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1 All authors: Interventional Ultrasound Service, D. Cotugno Hospital, Via Quagliariello 54, Naples 84100, Italy.
Received October 13, 2003;
accepted after revision February 21, 2004.
Address correspondence to G. Ferraioli
(ferraiol{at}tin.it).
Abstract
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SUBJECTS AND METHODS. Between October 2002 and March 2003, 74 patients with cirrhosis (60 men and 14 women; age range, 47-80 years; mean age, 67 years) who had a single nodule of hepatocellular carcinoma were selected to be studied from a cohort of 437 patients with cirrhosis. The size range of the 74 nodules was 9-65 mm (mean, 28.2 mm). Twenty-eight (38%) were 20 mm smaller (range, 9-20 mm; mean, 16.6 mm), and 46 (62%) were larger than 20 mm (range, 21-65 mm; mean, 35.2 mm). Contrast-enhanced sonography was performed at a low mechanical index after IV administration of the contrast agent SonoVue. CT scans were obtained in all patients. The enhancement pattern related to tumor hypervascularity was analyzed. The chi-square test was used for statistical analysis.
RESULTS. For the 28 hepatocellular carcinomas 20 mm or smaller, contrast-enhanced sonography showed 15 (53.6%) as hypervascular and 10 (35.7%) as avascular; three (10.7%) carcinomas were missed. On CT, 12 (42.9%) of the 28 hepatocellular carcinomas appeared hypervascular, 13 (46.4%) appeared hypovascular, and three (10.7%) were missed. For the 46 hepatocellular carcinomas larger than 20 mm, contrast-enhanced sonography showed 42 (91.3%) as hypervascular and four (8.7%) as avascular. On CT, 35 (76.1%) hepatocellular carcinomas appeared hypervascular, eight (17.4%) appeared hypovascular, and three (6.5%) were missed. Differences between CT appearance of hepatocellular carcinomas and contrast-enhanced sonographic appearance of the carcinomas were not statistically significant. Concordance between contrast-enhanced sonographic and CT appearances was observed in 61 (82.4%) of 74 cases.
CONCLUSION. Contrast-enhanced sonography is similar to CT for detecting hepatocellular carcinoma hypervascularity. It could be complementary to conventional unenhanced sonography for evaluation of liver nodules.
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Findings of a solid liver mass on sonography are often nonspecific, thus requiring contrast-enhanced CT or MRI characterization [10-16]. In addition to imaging studies, a needle biopsy is recommended for all nodules with a diameter smaller than 2 cm [9]. However, concerns have been raised about the risk of seeding during fine-needle biopsy aspiration of hepatocellular carcinoma in patients who will undergo liver transplantation or surgical resection [17-19] that has been estimated to be up to 3.4% [20].
In the last few years, different gases and coating materials have been used to develop a wide variety of contrast agents in an attempt to improve the low specificity of sonography for the characterization of focal liver lesions. Levovist (SH U 508A [a combination of galactose microparticles and palmitic acid], Schering), a sonographic contrast agent first used for the enhancement of Doppler ultrasound signals, has been tested as an aid to differentiating hepatic lesions on the basis of their appearance after IV contrast injection [21-23]. Levovist-enhanced sonography requires interval-delay imaging; that is, the imaging process must be interrupted for several seconds. A new generation of sonographic intravascular contrast agents with higher reflectivity than that of the previous generation is now available. SonoVue (BR1, Bracco Diagnostics) is a sulfur hexafluoride gas stabilized with phospholipids that presents a high reflectivity at a low mechanical index and is characterized by a low solubility in water and a low diffusion in blood. Like other newly available contrast agents such as Definity (phospholipid-coated microbubbles filled with perfluorocarbon gas, Dupont/ImaR), SonoVue persists in the bloodstream much longer after IV injection than the previous contrast agents used in sonography, so it can actually be considered a blood pool contrast agent. The contrast-enhancing effect of SonoVue does not require the rupture of the microbubbles but is based on the continuous resonance of the microbubbles under an ultrasound field with a low mechanical index. This mechanism of enhancement allows real-time imaging of the microcirculation that lasts several minutes, so that the early arterial and late parenchymal phases of the contrast medium diffusion can be analyzed.
