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Digestive and Liver Disease 39 (2007) 883–890

Brief Clinical Observation

Malignant progression of a small HCC nodule: Hypovascular ‘earlyHCC’ converted to hypervascular ‘small HCC’ within six months

R. Golfieri a,∗, F. Coppola a, F. Fusco a, S. Li Bassi b, P. Caraceni b, M. Bernardi b, F. Trevisani b

a Department of Radiology, Sant’Orsola-Malpighi Hospital, University of Bologna, Italyb Department of Internal Medicine Cardioangiology Hepatology, Sant’Orsola-Malpighi Hospital, University of Bologna, Italy

Received 24 February 2006; accepted 5 September 2006Available online 12 October 2006

bstract

We report a case of hepatocellular carcinoma superimposed on chronic hepatitis C virus (HCV) hepatitis in which final diagnosis ofepatocellular carcinoma was delayed because there was no consensus on hypervascularity with two diagnostic methods at the time ofresentation. A 3 cm lesion was initially observed as hypovascular at multidetector-row computed tomography. Conversely, two months laterhe lesion appeared hypervascular at contrast-ultrasonography and gadolinium-enhanced dynamic magnetic resonance, and hyperintense afteruperparamagnetic iron oxide-enhanced T2W studies. Only in the late follow-up it was definitively confirmed as hypervascular in the arterialhase of multidetector-row computed tomography.

This case clearly highlights some pitfalls in the European Association for the study of the liver guidelines for hepatocellular carcinoma

anagement, which were readdressed in the last American Association for the Study of Liver Diseases (AASLD) and in the forthcoming

nternational proposals, leading to more pragmatic suggestions for clinical practice.2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

eywords: Contrast media; Diagnosis; Guidelines; Hepatocellular carcinoma; Liver; Magnetic resonance imaging

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. Introduction

Arterial hypervascularisation at contrast-enhanced imag-ng of a lesion detected in a cirrhotic liver is currently regardeds a hallmark of hepatocellular carcinoma (HCC) becauseon-neoplastic and pre-neoplastic nodules still have a preva-ent portal vascularity [1,2]. Many of these pre-neoplasticesions with uncertain malignant potential, such as macrore-enerative nodules, low-grade dysplastic nodules (LGDN)r high-grade dysplastic nodules (HGDN) can be found in

p to 42% of cases in explanted livers and may progresso a classic hypervascular HCC [3–7]. During malignantransformation, the intranodal portal venous supply gradu-

∗ Corresponding author at: Department of Radiology, Sant’Orsola-alpighi Hospital, Via Albertoni 15, 40138 Bologna, Italy.

el.: +39 051 6362303.E-mail address: golfieri@aosp.bo.it (R. Golfieri).

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590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elseoi:10.1016/j.dld.2006.09.002

lly decreases, whereas the arterial supply increases parallelo the nodule’s increasing grade of malignancy.

As a marker of malignancy, the European Association forhe Study of the Liver (EASL) document for the clinical

anagement of HCC [8] only takes into account hypervas-ularisation observed during the arterial phase of a triphasicomputed tomography (CT), magnetic resonance (MR) scanr angiogram. In particular, for new nodules larger than 2 cmetected in a cirrhotic liver during a surveillance programme,he arterial hypervascular pattern confirmed by at least twomaging techniques, even in the absence of a diagnostic≥400 ng/mL) rise in �-fetoprotein (AFP), was suggesteds a suitable criterion for diagnosis of HCC. More recently,second hallmark of malignancy, the ‘washout’ pattern in

he portal venous phase of a triphasic CT and MR scan, wasound to be common in HCC [9].

We describe a case of HCC superimposed on chronic HCVepatitis in which the final diagnosis of HCC was delayed

vier Ltd. All rights reserved.

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ince two diagnostic imaging methods failed to display theame hypervascular pattern at the time of its presentation.his case clearly highlights some pitfalls of the EASL guide-

ines for HCC management, which have been readdressed inhe last AASLD proposals [10], leading to more modern andragmatic suggestions for clinical practice.

