Advances in Molecular Imaging, 2013, 1, 1-7
http://dx.doi.org/10.4236/ami.2013.31001 Published Online January 2013 (http://www.scirp.org/journal/ami)
Assessing the Malignancy of Hepataocellular Carcinoma in
Cirrhosis Using the Hepatocellular Contrast Agent
Gd-EOB-DTPA and Correlation with the Cytometric DNA
Index
R. Röttgen1, S. Kobi1, C. Grieser1, F. Streitparth1, H. Al-Abadi2, A. Duerr2, W. Faber2, J. Pratschke3,
P. Neuhaus2, B. Hamm2, L. Lüdemann4
1Klinik für Radiologie, Charite’ Campus Virchow Augustenburger Platz 1, Berlin, Germany
2Klinik für Allgemein-Visceral- und Transplantationschirurgie, Charite’ Campus Virchow Augustenburger Platz 1, Berlin, Germany
3Klinik für Visceral-, Transplantations- und Thoraxchirurgie, Universitätsklinikum Innsbruck, Innsbruck, Austria
4Abteilung für Strahlenphysik, Universitätsklinikum Essen, Essen, Germany
[e-mail], [e-mail], wladim [e-mail], johann.pratsch [e-mail],
[e-mail], [e-mail] , lutz.luedemann@u k - e ssen.de
Received November 26, 2012; revised December 27, 2012; accepted January 5, 2013
ABSTRACT
Aim: Investigation whether the signal intensity of hepatocellular carcinoma (HCC) on dynamic magnetic resonance
imaging (MRI) with hepatocellular contrast medium (CM) correlates with the histologic malignancy grade and cy-
tometric DNA index. Material and Methods: MRI at 1.5 T with hepatocellular CM Gd-DTPA-EOB of 63 patients (52
men, 11 women; 64.0 ± 8.5 years) with HCC in cirrhosis. SI of the tumor and liver tissue in sequences (T1, T1fs, T2fs,
T1fs + CM (arterial, venous, late venous phase) were correlated lik e the asymmetry coefficient of the SI in the arterial
and venous phases respective the native and late venous phases of the tumor with the histologic malignancy grade and
DNA index indicating the grade of abnormal DNA steam line respective aneuploid DNA. Results: SI did not signifi-
cantly correlate with the histologic malignancy grade or DNA index for precontrast or postcontrast images. There is a
significant correlation for the asymmetry coefficient of the SI in the arterial and venous phases with the DNA-index (p
values of 0.00089 (Pearson) and 0.0082 (Spearman). Conclusion: A highly arterialized hepatocellular carcinoma with
rapid washout in the venous phase corresponds to a higher malignant potential. These findings suggest that the MR pa-
rameters investigated here may predict the malignant potential and prognosis of HCC before surgery.
Keywords: Hepatocellular Carcinoma; DNA Index; DNA Cytometry; Malignancy Grading
1. Introduction
Magnetic resonance imaging (MRI) with contrast me-
dium is currently the best imaging modality for the de-
tection and characterization of hepatocellular carcinoma
(HCC) [1,2]. It is based on the signal enhancement pat-
tern after administration of contrast medium, particularly
extracellular or tissue-specific hepatobiliary agents [2].
Gd-EOB-DTPA (Primovist®, Bayer Healthcare, Berlin,
Germany) is an MR contrast agent combining the proper-
ties of extracellular and hepatocellular agents. This
means that images can be acquired both in the dynamic
phase when the contrast agent is still in the intravascular
space and in the hepatobiliary phase when the agent is
metabolized by the hepatocytes. Accumulation in heap-
tocytes occurs within a few minutes of injection, ena-
bling clear delineation of a HCC from healthy liver tis-
sue.
Dynamic MRI with a fast T1-weighted gradient echo
sequence obtained during the arterial (Figure 1), portal
venous (Figure 2), and late venous phases (Figure 3)
after intravenous bolus administration of the contrast
medium has been shown to be useful for characterizing
HCC, which typically exhibits early arterial enhancement
because it is highly arterialized [3]. Accumulation of
contrast medium indicates a tumor of hepatocellular ori-
gin. In the routine clinical setting, however, differentia-
tion of HCC from regenerative nodules in the cirrhotic
liver continues to pose a challenge. In general, though,
the use of morphologic imaging criteria allows adequate
characterization of an intrahepatic tumor, and histologic
confirmation of the diagnosis of HCC is generally not
necessary before surgery.
C
opyright © 2013 SciRes. AMI

