ORIGINAL ARTICLE
T2-weighted and T1-weighted Dynamic Superparamagnetic Iron Oxide (Ferucarbotran) Enhanced MRI of Hepatocellular Carcinoma and Hyperplastic Nodules Ran-Chou Chen,1,3* Jiunn-Ming Lii,1 Chen-Te Chou,3,4 Ting-An Chang,2 Wei-Tsung Chen,1 Chao-Shiang Li,1 Hsing-Yang Tu1 Background/Purpose: Iron oxide contrast medium (ferucarbotran) shortens both T1 and T2 relaxation time. We used the T2- and the T1-weighted dynamic ferucarbotran-enhanced magnetic resonance (MR) imaging to predict the histologic grade of hepatocellular carcinoma (HCC) and to distinguish HCC from hyperplastic nodules. Methods: Forty-three patients with 48 representative hepatic lesions (13 well differentiated HCC, 19 moderately differentiated HCC, 4 poorly differentiated HCC, 12 hyperplastic nodules) were included in the study. T1-weighted image, T2-weighted turbo spin echo, and T2*EPI (echo-planar) images were obtained before and after ferucarbotran injection. The percentage T2 signal intensity loss (T2 PSIL) of the tumors was calculated at 5 minutes and 25 minutes after contrast injection. The enhancement in dynamic T1 images was interpreted by two independent radiologists. Results: The T2 PSIL of well differentiated HCC was 39.5 ± 8.23%, moderately differentiated HCC was 26.4 ± 13.78%, poorly differentiated HCC was 4.4 ± 9.42%, and hyperplastic nodules was 44.3 ± 11.04%. Comparison of T2 PSIL showed significant differences in the three histologically graded HCCs (p < 0.001), but not between the well differentiated HCCs and hyperplastic nodules (p > 0.05). Delayed post-contrast (25 minutes) T2-weighted images were not necessary and shortened the examination time. In the post contrast dynamic T1 study, no significant differences between all the groups was seen. Conclusion: Ferucarbotran MR images help in differentiating the different histologic grades of HCC but T2 PSIL could not differentiate hyperplastic nodules from well differentiated HCC. Dynamic post contrast T1-weighted images provide no additional information. [J Formos Med Assoc 2008;107(10):798–805] Key Words: hepatocellular carcinoma, hyperplasia, liver cell adenoma, magnetic resonance, ultrasmall superparamagnetic iron oxide
The discrimination of hepatocellular carcinoma (HCC) from regeneration nodules and dysplastic nodules on the basis of imaging findings is not always easy, especially in patients with liver cirrhosis who have a higher risk of HCC.1 Recently, magnetic
resonance imaging (MRI) has become the imaging modality of choice for the characterization of hepatic tumors.2 The application of superparamagnetic iron oxide (SPIO) contrast agent in MRI provided higher accuracy in characterizing ©2008 Elsevier & Formosan Medical Association
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Departments of 1Radiology and 2Pathology, Taipei City Hospital Ren-Ai Branch, 3Department of Biomedical Imaging and Radiological Science, National Yang-Ming Medical University, Taipei, and 4Department of Medical Imaging, Changhua Christian Hospital, Changhua, Taiwan. Received: January 30, 2008 Revised: April 10, 2008 Accepted: May 15, 2008
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*Correspondence to: Dr Ran-Chou Chen, Department of Biomedical Imaging and Radiological Science, National Yang-Ming Medical University, 155, Section 2, Linong Street, Taipei 112, Taiwan. E-mail:
[email protected]
J Formos Med Assoc | 2008 • Vol 107 • No 10
Ferucarbotran-enhanced MR of HCC and hyperplastic nodules
hepatic nodules than dual-phase or triple-phase dynamic computed tomography (CT).3–5 SPIO contrast agent decreases the T2 value of liver parenchyma and therefore increases the contrast between neoplasms and surrounding liver parenchyma in T2-weighed images.6,7 Kawamori et al reported the usefulness of SPIO-enhanced MRI in the differentiation of HCC from hyperplastic nodules in a rat model.8 Imai et al also found SPIO contrast agent (ferumoxide)-enhanced MRI useful in predicting the histologic grading of HCC, but not in differentiating dysplastic nodules from welldifferentiated HCC.9 The prevalence of HCC in Taiwan is very high and occurs mainly in patients with hepatitis B or C. However, to our knowledge, there is no report on the use of SPIO-enhanced MRI in diagnosing HCC in Taiwan. Ferucarbotran (Resovist; Schering, Berlin, Germany) is a dextron coated iron oxide contrast medium, which causes shortening of both T1 and T2 relaxation time. As a result, it reduces the signal intensity of liver parenchyma on T2- and T2*weighted imaging and increases T1 signal intensity of hepatic tumors depending upon the tumor vascularity on dynamic T1-weighted imaging.10 The purpose of this study was to investigate the usefulness of ferucarbotran-enhanced MRI in determining the histologic grading of HCC and distinguishing HCC from hyperplastic nodules on the basis of signal intensity changes.
