Review
Gastrointestinal Imaging
June 1, 2017

Cross-Sectional Imaging of Intrahepatic Cholangiocarcinoma: Development, Growth, Spread, and Prognosis

Abstract

OBJECTIVE. Intrahepatic cholangiocarcinoma (ICC) is a malignant tumor that arises from the intrahepatic bile ducts. Although the pathologic and imaging features of ICC have been clearly identified, recent updates have addressed the pathologic classification and imaging features of ICC using new imaging techniques. First, a proposed new pathologic ICC subclassification includes perihilar large duct and peripheral small duct ICCs. Second, advanced MR-based imaging features of ICC, such as hepatobiliary phase imaging using hepatocytespecific 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 accurate diagnosis and could facilitate prediction of clinical outcomes for patients with ICC.
Intrahepatic cholangiocarcinoma (ICC), which accounts for approximately 5–10% of all cholangiocarcinomas, is the second most common type of primary hepatic malignancy. This article discusses key concepts and recent advances in understanding of ICC development, growth, and spread, and emphasizes 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 [13]. 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 diameter [5]. The majority manifest as well-defined lobulated masses with varying degrees of central sclerotic changes [1]. Multicentricity around the main tumor is common, probably because mass-forming ICC commonly invades the adjacent portal vein branches [5, 6]. Periductal infiltrating tumors extend longitudinally along the bile ducts and cause bile duct wall thickening [2, 4]. Progressive periductal invasion causes luminal stenosis and proximal biliary dilatation [1]. Although periductal infiltrating type is the most common type of hilar cholangiocarcinoma, it is much less common in ICC, constituting approximately 16% of ICCs [2, 4, 5]. Intraductal growing ICC is the rarest type of ICC (approximately 6%) and presents as a papillary tumor within the dilated bile duct lumen; this type shares morphologic features with intraductal 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 produces a large amount of mucin, causing partial biliary obstruction [79]. ICCs arising from the intrahepatic small bile ducts, bile ductules, 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 intraductal growing type combined with the mass-forming type. However, each of the three gross morphologic types may coexist in individual cases. Table 1 summarizes the clinicopathologic and radiologic findings of ICC according to morphologic subtype.
TABLE 1: Clinicopathologic and Radiologic Findings of Intrahepatic Cholangiocarcinoma (ICC) According to Morphologic Subtype
Gross MorphologyEnhancementPathologic Correlation of Enhancement PatternAncillary FeaturesDifferential DiagnosisPrognosis
Mass-formingHypoattenuated or hypointense mass with peripheral arterial enhancement and gradual centripetal enhancementAbundant tumor cells at the periphery and fibrous stroma, necrosis in the center of the ICCCapsular retraction, satellite nodules, peripheral bile duct dilatationHCC (in the setting of chronic liver disease), metastasis, hemangioma (vs mucinous type of ICC)Poor
Periductal infiltratingUsually hyperattenuation or hyperintensity compared with the surrounding liver in hepatic arterial and portal venous phasesInfiltrative tumor with frequent perineural and lymphatic invasionIrregular narrowing of involved bile ducts, proximal bile duct dilatationIgG4-related sclerosing cholangitis, other benign cause of biliary strictureModerate
Intraductal growingHypoattenuation or hypointensity (only faint contrast enhancement) compared with the surrounding liverPapillary tumor within the bile duct confined to mucosal surface with small fibrovascular stalkSegmental or diffusely dilated bile ducts with or without polypoid or papillary intraductal tumorsIntrahepatic bile duct stoneGood

