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Enhancement Patterns of Hepatocellular Carcinoma at Contrast-enhanced US: Comparison with Histologic Differentiation¹

¹ From the Department of Medical Imaging, University of Toronto, Toronto General Hospital, 585 University Ave, Toronto, ON, Canada M5G 2N2 (H.J.J., T.K.K., S.R.W.); and Department of Medical Imaging Research, Sunnybrook and Women's Health Sciences Centre, Toronto, Canada (P.N.B.). From the 2005 RSNA Annual Meeting. Received September 1, 2006; revision requested October 30; revision received November 22; final version accepted January 11, 2007. Address correspondence to H.J.J. (e-mail: hyun-jung.jang{at}uhn.on.ca).

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 
Purpose: To retrospectively compare the arterial and portal venous phase enhancement patterns of hepatocellular carcinoma (HCC) at contrast material–enhanced ultrasonography (US) with the degree of HCC histologic differentiation.

Materials and Methods: This study was approved by the research ethics board, and informed consent was obtained. The study population included 112 consecutive patients (91 men, 21 women; aged 25–86 years) with 112 histologically proved HCCs: 23 well differentiated, 77 moderately differentiated, and 12 poorly differentiated. All underwent continuous real-time low-mechanical-index contrast-enhanced US from wash-in of contrast material to 300 seconds by using a blood-pool microbubble agent. Initial image interpretation included arterial enhancement, dysmorphic intratumor arteries, and presence and time of negative enhancement (washout). Enhancement patterns were compared with histologic differentiation by using the Fisher exact test.

Results: In the arterial phase, 97 of 112 (87%) HCCs showed hypervascularity, with a significantly higher proportion in moderately differentiated HCCs (74 of 77, 96%) when compared with well- (14 of 23, 61%; P < .001) and poorly differentiated HCC (nine of 12, 75%; P < .004). Eight of 112 (7%) were isovascular and seven (6%) were hypovascular. Dysmorphic arteries were seen in 81 (72%) HCCs. Of 97 hypervascular tumors, only 42 (43%) showed typical washout by 90 seconds. Late washout appeared in 25 (26%) HCCs in the 91–180 seconds phase and in 21 (22%) in the 181–300 seconds phase. The remaining nine showed no washout up to 300 seconds and seven (78%) were well-differentiated HCCs.

Conclusion: Moderately differentiated HCC generally shows classic enhancement features, while well- and poorly differentiated tumors account for most atypical variations. Extended observation in the portal phase is important as late washout occurs with slightly more frequency than washout in the conventionally defined portal venous phase.

© RSNA, 2007

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 
The appearance of hepatocellular carcinoma (HCC) on contrast material–enhanced computed tomography (CT) scans and magnetic resonance (MR) images has been well described (1–5). The classic description includes a hypervascular lesion in the hepatic arterial phase with negative enhancement in the portal venous phase. Worldwide, ultrasonography (US) is the most commonly used imaging technique for screening patients at risk for HCC (6,7). Clinical use of microbubble contrast agents has expanded the role of US from that of detection to also characterization of HCC based on the enhancement features at contrast-enhanced US (8–17).

Current low-mechanical-index techniques for contrast-enhanced US by using second-generation microbubble agents have advantages in characterizing HCC, including real-time demonstration of continuous hemodynamic changes in both the liver and the liver lesion. Microbubbles are pure intravascular tracers that remain in the blood pool. Since arterial phase hypervascularity is considered one of the most reliable characteristics of HCC differentiating it from benign cirrhotic nodules, contrast-enhanced US studies have emphasized the accuracy of detection of arterial hypervascularity in comparison with CT (18–20). However, relatively little attention has been given to the capability of contrast-enhanced US to show the infrequent hypovascular variant. Further, it is generally believed that negative enhancement, or washout, in the portal venous phase on contrast-enhanced US scans is one of the most specific indicators of hepatic malignancy; sustained enhancement in the portal venous phase strongly suggests a benign lesion (21–23).

