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

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

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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, Italy b  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 Abstract We report a case of hepatocellular carcinoma superimposed on chronic hepatitis C virus (HCV) hepatitis in which final diagnosis of hepatocellular carcinoma was delayed because there was no consensus on hypervascularity with two diagnostic methods at the time of presentation. A 3cm lesion was initially observed as hypovascular at multidetector-row computed tomography. Conversely, two months laterthe lesion appeared hypervascular at contrast-ultrasonography and gadolinium-enhanced dynamic magnetic resonance, and hyperintense aftersuperparamagnetic iron oxide-enhanced T2W studies. Only in the late follow-up it was definitively confirmed as hypervascular in the arterialphase of multidetector-row computed tomography.This case clearly highlights some pitfalls in the European Association for the study of the liver guidelines for hepatocellular carcinomamanagement, which were readdressed in the last American Association for the Study of Liver Diseases (AASLD) and in the forthcominginternational proposals, leading to more pragmatic suggestions for clinical practice.© 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords:  Contrast media; Diagnosis; Guidelines; Hepatocellular carcinoma; Liver; Magnetic resonance imaging 1. Introduction Arterial hypervascularisation at contrast-enhanced imag-ingofalesiondetectedinacirrhoticliveriscurrentlyregardedas a hallmark of hepatocellular carcinoma (HCC) becausenon-neoplastic and pre-neoplastic nodules still have a preva-lent portal vascularity [1,2]. Many of these pre-neoplastic lesions with uncertain malignant potential, such as macrore-generative nodules, low-grade dysplastic nodules (LGDN)or high-grade dysplastic nodules (HGDN) can be found inup to 42% of cases in explanted livers and may progressto a classic hypervascular HCC [3–7]. During malignant transformation, the intranodal portal venous supply gradu- ∗ Corresponding author at: Department of Radiology, Sant’Orsola-Malpighi Hospital, Via Albertoni 15, 40138 Bologna, Italy.Tel.: +39 051 6362303.  E-mail address: (R. Golfieri). ally decreases, whereas the arterial supply increases parallelto the nodule’s increasing grade of malignancy.As a marker of malignancy, the European Association forthe Study of the Liver (EASL) document for the clinicalmanagement of HCC [8] only takes into account hypervas- cularisation observed during the arterial phase of a triphasiccomputed tomography (CT), magnetic resonance (MR) scanor angiogram. In particular, for new nodules larger than 2cmdetectedinacirrhoticliverduringasurveillanceprogramme,the arterial hypervascular pattern confirmed by at least twoimaging techniques, even in the absence of a diagnostic( ≥ 400ng/mL) rise in   -fetoprotein (AFP), was suggestedas a suitable criterion for diagnosis of HCC. More recently,a second hallmark of malignancy, the ‘washout’ pattern inthe portal venous phase of a triphasic CT and MR scan, wasfound to be common in HCC [9].WedescribeacaseofHCCsuperimposedonchronicHCVhepatitis in which the final diagnosis of HCC was delayed 1590-8658/$30 © 2006 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.doi:10.1016/j.dld.2006.09.002  884  R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890 since two diagnostic imaging methods failed to display thesame hypervascular pattern at the time of its presentation.ThiscaseclearlyhighlightssomepitfallsoftheEASLguide-lines for HCC management, which have been readdressed inthe last AASLD proposals [10], leading to more modern and pragmatic suggestions for clinical practice. 2. Case report A 39-year-old woman with a history of breast fibroade-noma treated by nodulectomy at the age of 16 years wasadmitted to the gynaecology unit of our hospital for resec-tion of an ovarian cyst in February 2003. On that occasion,hepatitis-C antibody positivity was discovered. Liver testswere normal and a hepatic ultrasonography (US) did notshow focal lesions. Although the patient belonged to a cate-gory of infected patients at low risk of HCC occurrence [10],her referring physician started a surveillance programme forHCC with annual US and AFP monitoring.In February 2004, US disclosed a new 3.3cm × 2.5cmhypoechoic lesion in segment VIII of the liver suspected tobe a nodule of focal nodular hyperplasia (FNH). The AFPvalue was normal (2ng/mL). The patient refused to undergoaliverbiopsyandthereforeathree-monthimagingfollow-upwas 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, in the cephalic portion of segment VIII appearing isodense inthe pre-contrast and post-contrast arterial phases, becominghypodense with a peripheral rim enhancement in the por-tal and delayed phases. Based on this pattern, a metastasiswas suspected. On that occasion, the patient momentarilydeclined further investigations.In September 2004, an  abdominal Doppler-US  (Fig. 2)confirmed the nodular lesion, unchanged in size, with a‘spider-like’ vascular pattern, high frequency arterial sig-nal and normal resistive index (RI) at Doppler examination.In contrast-enhanced (Sonovue ® , Bracco, Italy) US  (CE-US)  examination a vascular enhancement in both the arterial(within 20s) and portal venous phases was detected. Thiswasthefirst demonstration of arterial hypervascularity of thelesion, but the vascular pattern was atypical for either metas-tasis or HCC. Fig. 1. First MD-CT examination (  June 2004 ) in arterial (a), portal venous (b) and delayed phases (c) after bolus injection showing the hypovascular lesionin segment VIII as isodense in the arterial phase, becoming centrally hypodense with a peripheral rim enhancement in the portal and delayed phase (b, c): ametastasis-like appearance.   