DOI:10.2214/AJR.07.2171
AJR 2007; 189:663-670
© American Roentgen Ray Society
Gadolinium-Enhanced MRI for Tumor Surveillance Before Liver Transplantation: Center-Based Experience
Thomas C. Lauenstein1,
Khalil Salman1,
Roger Morreira2,
Thomas Heffron3,
James R. Spivey4,
Enrique Martinez5,
Puneet Sharma1 and
Diego R. Martin1
1 Department of Radiology, Emory University Hospital, Emory Clinic, Bldg. A,
Ste. AT-627, 1365 Clifton Rd., Atlanta, GA 30322.
2 Department of Pathology, Emory University Hospital, Atlanta, GA.
3 Department of Surgery, Division of Transplantation, Emory University Hospital,
Atlanta, GA.
4 Division of Digestive Diseases, Liver Transplant Center, Emory University
Hospital, Atlanta, GA.
5 Department Gastroenterology, Emory University Hospital, Atlanta, GA.
Received January 26, 2007;
accepted after revision April 20, 2007.
Address correspondence to D. R. Martin.
(dmartin{at}emory.edu).
Abstract
OBJECTIVE. The purpose of this study was to evaluate prospectively
acquired institutional results to determine the accuracy of
gadolinium-enhanced MRI in liver tumor surveillance before
transplantation.
SUBJECTS AND METHODS. One hundred fifteen patients underwent MRI of
the abdomen within 90 days before liver transplantation. Images were acquired
with gadolinium-enhanced 3D gradient-echo sequences in the arterial, venous,
and delayed phases. Detection of hepatocellular carcinoma (HCC) was based on
the imaging criteria arterial phase enhancement, delayed phase hypointensity,
and development of an enhancing outer margin capsule. Imaging findings were
compared with findings at histopathologic evaluation of the explanted
liver.
RESULTS. Thirty-six HCCs in 27 patients were detected at
histopathologic evaluation. Patient-based analysis showed the sensitivity of
MRI was 88.9% (24/27); specificity, 97.7% (false-positive findings in two
patients); and accuracy, 95.7%. MRI depicted 28 of 36 HCCs, resulting in a
lesion-based sensitivity of 77.8%. Although all 18 HCCs 2 cm or larger were
depicted with MRI, only 10 of 18 HCCs smaller than 2 cm were correctly
diagnosed. However, two HCCs measuring smaller than 2 cm at pathologic
examination were rated as dysplastic nodules on MRI.
CONCLUSION. Contrast-enhanced MRI can be used as a primary
diagnostic method for accurate detection and characterization of HCC 2 cm or
larger as required by the criteria of the Model for End-Stage Liver Disease
used by the United Network for Organ Sharing. MRI can be considered a standard
tool for surveillance before liver transplantation. Reduction in cost and risk
may be derived from the diminished need for other diagnostic imaging studies
and biopsy and the avoidance of use of iodinated contrast agents in imaging of
patients with cirrhosis, many of whom have impaired renal function.
Keywords: gadolinium • hepatocellular carcinoma • liver • MRI • transplantation
Introduction
Accurate detection of hepatocellular carcinoma (HCC) in the background of
advanced cirrhosis is crucial because of the importance in triage of patients
on liver transplantation waiting lists, the need for optimal use of a limited
number of donor livers, and the objective of curative treatment by
transplantation in optimally selected patients. The number and size of lesions
are the major criteria in scoring methods such as the Model for End-Stage
Liver Disease used by the United Network for Organ Sharing in the United
States [1]. HCC is a common
tumor in patients with chronic liver disease and cirrhosis
[2] and causes approximately
500,000 deaths per year worldwide
[3]. Diffuse chronic liver
disease and cirrhosis are a massive world health problem. In the United
States, rates of cirrhosis and HCC have been increasing, HCC being the most
common malignant tumor of the liver
[4].
