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1 Gastroenterological Center, Yokohama City University Medical Center, 4-57,
Urafune-cho, Minamai-ku, Yokohama, 232-0024 Japan.
2 Department of Pathology, Yokohama City University Medical Center, Yokohama,
232-0024 Japan.
3 Clinical Laboratory, Yokohama City University School of Medicine, 3-9,
Fukuura, Kanazawa-ku, Yokohama, 236-0004 Japan.
Received October 17, 2002;
accepted after revision January 14, 2003.
Address correspondence to K. Tanaka.
Abstract
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SUBJECTS AND METHODS. Twenty-nine patients with 29 hepatocellular carcinoma lesions were examined. Tumor vascularity was evaluated before and 7 days after transcatheter arterial chemoembolization with contrast-enhanced harmonic wideband gray-scale sonography performed after injection of the contrast agent Levovist. Several biopsy specimens were obtained from the evaluated lesions, and the histologic findings were compared with the results of contrast-enhanced sonography.
RESULTS. Contrast-enhanced harmonic wideband gray-scale sonography performed after transcatheter arterial chemoembolization showed tumor vascularity in 16 of the 29 lesions, but none in the other 13 lesions. At histologic examination, 13 of the 16 lesions with tumor vascularity had residual tumor revealed, and the 13 lesions without tumor vascularity were found to have no histologically evident tumor residue, although three of these lesions showed tumor progression detected on CT during a 9- to 12-month follow-up period. Contrast-enhanced harmonic wideband gray-scale sonographic images were compared with the histologic findings as the gold standard, and the sensitivity and specificity of these images for discerning viable and nonviable hepatocellular carcinoma after transcatheter arterial chemoembolization were 100% and 81%, respectively.
CONCLUSION. Contrast-enhanced harmonic wideband gray-scale sonography is potentially useful for evaluating the therapeutic effects of transcatheter arterial chemoembolization on hepatocellular carcinoma.
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In 1992, Tanaka et al. [8] used color Doppler sonography to assess the therapeutic effects of transcatheter arterial chemoembolization in patients with hepatocellular carcinoma, and power Doppler sonography has recently been shown to be an especially effective and noninvasive technique for assessing the vascularity and recurrence of hepatocellular carcinoma and for precisely identifying areas of residual tumor after transcatheter arterial chemoembolization [9–11]. The limitation of power Doppler sonography is its high susceptibility to tissue motion artifacts, which limits the usefulness of the technique in patients with poor breath-holding ability and in patients with hepatic masses near the heart or great vessels [10].
Harmonic sonography is a newly developed technique in which microbubble contrast agents are used and artifacts are reduced. Contrast-enhanced phase-inverted wideband harmonic gray-scale sonography, in which two pulses are transmitted down each ray line, has been shown to be a promising new technique with high sensitivity for microbubble detection [12–14]. Its sensitivity in detecting tumor blood perfusion has been found to be excellent [14–17]. Numata et al. [18] recently reported that contrast-enhanced wideband harmonic gray-scale sonography is useful for evaluating the therapeutic effects of transcatheter arterial chemoembolization on hepatocellular carcinoma. Although these researchers found a close correlation between contrast-enhanced wideband harmonic gray-scale sonographic and CT findings after transcatheter arterial chemoembolization [18], to our knowledge no formal studies have correlated contrast-enhanced wideband harmonic gray-scale sonographic and pathologic evidence of transcatheter arterial chemoembolization-induced necrosis in patients with hepatocellular carcinoma.
In the current study, we used this novel contrast-enhanced sonographic technique to evaluate residual tumor in patients with advanced hepatocellular carcinoma who were receiving transcatheter arterial chemoembolization. We compared the sonographic results with the histologic findings of multiple biopsy specimens. This approach permitted assessment of whether contrast-enhanced harmonic gray-scale sonography is potentially useful for evaluating residual hepatocellular carcinoma after transcatheter arterial chemoembolization and for predicting local residue of the treated tumor during the follow-up period. We hypothesized that this approach might be useful for evaluating the need for additional treatment after transcatheter arterial chemoembolization, which might improve the overall clinical outcome of the patients.
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Seventeen of the patients were men, and 12 were women; the patients ranged in age from 58 to 79 years (mean, 69.9 years). The 29 patients had a total of 49 hepatocellular carcinoma lesions: the tumor was solitary in 11 patients, whereas the other patients had two or more lesions each. Because of the difficulty of performing repeated multiple needle biopsies in each patient, only the largest lesion in patients with multiple lesions was included in this study. The diagnosis of hepatocellular carcinoma in all patients was confirmed by histologic examination of specimens obtained by biopsy with an 18-gauge biopsy needle (Biopty-Cut, Bard, Covington, GA) under conventional sonographic guidance. All patients had cirrhosis, the cause of which was hepatitis B in four patients and hepatitis C in 25 patients.