The purpose of this study was to investigate the sonographic appearance of hepatocellular carcinoma using a nondestructive contrast agent to define the imaging characteristics of hepatocellular carcinoma by comparing the results to those obtained with contrast-enhanced helical CT.
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Subjects
Between October 2002 and March 2003, 437 patients (321 men and 116 women;
age range, 42-85; mean age, 65 years) with cirrhosis who were thought to have
at least one nodule of hepatocellular carcinoma on the basis of sonographic
findings were referred to our institution for further evaluation. Of these 437
patients, 79 consecutive patients with a single liver nodule were selected for
the study. Five patients were excluded because the results of nodule histology
or cytology were not conclusive (three cases) or because the lesion turned out
not to be hepatocellular carcinomas (two cases). Thus, our study group
consisted of 74 patients (60 men and 14 women; age range, 47-80 years; mean
age, 67 years). On contrast-enhanced helical CT, two additional lesions
(sizes, 13 and 15 mm) were found in two patients that were both localized in
the subcapsular portion of hepatic segment VIII. These patients were included
in the subsequent analysis, and only the nodule seen on conventional
sonography was studied using the contrast agent.
The diagnosis of liver cirrhosis was based on liver biopsy findings in 61
of the 74 patients and on clinical data in the remaining patients. The cause
of cirrhosis was related to hepatitis C virus in 61 patients, alcoholism in
four patients, a combination of alcoholism and hepatitis C virus in two
patients, and hepatitis B virus in five patients; in two patients, the cause
was cryptogenic. The tumors were located in the right lobe of the liver in 57
patients and in the left lobe in 17 patients. The 74 tumors ranged in size
from 9 to 65 mm (mean, 28.2 mm). Twenty-eight (38%) of the hepatocellular
carcinomas were 20 mm or smaller in diameter (range, 9-20 mm; mean, 16.6 mm),
and 46 (62%) were larger than 20 mm (range, 21-65 mm; mean, 35.2 mm).
According to the degree of cirrhosis-related impairment of liver function, 41
patients were in Child-Pugh class A and 33 in class B. Serum levels of
-fetoprotein were below 20 ng/mL in 57 patients and between 20 and 40
ng/mL in 17 patients.
The treatment was approved by our institutional review board, and informed consent was obtained from all patients after the nature of the procedure had been fully explained.
Equipment
All abdominal sonography was performed using a commercially available
scanner with a software for contrast media (Prosound SSD-5500 PureHD Extended,
Aloka) with a 3.0-6.0-MHz convex array broadband probe. Triphasic
contrast-enhanced helical CT scans were performed using a helical CT scanner
(Somatom Balance, Siemens Medical Solutions).
Contrast Agent
SonoVue is a suspension of stabilized sulfur hexafluoride (SF6)
microbubbles in saline (0.9% sodium chloride) commercially available in
Europe. SonoVue was supplied as a sterile lyophilized powder (25 mg) in a
gaseous atmosphere (SF6) in 10-mL vials. The SonoVue preparation
was reconstituted just before administration by adding 5 mL of sterile saline
to the vial using standard clinical aseptic techniques.
Procedure
Before contrast agent injection, we determined the scanning plane of the
liver that included the nodule. After the baseline sonographic examinations,
all patients underwent sonography using SonoVue. A volume of 2.4 mL of SonoVue
was injected IV in bolus via a 20-gauge needle followed by a 5.0-mL saline
flush.
Contrast-enhanced sonography was performed using a low-pressure setting (mechanical index, 0.04) that was automatically defined by the contrast media software of the sonography unit. Gain ranged from 30 to 90 dB according to the patient's body habitus, the dynamic range was set up to 184 dB, and the frame rate was 13 per second. The line density and frame rate were set to a high level. Images were stored on super-VHS videotapes.
Immediately after contrast medium injection, we continuously scanned the hepatic lesion to be studied sonographically for up to 5 min until the enhancement effect began to decrease. The contrast enhancement pattern was determined by evaluating the behavior of the hepatic lesion throughout the sonographic examination after IV injection of the contrast agent. The whole vascular phase was studied, consisting of the arterial phase (15-30 sec after the injection), the portal phase (30-60 sec), and the sinusoidal phase (60-240 sec). Washout was evaluated as a criterion on contrast-enhanced sonography as it was on CT studies and thus was estimated as a change from a hyperechoic lesion relative to the liver at arterial phase to an iso- or hypoechoic lesion relative to the liver at portal and sinusoidal phases. The same operator with more than 20 years of experience with sonography and who was unaware of CT findings performed all contrast-enhanced sonographic studies. He was asked only to describe the pattern of nodule vascularity, if any. A second injection of SonoVue was needed in one patient.
CT was performed according to the technique described by Lim et al. [24], using a helical CT scanner (Somatom Balance, Siemens Medical Sotions). Data acquisitions were obtained through the whole liver in a craniocaudal direction (thickness, 5 mm; table speed, 7.5 mm/sec; pitch, 1.5) during a single breath-hold helical acquisition of 20-25 sec, depending on liver size. Successively, contiguous images were reconstructed. In a triphasic evaluation model, arterial, portal, and delayed phase images were obtained at 30, 60, and 180 sec, respectively, after the start of the injection of 120 mL of nonionic iodinated contrast material (Iopamiro 370 [iopamidol], Bracco). A power injector (Stellant CT Injection System, Medrad) delivered the contrast material via the antecubital vein at a flow rate of 3 mL/sec. The same operator, who had a 15 years' experience with CT and who was unaware of the results of contrast-enhanced sonography, interpreted all CT scans.
Biopsies were performed using a 19-gauge modified Menghini needle in 48 patients. In the remaining patients, fine-needle-aspiration biopsies were performed.
Image Interpretation
Contrast-enhanced sonographic criteria.—The IV injection of
sonographic contrast agents that remain within the blood pool results in echo
enhancement from systemic arteries of up to 30 dB
[25]. In our study, the
enhancement pattern of the tumor as compared with that of the surrounding
liver parenchyma was analyzed. In particular, after IV injection of the
contrast medium, the appearances of focal areas of hyperechogenicity, which
are related to hypervascularity, in the nodule seen on baseline unenhanced
gray-scale imaging was carefully studied (see Results).
Contrast-enhanced helical CT criteria.—Hepatocellular carcinomas were classified as hypervascular if a nodular focus of homogeneous or heterogeneous enhancement was identified on arterial phase images, hypovascular if the lesions were best depicted on portal venous or equilibrium phase images as hypoattenuating relative to adjacent liver tissue, or missed if CT failed to show the nodular lesions.
The statistical analysis was performed using the chi-square test. A p value of less than 0.05 was considered to indicate a statistically significant difference. Concordance between the findings of contrast-enhanced sonography and contrast-enhanced helical CT was calculated.
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When the low mechanical index of the contrast media setting on the scanner
was switched on, no backscattering from tissues was seen except for the echoes
from the diaphragm. At a mean ± SD time of 11 ± 2 sec after the
injection of the contrast agent, the hepatic arterial vascular bed was
visualized in real time as hyperechoic lines going from the hepatic hilum into
the liver parenchyma. We observed two patterns of tumor hypervascularity: The
first pattern was a homogeneous and rapid filling of the lesion (15-20 sec
after the injection) that became intensely hyperechoic relative to the
surrounding liver tissue with a rapid washout of the contrast agent, thus
having the appearance of hypoechoic lesion in the portal and sinusoidal phase
images (Figs. 1A,
1B,
1C,
1D), and the second pattern was
a reticular, inhomogeneous filling of the lesion that became hyperechoic
relative to the surrounding liver tissue during the arterial phase (15-20 sec
after the injection) and that showed a delayed (
4 min) washout, thus
remaining hyperechoic relative to the surrounding liver tissue during the
portal and sinusoidal phases (Figs.
2A,
2B,
2C,
2D).
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After IV injection of the contrast medium, some lesions did not show any enhancement, whereas others lost the appearance of nodular masses and were not seen anymore. Therefore, the tumors were classified as belonging to one of three groups. We classified a tumor as hypervascular if the nodule showed an early, intense, and homogeneous enhancement during the arterial phase (15-30 sec after the IV bolus) with a rapid washout of the contrast agent so that it was hyperechoic relative to the liver on the arterial phase images and hypoechoic relative to the liver on the portal phase images or if the nodule showed an early and heterogeneous enhancement during the arterial phase lasting a longer time so that the lesion was hyperechoic relative to the liver during the arterial, portal, and sinusoidal phases. A tumor was classified as avascular if no enhancement of the tumor was observed after the injection of the contrast agent (i.e., the lesion was hypoechoic relative to the liver during the arterial, portal, and sinusoidal phases) (Figs. 3A, 3B) and as missed if a nodular lesion seen on conventional unenhanced sonography was not visible as a space-occupying lesion after contrast agent injection. Contrast-enhanced sonography was technically inadequate in one case even after a second IV injection of the contrast agent.
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After IV injection of the contrast agent SonoVue, 57 (77%) of the 74 hepatocellular carcinomas showed a hypervascular pattern, and 14 (18.9%) were avascular. Three tumors (4.1%) were missed. Contrast-enhanced helical CT showed hypervascular tumors in 47 (63.5%) of 74 cases and hypovascular tumors in 21 (28.4%) of 74 cases. Six tumors (8.1%) were missed.
None of the differences between the results of contrast-enhanced helical CT and contrast-enhanced sonography was statistically significant.
Hepatocellular Carcinomas with a Diameter of 20 mm or Smaller
Contrast-enhanced sonographic patterns of the 28 hepatocellular carcinomas
with a diameter of 20 mm or smaller are reported in
Table 2, and contrast-enhanced
CT patterns of these carcinomas are reported in
Table 3. Six (40%) of the 15
hypervascular tumors showed a reticular pattern on sonography. None of the
differences between contrast-enhanced helical CT and contrast-enhanced
sonographic results was statistically significant.
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Hepatocellular Carcinomas with a Diameter Larger Than 20 mm
Contrast-enhanced sonographic patterns of 46 hepatocellular carcinomas are
reported in Table 2, and
contrast-enhanced CT patterns of the carcinomas are reported in
Table 3. Two (4.8%) of the 42
hypervascular tumors showed a reticular pattern on sonography. None of
differences between contrast-enhanced helical CT and contrast-enhanced
sonography results was statistically significant.
Comparison of Contrast-Enhanced Sonography and Contrast-Enhanced Helical CT
The sensitivities of contrast-enhanced sonography and contrast-enhanced
helical CT for characterizing hepatocellular carcinomas are reported in
Table 4. There was concordance
between contrast-enhanced sonographic and contrast-enhanced helical CT
findings in 61 (82.4%) of 74 cases (Table
5).
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The guidelines of the European Society for the Study of Liver Disease [9] recommend that the imaging detection of a liver nodule 2.0 cm or smaller should always be confirmed with needle biopsy, whereas the coincident findings on at least two imaging techniques (sonography, CT, or MRI) of a tumor larger than 2.0 cm may be used to confidently establish the diagnosis without the confirmation of a positive biopsy result. However, the risk of seeding hepatocellular carcinoma during a needle biopsy cannot be disregarded because tumor seeding may have a major impact on a patient's prognosis, hindering liver transplantation or surgical resection [17-20]. Therefore, accurate and sensitive imaging techniques are needed to reliably depict subtle nodules of hepatocellular carcinoma.
