1044 AJR:193, October 2009

ample, patients with HCC not responding to TACE may benefit from treatments such as radiofrequency ablation [8] and systemic therapy [9–11], whereas patients who have partial responses can be treated with repeated TACE [12]. MRI assessment of the response of HCC to TACE relies on change in tumor diameter, which is a late finding, and on the presence of tumor necrosis and residual en-hancement at contrast-enhanced MRI, which can be difficult to evaluate owing to the pres-ence of changes in signal intensity (hyperin-tensity on unenhanced T1-weighted images) related to a combination of iodized oil injec-tion and hemorrhagic necrosis [13, 14].

Several reports have appeared on the use of diffusion-weighted MRI (DWI) in the evaluation of response of HCC to TACE and radioembolization [15–19]. The studies

Assessment of Tumor Necrosis of Hepatocellular Carcinoma After Chemoembolization: Diffusion-Weighted and Contrast-Enhanced MRI With Histopathologic Correlation of the Explanted Liver

Lorenzo Mannelli1 Sooah Kim1 Cristina H. Hajdu2 James S. Babb1 Timothy W. I. Clark1 Bachir Taouli1

Mannelli L, Kim S, Hajdu CH, Babb JS, Clark TWI, Taouli B

1Department of Radiology, MRI, New York University Medical Center, 530 First Ave., New York, NY 10016. Address correspondence to B. Taouli (bachir.taouli@mountsinai.org).

2Department of Pathology, New York University Langone Medical Center, New York, NY.

Gastrointest ina l Imaging • Or ig ina l Research

AJR 2009; 193:1044–1052

0361–803X/09/1934–1044

© American Roentgen Ray Society

The incidence of hepatocellular carcinoma (HCC) has doubled over the past two decades in the United States, and it is currently

estimated to be 8,500–11,500 cases a year [1]. Fewer than 30% of patients with HCC are candidates for potentially curative treat-ments such as surgical resection and liver transplantation [2]. Surgical resection is lim-ited mostly by the impaired liver function of cirrhosis, and liver transplantation is justi-fied only for patients with limited tumor bur-den [3]. Transarterial chemoembolization (TACE) has been found in randomized con-trol trials [4–6] to improve survival among patients with unresectable HCC and is used as a bridge to liver transplantation [7]. As-sessment of HCC response to TACE is crucial for subsequent therapeutic planning. For ex-

Keywords: chemoembolization, diffusion-weighted MRI, hepatocellular carcinoma, MRI, subtraction

DOI:10.2214/AJR.08.1461

Received June 29, 2008; accepted after revision March 23, 2009.

OBJECTIVE. The purpose of this study was to compare, with histopathologic examina-tion of the liver explant as the reference standard, diffusion-weighted MRI with contrast-en-hanced subtraction MRI in the assessment of necrosis of hepatocellular carcinoma (HCC) af-ter trans arterial chemoembolization (TACE).

MATERIALS AND METHODS. The cases of 21 patients with HCC who underwent MRI after TACE were evaluated. Two independent observers calculated the apparent diffu-sion coefficient (ADC) of HCC and measured percentage tumor necrosis on subtraction im-ages. The ADCs of necrotic and viable tumor tissues were compared. ADC and percentage necrosis on subtraction images were correlated with percentage necrosis found at pathologic examination. Receiver operating characteristics analysis was performed on the diagnosis of complete tumor necrosis.

RESULTS. Twenty-eight HCCs (mean diameter, 2.3 cm) were evaluated. There were sig-nificant differences between the ADC of viable tissue and that of necrotic tumor tissue (1.33 ± 0.41 vs 2.04 ± 0.38 × 10−3 mm2/s, p < 0.0001). There was significant moderate correlation between ADC and the pathologic finding of percentage necrosis (r = 0.64, p < 0.001) and sig-nificant strong correlation between subtraction image and pathologic percentage necrosis (r = 0.89–0.91, depending on the phase; p < 0.001). In the diagnosis of complete tumor necrosis, ADC had an area under the curve, sensitivity, and specificity of 0.85, 75%, and 87.5% com-pared with 0.82–0.89, 100%, and 58.3–79.1% for subtraction imaging (p > 0.5 between ADC and subtraction imaging).

CONCLUSION. Compared with diffusion-weighted imaging, contrast-enhanced MRI with subtraction technique had more significant correlation with the histopathologic findings in the evaluation of necrosis of HCC after TACE. There was no difference, however, between the two methods in diagnosis of complete tumor necrosis.