. Case report

A 39-year-old woman with a history of breast fibroade-oma treated by nodulectomy at the age of 16 years wasdmitted to the gynaecology unit of our hospital for resec-ion of an ovarian cyst in February 2003. On that occasion,epatitis-C antibody positivity was discovered. Liver testsere normal and a hepatic ultrasonography (US) did not

how focal lesions. Although the patient belonged to a cate-ory of infected patients at low risk of HCC occurrence [10],

er referring physician started a surveillance programme forCC with annual US and AFP monitoring.In February 2004, US disclosed a new 3.3 cm × 2.5 cm

ypoechoic lesion in segment VIII of the liver suspected to

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ig. 1. First MD-CT examination (June 2004) in arterial (a), portal venous (b) andn segment VIII as isodense in the arterial phase, becoming centrally hypodense w

etastasis-like appearance.

Disease 39 (2007) 883–890

e a nodule of focal nodular hyperplasia (FNH). The AFPalue was normal (2 ng/mL). The patient refused to undergoliver biopsy and therefore a three-month imaging follow-upas recommended and the patient was referred to our Unit.In June 2004, a multidetector-row CT (MD-CT) scan

Fig. 1) confirmed the nodular lesion, unchanged in size, inhe cephalic portion of segment VIII appearing isodense inhe pre-contrast and post-contrast arterial phases, becomingypodense with a peripheral rim enhancement in the por-al and delayed phases. Based on this pattern, a metastasisas suspected. On that occasion, the patient momentarilyeclined further investigations.

In September 2004, an abdominal Doppler-US (Fig. 2)onfirmed the nodular lesion, unchanged in size, with aspider-like’ vascular pattern, high frequency arterial sig-al and normal resistive index (RI) at Doppler examination.n contrast-enhanced (Sonovue®, Bracco, Italy) US (CE-S) examination a vascular enhancement in both the arterial

within 20 s) and portal venous phases was detected. Thisas the first demonstration of arterial hypervascularity of the

esion, but the vascular pattern was atypical for either metas-asis or HCC.

delayed phases (c) after bolus injection showing the hypovascular lesionith a peripheral rim enhancement in the portal and delayed phase (b, c): a

R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890 885

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ig. 2. The US-Doppler study of the liver (September 2004) confirms the 3.3‘spider-like’ vascular pattern and enhancement at CE-US examination afte

Due to the confounding findings of Doppler-US, CE-S and their discrepancy with the previous CT pattern of

he lesion, a double-contrast hepatic magnetic resonancemaging (MRI) examination was performed disclosing theollowing features (Fig. 3):

(a) The lesion did not show uptake of superparamagneticiron oxide (SPIO) contrast agent (Ferucarbotran, Reso-vist®, Shering, Germany) appearing homogeneouslyhyperintense in fast spin echo (FSE) T2-weighted seq- f

poechoic nodule with high frequency arterial signal and normal RI (a), withvue® injection in the arterial phase (b) and in the portal venous phase (c).

uences acquired 10 min and 20 min after SPIO i.v. admin-istration, thus indicating the absence of Kupffer cells.

b) A significant contrast-enhancement was seen in GRE 3DT1-weighted dynamic multiphase gadolinium-enhancedimages during the arterial phase, and a wash-out in portaland delayed venous phases with a thin rim of peripheral

enhancement.

These findings were considered to be highly suspiciousor HCC. However, they could not be considered diagnos-

886 R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890

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ig. 3. Double contrast MRI (September 2004): FS-FSE T2-weighted sequenue to absent Kupffer cell uptake of SPIO. GRE 3D T1-weighted images obhe arterial phase (b) with a rapid ‘wash-out’ in the portal venous phase (c).

ic since the patient did not have established liver cirrhosis8,10].

