An Algorithm for the Diagnosis of Focal Liver Masses Using Microbubble Contrast-Enhanced Pulse-Inversion Sonography

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1 lgorithm for Sonography of Focal Liver Masses Hepatobiliary Imaging Original Research D E M N E U T R Y L I M I G O F I N G Stephanie R. Wilson 1,2 Peter N. Burns 1,3 Wilson SR, Burns PN Keywords: contract media, dynamic sonography, liver, oncologic imaging, sonography DOI: /JR Received January 4, 2005; accepted after revision March 23, Supported by a phase 2 clinical trial funded by Bristol- Myers Squibb Medical Imaging, by the anadian Institutes of Health Research, and by the Terry Fox Programme of the National ancer Institute of anada. 1 Department of Medical Imaging, University of Toronto, Toronto, ON, anada. 2 The Toronto General Hospital, University Health Network, 585 University ve., Toronto, ON M5G 2N2, anada. ddress correspondence to S. R. Wilson (Stephanie.Wilson@uhn.on.ca). 3 Department of Medical Biophysics, University of Toronto Imaging Research, and Sunnybrook and Women s ollege Health Sciences entre, Toronto, ON, anada. JR 2006; 186: X/06/ merican Roentgen Ray Society n lgorithm for the Diagnosis of Focal Liver Masses Using Microbubble ontrast-enhanced Pulse-Inversion Sonography OBJETIVE. The objective of this study was to develop an algorithm for liver mass diagnosis using microbubble contrast-enhanced pulse-inversion sonography. SUBJETS ND METHODS. Ninety-six lesions in 92 patients were evaluated with DMP 115 (Definity)-enhanced pulse-inversion sonography, comprising 44 malignancies (29 hepatocellular carcinomas, 12 metastases, two peripheral cholangiocarcinomas, and one hepatic lymphoma) and 52 benign lesions (26 hemangiomas, 20 focal nodular hyperplasias, and six others). ll had continuous low-mechanical-index imaging through the arterial and portal venous phase. three-person blind review evaluated single images at baseline, early and peak arterial phases, and through the extended portal phases with a movie showing arterial phase wash-in. Reviewers assessed lesional vascularity and enhancement blindly but did not make a diagnosis. ombinations of answers were compared with independently determined final diagnoses to develop an algorithm for liver mass diagnosis. RESULTS. Portal phase enhancement comprises the first step of the algorithm, with positive or sustained enhancement identifying 48 (92%) of 52 benign lesions and negative enhancement or washout present in 41 (93%) of 44 malignancies. Sustained portal phase enhancement with arterial phase peripheral nodularity and centripetal progression predicted 24 (92%) of 26 of the hemangiomas; diffuse arterial phase enhancement greater than the liver identified 19 (95%) of 20 of the focal nodular hyperplasias. With negative portal phase enhancement, arterial phase information was less effective at differentiating hepatocellular carcinoma (25 [86%] of 29 cases) from another hepatic malignancy (11 [73%] of 15 cases). ONLUSION. simple diagnostic algorithm for interpretation of microbubble-enhanced sonography provides sensitive and accurate diagnosis of commonly encountered liver masses. edical imaging has played an M evolving role in the diagnosis of focal liver masses in the past 3 decades. With the advent of X-ray angiography [1], it was recognized that the vascular appearances of liver tumors allowed for their differentiation in the majority of patients. Hepatocellular carcinoma (H) showed tortuous, dysmorphic vessels; hemangioma showed peripheral puddles and pools of contrast agent; focal nodular hyperplasia (FNH) frequently showed profuse vascularity with well-defined stellate vessels. lthough hepatic angiography was once popular, it is invasive, requiring arterial access, and never attained widespread availability. ngiographic techniques were later augmented by nuclear medicine methods, including RB scintigraphy and sulfur colloid liver and spleen imaging, which in some cases could provide confirmation of the diagnosis of a benign lesion. In more recent years, reliable noninvasive diagnosis of focal liver lesions has come to be based on the vascular enhancement patterns seen after bolus peripheral venous contrast injections on T [2 4] and MRI [5 8] in the arterial and portal phases. Microbubble contrast agents for sonography were introduced in the 1990s and have steadily gained popularity for the investigation of liver masses [9]. unique component of a contrast-enhanced sonography study is the real-time evaluation of lesional and hepatic vasculature when performed with a lowmechanical-index, bubble-specific nonlinear imaging technique. Pulse-inversion imaging, used here, is one such technique that suppresses echoes from tissue in favor of those from bubbles [10]. When used at a low mechanical index, pulse-inversion imaging does not cause disruption of the microbubbles and therefore preserves their integrity, allowing JR:186, May

