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Clinical Efficacy of Contrast-Enhanced Coded Harmonic Angiography of
US in the Diagnosis of Hepatic Hemangiomas
Jae Young Lee MD, Byung Ihn Choi MD, Joon Koo Han MD, Ah Young Kim MD,
Shang Hun Shin MD, Sung Gyu Moon MD
The Department of Radiology, Seoul National University College of Medicine
Introduction
Cavernous hemangiomas demonstrate peripheral nodular enhancement on dynamic contrast-enhanced
computed tomography (CT) or magnetic resonance (MR) imaging, which is highly specific for the diagnosis
of hemangiomas (1-3). If ultrasonography (US) can demonstrate this typical finding, clinical impact is great
because other costly confirmatory studies such as MR or CT can be avoided.
Microbubble contrast agents for US have recently become commercially available. Although several
studies have tried to demonstrate typical enhancement pattern of hemangiomas on Doppler US studies
with use of contrast agents (4-8), it was unsuccessful to depict the intratumoral enhancement similar to that
of dynamic contrast-enhanced CT or MR. On contrast-enhanced power Doppler US, hemangiomas showed
either no internal arterial vascularity or minimal or sparse marginal flow (4). It might be unreasonable to
hope that any Doppler method with 2-3 MHz Doppler carrier frequency could be used to detect very slow
capillary flow within the hemangioma (9).
Recently, contrast-enhanced coded harmonic angiography (CHA) was introduced. CHA is obtained by
depicting blood reflectors directly and offering image optimized for visualization of contrast agent signal
using coded harmonic technique. We expected that this US technique could effectively depict typical
enhancement pattern of hepatic hemangiomas and could help in the specific diagnosis of these tumors.
We performed this prospective study to determine the role of CHA using microbubble contrast agents
for characterization of hepatic hemangiomas as compared with dynamic MR.
MR imaging examinations were performed with a 1.0-T system (Magnetom Expert; Siemens Medical
Systems, Erlangen, Germany). The imaging sequences included breath-hold precontrast and serial
contrast-enhanced T1-weighted fast low-angle shot imaging (160/6.6 [repetition time msec/echo time
msec], 70’ flip angle) immediately and at 1, 3, and 5 minutes after injection of contrast material (Magnevist;
Schering).
Analysis
US images were displayed on a computer screen and were evaluated by two readers with decisions
made by means of consensus. MR images were evaluated by one reader who was blinded to the US
findings.
At CHA, the reviewers first determined the presence or absence of peripheral contrast-enhanced nodule,
progressive centripetal enhancement, and complete fill-in. The time that nodular enhancement begins to
appear, that the tumor is maximally enhanced, and that contrast-agent effect on tumor is disappeared, was
measured. According to the ratio of contrast-enhanced area to total area of tumor at the time of maximal
contrast enhancement of a tumor, the degree of enhancement was classified as follows: grade 1 (1-20%),
grade 2 (21-40%), grade 3 (41-60%), grade 4 (61-80%), and grade 5 (81-100%).
At MR, the reviewer determined the enhancement pattern of tumors. On MR images, the enhancement
degree was determined with images obtained 5 minutes after injection of the contrast agent according to
criteria identical to that of US.
Materials and Methods
Subjects
Sixteen patients with confirmed 20 hemangiomas by dynamic contrast-enhanced MR imaging were
included in this study. All of 18 patients were examined with CHA in conjunction with a microbubble
contrast agent during a 1-month period. The patients were 33-61 years old (mean age, 53 years). Eleven of
the 18 patients were women; five were men.
Imaging
The US contrast agent used in the present study, was SH U 508A (Levovist; Schering, Berlin, Germany).
Before the US examination, this agent was prepared by mixing 2.5 g of the SH U 508A granules with 7 mL of
sterile distilled water and shaking for 5-10 seconds. After standing for 2 minutes for equilibration, the
contrast agent suspension with a concentration of 300 mg/mL was injected intravenously at a rate of about
0.5 mL/sec through a 20-22 –gauge cannula.
US was performed by one examiner (J.Y.L.) with a LOGIQ 700 expert unit (GE medical systems,
Milwaukee, Wis) and a 2-4-MHz curved linear-array transducer. On conventional gray-scale image, a
scanning plane that the hemangioma was the best visible was determined. At that scanning plane, the size,
depth, and echo of the tumor were recorded. To avoid sonic beam attenuation by ribs, subcostal approach
was used.
Color and Power Doppler studies were performed to prevent adjacent passing vessels from mimicking
enhanced peripheral nodules of a hemangioma. Then, CHA was performed. Depth and scan- width was set
as narrow as possible in order to minimize destruction of contrast-agent out of region of interest. The
acoustic power of CHA was set at default (maximal) setting.