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 adenocarcinomas with or without micropapillary structures and exhibit varying degrees of stromal fibrosis [3]. Histologic variants of ICCs include adenosquamous and squamous carcinoma, mucinous carcinoma, signet-ring cell carcinoma, clear cell carcinoma, mucoepidermoid carcinoma, lymphoepithelioma-like carcinoma, and sarcomatous ICC [3].
ICC can also be classified into two types according to the site of involvement and histologic 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 explain the different location, background condition, postulated cell of origin, premalignant lesions, clinical and genetic features between these two types of ICCs, and has the potential to predict prognosis [1, 11]. Perihilar 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]. Perihilar large duct ICCs are more likely to have ill-defined or infiltrating tumor margins and increased necrosis [1]. Perineural, vascular, and lymphatic invasion and lymph node metastases are more frequently associated with perihilar large duct ICCs than with peripheral small duct ICCs [1, 10].
In contrast, peripheral small duct ICCs exhibit 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 carcinoma or might originate from hepatic progenitor cells, because they are target cells for carcinogenesis in patients with chronic liver disease or liver cirrhosis. Such ICCs are usually of the mass-forming type and tend to be smaller at the time of detection [4]. Peripheral 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 stromal fibrosis, which is an important characteristic [3]. Tumor stromata actively and continuously provide support to tumor cells and contribute to cancer progression and invasion [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 diffuse arrangement of fibroblasts and collagenous 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 feature 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 lesions were proposed in the 2010 WHO classification: biliary intraepithelial neoplasia (BilIN), IPNB, and mucinous cystic neoplasm (MCN) [3]. Among these, two types of premalignant lesions—microscopic BilIN and grossly visible IPNB—were described in the development and progression of cholangiocarcinomas from intrahepatic large ducts [13]. However, to our knowledge, associations between these preneoplastic or dysplastic lesions and peripheral small duct ICCs have not been established [13]. Imaging modalities such as CT and MRI, including 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, conventional imaging studies are limited with respect to its detection [14].
BilIN is a microscopic change in the biliary epithelium characterized by the presence of abnormal epithelial cells with nuclear atypia and micropapillary projections into the bile duct [4, 15]. BilIN are graded as BilIN-1 (low-grade dysplasia), BilIN-2 (intermediate-grade dysplasia), or BilIN-3 (high-grade dysplasia) according to the degree of cellular and structural atypia [15]. These lesions represent a multistep carcinogenesis of cholangiocarcinoma. In terms of gross morphology, a BilIN may be a precursor lesion of periductal infiltrating ICC [4].
IPNB is a biliary neoplasm that encompasses the previous entities of biliary papilloma and papillomatosis. IPNB is characterized by the presence of dilated bile ducts with intraductal papillary or villous neoplasm that covers fine fibrovascular stalks [3]. Approximately one-third of IPNBs produce abundant mucin in the ductal lumen [16]. IPNB can be classified as low-, intermediate-, or high-grade intraepithelial dysplasia, according to the degree of cellular or nuclear and structural atypia [17]. IPNB is often associated with an invasive component and in such cases is described as IPNB with an associated invasive carcinoma. IPNB has recently been suggested as a precursor lesion in the dysplasia-carcinoma sequence and can progress to intraductal growing ICC [4]. On imaging studies, IPNB appears as a small flat or fungating mass within the dilated bile ducts [7, 9]. Compared with CT, MRI has benefits for the detection and characterization of IPNB [18]. In particular, MRCP can visualize the communication between the cystic lesion (dilated bile duct) and biliary tree, the intraductal tumors, and the whole biliary tree without missing ducts [19]. Intraductal tumors 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 observed, including the disproportional dilatation of segmental or lobar bile ducts, generalized dilatation, and aneurysmal dilatation [21]. Dilatation of the downstream bile duct consequent to mucin production is a characteristic feature of IPNB [19]. According to a recent study, intraductal linear or curvilinear hypointense striations (thread sign) can be observed with MRI in IPNBs; this sign is highly specific for IPNB [22] (Fig. 1).
Fig. 1A —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.
Fig. 1B —66-year-old man with intraductal papillary neoplasm of bile duct (IPNB).
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.
Fig. 1C —66-year-old man with intraductal papillary neoplasm of bile duct (IPNB).
C, Two-dimensional MRCP shows diffuse disproportional biliary dilatation without obstructive lesion. Note patent ampulla of Vater (arrowhead).
Fig. 1D —66-year-old man with intraductal papillary neoplasm of bile duct (IPNB).
D, Percutaneous transhepatic cholangioscopic image reveals thick mucus in left intrahepatic bile duct and papillary mucosa in segment III bile duct (arrows).