Experience with contrast-enhanced US suggests that there are definite exceptions to these expectations for the enhancement pattern of malignancy (eg, persistent positive enhancement in the typical portal venous phase or absent arterial hypervascularity). It has recently been speculated that variations of enhancement patterns may be related to the pathologic function of HCC (23,24). Thus, our purpose was to retrospectively compare the arterial and portal venous phase enhancement patterns of HCC on contrast-enhanced US scans with the degree of HCC histologic differentiation.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 
Patients
The study was approved by the research ethics board of our institution (University of Toronto, Toronto, Canada). Written informed consent was obtained from each patient for the use of contrast-enhanced US data for research purposes. Over a 23-month period, contrast-enhanced US was performed on 812 hepatic nodules in 657 patients. Of these, 120 nodules in 112 consecutive patients (91 men and 21 women; age range, 25–86 years; mean age, 57 years) had a final diagnosis of HCC at pathologic examination. Eight patients had two pathologically proved HCCs. To avoid potential bias caused by possible dependencies between the lesions, a single HCC from each patient that was scanned first during the examination was chosen for the analysis. Our study group comprised 112 consecutive patients with 112 pathologically proved HCCs. Lesion size ranged from 0.8 to 12.7 cm (mean ± standard deviation, 3.6 cm ± 2.5).

One hundred six of 112 (95%) patients were at high risk for the development of HCC, including chronic hepatitis or cirrhosis related to hepatitis C (n = 49), hepatitis B (n = 35), combined hepatitis B and C (n = 1), alcoholic hepatitis (n = 6), combined viral and alcoholic hepatitis (n = 3), nonalcoholic steatohepatitis (n = 4), autoimmune hepatitis (n = 1), -1-antitrypsin deficiency (n = 1), Gaucher disease (n = 1), hemochromatosis (n = 1), and cryptogenic cirrhosis (n = 4). The remaining six of 112 (5%) patients had HCC in an essentially normal liver at pathologic examination with no identifiable clinical risk factor for HCC.

Diagnostic confirmation of the 112 nodules was made at resection or transplantation (n = 57) or percutaneous biopsy (n = 55). Differentiation of those lesions included 77 moderately differentiated, 23 well-differentiated, and 12 poorly differentiated HCCs. Pathologic evaluation of the livers was also available in 91 of 112 patients and classified as showing progressive degrees of fibrosis and inflammation (n = 75) or no fibrosis (n = 16).

Procedure
US scans were obtained by three radiologists (H.J.J., T.K.K., S.R.W.) experienced with routine US (11, 13, and 25 years of experience) and contrast-enhanced US (3, 6, and 10 years). The equipment used had a contrast-specific mode with a low mechanical index (0.06–0.2) and consisted of Acuson Sequoia (Siemens, Mountain View, Calif) (n = 70), ATL HDI 5000 (Philips, Bothell, Wash) (n = 18), IU-22 (Philips) (n = 10), and Aplio (Toshiba Medical Systems, Tokyo, Japan) (n = 14) scanners.

The microbubble contrast agent was perflutren lipid microspheres (Definity; Bristol-Myers Squibb, Billerica, Mass) administered with intravenous bolus injection (0.1–0.3 mL per injection) to a maximum dose of 10 µL/kg, followed by 5 mL saline flush. Since the amount of injected contrast agent is only 0.1–0.3 mL and stays within the intravenous line until flushed, zero time was recorded at the completion of the saline flush. Dynamic scanning focused on the lesion and was performed continuously from the arterial phase wash-in of contrast material to the peak of arterial enhancement, and then for up to 300 seconds after, which is referred to here as the extended portal venous phase. Since microbubble contrast agents are purely intravascular, contrast-enhanced US has no equilibrium phase as seen at CT or MR imaging.

For the first injection, a stationary field of view, the lesion of interest and adjacent liver were included and were both observed continuously for 300 seconds. Two consecutive 15-second cine clips were recorded from wash-in to show the arterial features through the peak of enhancement. Still images were stored at peak arterial enhancement retrospectively on review of the clips, at the first sign of washout, and during continuous scanning at variable intervals of less than 30 seconds. Subsequent injections focused on arterial phase vessel morphology and enhancement and the liver in the portal phase to look for any further abnormalities. Injections were repeated (range, 2–7; median, 3) to obtain images for the same lesion or to evaluate a different lesion. Each injection was separated by 6–7 minutes, allowing complete disappearance of the preceding bolus.

Dual function of the US machine provides simultaneous visualization of the baseline conventional image on one screen and the dark, tissue-suppressed image on the other, thereby displaying the vascular degree of the lesion compared with the rest of the liver as the contrast agent arrives in the field of view. This is of particular value for small and subtle mass lesions. Dual function is rarely required for lesions over 3 cm. Seventy scans were obtained with dual screens; the remaining 42, a single screen.

Image Interpretation
Two of the three radiologists (H.J.J., T.K.K., S.R.W.) were present for each examination, and interpretations were made by consensus at the time of the scan. Since contrast-enhanced US was performed as a routine diagnostic procedure, the radiologists were not blinded to the patient's clinical information nor to previous imaging findings, if available.

