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1 All authors: Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Korea.
Received June 1, 2000;
accepted after revision July 25, 2000.
Address correspondence to S. H. Kim.
Abstract
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SUBJECTS AND METHODS. Twenty patients with 30 hepatocellular carcinomas underwent ferumoxides-enhanced MR imaging and combined helical CT during arterial portography and CT hepatic arteriography. The diagnosis was established by pathologic examination after surgical resection in 18 patients and by biopsy in two. The MR protocol included fast spin-echo with two echo times, T2*-weighted fast multiplanar gradient-recalled acquisition in the steady state, proton density—weighted fast multiplanar spoiled gradient-recalled echo, and T1-weighted fast multiplanar spoiled gradient-recalled echo images. The MR images of all sequences and the paired CT during arterial portography and CT hepatic arteriography images were independently evaluated by three radiologists on a segment-by-segment basis. Diagnostic accuracy was assessed with receiver operating characteristic analysis.
RESULTS. The accuracies (Az values) of ferumoxides-enhanced MR imaging and combined CT during arterial portography and CT hepatic arteriography for all observers were 0.964 and 0.948, respectively. The mean sensitivities of MR imaging and CT were 93% and 91%, respectively. The differences were not statistically significant. The mean specificity of MR imaging (99%) was significantly higher than that of combined CT during arterial portography and CT hepatic arteriography (94%).
CONCLUSION. Ferumoxides-enhanced MR imaging can be used successfully in place of combined CT during arterial portography and CT hepatic arteriography for the preoperative evaluation of patients with hepatocellular carcinomas.
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Recently, the usefulness of ferumoxides-enhanced MR imaging has been reported for the detection of hepatic tumors, including hepatocellular carcinomas [5,6,7,8]. Ferumoxides particles coated with dextran administered IV are cleared by phagocytosis of the reticuloendothelial system, including the Kupffer's cells of the liver, and predominantly shorten the T2 of the liver parenchyma [9]. Most focal hepatic lesions, particularly malignant tumors, are devoid of Kupffer's cells; therefore, the ferumoxides particles taken up by Kupffer's cells of the normal hepatic parenchyma improve the contrast between the lesions and normal liver tissue. The T2-weighted fast spin-echo and T2*-weighted gradient-recalled echo in ferumoxides-enhanced MR imaging have been introduced as optimal pulse sequences [6, 10,11,12,13,14]. However, for the detection of hepatocellular carcinomas, it is still not clear whether ferumoxides-enhanced MR imaging with the most recent optimized sequences can replace combined CT during arterial portography and CT hepatic arteriography, which are more invasive techniques.
To our knowledge, there has been no comparative study of ferumoxides-enhanced MR imaging and combined CT during arterial portography and CT hepatic arteriography for detection of hepatocellular carcinomas. The purpose of this study was to compare the diagnostic accuracy of ferumoxides-enhanced MR imaging with that of combined helical CT during arterial portography and CT hepatic arteriography in the preoperative detection of hepatocellular carcinomas by means of receiver operating characteristic (ROC) analysis.
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Hepatic surgeries were performed within 3 weeks of imaging. Imaging studies were correlated with the histopathologic results of the resected hepatic specimens. In each patient, the absence of hepatocellular carcinoma in the remaining hepatic segments was ascertained on intraoperative sonography (n = 7) and on follow-up CT for at least 6 months (n = 20).
CT During Arterial Portography and CT Hepatic Arteriography
After bilateral femoral artery punctures, two 5-French catheters were
selectively placed, one in the superior mesenteric artery and the other in the
common hepatic artery or replaced right hepatic artery, depending on the
arterial variation. Before CT during arterial portography and CT hepatic
arteriography, celiac and superior mesenteric angiography was performed for
examination of the vascularity of a hepatocellular carcinoma and the vascular
anatomy, with 50-60 mL of nonionic contrast material, iopromide (Ultravist
300; Schering, Berlin, Germany), containing 300 mg I/mL. As a hepatic arterial
anatomic variation, there were two patients in whom the right hepatic artery
arose from the superior mesenteric artery and one patient in whom the common
hepatic artery arose from the superior mesenteric artery. After angiography,
the patients were transferred to CT units. For CT during arterial portography,
a catheter was placed in the superior mesenteric artery and 90 mL of nonionic
contrast medium was injected at a speed of 2.5 mL/sec with a power injector.