Mannelli et al.MRI of Hepatocellular Carcinoma

Gastrointestinal ImagingOriginal Research

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showed differences in the apparent diffusion coefficients (ADCs) of viable and necrotic portions of HCC after TACE and measurable differences before and after TACE. To our knowledge, only two studies [15, 20], from the same group of investigators, have been conducted to correlate the ADC of HCC after TACE with the histopathologic degree of ne-crosis. One study [20] was experimental, and the other [15] had only a small sample (eight patients with nine lesions). The latter showed excellent correlation (r = 0.95) between ADC and percentage necrosis at histopathologic examination. In addition, to our knowledge, there have been no reports of correlation be-tween ADC and contrast-enhanced subtrac-tion MRI findings in the assessment of HCC after TACE. The purpose of our study was to compare, using the histopathologic findings on the liver explant as the reference standard, DWI and contrast-enhanced MRI performed with subtraction technique in the assessment of HCC necrosis after TACE.

Materials and MethodsPatients

A retrospective review was performed with an exemption granted by our institutional review board, and informed consent was waived. The study was HIPAA compliant with all patient iden-tifiers removed before data interpretation. Over a period of 33 months (June 2005–February 2008), our MRI database was retrospectively queried to identify the cases of patients with HCC who un-derwent MRI with DWI after TACE and liver transplantation within 90 days after MRI. This search yielded 31 cases. Ten of the 31 patients were excluded for the following reasons: greater than 90-day delay between MRI and transplan-tation (n = 6), nondiagnostic quality of diffusion images (n = 3), and lesion located at liver dome and not covered at DWI (n = 1). The final cohort included 21 patients (19 men, two women; mean age, 57.7 years; range 37–70 years). All patients had liver cirrhosis related to chronic viral hepa-titis C (n = 15), chronic viral hepatitis B (n = 5), or primary biliary cirrhosis (n = 1). The patients underwent liver transplantation a mean of 42 days (range, 10–90 days) after MRI.

TACE TechniqueAt our institution, all patients with HCC mea-

suring 2 cm or more in diameter are systematical-ly treated with TACE and placed on the list for liver transplantation. All TACE procedures were performed under conscious sedation. After vas-cular access was gained, celiac and superior mes-enteric angiography was performed with low-os-

molar nonionic contrast material administered through a catheter (Simmons 1, Angiodynamics) for evaluation of the tumor vessel supply and ab-errant hepatic arterial supply and for confirmation of patency of the portal vein.

After diagnostic angiography, selective hepatic artery catheterization was performed coaxially with a 3-French microcatheter (Progreat, Terumo).

A digi tal roadmap was used for superselective catheterization of distal HCC branch vessels. A chemo embolic suspension of doxorubicin hydro-chloride (Adriamycin, Bedford Laboratories) 50 mg lyophilized powder reconstituted in 10 mL of nonionic contrast material and iodized oil (Ethiod-ol, Upjohn) was prepared in the interventional suite and administered in 1-mL aliquots under

TABLE 1: Apparent Diffusion Coefficient and Estimated Percentage of Tumor Necrosis

Patient No.

Apparent Diffusion Coefficient (× 10−3 mm2/s)a

Percentage Necrosis in Portal Venous Phase

Percentage Necrosis at Pathologic

ExaminationObserver 2 Observer 3 Observer 2 Observer 3

1 1.69 1.62 20 10 20

2 1.82 1.83 100 100 40

3 1.95 1.97 70 60 50

4

Lesion 1 1.43 1.40 20 2 10

Lesion 2 1.71 1.64 10 0 0

5 2.33 2.06 100 100 100

6 2.28 2.22 90 70 80

7 2.55 2.89 100 100 100

8 1.62 1.82 100 100 95

9

Lesion 1 0.65 0.47 20 20 0

Lesion 2 1.33 0.99 30 3 60

10 0.91 0.31 40 0 0

11 1.84 1.79 0 4 5

12 1.69 1.71 85 90 100

13 2.02 2.24 80 100 95

14 1.46 1.40 100 100 99

15 2.65 2.74 100 100 100

16 2.48 1.98 90 80 90

17 2.05 2.29 65 80 60

18

Lesion 1 1.80 1.65 45 40 20

Lesion 2 2.50 2.49 100 100 80

19 1.49 1.50 10 20 10

20

Lesion 1 1.48 1.5 90 80 99

Lesion 2 1.75 1.78 100 100 99

Lesion 3 1.25 1.27 0 0 0

Lesion 4 1.32 1.32 0 0 0

21

Lesion 1 1.35 1.39 15 20 20

Lesion 2 0.96 0.88 0 0 0

Note—Values obtained with contrast-enhanced MRI subtraction for two observers (only portal venous phase data are shown) and from histopathologic examination of 28 hepatocellular carcinomas in 21 patients.

aMean apparent diffusion coefficient of whole lesion.