Mode of Histologic Progression of Intrahepatic Cholangiocarcinomas

Perihilar large duct ICCs and peripheral small duct ICCs may undergo different pathways of carcinogenesis and modes of histologic progression (Fig. 2). In cases of perihilar large duct ICCs, ICCs might originate from the peribiliary glands, and chronic inflammation can induce BilIN or periductal infiltrating ICC [1, 23]. Another possible carcinogenic pathway of perihilar large duct ICCs includes IPNB or intraductal growing ICC [1, 23]. These ICCs progress with invasion to the surrounding liver parenchyma and spread along the portal tracts, later exhibiting 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 liver cirrhosis have been hypothesized to affect the carcinogenesis of these tumors [24]. Early-stage peripheral small duct ICCs are associated with preserved portal tracts and cancer cell proliferation in the periportal area [10]. As peripheral small duct ICCs progress, distorted portal tracts within the tumor and solid growth of tumor may be observed [10]. Advanced peripheral small duct ICC often appears as extensive fibrotic scarring in the tumor center, with necrosis and intrahepatic metastasis [1].
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)

Imaging

Imaging Features of Mass-Forming Intrahepatic Cholangiocarcinoma

Mass-forming ICC usually appears as an irregular but well-defined mass and is frequently associated with peripheral biliary dilatation [25]. This type of tumor frequently invades the adjacent peripheral branches of the portal vein and thus generally extends to the hepatic parenchyma with multicentricity around the main tumor [6]. At later stages, mass-forming ICC invades the Glisson sheath and spreads via both the portal and lymphatic systems [6]. The typical CT finding of a mass-forming ICC is a hypoattenuated mass with irregular peripheral enhancement in the hepatic arterial phase and gradual centripetal enhancement on dynamic studies [5, 26]. This enhancement pattern can be explained histologically. The peripheral portion of ICCs contains abundant viable 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 studies [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 [2729]. The mass typically shows high signal intensity on T2-weighted imaging and low signal intensity on T1-weighted imaging. On dynamic contrast-enhanced MRI with extracellular contrast material, the mass also exhibits prominent peripheral rim enhancement with centripetal or gradual progressive enhancement [27, 29]. Recent reports have described the findings of mass-forming ICCs on gadoxetate disodium–enhanced MR images [30, 31]. The prominent rimlike arterial enhancement 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 between the portal venous and hepatobiliary phases) of gadoxetate disodium–enhanced MRI because of progressive enhancement of the background liver [30]. Most mass-forming ICCs do not take up hepatobiliary agents because of the absence of organic anionic transporter peptide expression; these tumors are thus hypointense in the hepatobiliary phase [31, 32]. However, mass-forming ICCs occasionally exhibit intermediate or mixed hyperintensity during the hepatobiliary phase because of contrast agent pooling in the fibrous stroma, which corresponds to a large extracellular space relative to normal tissue [3032]. According to a recent study, most mass-forming ICCs showed heterogeneous hypointensity with intermingled hyperintensity on hepatobiliary phase images rather than homogeneous hypointensity [31]. A target appearance during the hepatobiliary phase is more frequently associated with tumors with abundant central stromal fibrosis [30]. On DWI, 52–75% of mass-forming ICCs exhibit characteristic targetlike diffusion restriction at high b values [3335]. This target appearance on DWI is thought to be related to the histologic components of ICC, but identifying a perfect radiologic-pathologic correlation is difficult [30, 33, 34]. A central dark area on DWI may reflect fibrosis and necrosis of the tumor, whereas a peripheral restricted area on DWI might represent highly cellular and vascular tumor cells [30, 33, 34]. This target sign on DWI is also useful for distinguishing ICC from hepatocellular carcinoma (HCC) [33, 34]. According to one study to determine the MRI features that differentiate small (≤ 3 cm) mass-forming 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]. Similarly, 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 a target appearance on DWI, so differentiation of ICC from HCC using DWI may not always be simple. Furthermore, small (≤ 3 cm) scirrhous HCC with abundant fibrous stroma frequently exhibited a target appearance on DWI, similar to ICC (71.4% for scirrhous HCC vs 66.7% for ICC) [35].