At the examination, they recorded by visual inspection and review of cine clips and still images the following: In the arterial phase (range, 0–40 seconds, following completion of the saline flush), (a) the presence or absence of dysmorphic intratumor arteries (tortuous, chaotic in distribution, and more numerous than expected for the region in the liver) and (b) the degree of vascularity (relative to parenchyma; hypervascular, isovascular, or hypovascular) and enhancement (eg, isovascularity shows similar number of vessels and identical enhancement to the adjacent liver becoming invisible in the arterial phase), and in the portal venous phase (range, 40–300 seconds, the end of the observation period) of hypervascular HCCs, (a) the presence of negative lesion enhancement relative to the liver (washout) and (b) the time of onset of washout (hypoechoic part relative to the liver becomes visible).

A timer on the US screen displayed the time elapsed from the saline flush and was used to determine time to washout. The washout times were categorized in one of four ways: less than 90 seconds, 91–180 seconds, 181–300 seconds, or no washout visible (persistently hyperechoic or isoechoic) up to 300 seconds. We considered less than 90 seconds as the typical portal phase defined by CT convention. We chose 180 seconds because it is the usual time that delayed phase images are obtained if included in the liver CT protocol (2,3). We observed for up to 300 seconds, as this is considered the completion of the effective liver enhancement using perflutren microbubbles. Interpretation of both arterial and portal venous phase enhancement was possible with all 112 lesions.

Portal venous phase appearance of nonhypervascular HCCs was also evaluated in terms of relative echogenicity compared with the surrounding parenchyma to assess for increasing extent or degree of hypoechogenicity, or washout, during portal venous phase observation.

Comparison with Histologic Examination
The distribution of relative arterial vascularity (hyper-, iso-, or hypovascular) was compared with the histologic differentiation (well, moderately, or poorly differentiated). Portal venous phase washout of hypervascular HCCs was compared with the degrees of tumor differentiation and liver fibrosis. Histologic grading was performed retrospectively from the pathologic reports given by one of two experienced hepatic pathologists. Correlation of the nodule between surgery and contrast-enhanced US was made by one radiologist (H.J.J.) on the basis of size and segmental location recorded on the pathologic reports.

Statistical Analysis
The Fisher exact test (R version 2.0.1) (25) was used to compare the distribution of relative arterial vascularity (hyper-, iso- or hypovascular) on the basis of histologic differentiation and the time of washout of hypervascular tumors with a similar correlation. For the analyses of HCC vascularity and hypervascular HCC washout time, an overall test of differences between the three groups was performed, followed by three pairwise comparisons: well differentiated to moderately differentiated, well differentiated to poorly differentiated, and moderately differentiated to poorly differentiated.

For a subset of patients with hypervascular HCCs, washout times were compared for patients with no fibrosis and those with severe fibrosis (grade 4 on a scale of 1-4, Laennec) by using the Fisher exact test. A P value of less than .05 was considered to indicate a significant difference. We included livers with severe fibrosis at transplantation or surgical resection only to exclude the bias that fibrosis of the parenchyma around the mass at percutaneous biopsy could be overgraded due to the mass effect. Nonfibrotic livers were diagnosed by using either a surgical specimen or percutaneous biopsy.

	RESULTS

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Arterial Vascularity of 112 HCCs
Dysmorphic intratumor arteries were well identified in 81 of 112 (72%) HCCs (Fig 1). During the hepatic arterial phase, the majority (n = 97, 87%) of lesions showed classic hypervascularity. Eight (7%) were isovascular and seven (6%) were hypovascular in the arterial phase.

View larger version (183K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: Sagittal contrast-enhanced US scans in 56-year-old man with hypervascular HCC (arrows) with typical dysmorphic arteries. (a) Scan of left lobe at 13 seconds during wash-in (early arterial) phase shows intratumor vessels that are tortuous, chaotic in distribution, and more numerous than expected for liver region. (b) Mass has marked hypervascularity compared with parenchyma at 21 seconds.

View larger version (192K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: Sagittal contrast-enhanced US scans in 56-year-old man with hypervascular HCC (arrows) with typical dysmorphic arteries. (a) Scan of left lobe at 13 seconds during wash-in (early arterial) phase shows intratumor vessels that are tortuous, chaotic in distribution, and more numerous than expected for liver region. (b) Mass has marked hypervascularity compared with parenchyma at 21 seconds.

