HEPATOCYTE SPECIFIC CONTRAST MEDIA: WHERE DO WE STAND? Andrew T. Trout, MD @AndrewTroutMD
Disclosures No relevant disclosures
Outline Review of hepatocyte specific contrast media Review of hepatocellular carcinoma Review of focal nodular hyperplasia (FNH) Review of hepatocellular adenoma subtypes The trouble begins
Hepatocyte Specific Contrast Media Gadoxetate disodium [Eovist, Primovist] Initial extracellular phase followed by 50/50 biliary/renal excretion Gadobenate dimeglumine [MultiHance]
Blood Bile Hepatocyte Specific Contrast Media Uptake Organic anion transporting polypeptides OATP8 (OATP1B3) OATP-C (OATP1B1) Excretion Multidrug resistance-associated proteins MRP2 - canalicular MRP3 - sinusoidal OATP MRP3 MRP2
Blood Bile Hepatocyte Specific Contrast Media HBP uptake depends one or more factors: OATP expression MRP expression Presence of functioning bile ducts OATP MRP3 MRP2 Tsuboyama T, et al. Radiology. 2010 Jun;255(3):824-33
Blood Bile Hepatocyte Specific Contrast Media HBP hyperintensity due to one or more factors: OATP expression MRP2 expression Mal-located MRP2 To pseudoglands (some HCC) Abnormal bile ducts OATP MRP3 MRP2 Tsuboyama T, et al. Radiology. 2010 Jun;255(3):824-33 Yoneda N, et al. Jpn J Radiol. 2012 Jul;30(6):499-508
Hepatocyte Specific Contrast Media In general, bad things are dark on the hepatobiliary phase Non-functioning hepatocytes Decreased OATP8 expression w/ progression of hepatocarcinogenesis May precede neoangiogenesis In general, benign things are bright on the hepatobiliary phase Lots of exceptions
Hepatocyte Specific Contrast Media Good article! Washout caution (gadoxetate disodium) Overlap between HBP and equilibrium phases may get pseudo-washout due to early background hepatocyte uptake Call washout only if unequivocal in portal venous phase
Hepatocellular Carcinoma Hepatocarcinogenesis (in the cirrhotic liver) generally a relatively scripted process Progressive neoangiogenesis Increasing numbers of unpaired arteries Gradual diversion of venous drainage from hepatic to portal veins Progressive loss of OATP transporters during process of hepatocarcinogenesis Process accounts for imaging appearance with increasing arterial hyperenhancement, PV washout and hypoenhancement in HBP Park HJ, et al. Liver Cancer. 2017 Jun;6(3):189-203
Focal Nodular Hyperplasia (FNH) Hyperplastic, hypercellular nodule Hepatocytes w/o atypia Abnormal duct proliferation Lack of mature bile ducts Central scar with large artery Normal background liver Believed to be hyperplastic response to vascular abnormality T2w Pre Art PV International Working Party. Hepatology. 1995 Sep;22(3):983-93 HBP
FNH vs. FNH-like lesions FNH-like lesions Arising in abnormal liver FNH occur only in normal liver Can look like low-grade HCC (and adenoma) May just be inflammatory adenomas Choi JY, et al. J Gastroenterol Hepatol. 2011 Jun;26(6):1004-9 Quaglia A, et al. Histopathology. 2003 Jan;42(1):14-21 Yoneda N, et al. Radiographics. 2016 Nov-Dec;36(7):2010-2027
Hepatocellular Adenomas Inflammatory Hepatocyte nuclear factor-1α (HNF-1α)- inactivated β-catenin activated Unclassified
Inflammatory Adenomas Used to be classified as a subtype (telangiectatic) of FNH Up to 50% of adenomas Risk factors: obesity, metabolic syndrome, EtOH Higher rate of malignant degeneration (esp. w/ β- catenin mutation) Higher rate of hemorrhage McInnes MD, et al. Radiology. 2015 Nov;277(2):413-23 Thomeer MG, et al. J Magn Reson Imaging. 2014 May;39(5):1259-64
HNF-1α-inactivated Adenomas Steatotic adenomas Majority show loss of signal on opposed-phase 35-50% of adenomas Most common in women on OCPs Commonly multiple IP T2w Art OP Pre PV Ba-Ssalamah A, et al. Radiology. 2015 Oct;277(1):104-13 Yoneda N, et al. Radiographics. 2016 Nov-Dec;36(7):2010-2027 HBP
β-catenin activated Adenomas More frequent in men than other adenomas Assoc w/ glycogen storage disease, familial adenomatous polyposis Greatest risk of malignant transformation Yoneda N, et al. Radiographics. 2016 Nov-Dec;36(7):2010-2027
