Accepted Manuscript Radiological diagnosis in cholangiocarcinoma: application of computed tomography, magnetic resonance imaging, and positron emission tomography Kristina I. Ringe, MD, Frank Wacker, MD PII:

S1521-6918(15)00020-7

DOI:

10.1016/j.bpg.2015.02.004

Reference:

YBEGA 1329

To appear in:

Best Practice & Research Clinical Gastroenterology

Received Date: 8 December 2014 Accepted Date: 7 February 2015

Please cite this article as: Ringe KI, Wacker F, Radiological diagnosis in cholangiocarcinoma: application of computed tomography, magnetic resonance imaging, and positron emission tomography, Best Practice & Research Clinical Gastroenterology (2015), doi: 10.1016/j.bpg.2015.02.004. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Radiological diagnosis in cholangiocarcinoma: application of computed

Kristina I. Ringe MD*, Frank Wacker MD

RI PT

tomography, magnetic resonance imaging, and positron emission tomography

Hannover Medical School, Department of Diagnostic and Interventional Radiology,

EP

TE D

M AN U

SC

Carl-Neuberg Str. 1, 30625 Hannover, Germany

*Corresponding author:

AC C

Kristina Imeen Ringe MD Hannover Medical School, Department of Diagnostic and Interventional Radiology, Carl-Neuberg Str. 1, 30625 Hannover, Germany Phone: +49-511-532-3421, Fax: +49-511-532-9421 Email: [email protected]

1

ACCEPTED MANUSCRIPT Abstract The purpose of radiological imaging in patients with suspected or known cholangiocarcinoma assessment

of

(CCA)

is

resectability.

tumor

detection,

Different

imaging

lesion

characterization

modalities

are

and

implemented

RI PT

complementary in the diagnostic work-up. Non-invasive imaging should be performed prior to invasive biliary procedures in order to avoid false positive results. For assessment of intraparenchymal tumor extension and evaluation of biliary and

SC

vascular invasion, MRI including MRCP and CT are the primarily used imaging modalities. The role of PET remains controversial with few studies showing benefit

M AN U

with the detection of unexpected metastatic spread, the differentiation between benign and malignant biliary strictures, and for discriminating post therapeutic changes and recurrent CCA.

TE D

Key words

Cholangiocarcinoma; Computed tomography; Magnetic resonance imaging; Positron

AC C

EP

emission tomography

2

ACCEPTED MANUSCRIPT Radiological imaging in cholangiocarcinoma Cholangiocarcinoma (CCA) is the second most prevalent liver cancer after hepatocellular

cancer

(HCC)

and

accounts

for

approximately

3%

of

all

gastrointestinal tumors [1]. According to the localization, CCA can be distinguished

RI PT

into intra- and extrahepatic origin, whereby the latter includes hilar tumors, a particular tumor entity owing to its localization which is also referred to as Klatskin tumor [2]. The main purpose of noninvasive radiological imaging in patients with

SC

suspected or known CCA is threefold: First, tumor detection; second, lesion characterization; and third, assessment of resectability mainly determined by

M AN U

intraparenchymal tumor extension, as well as biliary and vascular invasion. Further, radiographic screening is performed in high-risk patients (as in the setting of primary sclerosing cholangitis (PSC), hepatolithiasis, parasitic biliary infections and choledochal cyst [3]) for early detection of malignancy. In order to assess tumor

TE D

etiology and extent as precisely as possible, different imaging modalities are often implemented complementary in the diagnostic work-up, including computed tomography (CT), magnetic resonance imaging (MRI) and positron emission

EP

tomography (PET).

AC C

CT imaging:

Over the last couple of years CT imaging has evolved from single slice scanners to multidetector row technology (MDCT), facilitating acquisition of high-resolution images with isotropic submillimeter voxels in a matter of seconds. Therefore, CT is considered the workhorse in diagnosis, staging and follow-up of oncologic patients. In patients with suspected or known cholangiocarcinoma biphasic image acquisition is performed, including late arterial phase and portal venous phase scanning,

3

ACCEPTED MANUSCRIPT approximately 20-30 and 60 seconds after intravenous injection of a iodinated contrast agent (e.g. 80ml of iomeprol 400 injected through an antecubital vein at a flow of 4ml per seconds, followed by a saline flush of 40ml). The arterial phase should cover the upper abdomen, the portal venous phase the abdomen and pelvis

RI PT

as well as the thorax if imaging is performed for staging purposes. A precontrast CT may be useful for detection and differentiation of stones, but is not mandatory. When dual energy CT is available, non-contrast CT images can be calculated. Some

SC

authors advocate additional equilibrium phase imaging approximately 2-3 minutes after i.v. contrast injection [4].

M AN U

CT cholangiography may be performed using an intravenous drip infusion of a positive contrast agent (e.g. 100ml meglumine iotrexate) administered prior to the scan over a period of 30 minutes. In patients with normal liver function the contrast agent is excreted primarily via the hepatobiliary system, allowing for image

TE D

acquisition approximately 5-10 minutes after the infusion is finished [5]. Since the contrast agent is only available in a few countries and has a risk of severe side effects, its use is restricted to patients who cannot undergo magnetic resonance

EP

cholangiopancreaticography (MRCP).

Postprocessing of CT includes multiplanar reformations (MPR), axial and coronal

AC C

maximum intensity projections (MIP) and 3D volume rendered (VR) images for orientation and better appreciation of vascular and biliary anatomy especially prior to surgery.

MR imaging: MRI is a mainstay in liver imaging owing to its inherent high soft tissue contrast and the possibility to assess the hepatobiliary system without the need of a contrast agent

4

ACCEPTED MANUSCRIPT or radiation exposure. MRCP has become a well-established technique for evaluation of the intra- and extrahepatic biliary system. Due to its non-invasiveness and the excellent image quality with modern MR imagers, this technique is now increasingly replacing diagnostic endoscopic retrograde pancreaticography (ERCP) [6]. Most MR

RI PT

cholangiography techniques are based on heavily T2 weighted fast spin-echo (FSE) pulse sequences, yielding a luminal image of the bile ducts that is based on the inherent high signal of slow-flowing or stationary bile. In addition, the recent

SC

development of a hepatocyte-specific contrast agent (Gd-EOB-DTPA, gadoxetate disodium, Eovist® or Primovist®, Bayer HealthCare) allows for contrast-enhanced

M AN U

depiction of the intra- and extrahepatic bile ducts using T1 weighted imaging. Gadoxetate disodium is taken up into the hepatocytes by the ATP-dependent organic anion transporting polypeptide 1 (OATP1) and subsequently excreted into the biliary canaliculi by the canalicular multispecific organic anion transporter (cMOAT) [7, 8].

