HEPATOBILIARY-PANCREAS

Intrahepatic mass-forming cholangiocarcinoma: prognostic valueof preoperative gadoxetic acid-enhanced MRI

Jieun Koh1& Yong Eun Chung1 & Ji Hae Nahm2

& Ha Yan Kim3& Kyung-Sik Kim4

&

Young Nyun Park2& Myeong-Jin Kim1

& Jin-Young Choi1

Received: 29 September 2014 /Revised: 11 May 2015 /Accepted: 12 May 2015 /Published online: 23 May 2015# European Society of Radiology 2015

AbstractObjectives To assess whether gadoxetic acid-enhanced MRIcould be used as a prognostic factor for intrahepatic mass-forming cholangiocarcinomas (IMCCs).Methods Forty-one patients with pathologically proven IMCCswho underwent preoperative gadoxetic acid-enhancedMRIwereincluded. The signal intensity of the IMCCs on hepatobiliaryphase (HBP) MRI was qualitatively analyzed by two radiolo-gists, and categorized into intermediate or hypointense groups.Analysis of clinicopathological prognostic factors and correla-tions of imaging and histology were also performed. Survivaltime and time to recurrence (TTR) were analyzed.Results Of the 41 IMCCs, 23 were in the intermediate groupand 18 were in the hypointense group on HBP MRI. IMCCsin the intermediate group were associated with shorter surviv-al time (P=0.048) and TTR (P=0.002) than the IMCCs of thehypointense group. Only the intermediate group on HBPMRIhad a significantly shorter TTR on multivariate analysis(P=0.012). The IMCCs of the intermediate group showed atendency for more abundant tumour fibrous stroma than thoseof the hypointense group (P=0.027).

Conclusions The enhancement of IMCCs on HBP gadoxeticacid-enhanced MRI appears to correlate with tumour aggres-siveness and outcomes due to the tumour fibrous stromal com-ponent. Thus, HBP images could be a useful prognostic factorfor IMCCs after surgery.Key points• The enhancement of IMCCs on HBP correlates with thetumour fibrous stroma.

• The enhancement of IMCCs on HBP MRI appears to corre-late with prognosis.

•Gadoxetic acid-enhancedMRI is helpful for predicting prog-nosis of IMCCs after surgery.

Keywords Intrahepatic cholangiocarcinoma .MRI .Contrastagent . Prognosis . Gadoxetic acid

AbbreviationsIMCC Intrahepatic mass-forming cholangiocarcinomaHBP Hepatobiliary phaseTTR Time to recurrenceGRE Gradient echoADC Apparent diffusion coefficientSI Signal intensitySNR Signal-to-noise ratioCNR Contrast-to-noise ratioICG 15 Indocyanine green 15AFP Alpha-fetoproteinCA 19-9 Carbohydrate antigen 19-9CEA Carcinoembryonic antigenPIVKA-II Proteins induced by vitamin K absence or

antagonist-IIAJCC American Joint Committee on Cancer

* Jin-Young Choigafield2@gmail.com

1 Department of Radiology, Research Institute of RadiologicalScience, Yonsei University, College of Medicine, 50 Yonsei-ro,Seodaemun-gu, 120-752 Seoul, Korea

2 Department of Pathology, Yonsei University, College of Medicine,Seoul, Korea

3 Biostatistics Collaboration Unit, Severance Hospital, YonseiUniversity, College of Medicine, Seoul, Korea

4 Department of General Surgery, Yonsei University, College ofMedicine, Seoul, Korea

Eur Radiol (2016) 26:407–416DOI 10.1007/s00330-015-3846-5

Introduction

Cholangiocarcinoma arises from the ductular epithelium ofthe biliary tree [1], and can be classified into three types ac-cording to growth characteristics: mass-forming, periductal-infiltrating, and intraductal-growing [2, 3]. Approximately5–10 % of cholangiocarcinomas arise from the intrahepaticbile duct [4], most of which are the mass-forming type [5].Intrahepatic mass-forming cholangiocarcinoma (IMCC) oftenspreads along the microvessel system, leading to intrahepaticmetastasis and decreased long-term survival [6, 7]. Surgery isthe only curative treatment modality for IMCC [1, 8], and the5-year survival rate remains low, at less than 5 % [9]. Previousstudies have reported several prognostic factors for IMCC,including lymph node metastasis, curative resection, tumourstage, vascular invasion, intrahepatic metastasis, and preoper-ative tumour markers [7, 10, 11].

