| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Original Research |
1 All authors: Diagnosis Imaging Center, Hospital Clinic, Villarroel 170, Barcelona 08036, Spain.
Received June 26, 2004;
accepted after revision January 6, 2005.
Address correspondence to C. Nicolau
(cnicolau{at}clinic.ub.es).
Abstract
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
SUBJECTS AND METHODS. In 152 patients (105 with chronic liver disease), 152 solid focal liver lesions characterized either by fine-needle biopsy or by dynamic CT or MRI were studied. The final diagnoses were metastasis for 24, hepatocellular carcinoma for 75, focal nodular hyperplasia for 13, regenerating or dysplastic nodule for 14, hemangioma for 22, cholangiocarcinoma for two, and another focal liver lesion for two. Real-time sonography was performed after a bolus injection of 2.4 mL of SonoVue, using a low mechanical index (< 0.2). All lesions were evaluated in the arterial, portal, and late phases; classified as benign or malignant; and correlated with final diagnoses.
RESULTS. For discrimination between malignant and benign focal liver lesions, evaluation of all vascular phases improved the sensitivity from 78.4% to 98% and the accuracy from 80.9% to 92.7%, compared with evaluation of the late phase alone. The increase in accuracy was higher in patients with chronic liver disease (16.3%) than in those without (2.1%).
CONCLUSION. Evaluation of SonoVue enhancement in all three vascular phases is superior to evaluation of SonoVue enhancement in the late phase alone, especially in patients with chronic liver disease.
Keywords: abdominal imaging • contrast media • dynamic sonography • liver disease • sonography
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
New sonographic contrast agents with a highly flexible shell can be used with a low mechanical index, allowing continuous real-time imaging of contrast enhancement during the arterial, portal, and late phases [3, 10]. However, there have been only a few reports of large numbers of patients examined with real-time imaging techniques combined with new contrast agents [11-13]. SonoVue (Bracco) is a blood-pool sonographic contrast agent that consists of microbubbles of a sulfur hexafluoride gas stabilized by a phospholipid shell [14]. Its usefulness in improving the display of focal tumor vascularity and normal parenchymal liver vascularity using Doppler sonography has been shown [15], and it allows continuous real-time examination during the different phases of contrast enhancement using a low mechanical index. Furthermore, it has a specific late phase with selective enhancement of the parenchyma of the liver and spleen [16]. The exact site of the contrast agent accumulation remains unknown, but unlike Levovist, it may accumulate in the normal sinusoids [17]. In preliminary studies, SonoVue appeared to behave similarly to first-generation contrast agents in the late phase, with absence of enhancement in malignant focal liver lesions [18].
The aim of our study was to evaluate the diagnostic efficacy of the late vascular phase of SonoVue versus all vascular phases in differentiation between benign and malignant focal liver lesions.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
From January 2002 to March 2003, 152 patients with at least one focal liver lesion detected on unenhanced sonography were included in this prospective study. We included only patients with a focal liver lesion detected by sonography who had a final diagnosis confirmed by histologic examination or by CT or MRI. In all patients with a benign diagnosis on CT or MRI, a follow-up sonographic study of at least 9 months was required to confirm that the lesion was benign, and the size of the lesion had to have remained stable during the interval between the two sonographic studies. In patients with multiple liver lesions, only one lesion was analyzed; thus, 152 tumors were studied. The study group included 76 men and 76 women (age range, 25-88 years; mean, 60 ± 12.5 [SD] years). The sonographic study was performed because of a history of chronic liver disease in 105 patients, clinical suspicion of metastases in 31, and underlying gastrointestinal symptoms or abnormal liver chemistry without known hepatopathy in 16. Among patients with chronic liver disease, 84 were positive for the hepatitis C virus, eight had alcoholic liver cirrhosis, seven were positive for the hepatitis C and B viruses, one had alcoholic liver cirrhosis and was positive for the hepatitis C virus, four had cryptogenic cirrhosis, and one had primary biliary cirrhosis. Patients with suspected metastatic liver disease had the following diagnoses: adenocarcinoma of the colon (n = 13), adenocarcinoma of the pancreas (n = 2), adenocarcinoma of the stomach (n = 2), melanoma (n = 4), carcinoma of the lung (n = 3), breast carcinoma (n = 2), carcinoma of the esophagus (n = 2), laryngeal carcinoma (n = 2), and primitive neuroendocrine tumor (n = 1).
