G a s t r o i n t e s t i n a l I m a g i n g • R ev i ew

Seo et al.
Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma

Gastrointestinal Imaging
Review
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Cross-Sectional Imaging of
Intrahepatic Cholangiocarcinoma:
Development, Growth, Spread,
and Prognosis
Nieun Seo1 OBJECTIVE. Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that arises
Do Young Kim 2 from the intrahepatic bile ducts. Although the pathologic and imaging features of ICC have
Jin-Young Choi1 been clearly identified, recent updates have addressed the pathologic classification and imag-
ing features of ICC using new imaging techniques. First, a proposed new pathologic ICC sub-
Seo N, Kim DY, Choi JY classification includes perihilar large duct and peripheral small duct ICCs. Second, advanced
MR-based imaging features of ICC, such as hepatobiliary phase imaging using hepatocyte-
specific contrast material and DWI, have recently been described. These imaging features are
important when differentiating ICCs from hepatocellular carcinomas. Finally, some imaging
features of ICC, such as prominent arterial enhancement or degree of delayed enhancement,
exhibit potential as prognostic imaging biomarkers.
CONCLUSION. Comprehensive and updated knowledge of ICC is necessary for ac-
curate diagnosis and could facilitate prediction of clinical outcomes for patients with ICC.

ntrahepatic cholangiocarcinoma gitudinally along the bile ducts and cause

I (ICC), which accounts for ap-

Keywords: CT, intrahepatic cholangiocarcinoma, MRI,
prognosis
DOI:10.2214/AJR.16.16923
Received June 8, 2016; accepted after revision
November 19, 2016.
1
Department of Radiology, Severance Hospital,
Yonsei University College of Medicine, 50 Yonsei-ro,
Seodaemun-gu, Seoul 03722, Korea. Address
correspondence to J. Y. Choi (gafield2@yuhs.ac).
2
Department of Internal Medicine, Yonsei Liver Center,
Severance Hospital, Yonsei University College of
Medicine, Seoul, Korea.
WEB
This is a web exclusive article.
AJR 2017; 209:W64–W75
0361–803X/17/2092–W64
© American Roentgen Ray Society
proximately 5–10% of all cho-
langiocarcinomas, is the second
most common type of primary hepatic ma-
lignancy. This article discusses key concepts
and recent advances in understanding of ICC
development, growth, and spread, and em-
phasizes imaging features obtained using
new imaging techniques.
Pathology
Gross Features of Intrahepatic
Cholangiocarcinoma
ICC can be classified on the basis of the
macroscopic tumor growth pattern as mass-
forming type, periductal infiltrating type,
or intraductal growing type according to
the classification of the Liver Cancer Study
Group of Japan [1–3]. The mass-forming
type is the most common, accounting for
78% of all cases of ICC [2, 4]. Tumors of this
type are usually large, up to 15 cm in diam-
eter [5]. The majority manifest as well-de-
fined lobulated masses with varying degrees
of central sclerotic changes [1]. Multicentric-
ity around the main tumor is common, prob-
ably because mass-forming ICC commonly
invades the adjacent portal vein branches [5,
6]. Periductal infiltrating tumors extend lon-
bile duct wall thickening [2, 4]. Progressive
periductal invasion causes luminal stenosis
and proximal biliary dilatation [1]. Although
periductal infiltrating type is the most com-
mon type of hilar cholangiocarcinoma, it is
much less common in ICC, constituting ap-
proximately 16% of ICCs [2, 4, 5]. Intraduct-
al growing ICC is the rarest type of ICC (ap-
proximately 6%) and presents as a papillary
tumor within the dilated bile duct lumen; this
type shares morphologic features with intra-
ductal papillary neoplasm of the bile duct
(IPNB) [1, 2, 4]. Intraductal growing ICCs
are usually small, sessile, or polypoid and
spread along the mucosa with multiplicity
[7, 8]. Sometimes, this type of tumor produc-
es a large amount of mucin, causing partial
biliary obstruction [7–9]. ICCs arising from
the intrahepatic small bile ducts, bile duct-
ules, or progenitor cells are usually the mass-
forming type, whereas those arising from the
intrahepatic large bile ducts may appear as
either the periductal infiltrating or intraduct-
al growing type combined with the mass-
forming type. However, each of the three
gross morphologic types may coexist in in-
dividual cases. Table 1 summarizes the clini-
copathologic and radiologic findings of ICC
according to morphologic subtype.