Therefore, a US-guided fine needle biopsy (FNB) waserformed demonstrating moderately active chronic hepati-is with bridging fibrosis, without malignant hepatocytes. Aalse negative result was suspected, and a second biopsy wasroposed to the patient who refused the procedure. A strin-ent follow-up was then planned.

In November 2004, AFP was still normal (2 ng/mL). Aecond MD-CT (CT Somatom Sensation 16 slices, Siemens,rlangen, Germany) showed that the lesion, unchanged inize, had a radically modified vascular pattern with respect tohe MD-CT performed in June. After contrast medium admin-stration, a clear enhancement was evident in the arterialhase with a rapid wash out in the portal venous and delayedhases, together with an irregular hyperattenuating capsule.

hese features were considered typical of HCC (Fig. 4).

At that time, the hypervascularity of the nodule was tes-ified by three imaging techniques. Although the patient hadhronic hepatitis, we judged these coincident findings as com-

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(a) after i.v. administration of Resovist®, showing the lesion as hyperintensefter gadolinium-based contrast media: significant contrast enhancement in

l appearance for HCC.

elling evidence of malignancy, and the lesion was treateds HCC. Hence, in December 2004 the patient underwent aepatic resection, confirming the 3 cm lesion in segment VIII.he histological examination of the surgical specimen estab-

ished an Edmondson–Steiner grade 3 HCC overimposed onmild degree of chronic hepatitis.

. Discussion

Minute HCCs (≤2 cm) are divided into two categories,istinctly and indistinctly nodular [10,11]. The ‘distinctlyodular’ type is well-demarcated and often encapsulatedmore than 50%), frequently detected as a hypervascularodule. The ‘indistinctly nodular’ type is vaguely nodularnd retains the basic architecture of the background cirrhotic

iver: they are very well-differentiated cancers with mildellular atypia. Microvascular invasion is very uncommonnd intrahepatic metastases are not observed (‘carcinoma initu’). These tumours are detected as clear nodular lesions

R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890 887

Fig. 4. Second post-contrast MD-CT study (November 2004) confirming the lesion as being a HCC, with a hyperdense pattern during the arterial phase,surrounded by a vascular rim (a), with a rapid wash-out in the portal venous (b); the volume rendering 3D vascular reconstruction during arterial phasee

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nhancement better depicts the arterial hypervascularity of the lesion (c).

n US but generally are not displayed as hypervascular nod-les because the intranodal blood supply shifts from beingrimarily portal to being hepatic arterial in proportion to theising grade of malignancy. In Japan, the indistinctly nodularype is considered the true ‘early HCC’ – also named ‘veryarly HCC’ – and its histological features are very similar tohose of HGDN.

The intermediate lesions, i.e. HGDN, early HCC and well-ifferentiated HCC (Edmondson–Steiner grade 1), represent‘grey area’ of malignant transformation in which the imag-

ng features based on arterial hypervascularity can be mis-eading, since some HGDN may appear hypervascular andome early well differentiated HCC hypovascular [7,10–12].

recent investigation, focused on small HCC nodules [13],

emonstrated that arterial hypovascularity in HCC dependsn lesion size: a hypovascular pattern was reported in 8.3%f small (≤3 cm) HCCs, rising to 17% in the subgroup withdiameter between 1 cm and 2 cm.

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We report a case of a 3 cm HCC that showed a hypervas-ular pattern at CE-US study in both the arterial and portalenous phases, a finding non-coincident with: (a) the arte-ial hypovascularity seen at a previous MD-CT; (b) evenore confounding, an arterial wash in and a portal wash

ut detected at concomitant gadolinium-enhanced DynamicRI. The latter procedure, performed with double contrast,

isclosed a hyperintense pattern in the SPIO-enhanced T2-eighted sequence.The first discrepancy can be attributable to the time elapsed

etween the first MD-TC and the subsequent imaging investi-ations, during which the lesion remained unchanged in sizeut became hypervascular. The progression of hypovascularCCs to hypervascular nodules at follow-up dynamic CT

as been reported to occur in a mean time of 726 days (range08–2728), with the shortest time for nodules larger than5 mm [29,30] and with partially absent portal venous sup-ly, as demonstrated at CT during arterial portography [31].

