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First published online September 27, 2006
British Journal of Radiology (2007) 80, 321-330
© 2007 British Institute of Radiology
doi: 10.1259/bjr/54805002
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Full paper

Correlation between enhancement pattern of hepatocellular carcinoma on real-time contrast-enhanced ultrasound and tumour cellular differentiation on histopathology

G-J Liu, MD 1 H-X Xu, MD, PhD 1 M-D Lu, MD, DMSc 2 X-Y Xie, MD, PhD 1 Z-F Xu, MD 1 Y-L Zheng, MD 1 and J-Y Liang, MD 1

Departments of 1 Medical Ultrasonics and 2 Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China

Correspondence: Ming-de Lu, Department of Hepatobiliary Surgery, The First Affiliated Hospital of Sun Yat-Sen University, 58 Zhongshan Road 2, Guangzhou, 510080, People's Republic of China. E-mail: lumd{at}21cn.com


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 References
 
The objective of this study was to evaluate the correlation between the enhancement pattern of hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS) and tumour cellular differentiation on histopathology. 189 HCC lesions in 189 patients were retrospectively evaluated with CEUS and histopathological examination. CEUS was performed with SonoVue and contrast pulse sequencing. Histopathological diagnoses were made according to the Edmonson grading system. Significant differences were shown between the time that the HCC became hypoenhancing or remained echogenic in late phase and tumour cellular differentiation (p = 0.006; p = 0.036), but not with the time of commencement of hyperenhancing or commencement of isoenhancing in arterial phase and portal phase (p = 0.164, p = 0.113; p = 0.186, p = 0.070). The timing of HCC becoming hypoenhancing on CEUS is correlated with tumour cellular differentiation; well differentiated tumours wash out more slowly than poorly differentiated ones.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 References
 
Hepatocellular carcinoma (HCC) is the most common malignancy in the liver. The most common screening method for HCC is ultrasound examination and measurement of serum levels of alpha-fetoprotein [1]. However, the conventional grayscale ultrasound and colour or power Doppler ultrasound show limited ability in characterizing liver tumours [2–5]. Evaluation of the intranodular blood supply of the lesions in a cirrhotic liver is considered to be useful in differential diagnosis and estimation of the histological grade of malignancy of nodules with various imaging techniques [6–15]. Kumada et al [7] found that Doppler ultrasound findings well reflected differentiation of HCC. Chen et al [10] found that both carbon dioxide (CO2) ultrasound and angiography were equally effective in demonstrating the vascularities in dysplastic nodules and moderately to poorly differentiated HCCs. CO2 ultrasound was significantly superior to angiography when identifying the vascularity in well-differentiated HCCs. With the development of a second generation of ultrasound contrast agents (UCAs) and real-time contrast-specific imaging techniques, contrast-enhanced ultrasound (CEUS) has been widely used in clinical works and has greatly improved the diagnostic ability of ultrasound in focal liver diseases [15–20]. A recent study has reported that the echogenicity of HCC in different vascular phases on CEUS correlated with tumour cellular differentiation by using coherent-contrast imaging (CCI) and SonoVue [15]. Recently we retrospectively evaluated the enhancement pattern of HCC on real-time CEUS, and correlated the enhancement time and enhancement level in different vascular phases to the tumour cellular differentiation.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 References
 
Patients
189 HCC patients admitted to our hospital between March 2004 and November 2005 were included in this study. There were 162 men and 27 women with a mean age of 49.4 years±11.9 (range 20–82 years). Among these 189 patients, 159 had a solitary lesion, 24 had 2 lesions, and 6 had multiple lesions. The clearest lesion on baseline grayscale ultrasound was selected for study in patients with more than one lesion. The mean size of the lesions was 5.88 cm±3.84 (range 1.2–17.0 cm) in diameter; the depth from the bottom of the lesion to the abdominal wall was 6.74 cm±4.08 (range 3.4–20 cm). All patients were confirmed by histopathological examination, with specimens obtained from surgery in 60 patients and percutaneous ultrasound-guided biopsy in 129 patients. Informed consent for the entire procedure was obtained from all patients and the study was approved by the ethics committee of the hospital.