W64 AJR:209, August 2017

 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma
TABLE 1: Clinicopathologic and Radiologic Findings of Intrahepatic Cholangiocarcinoma (ICC) According to
Morphologic Subtype
Gross Morphology Enhancement
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Mass-forming Hypoattenuated or
hypointense mass with
peripheral arterial
enhancement and gradual
centripetal enhancement
Periductal infiltrating Usually hyperattenuation or
hyperintensity compared
with the surrounding liver
in hepatic arterial and
portal venous phases
Intraductal growing Hypoattenuation or
hypointensity (only faint
contrast enhancement)
compared with the
surrounding liver
Note—HCC = hepatocellular carcinoma.
Subtypes, Pathologic Features, and Tumor
Stroma in Cholangiocarcinomas
Several histologic classification systems
exist for ICC. According to the 2010 World
Health Organization (WHO) classification,
ICC comprises adenocarcinoma (classic
type) and other histologic variants [3]. Most
ICCs are well-differentiated adenocarcino-
mas with or without micropapillary struc-
tures and exhibit varying degrees of stromal
fibrosis [3]. Histologic variants of ICCs in-
clude adenosquamous and squamous carci-
noma, mucinous carcinoma, signet-ring cell
carcinoma, clear cell carcinoma, mucoepi-
dermoid carcinoma, lymphoepithelioma-like
carcinoma, and sarcomatous ICC [3].
ICC can also be classified into two types
according to the site of involvement and his-
tologic features: perihilar large duct ICC,
which involves the intrahepatic large bile
ducts, and peripheral small duct ICC, which
involves the intrahepatic small bile ducts
[10]. This new subtype classification can ex-
plain the different location, background con-
dition, postulated cell of origin, premalig-
nant lesions, clinical and genetic features
between these two types of ICCs, and has the
potential to predict prognosis [1, 11]. Perihi-
lar large duct ICCs include large to midsize
tubular or papillary proliferations of the tall
columnar epithelium [1]. Perihilar large duct
ICCs produce more mucin than do peripheral
small duct ICCs, and this mucin production
affects the pathologic conditions. The gross
features of perihilar large duct ICC mostly
include those of the periductal infiltrating
or intraductal growth types [1, 10]. Perihi-
lar large duct ICCs are more likely to have
AJR:209, August 2017 W65
Pathologic Correlation of
Enhancement Pattern Ancillary Features
Abundant tumor cells at the Capsular retraction, satellite
periphery and fibrous nodules, peripheral bile
stroma, necrosis in the duct dilatation
center of the ICC
Infiltrative tumor with Irregular narrowing of
frequent perineural and involved bile ducts,
lymphatic invasion proximal bile duct dilatation
Papillary tumor within the Segmental or diffusely
bile duct confined to dilated bile ducts with or
mucosal surface with small without polypoid or
fibrovascular stalk papillary intraductal tumors
ill-defined or infiltrating tumor margins and
increased necrosis [1]. Perineural, vascular,
and lymphatic invasion and lymph node me-
tastases are more frequently associated with
perihilar large duct ICCs than with peripher-
al small duct ICCs [1, 10].
In contrast, peripheral small duct ICCs ex-
hibit small tubular or trabecular proliferation
of low columnar to cuboidal cells. Mucin
hypersecretion is much rarer in peripheral
small duct ICCs than in perihilar large duct
ICCs [2]. According to a study by Cardinale
et al. [12], peripheral small duct ICC might
be transformed from cholangiolocellular car-
cinoma or might originate from hepatic pro-
genitor cells, because they are target cells for
carcinogenesis in patients with chronic liver
disease or liver cirrhosis. Such ICCs are usu-
ally of the mass-forming type and tend to be
smaller at the time of detection [4]. Periph-
eral small duct ICCs have more expansive
tumor borders and are less likely to exhibit
perineural or lymphatic invasion compared
with the perihilar large duct type [1, 10].
Most ICCs exhibit varying degrees of stro-
mal fibrosis, which is an important charac-
teristic [3]. Tumor stromata actively and con-
tinuously provide support to tumor cells and
contribute to cancer progression and inva-
sion [1]. There are some differences in tumor
stroma between perihilar large duct ICCs
and peripheral small duct ICCs. Perihilar
large duct ICCs occasionally exhibit a dif-
fuse arrangement of fibroblasts and collage-
nous stroma associated with Glisson fibrous
capsules, and CD10-positive myofibroblasts
are predominant in this type of ICCs. On the
other hand, peripheral small duct ICCs fea-
Differential Diagnosis Prognosis
HCC (in the setting of chronic Poor
liver disease), metastasis,
hemangioma (vs mucinous
type of ICC)
IgG4-related sclerosing Moderate
cholangitis, other benign
cause of biliary stricture
Intrahepatic bile duct stone Good
ture abundant central fibrous stromata and
dense peripheral cancer cells. The central
fibrous area often shows acellular stromata
and edematous change [1].
Cholangiocarcinogenesis
Premalignant Lesions
Three types of premalignant bile duct le-
sions were proposed in the 2010 WHO clas-
sification: biliary intraepithelial neoplasia
(BilIN), IPNB, and mucinous cystic neo-
plasm (MCN) [3]. Among these, two types
of premalignant lesions—microscopic BilIN
and grossly visible IPNB—were described
in the development and progression of chol-
angiocarcinomas from intrahepatic large
ducts [13]. However, to our knowledge, as-
sociations between these preneoplastic or
dysplastic lesions and peripheral small duct
ICCs have not been established [13]. Imag-
ing modalities such as CT and MRI, includ-
ing MRCP, have an essential role for early
diagnosis, preoperative evaluation of disease
extent and multiplicity, and postoperative
follow-up of IPNB. Unlike IPNB, because
BilIN is a microscopic alteration, conven-
tional imaging studies are limited with re-
spect to its detection [14].
BilIN is a microscopic change in the bil-
iary epithelium characterized by the pres-
ence of abnormal epithelial cells with nucle-
ar atypia and micropapillary projections into
the bile duct [4, 15]. BilIN are graded as Bi-
lIN-1 (low-grade dysplasia), BilIN-2 (inter-
mediate-grade dysplasia), or BilIN-3 (high-
grade dysplasia) according to the degree of
cellular and structural atypia [15]. These le-
sions represent a multistep carcinogenesis of