Another consideration is that although liver lesions are common and usually
benign, the specificity and accuracy of diagnostic imaging are critical in the
evaluation of patients at risk of neoplasia. In this setting, MRI has been
found [5,
6] more accurate than CT in the
depiction of hepatic lesions, with emphasis on superior diagnostic specificity
for lesions. MRI also has been found
[7–10]
to be an effective imaging method for HCC in particular. In the largest series
to date [9], to our knowledge,
findings on MRI of 555 patients older than 11 years and 279 liver
transplantation patients correlated with the histopathologic findings in the
explant. In that study, only five HCC lesions in four patients were missed on
MRI, and all the missed lesions were 2.2 cm in diameter or smaller. In most
cases of missed lesions, the images were degraded by motion, or the small
tumor was found to be isointense on arterial phase imaging. The range of
overall sensitivity for detection of HCC with MRI has been reported to be
68–91% [7,
11]. However, those studies
involved only a small number of patients (< 40) with small (< 2 cm)
liver lesions, potentially influencing the lower apparent sensitivity.
Limitations in detection and characterization of small HCC remain an area for
further investigation [8,
12].
On the basis of our experience and the body of current published evidence,
we implemented a diagnostic imaging strategy in which gadolinium-enhanced MRI
was used for HCC surveillance of patients with cirrhosis awaiting liver
transplantation. The aim of this study was to evaluate the accuracy of
gadolinium-enhanced liver MRI in tumor surveillance using our center's data
for the assessment, explanted liver for histopathologic correlation, and the
Model for End-Stage Liver Disease scoring criteria for determining the
accuracy of triage.
Subjects and Methods
Patients
Prospective informed consent and permission for subsequent retrospective
analysis were obtained from all patients undergoing MRI for liver tumor
surveillance. The trial was approved by our institutional review board and was
compliant with the Health Insurance Portability and Accountability Act.
Between January 2004 and March 2006, 210 patients received a liver
transplant at our institution. One hundred thirty of the 210 patients
underwent MRI of the liver within 90 days (range, 3–89 days; mean, 46.5
days) before transplantation. The other 80 patients underwent MRI more than 90
days before transplantation, had contraindications to MRI, or underwent CT.
Fifteen patients were excluded because they had undergone liver
chemoembolization therapy for tumors (n = 13) or were unable to
complete MRI (n = 2). Thus the final study cohort consisted of 115
patients: 38 women and 77 men (average age, 53.9 years; range, 22–73
years). The underlying causes of liver cirrhosis were hepatitis C (n
= 38), hepatitis B (n = 10), hepatitis B and C (n = 2),
ethanol abuse (n = 24), ethanol abuse and hepatitis C (n =
6), cryptogenic cirrhosis (n = 10), nonalcoholic steatohepatitis
(n = 4), primary sclerosing cholangitis (n =6), autoimmune
hepatitis (n = 4), primary biliary cirrhosis (n = 2), and
other diseases (n = 9).
MRI
All MRI examinations were performed with a current-generation 1.5-T MRI
unit (Magnetom Avanto, Siemens Medical Solutions; Gyroscan Intera, Philips
Medical Systems; or Twin-EXCITE, GE Healthcare). A torso phased-array surface
coil was used for signal reception. Routine imaging consisted of unenhanced
MRI in the axial plane. T1-weighted images were acquired with a breath-hold
spoiled gradient-echo dual-echo in-phase and out-of-phase sequence (TR/TE,
120–170/2.2–4.4; flip angle, 80–90°). T2-weighted images
were acquired with a HASTE sequence (effective TR, infinite; effective TE,
80–90 milliseconds). Section thickness was 7–8 mm, and the matrix
size was 128–192 x 256 (phase x frequency encoding) for all
sequences. Gadolinium was administered to all patients with a power injector
in a bolus of 0.1 mmol/kg of gadolinium chelate (Magnevist, Berlex
Laboratories; or Omniscan, Amersham Health) at 2 mL/s followed by a saline
flush. Four sets of breath-hold serial axial T1-weighted 3D spoiled
gradient-echo fat-suppressed images were acquired before contrast
administration and during the contrast-enhanced hepatic arterial dominant
phase, venous phase, and delayed late vascular and interstitial phases.