View larger version (24K): [in this window] [in a new window] [Download PPT slide]   Figure 2: Chart shows arterial vascularity of 112 HCCs according to histopathologic differentiation. Hypervascularity is more frequently seen in moderately differentiated HCC than in well- (P < .001) or poorly differentiated HCC (P < .004). There is no significant difference between well- and poorly differentiated groups (P = .213).

View larger version (35K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Chart shows washout time of 97 hypervascular HCCs according to histopathologic differentiation. Washout time was significantly less in moderately (P < .001) and poorly differentiated (P < .002) HCCs than in well-differentiated tumors. There was no significant difference between washout in moderately and poorly differentiated HCCs (P = .249). Results show a shift toward earlier washout for more advanced pathologic review.

View larger version (172K): [in this window] [in a new window] [Download PPT slide]   Figure 4a: Contrast-enhanced US scans in 55-year-old man with hepatitis C cirrhosis and HCC (arrows) show classic enhancement features. (a) Oblique intercostal arterial phase image at 25 seconds shows hypervascularity of nodule. (b) Nodule shows mild partial washout compared with parenchyma at 78 seconds in conventional portal venous phase. (c) Washout becomes more obvious at 215 seconds on oblique intercostal image. Pathologic review from explant liver revealed moderately differentiated HCC.

View larger version (188K): [in this window] [in a new window] [Download PPT slide]   Figure 4b: Contrast-enhanced US scans in 55-year-old man with hepatitis C cirrhosis and HCC (arrows) show classic enhancement features. (a) Oblique intercostal arterial phase image at 25 seconds shows hypervascularity of nodule. (b) Nodule shows mild partial washout compared with parenchyma at 78 seconds in conventional portal venous phase. (c) Washout becomes more obvious at 215 seconds on oblique intercostal image. Pathologic review from explant liver revealed moderately differentiated HCC.

View larger version (188K): [in this window] [in a new window] [Download PPT slide]   Figure 4c: Contrast-enhanced US scans in 55-year-old man with hepatitis C cirrhosis and HCC (arrows) show classic enhancement features. (a) Oblique intercostal arterial phase image at 25 seconds shows hypervascularity of nodule. (b) Nodule shows mild partial washout compared with parenchyma at 78 seconds in conventional portal venous phase. (c) Washout becomes more obvious at 215 seconds on oblique intercostal image. Pathologic review from explant liver revealed moderately differentiated HCC.

View larger version (168K): [in this window] [in a new window] [Download PPT slide]   Figure 5a: Oblique contrast-enhanced US scans in 56-year-old man with hepatitis C and alcoholic cirrhosis and stable mass for 6 months show atypical enhancement features of HCC. (a) Intercostal image at 19 seconds shows markedly hypervascular mass. (b) Intercostal image at 300 seconds shows homogeneous persistent positive enhancement of mass (arrows) compared with parenchyma. Percutaneous biopsy revealed well-differentiated HCC.

View larger version (173K): [in this window] [in a new window] [Download PPT slide]   Figure 5b: Oblique contrast-enhanced US scans in 56-year-old man with hepatitis C and alcoholic cirrhosis and stable mass for 6 months show atypical enhancement features of HCC. (a) Intercostal image at 19 seconds shows markedly hypervascular mass. (b) Intercostal image at 300 seconds shows homogeneous persistent positive enhancement of mass (arrows) compared with parenchyma. Percutaneous biopsy revealed well-differentiated HCC.

View larger version (177K): [in this window] [in a new window] [Download PPT slide]   Figure 6a: Sagittal contrast-enhanced US scans in 53-year-old man with hepatitis C cirrhosis show gradually enlarging nodule with atypical enhancement features of HCC. Nodule was not seen at subsequent multiphasic CT (not shown). (a) At arterial phase (34 seconds), nodule (arrows) is hypovascular compared with adjacent parenchyma. (b) At 87 seconds in typical portal phase, nodule is completely isoechoic to parenchyma and stays isoechoic and indistinguishable from parenchyma for the extended portal phase (not shown). Percutaneous biopsy revealed well-differentiated HCC.

View larger version (188K): [in this window] [in a new window] [Download PPT slide]   Figure 6b: Sagittal contrast-enhanced US scans in 53-year-old man with hepatitis C cirrhosis show gradually enlarging nodule with atypical enhancement features of HCC. Nodule was not seen at subsequent multiphasic CT (not shown). (a) At arterial phase (34 seconds), nodule (arrows) is hypovascular compared with adjacent parenchyma. (b) At 87 seconds in typical portal phase, nodule is completely isoechoic to parenchyma and stays isoechoic and indistinguishable from parenchyma for the extended portal phase (not shown). Percutaneous biopsy revealed well-differentiated HCC.