cholangiocarcinoma. In terms of gross mor-
phology, a BilIN may be a precursor lesion of
periductal infiltrating ICC [4].
IPNB is a biliary neoplasm that encom-
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passes the previous entities of biliary papil-
loma and papillomatosis. IPNB is character-
ized by the presence of dilated bile ducts with
intraductal papillary or villous neoplasm that
covers fine fibrovascular stalks [3]. Approx-
imately one-third of IPNBs produce abun-
dant mucin in the ductal lumen [16]. IPNB
can be classified as low-, intermediate-, or
high-grade intraepithelial dysplasia, accord-
ing to the degree of cellular or nuclear and
structural atypia [17]. IPNB is often associ-
ated with an invasive component and in such
cases is described as IPNB with an associ-
ated invasive carcinoma. IPNB has recently
been suggested as a precursor lesion in the
dysplasia-carcinoma sequence and can prog-
ress to intraductal growing ICC [4]. On im-
aging studies, IPNB appears as a small flat or
fungating mass within the dilated bile ducts
[7, 9]. Compared with CT, MRI has bene-
fits for the detection and characterization of
IPNB [18]. In particular, MRCP can visual-
ize the communication between the cystic le-
sion (dilated bile duct) and biliary tree, the
intraductal tumors, and the whole biliary tree
without missing ducts [19]. Intraductal tu-
mors exhibit contrast enhancement and high
signal intensity on DWI [20]. In the presence
of IPNB, the bile ducts become dilated when
the tumor or mucin disturbs the bile flow [21].
Several biliary dilatation patterns can be ob-
served, including the disproportional dilata-
tion of segmental or lobar bile ducts, gener-
alized dilatation, and aneurysmal dilatation
[21]. Dilatation of the downstream bile duct
consequent to mucin production is a charac-
teristic feature of IPNB [19]. According to a
recent study, intraductal linear or curvilin-
ear hypointense striations (thread sign) can
be observed with MRI in IPNBs; this sign is
highly specific for IPNB [22] (Fig. 1).
Mode of Histologic Progression of
Intrahepatic Cholangiocarcinomas
Perihilar large duct ICCs and peripheral
small duct ICCs may undergo different path-
ways of carcinogenesis and modes of histo-
logic progression (Fig. 2). In cases of peri-
hilar large duct ICCs, ICCs might originate
from the peribiliary glands, and chronic in-
flammation can induce BilIN or periduc-
tal infiltrating ICC [1, 23]. Another possible
carcinogenic pathway of perihilar large duct
ICCs includes IPNB or intraductal growing
W66 AJR:209, August 2017
Seo et al.
ICC [1, 23]. These ICCs progress with inva-
sion to the surrounding liver parenchyma and
spread along the portal tracts, later exhibit-
ing combined morphologic features of mass-
forming, periductal infiltrating, or intraductal
growth tumors [1, 10]. Regarding peripheral
small duct ICCs, the interlobular bile ducts
or canals of Hering may be candidate cells
of origin, and chronic liver disease and liv-
er cirrhosis have been hypothesized to affect
the carcinogenesis of these tumors [24]. Ear-
ly-stage peripheral small duct ICCs are asso-
ciated with preserved portal tracts and cancer
cell proliferation in the periportal area [10].
As peripheral small duct ICCs progress, dis-
torted portal tracts within the tumor and solid
growth of tumor may be observed [10]. Ad-
vanced peripheral small duct ICC often ap-
pears as extensive fibrotic scarring in the tu-
mor center, with necrosis and intrahepatic
metastasis [1].
Imaging
Imaging Features of Mass-Forming
Intrahepatic Cholangiocarcinoma
Mass-forming ICC usually appears as an
irregular but well-defined mass and is fre-
quently associated with peripheral biliary
dilatation [25]. This type of tumor frequent-
ly invades the adjacent peripheral branches
of the portal vein and thus generally extends
to the hepatic parenchyma with multicen-
tricity around the main tumor [6]. At later
stages, mass-forming ICC invades the Glis-
son sheath and spreads via both the portal
and lymphatic systems [6]. The typical CT
finding of a mass-forming ICC is a hypoat-
tenuated mass with irregular peripheral en-
hancement in the hepatic arterial phase and
gradual centripetal enhancement on dynam-
ic studies [5, 26]. This enhancement pattern
can be explained histologically. The periph-
eral portion of ICCs contains abundant via-
ble tumor cells, whereas the central portion
is composed of coagulative necrosis with few