TE D

This new addition to the armamentarium of MRI holds promising results for assessment of hepatobiliary malignancy [9, 10]. MRCP sequences are particularly helpful for evaluation of tumor extent. However, in

EP

case of a periductal infiltrating or intraductal growth type tumor [11, 12], classic preand postcontrast morphological sequences are essential for tumor detection and

AC C

characterization as well as differentiation of benign from malignant bile duct strictures. A comprehensive MR examination of the liver thus includes T1 and T2weighted sequences before contrast injection, diffusion-weighted imaging (DWI), a heavily T2-weighted fast spin-echo MRCP sequence, and a dynamic series of fatsuppressed T1-weighted images after the administration of a gadolinium-containing contrast agent (e.g. Gd-BOPTA, 0.1ml/kg at a flow of 2ml per seconds followed by a

5

ACCEPTED MANUSCRIPT saline flush of 30ml). If gadoxetate disodium is used, additional hepatocyte phase images are acquired approximately 20 minutes after contrast injection. Advantages of MRI and MRCP, especially over ERCP, include its non-invasive character, the possibility to depict the biliary system proximal to an occlusion and the

RI PT

assessment of the periductal tissue and vascular anatomy at the same time. On the other hand, MRI is prone to artifacts, requires experienced technicians, and some patients may not be suitable due to contraindications (e.g. patients with severe

SC

claustrophobia, intracranial aneurysm clips, cardiac pacemakers, cochlear implants).

M AN U

PET imaging: 18

F-Fluoro-2-deoxy-D-glucose (FDG) integrated positron emission tomography (PET)

is a non-invasive imaging technique that allows in vivo assessment of the metabolic processes underlying malignant disease [13]. After transportation into tumor cells by 18

FDG is phosphorylated by

TE D

membrane glucose transporting proteins (GLUT),

hexokinase to FDG-6-phosphate, a highly polar molecule that cannot diffuse out of the cell. Overexpression of hexokinase in malignant cells leads to an increased

EP

metabolism in cancer tissue which can then be visualized by PET [14]. While PET alone is limited by poor temporal and spatial resolution and somewhat

AC C

restricted anatomic localization of positive lesions, these limitations can be reduced by coupling with multidetector CT. CT can be performed diagnostically with the use of an intravenous and oral contrast agent. However, in most centers, only a low-dose CT is routinely performed [15]. Pitfalls in PET/CT imaging include misinterpretation of normal physiological activity of the bowel and genitourinary system, misregistration [16], and the low sensitivity in detecting small volume disease due to partial volume averaging of the signal from a subcentimeter lesion [17]. While false negative

6

ACCEPTED MANUSCRIPT findings are possible in lesions with high mucin content [18], benign conditions such as post-surgical or post-radiation therapy inflammatory changes may lead to non-

RI PT

tumor related FDG-accumulation [16].

Imaging features and characterization of cholangiocarcinoma

Based on morphologic growth characteristics, CCA can be classified as either mass-

SC

forming, periductal infiltrating or intraductal type, as suggested by the Liver Cancer Study Group of Japan [19], with each type having its own characteristic imaging

M AN U

features [4]. Imaging, be it CT, MRI or PET, is recommended before invasive biliary procedures (e.g. stent placement), as any manipulation can cause mild inflammation of the bile duct walls and subsequently increased contrast enhancement, which may

Intrahepatic CCA:

TE D

be indistinguishable from superficial tumor spread.

At CT, intrahepatic CCA appears most commonly as a mass lesion with incomplete

EP

peripheral enhancement in the arterial phase that may become iso- or hypodense during the portal venous phase (Figure 1). Progressive enhancement may be

AC C

observed on delayed images with higher enhancement than the adjacent normal liver parenchyma, persisting into the late phase [20]. The degree of enhancement on delayed phase imaging (approximately 3-6 minutes after contrast injection) is closely related to the amount of abundant fibrous stroma and frequency of perineural invasion. This finding may serve as a prognostic factor in patients with mass-forming CCA [21] and may help to differentiate CCA from HCC, with the latter typically

7

ACCEPTED MANUSCRIPT showing intense or diffuse heterogeneous enhancement on arterial phase and washout on delayed images [22, 23].

At MRI, mass-forming intrahepatic CCA appears hypointense on T1-weighted and

RI PT

mild to moderately hyperintense on T2-weighted images, depending on the amount of fibrous tissue and mucin content [8]. The enhancement pattern after contrast injection is similar to that of CT. An atypical appearance with marked arterial

SC

enhancement involving larger areas of the tumor is more frequently observed in patients with liver cirrhosis and has been associated with a better prognosis [24].

M AN U

Because of its fibrous components, progressive enhancement may be typical for CCA when extracellular contrast agents are used. However, the hepatocyte-specific contrast uptake of gadoxetate disodium leads to enhancement of the surrounding normal liver, thus causing the CCA to appear hypointense to the background liver [8,

TE D

25]. This hypointense appearance of CCA during hepatocyte phase imaging improves lesion demarcation and detection of satellite nodules (Figure 2). In this context decreased uptake of gadoxetate disodium in the parenchyma surrounding

EP

the tumor is indicative of decreased hepatocyte function [26]. Capsular retraction of the liver parenchyma due to the dense fibrotic nature of the tumor may be seen in up

AC C

to 21% of patients [27]. Other findings at CT or MRI include satellite nodules, vascular encasement, hepatolithiasis, dilatation and mural thickening of peripheral intrahepatic bile ducts and segmental or lobar atrophy [20, 28, 29]. In case of periductal infiltrating tumor type, diffuse periductal thickening and increased enhancement due to tumor infiltration may be observed, along with abnormally dilated or irregularly narrowed bile ducts and peripheral ductal dilatation [4]. At the same time it can be very challenging to differentiate a benign focal stricture

8

ACCEPTED MANUSCRIPT from a true malignancy. It has been suggested that findings of a long segment stricture with an irregular margin, asymmetric narrowing, ductal enhancement and lymph node enlargement as well as a periductal soft-tissue mass suggest a malignant pathogenesis [30, 31]. The radiologic manifestation of intraductal type

RI PT

CCA is very diverse. According to a review by Chung and colleagues [4] following imaging features may be observed: 1. Diffuse and marked bile duct dilatation with a grossly visible mass; 2. Diffuse and marked bile duct dilatation without a visible

SC

mass; 3. An intraductal polypoid mass within localized ductal dilatation; 4. Intraductal

proximal bile duct dilatation.

