Yonago Acta medica 1997;40:117–123

Chondroitin Sulfate Iron Colloid-Enhanced MR Imaging in Patients with
Small Hepatocellular Carcinomas: Correlations with Hemodynamic andPathologic Examinations
Masayuki Kamba, Yuji Suto, Fumiko Kodama, Shuji Sugihara and Kotaro
YoshidaDepartment of Radiology, Faculty of Medicine, Tottori University, Yonago 683, JapanTo determine the usefulness of chondroitin sulfate iron colloid (CSIC)-enhanced
magnetic resonance imaging (MRI) in evaluation of the histologic grade of hepatocellular carcinoma (HCC), we performed a comparative study with computed tomography during arterial portography (CTAP) and CT arteriography. Twenty-one surgically resected HCCs 3 cm or less in diameter were examined. There were five welldifferentiated, six well- to moderately-differentiated and ten moderately- or poorlydifferentiated HCCs. T2-weighted spin echo images (repetition time: 2,000 ms, echo
time: 90 ms) were taken before and after intravenous injection of 23.6 µmolFe/kg of
CSIC. The differences between precontrast and postcontrast contrast-to-noise ratios(enhancement index) was correlated with the findings of CTAP, CT arteriography andhistological examination. The enhancement index increased with statistical significance as the intranodular arterial perfusion increased (P < 0.01), and as the intranodular portal perfusion decreased (P < 0.01). Though the enhancement index tended
to increase as the grade of malignancy increased, no statistical significance was found.
CSIC-enhanced MRI allowed a noninvasive evaluation of the intranodular reticuloendothelial function. We consider this procedure as a supplementary method forevaluation of the histologic grade of HCC prior to performing invasive procedures
such as angiography and biopsy.
Key words: computed tomography; contrast enhancement; iron colloid; hepatocellular carcinoma;
magnetic resonance imaging

We have used chondroitin sulfate iron colloid(CSIC; Blutal, Dainippon Pharmaceutical Co.,
Osaka, Japan) as a magnetic resonance (MR)
contrast agent to detect hepatocellular carcinoma (HCC) (Kato et al., 1993; Kamba et al.,1994). Intravenous CSIC is rapidly taken up
mainly into the reticuloendothelial cells, andconsequently it reduces the signal intensity of
the liver because of a T2-shortening effect(Kato et al., 1993). CSIC enhances the contrast
between liver parenchyma and HCC, where thereticuloendothelial function is impaired orabsent in the latter (Kato et al., 1993; Kamba etal., 1994; Suto et al., 1993). This improves thedetection of HCC (Kato et al., 1993; Kamba etal., 1994). A correlation has been found between the enhancement of tumor-liver contrast
after CSIC administration and the histologic
grade of HCC (Suto et al., 1995; Kamba et al.,1996).
On the other hand, computed tomographyduring arterial portography (CTAP) and CT
arteriography are usually used to evaluate thehistologic grade of HCC from the hemodynamic aspect (Matsui et al., 1991; Takayasu et al.,1995). In this study, we compared CSIC-

Abbreviations: C/N, contrast-to-noise ratio; CSIC, chondroitin sulfate iron colloid; CT, computed
tomography; CTAP, CT during arterial portography; HCC, hepatocellular carcinoma; MR, magnetic
resonance117

M. Kamba et al.

enhanced MR imaging with CTAP and CT
arteriography to confirm the usefulness of
CSIC-enhanced MR imaging as a noninvasive
method for evaluating the histologic grade of
HCC.

Subjects and Methods

with a 2-mm gap. The field of view was 370
mm, and the matrix was 160 × 256. MR images
were taken before and 1 h after intravenous
injection of 23.6 µmolFe/kg body weight ofCSIC. All patients gave written consent toparticipate in this MR study.
Regions of interest were selected to measure
the signal intensity of the lesion and surrounding hepatic parenchyma. The SD of the background noise was measured from a region outside the body along the phase-encoding direction. The contrast-to-noise ratio (C/N) was
calculated by dividing the difference in signal
intensity between the lesion and liver by the SDof the background noise. The enhancement
index was calculated by subtracting the precontrast C/N from the postcontrast C/N.
CTAP and CT arteriography were performed with a Vertex 3000 (Yokogawa Medical
Systems, Tokyo, Japan) or a Somatom Plus-S(Siemens). Fifteen or seventeen sequential
images of the entire liver were taken with theVertex 3000 scanner in two or three repeat
series of five to eight contiguous scans with a
10-mm slice thickness and 10-mm table increments (scan time: 1.8 s/section). For CTAP,
100 mL of nonionic contrast material [iohexol(Omnipaque; Daiichi Pharmaceutical, Tokyo)
or iopamidol (Iopamiron; Nihon Schering,Osaka), 300 mgI/mL] was injected at a rate of
1.0 to 1.3 mL/s via a catheter placed in the superior mesenteric artery. Scanning began 25 to 30
s after starting injection. For CT arteriography,

