Imaging diagnosis and staging of hepatocellular carcinoma

SUPPLEMENT

Imaging Diagnosis and Staging ofHepatocellular CarcinomaJeong Min Lee,1 Franco Trevisani,2 Valerie Vilgrain,3 and Christoph Wald4

1Department of Radiology, Seoul National University College of Medicine, Seoul, Korea; 2Unit of MedicalSymptomatology, Department of Clinical Medicine, University of Bologna, Bologna, Italy; 3Department ofRadiology, Beaujon Hospital, Universite Paris 7, Assistance Publique–Hopitaux de Paris, Paris, France; and4Lahey Clinic Medical Center, Tufts University Medical School, Burlington, MA

Received February 10, 2011; accepted June 11, 2011.

Despite the incremental technological advances incross-sectional imaging techniques [ultrasound (US),computed tomography (CT), and magnetic resonanceimaging (MRI)], there is still some concern that theimaging technology available today is inadequate forappropriate prioritization for liver transplantation(LT) because it cannot provide a sufficiently accu-rate diagnosis of hepatocellular carcinoma (HCC) ona per-nodule basis or sufficiently accurate diseasestaging on a per-patient basis. In a recent study, aretrospective analysis of data from the United Net-work for Organ Sharing (which oversees solid organtransplantation in the United States) comparedpreoperative findings by cross-sectional imaging withpostoperative explant pathology findings; in compari-son with the pathological stages of the explanted liv-ers, imaging was found to have underestimated oroverestimated the tumor burden in approximatelyone-fourth of the cases.1 One might speculate thatthis finding not only is due to the inherent short-comings of the cross-sectional imaging techniquesthat are generally available for the liver but alsoreflects significant differences in the technical speci-fications of scanner hardware and software, imagingprotocols, and interpretive expertise, the lack ofstandardization of the language used in imagingreports, and the absence of widely accepted diagnos-tic criteria.

Here we discuss possible pathways to consensuspositions on the following issues:

1. The minimal technical requirements for US, CT,and MRI.

2. The minimal requirements for operator expertise.3. The standardization of imaging reports.4. The classification of nodules on the imaging

workup.5. The staging of HCC.6. The standardization of the evaluation of the

results of locoregional therapy (LRT).7. The standardization of surveillance for an early

HCC diagnosis in patients listed for LT.

MATERIALS AND METHODS

We performed a systematic review of the relevant liter-ature and synthesized the available evidence withpeer group appraisals and expert reviews. The con-sensus statements consist of recommendations andscientific comments that are based on a comprehen-sive review of the literature for each topic. The qual-ity of the existing evidence and the strength of therecommendations have been ranked from 1 (highest)to 5 (lowest) and from A (strongest) to D (weakest),respectively, according to the Oxford evidence-basedapproach to developing consensus statements.2

Abbreviations: 3D, three-dimensional; [18F]FDG, [18F]fludeoxyglucose; FAT SAT, fat saturated; CT, computed tomography; FNB,fine needle biopsy; HCC, hepatocellular carcinoma; LRT, locoregional therapy; LT, liver transplantation; MDCT, multidetectorcomputed tomography; mRECIST, modified Response Evaluation Criteria in Solid Tumors; MRI, magnetic resonance imaging;PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors; TACE, transarterial chemoemboliza-tion; US, ultrasound.

Potential conflict of interest: Nothing to report.

