9. Definite HCC
• Wash in (arterial phase hyperenhancement) /
Wash out– AASLD, EASL criteria (>1 cm) and
JSH (any size)
• Dynamic MDCT, MRI (Primovist enhanced MRI),
CEUS
• Only 71% - have ‘wash in’ and ‘wash out’ on
more than one test
Marrero JA et al Liver Transpl 2005;11:281-289
11. Ancillary MRI criteria -
Malignant liver nodules
• T2W Hyperintensity
• Capsular enhancement – LI RADS
• T1 hypointensity
• Lesion size
• Lesional fat
• Lesion growth on follow up
• ‘Nodule in nodule’ pattern
12. PRIMOVIST alone has higher sensitivity
-? Compromised specificity
• Comparing primovist and magnevist,
• Significant increased sensitivity with primovist.
• Hepatocellular phase imaging with Primovist improves HCC detection.
• Primovist MRI has higher diagnostic accuracy (0.88 vs 0.74, p<.
001) and higher sensitivity (0.85 vs0.69, p<.001) than triple phase
MDCT
• Particularly in smaller lesions (<2cm)
• MRI with primovist has equal accuracy as dual-contrast MRI for
HCC detection
• Combined use of extracellular gadolinium and SPIO.
Marin D et al Radiology 2009;251:85-95
Park G et al BJR 2010;83:1010-1016
Kim YK et al Invest Radiol 2010:45:740-746
Martino et al Radiology 2010;256:806
13.
14. Hypervascular nodule
Size does not matter!
Hypervascular nodule without washout
Primovist
Negative uptake
HCC
Positive uptake
Biopsy or Follow up
Kudo M Oncology 2010;78:87-93
15. Hypovascular Nodule- size matters!
Hypovascular nodule
Primovist
Negative uptake
≥1.5cm
HCC – 98%
LGDN – 2%
Positive uptake
<1.5cm
≥1.5cm
<1.5cm
Follow up
Biopsy or
FU
Follow up
17% progress to
HCC in 1 year
HCC
LGDN
17. DIFFUSION WEIGHTED MRI - ↑ Specificity
• SI ratio significantly differentiates malignant and benign
lesions at all b-values.
• Optimal threshold b=600
• SI ratio 1.25.
• For detection of HCC, DWI with b=600 has
• sensitivity of 95.2% compared to 80.6% for
conventional MRI (p=0.023)
• specificity of 82.7% compared to 65.4% (p=0.064%).
• The improved accuracy was most beneficial for differentiating
lesions smaller than 2cm.
Vandecaveye V Eur Radiol 2009;may:1431
19. Small HCC -No lesion seen on T1, T2 or enhanced MRI.
SI ratio=1.5 at b600
20. CURRENT APPROACH
• Combined Primovist enhanced MRI
and Diffusion weighted imaging – able
to image the step wise pathogenesis of
HCC
• Dynamic Primovist MRI - Wash in / Wash out
• Hepatobiliary phase Primovist enhanced MRI - OATP8
expression
• DWI - cell density
• Ancillary features
21. COMBINED PRIMOVIST MRI AND DWI
• Criteria for HCC
• Hypervascular nodules with washout
• Hypervascular nodules without washout, hypointense on HBP
phase (irrespective of DWI)
• Hypervascular nodules without wash out, iso/hyperintense on
HBP phase + Hyperintense DWI
• Hypovascular nodules, hypointense on HBP phase +
Hyperintensity DWI
• Combined Primovist and DWI has better diagnostic
accuracy and sensitivity (93.3%) in detection of HCC <
2cm
• False positive – HGDN
Park MJ et al Radiology 2012:264;761-770
39. FOCAL NODULAR LIVER LESIONS:
1994 INTERNATIONAL CLASSIFICATION
• Regenerative nodule
• Cirrhotic nodule
• Low grade dysplastic nodule (adenomatous
hyperplasia)
• High grade dysplastic nodule (adenomatous
hyperplasia with atypia)
• Dysplastic nodule with subfoci of HCC (early HCC)
• HCC (overt HCC)
International Working Party. Hepatology
1995;22:983-993
40. DEVELOPMENT OF HCC IN
CIRRHOTIC LIVER
• Temporal progression from regenerative nodules
to dysplastic nodules to well differentiated HCC.
• HCC may develop independently of RN and DN.
41. PRIMOVIST MRI MOST SENSITIVE TECHNIQUE IN
DETECTING EARLY HEPATOCARCINOGENESIS
42. CONSENSUS STATEMENTSJAPAN SOCIETY OF HEPATOLOGY
• Typical HCC can be diagnosed by imaging regardless
of the size if a typical vascular pattern is obtained on
dynamic CT, dynamic MRI, CEUS or a combination of
CTHA and CTAP.
• Different from Western guidelines, only one dynamic
study showing the typical pattern is sufficient to
diagnose HCC.
• The typical imaging pattern include hypervascularity in
the arterial phase and washes-out in the portal venous
phase.
