Solid Hypervascular Liver Lesionswichita.kumc.edu/Documents/...vs_Malignant_2011.pdf · accurate for distinguishing benign lesions from malignant or high-risk lesions. Biopsy should

ORIGINAL ARTICLE

Solid Hypervascular Liver LesionsAccurate Identification of True Benign Lesions on Enhanced Dynamic and

Hepatobiliary Phase Magnetic Resonance Imaging After GadobenateDimeglumine Administration

Giovanni Morana, MD,* Luigi Grazioli, MD,† Miles A. Kirchin, PhD,‡ Maria Pia Bondioni, MD,†Niccolo Faccioli, MD,§ Alessandro Guarise, MD,* and Gunther Schneider, MD¶

Purpose: To evaluate hepatobiliary phase magnetic resonance imaging withgadobenate dimeglumine for differentiation of benign hypervascular liverlesions from malignant or high-risk lesions.Methods and Materials: Retrospective assessment was performed of 550patients with 910 hypervascular lesions (302 focal nodular hyperplasia�FNH�, 82 nodular regenerative hyperplasia �NRH�, 59 hepatic adenoma orliver adenomatosis �HA/LA�, 329 hepatocellular carcinomas �HCC�, 12fibrolamellar-HCC �FL-HCC�, 21 peripheral cholangiocarcinomas �PCC�,105 metastases). Imaging was performed before and during the arterial,portal-venous, equilibrium, and hepatobiliary phases after gadobenate dime-glumine administration (0.05 mmol/kg). Histologic confirmation was avail-able for �1 lesion per patient, except for patients with suspected FNH(diagnosis based on characteristic enhancement/follow-up). Lesion differen-tiation (benign/malignant) on the basis of contrast washout and lesionenhancement (hypo-/iso-/hyperintensity) was assessed (sensitivity, specific-ity, accuracy, PPV, and NPV) relative to histology or final diagnosis.Results: On portal-venous or equilibrium phase images, washout was notseen for 208 of 526 (39.5%) malignant (HCC, FL-HCC, PCC, metastases)and high-risk (HA/LA) lesions. Conversely, only 5 of 384 (1.3%) true benignlesions (FNH/NRH) showed washout. Taking washout as indicating malig-nancy, the sensitivity, specificity, and accuracy for malignant lesion identi-fication during these phases was 61.8%, 98.7%, and 77.4%. On hepatobiliaryphase images, 289 of 302 FNH, 82 of 82 NRH, 1 of 59 HA or LA, 62 of 341HCC or FL-HCC, and 2 of 105 metastases were hyperintense or isointense.Taking iso- or hyperintensity as an indication for lesion benignity, thesensitivity, specificity, accuracy, PPV, and NPV for benign lesion identifi-cation was 96.6%, 87.6%, 91.4%, 85.1%, and 97.3%, respectively.Conclusions: Hepatobiliary phase imaging with gadobenate dimeglumine isaccurate for distinguishing benign lesions from malignant or high-risklesions. Biopsy should be considered for hypointense lesions on hepatobili-ary phase images after gadobenate dimeglumine.

Key Words: focal liver lesions, magnetic resonance imaging, contrastagents, gadobenate dimeglumine (MultiHance), hepatobiliary phase MRimaging

(Invest Radiol 2011;46: 225–239)

Contrast-enhanced magnetic resonance (MR) imaging is a highlyaccurate noninvasive imaging modality for the detection and

characterization of solid hypervascular focal liver lesions (FLLs),and is invariably the imaging method of choice for improveddifferential diagnosis in cases of equivocal or indeterminate lesionson ultrasound or computed tomography (CT).1–4 However, it is notalways possible to accurately diagnose a given lesion on conven-tional T1-weighted (T1w) dynamic phase imaging because of over-lapping enhancement patterns between different lesion types.5

Moreover, the frequent atypical appearance of certain lesion typesmight further complicate the diagnosis. The development of gado-linium-based contrast agents with liver-specific properties has mark-edly improved the accuracy of MR imaging for the identification andcharacterization of FLLs.6–21

Gadobenate dimeglumine (MultiHance; Bracco ImagingSpA, Milan, Italy) is a gadolinium-based MR contrast agent whichhas the combination of the properties of a conventional nonspecificgadolinium-based agent and that of an agent targeted specifically tohepatocytes.8–10 This feature permits improved lesion detectionrelative to that achievable on unenhanced and dynamic phase im-aging alone,11,12 and an additional means for lesion characterizationon the basis of the functional characteristics of lesions; lesions thatcontain functioning hepatocytes are able to take up the Gd-BOPTAcontrast-effective molecule of gadobenate dimeglumine in a mannersimilar to that of normal liver parenchyma, whereas lesions that donot contain functioning hepatocytes are generally unable to take upGd-BOPTA, and thus appear hypointense relative to enhancednormal liver parenchyma on delayed T1w hepatobiliary phase im-ages.13–16 Previous studies have shown that this differential hepa-tobiliary phase uptake is of particular benefit in the case of focalnodular hyperplasia (FNH), both for the improved characterizationof lesions with atypical enhancement features on dynamic phaseimaging17 and for the accurate differentiation of FNH from hepaticadenoma (HA).18

Unfortunately, the spectrum of hypervascular FLLs en-countered in routine practice extends beyond benign FNH.22

Among the most common hypervascular lesions, FNH and nod-ular regenerative hyperplasia (NRH) are considered truly benignbecause these lesions show no propensity for malignant transfor-mation and are rarely associated with complications such asrupture, hemorrhage, or torsion, which typically necessitateemergency intervention.23 Consequently, these lesions are usu-ally managed conservatively with patients undergoing routinefollow-up. Conversely, other common hypervascular lesions (eg,hepatocellular carcinoma �HCC�, peripheral cholangiocarcinoma�PCC�, liver metastases from primary extrahepatic tumors) maybe highly malignant in nature and frequently prone to complica-tions. These lesions usually require prompt surgical or ablativetreatment whenever feasible and whenever such treatment wouldbenefit the patient. A distinct type of solid hypervascular lesion

Received May 18, 2010; accepted for publication (after revision) September 11,2010.