2 continuous assessment of the vessels as the contrast agent traverses the imaging field. The detailed depiction of vessels often shows their distribution and morphology and is thus in some ways comparable with angiographic assessment of tumor vessels, providing information that is only occasionally seen on T or MRI. In addition, contrast-enhanced sonography also shows the lesional and parenchymal enhancement analogous to that seen on T and MR images, but with higher temporal resolution (typically frames per second). Microbubble enhancement has added significantly to the ability of gray-scale sonography in the evaluation of focal liver disease, with a number of early reports suggesting promise for the method in the differential diagnosis of liver masses [11 17]. In this study, we used blinded interpretations of 100 liver contrast studies combined with a knowledge of the vascular features of hepatic lesions seen on angiography, T, and MRI to develop and assess a simple algorithm for the differential diagnosis of focal liver masses using microbubble-enhanced pulse-inversion sonography. Subjects and Methods This study was an open-label, nonrandomized, single-center phase 2 trial to assess liver lesion characterization with the microbubble contrast agent DMP 115 (Definity, Bristol-Myers Squibb). The trial had approval of the institutional ethics review board; all patients gave informed consent. Execution of the protocol was overseen by an independent external monitor. The primary objective was the development of an algorithm for liver mass diagnosis. Safety monitoring was limited to vital signs at 30, 60, and 120 min after the sonography procedure. Telephone contact was made 24 hr after the study visit to document any adverse events. Patients Patients were accepted in the study if they were referred for sonography at our institution for evaluation of an unknown focal liver mass or if a previously undiagnosed focal liver mass was detected during sonography performed for another reason. Patients were recruited nonconsecutively and accepted if their lesion was clearly appreciated on a baseline sonography scan and the likelihood of a confirmatory diagnosis was high. One hundred such patients were recruited for the contrast sonography study. fter examination, eight subjects were eliminated (five technically inadequate examinations, one with no confirmed lesion, one intraductal Klatskin cholangiocarcinoma with no liver involvement, and one protocol deviation with radiofrequency ablation before the sonography), leaving a study population of 92 patients. There were 46 men and 46 women, with a mean age of 51 years (range, years). When patients had more than one lesion with the same diagnosis within a single field of view, this was counted as a single lesion. Four patients had two separate lesions in different lobes of the liver, not visible in a single view. Of these, three had the same diagnosis for each lesion and one patient had two diagnoses, FNH and hemangioma, yielding a total of 96 lesions studied in 92 patients. Lesions varied in maximum diameter from 1 to 13 cm (mean, 4.5 cm). Seventeen lesions were less than 2 cm in diameter and another 17 lesions were larger than 8 cm. Final diagnoses for the 96 lesions included H (n = 29; mean diameter, 5.3 cm); non- H malignancies (n = 15; mean diameter, 4.2 cm), comprising 12 metastases, two peripheral cholangiocarcinomas, and a single hepatic lymphoma; FNH (n = 20; mean diameter, 3.8 cm); hemangioma (n = 26; mean diameter, 4.9 cm); and six other benign lesions (mean size, 2.6 cm) including three regenerative nodules, two adenomas, and one lipoma. Final diagnosis was made by histopathology in 34 of 44 malignant lesions, including one lymphoma, nine of 12 metastases, 22 of 29 Hs, and two peripheral cholangiocarcinomas. In the remaining 10 patients with malignant disease, seven Hs and three metastases, diagnoses were established with T (n = 7), MRI (n = 2), and T and MRI (n = 1) using standard diagnostic criteria. These include a hypervascular mass in the arterial phase with negative enhancement in the portal venous phase for hepatomas [18] and a variably enhancing mass often with rim enhancement or hypovascularity in the arterial phase with negative enhancement in the portal venous phase for metastases. linical evidence for the seven Hs without biopsy included α-fetoprotein level over 400 (n = 4), positive viral serology for hepatitis B or (n = 6), and proven alcoholic cirrhosis (n =1). The clinical evidence for the diagnosis of the three metastases without biopsy included overwhelming evidence of malignancy with bone metastases (n = 1) and new liver lesions in patients with a known primary malignancy (n = 3). Final diagnosis was made by histopathology in seven of 52 benign lesions, including one of two adenomas, two of 20 FNHs, two of three regenerative nodules, one lipoma, and one of 26 hemangiomas. In the 45 benign lesions without biopsy, 28 had diagnoses confirmed by T and 13 by MRI using standard diagnostic criteria. Hemangioma is characterized by peripheral nodular enhancement with centripetal progression of enhancement often to complete fill [19] and FNH by homogeneous hypervascularity in the arterial phase with sustained enhancement in the portal venous