There have been a few reports indicating that the imagingfindings of IMCC correlate with prognosis [12–15]. IMCCswith abundant tumour fibrous stroma, defined as “scirrhoustype”, exhibit a delayed enhancement area on CT, which cor-relates with poor prognosis [12]. In one study, the enhance-ment patterns of IMCCs on gadoxetic acid-enhanced MRIappeared to be related to the extent of stromal fibrosis, andIMCCs showing a target appearance on hepatobiliary phase(HBP) MRI were associated with central stromal fibrosis [16].In another study, the relative enhancement of IMCC on theHBP correlated with histological differentiation, showinghigher enhancement in moderately differentiated than in poor-ly differentiated tumours. In addition, tumours with higherenhancement on HBP were correlated with fewer lymph nodemetastases [17]. Therefore, we hypothesized that the enhance-ment pattern and degree of IMCC on HBPMRI may correlatewith the amount of tumour fibrous stroma, possibly affectingprognosis. The aim of this study was to assess whethergadoxetic acid-enhanced MRI could be used as a prognosticfactor for IMCCs.

Materials and methods

The institutional review board approved this retrospectivestudy, with a waiver of informed consent.

Study population

We searched the electronic medical record database fromJanuary 2008 to March 2013 using the following search pa-rameters: 1) a diagnosis of “intrahepatic cholangiocarcino-ma”, 2) patients who were scheduled for hepatectomy, and3) patients who underwent preoperative gadoxetic acid-enhanced MRI. Initially, 185 patients were included. Patientswithout mass-forming intrahepatic cholangiocarcinoma (n=

144), such as Klatskin tumour or periductal infiltrating type,were excluded, and a total of 41 patients were included in thisstudy (mean age, 62.2 years, range 36–79 years; 25 men, 16women).

MRI protocol

A magnetic strength of 3 T was used for 35 patients(Magnetom Trio a Tim, Siemens Medical Solutions,Erlangen, Germany, n=15; Achieva; Philips MedicalSystems, Best, the Netherlands, n=18; Discovery, GEMedical Systems, Milwaukee, Wisconsin, USA, n=2), while1.5 Twas used for six patients (Achieva 1.5 T, PhilipsMedicalSystems, Best, the Netherlands, n=4; Magnetom Vision,Siemens Medical Solutions, Erlangen, Germany, n=2). A sin-gle dedicated body phased-array coil was applied anteriorlyand spine array coils were applied posteriorly.

After localizing, in-phase (repetition time [TR]/effectiveecho time [TE]/flip angle [FA], 150–192 ms/2.30 and2.46 ms/65–80° for 3T, 167 ms/2.30 ms/80° for 1.5T) andopposed-phase (TR/TE/FA 150–192 ms/1.14 and 1.23 ms/65–80° for 3T, 167 ms/4.60 ms/80° for 1.5T) images wereobtained using two-dimensional dual-echo breath-hold T1-weighted spoiled gradient echo (GRE) with a matrix of256×192 or 256×256, 7-mm slice thickness, and a 0.7–1-mm gap. A navigator-triggered T2-weighted turbo spin-echosequence (2923–5371 ms/73–88 ms; flip angle, 140–150°;matrix, 256×192 or 302×202; slice thickness, 5 or 4 mm;section gap, 1 mm) and a breath-hold, heavily T2-weightedturbo spin-echo image (450–470ms/96–190ms; flip angle, 90or 150°; matrix, 256×192 or 320×179; slice thickness, 4 mm;section gap, 1 mm) were sequentially obtained. Dynamic im-ages were acquired using three-dimensional T1-weightedspoiled GRE sequence with chemically selective fat suppres-sion (3.3–4.48 ms/1.16–2.19 ms; flip angle, 13–15°; matrix,320×224 or 256×256; slice thickness, 2.5 mm; zero intersec-tion gap) at 25–35 s (arterial phase), 55–65 s (portal phase),85–95 s (transitional phase), and 15–20 min (hepatobiliaryphase) after a bolus injection of gadoxetic acid (Primovist,Bayer Schering Pharma, Berlin, Germany) at 0.025 mmol/Kg body weight, followed by a saline flush of 15–20 mL atan injection rate of 2 mL/s, and acquisition duration was 15 sfor each sequence. Diffusion-weighted images (1500–6100 ms/44–70 ms; echo train length, 57 or 108; slice thick-ness and gap, 5/1 mm;matrix, 192×108 or 124×124, b-valuesof 50 s/mm2, 400 s/mm2, and 800 s/mm2) were also obtained,and apparent diffusion coefficient (ADC) maps were createdfrom the diffusion-weighted images.