From the *Department of Diagnostic Radiology, Ospedale Ca Foncello, Treviso,Italy; †Department of Radiology, Spedali Civili Brescia, University ofBrescia, Brescia, Italy; ‡Worldwide Medical & Regulatory Affairs, BraccoImaging SpA, Milan, Italy; §Department of Radiology, University of Verona,Verona, Italy; and ¶Department of Diagnostic and Interventional Radiology,University Hospital of Saarland, Homburg/Saar, Germany.

Reprints: Giovanni Morana, MD, Department of Diagnostic Radiology, OspedaleCa Foncello, 31100 Treviso, Italy. E-mail: [email protected].

Copyright © 2011 by Lippincott Williams & WilkinsISSN: 0020-9996/11/4604-0225

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is HA. Although benign in nature, these lesions are frequentlyassociated with rupture and intralesional hemorrhage, particu-larly if larger than 5 cm in size. Consequently, these lesions areconsidered high risk, and surgical resection is usually indicatedfor larger lesions.24 –26

The purpose of the present retrospective analysis was todetermine the diagnostic accuracy of hepatobiliary phase MR im-aging with gadobenate dimeglumine for the differentiation of truebenign liver lesions (FNH, NRH) from malignant and high-riskhypervascular lesions in patients referred for MR imaging of theliver as part of clinical routine examination.

METHODS AND MATERIALS

Study Population, Lesions, ConfirmationA total of 550 consecutive patients (290 women, 260 men;

mean age � SD, 53.4 � 16.9 years; range, 7–86 years) referred forMR imaging of the liver at 1 of 4 centers in Europe and who had oneor more solid hypervascular FLLs confirmed histologically or bymeans of routine follow-up were evaluated. All patients were eval-uated as part of routine clinical practice, and were informed of thenature of the MR imaging examination and the reason why it wasbeing performed. Approval for the retrospective analysis of patient

TABLE 1. Patient Demographic Characteristics and Summary of Evaluated Lesions and Approach to Lesion Diagnosis

Lesion Type

Patients Lesions Basis for Lesion Diagnosis

Number Male/Female Age Number Size (cm) Range (cm) Follow-Up Biopsy Resection TACE OLT Autopsy

FNH 204 35/169 41.1 � 13.5 302 3.6 � 2.2 0.7–12.0 206 80 16 — — —

NRH 16 9/7 42.1 � 18.4 82 1.8 � 1.0 0.8–5.5 52 21 9 — — —

HA/LA 37 (31/6) 7/30 41.1 � 13.1 59 4.3 � 3.3 1.0–17.0 — 39 15 — 5 —

HCC/FL-HCC 225 (218/7) 173/52 64.9 � 10.9 341 3.8 � 3.1 1.0–18.2 — 174 114 40 5 8

PCC 20 8/12 65.4 � 12.2 21 4.2 � 2.2 0.7–14.0 — 10 11 — — —

Metastases 49 28/21 58.9 � 11.1 105 2.8 � 2.2 0.9–10.5 — 54 31 20 — —

Total 551* 260/291* 53.4 � 16.7 910 3.5 � 2.7 0.7–18.2 258 378 196 60 10 8

*One female patient had both FNH and HA lesions.TACE indicates transarterial chemoembolization; OLT, orthotopic liver transplant; FNH, focal nodular hyperplasia; NRH, nodular regenerative hyperplasia; HA/LA, hepatic

adenoma/liver adenomatosis; HCC, hepatocellular carcinomas; FL-HCC, fibrolamellar-HCC; PCC, peripheral cholangiocarcinomas.

TABLE 2. Definitions for Analysis of Diagnostic Performance

Imaging Phase Enhancement Feature

True BenignLesions

(FNH; NRH)

Malignant/High-Risk Lesions(HCC/FL-HCC; PCC;Metastases; HA/LA)

Portal-venous and equilibrium phases:washout as a sign of malignancy

Washout FP TP

Lack of washout TN FN

Hepatobiliary phase: hyper/isointensityas a sign of benignity

Hyperintense TP FP

Isointense TP FP

Hypointense homogeneous FN TN

Inhomogeneous hypo/isointense FN TN

Inhomogeneous hypo/hyperintense FN TN

FNH indicates focal nodular hyperplasia; NRH, nodular regenerative hyperplasia; HCC, hepatocellular carcinomas; FL-HCC, fibrolamellar-HCC; PCC, peripheral cholangiocarcinomas; HA/LA, hepatic adenoma/liver adenomatosis; FP, false positive; TN, true negative; TP, truepositive, FN, false negative.

TABLE 3. Lesion Appearance on Unenhanced Images and T1w Dynamic Phase Images After Gadobenate DimeglumineAdministration

Lesion Type

Precontrast T2w Precontrast T1w

Hyperintensity Isointensity Hypointensity N.S. Hyperintensity Isointensity Hypointensity N.S.

