European Radiology

, Volume 20, Issue 3, pp 743–753

Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: differential diagnosis with contrast-enhanced ultrasound

Authors

  • Li-Da Chen
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Xiao-Yan Xie
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Xiao-Hua Xie
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Zuo-Feng Xu
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Guang-Jian Liu
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Zhu Wang
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
  • Man-Xia Lin
    • Department of Medical Ultrasonics, The First Affiliated Hospital, Institute of Diagnostic and Interventional UltrasoundSun Yat-Sen University
    • Department of Hepatobiliary Surgery, The First Affiliated HospitalSun Yat-Sen University
Ultrasound

DOI: 10.1007/s00330-009-1599-8

Cite this article as:
Chen, L., Xu, H., Xie, X. et al. Eur Radiol (2010) 20: 743. doi:10.1007/s00330-009-1599-8

Abstract

Objective

We assessed the usefulness of contrast-enhanced ultrasound (CEUS) in the differentiation of intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC).

Methods

The CEUS enhancement patterns of 50 ICCs were retrospectively analysed and compared with 50 HCCs. Two readers independently reviewed the baseline ultrasound (BUS) and CEUS images and the diagnostic performances were evaluated by receiver operating characteristic (ROC) analysis. Time–intensity curves (TIC) were plotted for quantification analysis.

Results

In the arterial phase, peripheral rim-like hyperenhancement, heterogeneous hyperenhancement, homogeneous hyperenhancement and heterogeneous hypoenhancement were found in 25, 10, 3 and 12 of the ICCs versus 2, 29, 19 and 0 of the HCCs (P < 0.001), respectively. The diagnostic performance of both readers in terms of the area under the ROC curve (0.745 vs. 0.933 for reader 1, and 0.803 vs. 0.911 for reader 2), sensitivity (28% vs. 90%, and 44% vs. 82%) and accuracy (64% vs. 90%, and 71% vs. 90%) improved significantly after CEUS (all P < 0.05). The interobserver agreement increased from κ = 0.575 at BUS to κ = 0.720 after CEUS. TICs demonstrated that the intensities of the peripheral and central portions of the ICCs were lower than those of HCCs (both P < 0.05).

Conclusion

CEUS improves the diagnostic performance significantly in the differentiation between ICC and HCC.

Keywords

Contrast-enhanced ultrasoundIntrahepatic cholangiocarcinomaHepatocellular carcinomaDifferential diagnosisCharacterisation

Introduction

Hepatocellular carcinoma (HCC) is the sixth most common neoplasm worldwide. Its incidence has increased in recent years and is currently the leading cause of death amongst cirrhotic patients [1, 2]. Intrahepatic cholangiocarcinoma (ICC) accounts for 5–30% of primary liver cancers, and its incidence rate has also increased in recent years [3]. ICC and HCC have different biological behaviour and prognosis [1, 46]. Differentiation between them is essential for surgical planning and prognosis assessment. It is difficult for baseline ultrasound (BUS) to distinguish between them because ICC has no specific features [79]. Recent studies have proven that contrast-enhanced ultrasound (CEUS) improved the diagnostic performance in characterisation of focal liver lesions (FLLs) compared with BUS [10]. However, so far there have been no studies evaluating the use of CEUS in differentiating between ICC and HCC. As shown in previous studies, ICC typically produces a peripheral rim-like enhancement in the arterial phase of CEUS [11, 12], whereas HCC is homogeneously or inhomogeneously hyperenhancing [13, 14]. We supposed that CEUS would therefore improve the ability to differentiate between these two entities. In this study, we compared the CEUS imaging characteristics of ICC and HCC, assessed the diagnostic value of CEUS in the differential diagnoses between them using receiver operating characteristic (ROC) analysis, and evaluated the difference in blood perfusion for these two entities quantitatively.

Materials and methods

Patients

Between March 2004 and June 2007, 3,407 consecutive patients underwent CEUS examination in our hospital for characterisation of FLLs. They were referred for further confirmation of the nature of lesions after FLLs were identified on BUS. The inclusion criteria for CEUS examination were as follows:
  1. 1.