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continuous fluoroscopic monitoring. After delivery of two thirds of the target dose, the other third of the chemoembolic aqueous-oil suspension was mixed with 0.5 vials of 300–500 μm trisacryl gela-tin microspheres (Embospheres, BioSphere Medi-cal) and administered until the intended treatment end point of absence of tumor vascularity with preservation of proximal hepatic artery vessels was reached. The treatment end point was confirmed with completion digital subtraction angiography.

MRIMRI was clinically indicated for assessment

of the response to TACE and was performed with different clinical 1.5-T systems (Magnetom Avan-to, Sonata, and Symphony, Siemens Healthcare) and torso phased-array coils (eight elements for the Sonata and Symphony systems, 12 elements for the Avanto system). Gradient strengths were 33 mT/m (Symphony), 40 mT/m (Sonata), and 45 mT/m (Avanto). Patients underwent imaging a mean of 38 days (range, 10–97 days) after TACE.

DWI—A breath-hold (n = 10) or respiration-triggered (navigator echo technique) (n = 11) fat-suppressed single-shot echo-planar imaging DWI sequence was performed in the axial plane with tridirectional diffusion gradients and three b val-ues ( 0, 50, and 500 s/mm2) within the same acqui-sition and before contrast injection. Parallel imag-ing factor 2 (generalized autocalibrating partially parallel acquisition) was used to improve image quality [21]. The other parameters were TR/TE, 1,300 for breath-hold to 2,600 (one respiratory cy-cle) for respiratory triggering/67–82; matrix size, 144 × 192; slice thickness, 7 mm; interslice gap, 1.4 mm; field of view, 300–400 mm2 with 80% rectangular field of view; number of signals aver-aged, 2 for breath-hold, 4 for respiratory trigger-ing; acquisition time, < 25 seconds for breath-hold acquisition, approximately 4–5 minutes for respi-ration-triggered acquisition.

Routine liver MRI protocol—The liver MRI protocol included the following breath-hold se-quences: axial fat-suppressed T2-weighted se-quence, dual-echo in- and out-of-phase T1-weight-ed gradient-recalled-echo sequence, and a 3D T1-weighted fat-suppressed spoiled recalled-echo sequence (volumetric interpolated breath-hold ex-amination [VIBE]). The images were obtained before and after dynamic injection of 20 mL of gadopentetate dimeglumine (Magnevist, Bayer HealthCare) followed by a 20-mL saline flush (2 mL/s) with a power injector (Spectris, Medrad) in three phases (arterial, portal venous, and equi-librium) of a 3D gradient-recalled echo sequence. For determination of the timing for the hepatic ar-terial phase, a 1-mL test bolus of contrast material was administered to establish the time to peak ar-terial enhancement. The portal venous and equi-

librium images were acquired 60 and 180 seconds after administration of the contrast material. All patients were imaged in end expiration to limit the risk of image misregistration. Acquisition param-eters were 3.3–4.5/1.4–1.9; flip angle, 12°; num-ber of signals averaged, 1; parallel imaging factor, 2; matrix size, 128–192 interpolated to 256 × 256; field of view, 300–400 mm with 80% rectangu-lar field of view; interpolated slice thickness, 2–3 mm; slab thickness, 160–200 mm.