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he rapid hypervascular transformation seen in our case (over80 days) fits with this information.

The arterial hypervascularity and the portal wash out atmaging are signs of the neoangiogenetic process, with aecrease in the number of portal tracts and the developmentf intratumoural arterioles as small HCC become increas-ngly de-differentiated [32]. Therefore, even with unchangedize, a well-differentiated nodule can develop a shift in bloodupply with a parallel increase in neoangiogenesis while pro-ressively de-differentiating to a higher Edmondson–Steinerrade. In the present case, the different patterns observed inhe two MD-CT performed five months apart testify to theevelopment of a neoangiogenetic process in a nodule whichventually proved to be an Edmondson grade 3 HCC. By con-rast, fatty changes within an early well-differentiated HCCwhose prevalence is about 40% in size 1–1.5 cm and 15% in–3 cm lesions) and lack of capillarisation could have deter-ined the hypodense pattern at the first MD-CT examination

11].Therefore, in the present case we involuntarily witnessed

he malignant progression of an HCC nodule appearing like avery early HCC’ (despite a size >2 cm) at the first two obser-ations to a ‘small HCC’ with typical vascular appearance athe time of the final double contrast MRI and MD-CT study.

The second discrepancy, between the results seen in theortal phase of the concomitant CE-US and gadolinium-nhanced MRI, is less trivial and may have resulted fromhe more operator-dependent nature of US investigation.

Given the conflicting results, an FNB was performed andid not disclose malignancy. This procedure is reported toave an excellent specificity (100%) and a 75–90% sensitiv-ty in nodules ≤3 cm [14–17]. A false negative result of FNBf lesions >3 cm is rarely due to incorrect needle targeting,articularly when the nodule is located in a liver section easyo reach, as was the case of our patient (Fig. 2). More likely,t can be due to the difficulty in identifying the pathologicaleatures of early or ‘very early’ HCC which may have a non-niform distribution of the subtle malignant characteristicsithin the tumour mass [10,11]. Therefore, as clearly stated

n all guidelines [8,10], a negative examination of biopsypecimens does not exclude malignancy and can never beaken as conclusive [18,19]. The combination of an intran-dular and extranodular biopsy has been found to improve theiagnostic accuracy of the procedure from 54% to 84% [28]ut this technique also increases the risk of the manoeuvre,nd is neither ordinarily performed in clinical practice nor ist considered mandatory. The second biopsy we proposed tour patient after the first negative result would probably haveeen useful, but she declined the procedure.

Our case triggers a discussion on the appropriateness ofhe diagnostic workup proposed by the EASL guidelines [8]ecommending that the diagnosis of HCC be made with-

ut biopsy in patients who have a nodule >2 cm that showshe characteristic arterial hypervascularity on two imaging

odalities including CT, MRI and angiography, but consid-ring neither CE-US technique nor the vascular pattern of

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Disease 39 (2007) 883–890

he portal phase. In the present case these criteria delayed thenal diagnosis, and its history stimulates the clinician to pose

wo questions challenging the EASL recommendations: (1)hould the finding of hypervascularity with only one tech-ique be regarded as a false-positive result or be considered aentinel of malignancy? (2) should the wash out of the nodulen portal and delayed phases be taken into account to state

alignancy? The first question was recently addressed byolondi et al. [13] who showed that nodules between 1 cmnd 3 cm with a discordant pattern of arterial hypervascularityurned out to be HCC in the vast majority of cases, the rem-ants being macronodules committed to HCC development.s far as the second question is concerned, recent evidenceas been provided that a rapid wash out should be consideredhe second sign of malignancy for hepatic nodules [9].