Fig. 3A —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.
Fig. 3B —66-year-old man with mass-forming intrahepatic cholangiocarcinoma.
B, Transitional phase T1-weighted image obtained at 3 minutes depicts gradual centripetal enhancement of hepatic mass (arrowheads).
Fig. 3C —66-year-old man with mass-forming intrahepatic cholangiocarcinoma.
C, DW image (b = 800 s/mm2) (C) and apparent diffusion coefficient map (D) show targetlike diffusion restriction (arrows) of hepatic mass.
Fig. 3D —66-year-old man with mass-forming intrahepatic cholangiocarcinoma.
D, DW image (b = 800 s/mm2) (C) and apparent diffusion coefficient map (D) show targetlike diffusion restriction (arrows) of hepatic mass.
Mass-forming ICCs can exhibit various atypical patterns. For example, some mass-forming ICCs, especially small intrahepatic ICCs, may show homogeneous hypervascular enhancement, and this feature might correlate with a well-differentiated tumor with vascular fibrotic stroma in the absence of remarkable necrosis [36]. According to a previous CT-based study, the enhancement patterns of ICC and HCC overlap for tumors smaller than 3 cm in diameter [37]. Therefore, 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 arterial 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 categorized as LR-M on gadoxetate disodium–enhanced MRI [40]. In that study, 2.9–11.4% of ICCs were misassigned as LR-5/5v (definitely HCC) [40]. Because management and prognosis of these two types of tumors are different, differentiation between ICC and HCC is essential in clinical practice.
Several imaging features can help in the differentiation of ICC from HCC (Table 2). Imaging features, including a lobulated shape, rim enhancement during the arterial phase, and a target appearance with a peripheral hyperintense rim on DWI favor ICC over HCC [3335, 41, 42]. On the other hand, MRI findings, such as intralesional fat, diffuse hyperintensity on unenhanced T1-weighted imaging, nodule-in-nodule appearance, and capsular appearance during the portal venous or transitional phase are suggestive of HCC rather than ICC [33, 41, 43]. Hepatobiliary phase imaging of gadoxetate disodium–enhanced MRI provides additional value in the differentiation between ICC and HCC [33, 42]. On hepatobiliary phase images, 75.0–85.7% of ICCs showed a multilayered pattern with hypointense rim, whereas HCCs typically showed homogeneous hypointensity [33, 42]. In addition, although only 5–12% of HCCs exhibit diffuse hyperintensity in the hepatobiliary phase, this feature rarely occurs in ICC, so the presence of this feature favors a diagnosis of HCC over ICC [38, 41, 43]. However, the superiority of gadoxetate disodium–enhanced MRI to MRI with extracellular contrast material for the diagnosis of ICC has not been determined. Further studies regarding this issue should be conducted.
TABLE 2: Differences of Imaging Features Between Mass-Forming Intrahepatic Cholangiocarcinoma (ICC) and Hepatocellular Carcinoma (HCC)
MRI FeaturesMass-Forming ICCHCCCorresponding Pathology
ICCHCC
Dynamic patternRimlike peripheral arterial enhancement and progressive centripetal enhancementArterial phase hyperenhancement and washout in portal or delayed phaseAbundant tumor cells at the periphery and fibrous stroma or necrosis in the center of the ICCIncreased unpaired artery and decreased portal blood flow
FatNoIntralesional fatNAFat accumulation within hepatocytes during early phases of hepatocarcinogenesis
CapsuleNoEnhancing capsular appearance on portal venous phaseNAFibrous capsule, sinusoidal dilatation in progressed HCC, or both
DWITargetlike central hypointensity with peripheral high signal intensityHomogeneous or heterogeneous diffusion restrictionHigh cellular and vascular tumor cells at peripheral portion and fibrosis or necrosis at the central areaRare central fibrosis except for scirrhous HCC
Hepatobiliary phaseHypo- or mixed hypointense signal, sometimes target appearance with peripheral hypointense rimUsually homogeneous or heterogeneous hypointensity, sometimes hyper- or isointensityTumor with abundant central stromal fibrosisRare central fibrosis except for scirrhous HCC. The signal intensity on hepatobiliary phase is mainly determined by OATP expression