Image analysis—MR images were reviewed by one of the authors (observer 1), who had 5 years of experience in abdominal MRI and who was aware of the location of the treated HCCs. This observer used the gadolinium-enhanced T1-weighted im-ages to select liver lesions suitable for ADC calcu-lation on the basis of review of the pathologic data in conjunction with a hepatopathologist (see later,

A

Fig. 1—58-year-old man (patient 12) with chronic hepatitis C cirrhosis and completely necrotic hepatocellular carcinoma (HCC) after transarterial chemoembolization.A, Axial contrast-enhanced gradient-recalled echo T1-weighted arterial phase subtracted MR image shows nearly completely necrotic tumor (arrow) of right posterior hepatic lobe. Lesion was estimated 85% necrotic by observer 1 and 90% necrotic by observer 2.B, Axial apparent diffusion coefficient (ADC) map calculated from single-shot echo-planar diffusion-weighted images (b = 0, 50, and 500 s/mm2) shows HCC (arrow) with measured ADC of 1.71 ×10–3 mm2/s.C, Coronal photograph of explant shows 100% necrotic tumor (arrow).D, Photomicrograph shows necrotic areas (outline) separated from nontumoral liver tissue by fibrotic capsule. (H and E, ×20)

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Reference Standard). The image of the index HCC lesions were saved on a workstation (Syngo, Sie-mens Healthcare) in a separate series with patient-identifying information removed. The images were labeled lesion 1, lesion 2, and so on, to ensure that observers 2 and 3 (1 and 2 years of experience in abdominal MRI) assessed the same lesions. The segmental location and size of the HCCs also were determined by observer 1.

Observers 2 and 3, who were blinded to the his-topathologic results, independently reviewed DWI and subtracted images of the index lesions on the same workstation as had observer 1. Before start-ing the study and using images of patients not in this study, observers 2 and 3 underwent training in assessment of ADC and image subtraction of HCC lesions that was supervised by observer 1.

ADC measurement—Pixel-based ADC maps were generated on the workstation. ADC was calculated

with linear regression analysis of the function S = S0 × exp(–b × ADC), where S is the signal intensity after application of the diffusion gradient, and S0 is the signal intensity at a b value of 0 s/mm2. The three b values (0, 50, and 500 s/mm2) were used for ADC calculation. Observers 2 and 3 measured the mean and SD of ADC in index HCC lesions by drawing a region of interest over the whole HCC (necrotic plus viable HCC) on ADC maps and then drawing regions of interest including the necrotic and viable HCC re-gions separately, using diffusion and subtracted im-ages as the reference. The ADC of liver parenchyma was measured by drawing a region of interest in the right posterior lobe, away from the lesions.

Image subtraction—The workstation software was used to subtract unenhanced VIBE images from contrast-enhanced VIBE images in the ar-terial, portal venous, and equilibrium phases. No postprocessing slice level correction was used,

and three subtraction image sets corresponding to each set of contrast-enhanced images were ob-tained for each patient. The two observers were asked to visually assess the percentage tumor ne-crosis in each subtracted phase (arterial, portal ve-nous, and equilibrium). Necrosis was defined as nonenhancing tissue on contrast-enhanced sub-tracted images. For both DWI and subtracted im-ages, all tumor-bearing slices were assessed. The assessment of necrosis was based solely on the subtraction data.

Reference StandardA hepatopathologist with 4 years of experi-

ence and a radiologist (observer 1) reviewed gross and microscopic pathologic slides of all patients in conjunction with conventional MRI findings to ensure that the same lesions were assessed at imaging and pathologic examination. The he-patopathologist retrospectively reviewed the tu-mor paraffin blocks of all patients and reassessed the percentage necrosis of each HCC lesion. The pathologist was blinded to the MRI findings de-termined by observers 2 and 3 and to the initial clinical MRI report. At the first pathologic exami-nation, the livers were sliced in the coronal plane in 4- to 5-mm contiguous slices, and photographs of the significant gross findings were obtained. All paraffin blocks were stained with H and E, and the pathologist reviewed them at ×20 magnification to assess percentage of tumor necrosis, lesion size, histologic subtype of HCC, and differentiation.

Statistical AnalysisMixed-model regression was used to evaluate

the correlation between ADC and subtraction-based findings of percentage necrosis in each phase and between ADC or subtraction finding

A

Fig. 2—69-year-old man (patient 6) with chronic hepatitis C cirrhosis and partially necrotic hepatocellular carcinoma (HCC) after transarterial chemoembolization.A, Axial contrast-enhanced gradient-recalled echo T1-weighted arterial phase subtracted MR image shows incompletely necrotic tumor with enhancing viable tumor (arrowhead) and lack of enhancement of necrotic portion (arrow). Lesion was estimated 90% necrotic by observer 1 and 70% necrotic by observer 2.B, Axial apparent diffusion coefficient (ADC) map calculated from single-shot echo-planar diffusion-weighted images (b = 0, 50, and 500 s/mm2) shows necrotic area (arrow) with higher ADC (2.44 × 10–3 mm2/s) than viable portion (arrowhead) anterior to it (1.27 × 10–3 mm2/s).C, Coronal photograph of explant shows 80% necrotic tumor with viable (arrowhead) and necrotic portions (arrows).D, Photomicrograph shows necrotic area (black outline) and viable HCC (white outlines). (H and E, ×20)

