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Functional liver imaging
Bernard Van Beers
Department of Radiology
Beaujon University Hospital Paris Nord
Laboratory of Imaging biomarkers
UMR 1149 Inserm - University Paris Diderot France
Functional imaging
• Morphological imaging
– Based on size, shape and signal intensity
– Often qualitative
• Functional imaging
– Based on function
• Perfusion
• Diffusion
• Elastography
– Often quantitative: imaging biomarkers
• Rationale
– Provide information that can not been easily observed
Biomarkers Definition Working Group, 2001
Imaging biomarkers: RECIST criteria
• RECIST: response evaluation criteria in solid tumors
• Measurement of tumor diameter at CT
– Complete response: disappearance of the lesions
– Objective response: decrease ≥ 30%
– Stable disease
– Progressive disease: increase ≥ 20%
• Used since more than 10 years to assess response to treatment in drug development studies
Therasse P et al. JNCI 2000; 92: 205-216Jain RK et al. J Clin Oncol 2013; 266: 812-821
Limitations of RECIST criteria
• RECIST : semi-quantitative score with arbitrary cutoffs
• Decrease in size is not always observed because tumor tissue may be completely replaced with necrosis or fibrosis, especially when targeted treatments are used
Chun YS et al. JAMA 2009; 302: 2338-2344
Colorectal liver metastases treated with chemotherapy and bevazucimab
Ronot M et al. Oncologist 2014; 19: 394-402
Size criteria in HCC treated with sorafenib
Ronot M et al. Oncologist 2014; 19: 394-402
Size criteria in HCC treated with sorafenib
Limitations of mRECIST/EASL
• 2D measurements in very heterogeneous tumors
March JuneApril
Hanahan D et al. Cell 2011; 144: 646-674
Beyond RECIST
• Functional biomarkers
– FDG PET: metabolism
– Dynamic contrast-enhanced CT/MRI: angiogenesis
– Diffusion MRI: cellularity
– MR elastography: visco-elasticity
Response to treatment: volumetric assessment of ADC and enhancement
Bonekamp S et al: Radiology 2013; 268: 431-439
HCC after TACE
Bonekamp S et al: Radiology 2013; 268: 431-439
Volumetric ADC increase ≥ 25% and portal venous enhancement decrease ≥ 65% 3 – 4 weeks after TACE are better predictors of survival than RECIST, mRECIST and EASL criteria
Improvement of diagnostic performance with functional MRIrelative to RECIST
• Shift from morphological to functional parameters
• Shift from manual one-dimensional to automatic three-dimensional approach• Tumor heterogeneity is taken into account: texture analysis• Reproducibility is improved
• Multiparametric approach
Bonekamp D et al. Eur J Radiol 2014
Early diffusion and perfusion changes after TACE of HCC
Diffusion and perfusion changes are already observed at MR imaging one week after TACE
Boustany G et al. 2015
Pharmacokinetic modeling for liver perfusion
• Enhancement depends on local perfusion/ permeability but also on arterial input function
• Pharmacokinetic modeling improves the assessment of results between patients and in longitudinal studies
• BUT• Long acquisition times: respiratory artefacts• Specific image acquisition scheme that is suboptimal for
morphological analysis
t
utk
pportalpaarterialatissue dueuCkuCktC0
)(
112)()()(
Liver
Parenchyma
Ctissue(t)
vd
k1aCartery(t)
Endothelium
Liver: one-compartment model and
dual input with delays
k1a the hepatic artery inflow
k1p the portal vein inflow
k2 the reflux rate
vd=k2/(k1a+k1p) the distribution volume
Tc=1/k2 the mean transit time
Annet, Radiology 2003
Intravascular
Space
k1p
Cvein(t)
k2
Hepatic perfusion: kinetic model
tv
K
plasma
trans
tissuee
trans
etCKtC
)()(
Extravascular
Extracellular
Space
Ctissue(t)
ve
KtransCplasma(t)
Endothelium Kety : one-compartment model
Ktrans reflects the blood flow and/or
the endothelial permeability
depending on whether the perfusion
is flow- or permeability-limited
Tofts, J Magn Reson Imaging 1999
Leach, Brit J Cancer 2005
Intravascular
Space
Tumor: kinetic model
dC tissue (t) / dt = Ktrans Cplasma - k Ctissue
Perfusion MRI changes after treatment in liver metastases
Improvement of disease free survival in patients with liver colorectal metastases treated with chemotherapy and bevacuzimab when perfusion increase < 40% after one week and perfusion decrease > 40% after 10 weeks
De Bruyne S et al. Br J Cancer 2012
ADC: distinction between benign and malignant lesions
• High ADC in benign lesions with high fluid content such as hemangiomas
• No significant difference in ADC between benign hepatocellular lesions and malignant tumors
Doblas S et al. Invest Radiol 2013;48: 722-728
Garteiser P. et al. Eur Radiol 2012; 22: 2169-2177
Visco-elastic properties
Areas under ROC curves
• AUROCADC = 0.71
• AUROC Gl = 0.76
• AUROC malignancy index = 0.84
Imaging of liver chronic liver disease
• Inflammation and fibrosis: microscopic findings
• Changes
– Stiffness
– Diffusion
– Perfusion and hepatocyte transport
– T1 relaxation time
– Susceptibility
Mechanical waves captured by
sequence sensitive to movement
Wavelength depends on elasticity
Attenuation depends on viscosity
Dynamic elastography
Elastography
• Elastography: most established method to stage liver fibrosis