Image interpretation

Two abdominal imaging radiologists (J.Y.C. and Y.E.C., with13 and 7 years of experience, respectively) retrospectively and

408 Eur Radiol (2016) 26:407–416

qualitatively analysed the preoperative MR images andachieved consensus. A tumour was categorized in the inter-mediate group when there were more than 50 % hyper- orisointense areas as compared to the spleen, and it was catego-rized in the hypointense group when there was less than 50 %hyper- or isointensity as compared to the spleen on visualinspection on hepatobiliary phase; equivocal cases wereassessed using region-of-interest signal intensity measure-ments [18, 19]. On dynamic study images, tumours were cat-egorized as hypovascular when the tumour had less than two-thirds arterial enhancement or peripheral rim enhancement,and as hypervascular when there was more than two-thirdsarterial enhancement. The temporal enhancement patternwas also analyzed [17]. The two radiologists were blinded toall clinical history as well as laboratory and pathology reports.For quantitative image analysis, regions of interest weredrawn by one radiology resident (J.E.K.) measuring the signalintensity (SI) of the whole tumour area at the level of thelargest tumour area on hepatobiliary phase. The signal-to-noise ratios (SNRs) of the liver and the tumour were calculat-ed as follows: liver SNR=liver SI/SD of background noise,and tumour SNR=tumour SI/SD of background noise. Thecontrast enhancement ratio and contrast-to-noise ratio (CNR)of the tumour were calculated as follows: tumour contrastenhancement ratio=[(enhanced tumour SNR−unenhanced tu-mour SNR)/unenhanced tumour SNR] × 100, andCNR=(tumour SI− liver SI)/SD of background noise [20].On ADC maps, regions of interest were drawn by the sameradiology resident onto the largest tumour area.

Patient characteristics

The level of serum CEAwas below 2.5 ng/mL in 16 patientsand was equal to or above 2.5 ng/mL in 19 patients. Otherpatient characteristics, including laboratory data, are presentedin Table 1. Four patients had underlying liver cirrhosis.Preoperative concurrent chemoradiotherapy or chemotherapywas performed for seven patients. There was no further post-operative treatment for 25 patients, and the remaining patientsreceived adjuvant chemotherapy (n=12), adjuvant chemother-apy and radiotherapy (n=2), or adjuvant radiotherapy (n=2).

Clinical data analysis

Clinical data were assessed by reviewing electronic medicalrecords, including the date of surgery and surgical procedure,the date of recurrence, date of death, recurrence pattern, pre-operative and postoperative treatment, and treatment after re-currence. Laboratory data were also recorded, including thelevels of indocyanine green 15 (ICG 15), alpha-fetoprotein(AFP) , c a rbohyd ra t e an t i gen 19 -9 (CA 19-9 ) ,carcinoembryonic antigen (CEA), proteins induced by

vitamin K absence or antagonist-II (PIVKA-II), albumin,and bilirubin.

Pathologic evaluation

Pathology reports were retrospectively reviewed for grossmorphology, including tumour diameter, presence of tumournecrosis, haemorrhage or peliosis, and the presence of portalvein or bile duct invasion. Microscopic features were alsorecorded, including tumour differentiation (i.e. well-differen-tiated, moderately differentiated, poorly differentiated, andundifferentiated) as well as resection margin, serosal invasion,portal vein invasion, bile duct invasion, hepatic vein invasion,microvessel invasion, multi-centric occurrence, lymph nodemetastasis, and non-tumour liver pathology. Pathologic

Table 1 Preoperative laboratory and clinical data of 41 patients

Category Patient number

ICG 15 (%)

<10 17

≥10 6

Not available 18

AFP (IU/mL)

<7.0 25

≥7.0 3

Not available 13

CEA (ng/mL)

<2.5 16

≥2.5 19

Not available 6

CA19-9 (U/mL)

<37 13

≥37 23

Not available 5

PIVKA-II (mAU/mL)

<40 21

≥40 3

Not available 17

Albumin (g/dL)

<3 2

≥3 39

Total bilirubin (mg/dL)

<10 41

≥10 0

Receiving adjuvant chemotherapy

Yes 7

No 34

ICG 15 indocyanine green 15, AFP alpha-fetoprotein, CEAcarcinoembryonic antigen, CA 19-9 carbohydrate antigen 19-9, PIVKA-II proteins induced by vitamin K absence or antagonist-II

Eur Radiol (2016) 26:407–416 409

TNM classification was evaluated, and the final staging wasdetermined according to the American Joint Committee onCancer (AJCC) staging criteria.