View larger version (158K): [in this window] [in a new window] [Download PPT slide]   Figure 7a: Oblique subcostal left lobe US scans in 63-year-old man with hemochromatosis-related cirrhosis and multifocal nonenhancing lesions at multiphasic CT (not shown) with atypical enhancement features of HCC. (a) Arterial phase scan at 20 seconds shows ill-defined area (arrows) of sparse vascularity. (b) At 23 seconds, the area shows some progression of enhancement (arrows) in the periphery compared with a, but is still hypovascular compared with parenchyma. (c) At 186 seconds, there is increased area (arrows) and degree of hypoechogenicity of lesion compared with b, showing washout. Percutaneous biopsy revealed poorly differentiated HCC.

View larger version (161K): [in this window] [in a new window] [Download PPT slide]   Figure 7b: Oblique subcostal left lobe US scans in 63-year-old man with hemochromatosis-related cirrhosis and multifocal nonenhancing lesions at multiphasic CT (not shown) with atypical enhancement features of HCC. (a) Arterial phase scan at 20 seconds shows ill-defined area (arrows) of sparse vascularity. (b) At 23 seconds, the area shows some progression of enhancement (arrows) in the periphery compared with a, but is still hypovascular compared with parenchyma. (c) At 186 seconds, there is increased area (arrows) and degree of hypoechogenicity of lesion compared with b, showing washout. Percutaneous biopsy revealed poorly differentiated HCC.

View larger version (171K): [in this window] [in a new window] [Download PPT slide]   Figure 7c: Oblique subcostal left lobe US scans in 63-year-old man with hemochromatosis-related cirrhosis and multifocal nonenhancing lesions at multiphasic CT (not shown) with atypical enhancement features of HCC. (a) Arterial phase scan at 20 seconds shows ill-defined area (arrows) of sparse vascularity. (b) At 23 seconds, the area shows some progression of enhancement (arrows) in the periphery compared with a, but is still hypovascular compared with parenchyma. (c) At 186 seconds, there is increased area (arrows) and degree of hypoechogenicity of lesion compared with b, showing washout. Percutaneous biopsy revealed poorly differentiated HCC.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

Contrast-enhanced US, with its intravascular agent and real-time imaging, provides an excellent noninvasive tool to enable the evaluation of the continuous transition of vascular changes through hepatocarcinogenesis. In our study, well-differentiated HCC with arterial phase iso- or hypovascularity (nine of 23, 39%) and isovascularity throughout the portal phase (nine of nine, 100%) likely reflects decreased normal hepatic arterial flow without substantial development of neoplastic arteries while preserving portal venous flow. It is reasonable to expect that incomplete transition of hepatic artery and portal venous changes can be implicated in lack of hypervascularity in the arterial phase and delayed or no washout in the portal venous phase. Our data show that of three histopathologic differentiations, well-differentiated HCC has the largest percentage of iso- or hypovascular HCC in the arterial phase.

Both typical HCC and other hepatic malignancies lack portal venous supply. We do not know why decreased or absent portal venous flow of HCC is often not apparent until late, while other malignancies, including hypervascular metastases, have consistently been described as showing complete washout, or a "punched-out" defect during the portal phase at contrast-enhanced US (11,12,15,17).

Authors of studies using low-mechanical-index contrast-enhanced US reported that among various pathologic reports included in their studies, HCC was the only malignancy that often had an isoechoic appearance at delayed phase, and the lack of washout was prone to misdiagnosis of a benign lesion (8,30). In our study, washout was seen in all poorly differentiated HCCs, with the majority (seven of nine, 78%) showing early washout within 90 seconds. A possible explanation for the early washout of poorly differentiated HCC may derive from its total lack of similarity to the normal hepatocyte and its architecture, which can be still shown in well-differentiated HCC.

Arterial phase hypervascularity was essential to a positive diagnosis in 74 of 77 (96%) moderately differentiated HCCs and 97 of 112 (87%) of all HCCs from the study. In combination with washout in the typical portal phase, a correct diagnosis can be made confidently in a high-risk patient. In our early experience with real-time low-mechanical-index contrast-enhanced US, hypervascular HCCs that showed very late washout were often regarded as indeterminate. With more experience, however, the late washout pattern is no longer regarded as indeterminate.