Accordingly, the AASLD Practice Guidelines 2005 [10]equire only a single imaging modality – chosen among CE-S, dynamic CT or MRI – for diagnosis of malignancy in

esions >2 cm occurring in cirrhotic liver, provided that ithows both arterial hypervascularity in the arterial phase andash out in the portal or delayed venous phase. This can beemonstrated on triphasic CT scan with a lesion sensitivity of2–100% [20–23] or MRI with gadolinium injection with anven higher sensitivities, approaching 100% [22,24,25]. Onhe contrary, for lesions between 1 cm and 2 cm these guide-ines confirm the requirement of two coincidental findings ofrterial hypervascularity be maintained.

Another interesting question is whether, after a dynamicadolinium-enhanced MR positivity for arterial hypervas-ularity, the SPIO-MRI should be considered the secondmaging modality. In other words, should the finding of absentptake of RES-specific SPIO contrast agent be considered aecond proof of malignancy? For nodules ranging betweencm and 2 cm a sensitivity around 90% has been reported

or double contrast MRI [26,27], a figure much higher thanhose reported (56–80%) for dynamic MRI alone [21,22,24].

In the present case, the characteristics of the nodule atRI demonstrating both arterial hypervascularity and wash

ut in portal and delayed phases fully satisfied the AASLD005 guidelines, where a single imaging technique with aypical finding is required for the diagnosis of HCC. Hadhe new guidelines been applied, the definitive diagnosis ofCC could have been established with no need for further

onfirmation by FNB and a second MD-CT.Moreover, the coincidental positivities of double con-

rast MRI – i.e. the hyperintensity on T2W images afterPIO enhancement plus the hypervascularity in the arterialhase of gadolinium-enhanced 3D-MR – could be consid-red sufficient for diagnosis of malignancy even in lesions2 cm, especially when preceded by a positive CE-US. How-ver, further investigations are warranted to confirm ouruggestion.

Last but not least, our patient did not have an establishedirrhosis. Therefore, the application of the available guide-ines for cirrhosis may be considered inappropriate as her ‘ariori’ probability of developing an HCC was lower than that

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f cirrhotic patients. Pragmatically, this would imply that theature of any hepatic nodule appearing in a pre-cirrhotic liverhould be characterized exclusively by histology. However,his is not always possible in clinical practice since, in someases, the nodule is located in a position difficult to reach, andther patients may refuse the biopsy or, as in our case, its rep-tition after a negative result. In these cases, the physician isrompted to utilise the imaging work up and the accepted cri-eria to define the nature of the nodule in a setting – cirrhosisquite close to that of his/her patient.In conclusion, this case report highlights some still

ebated issues concerning the diagnosis of HCC:

The new AASLD guidelines are more appropriate for thepractical work-up of atypical cases like our patient. How-ever, there is still a need to review the correct sequenceof imaging methods for the diagnosis of HCC. In particu-lar, MD-CT has a lower sensitivity than dynamic MRI indetecting early arterial hypervascularisation, so that thesetwo imaging methods should not be considered equivalent[20–27].When a histological confirmation is needed, a single neg-ative FNB is not reliable when its result is discordant witha positive imaging finding (obtained with MR, CE-US orCT). In this case, AASLD guidelines recommend either animaging follow-up or to repeat biopsy.Double contrast MRI is an emerging single step imagingmethod which might replace the need for two coinciden-tal methods depicting hypervascularity in HCCs <2 cm.Prospective studies are needed to validate its diagnosticaccuracy in establishing the nature of a small developingnodule in a cirrhotic liver.

onflict of interest statementone declared.

eferences

[1] Sakamoto M, Hirohashi S. Natural history and prognosis of adenoma-tous hyperplasia and early hepatocellular carcinoma: multi-institutionalanalysis of 53 nodules followed up for more than six months and142 patients with single early hepatocellular carcinoma treated by sur-gical resection or percutaneous ethanol injection. Jpn J Clin Oncol1998;28:604–8.