43. CONSENSUS STATEMENTSJAPAN SOCIETY OF HEPATOLOGY
• Sonazoid-enhanced ultrasound is more sensitive for
detection of intranodular hypervascularity than MDCT
or dynamic MRI. Therefore to confirm true
hypovascularity, sonazoid-enhanced CEUS is
recommended.
• Nodules with hypovascularity and negative findings on
SPIO-MRI, Kupffer imaging of Sonazoid CEUS,
primovist MRI are likely to be benign. They can be
followed up without treatment.
47. PRIMOVIST CONTRAST ENHANCED
MRI- PROTOCOL OPTIMIZATION AND
EVALUATION OF HEPATIC NODULES IN
LIVER CIRRHOSIS
Dr. Tony Loke
Consultant Radiologist
United Christian Hospital
48. PRIMOVIST - GADOLINIUM-ETHOXYBENZYLDIETHYLENETRIAMINEPENTAACETIC ACID (GDEOB-DTPA)
• Combined extracellular hepatobiliary gadolinium
based contrast agents with liver specific properties
• Multihance and Primovist
• These agents able to assess both vascularity and
hepatocellular function.
49. PROTOCOL OPTIMIZATION - PHARMACOKINETIC
AND PHARMACODYNAMIC PROPERTIES OF
PRIMOVIST IN LIVER CIRRHOSIS.
• Patients with advanced cirrhosis, three important differences are
present.
• Diminished and delayed liver parenchyma enhancement
• diminished parenchymal enhancement in the hepatocyte phase
• time to peak enhancement may be delayed.
• Diminished and delayed biliary excretion.
• In the noncirrhotic liver, primovist produces intense biliary tree
enhancement beginning as early as 5 minutes after contrast injection.
• Enhancement of bile ducts in the cirrhotic liver is delayed and of limited
intensity
50. PROTOCOL OPTIMIZATION - PHARMACOKINETIC
AND PHARMACODYNAMIC PROPERTIES OF
PRIMOVIST IN LIVER CIRRHOSIS.
• Patients with advanced cirrhosis, three important differences are
present.
• Prolonged blood pool enhancement.
• 50% of primovist is cleared by the liver and 50% via the kidneys.
• Patients with advanced cirrhosis, the hepatic elimination pathway is
impaired and the blood vessels appear hyperintense for a longer
duration.
• The relatively low contrast enhancement in portal and hepatic veins
is relevant because it reduces the sensitivity for detecting venous
obstruction and invasion.
51. PROTOCOL OPTIMIZATION – PRIMOVIST
ENHANCED MRI IN CIRRHOTIC LIVER
• Problems with on-label approved dose Gd-EOB-DTPA of
0.025mmol/kg.
• Selecting the appropriate scan delay is difficult from low dose and
small amount of on-label approved dose
• Studies have shown the signal intensity of vessels in the arterial phase
is less with primovist than extracellular gadolinium-based agents using
on-label approved dose.
• Standard dose provide low sensitivity for detection of hypervascular
HCC/lesions despite its higher T1 relaxivitiy
Cruite I et al AJR 2010;195:29-41
52. PROTOCOL OPTIMIZATION-SOLUTION FOR
ACHIEVING OPTIMAL ARTERIAL PHASE
• Optimal arterial phase increases sensitivity for detection of hypervascular
lesions
• Perform consecutive arterial phase data sets.
• Administer the agent at a higher off-label dose (0.0375 – 0.05 mmol/kg).
• This is 50%-100% higher than the approved dose.
• Injecting all 10ml (20ml if patient exceeds the dose rate calculation) -rounded
up to the nearest bottle
• For patients with estimated GFR of less than 60mL/min, a weightadjusted dose is administered without rounding.
• Inject contrast at slower rate of 1cc/second followed by 20ml of saline chaser
at 2cc/second.
• 2cc/sec with higher dose
54. UCH PROTOCOL - PRIMOVIST ENHANCED MRI
LIVER
•
MRCP performed before contrast injection
•
Bolus timing method is used
• Contrast seen at LVOT or ascending aorta, patient asked to take 2 breath holds (8 -10
seconds) and 2 consecutive arterial phases imaging is acquired using 3D VIBE (15
seconds).
• late arterial phase is performed after 2 breath holds.
•
Hepatic phase is performed after another 2 breath holds
•
Equilibrium phase is performed at 120 minutes.
•
Diffusion weighted imaging and 2D axial SPAIR is performed while waiting for delayed 20
mins hepatocyte phase.
•
Hepatocyte phase - 20 minutes delay.
•
Hepatocyte phase - 40 minutes delay
• if hepatic veins and portal veins not cleared
• contrast not visible in biliary tree.
•
Hepatocyte phase - 60 minutes delay may be necessary.
56. WHEN TO USE PRIMOVIST IN PATIENTS WITH
LIVER CIRRHOSIS
• Primovist is routinely use in cirrhosis except for:
• Assessment of ablated lesions for residual or recurrent
disease.
• Reduced vascularity
• Patients whose bilirubin is above 3 mg/dL.