phase and delayed enhancement of a central scar [20]. Further, nine FNHs had a sulfur colloid liver spleen scan showing a positive uptake of radiotracer in the location of the liver mass, and three hemangiomas had a positive labeled RB scan. Sonography Technique and Interpretation Sonography scans were performed by a single physician. The majority were performed on an TL HDI 5000 (Philips Ultrasound). Scans were also performed on an cuson Sequoia (Siemens Medical Solutions). standard convex linear array transducer was used, operated in pulse-inversion mode at a mechanical index of less than In this mode, real-time imaging of microbubble contrast is seen throughout the arterial and portal phases in both vessels and liver parenchyma [10]. In all scans, the transmit focal zone was placed deep in relation to the lesion. The contrast agent was administered to a maximum total dose of 50 µl/kg. t the initiation of this trial, DMP 115 was given by IV infusion at ml/min. It was also administered by multiple small boluses of ml followed by a 5-mL saline flush, to the same maximum total dose. By the completion of the 19th patient, the infusion technique was abandoned and subsequent patients were examined using the multiple small bolus technique. single 1.3-mL vial of contrast agent sufficed for all patients; in most cases, less than half of the vial was used. Sonographic technique comprised continuous observation of the lesion from the time of injection for about 4 min, using the low-mechanical-index pulse-inversion technique. With the arrival of the first microbubbles in the field of view, the arterial phase was timed for sec. 90-frame digital cine loop was stored for later review, starting at the first arrival of the bubbles in the field of view and including the interval to peak enhancement. The beginning of the portal venous phase was timed from about 60 sec after completion of injection. s these microbubbles are purely intravascular and show no late or Kupffer phase enhancement [21], there was no interstitial or equilibrium phase. For the remainder of the observation period, therefore, the enhancement showed progressive decline until the baseline appearance was again observed (usually about 4 5 min after completion of the saline flush). We refer to this period of observation from 60 sec to the end of the observation period as the extended portal venous phase. From these scanning sequences, images were selected for interpretation as follows: to show lesional vascularity, arterial phase enhancement, and extended portal venous phase enhancement. Lesional vascularity Lesional vascularity refers to the presence, distribution, and morphology of lesional vessels. Specific morphologic features of interest include linear vessels, stellate vascular morphology, vascular dysmorphology, marginal vascularity, 1402 JR:186, May 2006

3 lgorithm for Sonography of Focal Liver Masses and the presence of peripheral puddles and pools of enhancement without linear vessel morphology. Lesional enhancement relative to the liver in the arterial phase s the entire image appears dark, or hypoechoic, at the initiation of a low-mechanical-index sequence, any echogenicity that subsequently appears in the liver or the lesion is attributed to the presence of the contrast agent. Therefore, arterial phase enhancement was assessed by comparing the echogenicity of the lesion relative to the echogenicity of the liver at the peak of contrast enhancement. Lesional enhancement relative to the liver in the extended portal venous phase s the liver derives most of its blood supply from the portal veins, normal liver enhancement progressively increases from the time of injection through the arterial phase to its peak in the portal phase, at which time the enhancement of the lesion is again compared with the enhancement of the adjacent liver parenchyma. The portal venous phase imaging was timed beginning at 60 sec after the completion of the flush. Images were recorded until completion of the scanning sequence, usually at about 4 min. If liver enhancement overtook that of the lesion (often referred to as portal phase washout), images were recorded at the peak of the contrast difference between the liver and lesion. three-person blind review was conducted to determine which combination of the resulting observations, if any, provided the ability to diagnose focal liver masses with microbubble-enhanced pulse-inversion sonography. The reviewers were all radiologists trained in the use and interpretation of contrast agents in the liver. clinical fellow in body imaging trained in contrast sonography who neither scanned the patients nor was a reader selected representative images and videotape files to show the baseline appearance, lesional vascularity, and arterial phase and portal venous phase enhancement of the lesion relative to the enhancement of the liver. Image sets were randomized and shown to the reviewers, who remained blinded to all clinical information and patient details. The reviewers were not asked to provide a diagnosis. The questions were designed to determine the