R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890  885Fig. 2. The US-Doppler study of the liver ( September 2004 ) confirms the 3.3cm hypoechoic nodule with high frequency arterial signal and normal RI (a), witha ‘spider-like’ vascular pattern and enhancement at CE-US examination after Sonovue ® injection in the arterial phase (b) and in the portal venous phase (c). Due to the confounding findings of Doppler-US, CE-US and their discrepancy with the previous CT pattern of the lesion, a  double-contrast hepatic magnetic resonanceimaging (MRI)  examination was performed disclosing thefollowing 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-uencesacquired10minand20minafterSPIOi.v.admin-istration, thus indicating the absence of Kupffer cells.(b) Asignificantcontrast-enhancementwasseeninGRE3DT1-weighted dynamic multiphase gadolinium-enhancedimagesduringthearterialphase,andawash-outinportaland delayed venous phases with a thin rim of peripheralenhancement.These findings were considered to be highly suspiciousfor HCC. However, they could not be considered diagnos-  886  R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890 Fig.3. DoublecontrastMRI( September2004 ):FS-FSET2-weightedsequences20  (a)afteri.v.administrationofResovist ® ,showingthelesionashyperintensedue to absent Kupffer cell uptake of SPIO. GRE 3D T1-weighted images obtained after gadolinium-based contrast media: significant contrast enhancement inthe arterial phase (b) with a rapid ‘wash-out’ in the portal venous phase (c). Typical appearance for HCC. tic since the patient did not have established liver cirrhosis[8,10].Therefore, a US-guided fine needle biopsy (FNB) wasperformed demonstrating moderately active chronic hepati-tis with bridging fibrosis, without malignant hepatocytes. Afalse negative result was suspected, and a second biopsy wasproposed to the patient who refused the procedure. A strin-gent follow-up was then planned.In November 2004, AFP was still normal (2ng/mL). Asecond MD-CT (CTSomatomSensation16slices,Siemens,Erlangen, Germany) showed that the lesion, unchanged insize,hadaradicallymodifiedvascularpatternwithrespecttotheMD-CTperformedinJune.Aftercontrastmediumadmin-istration, a clear enhancement was evident in the arterialphase with a rapid wash out in the portal venous and delayedphases, together with an irregular hyperattenuating capsule.These features were considered typical of HCC (Fig. 4).At that time, the hypervascularity of the nodule was tes-tified by three imaging techniques. Although the patient hadchronichepatitis,wejudgedthesecoincidentfindingsascom-pelling evidence of malignancy, and the lesion was treatedas HCC. Hence, in December 2004 the patient underwent ahepaticresection,confirmingthe3cmlesioninsegmentVIII.The histological examination of the surgical specimen estab-lished an Edmondson–Steiner grade 3 HCC overimposed ona mild degree of chronic hepatitis. 3. Discussion Minute HCCs ( ≤ 2cm) are divided into two categories,distinctly and indistinctly nodular [10,11]. The ‘distinctly nodular’ type is well-demarcated and often encapsulated(more than 50%), frequently detected as a hypervascularnodule. The ‘indistinctly nodular’ type is vaguely nodularand retains the basic architecture of the background cirrhoticliver: they are very well-differentiated cancers with mildcellular atypia. Microvascular invasion is very uncommonand intrahepatic metastases are not observed (‘carcinoma insitu’). These tumours are detected as clear nodular lesions   R. Golfieri et al. / Digestive and Liver Disease 39 (2007) 883–890  887Fig. 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 phaseenhancement better depicts the arterial hypervascularity of the lesion (c). on US but generally are not displayed as hypervascular nod-ules because the intranodal blood supply shifts from beingprimarily portal to being hepatic arterial in proportion to therising grade of malignancy. In Japan, the indistinctly nodulartype is considered the true ‘early HCC’ – also named ‘veryearly HCC’ – and its histological features are very similar tothose of HGDN.Theintermediatelesions,i.e.HGDN,earlyHCCandwell-differentiated HCC (Edmondson–Steiner grade 1), representa ‘grey area’ of malignant transformation in which the imag-ing features based on arterial hypervascularity can be mis-leading, since some HGDN may appear hypervascular andsome early well differentiated HCC hypovascular [7,10–12].A recent investigation, focused on small HCC nodules [13],demonstrated that arterial hypovascularity in HCC dependson lesion size: a hypovascular pattern was reported in 8.3%of small ( ≤ 3cm) HCCs, rising to 17% in the subgroup witha diameter between 1cm and 2cm.We report a case of a 3cm HCC that showed a hypervas-cular pattern at CE-US study in  both the arterial and portalvenous phases , a finding non-coincident with: (a) the arte-rial hypovascularity seen at a previous MD-CT; (b) evenmore confounding, an arterial wash in and a portal washout detected at concomitant gadolinium-enhanced DynamicMRI. The latter procedure, performed with double contrast,disclosed a hyperintense pattern in the SPIO-enhanced T2-weighted sequence.ThefirstdiscrepancycanbeattributabletothetimeelapsedbetweenthefirstMD-TCandthesubsequentimaginginvesti-gations, during which the lesion remained unchanged in sizebut became hypervascular. The progression of hypovascularHCCs to hypervascular nodules at follow-up dynamic CThas been reported to occur in a mean time of 726 days (range208–2728), with the shortest time for nodules larger than15mm [29,30] and with partially absent portal venous sup- ply, as demonstrated at CT during arterial portography [31].
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