    Age range 18–80 years

     
  2. 2.

    Absence of severe cardiopulmonary diseases

     
  3. 3.

    Not pregnant or lactating

     
  4. 4.

    Lesions had not been treated before

     

Written informed consent was obtained from each patient and the study was approved by the institutional ethics committee. Final diagnoses included various types of lesions, such as HCC, ICC, haemangioma, metastatic liver cancer, focal nodular hyperplasia, and others.

Among the 3,407 patients, all 50 patients (34 men and 16 women; mean age 58 ± 11 years, age range 28–76 years) with pathologically proven ICCs were retrospectively enrolled as the study population for the ICC group. Five patients in the ICC group had a history of cirrhosis. Seven patients had multiple lesions (2 lesions in 5 patients, and more than 5 lesions in 2) and 43 patients had a solitary lesion in each. In patients with multiple lesions, only the largest lesion visualised on BUS was selected for CEUS evaluation. Thus, 50 ICCs were included in the study, and the maximum diameters of the ICCs were 2.0–15.5 cm (mean ± SD, 7.2 ± 2.8 cm).

Among the 3,407 consecutive patients who presented during the corresponding period, 875 patients had HCCs. Fifty sample cases were randomly selected to form the HCC group by using the sequence numbers created by the SPSS 13.0 software package (SPSS Inc, Chicago, IL). The diagnosis was confirmed either by pathological analysis (n = 38) or by clinical criteria (n = 12) according to the literature [15]. The population comprised 43 men and 7 women (P < 0.05, compared with ICC) (mean age 53 ± 11 years, range 33–78 years. P < 0.02, compared with ICC). Twenty-six patients had a history of cirrhosis (P < 0.001, compared with ICC). Eleven patients had multiple lesions (2 lesions in 7 patients, 3 lesions in 1, 5 lesions in 1, and more than 5 lesions in 2) and 39 patients had a solitary lesion in each (P > 0.05, compared with ICC). In patients with multiple lesions, only the largest lesion was selected for CEUS evaluation. Therefore, 50 HCCs sized from 1.5 to 16.2 cm (mean ± SD, 6.1 ± 3.2 cm) (P > 0.05, compared with ICC) were observed.

BUS and CEUS examinations

BUS and CEUS examinations were performed with two systems:
  1. 1.

    Forty ICCs and 42 HCCs were examined with an Acuson Sequoia 512 (Siemens Medical Solutions, Mountain View, CA). The 4V1 vector transducer (frequency range 1.0–4.0 MHz) and low acoustic power real-time CEUS mode of contrast pulse sequencing (CPS; Siemens Medical Solutions) (mechanical index range 0.15–0.21) was applied.

     
  2. 2.

    Ten ICCs and 8 HCCs were examined with an Aplio XV (Toshiba Medical System, Tokyo, Japan), which was equipped with a 375BT convex transducer (frequency range 1.9–6.0 MHz) and contrast-specific mode of contrast harmonic imaging (CHI; Toshiba) with mechanical index of 0.05 to 0.08.

     

The contrast agent used was SonoVue® (BR1; Bracco SpA, Milan, Italy), a sulphur hexafluoride-filled microbubble that is covered by a phospholipid shell.

Two primary investigators, both with more than 8 years’ experience in liver BUS imaging and at least 5 years’ experience in liver CEUS, performed the imaging. They were not blinded to information on the patients’ clinical presentations and other imaging results. BUS was performed first. After identification of the target lesion the transducer was kept in a stable position while the imaging mode was changed to CEUS, and the mechanical index (MI) settings were adjusted to provide sufficient tissue cancellation with the maintenance of adequate depth penetration. Focus was positioned just below the bottom of the lesion and maintained the same position during the examination. The initial gain setting showed system noise in the far field of the contrast image that did not change during the whole examination. Then, a dose of 2.4 mL SonoVue was administered via the antecubital vein in a bolus fashion (within 1–2 s), followed by a flush of 5 mL of 0.9% normal saline by using a 20-gauge cannula. A stopwatch was started at the time of SonoVue administration. CEUS images were recorded continuously for a period of more than 240 s immediately after the injection, without any change in the machine settings. The arterial, portal and late phases were defined as 8–30 s, 31–120 s and 121–240 s after the injection, respectively. BUS images and CEUS cine clips were stored digitally on the hard disk in the imaging systems, and were transferred to a personal computer for subsequent analysis.