Note—NA = not applicable, OATP = organic anionic transporter polypeptide.

Imaging Features of Periductal Infiltrating Intrahepatic Cholangiocarcinoma

Although the periductal infiltrating type is the most common type of hilar cholangiocarcinoma, this type is rare among ICCs [5]. Combined periductal infiltrative and mass-forming tumors are more common than pure periductal infiltrative tumors in the periphery of the liver [25]. Periductal infiltrating tumors extend along the bile duct wall and cause bile duct narrowing and dilatation with tumor progression. This tumor type tends to spread along the bile duct toward the porta hepatis via the perineural tissue and lymphatic vessels of the Glisson sheath [6]. On CT and MRI, this type of tumor appears as an area of periductal thickening and increased enhancement; the appearance is attributable to tumor infiltration with irregular bile duct narrowing and proximal ductal dilatation [25]. On contrast-enhanced CT, approximately 80% of periductal infiltrating ICCs appear as hyperattenuation relative to the liver parenchyma during both hepatic arterial and portal venous phase scans [44]. This strong enhancement of periductal infiltrating ICC can be attributed to tumor invasion of the bile duct wall and involvement of 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 it is difficult to differentiate between such lesions 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 suggest a periductal infiltrating ICC rather than a benign stricture [45]. IgG4–related sclerosing cholangitis (SC), one of several benign 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 irregular eccentric wall thickening, marked wall thickening (> 3 mm) and contrast enhancement, and an invisible involved bile duct lumen [46]. In patients with an inconclusive diagnosis, 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 superficial mucosal spreading; these tumors grow slowly and may manifest as tumor multiplicity 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 surrounding 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 compared with the other two ICC subtypes [44, 48]. In some cases, only prominent intrahepatic bile duct dilatation, without an intraductal mass or stricture, may be seen because of bile flow disruption from the large amount of mucin [14, 25].
Fig. 4A —75-year-old woman with intraductal growing intrahepatic cholangiocarcinoma (ICC).
A, 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.
Fig. 4B —75-year-old woman with intraductal growing intrahepatic cholangiocarcinoma (ICC).
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.
Fig. 4C —75-year-old woman with intraductal growing intrahepatic cholangiocarcinoma (ICC).
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).
Fig. 4D —75-year-old woman with intraductal growing intrahepatic cholangiocarcinoma (ICC).
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).
Intraductal growing ICC should be differentiated from an intrahepatic bile duct stone. An intrahepatic duct stone appears as a hyperattenuating lesion on unenhanced CT and lacks contrast enhancement, whereas an intraductal 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 intraductal growing ICC. Imaging features, such as a hepatic parenchymal mass contiguous with the bile duct, hyperattenuated intraductal lesion during the hepatic arterial phase, and the presence of a fibrous capsule or pseudocapsule, suggest HCC with bile duct invasion rather than intraductal growing ICC [50]. In addition, these two types of intraductal tumors exhibit different enhancement patterns on dynamic CT. Intraductal growing ICC exhibits progressive enhancement during the hepatic arterial and portal venous phases, whereas HCC with bile duct invasion exhibits strong enhancement during the hepatic arterial phase and steady enhancement (similar degree of enhancement during the hepatic arterial phase) during the portal venous phase [50]. Contrast material washout during the portal venous phase was more frequently observed in HCCs with bile duct invasion (42.9%) than in intraductal growing ICCs (11.2%) [50] (Fig. 5).
Fig. 5A —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.
Fig. 5B —76-year-old man with hepatocellular carcinoma (HCC) with bile duct invasion.
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.
Fig. 5C —76-year-old man with hepatocellular carcinoma (HCC) with bile duct invasion.
C, Photograph of gross specimen reveals intraductal tumors and parenchymal mass that were histologically confirmed as HCC with bile duct invasion.

Prognostic Implications of Imaging Findings

Gross Morphology and Prognosis of Intrahepatic Cholangiocarcinoma

Significant associations of morphologic subtypes and tumor spread patterns with patient prognosis have been reported [48, 51, 52]. Intraductal growing ICCs are associated with the best prognosis, followed by periductal infiltrating and mass-forming ICCs [52, 53]. Intraductal growing ICCs frequently exhibit 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 submucosal 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 reflect favorable surgical outcomes in patients with mass-forming ICC [54, 55]. Mass-forming ICC rarely exhibits arterial hypervascularity on CT [29, 36, 55] (Fig. 6). In particular, because chronic viral hepatitis and liver cirrhosis have recently been recognized as important ICC risk factors, small ICCs with marked arterial enhancement throughout the tumor have been reported in patients with chronic liver disease or cirrhosis [37, 54, 55]. Histopathologically, ICC hypervascularity correlates with the presence of abundant tumor cells and sparse interstitial fibrosis [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]. Hypervascular ICCs were smaller and exhibited less portal vein invasion and intrahepatic metastasis relative to hypovascular ICC; accordingly, these less invasive histopathologic characteristics of hypervascular ICC might be associated with better surgical outcomes [54]. Early arterial ICC enhancement was more frequently associated with chronic 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 enhancement during the hepatobiliary phase than did moderately or poorly differentiated mass-forming ICCs [30].
Fig. 6A —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.
Fig. 6B —74-year-old woman with hypervascular mass-forming intrahepatic cholangiocarcinoma.
B, Portal venous phase image shows hypointense nodule (arrows), mimicking enhancement pattern of hepatocellular carcinoma.
Fig. 6C —74-year-old woman with hypervascular mass-forming intrahepatic cholangiocarcinoma.
C, Hepatobiliary phase image acquired 20 minutes after injection shows homogeneous hypointensity in nodule (arrows).

