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Hepatocellular Carcinoma Treated with Percutaneous Radio-frequency Ablation: Usefulness of Power Doppler US with a Microbubble Contrast Agent in Evaluating Therapeutic Response-Preliminary Results¹

¹ From the Departments of Radiology (D.C., H.K.L., S.H.K., W.J.L., H.J.J., J.Y.L.) and Internal Medicine (S.W.P., K.C.K., J.H.L.), Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea. Received November 30, 1999; revision requested December 30; revision received February 8, 2000; accepted February 22. Address correspondence to H.K.L. (e-mail: hklim@smc.samsung.co.kr).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the usefulness of power Doppler ultrasonography (US) with a microbubble contrast agent in assessing the therapeutic response of hepatocellular carcinomas (HCCs) treated with percutaneous radio-frequency (RF) ablation.

MATERIALS AND METHODS: Forty patients with 45 nodular HCC lesions 1.0–3.8 cm in diameter underwent power Doppler US before and after intravenous injection of a microbubble contrast agent. The same procedures were repeated after US-guided percutaneous RF ablation. The results of these studies were compared with those of three-phase helical computed tomography (CT) performed immediately after RF ablation.

RESULTS: Before RF ablation, nonenhanced power Doppler US demonstrated flow signals within tumor in 33 of 45 HCCs. After contrast agent administration, flow signals increased or newly appeared in all cases. After RF ablation, none of the ablated tumors showed intratumoral flow signals at nonenhanced power Doppler US, whereas six showed marginal intratumoral flow signals at contrast agent–enhanced power Doppler US. These six tumors were found to have small enhancing foci, suggestive of viable tumor, in corresponding areas at immediate follow-up CT. Additional RF ablation or transcatheter arterial chemoembolization was performed in these tumors.

CONCLUSION: The results of power Doppler US with a microbubble contrast agent in HCCs treated with RF ablation correlated well with those of contrast-enhanced CT. Preliminary data suggest that contrast-enhanced power Doppler US can be a promising noninvasive technique for assessing therapeutic response.

Index terms: Liver neoplasms, CT, 76.12112, 76.12113, 76.12114, 76.12115 • Liver neoplasms, US, 76.12981, 76.12984, 76.12985, 76.12988, 76.12989 • Radiofrequency (RF) ablation, 76.1269 • Ultrasound (US), contrast media, 76.12988 • Ultrasound (US), power Doppler studies, 76.12984

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Surgery is the principal curative treatment option for malignant neoplasms of the liver (1,2). However, resection of most hepatic cancers is not possible at the time of diagnosis owing to the status of the patients or tumors (3,4). In the past decade, minimally invasive techniques have become available for local tumor destruction (5). These techniques include percutaneous ethanol injection (6), hot saline injection (7), interstitial laser therapy (8), microwave coagulation therapy (9), and radio-frequency (RF) electrocautery therapy (10,11). Most of these procedures are possible for percutaneous use with a cannula or electrode with imaging guidance. One of these techniques, RF interstitial thermal ablation, which results in coagulation tumor necrosis, has been shown to be an effective and reliable method, and new techniques have been developed (12–20). RF ablation recently has been more widely used for the treatment of malignant hepatic tumors because it is associated with a higher rate of complete necrosis and fewer treatment sessions (18,21). Owing to these documented advantages of RF ablation over percutaneous ethanol injection, at present we prefer to use RF ablation in most patients with nodular hepatocellular carcinoma (HCC) at our institution.

The definitive goal of percutaneous RF ablation is complete ablation, or necrosis, of the entire tumor. Although contrast agent–enhanced computed tomography (CT) and magnetic resonance (MR) imaging have limitations as reference standards in the detection of small viable tumors after RF ablation, they generally have been used to determine the extent of RF-induced coagulation (13–15,22). The tumors that do not enhance after RF ablation can be considered to be successfully treated. On the contrary, focal enhancement in the tumor necessitates additional ablation to achieve complete treatment.