cancer cells and a varying degree of fibrous
stroma [27]. The fibrous stroma in the center
of the tumor is known to appear as an area
of delayed enhancement on dynamic stud-
ies [25, 27]. Other common findings include
capsular retraction, satellite nodules, and
macroscopic vascular invasion [5, 26].
The MRI features of mass-forming ICCs
are similar to the CT features [27–29]. The
mass typically shows high signal intensity
on T2-weighted imaging and low signal in-
tensity on T1-weighted imaging. On dynam-
ic contrast-enhanced MRI with extracellu-
lar contrast material, the mass also exhibits
prominent peripheral rim enhancement with
centripetal or gradual progressive enhance-
ment [27, 29]. Recent reports have described
the findings of mass-forming ICCs on gadox-
etate disodium–enhanced MR images [30,
31]. The prominent rimlike arterial enhance-
ment and progressive dynamic enhancement
pattern are similar to those observed on MR
images with extracellular contrast material
(Fig. 3). However, mass-forming ICCs may
exhibit a pseudowashout pattern during the
transitional phase (late dynamic phase be-
tween the portal venous and hepatobiliary
phases) of gadoxetate disodium–enhanced
MRI because of progressive enhancement of
the background liver [30]. Most mass-form-
ing ICCs do not take up hepatobiliary agents
because of the absence of organic anion-
ic transporter peptide expression; these tu-
mors are thus hypointense in the hepatobi-
liary phase [31, 32]. However, mass-forming
ICCs occasionally exhibit intermediate or
mixed hyperintensity during the hepatobili-
ary phase because of contrast agent pooling
in the fibrous stroma, which corresponds to
a large extracellular space relative to normal
tissue [30–32]. According to a recent study,
most mass-forming ICCs showed heteroge-
neous hypointensity with intermingled hy-
perintensity on hepatobiliary phase images
rather than homogeneous hypointensity [31].
A target appearance during the hepatobili-
ary phase is more frequently associated with
tumors with abundant central stromal fibro-
sis [30]. On DWI, 52–75% of mass-forming
ICCs exhibit characteristic targetlike diffu-
sion restriction at high b values [33–35]. This
target appearance on DWI is thought to be
related to the histologic components of ICC,
but identifying a perfect radiologic-patho-
logic correlation is difficult [30, 33, 34]. A
central dark area on DWI may reflect fibrosis
and necrosis of the tumor, whereas a periph-
eral restricted area on DWI might represent
highly cellular and vascular tumor cells [30,
33, 34]. This target sign on DWI is also use-
ful for distinguishing ICC from hepatocel-
lular carcinoma (HCC) [33, 34]. According
to one study to determine the MRI features
that differentiate small (≤ 3 cm) mass-form-
ing ICC from HCC, only a target appearance
on DWI was a significant predictor of ICC
(75.0% of ICC vs 3.1% of HCC) [34]. Similar-
ly, a target sign on DWI was more frequently
observed in mass-forming ICC (52%) than in
HCC (3%) in another study [33]. However, up
to approximately 50% of ICCs do not show
 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma
a target appearance on DWI, so differentia-
tion of ICC from HCC using DWI may not
always be simple. Furthermore, small (≤  3
cm) scirrhous HCC with abundant fibrous
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stroma frequently exhibited a target appear-
ance on DWI, similar to ICC (71.4% for scir-
rhous HCC vs 66.7% for ICC) [35].
Mass-forming ICCs can exhibit various
atypical patterns. For example, some mass-
forming ICCs, especially small intrahepatic
ICCs, may show homogeneous hypervascu-
lar enhancement, and this feature might cor-
relate with a well-differentiated tumor with
vascular fibrotic stroma in the absence of re-
markable necrosis [36]. According to a pre-
vious CT-based study, the enhancement pat-
terns of ICC and HCC overlap for tumors
smaller than 3 cm in diameter [37]. There-
fore, small ICCs are often misdiagnosed as
HCCs in the cirrhotic liver [37]. According
to the Liver Imaging Reporting and Data
System (LI-RADS), ICC in the cirrhotic
liver should be assigned an LR-M category
(probably malignant, nonspecific for HCC)
[38]. However, differentiation between the
two types of tumors in the cirrhotic liver is
occasionally difficult because, unlike ICCs
in normal liver, ICCs in cirrhotic liver tend
to be smaller or show atypical prominent ar-
terial enhancement [39, 40]. Using the 2014