Enhancement patterns

Immediately after the CEUS images were finished, all the BUS images and CEUS cine clips were analysed subjectively in consensus by the two primary investigators. The number, size and echogenicity of the lesion, as well as focal bile duct dilation around the tumour on BUS were recorded. On CEUS, the enhancement pattern in the arterial phase was classified as follows: peripheral rim-like enhancement i.e. a continuous ring of contrast enhancement seen at the periphery of the lesion; heterogeneous enhancement i.e. the whole lesion enhanced heterogeneously; homogeneous enhancement i.e. the entire lesion enhanced uniformly. The intratumoral blood vessels and tumour capsule that appeared during arterial phase were also evaluated. The enhancement level (hyper-, iso- or hypoenhancement, relative to the adjacent liver parenchyma) and their changes in the portal and the late phases, were evaluated.

Diagnostic performance

Digital images of BUS and CEUS stored in the personal computer were randomised for presentation so that the ICCs and HCCs were not grouped by diagnosis, and any identifying information (i.e. the sequence number, name, sex and age of each patient) was concealed. Review was performed by two readers independently who had at least 3 years’ experience in liver CEUS, were not involved in the imaging and were blinded to clinical histories, histopathological results and other imaging findings. The diagnostic criteria for ICC and HCC were determined according to previously published reports [1619] (Table 1). After reviewing the images, the readers were asked to make a diagnosis of ICC or HCC for each lesion. The diagnostic confidence was graded on the basis of a five-point scale: 1, definitely ICC; 2, probably ICC; 3, indeterminate; 4, probably HCC; 5, definitely HCC.
Table 1

Diagnostic criteria for ICC and HCC on baseline and contrast-enhanced ultrasound (US)

Entity

Baseline US criteria

Contrast-enhanced US criteria

ICC

Variable echogenicity, irregular lesion margin, peripheral bile duct dilatation

Peripheral irregular rim-like hyperenhancement, heterogeneous hypoenhancement or heterogeneous hyperenhancement during the arterial phase, hypoenhancement during the portal and late phases

HCC

Heterogeneous echogenic lesion, hypoechoic rim, peripheral or internal arterial flow signals

Homogeneous or heterogeneous hyperenhancement during the arterial phase, washout during the portal or late phase

Time–intensity curve

One investigator who did not participate in the image analysis obtained still frames from the CEUS cine clips (every 5 s from 15 s to 60 s, and every 30 s from 60 s to 180 s) of all 50 ICC and 50 HCC records, and all images were transformed into the 8-bit tag image file format. The images were assessed by using the public domain image analysis program ImageJ (developed at the National Institutes of Health and available at http://rsb.info.nih.gov/nih-image/). Region of interest (ROI) was determined as a circular region of 1.0 cm (if lesion size ≥ 3.0 cm) or 0.5 cm (if lesion size < 3.0 cm) in diameter. They were placed in liver parenchyma and the peripheral and central regions of the tumour, respectively, in the same location on each image with the same depth, avoiding any large hepatic vessels and necrotic areas. Then, echo intensities of ROIs of each image were measured. A time–intensity curve (TIC) was plotted as mean intensity versus time.

Statistical analysis

The diagnostic performance of BUS and CEUS in differentiating ICC and HCC was assessed by an ROC curve, which was expressed as the area under the ROC curve (Az). The comparison of Az was evaluated by univariate z score test. If the lesion was assigned a confidence grade of 1 (definitely ICC) or 2 (probably ICC), the diagnosis was defined as a positive result; the lesion assigned a confidence grade of 3 (indeterminate), 4 (probably HCC) or 5 (definitely HCC) was defined as a negative result. The McNemar test or the Chi-squared test was used to evaluate the difference between qualitative data. P < 0.05 was considered to be statistically significant. The κ statistic was used to assess interobserver agreement. Agreement was graded as poor (κ < 0.20), moderate (κ = 0.20 to <0.40), fair (κ = 0.40 to <0.60), good (κ = 0.60 to <0.80), or very good (κ = 0.80–1.00). The statistical analyses were performed using the SPSS 13.0 software package (SPSS Inc, Chicago, IL).