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and percentage necrosis at histopathologic exami-nation. A separate analysis was conducted for each measure. In each case, the standardized im-aging measure (ADC or percentage necrosis) was the dependent variable. The model included ob-server identification as a fixed classification factor (to account for interobserver variation) and sub-ject identification as a random classification factor (to account for statistical dependencies among as-sessments made for lesions within the same pa-tient). The standardized measure was correlated with the dependent variable as a numeric factor. Mixed-model analysis of covariance was used to compare the viable and necrotic portions of HCC lesions with respect to each ADC statistic. The values observed for ADC in each of the viable and necrotic portions of the lesions constituted the de-pendent variable in a separate analysis. Each mod-el included lesion identification as a blocking fac-

tor (for direct comparison of the necrotic and viable portions of the same lesion) and the nature of the tissue (necrotic versus viable), making each observation a classification factor. The correlation structure was modeled on the assumption that ob-servations would be correlated only when ac-quired from the same subject.

In the receiver operating characteristics analysis for prediction of necrosis at pathologic exami-nation with the three phases of subtraction and whole-lesion ADC, because there was a single as-sessment of necrosis at pathologic examination of each lesion and because there was excellent inter-observer agreement, the imaging data for each le-sion were represented as an average over the two observers. Receiver operating characteristics anal-ysis was performed for subtracted imaging and ADC prediction of complete (100%) tumor necro-sis at pathologic examination. The threshold of

each mea sure selected as the optimal diagnostic test criterion was the threshold observed to maxi-mize the average of sensitivity and specificity; the reported sensitivity and specificity were those achieved at the reported criterion. Areas under the curves for both methods were compared by use of a jackknife procedure. Interobserver agreement was expressed as intraclass correlation for percentage necrosis at each phase and for ADC measurement.

ResultsHistopathologic Findings

A total of 28 HCCs with an average diam-eter of 2.3 ± 1.1 cm (range, 0.7–6.2 cm) were evaluated. Sixteen patients had one HCC, four patients had two HCCs, and one patient had four HCCs. The average percentage ne-crosis at histopathologic examination was 52% ± 42% (range, 0–100%). Four HCCs were 100% necrotic, and six HCCs were 0% necrotic (Table 1).

The histologic subtypes of HCC were: tra-becular (n = 7), pseudoacinar (n = 6), trabec-ular and pseudoacinar (n = 5), trabecular and acinar (n = 3), mixed cholangio-HCC (n = 1), and unclassified (n = 6). The HCCs were classified as well differentiated (n = 4), mod-erately differentiated (n = 10), and poorly dif-ferentiated (n = 8); six HCCs were not classi-fied. Four of the six unclassified HCCs were completely necrotic, one was 99% necrotic, and one was 95% necrotic and contained a focus of viable tumor too small for classifica-tion. Twenty-two HCCs were located in the right hepatic lobe and six in the left lobe. The histopathologic review did not show granu-lation tissue; the tumors were either necrotic

A

Fig. 3—51-year-old man (patient 17) with chronic hepatitis B cirrhosis and partially necrotic hepatocellular carcinoma (HCC) after transarterial chemoembolization (TACE).A, Axial contrast-enhanced gradient-recalled echo T1-weighted portal venous phase subtracted MR image shows incompletely necrotic tumor with enhancing viable tumor (arrowhead) and lack of enhancement of necrotic portion (arrow). Lesion was estimated 65% necrotic by observer 1 and 80% necrotic by observer 2.B, Axial apparent diffusion coefficient (ADC) map calculated from single-shot echo-planar diffusion-weighted images (b = 0, 50, and 500 s/mm2) shows posterior necrotic area (arrow) with higher ADC (2.21 × 10–3 mm2/s) than anterior viable portion (arrowhead) (1.61 × 10–3 mm2/s).C, Coronal photograph of explant shows 60% necrotic tumor with viable (arrowheads) and necrotic (arrows) portions in same spatial distribution as ADC map.D, Photomicrograph shows necrotic area (black outline) and viable HCC (white outline) and embolic material (arrow) used for TACE. (H and E, ×20)

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or viable. The Pearson’s correlation between tumor size at pathologic examination (2.3 ± 1.1 cm) and that at MRI (2.5 ± 1.1 cm) was 0.81 (p < 0.001).