Acquisition parameters were TR/TE, 3.4–3.8/1.2–1.4; flip angle,
12°; sensitivity encoding factor, 2; section thickness, 2–3 mm;
matrix size, 192 x 256; field of view, 400 mm (rectangular field of
view, 75%); scan percentage, 80%; partial Fourier imaging in phase and slice
directions. Arterial phase images were acquired with a
real-time-bolus-tracking method triggered 8 seconds after the arrival of
contrast medium in the celiac arterial axis, during which time the patient was
given breath-hold instructions. The venous and later delayed phase images were
acquired 70 and 180 seconds, respectively, after contrast administration.
Acquisition time ranged from 12 to 15 seconds because of the varying fields of
view and because the number of sections (96–130) was individually
modified according to patient stature.
MR Image Analysis
All MRI data sets were transferred to and evaluated with a postprocessing
workstation (Advantage Windows, GE Healthcare). Two radiologists with 12 and 5
years of experience in liver MRI assessed the images in consensus. Both
reviewers were aware the subjects were patients at high risk before liver
transplantation, but they did not have access to the pathology reports.
Underlying criteria for the diagnosis of HCC included increased enhancement of
the lesion compared with normal liver tissue in the arterial contrast phase;
washout of lesions during the later contrast phases with isointensity or
hypointensity compared with adjacent liver tissue; and development of
peripheral rim enhancement, previously referred to as pseudocapsule
enhancement [13], on delayed
phase images. Lesions were rated as HCC if at least two of the three features
were present. Lesions with focal hepatic enhancement without washout or rim
enhancement were not considered HCC and were considered hypervascular
nonspecific lesions or dysplastic nodules on the basis of characteristics
described by Krinsky et al.
[10,
14]. Lesion size and location
were precisely described according to the segmental anatomy of the liver.
Histopathology
Explanted livers were serially sectioned into 5- to 10-mm contiguous
slices. On gross examination, suspicious nodules were identified as those
distinct from surrounding regenerative nodules in terms of size, texture,
color, and degree of bulging beyond the cut surface of the liver. All lesions
other than regenerative nodules were sampled for histologic examination. At
microscopic examination, malignant nodules were characterized on the basis of
histologic type, size, location, number, and stage (American Joint Committee
on Cancer TNM staging system)
[15]. Lesion size and location
were described in the manner used for the MRI evaluation and were compared
with the findings in the detailed MRI report.
Statistical Analysis
The pathologic findings served as the standard of reference. Subgroups were
formed for HCC 2 cm or larger and HCC smaller than 2 cm. This size
categorization was based on the Model for End-Stage Liver Disease score
criteria [1] in which
significance is attributed only to HCC tumors larger than 2 cm in diameter.
The diagnostic accuracy for MRI was at first assessed in a patient-based
analysis. Point estimates for sensitivity, specificity, and positive and
negative predictive values were calculated. Sensitivity also was determined in
a lesion-based evaluation. To account for discrepancies between MRI and
pathologic findings, two additional retrospective analyses were performed.
First, a possible overlap of hypervascular HCC and dysplasia on MRI was
evaluated in a second lesion-based analysis in which the MRI findings on
hypervascular lesions that did not exhibit washout or rim enhancement were
compared with the pathologic findings. Second, a retrospective analysis was
performed to examine the MR images in instances in which HCC was found at
pathologic examination but had not been visualized on MRI. Specific attention
was paid to the location of the tumor described in the pathology report. These
images also were assessed for technical factors, such as artifacts interfering
with image quality and timing of the arterial phase images.
Results
The histopathologic finding showed the presence of HCC in 27 of 115
patients. Tumors larger than 2 cm were found in 18 of the 27 patients; the
other nine patients had HCC measuring 2 cm or smaller. A total of 36 HCC
tumors were found at histopathologic examination; 18 of these 36 lesions were
larger than 2 cm, and 18 measured 2 cm or smaller. A single HCC was depicted
in 20 patients, and seven patients had more than one lesion (five patients
with two lesions and two patients with three lesions).
At patient-based analysis, HCC was detected with MRI in 24 of 27 patients,
resulting in an overall sensitivity of 88.9%. The specificity was 97.7%
because two patients had false-positive results. In all 18 patients with HCC
larger than 2 cm, the tumors were correctly identified with MRI. In only six
of the nine patients with HCC 2 cm or smaller found at pathologic examination
was HCC described in the MRI report. In the two cases of apparently
false-positive findings, one patient found to have HCC larger than 2 cm and
one patient found to have HCC 2 cm or smaller on MRI were found not to have
HCC at histopathologic examination of the explant. The results of the
patient-based analysis are displayed in Tables
1 and
2.