R. RÖTTGEN ET AL.
2
Figure 1. Asymmetry coefficient ACart-ven is plotted against
the DNA index. Different symbols indicate the different
tumor grades: filled black circle—grade 1; open square—
grade 2; filled black square—grade 3; asterisk—grade X.
The solid line represents the linear fit of the correlation
between the two parameters. The result of the linear fit is
described by the following equation: AC art-ven = −0.158 +
0.266*DNA index.
Figure 2. Asymmetry coefficient ACpre-late venous is plotted
against the DNA index. Different symbols indicate the dif-
ferent tumor grades: filled black circle—grade 1; open
square—grade 2; filled black square—grade 3; asterisk—
grade X. There is no correlation between the two parame-
ters.
Accurate diagnostic characterization and differentia-
tion of a malignant liver tumor is done using histologic
grading or DNA cytometry. The latter may have impor-
tant implications fo r treatment as it enables objectiv e and
reliable grading of the malignant potential. Photometric
DNA measurement is based on the quantitative determi-
nation of the DNA content of cell nuclei [4]. The mate-
rial for DNA analysis can be obtained by fine needle
aspiration and may provide important additional infor-
mation on the biologic behavior of a tumor that may alter
the therapeutic strategy and determines the prognosis.
Tumor cells are characterized by numerical and/or struc-
tural chromosome aberrations. Severe chromosomal ab-
erration identified as significant by DNA cytometry is
Figure 3. HCC in liver segment 4 during the arterial phase;
fat-saturated T1-weighted image acquired approx. 20 s af-
ter the start of intravenous contrast medium administration.
There is increased peripheral enhancement suggesting high
arterial perfusion of the lesion.
referred to as DNA aneuploidy and is an indicator of the
malignant potential of a tumor. Hence, DNA ploidy or
the DNA index has been identified to be an important
prognostic indicator in patients who underwent liver
transplantation because of HCC in cirrhosis [4-13].
Jonas et al. showed DNA ploidy to be a useful prog-
nostic factor in patients who received a liver transplant
for HCC in cirrhosis, demonstrating that its predictive
value is superior to tumor staging. In this study, ane-
uploidy, or a high DNA index, indicated a poorer prog-
nosis in liver transplant recipients than diploid and poly-
ploid carcinomas with a low DNA index [14].
The purpose of the study is to evaluate, if an assessing
of the malignancy of hepataocellular aarcinomas in cir-
rhosis using MRI with hepatocellular contrast agent will
be possible.
2. Patients and Methods
Sixty-three patients with histologically proofed HCC in
cirrhosis who underwent MRI of the liver with the heap-
tocellular MR contrast agent Gd-EOB-DTPA were ret-
rospectively included in the study. All of them underwent
resection or liver transplant. The patients had a mean age
of 63.0 ± 10.0 years (5 2 men, 64 .0 ± 8.5 year s, range 43 -
84; 11 women, 58.3 ± 14.9 years, range 32 - 82). Patho-
histologic grading of the patients included in the study
yielded 26 well differentiated (G1), 28 moderately dif-
ferentiated (G2), and 8 poorly differentiated HCCs (G3).
In one HCC, the degree of differentiation could not be
determined (GX).
3. DNA Cytometry
DNA cytometry was available for 52 HCCs.It is meas-
ured by up to 300 tumor cell nuclei, sometimes more,
and 30 located in the same preparation as lymphocytes
and leukocytes were used as analytical reference cells.