FNH (n � 302) 161 122 3 16 2 111 166 23

NRH (n � 82) 16 48 3 15 51 9 5 17

HA/LA (n � 59) 24 24 6 5 5 21 28 5

HCC/FL-HCC (n � 341) 248 87 5 1 84 87 168 2

PCC (n � 21) 1 2 18 — — 2 19 —

Metastases (n � 105) 101 3 — 1 2 2 101 —

Total (n � 910) 551 286 35 38 144 232 487 47

N.S. indicates not seen; T1w, T1-weighted; T2w, T2-weighted; FNH, focal nodular hyperplasia; NRH, nodular regenerative hyperplasia; HA/LA, hepatic adenoma/liveradenomatosis; HCC, hepatocellular carcinomas; FL-HCC, fibrolamellar-HCC; PCC, peripheral cholangiocarcinomas.

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data was obtained from the Ethics committee at each center. Writteninformed consent from individual patients was not required for thisretrospective analysis. MR examinations were performed consecu-tively at each center between March 2000 and September 2007, withpatient follow-up extended to March 2010 for patients managedconservatively (ie, for patients undergoing follow-up for diagnosedFNH or NRH).

All of the evaluated patients underwent unenhanced T2-weighted (T2w) and T1w imaging, followed by T1w dynamic anddelayed hepatobiliary phase liver imaging after gadobenate dime-glumine administration. Patients with obvious capillary or cavernoushemangiomas were not included; these lesions are readily diagnosedon unenhanced T2w and postcontrast T1w dynamic phase imagesbecause of their characteristic enhancement patterns,27 and thusdelayed hepatobiliary phase images are not typically acquired forthese lesions. Similarly, patients with hypovascular liver lesions onpostcontrast T1w arterial phase images were not evaluated, as theselesions are mostly malignant and referred for biopsy if not imme-diate intervention.28 Demographic characteristics of the patient pop-ulation and a summary of the lesions included in the analysis and theapproach to lesion diagnosis are given in Table 1.

A total of 910 hypervascular lesions comprising 302 FNH, 82NRH, 59 HA, 6 liver adenomatosis (LA), 329 HCC, 12 fibrolamel-lar-HCC �FL-HCC�, 21 PCC, and 105 hypervascular metastaseswere evaluated. The mean size of evaluated lesions was comparable,ranging between 1.8 � 1.0 cm for NRH and 4.2 � 2.2 cm for PCC(Table 1). The primary cancers in the patients with hepatic metas-tases were neuroendocrine pancreatic tumor (20 lesions in 6 pa-tients), renal cell carcinoma (18 lesions in 6 patients), breast cancer(15 lesions in 7 patients), carcinoid (11 lesions in 6 patients),insulinoma (9 lesions in 2 patients), melanoma (7 lesions in 6patients), colon cancer (7 lesions in 5 patients), lung adenocarci-noma (5 lesions in 2 patients), thyroid cancer (3 lesions in 1 patient),gastrointestinal stromal tumor (2 lesions in 2 patients), gastrinoma (2lesions in 1 patient), ovarian cancer (2 lesions in 1 patient), esoph-ageal cancer (1 lesion in 1 patient), Merkel cell tumor (1 lesion in 1patient), rhinopharyngeal cancer (1 lesion in 1 patient), and non–small-cell lung cancer (1 lesion in 1 patient).

All evaluated lesions were confirmed histologically, unlessthe lesion enhancement patterns on dynamic and delayed hepatobi-liary phase images in conjunction with clinical history and any otherpertinent diagnostic information (ie, findings from any previousimaging studies) were strongly indicative of a benign lesion. Lesionsstrongly suspected to be benign on the basis of characteristicmorphologic and enhancement features (eg, typical FNH and NRH)were included in the present analysis only if follow-up informationfor at least 2 years was available.29 Atypical FNH (ie, lesions that

demonstrated abnormal features such as heterogeneous enhance-ment; hypointensity in the portal-venous or equilibrium phases;absent central scar in larger lesions, typically �3 cm; scar hypoin-tensity on T2w images; or the presence of a pseudocapsule, hemor-rhage, or necrosis) or NRH were referred for biopsy or in some casesresected (Table 1).

All lesions suspected to be malignant were confirmedhistologically after biopsy or resection, or displayed identicalbehavior to previously biopsied lesions in the same patient duringtransarterial chemoembolization. Only histologically confirmedlesions were included in the analysis; additional lesions in thesame patient that were not evaluated histologically were notincluded regardless of whether the enhancement behavior wasidentical to that of the biopsied lesion. Therefore, no more than3 lesions per patient were evaluated, even among patients withmultiple ostensibly identical lesions.

For the purposes of the present analysis, LA lesions weregrouped with HA lesions because LA lesions are histologically andradiologically identical to HA lesions.30,31 Similarly, FL-HCC le-sions were grouped with the HCC lesions for subsequent analysis.

MR ImagingA similar MR imaging protocol was used at each institution.

All patients were imaged on a superconducting imager (MagnetomSymphony or MagnetomVision, Siemens Medical Systems, Erlan-gen, Germany) operating at 1.5 Tesla, using a body-array coil. MRimaging was performed using T2w Turbo Spin Echo sequences withor without fat saturation (T2wTSE; TR/TE � 4000 ms/90–108 ms,flip angle �FA� � 150 degree, echo train length � 29) or a T2whalf-Fourier acquisition single-shot turbo spin-echo (HASTE) se-quence (T2wHASTE; TR/TE � �/74 ms, FA �180 degree) andT1w Gradient Echo in-phase and out-of-phase sequences (T1wGRE;TR/TE � 140–160 ms/4.7 ms for in-phase/2.6 for out-of-phase,FA � 70 degree) or a T1w volumetric interpolated breath-holdexamination sequence (T1wVIBE; Repetition time (TR)/Echo time(TE) � 6.2 ms/2.5 ms, FA � 15 degree). Images were acquiredbefore the administration of contrast agent (T2wTSE and T1wGREor T1wVIBE images); during the dynamic phase of contrast agentenhancement (T1wGRE or T1wVIBE images only) at 25 to 30seconds (arterial phase), 70 to 90 seconds (portal-venous phase), and3 to 5 minutes (equilibrium phase) following the intravenous bolus(2–2.5 mL/s) administration of gadobenate dimeglumine at a dose of0.05 mmol/kg bodyweight; and during a later delayed hepatobiliaryphase (T1wGRE images only) between 1 and 3 hours postinjection.Images acquired in the postcontrast delayed phase were acquiredwith or without fat suppression. The slice thickness was 6 to 7 mmfor unenhanced images and images acquired during the delayed