Methods
Pretreatment imaging.—Before transcatheter arterial
chemoembolization, all 29 patients were examined using both contrast-enhanced
harmonic wideband gray-scale sonography and contrast-enhanced CT; the two
examinations were performed within 1 week of each other. Sonography was
performed with a Sonoline Elegra (Siemens Medical Systems, Issaquah, WA) using
a 3.5-MHz convex probe. Before the IV bolus injection of a 300 mg/mL
concentration of galactose–palmitic acid mixture contrast agent
(Levovist, Schering, Berlin, Germany; 0.5 mL/sec, total dose, 7 mL) was
administered, the liver was scanned using fundamental gray-scale sonography
(transmit, 3.4 MHz; receive, 3.4 MHz). After the contrast injection, the liver
was scanned with contrast-enhanced wideband harmonic gray-scale sonography
(transmit, 2.5 or 2.8 MHz; receive, 5.0 or 5.6 MHz) at a frame rate of
2–5 sec. The transmission power was 100%, and the mechanical index
values were between 1.5 and 1.9. The focus position was just below the bottom
of the tumor. After the bolus injection of Levovist, a 5% glucose solution was
continuously infused at 5.0 mL/min through a 20- or 22-gauge cannula placed in
an antecubital vein. After gently inspiring, the patients held their breath
for approximately 30 sec (between 20 and 50 sec after injection of the
contrast agent) while the tumor vessels were examined (observation of the
arterial phase) (Figs. 1A and
2A).
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After observing the arterial phase, we froze the image, reviewed the images frame-by-frame from cine loop memories, and then stored them on magnetic optical disks. This procedure took approximately 15–35 sec (mean time, 25 sec), and we used the time to allow pooling of the contrast agent in the hepatic parenchyma. We then scanned the entire tumor and examined it for enhancement approximately 1–3 min after injection of the contrast agent, with the patients holding their breath for a few seconds (observation of the portal phase) (Figs. 1B and 2B). If breath-holding was poor, we changed the frame rate from 2 to 5 frames per sec. We froze the image again, reviewed the images frame by frame with a cine loop, and stored them on a magnetic optical disk for hard-copy printing. The portal phase was scanned at least three times in all patients.
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We evaluated the images for the presence or absence of intratumoral vessels in the arterial phase and an area of hypervascular enhancement within the tumor in the portal phase. Lesions were judged to exhibit hypervascular enhancement if their enhancement was equal to or greater than that of the surrounding liver parenchyma in the portal phase, and this enhancement pattern was further divided into homogeneous and heterogeneous patterns of enhancement.
Contrast-enhanced CT was performed in all patients before treatment. Contiguous 5-mm-thick axial CT scans were obtained with a HiSpeed Advantage RP scanner (General Electric Yokogawa Medical Systems, Tokyo, Japan). A nonionic contrast material, 100–150 mL of iopamidol (Iopamiron, Nippon Schering, Osaka, Japan), was administered at a rate of 3 mL/sec, and CT scans of the entire liver were obtained twice: first at 30–40 sec (arterial phase) after IV injection of contrast material and then at 90 sec (portal phase). Lesions were considered to be hyper-vascular if they appeared denser than the surrounding liver during the arterial phase.
Treatment design.—We performed transcatheter arterial chemoembolization in all patients by selectively introducing a coaxial microcatheter into a segmental branch or a subsegmental branch of the hepatic artery and injecting a mixture of iodized oil (Lipiodol, Guerbet, Aulnay-sous-Bois, France; 3.0–6.0 mL/kg of body weight) and styrene maleic acid neocarzinostatin (SMANCS, Yamanouchi Pharmaceuticals, Tokyo, Japan; 3.0–6.0 mg/kg per body weight), or epirubicin hydrochloride (Farmorubicin, Pharmacia and Upjohn, Tokyo, Japan: 30–60 mg per body weight). We then performed embolization using 1 x 1 x 1 mm gelatin sponge (Spongel, Yamanouchi Pharmaceuticals) in all patients. These embolic materials were injected until the feeding arteries were completely obliterated. If the blood supply was from two different subsegmental arteries, both were embolized.