salient features of the lesional vascularity and enhancement as follows: First, in the arterial phase, are there discrete lesional vessels? If yes, how many? Is there a stellate pattern? Second, is there peripheral puddling or pooling of contrast? Third, is the predominant degree of arterial phase enhancement greater than, equal to, or less than the adjacent liver? Fourth, is the pattern of arterial phase enhancement diffuse, rim, peripheral nodular, or sparse? Fifth, if diffuse, is there a nonenhancing portion? If yes, is it a scar or necrosis? Sixth, is there centripetal progression of the enhancement? Seventh, in the extended portal venous phase, is there sustained enhancement of the lesion equal to or greater than the liver? Before interpretation, the reviewers were shown examples of contrast-enhanced sonograms to establish a standardized approach to the interpretation of the information provided on the imaging sequences. For the arterial phase, reviewers were asked to describe the enhancement of the lesion relative to the liver on the basis of its relative echogenicity. Lesional enhancement greater than the adjacent liver parenchyma was termed positive enhancement; less than the adjacent liver was termed negative enhancement. Lesions with the same enhancement as the liver were called isoechoic. To ensure consistency, reviewers were trained with examples of positive, negative, and isoechoic enhancement, and diffuse, sparse, rimlike, and peripheral nodular enhancement. nalysis In analyzing the results of the interpretation, consensus agreement was defined as the answer agreed upon by at least two of the three reviewers in their response to a question. onsensus answers to the questions in the blind review were then analyzed in conjunction with the final diagnosis of each mass to optimize an algorithm for the differential diagnosis of the masses with contrast-enhanced sonography. Results No adverse events were recorded during the study. nswers to questions in the blind interpretation are shown in Table 1 according to the final diagnosis of each mass. Eight questions were asked for each of 96 masses for a total of 768 answers. In only 10 of these (1.3%) was consensus (agreement between two of three) not reached by the three reviewers. With knowledge of the final diagnoses, analysis of the responses to the questions was applied empirically to develop the algorithmic procedure shown in Figure 1. The first step in the algorithm is to determine if the lesion shows sustained enhancement equal to or greater than that of the liver in the portal venous phase. Positive or sustained enhancement in the portal venous phase predicts the lesion to be benign, with a sensitivity of 92% (48/52) and a specificity of 93% (41/44). If sustained enhancement in the portal venous phase indicated a benign lesion, the additional presence of peripheral nodular enhancement in the arterial phase with centripetal progression correctly predicted the diagnosis of hemangioma in 24 (92%) of 26 cases (Figs. 2 and S2). Diffuse arterial phase enhancement greater than the adjacent liver correctly identified 19 (95%) of 20 FNHs (Figs. 3 and S3). lthough negative portal venous phase enhancement of the lesion relative to the liver was predictive of a malignant lesion, the arterial phase enhancement was less successful at differentiating the type of malignant lesion. rterial phase diffuse positive enhancement identified 23 (85%) of 29 Hs (Figs. 4 and S4), and negative enhancement identified 10 (71%) of 14 metastases (Figs. 5 and S5). The algorithmic diagnoses are shown in comparison with the final diagnoses in Table 2. Two incorrect algorithmic diagnoses are shown in Figures 6 and 7, both related to the appearance of the lesion in the portal venous phase that led to its misclassification as benign or malignant. Figures S2 S5 and S8 can be seen in the JR electronic supplement to this article, available at and present more detail than the figures printed here. Discussion haracterization of a focal liver mass using state-of-the-art sonography includes a grayscale morphologic evaluation coupled with vascular information derived from color or power Doppler sonography [22]. omparison of conventional sonography with contrast-enhanced T and MR images for liver mass characterization, however, shows that sonography is generally inferior at this task [23 26]. Most of the observations regarding lesional enhancement and vascularity that we use for diagnosis in this study were not detectable using any Doppler technique. This probably explains the poor performance of conventional unenhanced sonography for the diagnosis of focal liver lesions when compared with contrast-enhanced T and MRI [3]. Initial publications on the use of microbubble-enhanced sonography for improved characterization of focal liver masses used the first-generation air-based contrast agent SH U 508 (Levovist, Schering) and earlier versions of nonlinear imaging technology. lthough reports were optimistic [12 14], they also reflected the limited potential of air-based contrast agents that require a high mechanical index for their visualization. Bubble destruction at a high mechanical index eradicates the bubbles as they appear in the field of view. onsequently, only vessels with rapidly moving bubbles, which replenish those destroyed within the interframe interval, are seen in real time. lthough parenchymal perfusion can be seen by a single interval delay image JR:186, May