version of LI-RADS, one study showed that
approximately 80% of ICCs in the cirrhotic
liver or chronic hepatitis B were accurately
TABLE 2: Differences of Imaging Features Between Mass-Forming Intrahepatic Cholangiocarcinoma (ICC) and
Hepatocellular Carcinoma (HCC)
MRI Features Mass-Forming ICC
Dynamic pattern Rimlike peripheral arterial
enhancement and progressive
centripetal enhancement
Fat No
Capsule No
DWI Targetlike central hypointensity
with peripheral high signal
intensity
Hepatobiliary phase Hypo- or mixed hypointense
signal, sometimes target
appearance with peripheral
hypointense rim
Note—NA = not applicable, OATP = organic anionic transporter polypeptide.
AJR:209, August 2017 W67
categorized as LR-M on gadoxetate disodi- disodium–enhanced MRI to MRI with extra-
um–enhanced MRI [40]. In that study, 2.9– cellular contrast material for the diagnosis of
11.4% of ICCs were misassigned as LR-5/5v ICC has not been determined. Further stud-
(definitely HCC) [40]. Because management ies regarding this issue should be conducted.
and prognosis of these two types of tumors
are different, differentiation between ICC Imaging Features of Periductal Infiltrating
and HCC is essential in clinical practice. Intrahepatic Cholangiocarcinoma
Several imaging features can help in the Although the periductal infiltrating type
differentiation of ICC from HCC (Table is the most common type of hilar cholangio-
2). Imaging features, including a lobulated carcinoma, this type is rare among ICCs [5].
shape, rim enhancement during the arterial Combined periductal infiltrative and mass-
phase, and a target appearance with a periph- forming tumors are more common than pure
eral hyperintense rim on DWI favor ICC over periductal infiltrative tumors in the periph-
HCC [33–35, 41, 42]. On the other hand, MRI ery of the liver [25]. Periductal infiltrating
findings, such as intralesional fat, diffuse hy- tumors extend along the bile duct wall and
perintensity on unenhanced T1-weighted cause bile duct narrowing and dilatation with
imaging, nodule-in-nodule appearance, and tumor progression. This tumor type tends to
capsular appearance during the portal ve- spread along the bile duct toward the porta
nous or transitional phase are suggestive of hepatis via the perineural tissue and lym-
HCC rather than ICC [33, 41, 43]. Hepatobili- phatic vessels of the Glisson sheath [6]. On
ary phase imaging of gadoxetate disodium– CT and MRI, this type of tumor appears
enhanced MRI provides additional value in as an area of periductal thickening and in-
the differentiation between ICC and HCC creased enhancement; the appearance is at-
[33, 42]. On hepatobiliary phase images, tributable to tumor infiltration with irregu-
75.0–85.7% of ICCs showed a multilayered lar bile duct narrowing and proximal ductal
pattern with hypointense rim, whereas HCCs dilatation [25]. On contrast-enhanced CT,
typically showed homogeneous hypointensi- approximately 80% of periductal infiltrat-
ty [33, 42]. In addition, although only 5–12% ing ICCs appear as hyperattenuation relative
of HCCs exhibit diffuse hyperintensity in the to the liver parenchyma during both hepatic
hepatobiliary phase, this feature rarely oc- arterial and portal venous phase scans [44].
curs in ICC, so the presence of this feature This strong enhancement of periductal infil-
favors a diagnosis of HCC over ICC [38, 41, trating ICC can be attributed to tumor inva-
43]. However, the superiority of gadoxetate sion of the bile duct wall and involvement of
Corresponding Pathology
HCC ICC HCC
Arterial phase Abundant tumor cells at the Increased unpaired artery and
­hyperenhancement and periphery and fibrous stroma decreased portal blood flow
washout in portal or delayed or necrosis in the center of the
phase ICC
Intralesional fat NA Fat accumulation within
hepatocytes during early
phases of hepatocarcinogen-
esis
Enhancing capsular appearance NA Fibrous capsule, sinusoidal
on portal venous phase dilatation in progressed HCC, or
both
Homogeneous or heterogeneous High cellular and vascular tumor Rare central fibrosis except for
diffusion restriction cells at peripheral portion and scirrhous HCC
fibrosis or necrosis at the
central area
Usually homogeneous or Tumor with abundant central Rare central fibrosis except for
heterogeneous hypointensity, stromal fibrosis scirrhous HCC. The signal
sometimes hyper- or intensity on hepatobiliary
isointensity phase is mainly determined by
OATP expression