Imaging after transcatheter arterial chemoembolization treatment.—Contrast-enhanced wideband harmonic gray-scale sonography was performed 7 days after transcatheter arterial chemoembolization. Contrast-enhanced CT is somewhat limited as a means of evaluating the therapeutic efficacy of transcatheter arterial chemoembolization because of the iodized oil in the tumor. Contrast-enhanced wideband harmonic gray-scale sonography is not, however, influenced by iodized oil in the tumor. In addition, obtaining a diagnosis earlier than with other modalities allows subsequent treatment, such as percutaneous ethanol injection or radio-frequency ablation therapy, to be carried out.
We evaluated the sonograms for the presence or absence of intratumoral vessels in the arterial phase and an area of hypervascular enhancement in the tumor during the portal phase. If a hypervascular area was observed in the tumor after transcatheter arterial chemoembolization, we considered residual vascularity to be present.
Histologic assessment.—As the gold standard in our study, percutaneous needle biopsies of the tumor were performed before transcatheter arterial chemoembolization and 7 days after the procedure. We performed multiple percutaneous needle biopsies with an 18-gauge biopsy needle (Biopty-Cut, Bard) under sonographic guidance, and contrast-enhanced wideband harmonic gray-scale sonography was always repeated immediately before the procedure for needle guidance. If contrast-enhanced sonography revealed a hypervascular area in the tumor after treatment, we harvested two or more samples from the hypervascular area and another two samples from the nonenhanced area. If contrast-enhanced sonography showed no areas of hypervascular enhancement, we harvested four or more samples randomly throughout the tumor. The biopsy specimens were fixed in 10% formalin, sectioned, stained with H and E, and examined under a conventional optical microscope. Lesions were considered to represent residual viable tumor if viable tumor cells were observed in one or more biopsy specimens. Lesions were evaluated as showing absence of viable tumor (adequate tumor necrosis) if no viable tumor cells were observed in any of the biopsy specimens.
Imaging analysis.—The contrast-enhanced harmonic gray-scale sonographic examination and the pathologic examination were reviewed in a blinded fashion during three separate sessions at least 1 week apart. The evaluations were based on the judgments of four of the authors (two sonographers and two pathologists) who were unaware of the results of the other study. In addition, the studies were reviewed in three different randomly selected orders to further reduce the possibility of bias. Results were tabulated, and positive findings were compared at a consensus conference.
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After transcatheter arterial chemoembolization, enhancement in 13 of the 29 lesions completely disappeared on contrast-enhanced sonography (Fig. 1C). The remaining 16 lesions, however, showed residual enhancement: intratumoral vessels were observed in eight lesions during the arterial phase, and a hypervascular area was observed in all 16 during the portal phase (Fig. 2C). Histologic examination of the biopsy specimens revealed residual viable tumor in 13 lesions, but no viable tumor cells were detected histologically in any of the biopsy specimens from the other 16 lesions, indicating tumor necrosis.
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All 13 lesions in which viable tumors were detected histologically met our definition of enhancement by showing intratumoral vessels during the arterial phase (n = 6) or hypervascular areas during the portal phase (n = 13) of sonography. Thirteen of the 16 lesions in which no viable tumor cells were detected histologically met our criteria for absence of residual viable tumor (i.e., they lacked both intratumoral vessels and hypervascular areas). In the remaining three lesions in which no viable tumor cells were detected histologically, contrast-enhanced sonography revealed residual tumor enhancement at the tumor margin after transcatheter arterial chemoembolization. Two of the patients showed no evidence of local recurrence on CT during their respective 16 and 21 months of follow-up; the third patient showed progression of the treated tumor 12 months after transcatheter arterial chemoembolization. Among the 13 lesions in which no residual tumor vascularity was detected sonographically and no viable tumor cells were detected histologically, three lesions were found to have tumor progression of the treated tumor on CT 9–12 months after transcatheter arterial chemoembolization. These lesions were retreated with transcatheter arterial chemoembolization. Contrast-enhanced harmonic wideband gray-scale sonograms were compared with the gold standard of the histologic findings, and the sensitivity and specificity of sonography for discerning viable and nonviable hepatocellular carcinoma after transcatheter arterial chemoembolization were 100% and 81%, respectively.
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In our study, we used contrast-enhanced harmonic wideband gray-scale sonography as a means of overcoming the limitations of these modalities after transcatheter arterial chemoembolization with iodized oil and found that contrast-enhanced wideband harmonic gray-scale sonography is potentially useful for the evaluation of residual hepatocellular carcinoma after transcatheter arterial chemoembolization. The results of the pathologic evaluation of the tumor response after transcatheter arterial chemoembolization correlated well with the contrast-enhanced sonographic findings, and this technique is potentially useful for predicting recurrence of treated tumors during the follow-up period.