CT was then performed 25 sec after the start of injection. For CT hepatic
arteriography, the other catheter was placed in the common hepatic artery or
replaced right hepatic artery if it arose from the superior mesenteric artery.
Forty-five milliliters of contrast medium was injected at a speed of 1.5
mL/sec, and CT was performed 5 sec after the start of injection. When the
liver was supplied by two arteries, both arteries were selected one after the
other, and CT was performed twice. All CT was performed on a HiSpeed Advantage
helical scanner (General Electric Medical Systems, Milwaukee, WI). Images were
obtained in a craniocaudal direction with 7-mm collimation and 7-mm/sec table
speed; 120 kVp; and 180 mAs during a single breath-hold helical acquisition of
25-30 sec, depending on the liver size.
Ferumoxides-Enhanced MR Imaging
All MR images were obtained within 4 days of CT during arterial portography
and CT hepatic arteriography with a Horizon 1.5-T system (General Electric
Medical Systems) with a phased array multicoil system. Ferumoxides solution
(Feridex IV; Advanced Magnetics, Cambridge, MA) at a dose of 15 µmol/kg
diluted in 100 mL of 5% glucose solution was infused through a 5 µm filter
for approximately 30 min. MR imaging was initiated 30 min after the end of the
infusion.
The axial images of five sequences were obtained with a section thickness of 6-8 mm and an interslice gap of 2 mm. The MR protocol included fat-suppressed respiratory-triggered fast spin-echo images with 2 echo times (TR range/TE range, 3333-8571/18 and 90-117; echo train length, 10-18; excitations, 2; matrix size, 56 x 256; field of view, 30-36 cm), T2*-weighted fast multiplanar gradient-recalled acquisition in the steady state images (TR/TE range, 130/8.4-9.5; flip angle, 30°), proton density—weighted fast multiplanar spoiled gradient-recalled echo images (130/8.4-9.5; flip angle, 30°), and breath-hold in-phase T1-weighted fast multiplanar spoiled gradient-recalled echo images (200/4.2; flip angle, 90°; matrix size, 256 x 160).
Images Analysis
MR images with five sequences after ferumoxides enhancement and the
combined CT during arterial portography and CT hepatic arteriography images
were evaluated independently by three gastrointestinal radiologists. They knew
that the patients were referred for assessment of suspected hepatocellular
carcinomas, but they were not provided with any other information about the
patients. The MR images and CT scans were reviewed in separate sessions at
3-week intervals. The image review was conducted on a segment-by-segment basis
[14]. Hepatic segmentation
according to the Couinaud number system
[15] was drawn directly by the
study coordinator. Of the 160 segments from the 20 patients, 12 segments with
cysts and without hepatocellular carcinoma on helical multiphasic CT
(three-phase CT [n = 14] and two-phase CT [n = 6]) were
excluded. Two segments in one patient were totally occupied by a single
hepatocellular carcinoma and were considered as a single segment. A total of
147 segments (28 with at least one hepatocellular carcinoma and 119 without
hepatocellular carcinoma) were finally entered into the ROC analysis. Among
these 147 segments, two segments had two hepatocellular carcinomas, and two
other segments had one hepatocellular carcinoma and one benign lesion (a cyst
and a hemangioma). Each observer recorded the location (Couinaud's segment)
and size of each focal lesion and reported in consensus for each segment
whether the presence or absence of hepatocellular carcinoma could be
ascertained. One of five confidence levels was assigned to each decision as
follows: 1, definitely absent; 2, probably absent; 3, possibly present; 4,
probably present; and 5, definitely present. When a lesion was located in two
or more segments, the observers were asked to determine only the segment that
was mainly involved and to evaluate the probability of another lesion in the
other segments.
At the time of interpreting the combined CT during arterial portography and CT hepatic arteriography, the observers were instructed to indicate a score of 1 when no focal lesion was seen, 2 when there was a definite pseudolesion (wedge-shaped or flat pseudolesions due to perfusion abnormalities in typical locations, i.e., adjacent to the gall-bladder fossa, porta hepatis, or subcapsular areas) [16], 3 when a nodular lesion was seen in the typical locations of pseudolesions and could not be differentiated from a true lesion or when CT during arterial portography showed a poorly defined perfusion defect possibly containing a small hepatocellular carcinoma and CT hepatic arteriography showed enhancement at a slightly different area, and 5 when a discrete well-defined circular or oval nodular perfusion defect was found on CT during arterial portography and the lesion showed discrete enhancement on CT hepatic arteriography. A score of 4 was assigned on the basis of the subjective judgement of each observer. For the ferumoxides-enhanced MR images, the observers were instructed to indicate a score of 1 when no focal signal change was noted; 3 when the signal change was subtle, poorly defined, and not circular or oval; and 5 when the signal change was discrete, well-defined, and circular or oval. Scores of 2 and 4 were assigned on the basis of the subjective judgement of each observer [17].