Address reprint requests to Jeong Min Lee, M.D., Department of Radiology, Seoul National University College of Medicine, Daehangno 100,Jongno-Gu, Seoul, Korea 110-744. ; E-mail: [email protected] or [email protected]

DOI 10.1002/lt.22369View this article online at wileyonlinelibrary.com.LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

LIVER TRANSPLANTATION 17:S34–S43, 2011

S34 Liver Transplantation, Vol 17, No 10, Suppl 2 (October), 2011: pp S34-S43

RESULTS

Minimal Technical Requirements for

US, CT, and MRI

HCC can be diagnosed noninvasively (ie, on the basisof radiological findings) without biopsy if conclusiveimaging features are present.3-8 These noninvasivediagnostic criteria require a contrast-enhanced study(dynamic CT, MRI, or both). This is reflected in the2010 practice guideline recommendations of theAmerican Association for the Study of Liver Diseases.9

The arterial enhancement of a nodule and the pres-ence of washout on portal venous or delayed imagingare considered to be conclusive imaging features ofHCC.6,7,10 For the diagnosis of HCC, a multiphasiccontrast-enhanced imaging study, which includesoptional unenhanced imaging followed by arterial,portal venous, and delayed phases, is required.8,11,12

Although several studies have demonstrated that con-trast-enhanced US is very sensitive to the arterial vas-cularity of HCC,10,13 US contrast agents unfortunatelyare not widely available in many countries, includingthe United States. Furthermore, US is operator-dependent; the limited field of view does not permitsingle-contrast phase imaging of the whole organ; andthe body habitus of obese patients may interfere withhigh-quality imaging. US can be used for the diagno-sis of HCC mainly because the contrast enhancementpattern of a previously noted liver lesion can beobserved in high fidelity when the US examination isfocused on that lesion before, during, and after theinjection of the contrast agent. Although some reportshave suggested CT or MRI screening as an alternativesurveillance strategy for HCC because of the difficul-ties with US in obese individuals with fatty liver dis-ease and advanced cirrhosis,14-16 most practices inthe United States use US as a screening or surveil-lance tool for detecting HCC in cirrhotic livers, andonce there is a positive focal finding, they use eitherCT or MRI for the characterization and follow-up.17-21

CT scanning is not recommended for surveillancebecause of the high false-positive rate and the risksassociated with cumulative radiation exposure fromrepeated scans22; CT scanning is also not cost-effec-tive.21 Therefore, although contrast-enhanced USplays a role in characterizing nodules in cirrhotic liv-ers in some countries, contrast-enhanced CT and MRIare the most important and widely used techniquesfor the noninvasive diagnosis of HCC.23

Although conventional extracellular gadolinium che-lates and iodinated contrast agents are the most com-monly used contrast agents for dynamic MRI and CT,respectively, there have been several reports of prom-ising single-center experiences with new paramag-netic, hepatocyte-specific contrast media: gadoxetatedisodium (Primovist) and gadobenate dimeglumine(MultiHance). These contrast media combine the prop-erties of conventional extracellular contrast agentsand hepatobiliary agents and thus enable bothdynamic multiphasic imaging and the depiction of he-patocyte uptake by the contrast agent and subsequent

biliary excretion. Several previous studies have demon-strated that this kind of comprehensive vascular andfunctional evaluation of a nodule would improve thesensitivity and specificity of MRI for the diagnosis ofHCC (particularly for nodules < 2 cm)24-26 and lead toa better diagnostic performance in comparison withmultidetector computed tomography (MDCT).24,27,28

However, further studies are needed to assess (1) thereal diagnostic value of additional hepatobiliary infor-mation for establishing a noninvasive diagnosis of HCCand (2) the positive predictive value for establishing themalignancy of nodules identified in cirrhotic livers whenthey are seen only on hepatobiliary phase images. Inaddition, recent studies have demonstrated that theaddition of diffusion-weighted imaging to conventionalT2-weighted imaging and dynamic imaging can improvethe characterization of HCC and dysplastic nodules incirrhotic livers and the detection of HCC.29,30 Eventhough diffusion-weighted imaging is routinely includedin MRI examinations of the liver at many centers, sev-eral issues regarding the role of diffusion-weightedimaging in the diagnosis of HCC in cirrhotic liversremain unresolved. These include the wide variations inthe quality of the diffusion-weighted images generatedby the different commercially available imaging plat-forms, the lack of standardization of protocols andsequences, and the significant overlap of benign andmalignant liver lesions with respect to the qualitativeappearance of the images and the quantitative values ofthe apparent diffusion coefficients.31,32