The findings at ultrasonography (US), including color and power Doppler US, do not adequately represent the extent of induced necrosis after RF ablation (13–15,23,24). A microbubble US contrast agent amplifies the Doppler signal by increasing the signal reflection from the intravascular microbubbles. In one study (25), it was reported that contrast-enhanced power Doppler US depicted tumor vascularity in HCCs better than did nonenhanced power Doppler US. Therefore, we hypothesized that a microbubble US contrast agent could help to improve the accuracy of US in the detection of residual (ie, viable) foci in HCCs after RF ablation. An early experience with postprocedural assessment of hepatic metastases after RF ablation by means of US with a microbubble contrast agent has been reported (22). However, to our knowledge, no study has focused on contrast-enhanced US for the detection of residual foci in HCCs after RF ablation. The purpose of this study was to evaluate the usefulness of power Doppler US with a microbubble contrast agent in assessing the therapeutic response of HCCs treated with percutaneous RF ablation.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Seventy-eight patients with nodular HCCs were referred for US-guided percutaneous RF ablation at our institution between April and October 1999. Of these patients, 32 with a previous history of treatment with percutaneous ethanol injection or transcatheter arterial chemoembolization were excluded from this study. We also excluded six patients in whom contrast-enhanced US or follow-up CT was not performed. The remaining 40 patients (31 men, nine women; mean age, 57 years; age range, 35–82 years), who had 45 nodular HCCs, formed the study population. The patients had to meet the following criteria for treatment with RF ablation: single nodular HCC not greater than 4 cm in maximum diameter; multinodular HCCs (up to three in number), with each tumor 3 cm in maximum diameter or smaller; absence of portal venous thrombosis or extrahepatic metastases; Child-Pugh class A or B liver cirrhosis; and prothrombin time ratio greater than 50% and platelet count greater than 70,000/mm³ (70 cells x10⁹/L). This study was approved by the institutional review board, and written informed consent was obtained from all patients.

The diagnosis of HCC was confirmed by using US-guided percutaneous needle biopsy of 25 masses in 25 patients. The remaining 20 masses in 15 patients were considered to be HCCs on the basis of characteristic imaging (three-phase helical CT and angiography) findings and elevated serum tumor markers (-fetoprotein level >100 ng/mL [>100 µg/L]). The tumors were 1.0–3.8 cm in diameter (mean, 2.7 cm). The patients were not surgical candidates and were referred for RF ablation because of history of poor medical status (n = 19), prior hepatic resection (n = 4), tumors in both lobes (n = 3), or refusal to undergo surgery (n = 14). Hepatitis B surface antigen was positive in 26 (65%) patients, and immunoglobuling antibody for hepatitis-C virus was positive in 12 (30%) patients.

RF Ablation Technique
RF ablation was performed by using a 480-kHz monopolar RF generator (model 500 series; Radiofrequency Interstitial Thermal Ablation Medical System, Mountain View, Calif) and an active expandable RF needle electrode (model 30; Radiofrequency Interstitial Thermal Ablation Medical System) (18). The RF generator has displays that indicate the hook temperatures, tissue impedance value, and treatment time. The needle electrode has a 15- or 25-cm-long stainless steel shaft insulated by a plastic membrane and a 1-cm-long exposed tip with four retractable lateral hooks. The maximum deployment diameter of the hooks was 3 cm, and each hook had a thermistor in its tip for monitoring the temperature in the surrounding tissue.

RF ablation was performed in inpatients after they had fasted for 12 hours. Laboratory examinations, including complete blood count and blood coagulation tests, were performed before each session. We performed RF ablation with the induction of only local anesthesia (Lidocaine; Kwang Myung Pharmaceutical, Seoul, Korea) in the patients who had small tumors in the central part of the liver. For those with tumors greater than 3 cm in diameter and tumors in difficult (eg, subcapsular, subphrenic, and perivascular) areas, we used an intramuscular injection of pethidine hydrochloride (50 mg) (Pethidine; Samsung Pharmaceutical, Seoul, Korea) 10–20 minutes before the procedure. Whenever patients reported having intolerable pain during ablation, we used an intravenous additional administration of pethidine hydrochloride (50 mg) with continuous monitoring of the cardiovascular and respiratory systems. The skin was pricked with a small pointed lancet. The RF needle electrode was inserted into the tumor with US guidance.