Results

BUS

On BUS, the numbers of ICC that showed hypo-, iso- and hyperechogenicity were 13 (26%), 8 (16%) and 29 (58%); for HCC, the corresponding numbers were 18 (36%), (16%) and 24 (48%) (P > 0.05). Intrahepatic bile duct dilation around the tumour was seen in 13 (26%) ICCs and 4 (8%) HCCs (P < 0.05).

Enhancement patterns

In the arterial phase, four enhancement patterns were seen for ICCs: peripheral rim-like hyperenhancement in 25 (50%) lesions (mean size 7.9 ± 2.8 cm; range 3.8–15.5 cm) (Fig. 1), heterogeneous hyperenhancement in 10 (20%) (mean size 7.6 ± 2.5 cm; range 2.3–11.0 cm), homogeneous hyperenhancement in 3 (6%) (mean size 3.4 ± 1.3 cm; range 2.2–4.8 cm) (Fig. 2) and heterogeneous hypoenhancement in 12 (24%) (mean size 6.5 ± 2.6 cm; range 2.0–9.8 cm). There was a significant difference among the four enhancement patterns in terms of lesion size (P < 0.05). Homogeneous enhancement was only seen in small tumours (≤ 3.0 cm) (n = 3) and inhomogeneous enhancement was seen in large tumours (> 3.0 cm) (n = 47). Tumour vessels were displayed in 12 (24%) of the ICC lesions.
https://static-content.springer.com/image/art%3A10.1007%2Fs00330-009-1599-8/MediaObjects/330_2009_1599_Fig1_HTML.gif
Fig. 1

Intrahepatic cholangiocarcinoma (ICC) in a 59-year-old man. a An 11.1-cm lesion (arrows) in the liver shows mixed echogenicity on conventional ultrasound. b Contrast-enhanced ultrasound shows peripheral irregular rim-like hyperenhancement (arrow) in the lesion 22 s after contrast agent administration. c The lesion (arrows) shows hypoenhancement in comparison with adjacent liver tissue 48 s after contrast agent administration. d Microbubbles wash out from the lesion (arrows) more obviously and the lesion shows hypoenhancement 161 s after contrast agent administration

https://static-content.springer.com/image/art%3A10.1007%2Fs00330-009-1599-8/MediaObjects/330_2009_1599_Fig2_HTML.gif
Fig. 2

Intrahepatic cholangiocarcinoma (ICC) in a 33-year-old woman. a Conventional ultrasound shows a hypoechoic nodule (arrows) sized 2.1 cm in segment 5 of the liver. b On contrast-enhanced ultrasound, the lesion (arrows) appears as homogeneous hyperenhancement in comparison with the adjacent liver parenchyma 12 s after contrast agent administration. c The lesion (arrows) appears as an area of slight hypoenhancement 83 s after contrast agent administration. d The lesion (arrows) appears as hypoenhancement compared with adjacent liver parenchyma 142 s after contrast agent administration

For HCC, heterogeneous hyperenhancement in 29 (58%) lesions (mean size 7.5 ± 3.0 cm; range 2.8–16.2 cm) (Fig. 3) and homogeneous hyperenhancement in 19 (38%) (mean size 3.9 ± 2.3 cm; range 1.5–8.6 cm) (Fig. 4) were observed. Peripheral rim-like hyperenhancement (mean size 6.3 ± 3.0 cm; range 4.1–8.4 cm) was only seen in 2 (4%) lesions. None of the lesions showed hypoenhancement (P < 0.001, in comparison with ICC). Small tumours (n = 10) tended to appear as homogeneous enhancement, while large ones (n = 40) appeared as inhomogeneous enhancement. Statistical analysis indicated significant difference among the three types of enhancement patterns by lesion size (P < 0.001). Thirty-three HCCs showed intratumoral blood vessels (66%) (P < 0.001, in comparison with ICC).
https://static-content.springer.com/image/art%3A10.1007%2Fs00330-009-1599-8/MediaObjects/330_2009_1599_Fig3_HTML.gif
Fig. 3