For evaluation of imaging–pathology correlations, a pa-thologist (J.H.N.) who was blinded to the clinical informationreviewed the IMCC slides. The amount of tumour fibrosis wasevaluated using the tissue sections of the largest cut surface ofthe tumour, and the necrotic area was excluded for evaluatingfibrosis. The amount of fibrosis was graded into four scales;grade I represented<25% of stromal fibrosis, grade II≥25 and<50 %, grade III≥50 % and <75 %, and grade IV≥75 %.

Data and statistical analysis

Continuous variables were analyzed using the Student t test,and categorical variables were analyzed by the Fisher exacttest and Pearson chi-square test. Survival rates and time torecurrence were evaluated with the Kaplan-Meier methodand log-rank test. The Cox proportional hazards model wasused in the multivariate survival analysis. Patients withfollow-up loss or death from unrelated causes were regardedas censored data. For the evaluation of the imaging-histological correlations linear by linear association was used.A value of P<0.05 was regarded as significant. All statisticalanalyses were performed using SAS version 9.2 software(SAS Institute Inc., Cary, NC, USA).

Results

Clinicopathologic analysis

The mean tumour diameter was 4.8±2.4 cm (range 1.5–13 cm). Tumours were well differentiated in seven patients,moderately differentiated in 22 patients, poorly differentiatedin seven patients, and undifferentiated in one patient; differ-entiation was not reported in the pathology report in four pa-tients. The resection margin was clear in 30 patients.Microvessel invasionwas present in 30 patients and perineuralinvasion in 13 patients. Intrahepatic metastasis was present inthree patients. The majority of patients were in the advancedstage (stage 1, n=6; stage 2, n=11; stage 3, n=11; and stage 4,n=13).Most patients were above pT2, and 13 patients showedlymph node metastasis (Table 2).

Tumour recurrence was observed in 17 patients; amongthese, eight patients died from the recurrence. One patient diedoutside the hospital, and further follow-up was not possible.The organs where tumours recurred were the liver (n=13),lymph node (n=3), lung (n=5), peritoneum (n=3), and bone(n=1). Treatment after recurrencewas systemic chemotherapy(n=8), systemic chemotherapy and radiotherapy (n=2), hepat-ic resection (n=1), radiofrequency ablation (n=1), and sup-portive care (n=5).

Qualitative and quantitative image analysis

The signal intensity of the tumour as compared to the spleenon HBP MRI was qualitatively analyzed. The intermediategroup included 23 patients (56.1 %; Fig. 1), and one tumourexhibited hyperintense signal intensity compared to liver pa-renchymal enhancement. The remaining 18 patients (43.9 %)were regarded as belonging to the hypointense group (Fig. 2).Baseline characteristics and pathology data were analyzed be-tween the two groups, and no significant differences werefound (Table 2). The intermediate group showed variable pat-terns of enhancement on HBP MRI, including heterogeneous(n=10), central (n=9), and homogeneous enhancement (n=4). Two lesions showed T2 hypointense signal intensity andthe remaining 21 tumours showed T2 hyperintense signal in-tensity compared to surrounding liver parenchyma.

On dynamic study, 13 (31.7 %) tumours werehypervascular and 28 (68.3 %) were hypovascular on the ar-terial phase. Themost common temporal enhancement patternwas gradual enhancement, which demonstrated contrast en-hancement that increased over time (n=25). This was follow-ed by persistent enhancement, which showed contrast en-hancement that remained constant throughout the dynamicstudies (n=8), arterial enhancement with delayed washout(n=5), and studies with no enhancement or minimal enhance-ment (n=3).

The mean contrast enhancement ratio among all IMCCswas 60.6 %; the mean contrast enhancement ratio was73.1 % for the intermediate group and 44.5 % for thehypointense group (P=0.175). The mean CNR of theIMCCs was −112±81.2.

