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.

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.

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.

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 contrast-enhanced 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.

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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.

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Discussion

Peripheral nodular enhancement with centripetal progression in hepatic massesdistinguishes hemangiomas from other benign lesions and from the majority of malignant lesions on dynamic contrast-enhanced 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.

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.

References

1.Quinn SF, Benjamin GG. Hepatic cavernous hemangiomas: simple diagnostic sign with dynamic bolus CT. Radiology 1992; 182: 545-568.2.Whitney WS, Herfkens RJ, Jeffrey RB, et al. Dynamic breath-hold multiplanar spoiled gradient-recalled MR imaging with gadolinium enhancement for differentiating hepatic hemangiomas from malignancies at 1.5 T. Radiology 1993; 189:863-870.3.Semelka RC, Brown ED, Ascher SM, et al. Hepatic hemangiomas: a multi-institutional study of appearance on T2-weighted and serial gadolinium-enhanced gradient-echo MR images. Radiology 1994; 192:401-406.4.Kim TK, Han JK, Kim AY, Choi BI. Limitations of characterization of hepatic hemangiomas using an ultrasound contrast agent (Levovist) and power Doppler ultrasound. J Ultrasound Med 1999; 18:737-743.5.Lopez-Ben R, Robbin ML, Weber TM, Smith JK, Needleman L, Berland LL. Doppler sonographic enhancement of hepatic hemangiomas and hepatocellular carcinomas after perflenapent emulsion: preliminary study. J Ultrasound Med 1999; 18:109-116.6.Tano S, Ueno N, Tomiyama T, Kimura K. Possibility of differentiating small hyperechoic liver tumours using contrast-enhanced colour Doppler ultrasonography: a preliminary study. Clin Radiol 1997; 52:41-45. 7.Maresca G, Barbaro B, Summaria V, et al. Color Doppler ultrasonography in the differential diagnosis of focal hepatic lesions: the SH U 508 A (Levovist) experience. Radiol Med 1994; 87(suppl):41-49.8.Ernst H, Hahn EG, Balzer T, Schlief R, Heyder N. Color Doppler ultrasound of liver lesions: signal enhancement after intravenous injection of the ultrasound contrast agent Levovist. J Clin Ultrasound 1996; 24:31-35.9.Christopher DA, Burns PN, Starkoski BG, Foster FS. A high-frequency pulsed-wave Doppler ultrasound system for the detection and imaging of blood flow in the microcirculation. Ultrasound Med Biol 1997;23:997-101510.Wilson SR, Burns PN, Muradali D, Wilson JA, Lai X. Harmonic hepatic US with microbubble contrast agent: initial experience showing improved characterization of hemangioma, hepatocellular carcinoma, and metastasis. Radiology 2000; 215:153-161.11.Kim TK, Choi BI, Han JK, Hong HS, Park SH, Moon SG. Hepatic tumors: contrast agent-enhancement patterns with pulse-inversion harmonic US. Radiology 2000; 216:411-147.12.Burns PN, Wilson SR, Simpson DH, Chin CT, Lai X. Harmonic interval delay imaging: a new ultrasound contrast method for imaging the blood pool volume in the liver (abstr). Radiology 1998; 209(P):189. 13.Burns PN, Wilson SR, Muradali D, Powers JE, Fritzsch TT. Intermittent US harmonic contrast-enhanced imaging and Doppler improve sensitivity and longevity of vessel detection (abstr). Radiology 1996; 201(P):159. 14.Moriyasu F, Kono Y, Nada T, Matsumura T, Suginoshita Y, Kobayashi K. Flash echo (passive cavitation) imaging of the liver by using US contrast agents and intermittent scanning sequence (abstr). Radiology 1996; 201(P):196.

Results

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 contrast-agent 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 contrast-agent 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).

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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 shows a hyperechoic nodule (arrowheads) in the liver. Contrast-enhanced hepatic vessels are seen. (b,c) Two axial CHA images at 49 seconds after injection of the contrast 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.

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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 centripetal fill-in (arrows). (d) Axial MR

image at 3 minutes after injection of contrast agent shows peripheral nodular enhancement (arrow).

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).

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