Because the imaging diagnosis of HCC plays an im-portant role in the clinical care and decision makingof affected patients, it is crucial that imaging tests beperformed with meticulous attention paid to the tech-nical details. For example, several previous studies ofthe timing of arterial phase imaging with CT and MRIhave demonstrated that the optimal detection ofhypervascular HCC by CT or MRI requires the acqui-sition of images to be carefully timed to take placeduring the late arterial phase of contrast enhance-ment. Early arterial images are characterized by strongenhancement of the hepatic artery, but they do notallow enough time for contrast washin, so the enhance-ment of the tumors versus the background liver isinsufficient.33-35 Early arterial phase imaging is, there-fore, not recommended for HCC detection. Studiesshould be conducted with proven multiphasic contrast-enhanced imaging protocols. Suitable high-qualityscanners should be used, and the studies should definethe amount and injection rate of the contrast agent, theprecise individualized timing of the image acquisitionwith respect to the injection of the contrast agent, andthe suitable minimum slice thickness for the recon-struction of images (Tables 1–3).

Minimum Requirements for Operator Expertise

US

This cross-sectional imaging technique is highly oper-ator-dependent, has a limited field of view, does not

LIVER TRANSPLANTATION, Vol. 17, No. 10, 2011 LEE ET AL. S35

permit easy documentation of the whole organ, and isgreatly influenced by a patient’s phenotype (eg, ab-dominal fat, bowel gas, ascites, and chest walldeformities) as well as a patient’s compliance with

breathing commands during the acquisition ofimages. Moreover, because the cirrhotic liver typicallyis diffusely echogenic, the through-transmission ofsound to the more remote portions of the organ is

TABLE 1. Minimum Technical Specifications for Liver US

Feature Specification Comment

Probe type ElectronicFrequency range 3-5 MHz The broadband technique is preferable.Penetration/imageuniformity

Proper receiver gain and time gaincontrols allow the echo textureto be visible in the deep region.

The ability to image the entire liveruniformly without any artifacts

(eg, streaks or dropouts) is necessary.Accuracy of verticaland horizontaldistance measurements

The error is less than 5 mm.

Doppler technique At least color Doppler imaging should be available.Harmonic imaging The contrast-specific harmonic imaging

technique is preferable.

TABLE 2. Minimum Technical Specifications for Dynamic Contrast-Enhanced MRI of the Liver


Scanner type 1.5-T or greater main magneticfield strength

Low-field magnets not suitable

Coil type Phased array multichannel torso coil Unless patient-related factorsprecludes use (eg, body habitus)

Gradient type Current-generation high-speed gradients(providing sufficient coverage)

Injector Dual-chamber power injectorrecommended

Bolus tracking desirable

Contrast injection rate 2-3 mL/second of gadolinium chelate Preferably resulting invendor-recommended total dose

Minimum sequences Precontrast and dynamic post gadoliniumT1-weighted gradient echo sequence(3D preferable), T2 (with and without

FAT SAT), and T1w in- andout-of-phase imaging

Mandatory dynamic phaseson contrast-enhanced MRI(comments describe typicalhallmark image features)

1. Late arterial phase 1. Artery fully enhanced, beginningcontrast enhancement of portal vein

2. Portal venous phase 2. Portal vein enhanced, peak liverparenchymal enhancement, beginningcontrast enhancement of hepatic veins

3. Delayed phase 3. Variable appearance, >120 secondsafter the initial injection of contrast

Dynamic phases (timing) The use of a bolus tracking method fortiming contrast arrival for late arterial

phase imaging is preferable: portal venousphase (35-55 seconds after the initiationof a late arterial phase scan) and delayed

phase (120-180 seconds after theinitial contrast injection).

Slice thickness 5 mm or less for dynamic series, 8 mmor less for other imaging

Breath holding Maximum length of series requiring breathhold should be about 20 seconds

with a minimum matrix of 128 � 256.