All US procedures were performed with a 2–5-MHz convex-array transducer (HDI 5000; Advanced Technology Laboratories, Bothell, Wash) by using a free-hand technique. After deployment of the hooks, the RF generator was activated. RF energy sufficient to maintain a highest temperature of 100°C was delivered for 8–10 minutes for each ablation. The impedance values ranged from 30 to 60 . The diameters of the deployed hooks varied between 1 and 3 cm, depending on the tumor’s size and location. The temperature of each hook was maintained above 90°C. For tumors smaller than 2 cm in diameter, the needle tip was placed in the center of the tumor and the hooks were deployed to reach the deepest margin of the tumor. One ablation was usually enough to destroy the entire tumor. For larger tumors, we performed multiple overlapping ablations (range, two to six ablations) according to the size and shape of the tumor.

Imaging
In all patients, nonenhanced and contrast-enhanced power Doppler US was performed just before RF ablation. We performed posttreatment nonenhanced and contrast-enhanced power Doppler US the next morning (14–23 hours after RF ablation; mean, 18 hours) to avoid artificial signals that can result from intratumoral gas.

One experienced radiologist (H.K.L.), without knowledge of the immediate posttreatment CT findings, performed gray-scale and power Doppler US by using the 2–5-MHz convex-array transducer (HDI 5000). Power Doppler US was performed before and after injection of a microbubble contrast agent (SH U 508 A [Levovist]; Schering, Berlin, Germany). The power Doppler US parameters were optimized and the same as those used in the pretreatment studies. The color gain was dynamically adjusted to detect slow flow and to avoid noise. The pulse repetition frequency was maintained at 700 Hz.

The microbubble US contrast agent that we used, SH U 508 A, is a suspension of galactose in sterile distilled water. Tiny microbubbles are stabilized in the microparticle suspension. This agent was prepared by shaking it with 11 mL of water vigorously for 10 seconds. A suspension of microbubbles and galactose microparticles was created by means of disaggregation of the granules. After letting the suspension stand for 2 minutes, 12.5 mL of a 300-mg/mL suspension was administered through an antecubital vein at a rate of 3 mL/min with an infusion pump (IPX4; IVAC Medical Systems, Hampshire, UK). We started power Doppler US scanning 20 seconds after the initiation of the contrast agent injection and scanned intermittently to avoid early bubble destruction. With this technique, the enhancement effect lasted for more than 10 minutes.

The grade of tumor vascularity at power Doppler US was analyzed by three radiologists (D.C., W.J.L., H.K.L.) who did not know the results of immediate follow-up CT. Tumor vascularity was classified by using the following five-point scale: grade 0, no signal within the tumor; grade 1, a few spotty signals; grade 2, signals in less than 25% of the tumor; grade 3, signals in 25%–50% of the tumor; and grade 4, signals in more than 50% of the tumor (24). Final decisions on the findings were reached by means of consensus.

All postprocedural CT scans were obtained within 30 minutes after the ablation procedures by using a helical scanner (HiSpeed Advantage; GE Medical Systems, Milwaukee, Wis). A total of 120 mL of nonionic contrast material ([300 mg of iodine per milliliter] Ultravist 300; Schering) was administrated at a rate of 3 mL/sec with an automatic power injector (OP 100; Medrad, Pittsburgh, Pa). The images were obtained 30, 60, and 180 seconds after initiation of the contrast agent injection, for imaging during the hepatic arterial, portal venous, and equilibrium phases, respectively. The images were obtained in a craniocaudal direction with 7-mm collimation and 7 mm/sec table speed during a single breath-hold helical CT acquisition of 25–30 seconds, depending on liver size.