The mean ADC value among all IMCCs was 1.210×10−3 mm2/s. The mean ADC value in the intermediate groupwas 1.209×10−3 mm2/s, while in the hypointense group it was1.210×10−3 mm2/s (P=0.283).

There was a statistically significant correlation between thegrade of tumour fibrous stroma and MR signal intensity onHBP MRI of the IMCCs (P=0.027; Fig. 3). The hypointensegroup had a tendency toward a low grade of tumour fibrousstroma, whereas a high grade of tumour fibrous stroma wasmore frequently observed in the intermediate group.

Correlation of imaging and outcomes

The 5-year survival rate was 87 % in the hypointense groupand 53 % in the intermediate group. On the log-rank test, thesurvival rate was greater in the hypointense group than theintermediate group (P=0.048). The Cox proportional hazardmodel revealed a hazard ratio of 4.35, although this was notstatistically significant (0.89–21.22 with 95 % confidence in-terval, P=0.069). In univariate analysis of factors includingtumour marker, pathologic tumour characteristics, staging,pre- and postoperative treatment, and grade of tumour fibrous

410 Eur Radiol (2016) 26:407–416

stroma, none of these factors showed a statistically significantinfluence on survival time (Table 3).

There was a statistically significant difference in TTR be-tween the hypointense and intermediate groups, with thehypointense group having a longer TTR than the intermediategroup (P=0.002). The 5-year recurrence rate was 24 % in thehypointense group and 65 % in the intermediate group. Inunivariate analysis of TTR, microvessel invasion was anotherstatistically significant factor (P=0.043). Multivariate Cox re-gression analysis was performed with HBP images and

microvessel invasion, and only the HBP image remained sta-tistically significant (P=0.012) (Table 4).

Quantitative analysis indicated no correlation of tumourcontrast enhancement ratio and CNR with survival (P=0.859 and 0.714) or recurrence (P=0.417 and 0.152). Basedon arterial enhancement, there was no statistically significantdifference in survival rate or TTR between the hypervascularand hypovascular groups (P=0.670 and 0.124), and no statis-tically significant difference in survival rate or TTRwas foundamong the four temporal enhancement patterns (P=0.121 and

Table 2 Demographic, laboratory, and pathologic findings according to enhancement pattern on hepatobiliary phase imaging

Hypointense Intermediate P value(n=18) (n=21)

Age (years) 60±13 63±10 0.385

ICG 15 (%) 7.9±3.8 8.7±3.6 0.599

AFP (IU/mL) 4.6±5.0 8.8±24.2 0.582

CEA (ng/mL) 32.0±91.8 7.7±13.7 0.282

CA19-9 (U/mL) 2562.7±5993.7 4202.2±6598.4 0.451

PIVKA-II (mAU/mL) 66.3±122.4 27.0±11.2 0.313

Albumin (g/dL) 4.2±0.7 4.1±0.5 0.518

Total bilirubin (mg/dL) 0.8±0.3 0.6±0.3 0.094

AJCC staging 1 (n=6) 5 1 0.857

2 (n=11) 1 10

3 (n=11) 6 5

4 (n=13) 6 7

pT 1 (n=7) 5 2 0.14

2 (n=20) 6 14

3 (n=14) 7 7

pN 0 (n=28) 12 16 0.843

1 (n=13) 6 7

Tumour differentiation Well to moderate (n=29) 14 15 0.18

Poor or undifferentiated (n=8) 2 6

Positive resection margin (R1) (n=11) 4 7 0.726

Gross pathology

Tumour diameter (cm) 4.6±2.1 5.0±2.5 0.624

Tumour necrosis (n=19) 7 12 0.397

Tumour haemorrhage/peliosis (n=5) 3 2 0.638

Portal vein invasion (n=0) 0 0

Bile duct invasion (n=11) 5 6 1

Microscopic pathology

Serosal invasion (n=17) 6 11 0.350

Portal vein invasion (n=6) 2 4 0.679

Bile duct invasion (n=18) 7 11 0.752

Hepatic artery or vein invasion (n=0) 0 0

Microvessel invasion (n=30) 11 19 0.164

Perineural invasion (n=14) 5 9 0.52

Intrahepatic metastasis (n=3) 0 3 0.243

ICG 15 indocyanine green 15, AFP alpha-fetoprotein, CEA carcinoembryonic antigen, CA 19-9 carbohydrate antigen 19-9, PIVKA-II proteins inducedby vitamin K absence or antagonist-II