Compliance with breath holdinstructions is very important;

technologists need to understandthe importance of patient instruction

before and during the scan.

NOTE: Reprinted with permission from Liver Transplantation.36 Copyright 2010, American Association for the Study ofLiver Diseases.

S36 LEE ET AL. LIVER TRANSPLANTATION, October 2011

poor; this makes it fairly difficult to detect and char-acterize focal liver lesions.37 These limitations mayexplain the unsatisfactory pooled sensitivity (63%) ofUS as a surveillance test for revealing nonadvancedHCC (ie, HCC meeting the Milan criteria) in patientswith cirrhosis; this sensitivity further decreases to33% in studies using CT concurrently.38

Moreover, there are no particular training andlicensure requirements for performing US in manycountries. This procedure is performed worldwideby a very heterogeneous group of professionals, whoinclude radiologists, hepatologists, gastroenterolo-gists, internists, US technicians, and other physi-cian extenders working on behalf of physicians.Notably, in the United States, examinations are fre-quently performed by technicians, who during theexaminations select images to be archived for sub-sequent interpretation by radiologists. The inter-preting physician often does not have easy access tothe patient, so he cannot personally reevaluateareas of interest. Furthermore, this approach limitsthe evaluation of images to those identified by theUS operator as worthy of documentation.

To optimize the use of US, the procedure may needto be performed by a physician with specific trainingin the performance of liver US [regardless of thephysician’s formal training credentials (medical orother)]. The use of US by unskilled sonographers orphysicians should be considered inappropriate in thisparticular clinical context.39 Two separate and perti-nent practice guidelines for US are promulgated bythe American College of Radiology,40 and they outline

the following minimum training and competencystandards:

1. The performance and interpretation of diagnosticUS examinations (revised in 2006).

2. The performance of US examinations of the ab-domen and/or retroperitoneum.

Although these practice guidelines are valid only inthe United States, they constitute a widely publicizedand accepted framework for quality imaging examina-tions with this modality.

CT and MRI

A consensus conference panel of the United Networkfor Organ Sharing debated at length whether anyaccepted competency criteria were available fordescribing the particular competence of radiologistswho interpret liver imaging.36 Although formal train-ing in abdominal imaging could certainly be consid-ered an advantage in this respect, it was agreed thatan ongoing practice in an accredited, high-volume LTcenter is probably the best surrogate for professionalcompetence; peer pressure and peer reviews in thetypical interdisciplinary context found at such centersmay over time result in the assurance that theimagers are practicing according to the highest possi-ble standards. It was also recognized that testing aperson’s competence in any medical specialty is verydifficult, and there are very few accepted and provenmethods for ascertaining such competence. Certainly,the panel was not aware of any widely accepted

TABLE 3. Minimum Technical Specifications for Dynamic Contrast-Enhanced Computerized Tomography of the Liver


Scanner type Multidetector row scannerDetector type Minimum of 8 detector rows Need to be able to image the entire

liver during the brief late arterialphase time window

Reconstructed slice thickness Minimum reconstructed slicethickness of 5 mm

Thinner slices are preferable,especially if multiplanar

reconstructions are performed.Injector Power injector, preferably a dual-chamber

injector with a saline flushBolus tracking desirable

Contrast injection rate No less than 3 mL/sec of contrast,4-6 mL/sec better with at least

300 mg I/mL or a higher concentrationfor a dose of 1.5 mL/kg of body weight

Mandatory dynamic phaseson contrast-enhancedMDCT (comments describetypical hallmark imagefeatures)

1. Late arterial phase 1. Artery fully enhanced, beginningcontrast enhancement of portal vein

2. Portal venous phase 2. Portal vein enhanced, peak liverparenchymal enhancement, beginningcontrast enhancement of hepatic veins

3. Delayed phase 3. Variable appearance, >120 secondsafter the initial injection of contrast

Dynamic phases (timing) Bolus tracking or timing bolusrecommended for accurate timing

NOTE: Reprinted with permission from Liver Transplantation.36 Copyright 2010, American Association for the Study ofLiver Diseases.


methodology for testing or ascertaining competence inliver imaging and diagnosing HCC.