4 TBLE 1: onsensus Responses to Questions of Diagnosis and Sonographic Results Diagnosis Non-H FNH Hemangioma Other Benign H Malignancy ll Benign ll Malignant Enhancement on ontrast Sonography (n = 20) (n = 26) (n = 6) (n = 29) (n = 15) (n = 52) (n = 44) Discrete lesional vessels None 0 (0) 24 (92) 0 (0) 3 (10) 6 (40) 24 (46) 9 (20) Few 2 (10) 0 (0) 5 (83) 3 (10) 3 (20) 7 (13) 6 (14) Many 18 (90) 2 (8) 1 (17) 23 (79) 5 (33) 21 (40) 28 (64) Stellate lesional vessels 9 (45) 0 (0) 0 (0) 3 (10) 0 (0) 9 (17) 3 (7) Peripheral puddles/pooling 0 (0) 23 (88) 0 (0) 2 (7) 0 (0) 23 (44) 2 (5) Predominant arterial phase enhancement Less than liver 0 (0) 19 (73) 0 (0) 2 (7) 11 (73) 19 (37) 13 (30) Equal to liver 1 (5) 0 (0) 0 (0) 2 (7) 0 (0) 1 (2) 2 (5) Greater than liver 19 (95) 7 (27) 5 (83) 23 (79) 4 (2) 31 (60) 27 (61) rterial phase enhancement pattern Rim 0 (0) 2 (8) 0 (0) 0 (0) 2 (13) 2 (4) 2 (5) Sparse 0 (0) 0 (0) 0 (0) 0 (0) 5 (33) 0 (0) 5 (11) Diffuse 20 (100) 2 (8) 6 (100) 28 (97) 3 (20) 28 (54) 31 (70) Nonenhancing region seen on anteroposterior image 2 (10) 25 (96) 1 (17) 16 (55) 10 (67) 28 (54) 26 (59) entripetal progression of enhancement 0 (0) 23 (88) 0 (0) 2 (7) 0 (0) 23 (44) 2 (5) Sustained enhancement through portal venous phase 19 (95) 26 (100) 3 (50) 3 (10) 0 (0) 48 (92) 3 (7) Note onsensus responses to selected questions for each of the principal diagnoses, together with the combined results for all lesions, divided into benign and malignant groups. Numbers in parentheses are percentages. FNH = focal nodular hyperplasia, H = hepatocellular carcinoma. Fig. 1 lgorithmic procedure developed based on analysis of responses. H = hepatocellular carcinoma. in which the bubbles are disrupted, continuous perfusion imaging is not possible. The more recent introduction of secondgeneration perfluorocarbon agents, together with newer imaging techniques, has provided much better imaging capabilities. These agents may be imaged at a low mechanical index, preserving the microbubble population and allowing continuous imaging of both the lesion and its vessels. urrent investigators report improved ability to characterize liver lesions [16, 27, 28] and improved ability to distinguish benign from malignant lesions on the basis of their portal venous phase enhancement [15]. In this study, the development of an algorithm for the diagnosis of focal liver masses with contrast-enhanced sonography was based on responses to a questionnaire in a blind review format. The reviewers were not asked to make a diagnosis of the lesion, only to answer questions regarding their observations of the vascularity of the lesion and its enhancement over time. The diagnostic algorithm is based on enhancement appearances that have similarities to those used for interpretation of contrast-enhanced T and MRI scans and will therefore be familiar to body imagers. Thus, 1404 JR:186, May 2006

5 lgorithm for Sonography of Focal Liver Masses we anticipate that such an algorithm could be easily incorporated into clinical practice. One of the strongest outcomes of the analysis (thus chosen as the first step in the algorithmic approach to an unknown mass) quantifies the ability of microbubble sonography to differentiate malignant and benign lesions on the basis of their portal phase enhancement. The real-time nature of the sonography scan allows for detection of washout when it occurs, and our study design included continuous observation of the lesion for several Fig. 2 Hemangioma in asymptomatic 38-year-old woman. (See also Fig. S2, cine loop, in supplemental data online.), Sagittal baseline sonogram shows focal echogenic mass in right lobe of liver. B and, Sequential low-mechanical-index early arterial phase images show peripheral puddles of contrast enhanced more than adjacent liver parenchyma. D, Portal venous phase image shows liver is more enhanced. There has been centripetal progression of enhancement such that lesion is virtually filled in with contrast agent and is enhanced at least equal to adjacent parenchyma. Sustained enhancement correctly suggests benign diagnosis. B D JR:186, May