Extrahepatic CCA:

M AN U

castlike lesions with a mildly dilated bile duct; 5. A focal stricture-like lesion with mild

Extrahepatic CCA can be classified into hilar / central, middle and distal CCA. Owing

TE D

to its localization hilar CCA (Klatskin tumor) can be further classified according to Bismuth and Corlette [32]. Most hilar CCA are periductal-infiltrating tumors. MRI and MRCP are well accepted imaging techniques for extrahepatic CCA due to

EP

the inherent high soft tissue signal of MRI and the possibility of bile duct visualization above and below a stenosis with MRCP. Imaging features include dilatation of the

AC C

proximal bile ducts with a stricture or abrupt termination at the level of the tumor, typically showing a shoulder sign [29] best seen with MRCP. Irregular bile duct wall appearance can be an indicator of infiltration. Occasionally, tumors may present with an intraluminal papillary mass, which typically appears as a filling defect on MRCP (Figure 3). It has been suggested that thickening of the bile duct wall more than 5 mm as well as a relatively minor increase of wall thickness in association with high-

9

ACCEPTED MANUSCRIPT grade cholestasis in patients without recent gallbladder surgery, are highly suggestive of CCA [29]. Klatskin tumors are usually small superficially spreading lesions resulting in early cholestasis and proximal bile duct dilatation. Conspicuity on non-contrast CT and

RI PT

MRI is poor. Similar to intrahepatic CCA, minimal or moderate contrast enhancement may be appreciated especially in tumors with an extrahepatic mass, that becomes more prominent on delayed phase images [22] (Figure 4). Further, lobar atrophy of

SC

the liver in combination with marked bile duct dilatation should raise suspicion of CCA [22]. With conventional MR sequences it can be difficult to distinguish a

M AN U

malignant tumor from chronic inflammatory changes, as is often the case in patients with PSC. The use of hepatocyte specific MRI contrast agents may help to better differentiate the etiology in patients with central bile duct stenosis and may also improve the assessment of tumor extension [9]. Park and colleagues compared

TE D

MRCP and ERCP in 50 patients for differentiation of benign and malignant bile duct strictures. Accuracy of MRCP was comparable to that of ERCP. Sensitivity, specificity and accuracy for differentiation were 81%, 70% and 76% for MRCP, and

EP

74%, 70% and 72% for ERCP, respectively [30].

AC C

Role of PET/CT:

Most bile duct cancers are

18

F-FDG avid lesions (Figure 5). However, the number of

studies regarding the use of PET/CT for evaluation of CCA is limited and its role is still controversial. It has been suggested that the accuracy is dependent not only on the anatomic location of the lesion, but also on growth patterns and pathologic characteristics [15]. Preliminary data shows that PET/CT is accurate in predicting the presence of mass-forming CCA >1cm but limited in the evaluation of infiltrating type

10

ACCEPTED MANUSCRIPT tumors [33]. Due to low levels of FDG accumulation, infiltrating tumors can be associated with false negative results [34]. Quantitative analysis of tracer uptake may help to better differentiate malignant from benign lesions, in intra- as well as

RI PT

extrahepatic tumor manifestation [35, 36].

Detection of cholangiocarcinoma Initial tumor detection:

SC

While in the era of single slice CT reported sensitivities for tumor detection were only up to 69% [37, 38], current MDCT with isotropic submillimeter voxel sizes allow for

M AN U

reliable detection of essentially all lesions larger than 1cm. Valls and colleagues reviewed the CT scans of 24 patients with peripheral CCA ranging from 1.2 to 17cm. All lesions were visible at CT; associated bile duct dilatation was present in 13 patients (52%) and retraction of the liver capsule in 9 patients (36%) [39]. Regarding

TE D

detection of extrahepatic CCA, Tillich and colleagues evaluated 29 patients with hilar tumor location (size 8-20mm). All lesions were seen on hepatic arterial phase CT (100%), while 86% (n=25) were visible at portal venous phase imaging [40]. These

EP

results are substantiated by more recent studies reporting correct identification of

AC C

extrahepatic CCA in nearly 100% [41, 42].

Compared to MDCT, MRI has shown no clear benefit for the detection of CCA [12]. However, the use of hepatocyte specific contrast agents at MRI increases both, lesion conspicuity and characterization [43, 44]. It is also beneficial for the detection of tumor spread and intrahepatic metastasis [10, 25], which may alter the therapeutic approach in individual patients. MRCP adds significant value and is comparable to ERCP in differentiating malignant from benign strictures [30, 45]. Guibaud and

11

ACCEPTED MANUSCRIPT colleagues performed conventional T2-weighted MRCP in 126 patients with suspected biliary obstruction, including 12 patients with a malignant cause [46]. Sensitivity and specificity regarding the diagnosis of a malignant bile duct obstruction were 86% and 98%, respectively, with an overall diagnostic accuracy of 95%. More

RI PT

recently, Yeh et al compared T2-weighted MRCP and ERCP in 40 patients with malignant perihilar biliary obstruction, including 26 patients with hilar CCA [47]. ERCP and MRCP were equally effective in detecting the presence of biliary

SC

obstruction; however MRCP was superior in determining location and cause of jaundice. With conventional MRCP, that relies on the presence of a fluid signal alone,

M AN U

assessing the degree of a bile duct obstruction can be difficult [48]. In these cases, the passage of a hepatocyte specific contrast agent that is excreted with the bile can help to differentiate between complete and partial obstruction.

18

FDG PET/CT is subordinate in the diagnosis of primary hepatobiliary

TE D

The role of

tumors because CT and MRI are more sensitive for tumor detection and characterization [20]. This is especially true for hilar CCC, with sensitivities of

EP

PET/CT as low as 55% [49]. Infiltrating tumor type and lesions smaller than 1cm are difficult to detect due to limited PET resolution and relative high background uptake

AC C

of normal liver parenchyma [15, 33]. It is commonly accepted, that PET/CT has no significant advantage over other imaging techniques when it comes to detection and diagnosis of primary CCA [15, 49]. However, studies directly comparing PET/CT with CT and MRI are limited.

Detection of recurrent disease:

12

ACCEPTED MANUSCRIPT Imaging features of recurrent disease at CT, MRI and PET/CT are similar to those at initial tumor detection. However, differentiation of benign post therapeutic changes such as biliary strictures from tumor recurrence may be difficult. There is data showing that PET/CT is particularly useful in the setting of elevated tumor markers

RI PT

and negative or equivocal findings at CT [16]. Corvera and colleagues identified recurrent CCA with PET in 25/33 patients (76%). In two patients recurrence was not seen with other imaging studies, whereas in the remaining patients PET merely

SC

confirmed the diagnosis made with CT or MRI [50]. The ability of PET to improve diagnostic accuracy in patients with suspected CCA recurrence is confirmed by

M AN U

Jadvar and colleagues [51], reporting a 94% sensitivity and 100% specificity for PET, while sensitivity and specificity for CT were only 82% and 43%, respectively.