We evaluated the therapeutic efficacy of RF ablation on the basis of immediate postablation CT findings. The CT studies were reviewed retrospectively by three experienced radiologists (S.H.K., H.J.J., J.Y.L.) who were unaware of the results of RF ablation. The tumors were considered to be completely necrotic when there was no enhancing portion within the ablated lesion on both the hepatic arterial and portal venous phase images. When the ablation area showed nodular enhancement during either the hepatic arterial or portal venous phase, we considered the tumor to have a viable portion (13,22,24). One radiologist (D.C.), who was experienced in liver imaging, compared the posttreatment power Doppler US findings with those of CT.

During and after RF ablation, we recorded the patients’ complaints and any abnormal physical signs. After the procedure, all patients were hospitalized for at least 12 hours. If no complications occurred, the patients were then discharged. CT performed immediately after the procedure was used to detect acute complications related to RF ablation. To evaluate the therapeutic response, three-phase helical CT scans were obtained 1 month after the procedure with the technique described earlier. If the tumors were completely treated and no recurrence occurred, repeated CT was performed every 3 months.

	RESULTS

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Nonenhanced power Doppler US scans obtained before RF ablation showed flow signals within the tumor in 33 (73%) of 45 HCCs: grade 1 in 31 HCCs and grade 2 in two. After injection of the microbubble contrast agent, the flow signals increased in all 33 HCCs, and flow signals newly appeared in the remaining 12 HCCs. The signals after contrast agent administration were grade 1 in seven HCCs, grade 2 in 21, grade 3 in 15, and grade 4 in two. After RF ablation, the contrast-enhanced power Doppler US scans showed no intratumoral flow signals in 39 tumors (Fig 1) and focal peripheral flow signals in six (Fig 2), whereas none of the ablated tumors had flow signals at nonenhanced power Doppler US (Figs 1, 2). The six tumors that showed focal intratumoral flow signals at contrast-enhanced power Doppler US were found to have enhancing portions during the hepatic arterial and portal venous phases at immediate follow-up CT (Fig 2). The areas of the tumors where power Doppler signals were found correlated well with the enhancing portions at CT in all six tumors. Therefore, diagnostic agreement between contrast-enhanced US and immediate follow-up CT was achieved in 100% of the tumors. Of the 39 ablated HCCs without residual tumor at both immediate contrast-enhanced CT and power Doppler US after the initial RF ablation, three (8%) had CT findings of marginal recurrence at 7-month follow-up; these findings were not seen at immediate CT.

View larger version (181K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (155K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (126K): [in this window] [in a new window] [Download PPT slide]   Figure 1c. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (180K): [in this window] [in a new window] [Download PPT slide]   Figure 1d. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (196K): [in this window] [in a new window] [Download PPT slide]   Figure 1e. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 1f. HCC before and after RF ablation in an 82-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.4-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 8. (b) Nonenhanced oblique power Doppler US scan obtained before RF ablation shows grade 2 flow signals (arrowheads) within part of the tumor (arrows). (c) Contrast-enhanced oblique power Doppler US scan obtained before RF ablation shows markedly increased flow signals (arrowheads) (grade 4) within nearly the entire tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 20 minutes after RF ablation, shows an oval ablated area of low attenuation, which represents complete necrosis of tumor. Note that the ablated area is larger than the initial tumor in a. Also seen are peripheral reactive hyperemia (arrows) and wedge-shaped iatrogenic arterioportal shunt (arrowheads). (e) Nonenhanced oblique power Doppler US scan obtained 18 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced oblique power Doppler US scan obtained immediately after e shows no flow signal within the ablated area (arrows). Increased flow signals (arrowheads), indicative of reactive hyperemia, are seen around the ablated area. At the time this article was written, this patient had been alive for 8 months without tumor recurrence.