Standardization of Imaging Reports

The imaging report should always comment on thequality of the study (adequate or inadequate). If thestudy is inadequate or nondiagnostic, a repeat studyshould be performed before final decisions are madeabout the presence or absence of significant diseasessuch as HCC.41 For each detected focal liver lesion,the report should describe the following:

• The location of the segment or segments.• The maximum diameter.• The lesion definition (well defined, moderatelywell defined, or poorly defined).

• The echogenicity, attenuation, and signal inten-sity of the lesion during the various imagingphases versus the internal standards for the sur-rounding liver parenchyma.

• The presence of a capsule or pseudocapsule.• Vascular thrombosis (benign versus malignantaccording to the contrast enhancement character-istics of the thrombus).

• The involvement of the bile duct or a tumorthrombus of the bile duct.

• The characteristics of the precontrast and post-contrast dynamic imaging phases (late arterial,portal venous, and delayed) and the hepatocyteimaging phase (for the hepatospecific MRI con-trast agents).

Classification of Nodules on the Imaging

Workup

For de novo 1- to 2-cm nodules in a cirrhotic liver, thespecificity and positive predictive power of the typicalradiological pattern of HCC, which is characterized byincreased contrast enhancement (washin) during thelate arterial phase and then by washout during theportal venous or delayed phase with a single dynamictechnique (US, CT, or MRI), have been found to behigh in single-center studies, although the negativepredictive values have been only 42% to 50%.10,42,43

Therefore, any new nodule that is greater than 1 cmand shows this combination of imaging findings can beconsidered HCC when it is observed in a cirrhotic liverbecause metastatic disease, which can have a similarappearance, is exceedingly rare in cirrhotic livers (aconclusive diagnosis). The sensitivity of this single-technique policy to the malignancy of tiny lesions is65%, whereas the sensitivity of the 2-technique policy(suggested by the 2005 guidelines from the AmericanAssociation for the Study of Liver Diseases44) is only35%; thus, the adoption of the single-technique policycould eliminate the use of fine needle biopsy (FNB) fora final diagnosis in one-third of patients43 (Fig. 1).

For hypervascular nodules without washout thatare greater than 1 cm, the chance of being HCC is ashigh as 66%.42 Hence, this radiological pattern can be

considered worrisome for the diagnosis of HCC. Inthese cases, an additional imaging technique fordetecting washout is advisable so that the malignancycan be confirmed without FNB.

Additional imaging observations that are more com-monly found in association with HCC include the fol-lowing: high perfusion values for volume perfusionimaging with CT; hyperintensity on T2-weightedimages; no uptake of hepatocyte-specific contrastagents during the hepatobiliary phase with MRI;hyperintensity on diffusion-weighted MRI sequenceswith high b values; peripheral rim enhancement dur-ing the delayed phase, intralesional fat (which is bestassessed with in-phase and opposed-phase T1-weighted MRI sequences), an internal mosaic pattern,and vascular invasion on any dynamic postcontrastimaging; and the presence of a tumor capsule andinterval growth (maximum diameter increase) of 50%or more on serial MRI or CT images obtained lessthan 6 months apart.30,36,45-47 The presence of one orseveral of these features may increase the confidenceof the radiological diagnosis of HCC.

Hypovascular or isovascular HCC cannot be diag-nosed with the aforementioned radiological criteria.Therefore, image-guided FNB or follow-up imagingneeds to be considered for nodules that do not meetthe qualitative criteria for HCC but raise concernsabout HCC (eg, there is documented interval growth).