[2] Nakashima Y, Nakashima O, Hsia C, Kojiro M, Tabor E. Vasculariza-tion of small hepatocellular carcinoma: correlation with differentiation.Liver 1999;19:12–8.

[3] International Working Party. Terminology of nodular hepatocellularlesions. Hepatology 1995;22:983–9.

[4] Theise N, Schwartz M, Miller C, Thung S. Macroregenerative nod-ules and hepatocellular carcinoma in forty-four sequential adult liverexplants with cirrhosis. Hepatology 1992;16:949–55.

[5] Mion F, Grozel L, Boillot O, Paliard P, Berger F. Adult cirrhotic liverexplants: precancerous lesions and undetected small hepatocellular car-cinomas. Gastroenterology 1996;111:1587–92.

[6] Burrel M, Llovet J, Ayuso C, Iglesias C, Sala M, Miquel R, et al.MRI angiography is superior to helical CT for detection of HCC prior

[

[

Disease 39 (2007) 883–890 889

to liver transplantation: an explant correlation. Hepatology 2003;38:1034–42.

[7] Hayashi M, Matsui O, Ueda K, Kawamori Y, Gabata T, Kadoya M. Pro-gression to hypervascular hepatocellular carcinoma: correlation withintranodular blood supply evaluated with CT during intraarterial injec-tion of contrast material. Radiology 2002;225:143–9.

[8] Bruix J, Sherman M, Llovet J, Beaugrand M, Lencioni R, BurroughsA, et al. Clinical management of hepatocellular carcinoma. Conclu-sions of the Barcelona-2000 EASL conference. J Hepatol 2001;35:421–30.

[9] Marrero JA, Hussain HK, Nghiem HV, Umar R, Fontana RJ, LokAS. Improving the prediction of hepatocellular carcinoma in cir-rhotic patients with an arterially-enhancing liver mass. Liver Transpl2005;11:281–9.

10] Bruix J, Sherman M. Management of hepatocellular carcinoma.AASLD practice guidelines. Hepatology 2005;42:1208–35.

11] Kojiro M. Focus on dysplastic nodules and early hepatocellular carci-noma: an Eastern point of view. Liver Transpl 2004;10(Suppl. 1):S3–8.

12] Matsui O, Kadoya M, Kameyama T, Yoshikawa J, Takashima T,Nakanuma Y, et al. Benign and malignant nodules in cirrhotic livers:distinction based on blood supply. Radiology 1991;178:493–7.

13] Bolondi L, Gaiani S, Celli N, Golfieri R, Grigioni WF, Leoni S, etal. Characterization of small nodules in cirrhosis by assessment ofvascularity: the problem of hypovascular hepatocellular carcinoma.Hepatology 2005;42:27–34.

14] Bret PM, Labadie M, Bretagnolle M, Paliard P, Fond A, Valette PJ. Hep-atocellular carcinoma: diagnosis by percutaneous fine needle biopsy.Gastrointest Radiol 1988;13:253–5.

15] Sbolli G, Fornari F, Civardi G, Di Stasi M, Cavanna L, Buscarini E,et al. Role of ultrasound guided fine needle aspiration biopsy in thediagnosis of hepatocellular carcinoma. Gut 1990;31:1303–5.

16] Longchampt E, Patriarche C, Fabre M. Accuracy of cytology vs. micro-biopsy for the diagnosis of well-differentiated hepatocellular carcinomaand macroregenerative nodule. Definition of standardized criteria froma study of 100 cases. Acta Cytol 2000;44:515–23.

17] Fornari F, Filice C, Rapaccini GL, Caturelli E, Cavanna L, CivardiG, et al. Small (< or =3 cm) hepatic lesions. Results of sono-graphically guided fine-needle biopsy in 385 patients. Dig Dis Sci1994;39:2267–75.

18] Durand F, Regimbeau JM, Belghiti J, Sauvanet A, Vilgrain V, Ter-ris B, et al. Assessment of the benefits and risks of percutaneousbiopsy before surgical resection of hepatocellular carcinoma. J Hep-atol 2001;35:254–8.