Hepatocellular carcinoma (HCC) in a 49-year-old man. a Conventional ultrasound shows a 7.7-cm hypoechoic lesion (arrows) in segments 5 and 6 of the liver. b The lesion (arrows) appears as heterogeneous hyperenhancement 21 s after contrast agent injection. Intratumoral vessels (arrowhead) and the vessel along the margin of the lesion are visualised. c The lesion shows isoenhancement (arrows) 60 s after contrast agent injection. d Microbubbles wash out from the lesion (arrows) and the lesion shows hypoenhancement 120 s after contrast agent injection

https://static-content.springer.com/image/art%3A10.1007%2Fs00330-009-1599-8/MediaObjects/330_2009_1599_Fig4_HTML.gif
Fig. 4

Hepatocellular carcinoma (HCC) in a 41-year-old woman. a A 3.5-cm lesion (arrows) in segment 6 of the liver appears as hypoechogenicity on conventional ultrasound. b On contrast-enhanced ultrasound, the lesion (arrows) shows homogeneous hyperenhancement 13 s after contrast agent injection. c The lesion shows hypoenhancement (arrows) 105 s after contrast agent injection. d The lesion shows hypoenhancement (arrows) 165 s after contrast agent injection

In the portal phase, 36 (72%) ICCs that showed hyperenhancement in the arterial phase became hypoenhanced. Two (4%) ICCs that showed hyperenhancement in the arterial phase became isoenhanced. Twelve (24%) ICCs that showed hypoenhancement in the arterial phase remained hypoenhanced. Among 50 (100%) HCCs with hyperenhancement, 47 (94%) became hypoenhanced, 2 (4%) were isoenhanced and 1 (2%) remained hyperenhanced in the portal phase (P > 0.05, in comparison with ICC). In the late phase, all 50 ICCs and 50 HCCs were hypoenhanced.

Diagnostic performance

The diagnostic performance results are summarised in Table 2. The numbers of lesions assigned by reader 1 at BUS were definitely ICC in 0 (0%), probably ICC in 14 (14%), indeterminate in 49 (49%), probably HCC in 28 (28%) and definitely HCC in 9 (9%), respectively. After CEUS, the numbers were changed to 38 (38%), 12 (12%), 2 (2%), 4 (4%) and 44 (44%), respectively. For reader 2, the numbers were 3 (3%), 20 (20%), 23 (23%), 52 (52%) and 2 (2%) at BUS, and 20 (20%), 22 (22%), 6 (6%), 13 (13%) and 39 (39%) at CEUS. The number of indeterminate lesions decreased significantly after CEUS for both readers. The diagnostic performance of both readers in Az, sensitivity, negative predictive value (NPV) and accuracy improved significantly after CEUS (all P < 0.05). However, no statistically significant differences were found in specificity and positive predictive value (PPV) for both readers before and after CEUS (all P > 0.05; Table 2) (Fig. 5). The interobserver agreement increased from κ = 0.575 (95% confidence interval 0.472–0.678) at BUS to κ = 0.720 (95% confidence interval 0.651–0.789) after CEUS.
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Fig. 5

Diagnostic performance of contrast-enhanced ultrasound compared with conventional ultrasound in differentiating ICC from HCC. Receiver operating characteristic curves are plotted before (dotted line) and after (solid line) CEUS for reader 1 (a) and reader 2 (b)

Table 2

Diagnostic performance of contrast-enhanced ultrasound for diagnoses of ICC in a patient group of 50 ICCs and 50 HCCs

Performance parameters

Total (n = 100)

Before CEUS

After CEUS

P

Az

  Reader 1

0.745 (0.650–0.840)

0.933 (0.878–0.988)

<0.001*

  Reader 2

0.803 (0.715–0.891)

0.911 (0.849–0.973)

<0.05*

Sensitivity, %

  Reader 1

28 (14/50)

90 (45/50)