TABLE 3. (Continued)

T1w Arterial Phase T1w Portal-Venous Phase T1w Equilibrium Phase

Hyperintensity Isointensity Hypointensity N.S. Hyperintensity Isointensity Hypointensity N.S. Hyperintensity Isointensity Hypointensity N.S.

302 — — — 196 104 2 — 112 185 5 —

82 — — — 35 47 — — 17 65 — —

59 — — — 16 28 15 — 6 28 25 —

341 — — — 92 82 167 — 24 82 235 —

21 — — — 8 4 9 — 12 5 4 —

105 — — — 45 18 42 — 24 27 54 —

910 — — — 392 283 235 — 195 392 323 —

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hepatobiliary phase, and between 2.5 and 7 mm depending on thesequence (T1wVIBE or T1wGRE) for image acquisition during thepostcontrast dynamic phase. T2wHASTE images of the entire liverwere acquired either as a single slab with a total breath-holdacquisition time of 19 to 21 seconds or in 2 slabs of 11 slices withan acquisition time of 14 seconds each. T2wTSE and T1wGREimages of the entire liver were acquired in single breath-holdacquisitions of 19 to 23 seconds. The T1wVIBE images wereacquired with a single breath-hold acquisition of 18 seconds. Amatrix size of �160 � 256 was employed with a rectangularfield-of-view of 350 to 420 mm.

Image EvaluationAll MR images at each center were evaluated by a senior

radiologist (XX, YY, ZZ) with at least 18 years experience in liverimaging and more than 12 years specific experience of liver MRIwith gadobenate dimeglumine. All detected lesions were assessed interms of signal intensity enhancement on dynamic (arterial, portal-venous, and equilibrium phases) and delayed (1–3 hours) hepatobi-liary phase images. Lesions were classified primarily as hypoin-tense, isointense, or hyperintense relative to the surrounding normalliver parenchyma in the same imaging phase. In the portal-venousand equilibrium phases, lesions which showed a signal intensitylower than the surrounding normal parenchyma were considered tohave demonstrated contrast washout.

Secondary determinations were made of enhancement homo-geneity (homogeneous, inhomogeneous) and of the presence orabsence of features characteristic of specific lesion types (eg, centralscar in the case of FNH). Such features are frequently useful forlesion characterization, especially for benign lesions, enabling con-servative management whenever possible.

Statistical AnalysisDefinitions of lesion features used for determinations of

diagnostic performance are given in Table 2. Determinationsof diagnostic performance using contrast washout as indicative ofmalignancy during the portal-venous and equilibrium phases andlesion hyper- or isointensity as indicative of lesion benignity duringthe hepatobiliary phase were performed in terms of sensitivity(TP/�TP � FN�), specificity (TN/�TN � FP�), accuracy (�TP �TN�/�all lesions�), positive predictive value (PPV; TP/�TP � FP�),and negative predictive value (NPV; TN/�TN � FN�).

RESULTS

Precontrast Unenhanced ImagingThe appearance of the 910 evaluated lesions on precontrast

T2w and T1w images is summarized in Table 3. Detected lesions onunenhanced T2w images were predominantly hyperintense or isoin-tense to the surrounding normal liver parenchyma, although mostPCC lesions (18 of 21; 85.7%) were hypointense. Of the 38 lesionsnot seen on unenhanced T2w images, 31 (81.6%) were benign FNHor NRH. The appearance of lesions on unenhanced T1w images wasmore diverse, although most lesions were hypointense or isointense.Exceptions were NRH which in most cases appeared hyperintenseand HCC whose appearance ranged from markedly hypointense tomarkedly hyperintense. A total of 47 lesions were not visible onunenhanced T1w images. In most cases, these were again benignFNH or NRH.

Although unenhanced imaging frequently provided hints tothe diagnosis of a given lesion, it was insufficient in itself to permitreliable differentiation of benign from malignant disease.

Dynamic Phase ImagingBecause only hypervascular lesions were included in this

analysis, all evaluated lesions were hyperintense against the sur-

rounding normal parenchyma on arterial (25–30 inches) phaseimages (Table 3). Although in most cases (687 of 910 lesions�75.5%�) the arterial phase enhancement was homogeneous, inho-mogeneous hyperintensity reflecting areas of internal lesion necro-sis, fibrosis, or hemorrhage was noted in 21.2% (193 of 910) oflesions overall, predominantly among HCC or FL-HCC (Fig. 1),PCC, metastases (Fig. 2), and HA or LA. Peripheral rim enhance-ment, which is frequently a characteristic feature of hypervascularmetastases and PCC on dynamic MRI,29,30 was noted in 3.3% (30 of910) of lesions overall (11 of 21 �52.4%� PCC, 14 of 105 �13.3%�metastases (Fig. 3), and 5 of 341 �1.5%� HCC; Table 4).