• Three techniques with increasing diagnostic performance
– Transient elastography
– Shear wave elastography
– MR elastography
TE
SSI
3D MRESandrin L et al. IEEE Trans Ultrason Ferro Freq Contr 2002
Huwart L et al. NMR Biomed 2006
Bavu E. et al. Ultrasound Med Biol 2011
MR elastography
Elastography: reliability and reproducibility
• Reliability
– Transient elastography
• 85% of patients with BMI < 30 kg/m2
• 71% of patients with BMI ≥ 30 kg/m2
– Shear wave elastography
• 90 % of patients with BMI < 30 kg/m2
• 73% of patients with BMI ≥ 30 kg/m2
– MR elastography
• 95%, can be performed in obese patients and patients with ascites
• Reproducibility
– Ultrasound elastography: interobserver agreement: 85%
– MR elastography: better reproducibility than ultrasound elastography
Van Beers BE et al. Semin Liv Dis; in press
Ultrasound elastography: accuracy
• Meta analyses and comparative studies
• Transient elastography
– AUROC 0.84 for ≥ F2
– AUROC 0.94 for F4
• Shear wave elastography
– Two-dimensional shear wave elastography: better results for ≥ F2
Bavu E. et al. Ultrasound Med Biol 2011
F ≥2
MR elastography: accuracy
• MR elastography
– AUROCs > 0.9 for ≥ F2, ≥ F3 and F4
– Higher accuracy than transient and shear wave elastography
Huwart et al. Gastroenterology 2008Cui et al. Hepatology 2016Imajo K et al. Gastroenterology 2016Joon JH et al. Radiology 2014
Prognostic biomarker and cost-effectiveness
• Patients with high baseline stiffness values but also patients with increasing values during follow-up have impaired prognosis and survival
• Ultrasound elastography is cost-effective in patients with chronic HCV and HBV infection and NAFLD to diagnose advanced fibrosis and cirrhosis
• MR elastography is more cost-effective than liver biopsy to confirm advanced fibrosis
Corpechot C et al. Gastroenterology 2014Tapper EB et al. Am J Gastroenterol 2015Zhang E et al. Eur Radiol 2015
F1
F4
Potential indications for MR elastography
• Discordant results between ultrasound elastography and serum biomarkers
• Follow-up after treatment
• Assessment of cirrhosis severity and portal hypertension
• Diagnosis of non-alcoholic steatohepatitis: NASH
F1 F3
Loomba et al. Hepatology 2015; 61: 1239-1250
Cirrhosis and portal hypertension
• Portal hypertension: HPVG, endoscopy
• Elastography is an non-invasive alternative to HVPG measurements
• Feasibility of ultrasound elastography often limited, especially > 10 mm Hg
• MR elastography is promising
Garcia-Tsao G et al. Hepatology 2010Ronot M et al. Eur Radiol 2012Procopet B et al. J Hepatol 2015
MR elastography of portal hypertension
0 20 40 60 80 1000
20
40
60
80
100
Gl 84 Hz
Gd 84 Hz
Gl 56 Hz
Gd 56 Hz
G* 56 Hz
G* 84 Hz
1 - Specificity %
Sen
sitiv
ity %
Ronot M et al. Eur Radiol 2014
Viscosity (Gl) of the spleen is a marker of portal hypertension
Baveno VI consensus workshop on portal hypertension
• Stiffness > 15 kPa: compensated advanced chronic liver disease
• Stiffness > 20 kPa: significant portal hypertension (HVPG ≥ 10 mm Hg)
• Stiffness < 20 kPa associated with platelet count > 150,000 can safely avoid screening of esophageal varices by endoscopy
de Franchis R et al. J Hepatol 2015
Increase in liver stiffness is non specific
• Fibrosis
• Portal hypertension
• Liver congestion
• Bile duct obstruction
• Inflammation
– Acute flares in hepatitis B virus infection
– NASH
de Franchis R et al. J Hepatol 2015
Diagnosis of NASH
• Liver ultrasound showing steatosis
• Elevated aminotransferase levels
• Liver biopsy
– Diagnosis of NASH
– Diagnosis of F3 fibrosis: advanced fibrosis, best prognostic factor
Angulo P et al. Gastroenterology 2015
Alternatives to diagnose liver fibrosis: DW-MRI
• Decrease of ADC with increasing stage of fibrosis
• Diagnostic performance > MRE
• DW-MRI is influenced by steatosis and perfusion changes
Lewin M et al. Hepatology 2007Wang QB et al. hepatology 2012Leitao H et al. Radiology 2016
Gadoxetic acid-enhanced MR imaging
• Hepatocyte uptake through OATP1B1/B3, biliary efflux through MRP2, sinusoidal backflux through MRP3
• In NASH and liver fibrosis : decrease of OATP1B1/B3 et MRP2, increase of MRP3
Van Beers BE et al. J Hepatol 2012Giraudeau C et al. Eur Radiol 2016
Gadoxetic acid-enhanced MR imaging
F0 F2 F4
AUROC > 0.9
• Decrease of signal intensity in NASH and liver fibrosis
• AUROCs of gadoxetic acid-enhanced MRI in fibrosis: 0.80 - 0.85
Feier D et al. Radiology 2013Choi YR et al. Invest Radiol 2013
Gadoxetic acid-enhanced MR imaging
• Texture analysis of signal enhancement during the hepatobiliary phase
• AUROC > 0.9
Leporq B et al. 2016
F0 F2 F4
Dynamic gadoxetic acid-enhanced MRI
Lagadec M. et al. Radiology 2015Giraudeau C. et al. Eur Radiol 2016 Leporq B et al. ISMRM 2015
Conclusions
• Functional imaging may add important quantitative information
• Liver tumors
– Predictive of tumor aggressiveness and response to treatment
– Diffusion and perfusion measurements
– Taking whole tumor volume and its heterogeneity into account
– Multiparametric
• Chronic liver disease
– Predictive of disease stage and response to treatment
– Elastography and perfusion/hepatocyte transport measurements