Eur Radiol (2016) 26:407–416 411

Fig. 1 A 67-year-old womanwith IMCC. (a) Gadoxetic acid-enhanced T1-weighted 3Dgradient-echo image (TR/TE/FA=3.3 ms/1.16 ms/13°) in thelate arterial phase showsperipheral rim enhancement ofthe tumour. (b) The transitionalphase at 3 min demonstratescentripetal filling of the contrastagent. (c) On hepatobiliary phaseMRI, the tumour consisted ofmore than 50 % hyperintensitycompared to the spleen (arrow),and was categorized in theintermediate group. (d) On visualassessment of the microscopicimage (H and E, ×40), there was75 % stromal fibrosis, whichcorresponds to grade IV fibrosis(arrow). Recurrence was noted271 days after surgery, and thepatient died 304 days aftersurgery due to recurrence.IMCC=intrahepatic mass-forming cholangiocarcinoma

Fig. 2 A 67-year-old man with IMCC. (a) Gadoxetic acid-enhanced T1-weighted 3D gradient-echo image (TR/TE/FA=3.3 ms/1.16 ms/13°) inthe late arterial phase shows a mass with peripheral irregularenhancement. (b) The transitional phase at 3 min demonstrates thesubsequent filling of the contrast agent. (c) On the hepatobiliary phaseimage, most of the tumour was hypointense compared to the spleen

(arrow), and it was thus categorized in the hypointense group. (d) Onmicroscopic image (H and E, ×40), stromal fibrosis was noted in 35 % ofthe whole tumour, and the grade was II (arrows). Although the patientinitially had a large tumour, he survived for 1213 days without tumourrecurrence. IMCC=intrahepatic mass-forming cholangiocarcinoma

412 Eur Radiol (2016) 26:407–416

0.257, respectively). There was no statistically significant dif-ference in survival rate or TTR based on ADC value (P=0.102 and P=0.868, respectively).

Discussion

Our study demonstrated that IMCCs with greater than 50 %intermediate signal intensity on HBP imaging had worse out-comes than hypointense tumours. The intermediate signal in-tensity in IMCCs on HBP imaging was related to the amountof tumour fibrous stroma in the tumour based on the image–histology correlation, and was also correlated with prognosis.Therefore, gadoxetic acid-enhanced MRI including HBP im-aging is not only useful for preoperative assessment of tumourstaging, but also has incremental value in predictingprognosis.

Typical CT findings of IMCC show homogeneous attenu-ation and irregular peripheral enhancement, followed by grad-ual centripetal enhancement [21–23]. The enhancement pat-tern of IMCC on extracellular contrast agent-enhancedMRI issimilar to that of CT, showing peripheral and then centripetalenhancement [21]. IMCC may show varying degrees of de-layed enhancement on both CTandMR due to tumour fibrousstroma [21]. A relationship between delayed enhancementpattern on CT and patient survival has been reported [12]. Inone study, IMCCs with more than two-thirds of the tumourshowing delayed enhancement on CTwere found to correlatewith abundant tumour fibrous stroma and frequent perineuralinvasion and with a lower survival rate than IMCCs with lessthan two-thirds of the tumour showing delayed enhancement

[12]. However, in another study, a higher percentage of en-hancement in IMCC gadoxetic acid-enhanced HBP imagescorrelated with better differentiation of tumours and fewerlymph node metastases [17]. In the present work, we evaluat-ed whether survival or recurrence of IMCC were related togadoxetic acid-enhanced MRI findings, and found that theintermediate group had a worse prognosis than hypointensetumours, consistent with a previous study using CT [12]. Itremains to be determined whether delayed enhancement onCT and gadoxetic acid-enhanced MRI are comparable forpredicting prognosis.