On portal-venous (70–90 inches) phase images, only 392 of910 (43.1%) lesions were homogeneously or inhomogeneouslyhyperintense, whereas 283 of 910 (31.1%) lesions were isointenseand 235 of 910 (25.8%) lesions were hypointense (Table 3). Com-parison among individual lesion types revealed that although 40% ormore of all true malignant lesions and 25.4% (15 of 59) of HA or LAwere already hypointense during the portal-venous phase, between27.0% and 42.9% of these lesions were still homogeneously orinhomogeneously hyperintense.

A similarly high proportion of true malignant and high-risklesions retained a hyperintense or isointense appearance on equilib-rium phase acquisitions at 3-5 postinjection; overall, 57.6% (34 of59) of HA or LA lesions, 31.1% (106 of 341) of HCC or FL-HCClesions, 48.6% (51 of 105) of metastases, and 81.0% (17 of 21) ofPCC lesions were homogeneously or inhomogeneously hyperintenseor isointense during this phase (Table 3). Among these lesions, moreHA or LA, HCC or FL-HCC, and metastases appeared isointensethan hyperintense, reflecting continued contrast agent washout. Con-versely, most PCC lesions were predominantly hyperintense duringthe equilibrium phase because of contrast agent pooling.

Assuming that washout in the portal-venous and equilibriumphase images is indicative of a true malignant lesion (HCC, FL-HCC, PCC, or metastasis) or a high-risk lesion (HA or LA), theoverall sensitivity, specificity, accuracy, PPV, and NPV for thedifferentiation of benign from malignant or high-risk lesions onportal-venous and equilibrium phase imaging was 61.8%, 98.7%,77.4%, 98.5%, and 65.3%, respectively.

Despite the predominantly hyperintense or isointense appear-ance of the FNH and NRH lesions throughout the dynamic phase ofimage acquisition, the high proportion of malignant and HA or LAlesions showing similar enhancement behavior precluded reliabledifferentiation of benign and malignant lesions on the basis ofdynamic phase imaging alone.

Delayed Hepatobiliary Phase ImagingThe overall appearance of the 910 evaluated lesions during

the delayed hepatobiliary phase of contrast enhancement is summa-rized in Table 5. Although 289 of 302 (95.7%) FNH (Figs. 4, 5) andall (82 of 82 �100%�) NRH had a hyperintense or isointenseappearance, all but 62 HCC or FL-HCC, 2 metastases, and 1 HAlesion appeared homogeneously or inhomogeneously hypointense(Figs. 5–7). Regarding the 2 metastases, both lesions demonstrateda high degree of internal necrosis and appeared inhomogeneouslyhyperintense on delayed phase images because of clear contrastagent pooling within the lesion. Conversely, the inhomogeneousisointense appearance of the solitary HA reflected the presence ofextensive internal hemorrhage in a patient with severe hepaticsteatosis. As regards to the 13 FNH lesions that had an overallhypointense appearance on delayed phase images, this was in eachcase due to fibrosis within the lesion.

Assuming that lesion hyperintensity or isointensity on de-layed hepatobiliary phase images is indicative of a true benign lesion(FNH or NRH) and that lesion hypointensity indicates either a truemalignant lesion (HCC, FL-HCC, PCC or metastasis) or a high-risk




FIGURE 1. A 17-year-old girl with a large, lobulated tumor in the left liver lobe. The lesion (arrow) appears inhomogeneously isointenseor slightly hypointense on unenhanced T1w images (A) as well as on T2w TSE (B) and HASTE (C) images. Intense contrast enhancementduring the T1w arterial phase (D) after administration of 0.05 mmol/kg gadobenate dimeglumine, with no significant washout duringthe portal-venous (E) and equilibrium (F) phases, is suggestive of the dynamic contrast enhancement pattern displayed by FNH. On de-layed (2 hour) T1w hepatobiliary phase images (G), the lesion appears hypointense against the enhanced normal parenchyma, indicatinga tumor without functioning hepatocytes that is unable to take up Gd-BOPTA. Histology following resection confirmed the lesion as afibrolamellar carcinoma.




lesion (HA or LA), the overall sensitivity, specificity, accuracy,PPV, and NPV for the differentiation of benign from malignantlesions on hepatobiliary phase imaging in this analysis was 96.6%,87.6%, 91.4%, 85.1%, and 97.3%, respectively (Table 6).

Given that inhomogeneous or peripheral enhancement duringthe arterial phase is often a strong indicator of lesion malignancy, asimilar assessment was performed for just the 687 hypervascularlesions that demonstrated homogeneous enhancement on arterialphase imaging. Similar overall results were obtained (98.7%, 85.4%,

92.7%, 89.2%, and 98.1%, for sensitivity, specificity, accuracy,PPV, and NPV, respectively; Table 6).

Finally, because contrast washout during the portal-venous andequilibrium phases is often also indicative of lesion malignancy,32-34

assessment was similarly performed for just the 580 hypervascularlesions that did not demonstrate washout during these phases. Again,the results obtained were similar to those of the overall lesionpopulation (96.8%, 78.1%, 90.3%, 89.3%, and 92.9%, for sensitiv-ity, specificity, accuracy, PPV, and NPV, respectively; Table 6).

FIGURE 2. A 59-year-old woman with multiple hypervascular metastases from a primary neuroendocrine tumor. The unen-hanced T1w image (A) reveals 2 large hypointense lesions (arrows) in the right liver lobe. On T2w TSE (B) images, the lesionsare almost isointense with the normal parenchyma. The large lesion (arrow) appears inhomogeneously slightly hyperintenseduring the arterial phase (C) and iso- to hyperintense during the portal-venous phase (D). During the equilibrium phase (E),the lesions appear inhomogeneously hypointense. On the delayed (1 hour) T1w hepatobiliary phase image (F), the lesionsappear strongly inhomogeneously hypointense. Contrast agent pooling (arrow) is evident within the large lesion. The delayedT1w hepatobiliary phase image also reveals the presence of 2 additional lesions (arrows) in the left liver lobe.