Staging

TE D

Staging and assessment of resectability

Radiological staging in patients with CCA includes assessment of local tumor

EP

extension and intrahepatic spread, as well as detection of lymph node metastasis (Nstaging) and distant tumor spread (M-staging). In case of intrahepatic CCA it has

[52].

AC C

been shown that preoperative staging may fail to detect satellite lesions in up to 37%

When the local resectability is assessed, the detection of lymph node metastasis needs to be addressed. Lymphadenopathy of the portocaval and porta hepatis nodes is a common finding in up 73% of patients with CCA. The sensitivity of MDCT for detection of nodal metastases has been reported to range between 35-65% [42, 53, 54]. At MRI, enlarged (>1cm) tumor containing lymph nodes are best demonstrated using T2-weighted fat suppressed and T1-weighted post contrast images [22]. While

13

ACCEPTED MANUSCRIPT FDG-PET has been disappointing in the detection of regional lymph node metastases with sensitivities of just 12-38% [49, 55-57] its clinical benefit may be the identification of unsuspected secondary lesions or distant metastases not detected on CT or MRI. Studies reported an altered management in up to 30% of patients

RI PT

when PET was used in the preoperative evaluation with additional detection of occult metastases in 20-36% of cases [34, 49, 50]. Similarly, Albazaz and colleagues evaluated the clinical impact of FDG-PET/CT on the management in 87 patients with

SC

CCA [13]. They reported a major impact in 26% (n=14) of intrahepatic CCA and in 21% (n=7) of extrahepatic CCA (overall impact in 24%), including recurrence at sites

M AN U

not suspected at CT or MRI in 5 patients, characterization of indeterminate lesions in 4 patients and detection of new disease sites in 11 patients, respectively. Additional

TE D

PET resulted in upstaging in 19% and downstaging in 3% of patients.

Assessment of resectability

Surgical resection with negative histologic margins remains the mainstay and only

EP

curative treatment for patients with CCA, imposing specific requirements on preoperative imaging. Radiological criteria that suggest unresectability of CCA

AC C

include bilateral hepatic duct involvement up to secondary radicals, bilateral tumor extension to secondary bile duct confluence with bilateral invasion of the hepatic artery or portal vein, invasion of the long segment of the main portal vein or the main hepatic artery, atrophy of one hepatic lobe with contralateral vascular invasion or contralateral tumor extension to the secondary biliary confluence, metastasis to paraaortic lymph nodes and distant metastasis [33, 38]. Both, CT and MRI facilitate assessment of liver parenchyma, blood vessels and bile ducts (Figure 6).

14

ACCEPTED MANUSCRIPT

Workup for distal CCA is considered more straightforward with relatively clear criteria for resectability. Owing to its location and the variety of surgical approaches, hilar CCA is a distinct tumor entity. Klatskin tumors are also characterized by longitudinal

RI PT

infiltration of the bile duct wall based on microscopic diffusion along the mucosa and perineural space [58]. This is of vital importance for surgical resection and a main reason for discrepancy between imaging and surgery [59]. MDCT is reliable for

SC

detecting vascular invasion with positive predictive values up to 100% [60]. Underestimation of tumor extent along bile ducts reported with early generation CT

M AN U

[40, 60] has largely improved from 50% to up to 74.5-91.7% [41, 42] with the advent of MDCT. CT findings that best predict non-resectability are hepatic artery or portal vein involvement and peritoneal spread [61]. However, MDCT still has limitations in detecting bile duct variations as well as intraductal tumor extent. Unno et al. reported

TE D

an accuracy of 81% for detection of horizontal spread along the bile duct axis, whereas the detection of vertical spread to neighboring tissues was 100% [53]. Biphasic CT in combination with CT cholangiography can improve diagnosis of biliary

EP

tumor extension [5, 41]. Chen and colleagues evaluated resectability in 18 patients with hilar CCA by CT angiography and CT-cholangiography [42]. Diagnostic accuracy

AC C

for portal vein and hepatic artery invasion was 94.4% and 88.9%. Level and type of biliary obstruction according to the Bismuth classification was correctly diagnosed in 100%. Overall accuracy for assessment of resectability was 91.7% and for assessment of unresectability 83.3%. Similarly, Endo and colleagues reported accuracy rates regarding longitudinal tumor extension of 87%, with a sensitivity, specificity and accuracy of 100%, 80% and 87% for portal invasion and 75%, 91% and 87% for hepatic arterial invasion, respectively [62].

15

ACCEPTED MANUSCRIPT

Current fast techniques make MRI a valuable tool for patients with hepatobiliary malignancy. The reported diagnostic performance of contrast enhanced MRI including MRCP is similar to that of MDCT combined with direct cholangiography

RI PT

(ERCP) for assessment of biliary, vascular involvement, lymph node metastasis and tumor resectability [12, 38, 63].

SC

The accuracy of MR cholangiography for assessment of biliary tumor extent is comparable to that of ERCP with reported accuracies ranging from 70% to 96% [9,

M AN U

64-66]. MRCP has several advantages. It is non-invasive thus reducing the risk for complications. Assessment of suprahilar tumor extension is superior to ERC, where contrast filling of the proximal bile duct system is sometimes difficult due to high grade stenosis [40, 64, 67].

TE D

In our institution, we lean towards MRI and MRCP for assessment of resectability. We see additional value with the use of hepatocyte specific contrast agents and delayed phase MR imaging. This might help to visualize tumor spread along the bile

EP

ducts [9]. To achieve high quality MRI images, however, both operator expertise and patient compliance are mandatory. Therefore, the choice between CT and MRI

AC C

should be made based on institutional expertise as well as patient state. In the end, many patients end up getting both, CT and MRI if that helps with surgical planning.

Current imaging guidelines According to the current International Liver Cancer Association (ILCA) guideline on CCA, radiological studies are necessary for assessment of local tumor extent,

16

ACCEPTED MANUSCRIPT regional or distant spread and staging and resectability, which is best accomplished using CT and / or MRI [68]. In non-cirrhotic patients in whom a decision has been made to proceed with surgical resection, a presumed radiographic diagnosis (CT or MRI) is sufficient (recommendation B1). However, in most patients a pathological

RI PT

diagnosis is required for definitive diagnosis, and it is recommended in all patients who will be undergoing systemic chemotherapy, radiation therapy, or enrolling in a

SC

therapeutic clinical trial [68].