View larger version (166K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

View larger version (197K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

View larger version (132K): [in this window] [in a new window] [Download PPT slide]   Figure 2c. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 2d. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

View larger version (193K): [in this window] [in a new window] [Download PPT slide]   Figure 2e. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

View larger version (138K): [in this window] [in a new window] [Download PPT slide]   Figure 2f. HCC before and after RF ablation in a 45-year-old man. (a) Transverse helical CT scan obtained during the hepatic arterial phase before RF ablation shows 3.2-cm HCC (arrows) with homogeneous contrast enhancement in liver segment 3. (b) Nonenhanced longitudinal power Doppler US scan obtained before RF ablation shows hypoechoic mass with scant flow signal (arrowhead) (grade 1) within the tumor (arrows). (c) Contrast-enhanced longitudinal power Doppler US scan obtained before RF ablation shows numerous flow signals (arrowheads) (grade 3) within the tumor (arrows). (d) Transverse helical CT scan obtained during the hepatic arterial phase, 15 minutes after RF ablation, shows that most of the ablated area is of low attenuation, but a focal enhancing portion (arrowheads) is seen on the left side of the ablated area (arrows). The nodular enhancement represents a viable portion of the tumor. (e) Nonenhanced transverse power Doppler US scan obtained 20 hours after RF ablation shows ablated area of mixed echogenicity (arrows) without flow signal. (f) Contrast-enhanced transverse power Doppler US scan obtained immediately after e shows peripheral flow signals (arrowheads) within the ablated area (arrows), which represent residual tumor vessels. The residual tumor was treated with additional RF ablation the same day.

Of the six patients with residual intratumoral flow signals at contrast-enhanced power Doppler US and nodular enhancement at CT, five were treated with additional RF ablation. The remaining patient was treated with transcatheter arterial chemoembolization because the residual tumor was located in a difficult area—just below the cardiac base.

After RF ablation, we observed no major complications and two minor complications—small pneumothorax and intraperitoneal bleeding—which disappeared spontaneously with no specific treatment. The patients complained of various symptoms during RF ablation: transient abdominal pain (n = 10), tolerable right shoulder pain (n = 6), and nausea (n = 4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
To our knowledge, there have been no published data about the accuracy of CT in depicting residual tumors after RF ablation, and dynamic helical CT has limitations as a standard of reference. In spite of these problems, however, CT has been widely used in the evaluation of the therapeutic response after RF ablation. We believe that immediate or short-term follow-up CT is not enough to conclusively exclude small viable tumors. In the study of Solbiati et al (22), in two (14%) of 14 patients, residual tumor was missed at initial CT compared with at 6-month follow-up CT. In our study, three (8%) residual HCCs were missed at immediate CT and seen as small enhancing lesions at the margin of the ablated tumor at 7-month follow-up CT. At present, only long-term follow-up CT is the best way to confirm the completeness of the treatment.

Several investigators (25–27) have proposed that there is increased flow signal at power Doppler US with a microbubble contrast agent compared with that at nonenhanced Doppler US. Solbiati et al (22) suggested that contrast-enhanced US as an immediate follow-up imaging examination might depict nontreated foci after RF ablation for hepatic metastases. This group reported also that the sensitivity and specificity of contrast-enhanced US for the detection of residual tumor were 50% and 100%, respectively. In our study, the sensitivity was 100% when immediate follow-up CT was used as the standard of reference. HCCs are known to have more tumor vessels with arterial flow than metastatic tumors (28). The discrepancy in sensitivity between the two studies could be due to the difference in tumor vascularity between HCCs and metastatic tumors. The other possible explanation for the discrepancy may be the size of the residual tumors. The size of the residual tumors in our study (0.3–1.0 cm; mean thickness, 0.6 cm) was larger than that in the Solbiati et al study (less than 0.3 cm thick).