R. RÖTTGEN ET AL. 3
The DNA content determined by means of these nuclei
singlecellabsorptionphotometry. The measurement was
carried out in the fine-scanning method using a micro-
scope cytophotometer (Ahrens Medical Supply Tecnic,
argteheide, Germany). The control of the scanning table,
the measuring process and the registration of the absorp-
tion programmatically were effected by process com-
puter. The measured data of the respective total extink-
tion were printed along with the mean, standard deviation,
variance and coefficient of variation through a telephoto
type. The measurement of the integrated optical density
of nuclei is coupled interactive on the monitor of a con-
ventional microscope with a PC-based TV image analy-
sis system. The microscope is equipped with a color TV
camera and appropriate interference filters. Within the
relevant cell population of at least 300 cell nuclei are
measured randomly assigned. The measurement is done
automatically by clicking the relevant nuclei with a
mouse on the screen. A DNA histogram. determined per
measurement DNA content of about 300 cell nuclei is
combined in a cytophotogramm and as an absolute value
in AU (arbitraryunits) specified. The number of cyto-
morphometric nuclei measured is denoted by “n”. The
determination of the 2 c value, i.e., of the DNA-content
corresponding to a normal diploid set of chromosomes
occurs in lymphocytes or leukocytes as a calibration dip-
loid cell population. The so-called standard cells (stan-
dard calibration cell population) have to be set in the
same manner as the measured nuclei of the hepatocytes
Hepatozytenkerne, hydrolyzed and stained according to
Feulgen. The doubling of the 2 c-values is given in the
cytophotogram with 4 c and corresponds to a tetraplo id, a
further doubling (quadrupling) a oktaploiden (8 c) set of
chromosomes. The diagnosis of the DNA histograms are
qualitatively according to the ESCAP Consensus Report
in the categories of DNA diploid, DNA polyploid and
DNA-aneuploid and is performed according to the fol-
lowing criteria: diploid DNA: DNA base line (STL) >
1.80 c < 2.20 c polyploid DNA: DNA base line (STL) >
1.80 c < 2.20 and c > 3.60 c < 4.40 c.DNA aneuploid:
abnormal DNA stem line (STL) < 1.80 c > 2.20, or c <
3.60 c > 4.40 c and/or values > 9 c.
4. MRI-Examination
MRI examinations were performed on a 1.5-Tesla Gene-
sis Signa MR scanner (General Electric Medical Systems,
Wisconsin, USA) using an 8-channel surface receive
only coil. The following pulse sequences were analyzed:
 Native breath-hold T1-weighted 2D gradient echo
(GRE) sequence (fast spoiled gradient echo, FSGE);
repetition time (TR): 212 ms, echo time (TE): 4.6 ms,
flip angle (FA): 80˚, slice thickness (SL): 8 mm, in-
terslice gap: 0 mm, field of view (FOV): 36 × 36 cm,
image matrix: 512 × 512, acquisition rate: 24 slices in
15 s.
 Breath-hold axial T1-weighted 3D GRE sequence
with fat saturation (FS); TR: 119 ms, TE: 6.9 ms, FA:
70˚, SL: 8 mm, FOV: 36 × 36 cm, image matrix: 512
x 512, acquisition rate: 24 slices in 40 s.
 2D fast T2-weighted spin echo sequence (fast/turbo
spin echo, FSE) with FS; TR: 2100 ms, TE: 90 ms,
FA: 90˚, turbo factor, ETL: 21, axial, SL: 8 mm, gap:
0 mm, FOV: 36 cm × 36 cm, image matrix: 512 ×
512, acquisition rate: 28 slices in 1 min 9 s.
 Dynamic breath-hold axial 3D T1-weighted sequence;
arterial and venous phase (2 phases) after manual IV
bolus administration of 0.025 mmol/kg of Gd-EOB-
DTPA (0.1 ml). TR: 10.3 ms, TE: 5.2 ms, FA =15˚,
ETL: 59, SL: 5 mm, gap: 0 mm, FOV: 36 × 36 cm,
image matrix: 256 × 256, acquisition rate: 2 3D data-
sets with 40 slices in 20 s per phase. The arterial
phase was acquired 20 s after contrast medium ad-
ministration, the venous phase 50 s after administra-
tion.
 2D breath-hold T1-weighted GRE sequence (FSGE)
approx. 20 min after manual IV bolus administration
of 0.025 mmol/kg of Gd-EOB-DTPA (0.1 ml). TR:
212 ms, TE: 4.6 ms, FA: 80˚, SL: 8mm, gap: 0 mm,
FOV: 36 × 36 cm, image matrix: 512 × 512, FOV:
256 × 205, acquisition rate: 24 slices in 15 s.
The MRI datasets were analyzed on a workstation
(General Electrics picture archiving and communication
system—GE-PACS, GE Healthcare, USA, Software Cen-
tricity RA 1000, version 2027435-091 using two EIZO
RadiForce GS 220 monitors, gray-scales, EIZO Nanao,
Hakui Corporation, Japan). Signal intensities (SI) with
standard deviations (SD) were measured in regions of
interest (ROIs) placed in the HCC and in representable
noncancerous liver tissue on the standardized pulse se-
quences described above. SI in the tumor ROI was
measured over the entire tumor area visualized in the
slice with the largest axial tumor extent and in an area of
approx. 40 mm2 in the liver tissue.
For standardization of the measured SIs, ratios of SI in
the HCC and noncancerous liver tissue were calculated,
referred to as standardized signal intensity (I) below.



tumor
liver
SI
I= SI
Dynamic contrast enhancement was calculated using
the asymmetry coefficient ACart-ven, which describes the
difference in standardized SIs between the arterial and
venous phase.


  
art-ven
art ven
0.5 artven
SI SI
AC =SI +SI

The asymmetry coefficient AClate-ven describes the dif-
ference in standardized SIs before contrast medium ad-