At many institutions MRI including MRCP is used with increasing frequency as the

M AN U

imaging modality of choice for staging of bile duct malignancy because it is less invasive than CT (due to lack of radiation) and because it enables better visualization of peripheral ductal involvement [38, 69, 70]. Similarly, MRCP may be preferred over ERCP for definition of tumor extent in patients with proximal tumor localization

TE D

because of the lower risk of associated complications [71]. In a joint position paper from the Italian Society of Gastroenterology (SIGE), the Italian Association of Hospital Gastroenterology (AIGO), the Italian Association of Medical Oncology

EP

(AIOM) and the Italian Association of Oncological Radiotherapy (AIGO), MRI and endoscopic ultrasound (EUS) are advocated as the main diagnostic tools, but

AC C

recommending further that all available techniques (CT, ERCP, PET, PET/CT) should be used particularly for staging (Level IV, recommendation C) [72]. The British Society of Gastroenterology guidelines, which were first published in 2002 and updated in 2012, also advocate contrast enhanced MRI as the optimal imaging modality in case of CCA [73, 74]. However, MRI is inferior to CT for detecting distant metastases particularly in the lung [75, 76], and therefore patients with suspected

17

ACCEPTED MANUSCRIPT CCA should undergo MRI including MRCP as well as contrast enhanced high resolution CT of the chest, abdomen and pelvis (grade B recommendation).

The role of FDG-PET in the management of CCA remains controversial [68, 77].

RI PT

Currently there is no clear benefit of PET/CT over CT or MRI [68, 78]. Its potential role in preoperative staging needs further validation [56, 73, 79]. According to the European HPB Association Consensus Conference on CCA, PET/CT may be

SC

valuable for detection of unexpected metastatic spread, the differentiation between benign and malignant strictures, as well as for discriminating post therapeutic

AC C

EP

TE D

M AN U

changes from recurrent disease [55, 80, 81].

18

ACCEPTED MANUSCRIPT Practice points •

Radiological imaging is performed for tumor detection, characterization and assessment of resectability Radiographic features may be suggestive of CCA

•

Imaging should be performed prior to invasive biliary procedures

•

MRI including MRCP in combination with CT are the primarily used imaging

RI PT

•

modalities

PET may have a role in detection of distant lesions, differentiation of benign

SC

•

M AN U

from malignant strictures and diagnosis of recurrent disease

Research agenda •

The use of hepatocyte specific MRI contrast agents are promising and warrant further evaluation, especially regarding the detection of early tumor stages in

•

TE D

patients at high risk for CCA.

Comparative studies are necessary to assess the value of PET/CT over MRI

EP

and CT.

AC C

Conflict of interest

FW: institutional research support not related to the topic: DFG, BMBF, Siemens Healthcare, Promedicus Ltd.

Acknowledgement none

19

ACCEPTED MANUSCRIPT References [1] Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10-30. [2] Klatskin G. Adenocarcinoma of the Hepatic Duct at Its Bifurcation within the Porta

RI PT

Hepatis. An Unusual Tumor with Distinctive Clinical and Pathological Features. Am J Med 1965;38:241-256.

[3] Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology

SC

2004;66:167-179.

*[4] Chung YE, Kim MJ, Park YN, Choi JY, Pyo JY, Kim YC, et al. Varying

M AN U

appearances of cholangiocarcinoma: radiologic-pathologic correlation. Radiographics 2009;29:683-700.

[5] Ringe KI, Weidemann J, Ringe BP, Weismueller TJ, Galanski M, Lotz J. Advances in Biliary Imaging: CT and MR Cholangiography. Ann Gastroenterol

TE D

Hepatol. 2010;1.

[6] Hekimoglu K, Ustundag Y, Dusak A, Erdem Z, Karademir B, Aydemir S, et al. MRCP vs. ERCP in the evaluation of biliary pathologies: review of current literature. J

EP

Dig Dis 2008;9:162-169.

[7] van Montfoort JE, Stieger B, Meijer DK, Weinmann HJ, Meier PJ, Fattinger KE.

AC C

Hepatic uptake of the magnetic resonance imaging contrast agent gadoxetate by the organic anion transporting polypeptide Oatp1. J Pharmacol Exp Ther 1999;290:153157.

*[8] Ringe KI, Husarik DB, Sirlin CB, Merkle EM. Gadoxetate disodium-enhanced MRI of the liver: part 1, protocol optimization and lesion appearance in the noncirrhotic liver. AJR Am J Roentgenol 2010;195:13-28.

20

ACCEPTED MANUSCRIPT [9] Ringe KI, Ringe BP, Bektas H, Opherk JP, Reichelt A, Lotz J, et al. Characterization and staging of central bile duct stenosis-evaluation of the hepatocyte specific contrast agent gadoxetate disodium. Eur J Radiol 2012;81:30283034.

RI PT

[10] Kang Y, Lee JM, Kim SH, Han JK, Choi BI. Intrahepatic mass-forming cholangiocarcinoma: enhancement patterns on gadoxetic acid-enhanced MR images. Radiology 2012;264:751-760.

SC

[11] Manfredi R, Barbaro B, Masselli G, Vecchioli A, Marano P. Magnetic resonance imaging of cholangiocarcinoma. Sem Liv Dis 2004;24:155-164.

M AN U

[12] Park HS, Lee JM, Choi JY, Lee MW, Kim HJ, Han JK, et al. Preoperative evaluation of bile duct cancer: MRI combined with MR cholangiopancreatography versus MDCT with direct cholangiography. AJR Am J Roentgenol 2008;190:396-405. [13] Albazaz R, Patel CN, Chowdhury FU, Scarsbrook AF. Clinical impact of FDG

TE D

PET-CT on management decisions for patients with primary biliary tumours. Insights Imaging 2013;4:691-700.

*[14] Breitenstein S, Apestegui C, Clavien PA. Positron emission tomography (PET)

EP

for cholangiocarcinoma. HPB (Oxford) 2008;10:120-121. [15] De Gaetano AM, Rufini V, Castaldi P, Gatto AM, Filograna L, Giordano A, et al.

AC C

Clinical applications of (18)F-FDG PET in the management of hepatobiliary and pancreatic tumors. Abdom Imaging 2012;37:983-1003. [16] Cameron K, Golan S, Simpson W, Peti S, Roayaie S, Labow D, et al. Recurrent pancreatic carcinoma and cholangiocarcinoma: 18F-fluorodeoxyglucose positron emission

tomography/computed

tomography

2011;36:463-471.