Methods Patients This prospective study included 43 consecutive patients (32 men, 11 women; mean age, 59 years; age range, 28–85 years). The inclusion criteria were: (1) patients with suspicion of HCC or a hyperplastic nodule in the liver on abdominal ultrasonography or dynamic CT; and (2) patients agreeing to receive a histopathologic diagnosis of HCC or hyperplastic nodule based on biopsy or surgical resection. All patients consented to be included in the study and underwent ferucarbotran-enhanced MRI prior to interventions. The institutional review J Formos Med Assoc | 2008 • Vol 107 • No 10
board of this hospital approved the study. Hepatitis B virus (HBV)-related liver disease was diagnosed in 22 of the 43 patients, HCV-related liver disease in 16, both HBV and HCV in three and alcoholic hepatitis in two. Twenty-eight patients had a diagnosis of liver cirrhosis based on imaging and laboratory data. Abnormal liver function was present in 29 of the 43 patients. Histopathologic evaluation was performed after MRI in 48 lesions from 43 patients. Biopsies were performed using 21-gauge needles (Majima needle; Top, Tokyo, Japan) in 40 nodules and by resection in eight lesions. Pathology results revealed 12 hyperplastic nodules (including hyperplastic nodules and dysplastic nodules), 13 well differentiated HCC, 19 moderately differentiated HCC, and 4 poorly differentiated HCC. The pathologist (C.T.A) made the diagnosis based on the following histopathologic criteria. The criteria for hyperplastic and dysplastic nodules were slightly increased cellularity with or without low grade atypia, two to three cell-thick hepatocyte plates, no stromal invasion and negativity for CD34 stain.11,12 In well differentiated HCC, the criteria were increased cell density with an increased nuclear/cytoplasm ratio, minimal atypia, frequent pseudoglandular or acinar structures and frequent fatty changes.12,13 In moderately differentiated HCC, the criteria were thick trabeculae of three or more cells in thickness, tumor cells with abundant eosinophilic cytoplasm, and round nuclei with distinct nucleoli, frequent pseudoglandular cells with bile or proteinaceous fluid.13,14 In poorly differentiated HCC, the criteria were a solid growth pattern with slit-like blood vessels, high nucleus/cytoplasm ratio, and frequent pleomorphism including bizarre giant cells.13,14 The diameters of lesions ranged from 1.2 to 4 cm (mean, 2.3 cm).
MRI MRI of the liver was performed with a 1.5-T MR scanner (Philips Gyroscan ACS-NT, Netherlands) and a phased-array body coil. Turbo spin-echo (TSE) T2-weighted axial imaging (TR/TE, 2500/ 90 ms; TSE factor, 23) without and with fat saturation and coronal T2-weighted imaging were 799
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obtained under a respiratory trigger. T2*EPI (TR/TE, 500/14 ms; angle, 35°) was performed within one breath hold. Dual T1-weighted imaging (TR/TE, 210/2.3 ms and 4.6 ms; slice thickness, 8 mm; gap, 0.8 mm) was also acquired with one breath hold. Automatic shimming was used for fat suppression of images to maximize magnetic field homogeneity. Flow compensation was also used. Contrast enhanced MRI was performed by administering ferucarbotran (Resovist) as a bolus into peripheral veins, at a dosage of 0.9 mL for patients weighing less than 60 kg and 1.4 mL for patients weighing more than 60 kg. Dynamic T1-weighted fast field echo imaging (175–210/ 1.3–2.1; flip angle, 80°) was carried out before, 18–20 seconds after and 50–55 seconds after the contrast agent injection. T2-weighted imaging, fat-suppressed T2-weighted imaging, and T2*EPI imaging data were collected 5 minutes after ferucarbotran administration. The second post contrast T2-weighted imaging was performed using the same imaging protocol, about 25 minutes after contrast agent injection. The total scanning time was about 40 minutes.