Staging of HCC Before LT

Liver

A liver containing at least 1 HCC must be staged witha suitable imaging technique that provides completeanatomic coverage of the liver.48-50 Dynamic contrast-enhanced CT and MRI are the only acceptable imag-ing techniques for this purpose.51-56 The faster imag-ing acquisition and the typically wider bore of the

Figure 1. Diagnostic algorithm for a newly detected nodule in acirrhotic liver. Ø, nodule.


gantry of the machine may make CT preferable forpatients who are unable to adequately hold theirbreath or are claustrophobic. US is inadequatebecause of its inability to reliably acquire images ofthe entire organ during a particular contrast phase.56

Several reports have shown that dynamic MRI seemsto be more sensitive than CT for detecting smalllesions (<2 cm).6,26,52,57,58 In addition, a systematicreview of the accuracy of US, spiral CT, and MRI indiagnosing HCC in patients with chronic liver diseaserevealed the following pooled estimates: 60% specific-ity and 97% specificity for US (14 studies), 68% sensi-tivity and 93% specificity for CT (10 studies), and 81%sensitivity and 85% specificity for MRI (9 studies).59

The operative characteristics of CT are comparable,whereas MRI is more sensitive.52 However, a large-scale, systematic, prospective study is needed todetermine which imaging modality is best for diagnos-ing HCC.

Extrahepatic Staging

For LT candidates, patient staging should routinelyinclude CT scans of the chest, abdomen, and pelvis.60

Bone scintigraphy can be used for evaluating bonemetastases.61 MRI can be an alternative for theabdominal cavity.44,62

There are insufficient data for proposing [18F]flu-deoxyglucose ([18F]FDG) positron emission tomogra-phy (PET) for HCC staging before LT. PET scans canreveal extrahepatic metastases that are not foundwith CT, but PET has a low sensitivity for tiny and/orwell-differentiated HCCs when they are located withinthe liver because of the high background liver uptakeof fludeoxyglucose; the specificity of PET is also verylow.63 The use of dual-isotope PET ([18F]FDG and[11C]acetate) may increase the sensitivity for HCCbecause well-differentiated tumors have a high avidityfor acetate rather than glucose.64,65 However, the useof dual-isotope PET increases costs and a patient’s ex-posure to radiation, and it is not widely available.

Notably, there is growing evidence that [18F]FDGPET before LT has a strong and independent prognos-tic power. In comparison with their counterparts,PET-positive tumors more frequently display unfavor-able histological features (eg, high cellular dedifferen-tiation and microvascular invasion) heralding poorerrecurrence-free survival after LT.66,67 New studiesshould be aimed at assessing the potential role of PETin refining the priority criteria for patients listed forLT and in expanding the Milan criteria.

Standardization of the Evaluation of the

Results of LRT

The goal of LRT is the complete removal of a tumorwith hepatic resection or the complete necrosis of atumor with locoregional ablative therapy [percutane-ous thermal ablation, transarterial chemoemboliza-tion (TACE), or radioembolization]. Incomplete abla-tion has been reported to be a risk factor for post-LT

tumor recurrence.68 LRT may need to be repeated toachieve complete necrosis. The need for additionalinterventions is typically assessed by imaging; specifi-cally, an expert interprets images to determinewhether a residual tumor exists.

Complete tumor ablation may be indicated by acomplete absence of contrast-enhancing nodular tis-sue associated with the ablated lesion (any enhance-ment is evaluated in comparison with the backgroundhepatic parenchyma). However, even if no residualenhancing tissue is perceptible, a viable tumor mayremain in the treated areas, particularly when thelesions have a diameter greater than 3 cm before thetreatment.69,70 If there are areas of nodular or cres-centic, extrazonal or intrazonal, enhancing nodulartissue in close association with the ablated lesion,residual or recurrent HCC may be suspected.71

Initially, the Response Evaluation Criteria in SolidTumors (RECIST) guidelines were proposed for meas-uring the treatment response according to tumorshrinkage, and they have been widely accepted as avaluable tool for measuring the antitumor activity ofcytotoxic drugs. However, the conventional RECISTmethod, which takes into account only the overalldiameter of a nodule, can be misleading when it isapplied to HCC treated with either LRT or a systemictherapy such as sorafenib because treatment-inducedchanges in tissue viability often do not result in corre-sponding changes in the overall lesion size.72 Morerecently, a modified Response Evaluation Criteria inSolid Tumors (mRECIST) concept has been suggestedfor the evaluation of the treatment response inpatients with HCC.72 Further studies are needed toconfirm the validity of this concept.