A binomial ROC curve was fitted to the confidence rating of each observer with a maximum-likelihood estimation. The diagnostic accuracy of MR images or CT determined by each observer was evaluated by calculating the area under the ROC curve (Az). Composite ROC curves combining the performance of all observers into a single curve were obtained for MR images or CT scans with the maximum-likelihood curve-fitting algorithm to rate the pooled data of the three observers [18, 19]. The relative sensitivities for the detection of hepatocellular carcinomas by the three individual observers and the composite data were determined with the number of segments that were assigned a score of 3 or greater (possibly to definitely present) of a total of 28 segments with hepatocellular carcinomas, and the relative specificities were determined with the number of segments that were assigned a score of 1 or 2 (definitely absent or probably absent) of a total of 119 segments without hepatocellular carcinomas. We compared the relative sensitivities and specificities of MR imaging or CT scans using the McNemar test. Interobserver agreement for the evaluation of MR images or CT was assessed with the kappa value. A kappa value of more than 0.60 indicated substantial to excellent agreement [20].
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The mean sensitivities and the sensitivities for each observer and each modality are shown in Table 2. The mean sensitivities of MR imaging and CT were 93% and 91%, respectively. The differences were not statistically significant (all p>0.05, McNemar test). The sensitivities of MR imaging and CT were all 100% on analysis of lesions measuring 2 cm or larger (n = 18). All hepatocellular carcinomas missed on MR images and CT scans were smaller than 2 cm (Table 3). A hepatocellular carcinoma smaller than 1 cm was detected on MR images by all observers but was detected on CT scans by only one observer (Fig. 2A,2B,2C,2D). A 1.5-cm hepatocellular carcinoma was not detected on MR images by any observer (Fig. 3A,3B,3C,3D). Although it was not particularly included in the segment-by-segment analysis, a 0.3-cm daughter nodule was found on MR images but was not detected on CT scans (Fig. 4A,4B,4C,4D).
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The mean specificities and the specificities for each observer and each modality are shown in Table 2. The mean specificity was significantly better with MR imaging (99%) than with CT (94%; p<0.001, McNemar test). All observers interpreted four false-positive findings on MR images, but 22 false-positive findings on CT scans. On MR images, four false-positive lesions were smaller than 1 cm, and these were attributed to vessels (Fig. 5A,5B,5C,5D). Nineteen (86%) of 22 false-positive lesions on CT scans were attributed to various perfusion abnormalities (Figs. 4A,4B,4C,4D and 6A,6B,6C,6D). Five dysplastic nodules (low grade [n = 4] and high grade [n = 1]) in four surgical specimens were not interpreted as hepatocellular carcinomas on either CT scans or MR images.
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The kappa analyses of three observers with both modalities showed substantial to excellent agreement (Table 4). In particular, kappa values with MR imaging indicated excellent agreement.
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Although CT during arterial portography is sensitive for the detection of small hepatic lesions [1, 2, 27], there are many pseudolesions due to perfusion abnormalities related to portal venous obstruction, arterioportal shunt, or aberrant drainage of the gastric vein [16, 28, 29]. According to one report [30], CT during arterial portography showed adequate parenchymal enhancement in only 43% of cirrhotic livers. CT hepatic arteriography often has technical problems in opacification of the hepatic parenchyma homogeneously due to arterioportal shunt or aberrant hepatic arterial supply. This problem will cause difficulty in interpretation as a result of bizarre parenchymal enhancement (Figs. 4A,4B,4C,4D and 6A,6B,6C,6D). In a comparison study with three-phase helical CT, the combined CT during arterial portography and CT hepatic arteriography resulted in an unacceptably high false-positive rate without a substantial increase in sensitivity [31]. The reliance on CT during arterial portography and CT hepatic arteriography with their relatively low specificities becomes problematic if potentially curable surgical candidates avoid surgery because of false-positive findings. Moreover, CT during arterial portography and CT hepatic arteriography often show the extent of lesions inaccurately because of perfusion abnormalities (Fig. 6A,6B,6C,6D).