Delayed Enhancement

CT and MRI features reflective of stromal fibrosis may be predictive of prognosis [31, 57, 58]. Patients with scirrhous carcinoma, 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 Kajiyama et al. [61] found that scirrhous ICC with a > 70% scirrhous area that has fibrous stroma amount greater than that of tumor cells is associated with frequent lymphatic permeation, perineural invasion, and a significantly lower survival, compared with those with nonscirrhous ICC. On CT, the degree of delayed or prolonged hepatic tumor enhancement is known to correspond to the presence of fibrotic stroma in hepatic tumors, including ICCs [62]. Thus, delayed enhancement of an ICC on CT might be a prognostic factor. Using this assumption, Asayama et al. [57] found that the degree of delayed enhancement on CT could be a reliable prognostic factor in patients with mass-forming ICC [57]. In that study, delayed CT images were obtained 4–6 minutes after contrast injection. ICCs with more than two-thirds delayed enhancement were found to have more fibrous stroma during pathologic evaluation and exhibited more frequent perineural invasion 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 during 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 hepatobiliary phase reflects retained contrast material in the fibrous stroma; therefore, a greater degree of enhancement during the hepatobiliary phase indicates more abundant fibrous stroma [30, 31, 58] (Fig. 7). Two published studies regarding enhancement during the hepatobiliary phase and postsurgical prognosis have reported discordant results [31, 58]. Koh et al. [58] found that mass-forming ICCs with > 50% intermediate signal intensity during the hepatobiliary phase had more abundant fibrous stroma and were associated with a shorter survival time and time to recurrence relative to ICCs with hypointensity 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 differentiation 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 intensity 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].
Fig. 7A —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 arterial phase reveals lobulated mass with irregular peripheral enhancement (arrows) in segment VI of liver.
Fig. 7B —63-year-old man with mass-forming intrahepatic cholangiocarcinoma with delayed enhancement.
B, Hepatobiliary phase image obtained 20 minutes after injection depicts more than 50% hyperintensity (arrowheads) in mass.

Discussion

The concept of new pathologic subclassification and potential candidate cells of the origin 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 pathologists, controversies persist. In fact, the concept of cancer stem cells at the interlobular bile ducts or canals of Hering overlaps the cancer stem cell theory of combined hepatocellular-cholangiocarcinoma. Hepatic progenitor or stem cells in bile ductules, canals of Hering, or both can differentiate into either hepatocytes or cholangiocytes. Many features of peripheral small duct ICC resemble those of combined hepatocellular-cholangiocarcinoma with stem cell features. Cardinale et al. [12] suggested that peripheral small duct ICC can be derived from hepatic progenitor cells in the small bile duct or transform from combined hepatocellular-cholangiocarcinoma with stem cell features. Another study suggested that histologic features of combined hepatocellular-cholangiocarcinoma are similar to those of peripheral small duct ICCs, and the pattern of combined hepatocellularcholangiocarcinoma presumably represents a well-differentiated or low-grade histology of peripheral small duct ICCs [11]. Therefore, peripheral small duct ICC and combined hepatocellular-cholangiocarcinoma may represent a spectrum of diseases sharing hepatic progenitor or stem cell origins. Further studies 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 features and cholangiocarcinogenic pathways. ICC imaging features, determined using advanced MRI technologies such as gadoxetate disodium–enhanced MRI and DWI, have been discussed with radiologic-pathologic correlations. Some preoperative imaging findings, such as prominent arterial enhancement or delayed enhancement, may be prognostic factors of ICC.

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Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: W64 - W75
PubMed: 28570102

History

Submitted: June 8, 2016
Accepted: November 19, 2016
Version of record online: June 1, 2017

Keywords

  1. CT
  2. intrahepatic cholangiocarcinoma
  3. MRI
  4. prognosis

Authors

Affiliations

Nieun Seo
Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.
Do Young Kim
Department of Internal Medicine, Yonsei Liver Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Jin-Young Choi
Department of Radiology, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea.

Notes

Address correspondence to J. Y. Choi ([email protected]).

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