Lesion-based analysis revealed an overall sensitivity of 77.8% for MRI. MRI
showed 28 lesions had features of HCC, and the pathologic finding was that 36
tumors were HCC (Figs. 1A,
1B,
1C,
1D,
1E,
2A,
2B,
2C,
2D, and
2E). There were two
false-positive results. Retrospective evaluation of the MR images showed one
of these lesions to have typical imaging features of HCC (Figs.
3A,
3B,
3C, and
3D). At retrospective second
interpretation, the other false-positive lesion was believed to be more
consistent with a perfusion abnormality.
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Fig. 1E —58-year-old man with hepatitis C, cirrhosis, and 1.9-cm
hepatocellular carcinoma in segment VI of liver. Histopathologic photograph
shows malignant hepatocytes growing in solid pattern. (H and E)
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Fig. 2A —63-year-old man with hepatitis B, cirrhosis, and 2.3-cm
hepatocellular carcinoma at border of segments V and VIII. Unenhanced
T1-weighted MR image shows high signal intensity of lesion
(arrow).
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Fig. 2B —63-year-old man with hepatitis B, cirrhosis, and 2.3-cm
hepatocellular carcinoma at border of segments V and VIII. Arterial phase MR
image shows high signal intensity of lesion (arrow). Contrast
enhancement is difficult to appreciate because of intrinsic high T1-weighted
signal intensity within lesion.
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Fig. 2C —63-year-old man with hepatitis B, cirrhosis, and 2.3-cm
hepatocellular carcinoma at border of segments V and VIII. Venous (C)
and delayed (D) phase contrast-enhanced MR images show contrast washout
and rim enhancement (arrow), which are features of hepatocellular
carcinoma.
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Fig. 2D —63-year-old man with hepatitis B, cirrhosis, and 2.3-cm
hepatocellular carcinoma at border of segments V and VIII. Venous (C)
and delayed (D) phase contrast-enhanced MR images show contrast washout
and rim enhancement (arrow), which are features of hepatocellular
carcinoma.
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Fig. 2E —63-year-old man with hepatitis B, cirrhosis, and 2.3-cm
hepatocellular carcinoma at border of segments V and VIII. Photograph of gross
pathologic specimen shows round bile-stained subcapsular nodule
(arrow) and surrounding cirrhotic liver parenchyma.
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Fig. 3A —57-year-old man with hepatitis C, cirrhosis, and
1.3-cm-diameter lesion resembling hepatocellular carcinoma on border of
segments IVa and VIII. No hepatocellular carcinoma or other tumor was
identified at pathologic examination. Unenhanced T1-weighted image shows
lesion is inconspicuous.
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Fig. 3B —57-year-old man with hepatitis C, cirrhosis, and
1.3-cm-diameter lesion resembling hepatocellular carcinoma on border of
segments IVa and VIII. No hepatocellular carcinoma or other tumor was
identified at pathologic examination. Arterial phase MR image shows
enhancement (arrow).
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Fig. 3C —57-year-old man with hepatitis C, cirrhosis, and
1.3-cm-diameter lesion resembling hepatocellular carcinoma on border of
segments IVa and VIII. No hepatocellular carcinoma or other tumor was
identified at pathologic examination. Venous phase MR image shows contrast
washout and rim enhancement (arrow).
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Fig. 3D —57-year-old man with hepatitis C, cirrhosis, and
1.3-cm-diameter lesion resembling hepatocellular carcinoma on border of
segments IVa and VIII. No hepatocellular carcinoma or other tumor was
identified at pathologic examination. Delayed phase MR image shows contrast
washout and rim enhancement (arrow).
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Six of 36 lesions described as HCC at pathologic examination were not found
to have a corresponding enhancing liver lesion on prospective MRI.