FIGURE 3. A 55-year-old man with hypervascular metastases from a primary intestinal carcinoid. A small lesion (arrow) appears as homo-geneously hypointense on the unenhanced T1w image (A) and as slightly hyperintense on the T2w TSE image (B). During the T1w arte-rial phase (C) after administration of 0.05 mmol/kg gadobenate dimeglumine, the lesion appears slightly hyperintense. The lesion appearsisointense and hypointense on the portal-venous (D) and equilibrium (E) phase images, respectively. In the equilibrium phase, anothersmall hypointense lesion (arrow) can be seen in the sixth segment. On the delayed (2 hour) T1w hepatobiliary phase image (F), the le-sions are both strongly hypointense against the enhanced normal liver parenchyma. During this phase, another small hypointense lesion(arrowhead) can be seen.




DISCUSSIONIn the 12 years that gadobenate dimeglumine has been ap-

proved in Europe for MR imaging of the liver, numerous studieshave highlighted the value of delayed hepatobiliary phase acquisi-tions not only for the improved detection of metastatic or smallsatellite lesions,11,12 but also for the improved characterization ofequivocal or otherwise atypical lesions on routine dynamic phaseimaging.13–18 Moreover, comparative studies have also shown thathepatobiliary phase imaging with gadobenate dimeglumine is supe-rior to MR imaging with liver-specific superparamagnetic iron oxideparticles for both the detection and characterization of liver le-sions.12,35,36 Recently, Kim et al have shown that delayed hepato-biliary phase acquisitions are particularly beneficial for the im-proved characterization of HCC in cirrhotic livers.16

At variance with previous studies that focused on gado-benate dimeglumine-enhanced MR imaging of specific lesiontypes,12,15–18,35,36 our analysis addressed the overall value of de-layed hepatobiliary phase imaging with gadobenate dimeglumine forroutine clinical differentiation of true benign lesions for whichconservative treatment is typically indicated from malignant andhigh-risk lesions, for which therapeutic intervention is usually nec-essary whenever possible. Assuming that a hyperintense or isoin-tense appearance on hepatobiliary phase imaging indicates a lesionwith functioning hepatocytes that is able to take up the Gd-BOPTAcontrast-effective molecule of gadobenate dimeglumine17,18 in asimilar manner to that of surrounding normal liver parenchyma, andthat a hypointense appearance indicates a lesion without functioning

hepatocytes that is unable to take up Gd-BOPTA, we determinedoverall values for sensitivity, specificity, accuracy, PPV, and NPVof 96.6%, 87.6%, 91.4%, 85.1%, and 97.3%, respectively. On thebasis of these findings, an appropriate “rule of thumb” may be toconsider a hypointense lesion on delayed hepatobiliary phase imag-ing in normal liver as suspicious for malignancy for which confir-matory histologic information is required, whereas a hyperintense orisointense lesion in the absence of other suspicious findings (eg,elevated �-1 fetoprotein in case of HCC37) is more likely to bebenign in nature, and thus a candidate for regular follow-up.

Interesting exceptions are HA and LA lesions which arebenign in nature but which appear hypointense on delayed hepato-biliary phase imaging because they lack biliary ductules,38 and thusare unable to take up and excrete Gd-BOPTA through the hepato-biliary route. However, these lesions are highly susceptible tohemorrhage and thus are frequently considered for surgical resectionanyway, in much the same way as malignant lesions.24–26 Inagreement with previous findings,18 all but one of the HA or LAlesions included in this study were hypointense on delayed phaseimages; the one exception was an inhomogeneously isointenselesion in a patient with severe hepatic steatosis. Apart from thesevere steatosis in this patient, another possible explanation for theisointense appearance of the single HA in this study was that agadobenate dimeglumine dose of just 0.05 mmol/kg bodyweight wasused because this is the dose approved in Europe for MR imaging ofthe liver. Although the R1 relaxivity of gadobenate dimeglumine isapproximately twice that of conventional gadolinium contrast agentsat all magnetic field strengths,39 thereby permitting similar lesionconspicuity and diagnostic information with a reduced overalldose,40,41 it has nevertheless been shown that an increased dose of0.1 mmol/kg bodyweight leads to greater overall signal-to-noise andcontrast-to-noise ratios on delayed images.9,42 It is possible that anincreased dose in this particular patient might have led to greaternormal liver enhancement relative to that of the lesion, resulting ina more typical hypointense appearance. For other MR applications,a gadobenate dimeglumine dose of 0.1 mmol/kg bodyweight iseither approved or widely used off-label and numerous intraindi-vidual crossover studies with conventional gadolinium agents havereported significantly improved imaging performance with gado-benate dimeglumine at this dose.43–49 The increased R1 relaxivityand thus the improved imaging performance relative to conventionalagents at equivalent dose is because of weak, transient interactionsof the Gd-BOPTA contrast-effective molecule of gadobenate dime-glumine with serum proteins.50,51 Recent studies suggest that evenbetter diagnostic performance can be achieved by modifying therelevant acquisition and/or evaluation parameters to take account ofthe protein interaction and increased R1 relaxivity of gadobenatedimeglumine.52–54

As noted previously,15,17,18 certain HCC may appear atypi-cally hyperintense (Fig. 8) or isointense on hepatobiliary phaseimages, whereas certain FNH may appear atypically hypointense.These studies have addressed the appearance of these hepatocellularlesions in normal liver and, in the case of HCC, in cirrhotic liver.15

Among the lesions in the present analysis, most of false-positivelesions (62 of 65) were HCC that appeared either hyperintense (n �26 �7.6%�) or isointense (n � 36 �10.6%�) on delayed phase images.Conversely, the 13 (4.3%) false-negative lesions were all atypicalFNH that appeared inhomogeneously hypointense on delayed phaseimages. In the case of HCC, a hyperintense or isointense appearancemay be due to residual hepatocyte functionality in certain well-differentiated lesions or due to large amounts of intralesional fattymetaplasia.15 Conversely, certain FNH may appear atypically hy-pointense on delayed images because of extensive fibrosis within thelesion.17,18 Concerning the FNH lesions included in this analysis, a

TABLE 4. Homogeneity of Lesions on Arterial Phase ImagesAfter Gadobenate Dimeglumine Administration

Lesion TypeNo.