R. RÖTTGEN ET AL.
4
ministration and the late venous phase (20 min after IV
contrast medium administration).
 
  
pre-late-ven
pre
0.5 pr
AC post
e post
II
I+I

The fact that only these two asymmetry coefficients
could be calculated is due to the pulse sequences that
were available for analysis: Postcontrast images in the
arterial and venous phase were acquired with the T1-
weighted 3D sequence, while nonenhanced images and
the late venous phase were acquired using the T1-
weighted 2D sequence. This is why no asymmetry coef-
ficients could be calculated for nonenhanced SI and the
arterial phase or for the arterial or venous phase and the
late venous phase.
The standardized signal intensities, I, of HCCs deter-
mined from the above-described sequences and the two
asymmetry coefficients (ACart-ven, AClate-ven) were corre-
lated with histopathologic grades in all 63 patients and
with the cytometric DNA index in 52 patients.
5. Results
Analysis by degree of HCC differentiation did not reveal
any significant correlations for the standardized signal
intensities on the unenhanced pulse sequences and the
cytometric DNA index for any of the groups. The same
was true for the standardized signal intensities measured
on the contrast-enhanced images and their correlation
with the DNA indices for any of the pathohistologic
HCC grades.
With increasing DNA indices, we saw a tendency for
higher standardized sign al intensities in the arterial ph ase
and for lower standardized signal intensities in the ve-
nous phase.
In contrast, significant correlations were found for
ACart-ven and the DNA index using both Pearson’s corre-
lation analysis (linear) (p = 0.00089) and the Spearman
rho (nonlinear) (p = 0.0082). The second asymmetry in-
dex investigated, ACpre-late-ven, did not significantly corre-
late with the DNA index (p = 0.67; p = 0.40). No sig-
nificant correlation of the asymmetry index with the tu-
mor grade was found.
The Figures 4 and 5 illustrate the relationsh ips between
the two asymmetry coefficients, ACart-ven and ACpre-late-veno us,
and the DNA index.
6. Discussion
We found no correlation between the MR signal inten-
sities of HCCs on the pulse sequences investigated and
the tumor stage or cytometric DNA index for nonen-
hanced images or the arterial, venous, or late venous
phases of the dynamic series; however, we saw a ten-
dency for increasing DNA indices to be associated with
Figure 4. HCC in liver segment 4 during the venous phase;
fat-saturated T1-weighted image acquired approx. 50 s af-
ter the start of intravenous contrast medium administration.
The signal intensity of the lesion is lower than that of sur-
rounding liver tissue, which indicates rapid washout/reflux
in the venous phase.
Figure 5. HCC in liver segment 4 during the venous phase;
fat-saturated T1-weighted image acquired approx. 50 s af-
ter the start of intravenous contrast medium administration.
The signal intensity of the lesion is lower than that of sur-
rounding liver tissue, which indicates rapid washout/reflux
in the venous phase.
higher standardized sign al intensities in the arterial ph ase
and lower intensities in the ven ous phase. In contrast, we
found a significant correlation between asymmetry coef-
ficient ACart-ven and the DNA index but not for the second
asymmetry coefficient we investigated, i.e., the one be-
tween signal intensities on unenh anced images and those
measured in the late venous phase. These results suggest
that the malignant potential of HCC, expressed in the
DNA index, increases with an increasing difference in
standardized signal intensities between the arterial and
venous phases, as indicated by increasing values of
asymmetry coefficient ACart-ven.
In terms of function, this means that strong arterialize-
tion of a tumor with rapid washout in the venous phase
corresponds to a higher DNA index and hence a higher
malignant potential. Conversely, a lower value for ACart-ven
corresponds to a lower DNA index or malignant poten-