21

(PET/CT).

Abdom

Imaging

ACCEPTED MANUSCRIPT [17] Diederichs CG, Staib L, Vogel J, Glasbrenner B, Glatting G, Brambs HJ, et al. Values and limitations of 18F-fluorodeoxyglucose-positron-emission tomography with preoperative evaluation of patients with pancreatic masses. Pancreas 2000;20:109116.

RI PT

[18] Fritscher-Ravens A, Bohuslavizki KH, Broering DC, Jenicke L, Schafer H, Buchert R, et al. FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl Med Communi 2001;22:1277-1285.

SC

[19] Japan LCSGo. The general rules for the clinical and pathological study of primary liver cancer. 4th ed. Tokyo: Kanehara; 2000.

Imaging 2013;38:1071-1081.

M AN U

[20] Ayuso JR, Pages M, Darnell A. Imaging bile duct tumors: staging. Abdom

[21] Asayama Y, Yoshimitsu K, Irie H, Tajima T, Nishie A, Hirakawa M, et al. Delayed-phase dynamic CT enhancement as a prognostic factor for mass-forming

TE D

intrahepatic cholangiocarcinoma. Radiology 2006;238:150-155. [22] Worawattanakul S, Semelka RC, Noone TC, Calvo BF, Kelekis NL, Woosley JT. Cholangiocarcinoma: spectrum of appearances on MR images using current

EP

techniques. Magn Reson Imaging 1998;16:993-1003. [23] Rimola J, Forner A, Reig M, Vilana R, de Lope CR, Ayuso C, et al.

AC C

Cholangiocarcinoma in cirrhosis: absence of contrast washout in delayed phases by magnetic resonance imaging avoids misdiagnosis of hepatocellular carcinoma. Hepatology 2009;50:791-798. [24] Kim SA, Lee JM, Lee KB, Kim SH, Yoon SH, Han JK, et al. Intrahepatic massforming cholangiocarcinomas: enhancement patterns at multiphasic CT, with special emphasis on arterial enhancement pattern--correlation with clinicopathologic findings. Radiology 2011;260:148-157.

22

ACCEPTED MANUSCRIPT [25] Jeong HT, Kim MJ, Chung YE, Choi JY, Park YN, Kim KW. Gadoxetate disodium-enhanced

MRI

of

mass-forming

intrahepatic

cholangiocarcinomas:

imaging-histologic correlation. AJR Am J Roentgenol 2013;201:W603-611. [26] Ringe KI, Hinrichs J, Merkle EM, Weismuller TJ, Wacker F, Meyer BC.

RI PT

Gadoxetate disodium in patients with primary sclerosing cholangitis: an analysis of hepatobiliary contrast excretion. J Magn Reson Imaging 2014;40:106-112.

[27] Marsh Rde W, Alonzo M, Bajaj S, Baker M, Elton E, Farrell TA, et al.

SC

Comprehensive review of the diagnosis and treatment of biliary tract cancer 2012. Part I: diagnosis-clinical staging and pathology. J Surg Oncol 2012;106:332-338.

M AN U

[28] Gore RM, Shelhamer RP. Biliary tract neoplasms: diagnosis and staging. Cancer Imaging 2007;7:S15-23.

[29] Bilgin M, Shaikh F, Semelka RC, Bilgin SS, Balci NC, Erdogan A. Magnetic resonance imaging of gallbladder and biliary system. Top Magn Reson Imaging

TE D

2009;20:31-42.

[30] Park MS, Kim TK, Kim KW, Park SW, Lee JK, Kim JS, et al. Differentiation of extrahepatic bile duct cholangiocarcinoma from benign stricture: findings at MRCP

[31]

Patel

T.

EP

versus ERCP. Radiology 2004;233:234-240. Increasing

incidence

and

mortality

of

primary

intrahepatic

AC C

cholangiocarcinoma in the United States. Hepatology 2001;33:1353-1357. [32] Bismuth H, Nakache R, Diamond T. Management strategies in resection for hilar cholangiocarcinoma. Ann Surg 1992;215:31-318. [33] Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose PET imaging in the evaluation of gallbladder carcinoma and cholangiocarcinoma. J Gastroint Surg 2004;8:90-97.

23

ACCEPTED MANUSCRIPT [34] Kim YJ, Yun M, Lee WJ, Kim KS, Lee JD. Usefulness of 18F-FDG PET in intrahepatic cholangiocarcinoma. Eur J Nucl Med Mol Imaging 2003;30:1467-1472. [35] Choi EK, Yoo Ie R, Kim SH, O JH, Choi WH, Na SJ, et al. The clinical value of

from benign disease. Clin Nucl Med 2013;38:e106-111.

RI PT

dual-time point 18F-FDG PET/CT for differentiating extrahepatic cholangiocarcinoma

[36] Alkhawaldeh K, Faltten S, Biersack HJ, Ezziddin S. The value of F-18 FDG PET in patients with primary sclerosing cholangitis and cholangiocarcinoma using visual

SC

and semiquantitative analysis. Clin Nucl Med 2011;36:879-883.

[37] Nesbit GM, Johnson CD, James EM, MacCarty RL, Nagorney DM, Bender CE.

M AN U

Cholangiocarcinoma: diagnosis and evaluation of resectability by CT and sonography as procedures complementary to cholangiography. AJR Am J Roentgenol 1988;151:933-893.

[38] Choi JY, Kim MJ, Lee JM, Kim KW, Lee JY, Han JK, et al. Hilar

TE D

cholangiocarcinoma: role of preoperative imaging with sonography, MDCT, MRI, and direct cholangiography. AJR Am J Roentgenol 2008;191:1448-1457. [39] Valls C, Guma A, Puig I, Sanchez A, Andia E, Serrano T, et al. Intrahepatic

EP

peripheral cholangiocarcinoma: CT evaluation. Abdom Imaging 2000;25:490-496. [40] Tillich M, Mischinger HJ, Preisegger KH, Rabl H, Szolar DH. Multiphasic helical

AC C

CT in diagnosis and staging of hilar cholangiocarcinoma. AJR Am J Roentgenol 1998;171:651-658.

[41] Lee HY, Kim SH, Lee JM, Kim SW, Jang JY, Han JK, et al. Preoperative assessment of resectability of hepatic hilar cholangiocarcinoma: combined CT and cholangiography with revised criteria. Radiology 2006;239:113-121.

