Evangelos Chartampilas Bioclinic Hospital Thessaloniki, Greece
Hepatospecific contrast agents Gadobenate dimeglumine Gadoxetic acid (Primovist) (Multihance) 3-5% liver uptake 50% liver uptake Hepatobiliary phase: 2h Hepatobiliary phase: 20min Transported via MOAT Transported via OATP(B1,B3) Relaxivity r1 : 6,3 [l mmol -1 s] Relaxivity r1: 6,9 [l mmol -1 s] Dosage: 0.1 mmol/kg (0.2 mL/kg) Dosage:0.025 mmol/kg (0.1 mL/kg) � MOAT: multispecific organic anion transporter � OATP: organic anion transporting polypeptides
Transport mechanism for Gd-EOB-DTPA Choi Y, BJR 2015
Uses of hepatospecific contrast agents � As they are taken up by functioning hepatocytes (and then excreted in the bile), they can be used to: Evaluate liver function 1. In cirrhosis, fibrosis and reduced number of functioning � hepatocytes decrease contrast uptake Identify early hepatocellular carcinoma (HCC) 2. During hepatocarcinogenesis, the ability to take up the � contrast is gradually lost To differentiate FNH from adenoma 3. To depict the biliary tree (eg possible leaks) 4. To detect metastases 5.
Evaluation of liver function � Reduced liver enhancement in cirrhosis may be caused by � Decrease in the number of functioning hepatocytes � Impairment of transport mechanism � Slight decrease in OATP1 activity in cirrhotic rats and � Significant up-regulation of MRP2 activity, leading to elimination of the drug Tsuda N, Radiology 2010
Ways to evaluate liver function I Direct measurement of liver signal intensity 1. Liver to spleen ratio � Liver to muscle ratio � Relative enhancement (SI post –SI pre )/SI pre � Liver to spleen ratio and liver volume � ( � � � � ) Correlation with indocyanin green clearance, hepatic function parameters, Child-Pugh score and MELD score was found Motosugi U, JMRI 2009 Yamada A, Radiology 2011 Verloh N, Eur Radiol 2014 Lee S, JMRI 2016 ( ─ ) Non absolute, non comparable measurements
Direct measurement of liver signal intensity Normal liver Ishak 6 (cirrhosis) Lee S, JMRI 2016 Verloh N, Sci Rep 2015
Ways to evaluate liver function II MR perfusion (DCE-MRI) – labor intensive 2. 3. MR relaxometry Measurement of T1 relaxation time (ms) � � T1 values significantly longer in cirrhosis on gadoxetate enhanced MRI � ) Absolute values, ( � � � independent of technical factors ( ─ ) Technically demanding method
Evaluate cirrhotic nodule-early HCC Arterial Portal � Typical pattern of arterial enhancement and portal washout is absent in 20-50% in HCC<3cm � Arterial enhancement absent in 15-25% � Portal washout absent in 40-60% � The smaller the lesion, the higher the probability for atypical vascular kinetics � Diagnosis of early HCC is associated with longer time to recurrence and a higher 5-year survival rate
Early HCC -definition � Clinically: <2cm (very early) or <3cm and <3 in number (early)[Barcelona stage 0 & A ] � Both hypervascular in arterial phase (classic HCC) � Pathologically: < 2cm, in an early stage of carcinogenesis � Vascular invasion or intrahepatic metastasis extremely rare � Well differentiated HCC is not necessarily early HCC!