Retrospective second interpretation of these MRI studies showed no evidence of
a tumor corresponding to the lesions described in the pathology report. In
addition, imaging review of missed lesions showed no significant artifacts,
and the arterial phase contrast enhancement was found to be within the usual
parameters, as in all cases in this study. For two other of the 36 lesions
found at pathologic examination, corresponding lesions were identified on MRI
and had imaging features interpreted as nonspecific hypervascular foci
possibly including dysplastic nodules. Accounting for a potential overlap of
HCC and dysplasia at pathologic evaluation and for the possibility of disease
progression during the interval between MRI and transplantation increased the
lesion-based sensitivity of MRI to 30 (83.3%) of 36 lesions.
Although all 18 HCCs larger than 2 cm were prospectively identified on MRI
(sensitivity, 100%), 10 of 18 HCCs 2 cm or smaller were described as HCC on
the basis of MRI criteria (sensitivity, 55.6%). If the lesions 2 cm or smaller
depicted as nonspecific hypervascular foci or dysplastic nodules on MRI were
to be reinterpreted as HCC, the sensitivity for depiction of HCC 2 cm or
smaller would increase to 66.7%. The lesion-based results are shown in
Table 3.
Discussion
This study was a center-specific evaluation of the utility of MRI in liver
tumor surveillance in the care of patients with chronic liver disease awaiting
liver transplantation. The critical findings from this study are that tumors 2
cm or larger in diameter, considered significant according to Model for
End-Stage Liver Disease scoring criteria, can be identified on MRI with high
sensitivity (100%) and specificity (99%). In the group of explants studied,
there were no cases of inappropriate transplantation with false-positive or
false-negative results for HCC that would have retrospectively altered the
Model for End-Stage Liver Disease score or the priority ranking of any study
patient on the transplantation waiting list.
Clinical Significance
The current practice standard in the United States established by United
Network for Organ Sharing for triage of liver transplantation patients entails
a combination of Model for End-Stage Liver Disease score
[1] and exclusion behavioral
and social criteria, such as smoking and ethanol consumption. The Model for
End-Stage Liver Disease score is a mortality risk predictor and is calculated
with a formula that relies on serum creatinine concentration, total bilirubin
level, and international normalized ratio. Detection of HCC in the liver has
been incorporated into priority scoring in triage for the waiting list and can
be used to provide additional priority points to a patient. A solitary lesion
2–5 cm in diameter or multiple lesions numbering three or fewer with a
total combined diameter of 5 cm are considered curable disease. This criterion
is meant to reduce time to transplantation and improve chances for cure
because HCC is known to have high potential for rapid growth
[1,
16]. Any lesion larger than 5
cm is considered incurable and therefore is a contraindication to
transplantation. None of the patients in this study who underwent
transplantation had explant pathologic findings of tumors larger than 5 cm,
more than three tumors, or diffuse infiltrative disease. Thus no patient had
inappropriately received a transplant because of incurable disease. The
ability to detect tumors larger than 2 cm with high sensitivity is significant
because this size is the threshold for scoring additional priority points.
Alternative Diagnostic Strategies
Although the use of sonography for liver tumor surveillance has been
described [17], the use of
sonography in this role has been seriously questioned
[18]. Results of comparative
studies of sonography, CT, and MRI support the hypothesis that because of lack
of sensitivity, sonography should not be used for tumor surveillance in the
care of patients with cirrhosis
[19,
20]. Although results of
individual studies have suggested that CT and MRI may have similar sensitivity
in detection of HCC [21] and
that MRI may have higher relative specificity
[22], authors
[20] of a recent review have
argued that on average MRI has been shown to have better sensitivity and
specificity than CT. MRI strategies based on the use of various IV contrast
compounds have been evaluated. Paramagnetic gadolinium agents have been found
better than superparamagnetic iron oxide compounds and mangafodipir trisodium
alone in the detection of HCC
[11,
23,
24]. Radiologists should be
aware, however, of the risks of use of gadolinium contrast agents in imaging
of patients with reduced renal function. Gadodiamide has been found to induce
nephrogenic systemic fibrosis in 3–5% of cases of severe renal
insufficiency [25]. Repeated
use of contrast-enhanced CT has raised safety concerns regarding the as yet
undocumented risk of renal exposure to iodinated contrast agents in the
setting of hepatorenal disease
[26–29]
and the cumulative radiation exposure from repeated scans required for
surveillance
[30–33].