Enhancement index

CSIC is a stable iron colloid preparation with atrivalent iron ion (Okuhata, 1992). It is used inclinical practice in Japan for treatment of irondeficiency anemia, and its safety has alreadybeen established (Kato et al., 1993). It is aparamagnetic substance with a mean molecularweight of 75,000 (Okuhata, 1992). The particle
size of this substance is more than 100 nm inwater (Okuhata, 1992). Its T1 and T2 relaxivities are 0.44 and 2.3 s–1• mM–1, respectively,
as measured with a 1.5 T MR spectrometer at
22˚C (Okuhata, 1992).
From January 1991 to June 1994, 26 patients (17 men and 9 women, mean age: 58.7
years) with HCC underwent surgery after
CSIC-enhanced MR imaging, CTAP and CT
arteriography. Pathological examination disclosed 34 HCCs in the resected specimens.
CSIC-enhanced MR imaging revealed 31
HCCs, of which 5 were well-differentiated, 6well- to moderately-differentiated, and 20
moderately- or poorly-differentiated HCC. The
mean diameter was 1.42 cm (range: 1.0–2.0 cm)
for the well-differentiated HCCs, 1.57 cm(range: 1.2–2.5 cm) for the well- tomoderately-differentiated HCCs, and8
4.16 cm (range: 0.9–12.0 cm) for themoderately- or poorly-differentiated
HCCs. For this study, the moderately4
or poorly-differentiated HCCs of 3 cm
or less in diameter (10 nodules, range:
0.9–3.0 cm, mean: 1.95 cm) were selected0
to match the first two groups in size.
All patients were examined with a–4Magnetom H15 system with a body coildefectiso
hypo
operating at 1.5 T (Siemens, Erlangen,Germany). Spin echo T2-weighted Fig. 1. Relationship between the findings of CTAP and theimages (repetition time/echo time enhancement index. iso, isoattenuating; hypo, hypoattenu2,000/90 ms, 2 signal excitations) were ating; , well-differentiated HCC; , well- to moderatelytaken. The slice thickness was 10 mm differentiated HCC; , moderately- or poorly-differentiated
HCC.

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Iron colloid-enhanced MR imaging of HCC

nonionic contrast material (iohexol, 140 mgI/mL) was injected at a rate of 1.2 to 1.5 mL/s during scanning via a catheter placed in the common hepatic or replaced right hepatic artery.
Spiral volumetric scan (Kalender et al., 1990)
of the whole liver was done by a Somatom PlusS scanner during a single breathhold (up to 32 s)
with a 5-mm slice thickness and table movement of 5 mm/s (scan time: 1 s/section). For
CTAP, nonionic contrast material (iohexol, 140
mgI/mL) was injected at a rate of 3 mL/s via acatheter placed in the superior mesenteric artery. Scanning began 30 s after starting injection. For CT arteriography, nonionic contrast
material (iohexol, 140 mgI/mL) was injected at
a rate of 1.2 to 1.5 mL/s during scanning via acatheter placed in the common hepatic or
replaced right hepatic artery.
On CTAP, lesions with attenuation less than
the surrounding hepatic parenchyma wereclassified into two categories: “defect” lesions
whose attenuation was less than that of thehepatic portion of the inferior vena cava, and“hypoattenuating” lesions whose attenuation
was equal to or greater than that of the hepatic
portion of the inferior vena cava. Lesions withattenuation equal to that of the surrounding
hepatic parenchyma were described as “isoattenuating.”
The enhancement patterns of lesions seen on
CT arteriography were classified into three
categories according to their attenuation relative to that of the surrounding hepatic paren-chyma; hyperattenuating, isoattenuating andhypoattenuating.
The histologic grade of HCC was assessed
according to the criteria of the Third Edition of
the General Rules for the Clinical and Pathological Study of Primary Liver Cancer by theLiver Cancer Study Group of Japan (The Liver
Cancer Study Group of Japan, 1992).
Correlations between the enhancement index and the degree of enhancement on CTAP or
CT arteriography, and between the enhancement index and the histologic grade were analyzed by Spearman’s rank order test. The levelof statistical significance was set at P < 0.05.