Only well-delineated, arterially enhancing lesionscan be selected as target lesions for mRECIST. ThemRECIST concept for HCC includes the followingamendments to the RECIST guidelines for the deter-mination of the tumor response for target lesions72:

• Complete response: the disappearance of anyintratumoral arterial enhancement in all targetlesions.

• Partial response: at least a 30% decrease in thesum of the diameters of the viable target lesions(contrast enhancement in the arterial phase). Thebaseline sum of the diameters of the targetlesions is used as the reference.

• Progressive disease: at least a 20% increase inthe sum of the diameters of the viable (enhancing)target lesions. The smallest sum of the diametersof the viable (enhancing) target lesions recordedsince the initiation of the treatment is used as thereference.

• Stable disease: any cases not qualifying for a par-tial response or progressive disease. Persistent fatafter radiofrequency ablation in HCCs that con-tained fat before the treatment does not necessar-ily mean incomplete ablation.

Follow-up imaging with dynamic contrast-enhancedCT and MRI should be performed 1 to 3 months after


LRT to establish the need for further treatment.Although 1-month follow-up CT or MRI after LRT iswidely practiced at many centers, there are some diffi-culties in assessing the early tumor response, espe-cially before or at 1 month because of arteriovenousshunts.73,74 When lipiodol is used in conjunction withTACE, follow-up imaging with MRI may be preferablebecause the deposition of the extremely radiodensesubstance lipiodol may interfere with the CT evalua-tion of a marginal enhancement of the recurrenttumor after TACE. Lipiodol can, therefore, maskhypervascularity on CT imaging. Subtraction imagingmay be helpful in these cases. The intense andcomplete capture of lipiodol by the tumor tissue isassociated with extensive necrosis and is, therefore,considered by some to be a good prognostic factor. Inany case, the interpretation of post-LRT images ismade difficult by local alterations of the vasculatureand the perifocal inflammatory response incited bythe therapeutic procedures. Special expertise andexperience with the interpretation of such images are,therefore, critical.

For the best possible comparability of images, serialposttreatment imaging follow-up is ideally performedwith the same modality used to assess the presence ofthe tumor before or immediately after LRT.

Sorafenib, a multikinase inhibitor, was shown tosignificantly increase overall survival in a randomized,placebo-controlled, phase 3 trial of patients with HCC(the Sorafenib HCC Assessment Randomized Proto-col), and this was also confirmed in another prospec-tive trial from the Asia-Pacific region.75-77 Sorafenib iscurrently being tested in a randomized clinical trial asan adjuvant therapy for early and intermediate HCCstreated with surgical resection or LRT. If these trialsprovide positive results, sorafenib may become morewidely used as an adjuvant therapy for patients withHCC who are listed for LT and are undergoing LRT.78

This combined therapy could increase the risk of animaging misdiagnosis of a residual, locally treatedtumor and prevent the imaging characterization ofnew lesions.78 We can expect the sensitivity ofdynamic imaging techniques for HCC detection to bereduced in patients treated with the new antiangio-genic drugs because of their devascularizing effectson tumors, which can blunt or even suppress thearterial hypervascularity of HCC.79 Further studiesfor testing the ability of [18F]FDG PET/CT, perfusionCT, and diffusion-weighted MRI to improve the accu-racy of the radiological diagnosis and staging of HCCin patients undergoing antiangiogenic treatmentswould be worthwhile.80