Contrast-enhanced ultrasound (CEUS)
The CEUS examinations were performed for all patients with an Acuson Sequoia 512 scanner (Signature 7.2; Siemens, Mountain View, CA) with incorporated contrast pulse sequencing (CPS) contrast-specific software and a 4V1 vector transducer with a frequency of 1.0–4.0 MHz. SonoVue (BR1; Bracco, Milan, Italy) was used as the UCA in the present study. It is composed of phospholipid-stabilized microbubbles containing sulphur hexafluoride (SF6) gas. The UCA was reconstituted within seconds by the addition of 5 ml of 0.9% sodium chloride solution before use. Through a 20-gauge needle (PrecisionGlideTM; Becton Dickinson, Singapore) 2.4 ml of dispersion was injected into the antecubital vein with a bolus fashion, followed by a flush of 5 ml of 0.9% sodium chloride solution for each patient; no patient received an additional injection. First, the entire liver was scanned with grayscale imaging to identify the lesion. CPS was initiated just before UCA administration. The MI value indicated on the screen was between 0.1 and 0.2. Upon completion of the UCA injection, a stopwatch was started simultaneously. The target lesion and surrounding liver parenchyma were observed continuously for 6 min without exploration of the remaining liver areas. The arterial phase was defined as 7–30 s from the contrast agent injection, the portal phase was 31–120 s from the injection and the late phase was 121–360 s from the injection [20]. Dynamic imaging of the entire CEUS process, including the total arterial phase, total portal phase and several repetitive sections of late phase with interval of 45 s (i.e. 165–180 s from the injection, 225–240 s, 285–300 s, until 345–360 s), was stored in the hard disk incorporated in the scanner. All the dynamic imaging was recorded on a digital video recorder simultaneously. All procedures were performed in the same way by one or two skilled investigators with at least 3 years' experiences of CEUS who were unaware of clinical information, other imaging findings and the pathological diagnosis of the patients.

Pathological examination
All nodule specimens including surrounding cirrhotic liver were stained with haematoxylin–eosin, and each histopathological diagnosis was determined by a pathologist specializing in the liver according to the Edmondson grading system. Grade I consists of cells that are similar in size to normal hepatocytes and arranged in relatively thin trabeculae. Acini containing bile are rare. grade II consists of cells that are larger than normal hepatocytes with more hyperchromatic nuclei, which occupy a higher proportion of cells. The trabeculae are thicker, and acini with bile are common. grade III consists of hepatocytes with larger nuclei, occupying more than 50% of the cytoplasm. The trabeculae are still dominant, but solid areas and isolated cells may also be present. In addition, giant and bizarre cells are common. Bile is rarely present. grade IV consists of cells with nuclei occupying most of the cytoplasm, and the cytoplasm may not be eosinophilic. Mostly solid areas are found. Bile is rarely found. Intravascular and intrasinusoidal growth is commonly present [21].

Image analysis
On CEUS, digital cine clips and digital videotapes were retrospectively analysed in consensus by two investigators who were not involved in the ultrasound scanning and were unaware of the clinical and other imaging information of the patients. The time of initial lesion enhancement and initial liver parenchyma enhancement from the beginning of injection of UCA was recorded separately. The time of the lesion beginning to become isoenhancing or hypoenhancing, that is the time of hyperenhanced part of the lesion wash out to isoenhancement or hypoenhancement with respect to the surrounding liver parenchyma, was also recorded separately. The enhancement levels of the lesion in different vascular phases were also evaluated. The level of enhancement was subdivided into hypoenhancement, isoenhancement and hyperenhancement compared with the surrounding liver parenchyma.

Statistical analysis
Quantitative data are expressed as the mean ± SD. Taking grade I and grade II lesions as well-differentiated HCC, and grade III and grade IV as poorly differentiated HCC, all the lesions were divided into two groups. The correlation between enhancement time or lesion size with tumour cellular differentiation was analysed by t-test. The correlation between the lesions, enhancement level in different vascular phases and tumour cellular differentiation was analysed with the Fisher's exact test. A value of p<0.05 was considered statistically significant. The statistical analyses were performed using the SPSS 10.0 software package (SPSS Inc., Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 References
 
The final pathological diagnoses of all the lesions were as follows: grade I in 22 lesions ranging in diameter from 1.4 cm to 15.5 cm (mean ± SD 3.52±3.21 cm) with 21 male patients and 1 female patient; grade II in 114 lesions ranging in diameter from 1.2 cm to 18.0 cm (mean ± SD 6.32±4.07 cm) with 95 male patients and 19 female patients; grade III in 49 lesions ranging in diameter from 1.6 cm to 13.0 cm (mean ± SD 6.43±3.56 cm) with 42 male patients and 7 female patients; grade IV in four lesions ranging in diameter from 2.3 cm to 9.3 cm (mean ± SD 5.60±3.52 cm) with all male patients. There was no relationship between the size and tumour cellular differentiation of the lesion (t-test, p = 0.397).