Results

Enhancement index

The relationship between the findings of CSICenhanced MR imaging and those of CTAP issummarized in Fig. 1. Seventeen HCCs (ninemoderately- or poorly-differentiated, six wellto moderately-differentiated, and two welldifferentiated) showed defects on CTAP. The
mean enhancement index was 2.98. Sixteen lesions were positive for the enhancement index,
whereas one well- to moderately-differentiated
HCC was negative. Three HCCs (one moderately- or poorly-differentiated, and two welldifferentiated) were hypoattenuating on CTAP.
The mean enhancement index was 0.60. Twowell-differentiated HCCs were positive for theenhancement index, whereas one moderatelyor poorly-differentiated HCC was negative. One well-differentiated HCC was
8isoattenuating on CTAP, but it was negative for the enhancement index. A statistically significant correlation was found4
between the enhancement index andportal blood supply demonstrated by
CTAP (rS = 0.575, n = 21, P < 0.01).
0
The relationship between the findingsof CSIC-enhanced MR imaging and those–4of CT arteriography is summarized in Fig.
hypo
iso
hyper
2. Fourteen HCCs (eight moderately- or
Fig. 2. Relationship between the findings of CT poorly-differentiated, four well- toarteriography and the enhancement index. hypo, hypo- moderately-differentiated, and two wellattenuating; iso, isoattenuating; hyper, hyperattenuating; ,differentiated) were hyperattenuating on
well-differentiated HCC; , well- to moderately-differentiCT arteriography. The mean enhance-

ated HCC;, moderately- or poorly-differentiated HCC.

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M. Kamba et al.

Table 1. Relationship between the histologic grade of
HCC and the enhancement index
HCC

A

Well-differentiated[ 5]
Well- to moderately-differentiated [ 6]Moderately- or poorly-differentiated [10]Mean ± SD.
[ ], number of lesions.

B

D

C

E

Enhancementindex
1.68 ± 2.53
2.28 ± 2.77
2.82 ± 2.19

Fig. 3. A 48-year-old man with HCC. A: The precontrast T1-weighted image reveals a hyperintense nodule(arrow) with a central isointense component (arrowhead). B: The precontrast T2-weighted image shows acentral hyperintense component (arrowhead) within a peripheral isointense area. C: The central component
is enhanced on the CSIC-enhanced T2-weighted image (arrowhead), whereas the peripheral component isslightly hypointense in comparison with the surrounding liver (arrow). D: CTAP reveals a portal perfusion
defect corresponding to the central component (arrowhead). The peripheral component is isoattenuating. E:
CT-arteriography shows a central hyperattenuating area (arrowhead) and a peripheral hypoattenuating area(arrow). F (p. 121): A photomicrograph of the resected specimen shows a well-differentiated HCC (righthalf) and a moderately-differentiated HCC (left half). Hematoxylin and eosin stain, × 130. (Figures are
reprinted from Kamba et al., 1996)

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Iron colloid-enhanced MR imaging of HCC

ment index was 3.30. All the lesions were positive for the enhancement index. Six HCCs (twomoderately- or poorly-differentiated, two wellto moderately-differentiated, and two welldifferentiated) were isoattenuating on CT arteriography. One well- to moderately-differentiated, and one moderately- or poorly-differentiated HCC were negative for the enhancement
index. The mean enhancement index was 1.04.
One well-differentiated HCC was hypoattenuating on CT arteriography. The lesion was
negative for the enhancement index. A statistically significant correlation was found between the enhancement index and arterial blood
supply demonstrated by CT arteriography (rS =0.577, n = 21, P < 0.01).
Though the enhancement index tended toincrease as the grade of malignancy increased,
no statistically significant correlation was
found. Considerable overlap in the enhancement index was observed in the three histologic
grades (Table 1).