Lesions

Arterial Phase Enhancement

Homogenous Inhomogeneous Peripheral

FNH 302 296 6 —

NRH 82 82 — —

HA/LA 59 43 16 —

HCC/FL-HCC 341 206 130 5

PCC 21 1 9 11

Metastases 105 59 32 14

Total 910 687 193 30

FNH indicates focal nodular hyperplasia; NRH, nodular regenerative hyperplasia;HA/LA, hepatic adenoma/liver adenomatosis; HCC, hepatocellular carcinomas;FL-HCC, fibrolamellar-HCC; PCC, peripheral cholangiocarcinomas.

TABLE 5. Appearance of Lesions on T1w DelayedHepatobiliary Phase Images After Gadobenate DimeglumineAdministration

Lesion TypeNo.

Lesions Hyperintense Isointense Hypointense

FNH 302 218 71 13

NRH 82 75 7 —

HA/LA 59 — 1 58

HCC/FL-HCC 341 26 36 279

PCC 21 — — 21

Metastases 105 2 — 103

Total 910 321 119 470

T1w indicates T1-weighted; FNH, focal nodular hyperplasia; NRH, nodular regen-erative hyperplasia; HA/LA, hepatic adenoma/liver adenomatosis; HCC, hepatocellularcarcinomas; FL-HCC, fibrolamellar-HCC; PCC, peripheral cholangiocarcinomas.




relatively high proportion (80 of 302; 26.5%) were referred forbiopsy, despite the characteristic hyperintense appearance of thelesions on delayed hepatobiliary phase images. After resection, 16lesions were further assessed histologically. Among the 80 biopsiedFNH lesions were the 13 atypical hypointense lesions; the remainderwere predominantly lesions with atypical features on initial dynamicphase imaging (eg, an inhomogeneous appearance, calcification, aperipheral rim, absent central scar in larger lesions). Atypical im-aging findings on MR imaging are not uncommon for FNH.55,56

However, the appearance of these lesions on delayed hepatobiliaryphase images suggests that follow-up might have been an alternativeapproach to patient management rather than immediate biopsy.

A limitation of this analysis is that the lesions included wereamong the more common hypervascular lesion types encountered in

routine practice. Recently, a report from Marin et al57 has shownthat primary leiomyoma, which is a rare benign tumor of the liver,also appears hypointense on delayed hepatobiliary phase imagesafter gadobenate dimeglumine administration. Given the criteriaadopted for this analysis, a hypointense appearance on delayedimaging would be suggestive of a malignant lesion for which biopsyis indicated. However, although biopsy would have been unneces-sary in this case, it is clearly preferable to histologically assess asuspected malignant lesion that is subsequently confirmed as benignthan not to assess a lesion that is subsequently confirmed as malig-nant. Findings from routine practice should provide additional in-formation on whether other benign hypervascular lesions apart fromHA and leiomyoma have a hypointense appearance on delayedphase images. By analogy with HA, it may be envisaged that benign

FIGURE 4. A 32-year-old man with FNH and a history of seminoma. The lesion (arrows) appears isointense on the unenhancedT1w (A) and T2w HASTE (B) images. Strong contrast enhancement occurs during the T1w arterial phase (C) after administration of0.05 mmol/kg gadobenate dimeglumine, with no washout during the portal-venous (D) and equilibrium (E) phases. The enhance-ment behavior is typical of FNH, except that a central scar is not clearly appreciated. On the delayed (2 hour) T1w hepatobiliaryphase images (F), the lesion is homogeneously hyperintense against the normal liver parenchyma, indicating a lesion with function-ing hepatocytes that is able to take up Gd-BOPTA. Moreover, a central scar is better appreciated.




FIGURE 5. A 33-year-old woman with FNH and adenomatosis. The unenhanced T1w image without fat suppression (A) re-veals 1 slightly hyperintense lesion (arrow). The lesion shows signal suppression on the opposed phase T1w image (B), indi-cating fat within the lesion. The T2w TSE (C) image reveals 2 hyperintense lesions (arrows). On the T1w arterial phase image(D) after administration of 0.05 mmol/kg gadobenate dimeglumine, the lesions demonstrate homogeneous contrast enhance-ment. In this phase, a large hypervascular lesion can be seen in the fifth segment. In the T1w portal-venous phase (E), thelarger lesion appears isointense, whereas the 2 smaller lesions show contrast washout (asterisk) and retention of contrast agentresulting in a hyperintense appearance (arrow), respectively. On the equilibrium phase image (F), all but 1 lesion appearsisointense; only the lesion that showed contrast washout during the portal-venous phase appears hypointense. On the de-layed (2 hour) T1w hepatobiliary phase images acquired without (G) and with (H) fat suppression, the 2 smaller lesions ap-pear homogeneously hypointense, whereas the larger lesion is markedly hyperintense against the normal liver parenchyma.The 2 hypointense lesions are adenomas which lack biliary ductules, and thus are unable to take up and excrete Gd-BOPTAthrough the hepatobiliary route. The larger lesion is an FNH.