Unclassified Adenoma Everything else. No clear mutational etiology No consistent imaging features
Exceptions to the bad things are dark, benign things are bright on HBP rule:
HBP Hyperintense Adenomas Agarwal et al. 7 patients, 24 inflammatory adenomas 11 lesions in 4 patients had classic imaging features of FNH Most likely adenoma subtype to be iso- to hyperintense on HBP Agarwal S, et al. AJR Am J Roentgenol. 2014 Oct;203(4):W408-14 Thomeer MG, et al. J Magn Reson Imaging. 2014 May;39(5):1259-64
HBP Hyperintense Adenomas T2w Pre OP 9 year old w/ diminutive portal vein (Abernethy II) Inflammatory adenoma Art PV HBP
HBP Hyperintense Adenomas Yoneda et al. Case report of β- catenin activated adenoma Didn t look like benign lesion on any phase
HBP Hyperintense Adenoma T2w Pre IP OP 18 year old Art PV HBP Well differentiated hepatocellular neoplasm w/ β- catenin activation
HBP Hyperintense Adenomas Ba-Ssalamah et al. Review of 43 HCAs 6 β-catenin activated adenomas 5 / 6 HBP iso- to hyperintense Most β-catenin activated adenomas and 29% of inflammatory adenomas mimicked FNH (retained on HBP)
HBP Hyperintense Adenomas 11 year old T2w IP OP Inflammatory adenoma w/ β- catenin activation Pre Art PV HBP
6 studies, 309 patients 397 lesions: 164 adenomas, 233 FNH 257 w/ pathology Molecular subtyping in only 1 paper 91 100% sensitivity for dx of FNH 95% CI as low as 77% 87 100% specificity for dx of FNH 95% CI as low as 54% McInnes MD, et al. Radiology. 2015 Nov;277(2):413-23
Major concern re: bias Study that did molecular subtyping had lowest specificity for FNH (87%) Suggests higher specificity in other studies due to misclassification of inflammatory adenoma as telangiectatic FNH Study that did molecular subtyping had highest rate of adenomas iso to hyperintense on HBP Range: 0-67% McInnes MD, et al. Radiology. 2015 Nov;277(2):413-23
HBP Hyperintense HCC In general HCC appear hypointense on hepatocyte phase 6 15% are iso- or hyperintense Due to overexpression of OATP8 Kitao A, et al. Radiology. 2012 Dec;265(3):780-9
Kitao et. al. Radiology 2012 Hyperintense HCC More differentiated Lower serum tumor marker levels (e.g. AFP) ± less fibrous capsule and hepatic vein invasion Less portal vein invasion Lower recurrence rate ± longer survival Kitao A, et al. Radiology. 2012 Dec;265(3):780-9
Kitao et. al. Radiology 2012 Hyperintense HCC More differentiated LESS AGGRESSIVE Lower serum tumor marker levels (e.g. AFP) ± less fibrous capsule and hepatic vein invasion Less portal vein invasion Lower recurrence rate ± longer survival Kitao A, et al. Radiology. 2012 Dec;265(3):780-9
What to do? If its dark on HBP, view w/ suspicion Except: cysts, venous malformations ( hemangiomas ) If imaging features aren t classic for a benign lesion, be skeptical e.g. the T1 bright FNH e.g. the heterogeneously HBP hyperintense FNH
What to do? Incorporate other information History OCPs, EtOH, Obesity Adenoma Background liver Growth Hypointense rim on HBP or internal mosaic architecture can be helpful signs of HCC Hope TA, et. al. Abdom Imaging. 2015 Mar;40(3):613-25
Summary Hepatocyte specific contrast media can be a valuable tool in diagnosis of liver lesions Its not as simple as HBP bright = benign
SAM Question #1 Which of the following lesions is most likely to be iso- to hyperintense on the hepatobiliary phase when imaged with a hepatocyte specific contrast material? a) Hepatocellular carcinoma b) Inflammatory adenoma c) Metastasis d) HNF-1α inactivated adenoma
SAM Question #2 Hepatobiliary phase hypointensity of a lesion imaged with a hepatocyte specific contrast material can be explained by which of the following processes: a) Decreased OATP expression b) Abnormal background liver c) Rapid drainage of bile from the lesion d) Increased blood flow to the lesion
THANK YOU Andrew T. Trout, MD @AndrewTroutMD