Representative caseA patient with HCC exhibiting a concentric
structure of different histologic grades underwent surgery after CSIC-enhanced MR imaging, CTAP and CT arteriography (Fig. 3). The

central component (moderately-differentiated
HCC) was enhanced in comparison with thesurrounding liver after CSIC injection. The peripheral component (well-differentiated HCC)
was not enhanced. CTAP showed a portal
perfusion defect corresponding to the centralcomponent. The peripheral component was
isoattenuating. CT-arteriography showed acentral hyperattenuating area and a peripheral
hypoattenuating area.

Discussion
The reticuloendothelial function in HCC differs
according to the degree of differentiation. The
number of reticuloendothelial cells in HCC has
been reported to be lower in the less differentiated HCC (Sugihara et al., 1990; Tanaka et al.,1996). In this study, though the enhancement
index tended to increase as the grade of malignancy increased, no statistical significance wasverified because of a considerable overlap. We
previously reported a correlation between theenhancement of tumor-liver contrast after CSIC
administration and the histologic grade of HCC(Suto et al., 1995). In the present study, themean diameter of the moderately- or poorlydifferentiated HCCs was small in comparison

F
Legends toFig. 3F: p. 120

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M. Kamba et al.

with the previous study. The disagreement
between the two studies is at least partially related to partial volume effects due to the respiratory movements during image acquisition(Butts et al., 1995). Fast T2-weighted imaging
as currently offered on new scanners (Rydberg
et al., 1995) can overcome this problem and one
can expect that in reality the correlation between CSIC uptake and the degree of differentiation must be better than the correlation
found in this study.
Three of the 21 HCCs were negative for theenhancement index. Such lesions may be indistinguishable from adenomatous hyperplasia,
which has negative contrast enhancement because of the presence of reticuloendothelial
cells (Suto et al., 1993). The number of Kupffer
cells in 20 to 25% of moderately- or poorlydifferentiated HCCs is equal to that in noncancerous tissue (Tanaka et al,. 1996). The decrease in reticuloendothelial function demonstrated by CSIC-enhanced MR imaging indicates merely one aspect of differentiation of
HCC. It seems difficult to assess the histologic
grade of HCC precisely by the enhancement
index alone. The additional use of precontrast
signal intensity and morphologic features (e.g.,
capsule and mosaic pattern) must also be taken
into consideration (Kadoya et al., 1992).
The hemodynamic findings on CTAP and
CT arteriography were reported to be correlatedwith the histologic grade of HCCs. The intranodular portal blood flow tends to decrease as
the grade of malignancy increases (Matsui etal., 1991). The intranodular arterial and portal
blood supplies have been reported to be reciprocal (Matsui et al., 1991). The intermediate
lesions ranging from adenomatous hyperplasia
to well-differentiated HCCs tend to haveprogressively less intranodular portal blood
supply as the grade of malignancy increases(Matsui et al., 1991). Takayasu and colleagues,
however, recently reported that the relationshipbetween the hemodynamic characteristics andthe degree of dedifferentiation of HCC could
not be verified in well-differentiated HCCs
(Takayasu et al., 1995).
The enhancement index correlated with theintranodular blood supply on both CTAP and

CT arteriography rather than the histologic
grade. The CT findings may be biased as wellbecause of partial volume averaging. The lossof contrast in small lesions may be the reason
why the enhancement index correlated with thefindings of CTAP and CT arteriography rather
than the histologic grade.
In contrast to CTAP and CT arteriography,
CSIC-enhanced MR imaging is a noninvasive
procedure. In patients with marked portosystemic shunt and/or laminal flow of contrast
material, we found difficulty in assessing theintranodular portal blood supply. The hemodynamic evaluation of lesions within thewedge-shaped portal flow defect or arterioportal shunt was difficult. CSIC-enhanced MR
imaging was unaffected by portal flow abnormalities (Kamba et al., 1994). Spin echo imaging, which we have used, is inferior to CTAP
and CT arteriography in detecting small lesions
less than 1 cm in diameter because of its lower
spacial resolution (Kamba et al., 1994). High
resolution imaging by fast T2-weighted spinecho sequences (Semelka et al., 1993) can
overcome this problem.
CSIC-enhanced MR imaging allowed noninvasive evaluation of the intranodular reticuloendothelial function. The findings of CSICenhanced MR imaging correlated with thehemodynamic findings on CTAP and CT arteriography. We consider this procedure as a supplementary method for evaluation of the histologic grade of HCC prior to performing invasive
procedures such as angiography and biopsy.

122

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(Received April 21, Accepted June 4, 1997)123