FIGURE 6. A 65-year-old HCV� woman with a small HCC for 10 years. The unenhanced T1w image (A) reveals a small hy-pointense lesion in the sixth segment. The lesion appears slightly hyperintense on the T2w HASTE image (B). Strong homoge-neous contrast enhancement occurs during the T1w arterial phase (C) after administration of 0.05 mmol/kg gadobenatedimeglumine, with no washout during the portal-venous (D) and equilibrium (E) phases. On the delayed (2 hour) T1w hepa-tobiliary phase image (F), the lesion (arrow) is homogeneously hypointense against the normal liver parenchyma, indicating alesion that is unable to take up Gd-BOPTA.




FIGURE 7. A 75-year-old woman with chronic hepatitis and HCC. The unenhanced T1w image (A) reveals a homogeneous hypointenselesion (arrow). The lesion appears hyperintense on the T2w TSE (B) and HASTE (C) images. Signs of cirrhosis are also apparent with thesesequences. Strong homogeneous contrast enhancement occurs during the T1w arterial phase (D) after administration of 0.05 mmol/kggadobenate dimeglumine, which persists into the portal-venous phase (E). During the equilibrium phase (F) and on delayed (1 hour) T1whepatobiliary phase images acquired without (G) and with (H) fat suppression, the lesion is homogeneously hypointense against the nor-mal liver parenchyma, indicating a lesion that is unable to take up Gd-BOPTA.




lesions with compromised or absent biliary ductules are more likelyto appear hypointense. A second possible limitation is that alterna-tive MR approaches such as diffusion weighted imaging (DWI)were not included in the assessment. Although DWI sequences areknown to be of value for the characterization of certain hypervas-

cular liver lesions such as hemangiomas and cysts,58–60 they are oflimited use for the accurate differential diagnosis of solid hypervas-cular lesions.59–61 These sequences were used in comparatively fewsubjects in our cohort, and thus their potential added value was notassessed. Future work might be directed toward evaluating the

TABLE 6. Sensitivity, Specificity, Accuracy, PPV and NPV for the Differentiation of Benign From Malignant Lesions onDynamic (Portal-Venous and Equilibrium Phases: Washout) and Hepatobiliary Phase (Assuming Iso/Hyperintensity as a Sign ofBenignity) Imaging

Imaging Phase Lesions Sensitivity Specificity Accuracy PPV NPV

Portal-venous and equilibrium phases—washout 910 61.8% 98.7% 77.4% 98.5% 65.3%

Hepatobiliary phase: all lesions 910 96.6% 87.6% 91.4% 85.1% 97.3%

Hepatobiliary phase: lesions with homogenousenhancement on arterial phase imaging

687 98.7% 85.4% 92.7% 89.2% 98.1%

Hepatobiliary phase: lesions with no washout onportal-venous and equilibrium phase imaging

580 96.8% 78.1% 90.3% 89.3% 92.9%

PPV indicates positive predictive value; NPV, negative predictive value.

FIGURE 8. A 77-year-old woman with chronic hepatitis and HCC. The unenhanced T1w image (A) reveals a homogeneoushypointense lesion at the dome of the liver. The lesion appears slightly hyperintense on the HASTE (B) images. Inhomoge-neous contrast enhancement occurs during the T1w arterial phase (C) after administration of 0.05 mmol/kg gadobenatedimeglumine, with a washout into the portal-venous (D) and equilibrium phase (E). On delayed (2 hours) T1w hepatobiliaryphase images acquired without (F) fat suppression, the lesion is inhomogeneously hyperintense against the normal liver pa-renchyma, indicating a lesion that is able to take up Gd-BOPTA.




comparative benefits of DWI in combination with delayed hepato-biliary phase imaging.

A final limitation is that the analysis was retrospective innature. However, it should be borne in mind that consecutivepatients were included at each center and that image assessment wasbased solely on lesion enhancement relative to normal liver en-hancement. Nevertheless, a prospective study is perhaps warrantedto confirm the conclusions of this study.

Although this analysis focused solely on hypervascular liverlesions, the benefits of delayed hepatobiliary phase imaging withgadobenate dimeglumine have also been demonstrated recently forthe differentiation of benign from malignant lesions that have ahypointense appearance.28

In conclusion, this analysis demonstrates that delayed hepa-tobiliary phase imaging with 0.05 mmol/kg gadobenate dimeglu-mine is accurate for the correct differentiation of true benignhypervascular lesions from malignant and high-risk hypervascularlesions. However, it should be emphasized that delayed hepatobili-ary phase imaging is not necessary for all patients referred for MRIfor suspected liver lesions. Therefore, it would make little sense toperform hepatobiliary phase imaging in patients with lesions such asobvious cysts and hemangiomas, which can readily be characterizedon unenhanced and postcontrast dynamic phase images alone. Onthe other hand, the possibility to acquire hepatobiliary phase imagesis potentially highly advantageous for equivocal lesions or lesionswhich have an atypical appearance on dynamic phase imaging.Concerning workflow and logistical issues, it should be borne inmind that approximately only 6 to 8 minutes are needed to acquiredelayed hepatobiliary phase images (including patient positioning,etc.), and that delayed phase images can be acquired at any timebetween 1 and 3 hours after gadobenate dimeglumine injection, withlater delayed acquisitions often proving beneficial compared withearlier delayed acquisitions.17 Therefore, if additional delayed phaseacquisitions are deemed necessary for a given patient, the overallworkflow and timing are not greatly affected, especially becausedelayed acquisitions are not necessary for every patient.

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