Color Doppler sonography and power Doppler sonography without the use of contrast agents have been used to assess the residual viability of hepatocellular carcinoma treated with transcatheter arterial chemoembolization, and the results have shown both modalities to be simple and fast procedures, with sensitivities in the range of 75–87% and specificities in the range of 78–85% for revealing tumor recurrence after transcatheter arterial chemoembolization [8–11]. Catalano et al. [23] used contrast agents and reported finding that contrast-enhanced color Doppler sonography and power Doppler sonography are sensitive techniques for assessing the viability of hepatocellular carcinoma treated with transcatheter arterial chemoembolization. Other investigators have also reported that contrast-enhanced harmonic power Doppler sonography can be used to effectively evaluate the vascularity of hepatocellular carcinoma because power Doppler sonography is less susceptible to artifacts [24, 25].
However, with these techniques, color flow is sometimes seen outside the lesions, and the extent of viable lesions may be overestimated. Contrast-enhanced phase-inverted wideband harmonic gray-scale sonography is a promising new technique with high sensitivity for microbubble detection and reduced artifacts. The advantages of wideband harmonic sonography are elimination of the fundamental component signal from normal tissue without filtering and the high signal-to-noise ratio of the second harmonic signal obtained after summation of both signals received, resulting in high contrast resolution [12–14, 17, 18].
Before therapy, all hepatocellular carcinoma lesions showed tumor enhancement during the arterial or portal phase of contrast-enhanced wideband harmonic gray-scale sonography. During the arterial phase, tumor vessels supplied by the hepatic arterial circulation enhanced first, and during the portal phase, hepatocellular carcinoma lesions continuously enhanced until arterial blood flow in the tumor began to wash out. The liver parenchyma also enhanced because of both its hepatic arterial and portal blood flow. As a result, the difference between the enhancement of the hepatocellular carcinoma lesions and that of the liver parenchyma was unclear during the portal phase. In cases in which tumor blood flow disappeared completely after transcatheter arterial chemoembolization, no arterial inflow was detected during the arterial phase, and no enhancement of the hepatocellular carcinoma lesions was observed during the portal phase. As a result, these nonviable hepatocellular carcinoma lesions appeared as perfusion defects having ovoid or rounded shapes and distinct margins during the portal phase. Residual hepatocellular carcinoma lesions, on the other hand, were visualized as hypervascular areas in the tumor in the portal phase. However, previously, no formal studies investigated whether these areas correlated with histologically proven residual hepatocellular carcinoma.
Our results indicate a correlation between contrast-enhanced wideband harmonic gray-scale sonography and histopathologic characteristics in evaluating the therapeutic effects of transcatheter arterial chemoembolization on hepatocellular carcinoma. Furthermore, the contrast-enhanced wideband harmonic gray-scale sonograms after transcatheter arterial chemoembolization predicted recurrence of the treated tumor during the follow-up period.
Because we did not compare contrast-enhanced wideband harmonic gray-scale sonography and dual-phase contrast-enhanced CT, further study is needed before replacing axial CT or MR imaging with sonographic contrast techniques as the method of choice. However, contrast-enhanced wideband harmonic gray-scale sonography may be superior to CT for diagnosing viable portions of a hepatocellular carcinoma shortly after transcatheter arterial chemoembolization with iodized oil because no limitations are attributable to the oil. Furthermore, use of sonographic contrast agents may offer potential benefits over other imaging strategies. For example, sonographic contrast enhancement may permit the guidance of subsequent treatment of such lesions by sonographically guided methods [26, 27]. However, our study is limited by the short-term follow-up and the small number of patients studied. In addition, the smaller lesions in patients with multiple lesions were not biopsied. Thus, further research is needed to validate our initial findings and to determine whether early repeated intervention affects overall clinical outcome.
In conclusion, contrast-enhanced wideband harmonic gray-scale sonography with Levovist is potentially useful for detecting residual tumor after transcatheter arterial chemoembolization. In our study, we have shown that this modality can be used to distinguish between viable and necrotic portions of hepatocellular carcinoma lesions, thereby potentially reducing the need for CT to evaluate the therapeutic effects of transcatheter arterial chemoembolization during the course of treatment, and may also be useful for guiding additional treatment, such as percutaneous ethanol injection or radiofrequency ablation therapy.
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