the adjacent periductal blood vessels, which
provides an abundant vascular supply [44].
Early-stage periductal infiltrating ICCs are
difficult to detect on imaging studies because
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it is difficult to differentiate between such le-
sions and benign strictures. Longer segment
of stricture, thicker involvement, asymmetric
and irregular luminal narrowing, prominent
ductal enhancement, periductal soft-tissue
lesions, and lymph node enlargement sug-
gest a periductal infiltrating ICC rather than
a benign stricture [45]. IgG4–related scle-
rosing cholangitis (SC), one of several be-
nign biliary diseases, can mimic periductal
infiltrating ICC if it presents with prominent
bile duct wall thickening. Imaging features
that favor periductal infiltrating ICC over
­IgG4-SC include a solitary lesion with irreg-
ular eccentric wall thickening, marked wall
thickening (> 3 mm) and contrast enhance-
ment, and an invisible involved bile duct lu-
men [46]. In patients with an inconclusive di-
agnosis, steroid therapy may be attempted in
selected patients for diagnosis and treatment
of IgG4-SC [47].
Imaging Features of Intraductal Growing
Intrahepatic Cholangiocarcinoma
Intraductal growing ICC, the rarest ICC
subtype, exhibits a growth pattern of super-
ficial mucosal spreading; these tumors grow
slowly and may manifest as tumor multi-
plicity or skip lesions [48]. The key imaging
features of intraductal growing ICC include
segmental or diffusely dilated bile ducts,
with or without polypoid or papillary tumors
[14] (Fig. 4). On unenhanced CT images, an
intraductal tumor appears as a hypo- or iso-
attenuating mass compared with the sur-
rounding hepatic parenchyma [25]. After IV
contrast injection, intraductal tumors exhibit
enhancement, whereas the majority of these
tumors appear as hypoattenuating masses
compared with the liver parenchyma [44].
Because intraductal growing ICC is usually
confined to the bile duct mucosa with small
fibrovascular stalks, this type of ICC may
show faint contrast enhancement when com-
pared with the other two ICC subtypes [44,
48]. In some cases, only prominent intrahe-
patic bile duct dilatation, without an intra-
ductal mass or stricture, may be seen because
of bile flow disruption from the large amount
of mucin [14, 25].
Intraductal growing ICC should be differ-
entiated from an intrahepatic bile duct stone.
An intrahepatic duct stone appears as a hy-
perattenuating lesion on unenhanced CT and
W68 AJR:209, August 2017
Seo et al.
lacks contrast enhancement, whereas an in-
traductal tumor appears as an enhancing
mass with asymmetric wall thickening of the
adjacent bile duct [49]. In addition, HCC with
bile duct invasion can simulate an intraduct-
al growing ICC. Imaging features, such as a
hepatic parenchymal mass contiguous with
the bile duct, hyperattenuated intraductal le-
sion during the hepatic arterial phase, and
the presence of a fibrous capsule or pseudo-
capsule, suggest HCC with bile duct invasion
rather than intraductal growing ICC [50]. In
addition, these two types of intraductal tu-
mors exhibit different enhancement patterns
on dynamic CT. Intraductal growing ICC ex-
hibits progressive enhancement during the
hepatic arterial and portal venous phases,
whereas HCC with bile duct invasion exhib-
its strong enhancement during the hepatic
arterial phase and steady enhancement (sim-
ilar degree of enhancement during the he-
patic arterial phase) during the portal venous
phase [50]. Contrast material washout during
the portal venous phase was more frequent-
ly observed in HCCs with bile duct invasion
(42.9%) than in intraductal growing ICCs
(11.2%) [50] (Fig. 5).
Prognostic Implications of
Imaging Findings
Gross Morphology and Prognosis of
Intrahepatic Cholangiocarcinoma
Significant associations of morphologic
subtypes and tumor spread patterns with pa-
tient prognosis have been reported [48, 51,
52]. Intraductal growing ICCs are associated
with the best prognosis, followed by periduc-
tal infiltrating and mass-forming ICCs [52,
53]. Intraductal growing ICCs frequently ex-
hibit a superficial mucosal spread and do not
extend deeply into the submucosal layer [52,
53]. Therefore, a tumor-free resection margin
is sufficient in cases of intraductal growing
ICCs and results in long-term patient survival
[51]. In contrast, mass-forming or periductal
infiltrating ICCs commonly exhibit submuco-
sal or perineural extension along the bile duct
[6, 44]. Because mass-forming ICCs typically
invade the hepatic parenchyma via the portal
venous system and often invade the adjacent
portal vein, this tumor type is associated with
a poor clinical outcome [5, 6, 53].
Prominent Arterial Enhancement
Prominent arterial enhancement might re-
flect favorable surgical outcomes in patients
with mass-forming ICC [54, 55]. Mass-form-
ing ICC rarely exhibits arterial hypervas-
cularity on CT [29, 36, 55] (Fig. 6). In par-
ticular, because chronic viral hepatitis and
liver cirrhosis have recently been recognized
as important ICC risk factors, small ICCs
with marked arterial enhancement through-
out the tumor have been reported in patients
with chronic liver disease or cirrhosis [37,
54, 55]. Histopathologically, ICC hypervas-
cularity correlates with the presence of abun-
dant tumor cells and sparse interstitial fibro-
sis [36]. According to a previous study, 17.9%
(25/140) of patients with mass-forming ICCs
exhibited hypervascularity on arterial phase
CT; these patients had a significantly higher
5-year survival rate relative to patients with
hypovascular ICC (86% vs 27%) [54]. Hy-
pervascular ICCs were smaller and exhibit-
ed less portal vein invasion and intrahepat-
ic metastasis relative to hypovascular ICC;
accordingly, these less invasive histopatho-
logic characteristics of hypervascular ICC
might be associated with better surgical out-