Standardization of Surveillance for an Early

HCC Diagnosis in Patients Listed for LT

The early detection of HCC is of paramount impor-tance for making optimal treatment decisions, includ-ing LT prioritization and the selection of the mostsuitable LRT, for affected patients. As previously men-tioned, the diagnostic performance of US as a surveil-

lance test is rather poor because of limitations due toboth unfavorable patient characteristics and the nod-ular echo pattern of advanced cirrhosis in the liver.The drawbacks of US interfere with its ability to sur-vey the selected population of patients waiting forLT.58,81 The limited period of surveillance, the rela-tively low number of cases, and the high prognosticbenefit offered by LT make it advisable to survey non-HCC patients who are listed for LT with CT or, pref-erably, MRI at 6-month intervals.57 It should beremembered that all the imaging techniques have arelatively poor sensitivity for minute nodules, and asmany as 36% of synchronous HCC nodules that aredetected during the pathological examination of theexplant can be missed during the pre-LT imagingworkup.82 Even when state-of-the-art MDCT technol-ogy and carefully timed multiphase image acquisitionare used, as many as 11% of HCCs are missed, andthe sensitivity of CT falls to 43% if the typical radio-logical pattern is required for the diagnosis of HCC.42

Similarly, for tumors whose size is less than 2 cm, theMRI sensitivity falls to 85%, and conclusive resultsare achieved in only 62% of cases.10 It is apparentthat the diagnostic accuracy of all cross-sectionalimaging modalities for detecting HCC is poor inpatients with end-stage liver cirrhosis53,58,83; further-more, surveillance recommendations for patients withend-stage liver cirrhosis are very different from coun-try to country.44,84,85 A consensus on this topic couldnot be reached by the panelists. Therefore, furtherdata are needed; in particular, proof is required forwhich imaging modality is ideal for HCC surveillancein patients who are listed for LT because of severeliver dysfunction.

SUMMARY AND RECOMMENDATIONS

Dynamic and multiphasic contrast-enhanced CT orMRI is recommended as a first-line diagnostic tool forHCC when an imaging assessment for the presence ofHCC is indicated by screening or surveillance tests(level Ib, grade A).

For a given nodule in a cirrhotic liver, the presenceof hyperenhancement in the late arterial phase andthe subsequent washout of the contrast agent in theportal venous phase, delayed phase, or both are con-sidered diagnostic for HCC (level II, grade B).

HCC can be diagnosed by imaging if the nodule isgreater than 1 cm in diameter and these qualitativeimaging criteria are met (level II, grade B).

Patients who have nodules with an atypical patternof imaging findings (eg, an isovascular or hypovascu-lar appearance in the arterial phase or arterial hyper-vascularity alone without portal venous washout)should undergo image-guided FNB or follow-up imag-ing (level III, grade C).

Imagers should employ carefully timed multiphasiccontrast-enhanced imaging protocols on suitablehigh-quality scanners, and they should use a suffi-cient dose of the contrast agent, a sufficient injection


rate, and a suitable minimum slice thickness for thereconstructed images (level III, grade C).

A liver containing at least 1 HCC must be stagedwith an imaging technique that affords complete ana-tomic coverage of the liver. Dynamic and multiphasiccontrast-enhanced CT and MRI are the only accepta-ble imaging techniques for this purpose. Extrahepaticstaging should routinely include CT scans of thechest, abdomen, and pelvis. MRI can be an alternativefor the abdominal cavity (level III, grade C).

Complete tumor ablation after LRT for HCC may beindicated by a complete absence of contrast-enhanc-ing nodular tissue associated with the ablated lesion(any enhancement is evaluated in comparison withthe background hepatic parenchyma) on contrast-enhanced US, CT, or MRI images (level III, grade C).

Patients listed for LT without HCC should undergoserial imaging with CT or, preferably, MRI at 6-monthintervals to ensure that the tumor remains absent orthe tumor stage remains compatible with the trans-plant indication (level III, grade C).

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Imaging diagnosis and staging of hepatocellular carcinoma

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