sonograms available. Representative tumors were classified as enhanced on the early arterial phase or late venous phase. If both evaluators could not agree as to the presence of positive enhancement, the pattern was classified as isovascular enhancement.
Imaging analysis
Results
The same experienced radiologist measured signal intensities of the tumors directly from a monitor using an operator-defined region of interest, which was an ovoid area as large as possible within the tumor, ranging from 6–10 mm in diameter. The signal intensities of lesions on T2, fat suppressed T2 and T2*EPI were recorded in the temporal order of before, 5 minutes, and 25 minutes after contrast administration. The standard deviation of the background noise was measured in a background area anterior to the lesions and avoided the phase-shift artifact. The signal-to-noise ratios (SNR) of the lesions were then calculated. The percentage signal intensity loss (PSIL) was calculated with the formula: (SNR precontrast − SNR postcontrast)/SNR precontrast × 100%.15 The pre-contrast T1 signal intensity and the enhancement patterns on the T1-weighted dynamic study were evaluated by two radiologists who had all of the images in the MR series and
The relative changes in PSIL of hepatic tumors on post-contrast T2-weighted imaging with fat saturation compared to pre-contrast images are summarized in Table 1. The mean PSIL of hyperplastic nodules was 44.25 ± 15.23% and 49.78 ± 15.23% at 5 and 25 minutes after SPIO contrast injection, respectively (Figure 1). The mean PSIL for well differentiated HCC was 39.48 ± 8.25% and 39.4 ± 15.3% at 5 and 25 minutes after SPIO contrast administration (Figure 2). For moderately differentiated HCC, the mean signal intensity reduction was 26.04 ± 13.78% and 23.82 ± 16.81% at 5 and 25 minutes after SPIO contrast injection, respectively. For poorly differentiated HCC, the signal intensity reduction was only 4.35 ± 9.4% and 2.53 ± 23.13% at 5 and 25 minutes after SPIO contrast injection, respectively. Analysis of the HCCs of three different grades revealed that the PSIL increased as the degree of
Statistical analysis The results were expressed as mean ± standard deviation. Significant differences between HCC lesions of the three different histologic grades and hyperplastic nodules were determined by analysis of variance (ANOVA) followed by the Bonferroni test. The difference in PSIL on fat-suppressed T2weighted imaging between 5 and 25 minutes after ferucarbotran administration was compared by paired t test. A p value less than 0.05 was considered statistically significant. The interobserver difference was calculated by the Kappa test. The significance of ferucarbotran contrast enhancement on dynamic T1-weighted imaging for HCCs of different histologic grades was assessed by the χ2 test.
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Table 1. Percentage signal intensity loss (PSIL) after ferucarbotran of different histologic grades of hepatocellular carcinoma (HCC) and hyperplastic nodules*
Hyperplastic nodule Well differentiated HCC Moderately differentiated HCC Poorly differentiated HCC
n
PSIL in 5 min (%)
PSIL in 25 min (%)
12 13 19 4
44.25 ± 11.05 39.48 ± 8.25 26.04 ± 13.78 4.35 ± 9.4
49.78 ± 15.23 39.4 ± 15.3 23.82 ± 16.81 2.53 ± 23.13
*p < 0.001 for different histologic grades of HCCs; p > 0.05 for hyperplastic nodule and well differentiated HCC; p < 0.05 for 5 minutes vs. 25 minutes.