R. RÖTTGEN ET AL. 5
tial.
We attribute this result to the assumption that a high
malignant potential, as indicated by a high DNA index, is
associated with enhanced angiogenesis and results in
tumors with a larger number of arteries and veins. This
assumption would explain the stronger arterial and
weaker venous enhancement we saw in tumors with a
high DNA index, as opposed to tho se with a lower DNA
index. The presence of more vessels in a tumor means
that contrast medium inflow and outflow is both faster
and more pronounced.
Conversely, our initial hypothesis that contrast-en-
hanced MRI using Gd-EOB-DTPA would also improve
the characterization of HCC in cirrhosis with regard to
histopathological tumor grades was not confirmed here.
We found no statistically significant associations be-
tween standardized signal intensities in the arterial, ve-
nous and late phases of the dynamic contrast-enhanced
series and the histopathologic tumor grade. This disap-
pointing outcome might also in part be due to the fact
that HCC is a heterogeneous group with mixed types and
overlap between the different histological grades, making
it difficult at times to assign a tumor to a specific his-
tologic grade .
Based on the results presented here, the dynamic con-
trast behavior of HCC might supplement preoperative
MRI, providing useful diagnostic information that goes
beyond the Milan criteria in evaluating candidates for
liver transplant. Enhancement patterns might provide
clues about the malig na nt poten tial and th e progno sis that
cannot be derived from merely evaluating the morphol-
ogic imaging appearance of HCC. It might also be specu-
lated that our results on the potential role of con-trast
enhancement also apply to other, nonspecific contrast
agents.
Imaging detection of HCC in cirrhosis has been invest-
tigated in many studies [1,15-20]. Schneider et al. and
Hentrich et al. demonstrated the significance of con-
trast-enhanced dynamic MRI using the hepatobiliary
contrast agent Gd-BOPTA (Multi-Hance®) for the de-
tection and differentiation of benign and malignant he-
patic lesions [21]. Hentrich et al. showed that late en-
hancement is related to cellular differentiation with mod-
erately differentiated HCC exhibiting significantly stronger
uptake of contrast medium than poorly differentiated
HCC. Horigome et al. compared MRI including dynamic
contrast-enhanced imaging using Gd-DTPA (Magne-
vist®) with the histopathologic grades of tumor different-
tiation and showed that detection by MRI improves with
poorer differentiation and larger tumor size [22]. Jonas et
al. investigating patients who received a liver transplant
for HCC identified DNA ploidy as a valuable prognostic
factor that is superior to tumor stage and other prognostic
factors. In this study of patients who received a liver
transplant because of HCC, aneuploidy indicated a poor-
er prognosis compared with diploid or polyploid HCCs
[23]. In a univariate analysis, the same study group also
identified the cytometric DNA index as a prognostic pa-
rameter in liver transplant recipients after HCC in cirrho-
sis in addition to the Milan criteria, the histopathologic
tumor grade, vascular invasion, and the cytometric DNA
index. A multivariate analysis identified the DNA index
and vascular invasion as prognostic parameters [10].
The Milan criteria, which are used as a basis for se-
lecting patients with HCC in cirrhosis for liver trans-
plantation, take into account the number and size of le-
sions. In addition, information on differentiation and ma-
lignancy of an HCC would be also useful. Liver trans-
plant recipients meeting the Milan criteria have a mean
5-year survival rate of 62% to 70% when the degree of
differentiation of HCC is not taken into account. Patients
not meeting these criteria have poorer survival rates.
Several histopathologic studies of explanted livers re-
vealed microvascular tumor invasion as an independent
negative predictor of survival after liver transplan t. These
studies also showed a significantly higher incidence of
microvascular invasion with increasing tumor size
[11,24,25]. The risk of microvascular invasion is greater
than 50% for patients with HCC > 5 cm.
Other factors, apart from the Milan criteria, that have
been found to influence survival are the histopathologic
tumor grade, vascular invasion, and DNA cytometry
(DNA ploidy, DNA index) [10,11,23,25]. The signify-
cant association we found between the arterial-venous
asymmetry coefficient, i.e., the ratio of contrast enhance-
ment in the arterial phase to that in the venous phase, and
the DNA index suggests that a dynamic MRI study of the
liver using the hepatocellular contrast agent Gd-EOB-
DTPA provides information on malignancy or the bio-
logical aggressiveness of HCC. Used in patients with
HCC in cirrhosis, this asymmetry coefficient might pro-
vide supplementary information for selecting the sur-
gical procedure (extent of resection/liver transplant) or
serve as a progno s tic factor.
Additional studies—ideally in larger patient popula-
tions—are needed to confirm our findings. The Milan
criteria might then be supplemented by the preopera-
tively determined MRI criterion of the asymmetry coef-
ficient describing the ratio of arterial enhancement to
venous washout following administration of a hepato-
cytic contrast agent.
7. Summary
Our study investigating signal intensities and asymmetry
coefficients determined from preoperative MR images
obtained using the hepatocellular contrast agent Gd-
EOB-DTPA in patients with hepatocellular carcinoma
and cirrhosis revealed a statistically significant relation-

R. RÖTTGEN ET AL.
6
ship between the asymmetry coefficient of signal en-
hancement in the arterial and venous phases and the can-
cer’s malignant potential as reflected in the DNA index.
The asymmetry coefficient thus has the potential to en-
able preoperative assessment of the malignant potential
of HCC and its prognosis. Preoperative assessment of the
malignancy or aggressiveness of HCC using this MRI
asymmetry coefficient might be a useful supplement to
other imaging criteria such as lesion size, number, and
site.
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