24

ACCEPTED MANUSCRIPT [42] Chen HW, Pan AZ, Zhen ZJ, Su SY, Wang JH, Yu SC, et al. Preoperative evaluation of resectability of Klatskin tumor with 16-MDCT angiography and cholangiography. AJR Am J Roentgenol 2006;186:1580-1586. [43] Halavaara J, Breuer J, Ayuso C, Balzer T, Bellin MF, Blomqvist L, et al. Liver

RI PT

tumor characterization: comparison between liver-specific gadoxetic acid disodiumenhanced MRI and biphasic CT-a multicenter trial. J Comput Assist Tomogr 2006;30:345-354.

SC

[44] Hammerstingl R, Huppertz A, Breuer J, Balzer T, Blakeborough A, Carter R, et al. Diagnostic efficacy of gadoxetic acid (Primovist)-enhanced MRI and spiral CT for

M AN U

a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions. Eur Radiol 2008;18:457-467.

[45] Yu XR, Huang WY, Zhang BY, Li HQ, Geng DY. Differentiation of infiltrative cholangiocarcinoma from benign common bile duct stricture using three-dimensional

TE D

dynamic contrast-enhanced MRI with MRCP. Clin Radiol 2014;69:567-573. [46] Guibaud L, Bret PM, Reinhold C, Atri M, Barkun AN. Bile duct obstruction and

115.

EP

choledocholithiasis: diagnosis with MR cholangiography. Radiology 1995;197:109-

[47] Yeh TS, Jan YY, Tseng JH, Chiu CT, Chen TC, Hwang TL, et al. Malignant

AC C

perihilar biliary obstruction: magnetic resonance cholangiopancreatographic findings. Am J Gastroenterol 2000;95:432-440. [48] Lee NK, Kim S, Lee JW, Lee SH, Kang DH, Kim GH, et al. Biliary MR imaging with Gd-EOB-DTPA and its clinical applications. Radiographics 2009;29:1707-1724. *[49] Petrowsky H, Wildbrett P, Husarik DB, Hany TF, Tam S, Jochum W, et al. Impact of integrated positron emission tomography and computed tomography on

25

ACCEPTED MANUSCRIPT staging and management of gallbladder cancer and cholangiocarcinoma. J Hepatol 2006;45:43-50. [50] Corvera CU, Blumgart LH, Akhurst T, DeMatteo RP, D'Angelica M, Fong Y, et al. 18F-fluorodeoxyglucose positron emission tomography influences management

RI PT

decisions in patients with biliary cancer. J Am Coll Surg 2008;206:57-65.

[51] Jadvar H, Henderson RW, Conti PS. [F-18]fluorodeoxyglucose positron emission tomography and positron emission tomography: computed tomography in recurrent

SC

and metastatic cholangiocarcinoma. J Comput Assist Tomogr 2007;31:223-228.

[52] Okabayashi T, Yamamoto J, Kosuge T, Shimada K, Yamasaki S, Takayama T,

M AN U

et al. A new staging system for mass-forming intrahepatic cholangiocarcinoma: analysis of preoperative and postoperative variables. Cancer 2001;92:2374-2383. [53] Unno M, Okumoto T, Katayose Y, Rikiyama T, Sato A, Motoi F, et al. Preoperative assessment of hilar cholangiocarcinoma by multidetector row computed

TE D

tomography. J Hepatobiliary Pancreat Surg 2007;14:434-440. [54] Park MS, Lee DK, Kim MJ, Lee WJ, Yoon DS, Lee SJ, et al. Preoperative staging accuracy of multidetector row computed tomography for extrahepatic bile

EP

duct carcinoma. J Comput Assist Tomogr 2006;30:362-367. [55] Vilgrain V. Staging cholangiocarcinoma by imaging studies. HPB (Oxford)

AC C

2008;10:106-109.

[56] Kluge R, Schmidt F, Caca K, Barthel H, Hesse S, Georgi P, et al. Positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose for diagnosis and staging of bile duct cancer. Hepatology 2001;33:1029-1035. [57] Kato T, Tsukamoto E, Kuge Y, Katoh C, Nambu T, Nobuta A, et al. Clinical role of (18)F-FDG PET for initial staging of patients with extrahepatic bile duct cancer. Eur J Nucl Med Mol Imaging 2002;29:1047-1054.

26

ACCEPTED MANUSCRIPT [58] Khalili K, Metser U, Wilson SR. Hilar biliary obstruction: preliminary results with Levovist-enhanced sonography. AJR Am J Roentgenol 2003;180:687-693. [59] Shimada H, Niimoto S, Matsuba A, Nakagawara G, Kobayashi M, Tsuchiya S. The infiltration of bile duct carcinoma along the bile duct wall. Int Surg 1988;73:87-90.

RI PT

[60] Cha JH, Han JK, Kim TK, Kim AY, Park SJ, Choi BI, et al. Preoperative evaluation of Klatskin tumor: accuracy of spiral CT in determining vascular invasion as a sign of unresectability. Abdom Imaging 2000;25:500-507.

SC

[61] Aloia TA, Charnsangavej C, Faria S, Ribero D, Abdalla EK, Vauthey JN, et al. High-resolution computed tomography accurately predicts resectability in hilar

M AN U

cholangiocarcinoma. Am J Surg 2007;193:702-706.

[62] Endo I, Shimada H, Sugita M, Fujii Y, Morioka D, Takeda K, et al. Role of threedimensional imaging in operative planning for hilar cholangiocarcinoma. Surgery 2007;142:666-675.

TE D

[63] Zhang Y, Uchida M, Abe T, Nishimura H, Hayabuchi N, Nakashima Y. Intrahepatic peripheral cholangiocarcinoma: comparison of dynamic CT and dynamic MRI. J Comput Assist Tomogr 1999;23:670-677.

EP

[64] Manfredi R, Masselli G, Maresca G, Brizi MG, Vecchioli A, Marano P. MR imaging and MRCP of hilar cholangiocarcinoma. Abdom Imaging 2003;28:319-325.

AC C

[65] Cho ES, Park MS, Yu JS, Kim MJ, Kim KW. Biliary ductal involvement of hilar cholangiocarcinoma:

multidetector

computed

tomography

versus

magnetic

resonance cholangiography. J Comput Assist Tomogr 2007;31:72-78. [66] Lee SS, Kim MH, Lee SK, Kim TK, Seo DW, Park JS, et al. MR cholangiography versus

cholangioscopy

for

evaluation

of

longitudinal

cholangiocarcinoma. Gastrointest Endosc 2002;56:25-32.