Furthermore, our results showed that late washout of HCC is at least as likely as typical portal venous washout by 90 seconds. Therefore, an extended portal phase observation of up to 5 minutes is important to make a confident diagnosis of HCC, as it allows appreciation of eventual washout, which occurred in the majority (91%) of HCCs in our study. However, 9% of HCCs in our study showed no washout even with extended portal phase evaluation and were predominantly well differentiated (seven of nine, 78%). Our results suggest that even in the absence of arterial hypervascularity, obvious washout in the extended portal phase alone should also be considered suspicious for HCC: All three isovascular moderately differentiated and all three hypovascular poorly differentiated HCCs showed an increased extent or degree of hypoechogenicity over time in the extended portal phase.

Quaia et al (8) performed a multicenter evaluation of 454 solid tumors by using contrast-enhanced US. This included 232 HCCs in the early (20–30 seconds after injection of contrast agent) and the late (45–70 seconds) phase. Their results showed some similarity with our results, but were confined to a study of the conventional portal phase. Their findings imply that 226 of 232 (97%) HCCs showed hypervascularity in the arterial phase; 137 (61%) HCCs were hypoechoic (washout) and 89 (39%) were isoechoic (no washout) in the conventional portal phase.

The recent report of Fan et al (23) of 113 HCCs identified at contrast-enhanced US showed that 109 (96%) were hypervascular. However, 90 (80%) showed rapid washout and only five (4%) showed washout beyond 90 seconds, which differs from the 55 of 97 (57%) cases of our study that showed slow washout. The reason for this discrepancy is not clear.

Nicolau et al (24) described 104 HCCs and reported some variability in the portal washout, showing a trend for late washout to correlate with better differentiation and for early washout to correlate with poor differentiation, which is in agreement with our study. However, they showed arterial hypervascularity in all but four of 31 well-differentiated tumors. Our results of arterial phase hypovascularity of HCC are more akin to those of angiography or CT hepatic arteriography, both of which describe the frequent lack of hypervascularity of HCC when it is small and well differentiated (31).

We have experience with some HCCs exhibiting relatively early washout in a normal background liver and we presume that the hemodynamic changes related to a chronically diseased liver might affect the enhancement pattern of HCC. However, statistical analysis showed no significant difference in the washout time of HCCs in nonfibrotic livers when compared with those in advanced cirrhosis. The degree of fibrosis is only one of many complex changes from chronic liver disease. A study focusing more on correlation with pathologic parameters designed for contrast-enhanced US may be a subject of further investigation.

In our study, contrast-enhanced US depicted dysmorphic intratumor arteries in the majority (81 of 112, 72%) of HCCs. With the advantages of real-time imaging, as well as greater spatial resolution when compared with that of CT and color Doppler US, contrast-enhanced US frequently demonstrates characteristic intralesion vascular patterns during the early wash-in phase regardless of the rate of perfusion. The dysmorphic vessels of HCC seen at contrast-enhanced US are distinctly different from central stellate vessels demonstrated in focal nodular hyperplasia or peripheral nodular enhancement of hemangioma in the arterial phase (8,12,13). Therefore, careful analysis of vascular morphology during the wash-in of contrast material often contributes to the diagnosis of HCC and its differentiation from other benign tumors, particularly atypical HCCs with sustained enhancement (32).

There were some limitations in our study. First, for 55 nodules diagnosed at percutaneous biopsy only, there was an inherent limitation regarding how well representative the sampled areas are for pathologic grading. Second, for four HCCs in four patients, the interval between transplantation and contrast-enhanced US was longer than 3 months (range, 4–7 months). The possibility of interval progression in histologic differentiation cannot be excluded. However, for three of the four HCCs, percutaneous biopsy was also performed to establish eligibility for transplantation in close approximation to the contrast-enhanced US, which showed the same histologic differentiation as that of the explants. Finally, we acknowledge the subjective aspect of evaluating vessel dysmorphology but emphasize that this is an important integral part of contrast-enhanced US. The high resolution of US with real-time capability is a strong benefit of this procedure.

In summary, while most HCCs with moderate differentiation show typical arterial hypervascularity and portal venous phase washout, variations exist particularly for well- and poorly differentiated tumors. Extended observation of the portal phase is helpful in making a correct diagnosis of HCC since washout later than the typical portal phase occurs slightly more frequently than washout within 90 seconds. Further, sustained enhancement in the extended portal phase should not be considered diagnostic of a benign lesion in patients at risk for HCC and follow-up or biopsy is required, since it may occur especially in well-differentiated HCC. Knowledge of the extreme variability in enhancement, which may be encountered, is essential for the correct diagnosis of HCC in patients at risk for its development.