6 minutes. Therefore, we did not define a precise moment when the enhancement of the lesion relative to the liver would be evaluated in either phase. Rather, in the arterial phase, we chose an image that showed the peak of enhancement of the lesion; and in the portal venous phase, we observed the lesion until it B was obvious whether the lesion showed greater, equal, or lower enhancement than the adjacent liver. This evaluation generally differentiates benign from malignant lesions, which then allows for more specific diagnosis on the basis of the arterial phase enhancement pattern, including diffuse, sparse, rimlike, or Fig. 3 Focal nodular hyperplasia in asymptomatic 30-year-old woman. (See also Fig. S3, cine loop, in supplemental data online.), Baseline sagittal sonogram shows subtle focal hypoechoic mass in tip of right lobe of liver. B, rterial phase image shows tortuous feeding artery and hypervascular mass. Stellate vascularity is not optimally shown on this frame., Portal venous phase image shows positive enhancement of mass in excess of enhancement of liver. Tiny hypoechoic central scar is seen. Sustained enhancement correlates highly with benign diagnosis. peripheral nodular, and enhancement intensity relative to the adjacent liver and on the arterial phase vascular morphology. Benign lesions, hemangioma, and FNH were correctly predicted in more than 90% of cases. Both lesions consistently showed sustained enhancement such that the mass ap JR:186, May 2006

7 lgorithm for Sonography of Focal Liver Masses Fig. 4 Hepatocellular carcinoma in 79-year-old man. (See also Fig. S4, cine loop, in supplemental data online.), Baseline transverse sonogram of right liver lobe shows hypoechoic lobulated mass with hypoechoic central zone, suggesting necrosis. B, Low-mechanical-index arterial phase image shows dysmorphic lesional vascularity., t peak of arterial phase enhancement, mass is positively enhanced relative to liver. D, In portal venous phase, lesion is inhomogeneous and again slightly hypoechoic relative to enhanced liver. Washout is consistent with a malignant diagnosis. Nonenhancing central area on all images is related to tumor necrosis. B D peared equal to or greater in echogenicity than the adjacent liver for the duration of the scanning interval, often as long as 4 min. Peripheral nodular enhancement in the arterial phase, an essential component for the diagnosis of hemangioma, is distinctly different from the appearance of the vascularity seen with all other lesions. The microbubbles collecting in the vascular spaces of the hemangi- JR:186, May

8 oma show pooling of the contrast agent without the linear appearance of tumor vessels seen in other lesions. entripetal progression of this enhancement from the lesion periphery toward the center is seen on the real-time sonography examination regardless of the rapidity with which it occurs (Fig. S8). B Fig. 5 Metastatic colon cancer in 65-year-old man showing peripheral rim enhancement with rapid washout in portal venous phase. (See also Fig. S5, cine loop, in supplemental data online.), Baseline transverse sonogram of liver shows heterogeneity of echotexture of liver and pressure effect on portal vein but no discrete mass. B, Early arterial phase image shows dominant mass with marginal vascularity., Portal venous phase image shows, in addition to dominant mass, many other small nonenhancing tumor deposits. This shows value in detection and characterization of liver masses. Infrequently, a metastatic tumor might show peripheral enhancement in the arterial phase, which, on the basis of a single frame, may be similar to the peripheral nodular enhancement of a hemangioma. However, subsequent imaging of the metastasis reveals washout or negative enhancement of the lesion relative to the liver in the portal venous phase, which is easily distinguished from the centripetal progression with sustained portal venous enhancement that characterizes the hemangioma. The concept of washout of a lesion in the portal venous phase is recognized to be a re JR:186, May 2006

9 lgorithm for Sonography of Focal Liver Masses TBLE 2: Diagnoses Predicted by the lgorithm ompared with Final Diagnoses in 96 Lesions lgorithmic Diagnosis FNH (n = 20) H (n = 29) flection of not only the blood supply of the lesion but also the hemodynamics of the liver itself. The normal liver, with its dual blood supply, shows first enhancement in the arterial phase as the contrast agent fills the hepatic artery, with progressively greater enhancement as the contrast agent arrives in the portal vein. severely arterialized cirrhotic liver will show different hemodynamics, including greater relative enhancement of the liver in the arterial phase with less difference between the liver enhancement in the arterial and the portal venous phases. It is our belief, therefore, that H in a severely cirrhotic liver may not show this washout phenomenon until much later, if at all. study using T found similarly that enhancement of the cirrhotic liver was significantly lower during the portal venous and delayed phases, presumably because of decreased peripheral portal perfusion [29]. The addition of a delayed scanning sequence at 180 sec has improved both detection and characterization of H over a standard dual-phase T technique [30, 31]. Sonography contrast studies in the liver have also created our impression that small and well-differentiated H may not show this washout as reliably. These facts may have influenced our results, as we did not recruit small nodules in cirrhotic livers in this study. Rather, the Hs in this study were relatively large (mean diameter, 5.3 cm). lso, although many of our patients with Hs had significant risk factors for the