<0.001*

  Reader 2

44 (22/50)

82 (41/50)

<0.001*

Specificity, %

  Reader 1

100 (50/50)

90 (45/50)

NA

  Reader 2

98 (49/50)

98 (49/50)

>0.05

Accuracy, %

  Reader 1

64 (64/100)

90 (90/100)

<0.001*

  Reader 2

71 (71/100)

90 (90/100)

<0.001*

PPV, %

  Reader 1

100 (14/14)

90 (45/50)

>0.05

  Reader 2

96 (22/23)

98 (41/42)

>0.05

NPV, %

  Reader 1

58 (50/86)

90 (45/50)

<0.001*

  Reader 2

64 (49/77)

85 (49/58)

<0.01*

Numbers in parentheses for Az are 95% confidence intervals; numbers in parentheses for other parameters are numbers of lesions used to calculate the percentages

NA not applicable

*Statistically significant difference

After CEUS, the numbers of correctly diagnosed lesions increased significantly in ICC and HCC for reader 1, as well as in ICC for reader 2 (Table 3). Reader 1 did not make a correct diagnosis in 5 ICCs. Four lesions appeared to have homogeneous (n = 3) or heterogeneous (n = 1) hyperenhancement in the arterial phase, and faded out to show hypoenhancement during the portal and late phases. One demonstrated peripheral rim-like hyperenhancement in the arterial phase and isoenhancement during the portal phase. Four HCCs were incorrectly diagnosed as ICC by reader 1, including 2 lesions with a peripheral hyperenhancing rim in the arterial phase, 1 with homogeneous hyperenhancement in the arterial phase and 1 with heterogeneous hyperenhancement in the arterial phase and isoenhancement during the portal phase. Two HCCs with heterogeneous hyperenhancement in the arterial phase were judged to be indeterminate. Reader 2 did not make a correct diagnosis in 9 ICCs. Eight lesions showed homogeneous (n = 3) or heterogeneous (n = 5) hyperenhancement in the arterial phase. One showed heterogeneous hyperenhancement in the arterial phase and isoenhancement during the portal phase. As for reader 1, the same 4 HCCs were incorrectly diagnosed as ICC by reader 2. Three HCCs with heterogeneous hyperenhancement in the arterial phase were judged to be indeterminate.
Table 3

Comparisons of the correctly characterised lesions before and after contrast-enhanced ultrasound in 50 ICCs and 50 HCCs

Entity

CEUS

Number of lesions correctly characterised

Reader 1 (%)

Reader 2 (%)

ICC (n = 50)

Before

14/50 (28.0)

22/50 (44.0)

After

45/50 (90.0)

41/50 (82.0)

P

<0.001*

<0.001*

HCC (n = 50)

Before

27/50 (54.0)

40/50 (80.0)

After

44/50 (88.0)

43/50 (86.0)

P

<0.001*

>0.05

Numbers in parentheses are percentages

CEUS contrast-enhanced ultrasound

*Statistically significant difference

Time–intensity curve

The mean echo intensity of the peripheral portion of the ICC clearly increased from 83 dB (15 s) to the peak of 107 dB (25 s) in the arterial phase and then decreased gradually to 33 dB in the portal and late phases. The intensity of the peripheral portion of HCC increased from 82 dB (15 s) (P > 0.05, compared with ICC) to the peak of 124 dB (P < 0.05, compared with ICC) at 25 s and decreased to 49 dB (P > 0.05, compared with ICC) at 180 s. The mean intensity differences between ICC and the surrounding liver parenchyma at 25 s and 50 s were lower than those between HCC and surrounding liver parenchyma (both P < 0.05; Table 4) (Fig. 6a). Following the peak enhancement of ICC and HCC at 25 s, the surrounding liver parenchyma reached a maximum enhancement level (110 dB in ICC, and 115 dB in HCC at 40 s). Between the liver with ICC and HCC, there were no significant differences in the intensity of the surrounding liver parenchyma at 25 s, 50 s, 90 s and 150 s (all P > 0.05).
https://static-content.springer.com/image/art%3A10.1007%2Fs00330-009-1599-8/MediaObjects/330_2009_1599_Fig6_HTML.gif
Fig. 6

a Time–intensity curve of the peripheral portion in ICC and HCC, with the x-axis representing time (s) and the y-axis representing mean intensity (dB). The curves reveal a marked wash-in and washout of contrast agent in both tumours. b Time–intensity curve of the central portion in ICC and HCC. The curves reveal marked enhancement after contrast agent injection in HCC, but the enhancement in ICC is weak throughout the contrast-enhanced ultrasound