	ADVANCES IN KNOWLEDGE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 

• Moderately differentiated HCC accounts for the majority of tumors and shows classic enhancement features of arterial phase hypervascularity (74 of 77, 96%) and portal venous phase washout (72 of 74, 97%), while well- and poorly differentiated HCC accounts for the majority of atypical variations of enhancement.
  
• Extended observation of HCC in the portal phase of contrast-enhanced US is important as late washout (55 of 97, 57%) occurs more frequently than washout in the conventionally defined portal venous phase (<90 seconds, 42 of 97, 43%).
  
• Among 97 hypervascular HCCs, absence of portal venous washout is seen rarely (two of 74, 3%) in moderately differentiated HCC, not at all (zero of nine, 0%) in poorly differentiated tumors, and in half (seven of 14, 50%) of well-differentiated tumors, which are more closely aligned to normal liver.
  
• Increasing hypoechogenicity in the portal venous phase, or washout, in the absence of prior arterial phase hypervascularity may occur infrequently and its recognition is essential to avoid missing atypical HCC.
  

	IMPLICATIONS FOR PATIENT CARE

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 

• Knowledge of the broad variation in enhancement features of HCC can improve its diagnosis.
  
• Extended observation of the portal phase in contrast-enhanced US is helpful to make a correct diagnosis of HCC as late washout occurs with slightly more frequency than washout in a conventionally defined portal phase.
  
• Late washout of a focal liver mass in a patient at risk for HCC should motivate biopsy even in the absence of arterial hypervascularity.
  

	ACKNOWLEDGMENTS

 
The authors thank George Tomlinson, PhD, University of Toronto, Toronto General Research Institute, for assistance with statistical analysis.

	FOOTNOTES

 

Abbreviations: HCC = hepatocellular carcinoma

Authors stated no financial relationship to disclose.

Author contributions: Guarantor of integrity of entire study, H.J.J.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; literature research, all authors; clinical studies, H.J.J., T.K.K., S.R.W.; statistical analysis, P.N.B.; and manuscript editing, all authors

	References

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION ADVANCES IN KNOWLEDGE IMPLICATIONS FOR PATIENT CARE References

 