A
B
C
D
E
histologic differentiation of HCC decreased. PSIL was significantly different among all of the three different grades of HCC (p < 0.001, ANOVA followed by the Bonferroni test) and in PSIL between hyperplastic nodules and HCC (p < 0.001). Using J Formos Med Assoc | 2008 • Vol 107 • No 10
Figure 1. A 59-year-old male with a hyperplastic nodule. (A) The lesion at S5 is isointense in T2WI. (B) It has a low signal in fat saturation T2WI. (C) It has a high signal in T1WI. (D, E) On ferucarbotran-enhanced magnetic resonance imaging, the lesion showed a persistent low signal in T2 as compared with liver parenchyma in fat saturation T2WI and T2*EPI images, PSIL = 30.2%.
the Bonferroni test, the PSIL for moderately differentiated HCC was significantly lower than that for hyperplastic nodules (p = 0.001). The PSIL for poorly differentiated HCC was significantly lower than for hyperplastic nodules (p < 0.001). However, 801
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A
B
C
D
Figure 2. A 45-year-old male with well-differentiated hepatocellular carcinoma. (A, B) The hepatic tumor at S8 has an isointense to mild high signal in T2WI, and fat saturation T2WI. (C, D) In post ferucarbotran contrast-enhanced magnetic resonance imaging, the lesion is brighter, and PSIL = 13.9%.
Table 2. Enhancement in arterial and venous phases of dynamic T1 weighted images after ferucarbotran injection in different grades of hepatocellular carcinoma (HCC) and hyperplastic nodules*
Hyperplastic nodule Well differentiated HCC Moderately differentiated HCC Poorly differentiated HCC
n
Not enhanced
Arterial
Venous
12 13 19 4
8 8 5 2
4 3 14 2
0 2 0 0
*p > 0.05.
the PSIL of the well-differentiated HCC was not significantly different from that of hyperplastic nodules (p > 0.05). No significant change in the PSIL of T2-weighted images for each individual tumor was observed between data collected 5 and 25 minutes after SPIO contrast agent administration (p < 0.005, paired t test). On post-contrast dynamic T1-weighted images, eight (66.7%) of the 12 hyperplastic nodules were not enhanced, while four (33.3%) showed positive enhancement in the arterial and venous phases. Of the 13 well differentiated HCC, eight (61.54%) were not enhanced, three (23.07%) 802
showed positive enhancement in the arterial and venous phases, and two showed positive enhancement in the late venous phase. Of the 19 moderately differentiated HCCs, 14 (73.7%) showed positive enhancement in arterial and venous phases and the remaining five (26.3%) were not enhanced. Of the four poorly differentiated HCCs, two (50%) were not enhanced and two (50%) showed positive enhancement in the arterial and venous phases (Table 2). There was no significant difference in different gradings of HCC and hyperplastic nodules on post-contrast dynamic T1-weighted studies J Formos Med Assoc | 2008 • Vol 107 • No 10
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(p = 0.268). The interobserver agreement was excellent with a Kappa value of 0.813.