comes [54]. Early arterial ICC enhancement
was more frequently associated with chron-
ic viral hepatitis, well-differentiated tumors,
lower TNM stage, and better disease-free or
overall survival [56]. In a previous study of
gadoxetate disodium–enhanced MRI, well-
differentiated tumors showed greater en-
hancement during the hepatobiliary phase
than did moderately or poorly differentiated
mass-forming ICCs [30].
Delayed Enhancement
CT and MRI features reflective of stro-
mal fibrosis may be predictive of progno-
sis [31, 57, 58]. Patients with scirrhous car-
cinoma, characterized by extensive fibrosis
with scanty tumor cell infiltration, in many
organs (e.g., stomach, colon, and breast) are
known to have a very poor prognosis [59,
60]. Likewise, a pathologic study by Kajiya-
ma et al. [61] found that scirrhous ICC with
a > 70% scirrhous area that has fibrous stro-
ma amount greater than that of tumor cells
is associated with frequent lymphatic perme-
ation, perineural invasion, and a significant-
ly lower survival, compared with those with
nonscirrhous ICC. On CT, the degree of de-
layed or prolonged hepatic tumor enhance-
ment is known to correspond to the pres-
ence of fibrotic stroma in hepatic tumors,
including ICCs [62]. Thus, delayed enhance-
ment of an ICC on CT might be a prognos-
tic factor. Using this assumption, Asayama et
al. [57] found that the degree of delayed en-
hancement on CT could be a reliable prog-
nostic factor in patients with mass-forming
 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma
ICC [57]. In that study, delayed CT images
were obtained 4–6 minutes after contrast in-
jection. ICCs with more than two-thirds de-
layed enhancement were found to have more
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fibrous stroma during pathologic evaluation
and exhibited more frequent perineural inva-
sion and a poorer survival rate after surgery
than did those with small areas of delayed
enhancement [57].
On gadoxetate disodium–enhanced MR
images, the degree of enhancement dur-
ing the hepatobiliary phase also reflects the
amount of fibrous stroma and thus could be
a prognostic factor in patients with mass-
forming ICC [31, 58]. As mentioned in the
discussion regarding the imaging findings
of mass-forming ICC sections, intermediate
or high signal intensity during the hepatobi-
liary phase reflects retained contrast materi-
al in the fibrous stroma; therefore, a greater
degree of enhancement during the hepatobi-
liary phase indicates more abundant fibrous
stroma [30, 31, 58] (Fig. 7). Two published
studies regarding enhancement during the
hepatobiliary phase and postsurgical prog-
nosis have reported discordant results [31,
58]. Koh et al. [58] found that mass-forming
ICCs with > 50% intermediate signal inten-
sity during the hepatobiliary phase had more
abundant fibrous stroma and were associat-
ed with a shorter survival time and time to
recurrence relative to ICCs with hypointen-
sity during the hepatobiliary phase [58]. On
the other hand, another study of gadoxetate
disodium–enhanced MRI found that higher
enhancement during the hepatobiliary phase
was associated with moderate tumor differ-
entiation and fewer lymph node metastases,
suggesting the possibility of a better outcome
relative to hypointense tumors. However, the
authors of the latter study did not directly
evaluate the correlation between signal in-
tensity during the hepatobiliary phase and
patient survival [31]. The results of the study
by Koh et al. are consistent with those of a
previous study of CT [57].
Discussion
The concept of new pathologic subclassifi-
cation and potential candidate cells of the ori-
gin of peripheral small duct ICCs has been
addressed. However, because the concept of
cancer stem cells of peripheral small duct
ICCs is not yet widely accepted among pa-
thologists, controversies persist. In fact, the
concept of cancer stem cells at the interlob-
ular bile ducts or canals of Hering overlaps
the cancer stem cell theory of combined he-
AJR:209, August 2017 W69
patocellular-cholangiocarcinoma. Hepatic
progenitor or stem cells in bile ductules, ca-
nals of Hering, or both can differentiate into
either hepatocytes or cholangiocytes. Many
features of peripheral small duct ICC resem-
ble those of combined hepatocellular-cholan-
giocarcinoma with stem cell features. Cardi-
nale et al. [12] suggested that peripheral small
duct ICC can be derived from hepatic progen-
itor cells in the small bile duct or transform
from combined hepatocellular-cholangiocar-
cinoma with stem cell features. Another study
suggested that histologic features of combined
hepatocellular-cholangiocarcinoma are simi-
lar to those of peripheral small duct ICCs,
and the pattern of combined hepatocellular-
cholangiocarcinoma presumably represents a
well-differentiated or low-grade histology of
peripheral small duct ICCs [11]. Therefore,
peripheral small duct ICC and combined he-
patocellular-cholangiocarcinoma may repre-
sent a spectrum of diseases sharing hepatic
progenitor or stem cell origins. Further stud-
ies are needed to prove this hypothesis.
Conclusion
New pathologic concepts suggest that
ICCs can be classified as perihilar large
duct and peripheral small duct types. These
two types exhibit different pathologic fea-
tures and cholangiocarcinogenic pathways.
ICC imaging features, determined using ad-
vanced MRI technologies such as gadoxetate
disodium–enhanced MRI and DWI, have
been discussed with radiologic-patholog-
ic correlations. Some preoperative imaging
findings, such as prominent arterial enhance-
ment or delayed enhancement, may be prog-
nostic factors of ICC.
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(Figures start on next page)
 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma
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A B