• Sensitivity for lesion detection reduced from diminished liver
enhancement
• Evaluation of vascular patency
• PV and HV remains hyperintense from prolonged blood pool
• Evaluation of hemangiomas
• Appearance same as HCC
57. IS PRIMOVIST BETTER FOR DETECTING HCC?
-COMPARED WITH OTHER AGENTS /IMAGING
MODALITIES
• Combined dynamic and hepatocyte phase of Primovist has greater
diagnoctic accuracy for HCC detection than either dynamic or
MDCT alone
• Comparing primovist and magnevist, significant increase in
sensitivity was achieved with primovist.
• Hepatocellular phase imaging with Primovist improves HCC detection
compared with conventional extracellular gadolinium chelates.
• MRI with primovist has equal accuracy as dual-contrast MRI for HCC
detection (simultaneous use of conventional extracellular gadolinium and
superparamagnetic iron oxide agent).
Marin D et al Radiology 2009;251:85-95
Park G et al BJR 2010;83:1010-1016
Kim YK et al Invest Radiol 2010:45:740-746
58. PRIMOVIST UPTAKE BY HEPATOCYTE BY OATP1
EXCRETION TO BILE JUICE REGULATED BY MRP2
Kudo M J gastroenterology and hepatology 2010;25:439-452
60. HCC (87 lesions)
Hepatobiliary phase
In one study
Hypointense
92%
Isointense
6%
Hyperintense
2%
WDHCC (39 lesions)
Hepatobiliary phase
Another study
Hypointense
35
Isointense
2
Hyperintense
2
DN (8)
Hypointense
3
Isointense
3
Hyperintense
2
Kudo M J gastroenterology and hepatology 2010;25:439-452
61. CRITERIA FOR HCC
• Reading Hepatobiliary phase alone insufficient
• Result in false positives and negatives
• Hepatocyte phase
• Post contrast EOB ratio
• Read the whole exam
• T1 (hypointense)
• T2 (hyperintense)
• Dynamic contrast (hypervascularity +/- washout)
• DWI (restricted diffusion)
62. CRITERIA FOR HCC DIAGNOSIS
• A nodule with increased enhancement on arterial phase and washout on late venous or equilibrium phase
• A nodule with arterial enhancement and hyperintensity on T2WI
(and/or DWI)
• A nodule with isointensity during contrast enhanced arterial phase,
hyperintensity on T2WI (and/or DWI) and no uptake of contrast on
hepatobiliary phase (even < 1.5cm)
• Nodule > 1.5cm with no uptake of contrast agent on hepatobiliary
phase images.
63. HYPOVASCULAR NODULE – SIZE MATTERS
• Hypovascular nodules (on arterial phase) with
negative uptake on hepatobiliary phase are thought to
represent DN or WDHCC
• Lesion > 1.5 will progress to hypervascular nodules in 80%
in 1 year
• Lesion < 1.5 will progress to hypervascular nodules in 17%
in 1 year
Kudo M Oncology 2010;78:87-93
83. FALSE POSITIVE – HEPATOBILIARY PHASE
• Hypointense lesions seen only on hepatobiliary phase (without arterial
enhancement and T2 hyperintensity) can either be WDHCC or Cirrhotic
nodules
• HCC tend to be larger(>1.5cm) than benign nodules(0.5-1.2cm)
• Lesions <1.5cm seen on hepatobiliary phase can still be well-differentiated
HCC and should not be ignored.
• Close monitoring, biopsy or resected in patients with coexisting overt HCC.
• Hypervascular pseudolesions
• 15% shows negative uptake on hepatobiliary phase
• 13% showed T2 hyperintensity
• DWI normal
84. FALSE NEGATIVE - HEPATOBILIARY PHASE
• HCC which are T1 hyperintense may be isointense on
hepatobiliary phase.
• Look for hypervascularity on arterial phase, T2/DWI
hyperintensity
• Hepatic dysfunction or hyperbilirubinemia reduces hepatic
uptake of the contrast agent
• lesion conspicuity on hepatobiliary phase images is
decreased, although false-negative cases can occur in
patients with normal bilirubin level.
• Lesions are less conspicuous in fatty liver
• do 20 min delay without fat sat
• Paradoxical uptake – Green hepatomas
• 2.5 to 8.5% of HCC appear iso/hyperintense
• Altered transporter mechanism
85. SUMMARY- CRITERIA FOR HCC
• Hypervascular nodules with washout – irrespective of delayed
phase
• Hypervascular nodules and hyperintensity on T2WI (and/or DWI) –
irrespective of delayed phase
• Isointense nodule (arterial phase) with hyperintensity on T2WI
(and/or DWI) and negative uptake of contrast on hepatobiliary
phase (even < 1.5cm)
• Nodule > 1.5cm with no uptake of Primovist on hepatobiliary
phase images– irrespective of vascularity
86. SUMMARY
• Negative uptake in hypovascular lesions <1.5 cm can still be
HCC
• FU required as 17% becomes hypervascular in 1 year
• Positive uptake can still be HCC
• DWI (+/- hepatocyte SI ratio) to exclude pseudolesion
• Hypointense rim and/or focal defect on delayed phase
• Nodule in nodule and internal septation helps
• FU(+/-biopsy) necessary