Table 4

Intensity differences (dB) between different portions of the tumours (ICC and HCC) and surrounding liver parenchyma

Entity

25 s

50 s

90 s

150 s

Periphery

Centre

Periphery

Centre

Periphery

Centre

Periphery

Centre

ICC

7.8

19.1

13.5

24.3

23.5

28.6

20.4

25.9

HCC

31.1

36.0

31.2

46.8

24.4

48.0

23.4

34.2

P

<0.05*

<0.05*

<0.01*

<0.001*

>0.05

<0.001*

>0.05

<0.001*

*Indicates significant differences in the relative mean intensity between ICC and HCC at 25 s and 50 s for the peripheral portion, and at 25 s, 50 s, 90 s and 150 s for the centre portion

In ICC, the central portion exhibited a low, plateau-like curve, and the peak intensity of 62 dB appeared at 25 s and 30 s. The central portion of HCC enhanced markedly from 71 dB at 15 s after contrast agent injection, and then decreased immediately after it reached the peak level (112 dB) (P < 0.05, compared with ICC) at 25 s (Fig. 6b). The mean intensity differences between ICC and adjacent liver parenchyma were lower than those between HCC and adjacent liver parenchyma at 25 s, 50 s, 90 s and 150 s after contrast agent injection (all P < 0.05).

Discussion

It is difficult for BUS to differentiate ICC from HCC because the imaging findings of ICC on BUS are non-specific [79]. In recent years, CEUS has become an important technique for diagnosing FLLs and is increasingly accepted in clinical use [13]. On CEUS, it is well known that a typical HCC is characterised by arterial phase hypervascularity and rapid washout in the late phase [16, 18, 19]. On the other hand, few studies with small numbers of cases reported the enhancement appearance of ICC on CEUS [11, 16, 20]. For example, von Herbay et al. [20] found that 1 ICC out of 126 lesions showed diffuse early arterial contrast enhancement followed by sharp demarcation of the lesion in the late phase. Quaia et al. [16] found that 1 ICC out of 452 liver lesions had a persistent heterogeneous and hypoechoic appearance. Xu et al. [11] reported three types of enhancement patterns in 18 ICCs: heterogeneous hyperenhancement, irregular peripheral rim-like hyperenhancement, and heterogeneous hypoenhancement. However, the differentiation between ICC and HCC by using CEUS has not been investigated.

In this study, four enhancement patterns of ICC in the arterial phase of CEUS were observed, which was consistent with the previous report [21]. The most distinguishing feature was peripheral rim-like hyperenhancement, followed by heterogeneous hypoenhancement, heterogeneous hyperenhancement and homogeneous hyperenhancements. The enhancement patterns of ICC on CEUS may relate to the distribution of tumour vessels and pathological components in the tumour [22]. The peripheral rim-like hyperenhancement may reflect more tumour vessels in the peripheral portion of ICC, as opposed to slender tumour vessels in the central portion [23]. On the gross morphology of ICC, a large amount of fibrous stroma is frequently presented, particularly in the central area [24]. When there are abundant tumour vessels and tumour cells diffused in the whole tumour, diffuse hyperenhancement may be shown on CEUS. In contrast, hypoenhancement may be present if the component of the whole tumour is marked fibrous stroma [25]. In HCC, however, along with the stepwise progression of hepatocarcinogesis, an abnormal process of vascularisation by a shift from a venous to an arterial supply was demonstrated [26], hence 47 out of 50 HCCs in this study demonstrated the typical feature of homogeneous or heterogeneous hyperenhancement during the arterial phase and subsequent contrast washout in the portal phase.