After injection of the contrast agent, we obtained serial CHA images until the contrast-agent effect on
the tumor was disappeared. To maximize the destruction of the accumulated microbubbles at the tumor,
intermittent imaging technique (interval: 20-30 seconds, scan time: 2-5 seconds) was used and a focal zone
was placed central to the tumor. During scanning, probes was swept upward or downward, central to the
tumor as rapid as possible.
a
b
c
d
Fig. 1. Medium hemangioma (3.7 cm) in the right hepatic lobe (S8).
(a) Axial CHA image at 39 seconds after injection of contrast agent shows peripheral contrastenhanced nodules (arrows) in the liver. (b-d) Serial contrast-enhanced axial CHA images obtained (b)
58 seconds, and (c,d) 59 seconds after injection show peripheral nodular enhancement with
progressive centripetal fill-in.
a
b
c
d
e
f
g
Fig. 2. Large hemangioma (5.7 cm) in the left hepatic lobe (S4).
(a) Axial CHA image at 87 seconds after injection of contrast agent shows a hyperechoic nodules
(arrows) in the liver. (b-c) Serial contrast-enhanced axial CHA images obtained (b) 127 seconds, and (c)
128 seconds after injection show peripheral nodular enhancement with progressive centripetal fill-in.
The intensity of intratumoral enhancement is similar to that of the portal vein (arrow in b,c). (d-g) Axial
MR images immediately and at 1, 3, and 5 minutes after injection of contrast agent show peripheral
high signal intensity nodules with progressive centripetal fill-in in the hemangioma.
Results
Discussion
The tumor diameters on US images were 9-62 mm (mean, 29 mm). Four hemangiomas were equal to or
less than 15 mm (small), 16 were 16-50 mm (medium), and the remaining two were larger than 50 mm
(large). The echogenicity compared with that of adjacent liver parenchyma was high in 10, mixed (high and
low) in two, low in seven, and iso in one. The tumor depth were 20-101 mm (mean, 50 mm).
At CHA, 18 of 20 hemangiomas (90 %) showed peripheral nodular enhancement (Fig. 1-5). Seventeen of
18 hemangiomas (94%) with peripheral nodular enhancement had progressive centripetal fill-in. The
complete homogeneous fill-in was found in six lesions (33%). Among four small hemangiomas smaller than
or equal to 1.5 cm, three lesions (75%) had peripheral nodular enhancement, and three had progressive
centripetal enhancement (Fig. 4,5). Neither rim-like enhancement nor diffuse enhancement without the
phase of nodular enhancement was seen at CHA.
The nodular enhancement began to be seen between 15 seconds and 59 seconds (mean, 40 seconds).
The time of maximal enhancement was 55 to 128 seconds (mean, 89 seconds). The time of disappearance of
tumoral enhancement was 190 to 526 seconds (mean, 293 seconds).
Two of 20 hemangiomas (10%) did not show any enhancement: all were smaller than 2cm (each: 1.4 and
1.9 cm). These hemangiomas were located deeper than 9 cm in the scanning plane and showed contrastagent enhancement less than 20% (grade 1) on 5-minutes-delayed MR images
At MR, 19 of 20 hemangiomas (95%) showed peripheral nodular enhancement. One of two hemangiomas
without peripheral nodular enhancement had homogeneous hyperintensity without any visible preceding
peripheral enhancement at 5 minutes after administration of contrast material. However, at CHA, the lesion
showed definite peripheral contrast-enhanced nodules (Fig. 5).
Hyperechoic hemangiomas were not significantly different from other hemangiomas in terms of contrastagent enhancement (P > 0.05, Fisher’s exact test). Hemangiomas equal to or smaller than 1.5 cm were not
significantly less enhanced than those larger than 1.5 cm (P > 0.05, Fisher’s exact test). The degree of
contrast-agent enhancement in CHA was significantly well correlated with that in MR imaging (P < 0.05,
Spearman’s correlation).
Peripheral nodular enhancement with centripetal progression in hepatic massesdistinguishes
hemangiomas from other benign lesions and from the majority of malignant lesions on dynamic contrastenhanced CT or MR imaging (1-3). Thus, imaging technique requires the high ability to depict peripheral
nodular enhancement for the specific diagnosis of hemangiomas.
CHA is a new harmonic US technology for imaging contrast agents based on digitally encoded US
technology. CHA combines the benefits of B-flow and coded harmonic imaging techniques. B-flow
technique is the one optimized for direct visualization of blood cells on gray scale image. The coded
harmonic technique uses codes to subtract the unwanted echo components, that is, fundamental frequency
(fo) and to boost weak tissue harmonic signals. This technique results in improved contrast resolution and
spatial resolution. Combining the advantages of two techniques, CHA uses the codes for enhancement of
the harmonic return from the contrast agents, while suppressing the background signal, both the
fundamental and harmonic signal from the stationary tissue background. Thus, CHA with a microbubble
contrast agent offers the potential of providing extremely high quality and detailed vascular information
without the artifacts associated with the contrast agent.