To our knowledge, this study is the first to compare ferumoxides-enhanced MR imaging and combined CT during arterial portography and CT hepatic arteriography for the detection of hepatocellular carcinomas. This study revealed that ferumoxides-enhanced MR imaging, including currently optimized sequences, was at least as accurate as combined CT during arterial portography and CT hepatic arteriography for the depiction of hepatocellular carcinomas. It has been reported that the sensitivity of combined CT during arterial portography and CT hepatic arteriography is 89-95% for hepatocellular carcinomas [3, 4], whereas the sensitivity of MR sequences with ferumoxides enhancement was reported as 78-92% [6, 12]. According to the results of our study, the sensitivities of ferumoxides-enhanced MR imaging and combined CT during arterial portography and CT hepatic arteriography were 93% and 91%, respectively.
MR imaging had a higher specificity than CT during arterial portography and CT hepatic arteriography. Furthermore, ferumoxides-enhanced MR imaging is less invasive and less expensive. Other advantages of ferumoxides-enhanced MR imaging over CT during arterial portography and CT hepatic arteriography are the absence of radiation hazards, its mild side effects, and its wide optimal time window. Although CT during arterial portography and CT hepatic arteriography are relatively well established from a technical point of view, further development of optimized sequences will certainly result in a definite superior performance of ferumoxides-enhanced MR imaging in the future.
The efficacy of ferumoxides-enhanced MR imaging combined with the most recently optimized sequences, such as various gradientrecalled echo sequences, has not been evaluated in previous comparative studies. Gradient-recalled echo pulse sequences can be used to recruit the contributions of local field inhomogeneities to T2* relaxations as an origin of additional image contrast [32, 33]. Thus, in recent studies, protocols of MR imaging with ferumoxides enhancement have included gradient-recalled echo sequences [6, 10, 12, 13, 25]. The use of appropriate gradient-recalled echo pulse sequences may lead to a high level of sensitivity [13, 14]. In our study, T2*-weighted fast multiplanar gradient-recalled acquisition in the steady state and proton density-weighted fast multiplanar spoiled gradient-recalled echo sequences with some T2 effect were used.
The differentiation between malignant tumors and hepatic cysts may be difficult on ferumoxides-enhanced MR imaging. Cysts could have low signal intensity at T1-weighted fast multiplanar spoiled gradient-recalled echo sequence in our study. Oudkerk et al. [10] also recommended T1-weighted gradient-recalled echo (short TE) imaging after ferumoxides enhancement to detect and characterize focal liver lesions. T1-weighted sequences may allow good differentiation of malignancy from cysts on contrast-enhanced images. However, because of the T2 effect, cysts can have high signal intensity on gradient-recalled echo sequences with long TEs. In clinical practice, helical multiphasic (two-phase or three-phase) CT is generally used as the initial screening examination for patients with suspected hepatocellular carcinomas [34], and most cysts can be excluded with helical multiphasic CT.
This study has several limitations. First, although the standard of reference was the findings from histopathologic analysis in the 76 resected segments, surgical investigation and follow-up imaging findings were used as the standard of reference for the 84 unresected segments. Second, unenhanced MR images were not obtained because of the long time required for biphasic mode of MR imaging (unenhanced and ferumoxides-enhanced images). Unenhanced MR images are known to be necessary to decrease the number of false-positive findings attributed to small vessels [14]. However, the results of this study showed few false-positive lesions without unenhanced MR images. Finally, in the segments containing two hepatocellular carcinomas or a hepatocellular carcinoma and a benign lesion (14%, 4/28), the comparisons for these particular lesions could not be performed because of segment-by-segment analysis.
In summary, the results of this study confirmed that ferumoxides-enhanced MR imaging had the same diagnostic accuracy as combined helical CT during arterial portography and CT hepatic arteriography for depiction of hepatocellular carcinomas and had a higher specificity than CT during arterial portography and CT hepatic arteriography. Therefore, we recommend ferumoxides-enhanced MR imaging as an alternative to helical CT during arterial portography and CT hepatic arteriography for the preoperative examination of patients with hepatocellular carcinomas.
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