C D
Fig. 1—66-year-old man with intraductal papillary neoplasm of bile duct (IPNB).
A, Coronal CT image obtained in portal venous phase reveals diffuse dilatation of both intrahepatic and extrahepatic bile ducts without demonstrable
obstructive lesion at ampulla level.
B, T2-weighted turbo spin-echo image shows marked dilatation of bile duct with asymmetric prominent dilatation in segment III of liver (arrow). Note
intraductal hypointense striations in segment III bile duct (arrowheads); this thread sign favors diagnosis of IPNB.
C, Two-dimensional MRCP shows diffuse disproportional biliary dilatation without obstructive lesion. Note patent ampulla of Vater (arrowhead).
D, Percutaneous transhepatic cholangioscopic image reveals thick mucus in left intrahepatic bile duct and papillary mucosa in segment III bile duct
(arrows).

AJR:209, August 2017 W71

 Seo et al.
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Fig. 2—Progression model of intrahepatic cholangiocarcinoma (ICC). This figure shows different modes of histologic progression according to pathologic
subclassification. Perihilar large duct ICCs might originate from peribiliary glands, and chronic inflammation can induce biliary intraepithelial neoplasia (BilIN) or
intraductal papillary neoplasm of bile duct (IPNB). BilIN or IPNB can progress to periductal infiltrating or intraductal growing ICCs, which may exhibit combined features
of mass-forming ICC on invasion of surrounding liver parenchyma. Regarding peripheral small duct ICCs, interlobular bile ducts or canals of Hering are candidate cells of
origin, and chronic liver disease and liver cirrhosis might affect carcinogenesis of these tumors. Carcinogenesis of peripheral small duct ICC has not yet been established.
Peripheral small duct ICCs usually manifest as mass-forming ICCs. (Illustration by Choi JY)

Fig. 3—66-year-old man with mass-forming

intrahepatic cholangiocarcinoma.
A, T1-weighted 3D gradient-recalled echo image
obtained in arterial phase show lobulated mass with
peripheral enhancement (arrows) in right hepatic
lobe.
B, Transitional phase T1-weighted image obtained at
3 minutes depicts gradual centripetal enhancement
of hepatic mass (arrowheads).
A B (Fig. 3 continues on next page)

W72 AJR:209, August 2017

 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma

Fig. 3 (continued)—66-year-old man with mass-

forming intrahepatic cholangiocarcinoma.
C and D, DW image (b = 800 s/mm2) (C) and apparent
diffusion coefficient map (D) show targetlike diffusion
restriction (arrows) of hepatic mass.
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C D

A B C

Fig. 4—75-year-old woman with intraductal growing intrahepatic

cholangiocarcinoma (ICC).
A and B, Unenhanced (A) and portal venous phase (B) axial CT images reveal
dilated right posterior bile duct with multifocal intraductal enhanced soft-tissue
lesions (arrowheads, B). Intraductal lesions appear as areas of hypoattenuation
compared with surrounding liver parenchyma on both CT images.
C, T2-weighted turbo spin-echo image shows marked dilatation of right posterior
bile duct with multiple filling defects, which suggest intraductal growing tumors
(arrowheads). Ill-defined hyperintense lesion adjacent to dilated bile ducts is likely
abscess (arrow).
D, Photograph of gross specimen reveals numerous intraductal papillary tumors
within dilated bile ducts (arrowheads). Histologic examination confirmed well-
differentiated intraductal growth ICC. Note abscess formation in adjacent liver
parenchyma (arrow).
D

AJR:209, August 2017 W73

 Seo et al.
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A B
Fig. 5—76-year-old man with hepatocellular carcinoma (HCC) with bile duct invasion.
A, T1-weighted 3D gradient-recalled echo image obtained in arterial phase shows
hyperenhanced mass (arrows) extending through right anterior bile duct.
B, On portal venous phase image, tumor exhibited washout (arrows). Dilatation of
both intrahepatic bile ducts (arrowheads) is likely due to hilar duct involvement by
tumor.
C, Photograph of gross specimen reveals intraductal tumors and parenchymal
mass that were histologically confirmed as HCC with bile duct invasion.

A B C
Fig. 6—74-year-old woman with hypervascular mass-forming intrahepatic cholangiocarcinoma.
A, Gadoxetate disodium–enhanced T1-weighted 3D gradient-recalled echo image obtained in arterial phase depicts hypervascular mass with ill-defined left border
(arrows) in left hepatic lobe.
B, Portal venous phase image shows hypointense nodule (arrows), mimicking enhancement pattern of hepatocellular carcinoma.
C, Hepatobiliary phase image acquired 20 minutes after injection shows homogeneous hypointensity in nodule (arrows).

W74 AJR:209, August 2017

 Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma

Fig. 7—63-year-old man with mass-forming

intrahepatic cholangiocarcinoma with delayed
enhancement.
A, Gadoxetate disodium–enhanced T1-weighted
3D gradient-recalled echo image obtained in
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arterial phase reveals lobulated mass with irregular

peripheral enhancement (arrows) in segment VI of
liver.
B, Hepatobiliary phase image obtained 20 minutes
after injection depicts more than 50% hyperintensity
(arrowheads) in mass.

A B

AJR:209, August 2017 W75