27

extension

of

hilar

ACCEPTED MANUSCRIPT [67] Masselli G, Gualdi G. Hilar cholangiocarcinoma: MRI/MRCP in staging and treatment planning. Abdom Imaging 2008;33:444-451. *[68] Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW, Patel T, et al.

Hepatol 2014;60:1268-1289.

RI PT

Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J

[69] Kim JE, Lee JM, Kim SH, Baek JH, Moon SK, Yu IS, et al. Differentiation of intraductal

growing-type

cholangiocarcinomas

from

nodular-type

SC

cholangiocarcinomas at biliary MR imaging with MR cholangiography. Radiology 2010;257:364-372.

M AN U

[70] Zech CJ, Schoenberg SO, Reiser M, Helmberger T. Cross-sectional imaging of biliary tumors: current clinical status and future developments. Eur Radiol 2004;14:1174-1187.

[71] Services AH. Cholangiocarcinoma and gallbladder cancer. Version 3 ed. 2013.

TE D

Clinical Practice Guideline GI-010.

[72] Alvaro D, Cannizzaro R, Labianca R, Valvo F, Farinati F, Italian Society of G, et al. Cholangiocarcinoma: A position paper by the Italian Society of Gastroenterology

EP

(SIGE), the Italian Association of Hospital Gastroenterology (AIGO), the Italian Association of Medical Oncology (AIOM) and the Italian Association of Oncological

AC C

Radiotherapy (AIRO). Dig Liver Dis 2010;42:831-838. [73] Khan SA, Davidson BR, Goldin RD, Heaton N, Karani J, Pereira SP, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update. Gut 2012;61:1657-1669. [74] Vergel YB, Chilcott J, Kaltenthaler E, Walters S, Blakeborough A, Thomas S. Economic evaluation of MR cholangiopancreatography compared to diagnostic ERCP for the investigation of biliary tree obstruction. Int J Surg 2006;4:12-19.

28

ACCEPTED MANUSCRIPT [75] Ariff B, Lloyd CR, Khan S, Shariff M, Thillainayagam AV, Bansi DS, et al. Imaging of liver cancer. World J Gastroenterol 2009;15:1289-1300. [76] Maccioni F, Martinelli M, Al Ansari N, Kagarmanova A, De Marco V, Zippi M, et al. Magnetic resonance cholangiography: past, present and future: a review. Eur Revi

RI PT

Medi Pharmacol Sci 2010;14:721-725.

[77] Marrero JA, Ahn J, Rajender Reddy K, Americal College of G. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol

SC

2014;109:1328-1347

[78] Lan BY, Kwee SA, Wong LL. Positron emission tomography in hepatobiliary and

M AN U

pancreatic malignancies: a review. Am J Surg 2012;204:232-241.

[79] Kim JY, Kim MH, Lee TY, Hwang CY, Kim JS, Yun SC, et al. Clinical role of 18FFDG PET-CT in suspected and potentially operable cholangiocarcinoma: a prospective study compared with conventional imaging. Am J Gastroenterol

TE D

2008;103:1145-1151.

[80] Van Beers BE. Diagnosis of cholangiocarcinoma. HPB (Oxford) 2008;10:87-93. [81] Garcea G, Ong SL, Maddern GJ. The current role of PET-CT in the

AC C

EP

characterization of hepatobiliary malignancies. HPB (Oxford) 2009;11:4-17.

29

ACCEPTED MANUSCRIPT Figure legends Figure 1:

80-year-old female patient with mass-forming CCA in segment 4a and b. Contrast

RI PT

enhanced CT demonstrates typical imaging features with peripheral arterial rim enhancement (arrow in A) and centrally persistent portal venous phase enhancement (asterisk in B), correlating with the amount of fibrous stroma. In addition, capsular

M AN U

SC

retraction can be appreciated (arrowheads).

Figure 2:

70-year-old female patient with intrahepatic CCA. Arterial phase MRI (A) after gadoxetate disodium injection depicts peripheral enhancing lesions in the left lobe of

TE D

the liver (white arrows). Hepatocyte phase imaging (B) reveals multiple satellite lesions in the right lobe (black arrows) due to high contrast of surrounding liver

EP

parenchyma. Staging further demonstrates peritoneal carcinomatosis in the left lower

AC C

quadrant (arrowheads in C).

Figure 3:

MRI of a 65-year-old female patient with type 2 Klatskin tumor. T2 weighted MRCP (A, B) and portal venous phase imaging (C, D) in the axial (A, C) and coronal (B, D) plane. At MRCP, marked dilatation of the intrahepatic bile ducts (arrowheads) in the left and right and lobe of the liver can be appreciated, as well as a high-grade bile duct stenosis (asterisk in A) in the liver hilum. Portal venous phase MRI clearly

30

ACCEPTED MANUSCRIPT depicts a contrast enhancing mass (arrow in C and D) involving the primary confluence of the left and right hepatic duct. Patient successfully underwent hilar

RI PT

resection.

Figure 4:

SC

23-year-old male patient with PSC and extrahepatic distal CCA. Arterial (A, B) and portal venous phase (C) in the axial (A) and coronal (B, C) plane depicts a contrast

M AN U

enhancing mass in the liver hilum (*) infiltrating the hepatic artery (arrow) and portal vein (arrowhead). Marked dilatation of the common hepatic bile duct can be appreciated. At explorative laparotomy duodenal (D) and pancreatic (P) invasion was

EP

Figure 5:

TE D

confirmed.

18

FDG PET/CT (A-C) in a 40-year-old female patient with intrahepatic CCA. The

AC C

primary tumor in segment 5/6 can be well appreciated (*), In addition, a satellite lesion in segment 7 (arrow) as well as a lymph node metastasis (arrowhead) is depicted. However, FDG PET/CT fails to demonstrate bilateral pulmonary metastasis (circles) depicted at contrast enhanced CT (D,E) due to small lesion size. (The PET/CT has been kindly provided by the Department of Nuclear Medicine, Prof. Dr. F. Bengel).

31

ACCEPTED MANUSCRIPT Figure 6:

Biphasic contrast enhanced CT in a 70-year-old female patient with extrahepatic CCA extending from the common hepatic duct into the left hepatic duct (arrows in A

RI PT

and C), associated with hypotrophy of the left lobe (arrowhead in B). In addition, a large soft tissue mass in the liver hilum can be appreciated (asterisk in A and C) encasing the common hepatic artery and main portal vein. 3D volume rendered

SC

images demonstrate proximal infiltration of the left hepatic artery (dashed arrow in D) and left portal vein (dashed arrow in E). Staging further depicts a large abdominal

AC C

EP

TE D

M AN U

wall metastasis (asterisk in F and G).

32

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT