiocarcinoma, hepatic atrophy, and portal vein obliteration should be recognized because doing so improves the early diagnosis and proper treatment of patients with recurrent pyogenic cholangitis. In conclusion, cholangiocarcinoma associated with recurrent pyogenic cholangitis is predominantly located in atrophic hepatic segments or lobes and is associated with narrowing or obliteration of the portal vein. In peripheral cholangiocarcinoma, it is almost always a markedly hypoattenuating mass with thin, lobulated contrast enhancement at the tumor periphery. 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