MRI FindingsInterobserver agreement—There was a

high level of agreement between the two ob-servers regarding percentage necrosis in the three phases of contrast enhancement of the

subtraction images and regarding ADC. Intra-class correlation ranged from 0.92 to 0.95 for subtraction findings and was 0.93 for ADC.

ADC reproducibility—Reproducibility of ADC measurements between MRI units was assessed in a separate phantom experiment [22]. The calculated coefficients of variation (SD/mean) of the ADCs of water and aspar-agus were 3.7% and 13.3%. In another study with a different patient population [23], we

found the coefficient of variation was 12% in liver for ADC measured in breath-hold ver-sus respiration-triggered DWI acquisitions for the same patients.

ADC—ADCs were calculated for all 28 HCCs (Table 1). The mean ADC of whole HCC lesions (necrotic and viable portions if any) was 1.70 ± 0.54 × 10−3 mm2/s. There were significant differences in ADC between completely necrotic (Fig. 1) and nonnecrotic HCCs (p = 0.01) and between partially ne-crotic (Figs. 2 and 3) and nonnecrotic HCCs (p = 0.003) (Table 2). The ADC of necrot-ic tumor tissue (including totally necrotic HCCs and necrotic portions of partially ne-crotic HCCs) was significantly higher than that of viable tumor tissue (including nonne-crotic HCCs and that of nonnecrotic portions of partially necrotic HCCs (p < 0.0001). In addition, in partially necrotic HCCs, the ADCs of necrotic portions were significant-ly greater than those of viable portions (p = 0.001). The differences between completely necrotic and partially necrotic HCCs were not significant (p = 0.06) (Table 2).

There was significant moderate correlation between whole-lesion ADC and percentage necrosis at pathologic examination (r = 0.64; p < 0.001; 95% CI, 0.38–0.89) (Fig. 4A). There also was significant correlation between whole-lesion ADC and percentage necrosis on subtracted images in the arterial (r = 0.63, p < 0.001), portal venous (r = 0.67, p < 0.001), and equilibrium phases (r = 0.70, p < 0.001). The ADC of liver parenchyma was 1.46 ± 0.37 ×

TABLE 2: Apparent Diffusion Coefficients in 21 Patients With 28 Hepatocellular Carcinomas (HCC) Averaged Between Observers 2 and 3

Lesion Apparent Diffusion Coefficient (× 10−3 mm2/s)

All HCC (n = 28) 1.70 ± 0.54

Partially necrotic HCC (n = 18)

Whole lesion 1.78 ± 0.36

Necrotic portion 1.97 ± 0.34

Viable portion 1.46 ± 0.34

Totally necrotic HCC (n = 4) 2.32 ± 0.48

Nonnecrotic HCC (n = 6) 1.06 ± 0.43

Necrotic tumor tissuea 2.04 ± 0.38

Viable tumor tissueb 1.33 ± 0.41

Liver parenchyma (n = 21) 1.46 ± 0.37

Note—Values are mean ± SD. Significant differences (mixed-model analysis of covariance test) were found between completely necrotic and nonnecrotic HCC (p = 0.01), partially necrotic and nonnecrotic HCC (p = 0.003), necrotic and viable tumor tissue (p < 0.0001), viable and necrotic portions of partially necrotic HCC (p = 0.001), nonnecrotic HCC and liver (p = 0.05), totally necrotic HCC and liver (p = 0.0085), and partially necrotic HCC and liver (p = 0.01). Differences were between completely necrotic and partially necrotic HCC (p = 0.06) and between liver parenchyma and viable tumors (p = 0.29) were not significant.

aIncludes totally necrotic HCC and necrotic potions of partially necrotic HCC.bIncludes nonnecrotic HCC and viable portions of partially necrotic HCC.

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Fig. 4—Results of correlation analysis of 28 hepatocellular carcinomas in 21 patients.A, Scatterplot shows relation between whole-lesion apparent diffusion coefficient (averaged over two observers) and percentage necrosis at histopathologic examination (r = 0.64, p < 0.001).B, Scatterplot shows relation between percentage necrosis on portal venous subtracted images (averaged over two observers) and percentage necrosis at histopathologic examination (r = 0.91, p < 0.001).