The final diagnoses of the focal liver lesions (Table 1) were obtained by histologic examination in 120 (79%) of 152 patients; in the other 32 (21%) of 152 patients, the lesions were diagnosed through CT or MRI: For diagnoses made through fine-needle biopsy, all contrast-enhanced sonographic studies were performed immediately before the fine-needle biopsy, and for diagnoses made through CT or MRI, the interval between the CT or MRI and the contrast-enhanced sonography was 0-30 days.
|
Imaging Techniques
All sonographic studies were performed by one of the staff radiologists
using Sequoia 512 equipment (Acuson). First, a baseline sonogram of the liver
in fundamental mode, using gray-scale, was obtained with a multifrequency 4C1
convex array probe to identify the focal liver lesion. When the suspected
lesion was identified, it was measured routinely. Afterward, dynamic real-time
contrast-enhanced sonography was performed using contrast-coherent imaging,
which is a nonlinear imaging technology that provides high sensitivity in
microbubble detection. Contrast-coherent imaging was performed with the same
convex array probe, with a double focus in the area of interest, using the
following settings: insonating frequency, 3 MHz; acoustic power, -75 to -90
dB; and frame rate, 17-20 sec. A low mechanical index (< 0.2) was selected
to avoid microbubble disruption. Contrast-enhanced sonographic studies were
performed after the administration of 2.4 mL of SonoVue as a bolus with a
21-gauge peripheral IV cannula. A vial of this contrast agent contains sulfur
hexafluoride microbubbles stabilized by phospholipids, and the microbubble
dispersion must be prepared before use by injecting 5 mL of saline solution
into the contents of the vial and shaking vigorously for a few seconds. Every
injection was followed by a 5-mL saline flush. Two patients required a second
injection of 4.8 mL of contrast agent (a second vial was needed), because the
degree of contrast enhancement provided by the first dose was judged by the
radiologist to be insufficient to evaluate liver parenchyma enhancement.
The enhancement pattern of the focal liver lesions was studied during the vascular phase up to 3.5 min, including the arterial (0-49 sec), portal (50-120 sec), and late (> 120 sec) phases. Because we used a low mechanical index, a second injection of contrast agent was not needed to examine the late phase. The radiologists who performed the sonographic studies selected and stored the images on 3-sec digital cine loops or on super-VHS videotapes. Because the beginning of arterial enhancement depends on the arrival time of the contrast agent, videotape-clip or videotaped sequences showing maximal enhancement of the intrahepatic arteries near the focal liver lesions were selected for the arterial phase.
Imaging Analysis
The radiologists who performed the sonographic examination were unaware of
the final diagnosis but not of the patient's clinical data. Videotapes and
cine loops of the 152 liver tumors were retrospectively reviewed by two
independent radiologists who are experts in sonography and microbubble
contrast agents, and the analyses were determined by consensus. These two
reviewers were unaware of the definitive diagnosis and other imaging
information at the time of the retrospective analysis but not of the liver
parenchyma echostructure because it was impossible to hide the parenchyma
surrounding the liver lesions. All these lesions were evaluated before and
after contrast agent injection. From the baseline study, the echogenicity of
the lesions was determined with respect to the surrounding parenchymal liver.
From the contrast-enhanced sonographic study, the reviewers subjectively
determined the intensity of lesion enhancement compared with that of the
surrounding liver (hyperechoic, isoechoic, or hypoechoic relative to the
surrounding liver parenchyma) in three different phases: arterial (< 50
sec), portal (60-70 sec), and late (> 120 sec). They also evaluated the
dynamic enhancement pattern of the lesion: intratumoral, peripheral globular
(discontinuous ring of contrast-enhanced peripheral globules), rimlike (a
ringlike enhancement at the periphery of the tumor), and none. The suspected
nature of each lesion was expressed as benign or malignant on the basis of the
contrast enhancement pattern. In the late phase, isoechoic or hyperechoic
focal liver lesions were classified as suggestive of benignity and hypoechoic
lesions as suggestive of malignancy following previously described criteria
[4]
(Table 2). In the vascular
phase, focal liver lesions were classified by using our institutional criteria
[10]
(Table 2). The results were
compared with the final diagnosis based on the standard of reference in terms
of benignity or malignancy.
|
Statistical Analysis
The SPSS program (version 10.0, SPSS Inc.) was used for the statistical
analysis. The baseline characteristics of the patients and the size of focal
liver lesions are expressed as mean ± SE. The relationship between the
classification of benign or malignant at the late and vascular phases and the
final diagnosis was analyzed with the Fisher exact test. We calculated
accuracy for the diagnosis of malignancy in terms of sensitivity and
specificity. For all analyses, a p value of less than 0.05 was
considered statistically significant.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Of the 152 focal liver lesions, 28 (18.4%) were hyperechoic with respect to the surrounding liver, 23 (15.1%) were isoechoic, 88 (57.9%) were hypoechoic, and 13 (8.6%) were heterogeneous.
Contrast-Enhanced Sonography
Table 3 shows the
enhancement pattern of benign and malignant focal liver lesions in the
arterial, portal, and late phases.
|
In the arterial phase, 127 (83.6%) of the 152 lesions were hyperechoic, 13 (8.6%) were isoechoic, and 12 (7.9%) were hypoechoic with respect to the surrounding liver. There were no significant differences in the benignancy or malignancy of the focal liver lesions depending on their echogenicity in the arterial phase (p > 0.05).
In the portal phase, 14 (9.2%) of the 152 lesions were hyperechoic, 100 (65.8%) were isoechoic, and 38 (25%) were hypoechoic. There were significant differences in the benignancy or malignancy of the focal liver lesions depending on the echogenicity in the portal phase (p < 0.05), with a higher probability of benignancy if the lesion was hyperechoic in this phase and a higher probability of malignancy if the lesion was hypoechoic (Figs. 1A, 1B, and 1C).
|
|
|
|
|
|
|
|
|
|
|
|
|
Seven (14%) of 50 benign tumors were misdiagnosed as malignant because of their hypoechogenicity in the late phase. Three were hemangiomas (with a large part [> 50%] remaining hypoechoic at 180 sec after the contrast injection) (Figs. 5A, 5B, 5C, and 5D), three were regenerating or dysplastic nodules, and one was a fibrous tumor.
|
|
|
|
However, if we evaluated all three vascular phases instead of only the late phase, the accuracy of the diagnosis of malignancy improved from 80.9% to 92.8% (141/152) (p < 0.05), with an increase in sensitivity from 78.4% to 98% (100/102) and a decrease in specificity from 86% to 82% (41/50) for the diagnosis of malignancy (Table 4).
Table 5 shows the frequency and percentage of focal liver lesions correctly classified as benign or malignant in the vascular and late phases. Of the 22 isoechoic HCCs in the late phase, 20 were correctly diagnosed as malignant (because of their arterial enhancement) when all the vascular phases were analyzed, and two well-differentiated HCCs without enhancement in the arterial phase were misdiagnosed as benign. These two HCCs were the only malignant tumors diagnosed as benign when all vascular phases were analyzed. In contrast, nine (18%) of 50 benign focal liver lesions were misdiagnosed as malignant when the three vascular phases were analyzed: four of 22 hemangiomas (two without a clear centripetal filling in the portal and late phases, and two small hemangiomas in cirrhotic patients with intratumoral homogeneous enhancement in the arterial phase that was isoechoic in the late phase), one of 13 focal nodular hyperplasias (because of homogeneous enhancement in the arterial phase that was isoechoic in the late phase in a patient with chronic liver disease), two of two dysplastic nodules (because of enhancement in the arterial phase that was hypoechoic in the late phase), one regenerating nodule (because it did not enhance in either the arterial phase or the late phase), and one fibrous tumor (because arterial enhancement with quick washout was hypoechoic in the portal and late phases, suggesting metastasis).
|
On evaluating the possible influence of chronic liver disease, we detected a higher accuracy for contrast-enhanced sonography in the group of patients without chronic liver disease than in the group of patients with chronic liver disease, especially in the late phase: 93.6% versus 75.2% when the late phase was analyzed (p < 0.05) and 95.7% versus 91.5% when the vascular phase was analyzed (p > 0.05). In addition, accuracy improved significantly when the complete vascular phase was used, instead of only the late phase, in the group of 105 patients with chronic liver disease with an increase of 16.3%, but not in the group of 47 patients without it with an increase of accuracy of only 2.1%. For the former group, accuracy was 75.2% (79/105) and 91.4% (96/105), sensitivity was 71% (54/76) and 97.4% (74/76), and specificity was 86.2% (25/29) and 75.9% (22/29) for the late phase and the vascular phase, respectively. For the latter group, accuracy was 93.6% (44/47) and 95.7% (45/47), sensitivity was 100% (26/26) and 100% (26/26), and specificity was 85.7% (18/21) and 90.5% (19/21) for the late phase and the vascular phase, respectively.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
These difficulties in the characterization of liver lesions using the late phase can be overcome by evaluating all the vascular phases. A real-time evaluation of progressive contrast enhancement of the tumor microvasculature during the arterial, portal, and late vascular phases can be achieved by combining nondestructive low-mechanical-index imaging (< 0.2) with contrast agents such as SonoVue, Optison ([perflutren protein type A microspheres] Amersham), or Definity ([perflutren lipid microspheres] Bristol-Myers Squibb). Using a low mechanical index and evaluating all vascular phases, we achieved an increase of 12.2% in the global accuracy of differentiating between benignancy and malignancy with respect to evaluation of the late phase. Because both benign and malignant focal liver lesions may show enhancement in the arterial phase using contrast-enhanced sonography [20], they may be differentiated by adding the portal and late phases. Hypervascular metastases show a quick washout that begins in the arterial phase and causes them to appear hypoechoic in the portal and late phases, whereas benign tumors such as small hemangiomas and focal nodular hyperplasia remain isoechoic or even hyperechoic in the portal and late phases because of persistence of contrast agent in the lesion. Other characteristics that are useful for differentiation of focal liver lesions include the fact that centripetal enhancement is almost pathognomonic of hemangiomas [27] and that a centrifugal blood supply spreading from the center of the lesion to the periphery and the presence of a central scar are suggestive of focal nodular hyperplasia [10, 28].
Differential diagnosis in patients with chronic liver disease is more challenging. First, because of hemodynamic changes in cirrhotic patients, in some cases the parenchymal enhancement in the late phase may appear heterogeneous and less intense than expected. Thus, in this phase, focal liver lesions can be difficult to differentiate from liver parenchyma, and benign focal liver lesions may be misdiagnosed as malignant. Second, HCC is characterized by its hypervascularity in the arterial phase [22, 26, 29] with a washout in the portal phase. The presence of a hypoechoic lesion in the late phase in a cirrhotic patient is suggestive of HCC, but HCC cannot be excluded in patients with a focal liver lesion that remains isoechoic in the late phase, because some HCCs may remain undetected because of their isoechogenicity during this phase [12]. Finally, high-grade dysplastic nodules precede early HCC and sometimes show arterial enhancement, making them impossible to differentiate from well-differentiated HCC in patients with chronic liver disease.
One limitation of the study is the bias introduced by the fact that the reviewers knew the status of the liver echostructure. This bias in the classification of benignancy or malignancy could explain the high accuracy of our study compared with other studies using contrast-enhanced sonography. However, we think that focal liver lesions should be evaluated in a clinical context, taking the presence of chronic liver disease into account.
In conclusion, for differentiating between benign and malignant focal liver lesions, evaluation of SonoVue enhancement in all three vascular phases is superior to evaluation of SonoVue enhancement in the late phase alone, especially in patients with chronic liver disease.
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  F. Moriyasu and K. Itoh Efficacy of Perflubutane Microbubble-Enhanced Ultrasound in the Characterization and Detection of Focal Liver Lesions: Phase 3 Multicenter Clinical Trial Am. J. Roentgenol., July 1, 2009; 193(1): 86 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Luo, K. Numata, M. Morimoto, A. Nozaki, Y. Nagano, K. Sugimori, and K. Tanaka Three-Dimensional Contrast-Enhanced Sonography of Vascular Patterns of Focal Liver Tumors: Pilot Study of Visualization Methods Am. J. Roentgenol., January 1, 2009; 192(1): 165 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Chami, N. Lassau, D. Malka, M. Ducreux, S. Bidault, A. Roche, and D. Elias Benefits of Contrast-Enhanced Sonography for the Detection of Liver Lesions: Comparison with Histologic Findings Am. J. Roentgenol., March 1, 2008; 190(3): 683 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. K. Kim, H.-J. Jang, P. N. Burns, J. Murphy-Lavallee, and S. R. Wilson Focal Nodular Hyperplasia and Hepatic Adenoma: Differentiation with Low-Mechanical-Index Contrast-Enhanced Sonography Am. J. Roentgenol., January 1, 2008; 190(1): 58 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Lanka, H.-J. Jang, T. K. Kim, P. N. Burns, and S. R. Wilson Impact of Contrast-Enhanced Ultrasonography in a Tertiary Clinical Practice J. Ultrasound Med., December 1, 2007; 26(12): 1703 - 1714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Quaia, M. D'Onofrio, P. Cabassa, F. Vecchiato, S. Caffarri, F. Pittiani, K. M. Wittkowski, and M. A. Cova Diagnostic Value of Hepatocellular Nodule Vascularity After Microbubble Injection for Characterizing Malignancy in Patients with Cirrhosis Am. J. Roentgenol., December 1, 2007; 189(6): 1474 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Murphy-Lavallee, H.-J. Jang, T. K. Kim, P. N. Burns, and S. R. Wilson Are Metastases Really Hypovascular in the Arterial Phase?: The Perspective Based on Contrast-Enhanced Ultrasonography J. Ultrasound Med., November 1, 2007; 26(11): 1545 - 1556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.-J. Jang, T. K. Kim, P. N. Burns, and S. R. Wilson Enhancement Patterns of Hepatocellular Carcinoma at Contrast-enhanced US: Comparison with Histologic Differentiation Radiology, September 1, 2007; 244(3): 898 - 906. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Catalano, V. Migaleddu, E. Quaia, and G. Caruso Terminology for Contrast-Enhanced Sonography: A Practical Glossary J. Ultrasound Med., June 1, 2007; 26(6): 717 - 730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Wilson, H.-J. Jang, T. K. Kim, and P. N. Burns Diagnosis of Focal Liver Masses on Ultrasonography: Comparison of Unenhanced and Contrast-Enhanced Scans J. Ultrasound Med., June 1, 2007; 26(6): 775 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Catalano, F. Sandomenico, A. Nunziata, M. M. Raso, P. Vallone, and A. Siani Transient Hepatic Echogenicity Difference on Contrast-Enhanced Ultrasonography: Sonographic Sign and Pitfall J. Ultrasound Med., March 1, 2007; 26(3): 337 - 345. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