1. Lee KH, O'Malley ME, Haider MA, Hanbidge A. Triple-phase MDCT of hepatocellular carcinoma. AJR Am J Roentgenol 2004;182:643–649.[Abstract/Free Full Text]
2. Iannaccone R, Laghi A, Catalano C, et al. Hepatocellular carcinoma: role of unenhanced and delayed phase multi–detector row helical CT in patients with cirrhosis. Radiology 2005;234:460–467.[Abstract/Free Full Text]
3. Jang HJ, Lim JH, Lee SJ, Park CK, Park HS, Do YS. Hepatocellular carcinoma: are combined CT during arterial portography and CT hepatic arteriography in addition to triple-phase helical CT all necessary for preoperative evaluation? Radiology 2000;215:373–380.[Abstract/Free Full Text]
4. Hussain SM, Semelka RC, Mitchell DG. MR imaging of hepatocellular carcinoma. Magn Reson Imaging Clin N Am 2002;10:31–52.[CrossRef][Medline]
5. Kadoya M, Matsui O, Takashima T, et al. Hepatocellular carcinoma: correlation of MR imaging and histopathologic findings. Radiology 1992;183:819–825.[Abstract/Free Full Text]
6. Kim TK, Jang HJ, Wilson SR. Imaging diagnosis of hepatocellular carcinoma with differentiation from other pathology. Clin Liver Dis 2005;9:253–279.[CrossRef][Medline]
7. Marrero JA. Screening tests for hepatocellular carcinoma. Clin Liver Dis 2005;9:235–251.[CrossRef][Medline]
8. Quaia E, Calliada F, Bertolotto M, et al. Characterization of focal liver lesions with contrast-specific US modes and a sulfur hexafluoride–filled microbubble contrast agent: diagnostic performance and confidence. Radiology 2004;232:420–430.[Abstract/Free Full Text]
9. 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.[Abstract/Free Full Text]
10. 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;216:411–417.[Abstract/Free Full Text]
11. Dill-Macky MJ, Burns PN, Khalili K, Wilson SR. Focal hepatic masses: enhancement patterns with SH U 508A and pulse-inversion US. Radiology 2002;222:95–102.[Abstract/Free Full Text]
12. Brannigan M, Burns PN, Wilson SR. Blood flow patterns in focal liver lesions at microbubble–enhanced US. RadioGraphics 2004;24:921–935.[Abstract/Free Full Text]
13. Kim TK, Jang HJ, Wilson SR. Benign liver masses: imaging with microbubble contrast agents. Ultrasound Q 2006;22:31–39.[Medline]
14. Isozaki T, Numata K, Kiba T, et al. Differential diagnosis of hepatic tumors by using contrast enhancement patterns at US. Radiology 2003;229:798–805.[Abstract/Free Full Text]
15. Cosgrove D, Blomley M. Liver tumors: evaluation with contrast-enhanced ultrasound. Abdom Imaging 2004;29:446–454.[Medline]
16. Jang HJ, Lim HK, Lee WJ, et al. Focal hepatic lesions: evaluation with contrast-enhanced gray-scale harmonic US. Korean J Radiol 2003;4:91–100.[Medline]
17. Dietrich CF. Characterisation of focal liver lesions with contrast enhanced ultrasonography. Eur J Radiol 2004;51(suppl):S9–S17.[CrossRef][Medline]
18. Wen YL, Kudo M, Zheng RQ, et al. Characterization of hepatic tumors: value of contrast-enhanced coded phase-inversion harmonic angio. AJR Am J Roentgenol 2004;182:1019–1026.[Abstract/Free Full Text]
19. Giorgio A, Ferraioli G, Tarantino L, et al. Contrast-enhanced sonographic appearance of hepatocellular carcinoma in patients with cirrhosis: comparison with contrast-enhanced helical CT appearance. AJR Am J Roentgenol 2004;183:1319–1326.[Abstract/Free Full Text]
20. Koda M, Matsunaga Y, Ueki M, et al. Qualitative assessment of tumor vascularity in hepatocellular carcinoma by contrast-enhanced coded ultrasound: comparison with arterial phase of dynamic CT and conventional color/power Doppler ultrasound. Eur Radiol 2004;14:1100–1108.[CrossRef][Medline]
21. Wilson SR, Burns PN. An algorithm for the diagnosis of focal liver masses using microbubble contrast-enhanced pulse-inversion sonography. AJR Am J Roentgenol 2006;186:1401–1412.[Abstract/Free Full Text]
22. Hohmann J, Albrecht T, Hoffmann CW, Wolf KJ. Ultrasonographic detection of focal liver lesions: increased sensitivity and specificity with microbubble contrast agents. Eur J Radiol 2003;46:147–159.[CrossRef][Medline]
23. Fan ZH, Chen MH, Dai Y, et al. Evaluation of the primary malignancies in the liver using contrast-enhanced sonography: correlation with pathology. AJR Am J Roentgenol 2006;186:1512–1519.[Abstract/Free Full Text]
24. Nicolau C, Catala V, Vilana R, et al. Evaluation of hepatocellular carcinoma using SonoVue, a second generation ultrasound contrast agent: correlation with cellular differentiation. Eur Radiol 2004;14:1092–1099.[CrossRef][Medline]
25. R Development Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna. http://www.R-project.org. Accessed November 10, 2006.
26. Sakamoto M, Hirohashi S, Shimosato Y. Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 1991;22:172–178.[CrossRef][Medline]
27. Choi BI, Takayasu K, Han MC. Small hepatocellular carcinomas and associated nodular lesions of the liver: pathology, pathogenesis, and imaging findings. AJR Am J Roentgenol 1993;160:1177–1187.[Abstract/Free Full Text]
28. Matsui O, Kadoya M, Kameyama T, et al. Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 1991;178:493–497.[Abstract/Free Full Text]
29. Nakashima Y, Nakashima O, Hsia CC, Kojiro M, Tabor E. Vascularization of small hepatocellular carcinomas: correlation with differentiation. Liver 1999;19:12–18.[Medline]
30. Nicolau C, Vilana R, Catala V, et al. Importance of evaluating all vascular phases on contrast-enhanced sonography in the differentiation of benign from malignant focal liver lesions. AJR Am J Roentgenol 2006;186:158–167.[Abstract/Free Full Text]
31. Hayashi M, Matsui O, Ueda K, Kawamori Y, Gabata T, Kadoya M. Progression to hypervascular hepatocellular carcinoma: correlation with intranodular blood supply evaluated with CT during intraarterial injection of contrast material. Radiology 2002;225:143–149.[Abstract/Free Full Text]
32. Jang HJ, Kim TK, Wilson SR. Imaging of malignant liver masses: characterization and detection. Ultrasound Q 2006;22:19–29.[Medline]

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