development of H, they did not have end-stage cirrhotic livers. onsequently, it is likely that a similar study of the difficult noninvasive diagnosis of small nodules in severely cirrhotic livers would produce less impressive results. Our algorithm is highly simplified and only uses answers to seven questions. For example, questions about stellate vascularity and regions of nonenhancement in the arterial phase were asked but not used in the final algorithm. Final Diagnosis (%) Hemangioma (n = 26) Non-H Malignancy (n = 15) Other Benign (n = 6) FNH 19 (95) 1 (3) 2 (8) 0 (0) 3 (50) H 1 (5) 25 (86) 0 (0) 4 (27) 2 (33) Hemangioma 0 (0) 2 (7) 24 (92) 0 (0) 0 (0) Non-H malignancy 0 (0) 1 (3) 0 (0) 11 (73) 1 (17) Note FNH = focal nodular hyperplasia, H = hepatocellular carcinoma. Nonetheless, this should not be taken to indicate that these features are irrelevant to clinical interpretation. For example, in lesions with diffuse enhancement in the arterial phase, both tumor necrosis and a central scar may contribute to areas of nonenhancement. s necrosis is very common in H, especially with increasing tumor size, and scars are a regular feature of FNH, their identification and differentiation are important features for correct diagnosis. lthough, on a case-by-case basis, we know that this is very important, the questions about inhomogeneity within a diffusely enhancing tumor did not capture this distinction sufficiently in the blind review to make an impact on the developed algorithm. We expect that the failure of this question may have been influenced by the large number of hemangiomas that frequently show inhomogeneous enhancement in the arterial phase as only the peripheral nodules are enhanced. We had designed the question to differentiate FNH from H and had not anticipated this problem, and we suspect that had the hemangiomas been removed from the analysis, the responses regarding inhomogeneity of enhancement might have been more discriminating. Furthermore, experience suggests that identification of stellate vascularity and a highly tortuous feeding artery are highly suggestive of an FNH (Fig. 3). However, questions about vessel morphology did not differentiate FNH from other lesions in the blind review. Stellate vessels were specific but not sensitive for the diagnosis of FNH, identified in only nine of 20 lesions. To some extent, this may be because of technical limitations in the imaging method, which might be overcome using new techniques [32]. In this trial, the initial use of an infusion technique was discontinued in favor of bolus administration for two reasons. First, whereas bolus injection allowed for evaluation of arterial phase wash-in and arterial vascular morphology before the parenchymal image was dominated by the portal venous phase, drip infusion produced a gradual wash-in that concealed the onset of the portal phase. Second, although a single bolus injection of 0.2 ml was often sufficient to provide all of the answers to the questions in our blind review, the infusion technique produced a chronic but relatively weak enhancement of the liver parenchyma that required much higher doses of the contrast agent, sometimes requiring a second vial. Benign lesions erroneously identified as malignant by the algorithm included four benign lesions showing washout in the portal venous phase. These were one regenerative nodule, two adenomas, and one FNH (Fig. 6). Diagnosis was confirmed by biopsy in two lesions and by further imaging with 3-year follow-up in the other two. Three malignant lesions, all H, were misclassified as benign because they showed sustained enhancement in the extended portal venous phase (Fig. 7). Diagnosis of malignancy in these lesions was confirmed by biopsy in one case; the other two had confirmatory imaging, known cirrhosis, and significant elevation of the α-fetoprotein level. Limitations of our study include those inherent to all sonography studies, operator dependence and the negative influence of large patient habitus. Sonography is not as versatile for looking at the entire liver as T or MRI and certainly not for analyzing a liver with many masses not necessarily having the same diagnosis. Further, a cirrhotic liver is even more difficult to scan than a normal liver on the basis of its small size and more limited acoustic access. Five of the 100 examinations failed technically for a variety of reasons, including equipment failure. Study entry criteria specified an identified lesion visible on sonography, which introduced some selection bias in our patient population. We also analyzed the results of only four pathologies, so that additional pathologies were, by definition, misclassified. This included the hepatic adenomas (n =2), the solitary lipoma, and the regenerative nodules (n = 3). Furthermore, as the algorithm was developed on the basis of the findings from a blind interpretation, it is retrospective. prospective study is now required to test it in a new population of patients. The proposed algorithm relies heavily on the enhancement of the lesion in the extended portal venous phase. lthough we recognize the strength of the data in this analysis to differentiate a malignant from a benign lesion based solely on this observation, we think that in clinical practice, it is unrealistic to rely on a single observation to diagnose a liver mass. We em- JR:186, May

10 phasize, instead, multiple observations made throughout the entire study and stress the value added by the arterial phase observations as well. It is particularly important to appreciate that not all masses show typical enhancement features, and that reliance on a single feature will increase the likelihood of diagnostic error. Furthermore, in clinical practice, the arterial phase enhancement and lesional vessels are the first things seen when performing a contrast-enhanced sonography scan. Their appearance should be integrated with the portal venous phase behavior to arrive at a final diagnosis. Furthermore, portal venous phase behavior alone may be insufficient information for patient management, particularly for malignant lesions where treatment options are quite different for H and metastasis. Precise differentiation of these two lesions requires attention to the arterial phase. s hypervascular metastases and H show identical arterial phase features on contrast sonography, as they do on contrast-enhanced T or MRI, clinical history contributes crucially to their ultimate differentiation. There are also unique strengths of microbubble-enhanced sonography. First, as the studies are performed in real time, rapidly changing enhancement (for example, that which occurs in type 1 hemangiomas or in most metastases), may be shown easily Fig. 6 Misdiagnosis with algorithm of focal nodular hyperplasia as malignant lesion in 46-year-old asymptomatic woman., Baseline sonography shows small mass (arrow) in segment V of liver. B, rterial phase image shows diffuse uniform positive enhancement of mass (arrow) in excess of enhancement of background parenchyma., Portal venous phase sonogram shows hypoechoic mass (arrow) relative to enhancement of background liver. This negative enhancement with washout incorrectly suggests malignant lesion. In portal venous phase, all reviewers interpreted sonogram as showing negative enhancement with washout. lgorithm diagnosis is wrong, as it suggests hepatocellular carcinoma. Biopsy showed focal nodular hyperplasia (FNH). In our experience, only two FNHs have shown negative portal venous phase enhancement on contrast-enhanced sonography. We do not have an explanation for this. B 1410 JR:186, May 2006

11 lgorithm for Sonography of Focal Liver Masses B (Figs. 5 and 8). In our study, the peak of arterial phase enhancement of a lesion was highly variable among individual patients. These differences were inconsequential as the peak was appropriately recorded regardless of the time of its occurrence. Washout also occurs at varying intervals from the injection time, and this is captured if the lesion is observed for several minutes from the completion of the contrast agent injection. This temporal resolution is a unique feature of sonography imaging. It should be noted that the microbubbles themselves are intravascular and do not pass into the interstitium Fig. 7 Misdiagnosis with algorithm of hepatocellular carcinoma (H) as benign lesion in 47-year-old man with hepatitis B., Baseline transverse image of liver shows focal hypoechoic mass (arrow). B, rterial phase image taken with infusion technique shows hypervascular mass (arrow)., In portal venous phase, mass (arrow) continues to show inhomogeneous positive enhancement. ll three reviewers interpreted as showing sustained enhancement, incorrectly suggesting benign lesion per first step in algorithm. ontrast-enhanced images are taken in slightly different projection from baseline image. Biopsy showed H. of tumor or tissue, as they are approximately the same size as RBs. The enhancement seen is therefore truly representative of the vascular distribution of the bubbles, removing the potential for erroneous interpretation to which T and MRI are prone, where the contrast agents have a recognized ability to JR:186, May

12 pass through the vascular endothelium into the tumor or tissue interstitium. The designation equilibrium phase as related to T and MRI, therefore, does not apply to sonography. The term extended portal venous phase reflects the continuous imaging of the sonography contrast enhancement from the moment that the bubbles arrive in the portal vein until such time as the scan is discontinued. Finally, microbubble sonography shows lesional vessels much like an angiogram, providing some of the same diagnostic capability of angiographic techniques but without the need for arterial access. cknowledgment The authors acknowledge the advice and guidance of Martin Rosenberg of Bristol-Myers Squibb. FOR YOUR INFORMTION References 1. Soulen M. ngiographic evaluation of focal liver masses. Semin Roentgenol 1995; 30: Baron RL, Brancatelli G. omputed tomographic imaging of hepatocellular carcinoma. Gastroenterology 2004; 127[suppl 1]:S133 S Federle MP. 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