IMCCs usually demonstrate hypointensity on HBP MRIcompared to adjacent liver parenchyma because these tumoursdo not take up hepatobiliary agents due to a lack of organicanionic transporter peptide (OATP) expression [17, 24].Paradoxically, however, some IMCCs may have intermediateor mixed signal intensity on HBP MRI because of contrastagent pooling in the extracellular space or tumour fibrousstroma. In our study, almost all tumours (97.6 %) appearedhypointense compared to the adjacent liver parenchyma onHBP MRI, and only one tumour appeared hyperintense.With the signal intensity of the spleen set as the reference,56.1% of tumours fell within the intermediate group, showinga hyper or iso-intense area greater than 50 % of the area of thewhole tumour. Since intermediate signal intensity on HBPMRI reflects the contrast material retained in the tumour fi-brous stroma of IMCC, abundant tumour fibrous stroma cor-responds to a larger intermediate signal intensity area on HBPMRI [16]. This finding coincides with the results of our study:tumours with intermediate signal intensity on HBP MRI ex-hibited more abundant stroma on histopathologic examina-tion, which correlated with poor prognosis. This evidence

Fig. 3 Correlation of the signalintensity and grade of tumourfibrous stroma of IMCCs onhepatobiliary phase imaging.Percentage of stromal fibrosis onvisual assessment of thepathologic slide: Grade I<25 %,Grade II≥25 and <50 %, GradeIII≥50 % and <75 %, Grade IV≥75 %. IMCC=intrahepatic mass-forming cholangiocarcinoma