Enhancement time
The initial enhancement times of tumour and liver parenchyma were 13.4±3.3 s (range 7~26 s) and 18.0±4.1 s (range 8~30 s), respectively. The times of the tumour beginning to become isoenhancing or hypoenhancing compared with the surrounding liver parenchyma were 34.8±19.1 s (range 11~180 s) and 59.0±36.7 s (range 11~360 s), respectively (Table 1Go). In arterial phase, 179 lesions (94.7%) were enhanced earlier than liver parenchyma; 8 lesions (4.2%) were enhanced at the same time as the parenchyma; the other 2 lesions (1.1%) with 1 in grade I and 1 in grade II were enhanced a few seconds later than liver parenchyma. There was a significant difference between the time that tumours with different cellular differentiation became hypoenhancing (t-test, p = 0.006), but not with the time of commencement of hyperenhancment and commencement of isoenhancement (t-test, p = 0.164, p = 0.113), which indicates that tumours with better differentiation wash out more slowly than poorly differentiated ones (GoGoGoFigures 1–4Go).


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  		Table 1. Time of tumour enhancement in terms of the tumour cellular differentiation

 

Figure 1
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  		Figure 1. Hepatocellular carcinoma(HCC) (Edmonson grade I) in a 65-year-old man. (a) Baseline ultrasound image shows a hypoechoic HCC nodule in the right lobe of the liver 2.1 cm in diameter. (b) Arterial phase image obtained at 19 s after contrast agent administration shows a homogeneous hyperenhancement of the lesion. (c) Portal phase image obtained at 82 s. The nodule is isoechoic with respect to the surrounding liver. (d) Late portal phase image obtained at 190 s. The HCC is slightly hypoechoic with respect to the surrounding liver.

 

Figure 2
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  		Figure 2. Hepatocellular carcinoma(HCC) (Edmonson Grade II) in a 46 year old man. (a) Baseline ultrasound image shows an isoechoic HCC nodule in the right lobe of the liver 3.3 cm in diameter. (b) Arterial phase image obtained at 16 s after contrast agent administration shows a homogeneous hyperenhancement of the lesion. (c) Portal phase image obtained at 113 s. The nodule is slightly hypoechoic with respect to the surrounding liver. (d) Late portal phase image obtained at 240 s. The HCC is hypoechoic with respect to the surrounding liver.

 

Figure 3
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  		Figure 3. Hepatocellular carcinoma(HCC) (Edmonson grade III) in a 51-year-old man. (a) Baseline ultrasound image shows a hypoechoic HCC nodule in the right lobe of the liver 2.0 cm in diameter. (b) Arterial phase image obtained 23 s after contrast agent administration shows a homogeneous hyperenhancement of the lesion. (c) Portal phase image obtained at 48 s. The nodule is slightly hypoechoic with respect to the surrounding liver. (d) Late portal phase image obtained at 180 s. The HCC is hypoechoic with respect to the surrounding liver.

 

Figure 4
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  		Figure 4. Hepatocellular carcinoma(HCC) (Edmonson grade IV) in a 60-year-old woman. (a) Arterial phase image obtained 18 s after contrast agent administration shows a heterogeneous hyperenhancement of the lesion. (b) Portal phase image obtained at 32 s. The nodule is slightly hypoechoic with respect to the surrounding liver. (c) Portal phase image obtained at 90 s. The nodule is hypoechoic with respect to the surrounding liver. (d) Late portal phase image obtained at 180 s. The nodule is remarkably hypoechoic with respect to the surrounding liver.