Early HCC pathological � Small HCC <2cm � Grows by replacing and not expansively Vaguely nodular (early) � Fatty change is common � No fibrous capsule � Well differentiated � Unpaired arteries poorly developed Not easily seen in arterial phase Distinctly nodular (not early ) � May retain some portal venous supply Hytiroglou P, Gastroent. Clin. N. Am Not easily seen in portal phase 2007
Vascular kinetics and hepatospecific contrast uptake Early HCC Kitao et al, Eur Radiol 2011
Role of Gd-EOB-DTPA in diagnosis I � Loss of metabolic function might precede development of neoangiogenesis Bartolozzi, Abdom Imaging 2013 � More than 90% of early HCCs showed no or decreased expression of OATP1B3 transporters Hypointensity on hepatobiliary phase Ichikawa T, Liver Cancer 2014 � With the use of Gd-EOB-DTPA, diagnostic accuracy of HCC is ≥95% Sano K, Radiology 2011 Kitao A, Eur Radiol 2011
Role of Gd-EOB-DTPA in diagnosis II Borderline HCC (Kudo Μ, Dig Dis 2011)
Role of Gd-EOB-DTPA in diagnosis III � Comparison to other techniques Ichikawa T, Liver Cancer 2014
60-year-old man with cirrhosis SPIR DWI T1 pre-Gd Arterial HB
Hypointense nodules I � Not all hypointense nodules are early HCC; some represent dysplastic nodules � However even if early HCC is ruled out on biopsy, there is high probability this nodule will transform to hypervascular, typical HCC, especially when large (>10mm) � Other risk factors: presence of fat, restricted diffusion, T2 hyperintensity � Incidence rates are approximately 18%, 25% and 30% at 1, 2 and 3 years respectively Suh CH, AJR 2017 Joishi D, Magn Reson Med Sci. 2013 Kim, Radiology 2012
Hypointense nodules II � Whether HCC or HGDN, the hypovascular, hypointense lesion is suspicious (especially if large, ↑ T2, ↑ DWI or has intralesional fat) but not urgent � Management � Follow up? � Biopsy? � CEUS? � Benefit from intervention in early HCC? � RFA: despite lower local progression, similar OS and PFS with hypervascular (overt)HCC [ Lee DH, Radiology 2017] � Surgery: marginal survival benefit [ Midorikawa Y, J Hepatol 2013]
Hypovascular hypointense HCC Τ2 DWI Art HB
Hyperintense HCC � A significant percentage (9-20%) of typical hypervascular HCC show paradoxical gadoxetate uptake (iso/hyperintense in hepatobiliary phase) � Overexpression of OATP1B3 transporters � Less aggressive biological behaviour � Less frequent portal vein invasion � Lower recurrence rate compared to hypointense Choi JW, Radiology 2013 � Greater lipiodol uptake post TACE Kim JW, Eur J Radiol 2017
Hyperintense HCC & histology � Are hyperintense HCCs better differentiated? � Although controversial, most evidence suggests that there is an association between degree of enhancement on HB phase and degree of differentiation Jin YJ, Medicine 2017; Tong H, Clin Imaging 2017 Grade I Grade IV Well differentiated HCC Art T2 SPIR HB T1
Hyperintense HCC & differential � DDx: � Dysplastic nodules � Regenerative nodules � FNH like nodules � Focal defect in uptake, hypointense rim, nodule-in- nodule appearance , portal washout → HCC Suh JY, AJR 2011 HCC DN
Hyperintense HCC & differential � DDx: � Dysplastic nodules � Regenerative nodules � FNH like nodules � Focal defect in uptake, hypointense rim, nodule-in- nodule appearance , portal washout → HCC Regenerative Suh JY, AJR 2011 nodules HCC DN
Hyperintense HCC & differential � DDx: � Dysplastic nodules � Regenerative nodules � FNH like nodules � Focal defect in uptake, hypointense rim, nodule-in- nodule appearance , portal washout → HCC Pre Art PV HB Regenerative Suh JY, AJR 2011 nodules HCC FNH DN KimWJ, JMRI 2016
50-year-old man with cirrhosis DWI T1 FS ART HB 1,5 years later DWI T1 FS ART HB Typical HCC characteristics but the lesion unchanged in size!
Additional features with Gd-EOB-DTPA � Detection of microscopic vascular invasion � Seen as a hypointense halo in HB phase (Nishie A, J Gastroenterol Hepatol 2014)
Pitfalls with Gd-EOB-DTPA imaging � Genetic polymorphisms in the expression of OATP transporters may lead to reduced hepatic enhancement � Cirrhosis is associated with reduced liver enhancement � Bilirubin, PT activity, MELD score, indocyanine green clearance correlate with degree of HB enhancement � Patients with compromised liver function may not benefit from hepatospecific agent use � Acute transient dyspnea (14% with Gd-EOB-DTPA vs 5% with Gd-BOPTA) Davenport MS, Radiology 2013
Overall performance of Gd-EOB-DTPA � When the nodule is enhancing in the arterial phase and is hypointense in the HB → 100% specificity Wang YC, PLOS ONE 2017; Golfieri, JMRI 2012 � Excellent sensitivity (79–95%) and specificity (89– 92%) for lesions ≤ 2cm � Suboptimal performance for lesions ≤ 1cm � Arterial hyperenhancement and HB hypointensity most common pattern � Apply ancillary imaging features
38-year-old man with HBV cirrhosis US Art HB CT post TACE
Same patient, 4 years later US T2 DWI T1 pre Art Portal Images courtesy of Dr Michailidis N 30
Conclusions � Hepatospecific contrast agents are useful for the assessment of liver fibrosis � They have achieved a major breakthrough for diagnosis of early HCC � Closely follow-up hypovascular, HB hypointense nodules � Diagnosis of HCC is based on all sequences (T1, T2, DWI) � HCC may appear hyperintense in HB phase; associated with better prognosis
Thank you! Zongolopoulos “Umbrellas”,Thessaloniki
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