Discussion Early detection of HCC requires its differentiation from benign hyperplastic nodules. Accurate distinction of well differentiated from moderately differentiated HCC is also important to determine appropriate treatment plans and to improve prognosis.16 Contrast-enhanced ultrasonography, CT and MRI can facilitate the differential diagnosis of well to poorly differentiated HCCs based on the arterial vascularities of the tumors.17,18 However, the ability of CT and gadolinium-enhanced MRI in diagnosing well differentiated HCC is poor.19,20 Studies of SPIO contrast-enhanced MRI revealed that the different enhancement of the tumors depended upon the numbers and functions of Kupffer cells.16,21,22 Tanaka et al found that twothirds of well differentiated HCC contained Kupffer cells similar in number to the surrounding nontumorous tissues.7 Imai et al reported that the Kupffer cell count ratio decreased as the degree of differentiation of HCC declined.9 Here, the PSIL of ferucarbotran-enhanced MRI was significantly correlated with the three different histologic grades of HCC. Moderately differentiated and poorly differentiated HCC showed less signal loss on post contrast MRI than well differentiated HCC and hyperplastic nodules. Although there is much HCC in Taiwan, there is no report about SPIOenhanced MR studies in Taiwanese patients in the English literature. The signal intensity reduction for well differentiated HCC and hyperplastic nodules was not significantly different after SPIO contrast administration. This result is contrary to the results of a study by Takeshita et al, who found a significant difference in signal reduction between well differentiated HCC and dysplastic nodules.16 This discrepancy might have been due to the small sample size in their study. Our results are similar to the findings of Imai et al, suggesting that the histologic grade of HCCs can be predicted using J Formos Med Assoc | 2008 • Vol 107 • No 10
ferucarbotran-enhanced MRI. However, overlap in signal intensity loss between well differentiated HCC and hyperplastic nodules may limit its diagnostic value. The signal intensity change after administration of ferucarbotran or other SPIO contrast medium could be affected by non-tumorous liver parenchyma. Factors that could reduce SPIO uptake by the non-tumorous liver include the presence of fibrosis, cirrhosis, portal vein thrombosis, hepatic vein thrombosis, peritumoral vascular shunting and hepatitis. The presence of focal steatosis could increase uptake.23 This would result in image contrast between liver and lesion and affect the detection rate. Such phenomena might also explain different results among various studies.9,19,21 We quantitatively determined the PSIL of T2weighted images of tumors. Therefore, the background signals of non-tumorous liver parenchyma were not a dependent factor in the determination of PSIL values. Previous studies of the grading of HCC on MRI after ferumoxide administration found the usefulness of this contrast medium.9,16,18,21 A disadvantage of this SPIO contrast agent is that its use makes the MRI process more time-consuming. Ferucarbotran (Resovist) is the second SPIO contrast agent approved for clinical use. In this study, there was no difference in signal intensity reduction at 5 minutes and 25 minutes after ferucarbotran injection. Our data suggested that using the fatsuppressed T2-weighted imaging and/or T2*EPI 5 minutes after the injection of ferucarbotran would be enough for the examination. There was no additional information from T2-weighted imaging and T2*EPI 25 minutes after ferucarbotran injection. This would shorten the examination time and this observation has not been previously reported. In addition to the significant reduction in signal intensity observed in normal hepatic parenchyma and benign or well differentiated HCCs on post-ferucarbotran contrast-enhanced T2-weighted imaging, enhancement of the hepatic tumors by ferucarbotran was also demonstrated on T1weighted imaging similar to the conventional 803
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extracellular gadolinium MR contrast agent. Previous studies showed that use of ferucarbotran in dynamic T1-weighted imaging provided additional information about tumor vascularities in metastatic tumors, HCC, focal nodular hyperplasia and hemangioma.24,25 Analysis of our data revealed no significant difference in enhancement of variously graded HCCs and hyperplastic nodules using dynamic ferucarbotran-enhanced T1weighted imaging, suggesting that it may not be useful in facilitating their differentiation. Although it has been shown that ferucarbotran has an enhancing effect on T1-weighted imaging, its MR enhancement pattern differs from those obtained using iodinated contrast agents and gadolinium-based contrast agents.26 This may be due to the relatively weak SNR of ferucarbotran in T1-weighted imaging.27 A limitation of the study is that most of the histologic results were based on specimens obtained by needle core biopsy under ultrasound guidance, and some lesions might be underdiagnosed. The histopathologic diagnosis of hyperplastic nodules was sometimes difficult in small biopsy specimens. Further imaging studies with a longer duration of follow-up are needed to provide additional evidence to determine the importance of this limitation. In summary, we found that the use of ferucarbotran in MRI helped to differentiate various histologic grades of HCC but could not differentiate hyperplastic nodules from well differentiated HCC on T2-weighted imaging after calculating PSIL. T2-weighted imaging could be performed 5 minutes after ferucarbotran injection, and the delayed T2-weighted images 25 minutes after contrast injection were not necessary. Dynamic post-ferucarbotran contrast-enhanced T1-weighted images did not provide additional information about the histologic grade of HCC.
Acknowledgments The study was supported by grants from the Taipei Institute of Pathology, Taipei, Taiwan. 804
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