The enhancement patterns of ICC and HCC correlated with tumour size. That is, most small ICCs and HCCs (≤3 cm) were homogeneously enhancing, while those larger than 3 cm enhanced heterogeneously or showed a peripherally enhancing rim. This reflected the intratumoral haemodynamic changes in the course of tumour growth. When an ICC is small, it may be abundant in tumour cells with few fibrous tissues, which leads to homogeneous hypervascularity similar to that of HCC [27]. When grown large, more fibrous tissues and central necrosis appear, and the ICC would show peripheral hypervascularity or overall hypovascularity [28]. Consequently, it is difficult to distinguish small ICC from HCC on CEUS, especially in those with homogeneous hyperenhancement.

During the portal phase, most ICCs and HCCs showed hypoenhancement, which indicated a predominant hepatic artery supply, but a decreased portal venous flow in both tumours. In the late phase, microbubbles washed out more conspicuously in all tumours compared with surrounding liver parenchyma [18, 29], and this feature has a high degree of sensitivity and specificity in the diagnosis of malignant FLLs [16, 30]. The detection rate of tumour vessels was lower in ICC (24%) in comparison with that in HCC (66%), which might be a clue in distinguishing between these two entities.

The analysis of CEUS enhancement patterns and their changes over time showed a possible benefit in differentiating ICC from HCC. The ROC analysis of our study confirmed that when compared with BUS, CEUS improved diagnostic performance, as shown by marked increases in Az values, sensitivity, accuracy and NPV. The number of indeterminate lesions reduced significantly after the contrast agent administration. Furthermore, it allowed for a better interobserver agreement, which revealed increased reproducibility of the diagnostic performance.

The low-MI CEUS allows the quantitative evaluation of blood flow in FLLs [31]. In this study, the TIC analysis demonstrated marked arterial enhancement at the peripheral portion of both ICC and HCC after contrast medium injection, and clear washout during the portal and late phases. However, lower intensity and lower slope were confirmed in both the peripheral and central portions of ICC compared with those of HCC. In comparison with ICC, the abnormal artery supply of HCC was richer, and microvascularisation increased owing to tumour angiogenesis, as well as the presence of abnormal arterovenous shunts [32], so the intensity of HCC was higher than ICC in the arterial phase. On the other hand, the ICC washed out more thoroughly during the portal or late phase in comparison with HCC, both at the periphery and centre of the tumours, so that the intensity of ICC was lower than that of HCC. This phenomenon may indicate that more vessels that trapped microbubbles were present in the HCC.

The main limitation of the study was that some other frequently seen FLLs were not included in the study and some of them may be difficult to differentiate from ICCs and HCCs, such as metastatic liver carcinoma, abscess or other liver tumours [13, 33]. Therefore, the results of the study are only applicable when there is a need to make a distinction between ICC and HCC and the possibility of other tumours had already been excluded. This scenario is not rare in clinical practice after narrowing the range of differential diagnosis for FLLs. In this study, 5 ICCs which presented diffuse hyperenhancement in the arterial phase and washed out during the portal and late phases were misdiagnosed as HCC by both readers. And 2 HCCs with a non-enhancing area in the central portion and peripheral rim-like hyperenhancement in the arterial phase were incorrectly characterised as ICC. These findings may be related to the fact that both readers were blinded to the history of liver cirrhosis, elevation of serum biomarkers such as alpha-fetoprotein or CA 19-9, and other clinical presentations or laboratory findings. It was believed that access to this information would be helpful in solving these problems as it was shown that associated cirrhosis was more commonly found in the HCC group. Finally, as the number of small ICCs in our study is low, the usefulness of CEUS in diagnosing small ICCs needs further investigation with a large series of cases.

In summary, ICC has its own characteristics for the enhancement patterns in comparison with HCC on CEUS. CEUS improves the diagnostic performance significantly in the differentiation between ICC and HCC in comparison with BUS.

Acknowledgments

This work was supported in part by grant NCET-06-0723 from Chinese Ministry of Education and grant 2008-2-10 from the Public Welfare Research Special Project of the Chinese Ministry of Science and Technology.

Copyright information

© European Society of Radiology 2009