Evaluation of the financial effects of adoption of MRI as a primary
surveillance imaging strategy was beyond the scope of our study.
Cost-effectiveness would have to be evaluated in terms of factors such as
relative reimbursement and accuracy of patient selection for
transplantation.
None of the patients in this study who underwent transplantation had
undergone needle-guided biopsy before transplantation with complete reliance
on imaging findings. This observation is particularly important because of
concern about increased risk of complications after needle biopsy among
patients with cirrhosis [34].
Lesions smaller than 2 cm are technically more challenging to biopsy. In
addition, the diagnostic yield from percutaneous biopsy may be relatively low,
approximately 60% [35].
Limitations
A total of 23% of the patients in our series who underwent transplantation
had HCC. Although relatively high and raising the possibility of bias, this
percentage is in keeping with the finding of a 19% incidence of HCC in a large
recent trial [36]. Although
our study was biased toward patients awaiting transplantation who were at high
risk of HCC, this bias was inherent to our study design of contemporaneous MRI
and whole-organ pathologic examination.
The finding of lower sensitivity for tumors smaller than 2 cm has been
described previously
[7–10]
and introduces the potential for inappropriate transplantation in the
treatment of patients with multifocal small HCC who have four or more tumors.
None of our patients was in this category, and we conclude that this event
must be rare. Furthermore, regular tumor surveillance with routine imaging at
intervals of no more than 6–12 months has been suggested. HCC is
presumed to grow during imaging intervals and should become differentiated as
either a new or a growing nodule. This potential limitation should be the
focus of future investigation.
We found that one lesion had typical features of HCC on MRI but was not
described in the pathology report (Figs.
3A,
3B,
3C, and
3D). This finding may be a
limitation of gross analysis of liver specimens whereby it is not always easy
to ensure uniform thin sections and to exactly coordinate anatomic relations
between imaging and pathologic specimens, as has been discussed previously
[7]. We believe that the lesion
in this case probably was HCC that was not identified on gross analysis of the
specimen.
Another limitation of MRI–pathologic correlation is that
differentiation of a regenerative nodule, dysplasia, and HCC can be
challenging. These lesions are part of a spectrum from benign reactive to
malignant transformation. It is difficult to understand the precise relations
between the imaging and histologic features given that these methods are
examinations of fundamentally different components and properties of the
tissues. Histologic examination predominantly involves the cellular and
intracellular structures; gadolinium-enhanced MRI involves the amount of
vascular supply derived from the hepatic arterial branches.
We identified two of 36 pathologically defined HCCs smaller than 2 cm that
exhibited arterial enhancement with isointensity in later contrast phases and
no evidence of rim enhancement. This finding may represent a variable
appearance of HCC on MRI. An alternative explanation is that these lesions may
have continued to progress from dysplasia to malignancy during the interval
between imaging and transplantation. The histopathologic findings may have
been overinterpreted, or imaging may have been impaired as the result of
technical limitations. Regarding the latter possibility, retrospective review
of the images showed no technical cause of failure to identify tumor features.
Enhancing foci in cirrhotic liver have been described as being common, most
commonly not associated with malignancy
[10,
14]. Observations from our
study, however, suggest that enhancing foci in association with cirrhosis at
least should be monitored closely.
Six HCCs identified at pathologic examination were not seen on MRI, and all
were tumors smaller than 2 cm. On retrospective image review, no technical
factors were identified to account for this discrepancy. There was no evidence
of artifacts over the liver, and timing in the arterial phase was optimal. The
possibility of interval tumor progression and histologic overinterpretation
are alternative causes of MRI–pathologic discrepancies.
Conclusion
Our experience with MRI for liver tumor surveillance before transplantation
showed that this diagnostic method is accurate for triage according to the
accepted Model for End-Stage Liver Disease, may be a safe alternative that
avoids radiation, avoids the risk associated with use of iodinated contrast
medium, and minimizes the need for invasive biopsy.
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Abstract
Introduction