After RF ablation, residual tumor portions usually were small and intratumoral flow signals were weak. Hence, it was difficult to detect flow signals within ablated tumors at nonenhanced power Doppler US. In the six cases with residual tumor, nonenhanced power Doppler US could not demonstrate flow signals within the ablated tumors, whereas contrast-enhanced power Doppler US scans showed flow signals in all the tumors.

In the study of Solbiati et al (22), they could not perform contrast-enhanced US immediately after RF ablation in 16 of 20 patients because of the remaining hyperechogenicity of the ablated tumor. The increased echogenicity caused by microbubbles of gas produced by the thermal ablation is known to remain for 15–180 minutes (24). In our experience, increased echogenicity in the ablated area during and after RF ablation was almost always observed, even at temperatures below 100°C, and it remained for a variable period—30 minutes to 6 hours. We could not wait for a long time with the patient on the table, not only because of the inconvenience to the patient but also because of the busy schedule in the US suite. In our study, all contrast- enhanced power Doppler US examinations were performed the next morning (14–23 hours after RF ablation; mean, 18 hours). By that time, the echogenicity of the ablated area had returned to that of the nontreated tumor.

At CT performed immediately after RF ablation in our study, peripheral rim enhancement around the ablated tumor, which is considered to represent reactive hyperemia and well documented in studies with patients who underwent percutaneous ethanol injection (29), was observed in 33 (73%) of 45 HCCs. Contrast-enhanced power Doppler US after RF ablation depicted reactive hyperemia in 16 (36%) of 45 HCCs. The reactive hyperemia seen at contrast-enhanced power Doppler US may be mistaken for residual tumor vascularity. In the current study, the reactive hyperemia in all patients appeared as uniform increased flow signals around the ablated tumors (Fig 1f), whereas residual tumor vessels were seen as focal flow signals within the ablated tumors. The residual tumors in our study were relatively large and had a focal pattern. The small foci of viable tumor at the margin of ablated tumors, however, can overlap with reactive hyperemia. This problem may be solved at follow-up contrast-enhanced power Doppler US or CT.

During the additional ablation of residual tumor, contrast-enhanced US was helpful in identifying the residual tumor portion with intratumoral vessels. This real-time confirmation of the accurate placement of the needle electrode cannot be achieved at posttreatment CT.

This study had two potential limitations. In spite of efforts to optimize Doppler parameters, contrast-enhanced US is intrinsically operator dependent, as is conventional US. Cooperative training before the study may be mandatory to reduce interobserver variability and achieve an acceptable level of reproducibility. Another limitation of this study was the lack of pathologic correlation. In spite of the limitations of contrast-enhanced CT in evaluating the therapeutic effect after RF ablation, we used immediate follow-up CT as the standard of reference for comparison with contrast-enhanced power Doppler US. We did not perform biopsy of the masses treated with RF ablation to determine the therapeutic effect because biopsy results do not always confirm the presence or absence of viable tumor and the biopsy procedure might have lengthened the patients’ hospital stay.

Although more prospective comparative studies with large patient populations are needed, our preliminary data suggest that contrast-enhanced power Doppler US, owing to its high diagnostic agreement with contrast-enhanced CT, can be used as an alternative to immediate follow-up CT for evaluation of the therapeutic effect in HCCs treated with RF ablation and may help to target residual tumor during the additional ablation session.

	FOOTNOTES

 
Abbreviations: HCC = hepatocellular carcinoma, RF = radio frequency

Author contributions: Guarantors of integrity of entire study, H.K.L., D.C.; study concepts and design, H.K.L.; definition of intellectual content, H.K.L.; literature research, D.C.; clinical studies, H.K.L., S.H.K., W.J.L., H.J.J., J.Y.L., S.W.P., K.C.K., J.H.L.; data acquisition, D.C.; data analysis, H.K.L., D.C.; manuscript preparation, D.C.; manuscript editing, H.K.L.; manuscript review, H.K.L., W.J.L.

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TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 

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