 
Enhancement level
Arterial phase
178 lesions (94.2%) were hyperenhanced with 18 out of 22 tumours (81.8%) grade I, 108 out of 114 (94.7%) grade II, 48 out of 49 (98.0%) grade III and 4 out of 4 (100%) grade IV. 9 lesions (4.8%) were isoenhanced with 3 out of 22 tumours (13.6%) grade I and 6 out of 114 (5.3%) grade II (Figure 5Go). 2 lesions (1.0%) were hypoenhanced with 1 out of 22 (4.6%) grade I and 1 out of 49 (2.0%) grade III. There was no significant difference between the hyperenhancing lesions and isoenhancing or hypoenhancing lesions of different cellular differentiation in arterial phase (Fisher's exact test, p = 0.186) (Table 2Go).


Figure 5
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  		Figure 5. Hepatocellular carcinoma(HCC) (Edmonson grade I) in a 67-year-old man. (a) Baseline ultrasound image shows a hypoechoic HCC nodule in the right lobe of the liver 2.3 cm in diameter. (b) Arterial phase image obtained at 23 s after contrast agent administration shows a homogeneous isoenhancement of the lesion. (c) Portal phase image obtained at 52 s. The nodule is isoechoic with respect to the surrounding liver. (d) Late portal phase image obtained at 280 s. The HCC is isoechoic with respect to the surrounding liver.

 

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  		Table 2. Echogenicity of hepatocellular carcinomas(HCCs) in arterial phase in terms of the tumour cellular differentiation

 
Portal phase
Four lesions (2.1%) were hyperenhanced with 1 out of 22 (4.5%) grade I and 3 out of 114 (2.6%) grade II. 34 lesions (18.0%) were isoenhanced with 6 out of 22 (27.3%) grade I, 22 out of 114 (19.3%) grade II and 6 out of 49 (12.2%) grade III. 151 lesions (79.9%) were hypoenhanced with 15 out of 22 (68.2%) grade I, 89 out of 114 (78.1%) grade II, 43 out of 49 (87.8%) grade III and 4 out of 4 (100%) grade IV. There was no significant difference between the hypoenhancing lesions and hyperenhancing or isoenhancing lesions of different cellular differentiation in portal phase (Fisher's exact test, p = 0.070) (Table 3Go).


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  		Table 3. Echogenicity of hepatocellular carcinomas(HCCs) in portal phase in terms of the tumour cellular differentiation

 
Late phase
Three lesions (1.6%) were hyperenhanced with 1 out of 22 (4.5%) grade I and 2 out of 114 (1.8%) grade II. Eight lesions (4.2%) were isoenhanced with 2 out of 22 (9.1%) grade I and 6 out of 114 (5.3%) grade II. 178 lesions (94.2%) were hypoenhanced with 19 out of 22 (86.4%) grade I, 106 out of 114 (92.9%) grade II, 49 out of 49 (100%) grade III and 4 out of 4 (100%) grade IV. There was a significant difference between the hypoenhancing lesions and hyperenhancing or isoenhancing lesions of different cellular differentiation in late phase (Fisher's exact test, p = 0.036) (Table 4Go), which indicates that tumours with worse differentiation are more likely to be hypoenhanced in late phase than better differentiated ones.


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  		Table 4. Echogenicity of hepatocellular carcinomas(HCCs) in late phase in terms of the tumour cellular differentiation

 