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10−3 mm2/s (range, 0.65–2.12 × 10−3 mm2/s), lower than that of necrotic tissue (p = 0.0001) but not different from that of viable tissue (p = 0.29). There was no significant differ-ence between breath-hold and respiratory trig-gered acquisitions in regard to the ADC of liv-er parenchyma: 1.51 ± 0.31 versus 1.43 ± 0.47 (p = 0.54).

Image subtraction—The quality of image subtraction was considered good in all cases, and no slice-by-slice registration or addition-al registration software was necessary. The mean ± SD percentage necrosis for the three phases on subtracted images was arterial 58% ± 40%, portal venous 55% ± 42%, and equilibrium 53% ± 41% (range, 0–100%). There was significant strong correlation be-tween percentage necrosis at image subtrac-tion and percentage necrosis at histopatho-logic examination (arterial, r = 0.89; 95% CI, 0.68–0.94; portal venous, r = 0.91; 95% CI, 0.71–0.96; equilibrium, r = 0.89; 95% CI, 0.68–0.94) (p < 0.001 for all) (Fig. 4B). Ob-servers 2 and 3 assessed eight and nine HCCs as totally necrotic on portal venous phase images, but pathologic examination showed that only four HCCs were 100% necrotic and six additional HCCs were ≥ 90% necrotic (Table 1). The pattern of tumor enhancement of HCC was reviewed by observer 2 as fol-lows: 20 HCCs had nodular enhancement in the arterial phase (four having delayed cap-sular enhancement), and eight HCCs were completely necrotic.

Receiver operating characteristics analy-sis—The area under the curve showed no sig-nificant difference between ADC and image subtraction in prediction of complete tumor necrosis (p > 0.05). ADC had a sensitivity and specificity of 75% and 87.5% at an ADC

cutoff greater than 2.16 × 10−3 mm2/s (Table 3, Fig. 5).

DiscussionWe found that viable tumor had restricted

diffusion compared with necrotic portions of HCC after TACE, confirming previous find-ings [15, 16]. In addition, findings at con-trast-enhanced image subtraction MRI cor-related better than did ADC with the degree of tumor necrosis of HCC after TACE esti-mated at examination of the explant. How-ever, the accuracy of ADC was equivalent to that of image subtraction in the diagnosis of complete tumor necrosis.

Contrast-enhanced MRI has been used to assess changes due to tumor treatment and to quantify tumor necrosis in animal and hu-man tumor models [24–27]. Through quan-tification of brownian motion of water mol-ecules and microperfusion [28], DWI can be used to determine the degree of tumor via-bility by showing early posttreatment chang-es in ADC, as suggested by results with var-ious tumor models in animals [26, 29–32], including HCC models [20].

The quality of single-shot echo-planar im-ages of the abdomen has improved owing to technical improvements such as pulse trig-gering [33], parallel imaging [21], and re-spiratory triggering [23]. DWI of the liver has been used mostly for detection and char-acterization of liver lesions [34–43]. There have been several reports [15–19, 44] on the use of DWI to evaluate the response of HCC to TACE and radioembolization. These stud-ies have shown measurable differences in the ADCs of viable and necrotic areas of HCC after TACE, and some have shown serial dif-ferences before and after TACE [16–19, 44].

Despite the results with DWI, there are limited data correlating diffusion parameters with histopathologic measurements of necro-sis in HCC, especially in humans [15, 20]. Kamel et al. [15] used DWI and contrast-en-hanced MRI to evaluate nine HCCs in eight patients. Unlike us, those investigators ob-served stronger correlation between ADC and percentage necrosis at histopathologic examination (r = 0.95) than between contrast-enhanced MRI and histopathologic findings (r = 0.55). However, in addition to including only a small number of patients, Kamel et al. did not assess image subtraction or report the details of acquisition and processing of the histopathologic specimens. Geschwind et al. [20] assessed the efficacy of TACE in rabbits with VX2 liver tumors and in untreated rab-bits used as controls. Using histopathologic examination as the reference standard, those investigators found higher ADCs in areas of tumor necrosis than in viable tumor. They were not able to clearly delineate necrot-ic from viable tissue using conventional se-quences (T2-weighted and contrast-enhanced T1-weighted imaging) and did not use image subtraction. Other studies have shown that ne-crotic tumor portions can become enhanced, possibly owing to the presence of granulation tissue [45, 46] or to leakage of small gadolin-ium molecules to the interstitial space [30]. Our histopathologic review of treated HCCs did not reveal granulation tissue; the tumors were either necrotic or viable.