In this study, 90 % (18/20) of hemangiomas showed peripheral contrast-enhanced nodules at CHA. If
hemangiomas enhanced greater than grade 1 at MR are included, 100 % (16/16) of hemangiomas had
peripheral nodular enhancement at CHA. Thus, the results of the present study clearly demonstrate that
contrast-enhanced CHA has the high ability to depict peripheral nodular enhancement. Contrarily, in several
studies performed with contrast-enhanced Doppler US and conventional harmonic US, hemangiomas
showed either no intralesional vessels or sparse marginal vascularity (4-8, 10). Recently, Kim et al (11)
described contrast enhancement pattern of hepatic hemangiomas on pulse inversion harmonic US with the
best results among contrast-enhanced US imaging techniques in diagnosing hepatic hemangiomas. In their
study, 70% of hemangiomas (14/20) showed peripheral nodular enhancement. By simple comparison of
CHA and pulse inversion harmonic US, CHA has superior ability to depict peripheral contrast-enhanced
nodules. However, further studies in which two imaging techniques are directly compared are needed.
In terms of contrast enhancement according to hemangioma size, at CHA, 75 % of hemangiomas (3/4)
equal to or less than 1.5 cm showed peripheral nodular enhancement. In this study, a hemangioma with the
size of 0.9 cm in diameter showed definite peripheral enhanced nodules (Fig. 5). A multi-institutional study
of the appearance of hemangiomas on gadolinium-enhanced MR image described that peripheral nodular
enhancement was identified in 57% of small hemangioma less than 1.5 cm (3). This suggests that CHA is
useful in depicting typical pattern of contrast enhancement of small hemangiomas even less than 1.5 cm.
We used interval delay imaging (interval: 20-30 seconds, scan time: 2-5 seconds) to depict tumoral
vasculature in this study. Interval delay imaging is necessary to allow areas of slow flow to fill with intact
microbubbles during the imaging pause (12-14). In addition, we used the sweeping method, which is to
manually sweep the probe upward or downward, central to the tumor as rapid as possible. This allows all
microbubbles filled in a hemangioma to break at the nearly same time, which makes it possible to
investigate enhancement pattern of entire portion of a hemangioma at a given time. This increases the
possibility to detect peripheral nodular enhancement.
In terms of contrast enhancement according to lesion depth, at the depth less than 9 cm, 90% (18/20) of
hemangiomas showed peripheral nodular enhancement. Two hemangiomas located at the depth greater
than 9 cm were not enhanced. Scanning at the depth less than 9 cm is recommended.
a
b
c
d
e
Fig. 3. Medium hemangioma (2.2 cm) in the right hepatic lobe (S5).
(a,b) Two axial CHA images at 15 seconds after injection of contrast agent show (a) peripheral nodular enhancement and
(b) rimlike enhancement. This indicates the importance of manual sweeping method, which makes it possible to investigate
the entire portion of a tumor at each scanning time. (c) Axial CHA image at 32 seconds after injection of contrast agent
shows undulating nodular contours (arrows) of the inner margin of partial ring with progressive centripetal fill-in. (d) Axial
CHA image at 61 seconds after injection of contrast agent shows nearly complete centripetal fill-in of contrast enhancement.
(e) Axial MR image immediate after injection of contrast agent shows contrast enhancement pattern similar to that in a
(arrow).
Fig. 4. Small hemangioma (1.5 cm) in
the right hepatic lobe (S6).
Axial CHA image before injection of the
contrast agent shows a hyperechoic
nodule (arrowheads) in the liver. (b,c)
Axial CHA images at (b) 63 seconds
and (c) 88 seconds after injection of
contrast agent show peripheral nodular
enhancement
with
progressive
a
b
c
d
centripetal fill-in (arrows). (d) Axial MR
image at 3 minutes after injection of contrast agent shows peripheral nodular enhancement (arrow).
Fig. 5. Small hemangioma (0.9 cm) in
the right hepatic lobe (S5).
(a) Axial CHA image at 38 seconds
after injection of the contrast agent
d
shows a
hyperechoic nodule
(arrowheads) in the liver. Contrastenhanced hepatic vessels are seen.
(b,c) Two axial CHA images at 49
seconds
after
injection
of
the
contrast
a
b
c
e
agent show peripheral nodular
enhancement (long arrows) in the tumor. The intensity of intratumoral enhancement is similar to that of adjacent hepatic
vessels (short arrows in b,c). (d,e) Axial MR images at (d) 3 minutes and (e) 5 minutes after injection of contrast agent show
no enhancement in d and homogeneous enhancement in e.
Conclusion
Contrast-enhanced CHA has the high ability to depict peripheral contrast-enhanced nodules, highly
specific sign for diagnosis of hemangiomas. CHA also has the high ability to depict centripetal
enhancement, significantly correlated with that of MR. Thus, contrast-enhanced CHA is potentially useful
for the specific diagnosis of hemangiomas with characteristic enhancement features, even less than 1.5 cm.
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