   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
References
 
The grade of the tumour cellular differentiation is an important prognostic factor for HCC [22]. Several studies have been done to evaluate the relationship between tumour cellular differentiation and imaging findings by contrast-enhanced CT (CECT), contrast-enhanced magnetic resonance imaging (CEMRI), Doppler ultrasound (DUS) and CEUS, which have proved that the tumour cellular differentiation was well correlated with imaging findings [6–15]. Sakabe et al [8] found that high-density early-phase CT and low-density late-phase CT correlated significantly with moderately/poorly differentiated HCCs. In contrast, well-differentiated HCCs appeared as isodense lesions in the early and late phases. Yamashita et al [9] found that, on dynamic MR images, the peak contrast enhancement ratio correlated with tumour grade. The theoretical basis of estimation of tumour cellular differentiation is the multistep nature of HCC carcinogenesis and the haemodynamic changes in tumour blood flow. HCC frequently occurs in association with liver cirrhosis. A benign regenerative nodule may be the first step in the development of overt HCC, progressing in a multistep fashion through the intermediate phases of a low- and high-grade dysplastic nodule, and then to early HCC [23–25]. With the development of modern imaging techniques, we can evaluate the intratumoural vascularity and the haemodynamic changes of tumour blood flow not only with CECT or CEMRI, but also with the newly developed CEUS [25–28]. Hayashi et al [25] found that the intranodular portal venous supply, as evaluated with CT during arterial portography (CTAP), gradually decreased, whereas the intranodular arterial supply, as evaluated with CT during hepatic arteriography (CTHA), first decreased and then increased in accordance with an increase in the grade of malignancy of the hepatocellular nodule. Matsui et al [6] found that a portal blood supply was seen in 96% of cases of dysplastic nodule (DN) and only 6% of HCCs at CTAP. In contrast, an arterial supply greater than that of the surrounding liver was verified in 94% of the HCCs and only 4% of the cases of DN. The blood supply of areas of DN with atypical hepatocytes and the blood supply of well-differentiated HCCs (Edmondson grade I) tended to be intermediate between that of DN without atypia and that of HCC that was Edmondson and Steiner grade II or greater. Histopathological examination is the only way to clarify cellular differentiation of HCC. But it seems to be possible to estimate the histological grade of malignancy of HCC lesions by evaluating the intratumoural vascularity and the haemodynamic changes of tumour blood flow with modern imaging techniques.

CTAP and CTHA do estimate the intranodular portal venous supply and arterial supply more accurately than CECT or CEMRI, but they are more invasive and expensive, which limits their widespread use in clinical practice [25]. On the contrary, colour Doppler ultrasound is cheaper and more convenient in visualizing intranodular portal venous and arterial blood supply, but it has poor sensitivity and accuracy, and is easily influenced by the location of the lesion, the velocity of the blood flow, motion artefact and so on [4, 5]. With the development of a second generation of ultrasound contrast agents and contrast-specific imaging techniques, CEUS can visualize the real-time perfusion of the lesion; it has become a useful and less invasive method for characterizing and evaluating the intranodular blood supply of focal liver lesions.

Nicolau et al [15] found that echogenicity in the portal and late phases correlated with cellular differentiation on CEUS using coherent-contrast imaging (CCI) and SonoVue. In the early portal phase, 16 (15.3%) hypoenhanced HCCs have a significant probability of worse histological differentiation than 1 (1%) hyperenhanced HCC and 87 (83.6%) isoenhanced HCCs. In the late phase, 30 (28.8%) isoenhanced HCCs have a significant probability of better histological differentiation than 74 (71.2%) hypoenhanced HCCs.

With respect to the enhancement time of HCC, we found that the time of HCC became hypoenhancing was correlated with tumour cellular differentiation, with better differentiated HCCs washing out more slowly than worse differentiated ones. With regard to the enhancement level of HCC in different vascular phases, we found that the echogenicity of lesions in late phase correlated with tumour cellular differentiation. In the present study, the hyperenhanced lesions in late phase were 1 out of 22 (4.5%) grade I and 2 out of 114 (1.8%) grade II, and isoenhanced lesions were 2 out of 22 (9.1%) grade I and 6 out of 114 (5.3%) grade II. All the lesions with grade III and grade IV were hypoenhanced in late phase.

The small number of cases of grade I and grade IV is our main limitation in this study and we therefore cannot analyse whether there is a difference between the enhancement time and the enhancement level with every different grade. The other limitation of our study is that 68.3% of HCC nodules were diagnosed with percutaneous ultrasound-guided fine needle biopsy specimens, while the reported sensitivity of fine needle biopsy of the liver focal lesions only ranges from 67% to 100%, averaging about 85% [29]. Therefore further investigations including a larger number of lesions with better distribution in tumour cellular differentiation and clearer pathological confirmation are necessary to evaluate whether CEUS allows the diagnosis of cellular differentiation.

In conclusion, the enhancement pattern of HCC by CEUS using CPS and SonoVue correlates with the cellular differentiation. Well-differentiated tumours fade out more slowly than poorly differentiated ones. In late phase, hyperechoic lesions are likely to be better differentiated, whereas hypoechoic lesions are more likely to be worse differentiated.

Received for publication September 23, 2005. Revision received July 7, 2006. Accepted for publication August 21, 2006.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 References
 

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