Several mechanisms can explain the in-creased ADC in necrotic tissue. It may be

TABLE 3: Results of Receiver Operating Characteristics Analysis in Prediction of Histopathologic Finding of Complete Necrosis After Chemoembolization in 21 Patients with 28 Hepatocellular Carcinomas

Measure

Area Under

the Curve

Sensitivity (%) Specificity (%)

Estimate 95% CI Estimate 95% CI

Diffusion-weighted MRI

Apparent diffusion coefficienta 0.85 75 20.3–95.9 87.5 67.6–97.2

Subtraction imaging

Arterial phase 0.82 100 40.2–100.0 58.3 36.7–77.9

Portal venous phase 0.85 100 40.2–100.0 66.6 44.7–84.3

Equilibrium phase 0.89 100 40.2–100.0 79.1 57.8–92.8

Note—There was no significant difference between apparent diffusion coefficient and subtraction images (p > 0.05) in terms of area under the curve with use of a jackknife procedure.

aADC cutoff > 2.16 × 10−3 mm2/s.

100

20

0100

100% − Specificity (%)

Sen

siti

vity

(%

)

0

40

60

80

20 40 60 80

Fig. 5—Graph shows receiver operating characteristics curves comparing diagnostic utility of apparent diffusion coefficient (solid line) with that of portal venous phase subtraction images (dashed line) in diagnosis of complete (100%) tumor necrosis after transarterial chemoembolization. There were no significant differences between methods (areas under curve, 0.85 for both methods; p > 0.05).

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AJR:193, October 2009 1051

MRI of Hepatocellular Carcinoma

related to disruption or damage of cellular membranes, which allows water to diffuse more freely than in viable tumor [20, 47]. Another explanation, albeit nonexclusive, may be the decrease in tumor cellularity in treated lesions. Some studies [48–52] have linked ADC to tumor cellularity.

Assessment of the response of HCC to TACE is crucial for determining the need for repeated TACE or an alternative treatment such as local ablation or systemic treatment [9–11]. DWI is quick (performed in a breath-hold) and yields an ADC threshold for di-agnosis of complete tumor necrosis. The threshold value proposed in our study, how-ever, applies only to the sequence parameters used and may vary, particularly with the b values used for image acquisition. On the ba-sis of the results of this study, we believe that DWI can be used as an alternative to con-trast-enhanced MRI in the care of patients who cannot receive gadolinium contrast ma-terial, such as patients with renal insuffi-ciency at risk of nephrogenic systemic fibro-sis [53–55]. This method may be potentially useful for follow-up before and after TACE by showing changes in ADC.

There were several limitations to this study. First, the number of patients was relatively small. Selection, however, was limited to pa-tients who had undergone liver transplanta-tion so that we could perform histopathologic correlation. Second, because of the retrospec-tive nature of the study, the intervals between TACE and MRI and between MRI and ex-plantation varied. A prospective study would have been ideal for controlling the TACE–MRI interval. It is difficult to control the in-terval between MRI and explantation, how-ever, for patients undergoing cadaveric liver transplantation. Third, exact spatial registra-tion between DWI and histopathologic find-ings was not always possible. Fourth, we did not assess DWI as a standalone sequence in the diagnosis of tumor necrosis after TACE. Instead, image subtraction was used to define necrosis on images, and this decision may have introduced bias. It would be interesting to perform future studies comparing DWI with contrast-enhanced imaging in a more in-dependent manner.

We conclude that in evaluation of HCC after TACE, ADC calculated at DWI had a weaker correlation with histopathologic de-gree of tumor necrosis than did findings at contrast-enhanced MRI with image subtrac-tion. There was no difference, however, be-tween the two methods in the diagnosis of

complete tumor necrosis. We suggest that whenever possible, gadolinium contrast en-hancement and subtraction imaging be used for assessment of tumor necrosis after TACE. When gadolinium injection is not possible, DWI can be used instead of contrast-en-hanced MRI in the diagnosis of complete tu-mor necrosis.

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