The use of conventional or contrast-enhanced Doppler sonography to provide vascular information is often limited in hepatic masses that are small, deep in the abdomen, or subject to motion artifacts from either respiratory or cardiac activity [25]. Helical CT is so far considered the imaging technique of choice for the diagnosis and staging of hepatocellular carcinoma in cirrhosis [10-16].
Sonographic contrast agents can provide information about microvascular flow and perfusion not currently obtainable using conventional techniques. Microbubble contrast agents interact with the scanning process. The nature of this interaction depends on the scanning parameters, mainly the peak rarefactional pressure and the ultrasound frequency. A combination of these parameters is expressed by the mechanical index [25]. Using a low mechanical index to minimize the harmonic response from tissues with the second generation of contrast agents produces images of the microcirculation that are based only on the response of microbubbles.
In our study, the 28 tumors with a diameter of 20 mm or smaller showed a hypervascular pattern in 53.6% (15/28) of the cases on contrast-enhanced sonography and in 42.9% (12/28) of the cases on helical CT. For the 46 tumors with a diameter larger than 20 mm, the hypervascular pattern was observed in 91.3% (42/46) of the cases on contrast-enhanced sonography and in 76.1% (35/46) of the cases on helical CT. No statistically significant differences between contrast-enhanced sonography and contrast-enhanced helical CT were found in the visualization of the hypervascular pattern, which is considered specific for hepatocellular carcinoma. In our series of patients, approximately 10% of small hepatocellular carcinomas were seen as hypervascular lesions on contrast-enhanced sonography but showed a hypovascular pattern on contrast-enhanced CT; however, this difference was not statistically significant. The advantage of contrast-enhanced sonography with respect to contrast-enhanced helical CT could be due to continuous real-time imaging, which permits the detection of a fleeting hypervascularity that could be missed in a technique such as CT, which is dependent on interval-delay imaging acquisition. On the other hand, increased real-time imaging potentially increases overall examination time. For this reason, CT may remain the preferable technique.
There are some limitations to sonographic imaging. Sonography is a procedure that is still strongly influenced by the skillfulness of the operator (operator-dependent) and is susceptible to the patient's body habitus. Moreover, studying the characteristics of a focal lesion on contrast-enhanced sonography requires determining the scanning plane in which the lesion is located. Therefore, in patients with multiple lesions, it is not possible to study all the lesions simultaneously but only one at a time because of the rapid contrast filling and washout of most hypervascular lesions. CT has the advantage in imaging patients with multiple liver lesions, as many patients with cirrhosis have. For the purposes of this study, only patients with a single liver nodule were selected.
A contrast-enhanced dynamic study is considered an important factor in the detection of hepatocellular carcinoma. Of paramount importance is the observation of an early tumor enhancement, which is determined by its hypervascularity as observed on angiography [28]. In this study, both the sonography and CT operators were aware of the presence of the liver nodules but unaware of the findings on the other imaging technique. The use of an MDCT scanner could have improved the detection rate of hepatocellular carcinomas. Nonetheless, the design of the study was to compare the contrast-enhanced sonographic appearance of hepatocellular carcinomas with that of the carcinomas on a standardized widely available imaging technique such as helical CT.
Lesions seen as hyperenhancing on arterial phase CT that were proven not to be hepatocellular carcinomas have been reported [29]. However, hypervascular metastases should be taken into account when making a diagnosis [30]. All patients included in our study had a biopsy-proven hepatocellular carcinoma, thus excluding any false-positive detection rates.
The information concerning the sonographic appearance of hepatocellular carcinomas using a nondestructive contrast agent obtained in this study can be used in further studies to investigate how well contrast-enhanced sonography characterizes liver lesions and whether the technique could supplant biopsy.
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