Eur Radiol (2016) 26:407–416 413

Table 3 Prognostic factors according to univariate analysis

Factors Survival rate (%) P value Disease-free rate (%) P value

1 year 3 years 5 years 1 year 3 years 5 years

Hepatobiliary phase image 0.048 0.002

Hypointense (n=18) 94 87 87 88 76 76

Intermediate (n=21) 74 53 53 41 35 35

Temporal enhancement pattern 0.121 0.257

Gradual enhancement (n=25) 85 85 85 65 51 51

Persistent enhancement (n=8) 75 60 60 63 63 63

Arterial enhancement with delayed washout (n=5) 100 50 50 60 60 60

No or minimal enhancement (n=3) 67 33 33 33 33 33

ADC value 0.102 0.868

CEA (ng/mL) 0.122 0.372

<2.5 (n=16) 95 86 86 71 62 62

≥2.5 (n=19) 75 7 7 55 55 55

Albumin (g/dL) - -

<3 (n=2) 100 100 100 100 100 100

≥3 (n=39) 85 77 77 62 56 56

Tumour diameter (cm) 0.069 0.100

Tumour differentiation 0.665 0.616

Well (n=7) 100 100 100 88 75 75

Moderate (n=22) 86 82 82 – 64 59 59 0.457

Poor (n=7) 86 57 57 – 43 43 43 0.192

Undifferentiated (n=1) 100 100 100 – 100 100 100 –

Resection margin 0.973 0.284

Clear (R0) (n=30) 87 77 77 67 63 63

Not clear (R1) (n=11) 82 82 82 55 46 46

Microvessel invasion – 0.043

Not present (n=11) 100 100 100 91 91 91

Present (n=30) 80 70 70 53 47 47

Perineural invasion 0.662 0.265

Not present (n=27) 89 82 82 67 67 67

Present (n=14) 79 71 71 57 43 43

Intrahepatic metastasis – 0.107

Not present (n=38) 84 76 76 63 61 61

Present (n=3) 100 100 100 67 33 33

pT 0.800 0.118

1 (n=7) – 100 100 100 100 100

2 (n=20) 82 45 45 – 37 30 30 –

3 (n=14) 79 79 79 – 79 71 71 –

pN 0.257 0.424

0 (n=28) 89 82 82 68 61 61

1 (n=13) 77 69 69 54 54 54

AJCC Staging 0.884 0.356

1 (n=6) 100 100 100 100 100 100

2 (n=11) 91 73 73 – 36 27 27 –

3 (n=11) 82 82 82 – 82 73 73 –

4 (n=13) 77 69 69 – 54 54 54 –

Preoperative treatment – 0.668

No (n=34) 82 74 74 62 56 56

414 Eur Radiol (2016) 26:407–416

suggests a close link between tumour cells and tumour-associated stroma. The stroma actively provides continuoussupport to the tumour cells and modulates tumour progres-sion. Histologically, IMCC can be classified into two typesaccording to the amount of fibrosis in the lesion: tumours withabundant stroma, the so-called “scirrhous type”, are known tohave worse prognosis than “non-scirrhous-type” IMCCs [25].Scirrhous-type IMCCs frequently overproduce extracellularmatrix, degrade basement membrane, and modulate macro-molecules that play important roles in cellular growth, differ-entiation, cell–matrix adhesion, invasion, and eventually me-tastasis of cancer cells [26]. Scirrhous-type IMCCs also showfrequent lymphatic permeation, perineural invasion, andhigher proliferative activity [25]. As such, information onthe degree of stroma based onMRI may be useful for improv-ing surgical strategies in treating this neoplasm. Theoretically,extracellular contrast agent-enhanced MRI may also show de-layed enhancement in patients with IMCC due to contrastpooling in the tumour fibrous stroma. However, given thatgadoxetic acid-enhanced MRI including HBP images pro-vides increased lesion conspicuity as well as better delineationof daughter nodules and intrahepatic metastasis, this techniquecould be advantageous in preoperative staging as well as in theassessment of the tumour fibrous stroma [17].

Although IMCC is typically hypovascular, IMCC arisingfrom chronic viral hepatitis and the cirrhotic or pre-cirrhoticliver is more likely to be hypervascular after the malignanttransformation of the cholangiocytes [27]. It has been reported

that hypervascular versus hypovascular IMCC on arterialphase CT correlates with reduced malignant behaviour andbetter survival [13–15, 28]. In a previous study, well-differentiated tumours were found to have greater enhance-ment on gadoxetic acid-enhanced MRI than moderately orpoorly differentiated IMCCs [16]. However, in our study,hypervascular IMCCs comprised 31.7 % of tumours, andthere was no statistical difference between hypervascular andhypovascular IMCCs in either survival rate or TTR. Furtherevaluation of arterial enhancement and prognosis is needed ina larger study.

We acknowledge that this study has several limitations.First, due to the rare incidence of IMCC, only a small numberof patients were included, and the follow-up period was rela-tively short. Since most studies with IMCC include a smallpatient sample, statistical power may be somewhat weak, andso a larger study is needed to validate these results. Second,there may have been selection bias, as we included only sur-gically resected cholangiocarcinoma. Further study is neededin patients who receive non-surgical treatment. Third, quanti-tative analysis was performed on the whole tumour region,without quantitative comparison of the degree of enhancementamong different areas of the tumour. In addition, parallel im-agingmay have influenced the SNR, whichwould not accountfor the noise throughout the image. However k-space-basedparallel acquisition spreads the noise throughout images, thusreducing the influence on SNR calculation [20], which mayresult in a discrepancy between qualitative and quantitative

Table 3 (continued)

Factors Survival rate (%) P value Disease-free rate (%) P value

1 year 3 years 5 years 1 year 3 years 5 years

Yes (n=7) 100 100 100 71 71 71

Postoperative treatment 0.549 0.495

No (n=25) 91 69 69 60 60 60

Yes (n=16) 71 71 71 60 41 41

Histological tumour fibrous stroma grade 0.510 0.223

1 (n=2) 60 60 60 60 60 60

2 (n=15) 91 91 91 56 40 40

3 (n=17) 88 74 74 76 69 69

4 (n=7) 67 33 33 38 38 38

CEA carcinoembryonic antigen, ADC apparent diffusion coefficient

Table 4 Multivariate Coxregression for recurrence Factors Hazard ratio 95 % Confidence Interval P value

Hepatobiliary phase image Hypointense group 1 0.012Intermediate group 5.0–88 1.629–20.352

Microvessel invasion No 1 0.062Yes 6.947 0.910–53.058

Eur Radiol (2016) 26:407–416 415

analysis. Fourth, over the 5-year period of this study, variousMRI units and sequences were adopted, which may haveweakened reproducibility.

In conclusion, IMCCs with intermediate signal intensity onHBPMRI are associatedwith abundant tumour fibrous stromaand poor prognosis. Therefore, gadoxetic acid-enhanced MRIcould be a useful prognostic tool for IMCCs after surgery.

Acknowledgements The scientific guarantor of this publication isJin-Young Choi. The authors of this manuscript declare no relationshipswith any companies whose products or services may be related to thesubject matter of the article. This study was supported by a faculty re-search grant of Yonsei University College of Medicine for 6-2014-0126.Ha Yan Kim kindly provided statistical advice for this manuscript. One ofthe authors has significant statistical expertise. Institutional review boardapproval was obtained. Written informed consent was waived by theinstitutional review board. Methodology: retrospective, diagnostic orprognostic study, performed at one institution.

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