19] Rapaccini G, Pompili M, Caturelli E. Focal ultrasound lesions in livercirrhosis diagnosed as regenerating nodules by fine needle biopsy:follow-up of 12 cases. Dig Dis Sci 1990;35:422–7.

20] Noguchi Y. Detection of hepatocellular carcinoma: comparison ofdynamic MR imaging with dynamic double arterial phase helical CT.Am J Roentgenol 2003;80:455–60.

21] Rode A, Bancel B, Douek P, Chevallier M, Vilgrain V, Picaud G, et al.Small nodule detection in cirrhotic livers: evaluation with US, spiralCT, and MRI and correlation with pathologic examination of explantedliver. J Comput Assist Tomogr 2001;25:327–36.

22] De Ledinghen V, Laharie D, Lecesne R, Le Bail B, Winnock M,Bernard PH, et al. Detection of nodules in liver cirrhosis: spiral com-puted tomography or magnetic resonance imaging? A prospective studyof 88 nodules in 34 patients. Eur J Gastroenterol Hepatol 2002;14:159–65.

23] Valls C, Cos M, Figueras J, Andia E, Ramos E, Sanchez A, et al. Pre-transplantation diagnosis and staging of hepatocellular carcinoma inpatients with cirrhosis: value of dual-phase helical CT. Am J Roentgenol2004;182:1011–7.

24] Krinsky GA, Lee VS, Theise ND, Weinreb JC, Morgan GR, Diflo T, etal. Transplantation for hepatocellular carcinoma and cirrhosis: sensi-tivity of magnetic resonance imaging. Liver Transpl 2002;8:1156–64.

25] Colli A, Fraquelli M, Casazza G, Massironi S, Colucci A, Conte D,et al. Accuracy of ultrasonography, spiral CT, magnetic resonance, and

8 nd Liver

[

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[

[

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90 R. Golfieri et al. / Digestive a

alpha-fetoprotein in diagnosing hepatocellular carcinoma: a systematicreview. Am J Gastroenterol 2006;101:513–23.

26] Ward J, Guthrie J, Scott D, Atchley J, Wilson D, Davies M. Hepatocel-lular carcinoma in the cirrhotic liver: double-contrast MR imaging fordiagnosis. Radiology 2000;216:154–62.

27] Bhartia B, Ward J, Guthrie J, Robinson P. Hepatocellular carci-noma in cirrhotic livers: double-contrast thin-section MR imagingwith pathologic correlation of explanted tissue. Am J Roentgenol2003;180:577–84.

28] Borzio M, Borzio F, Macchi R, Croce AM, Bruno S, Ferrari A, et al.The evaluation of fine needle procedures for the diagnosis of focal liverlesions in cirrhosis. J Hepatol 1994;20:117–21.

29] Jin E, Ichikawa T, Nakajima H, Araki T, Kitamura T. Follow-updynamic CT study for hypovascular nodules in patients with cir-

[

Disease 39 (2007) 883–890

rhotic liver. Nippon Igaku Hoshasen Gakkai Zasshi 2004;64:127–31.

30] Ishikawa M, Sasaki K, Chikaishi H, Miyauchi T, Fukuda Y, MiyakeH, et al. A case of adenomatous hyperplasia in the liver with chronichepatitis C that transformed into hepatocellular carcinoma. Hepatol Res2002;24:316.

31] Hayashi M, Matsui O, Ueda K, Kawamori Y, Gabata T, KadoyaM. Progression to hypervascular hepatocellular carcinoma: corre-lation with intranodular blood supply evaluated with CT during

intraarterial injection of contrast material. Radiology 2002;225:143–9.

32] Nakashima Y, Nakashima O, Hsia CC, Kojiro M, Tabor E. Vascular-ization of small hepatocellular carcinomas: correlation with differenti-ation. Liver 1999;19:12–8.