Abdominal imaging hcc t loke

Diagnostic imaging of small HCC in liver cirrhosis : The current

approach

Dr.Tony Loke United Christian Hospital

Disclosure

No conflict of interest

Contents •  Step wise progression of hepatocarcinogenesis •  MR I can image this histhopathological process - Gadoxetic

enhanced MRI + DWI •  Definite Criteria for HCC – Low sensitivity •  Gadoxetic enhanced MRI alone - ↑sensitivity •  Diffusion weighted MRI -↑ specificity •  Combined Ga MRI and DWI – current approach •  Proposed Algorithm – Best diagnostic accuracy

Kudo M Oncology 2010;78:87-93

Multistep progression of Hepatocarcinogenesis

Intranodular blood supply- unpaired arteries / portal tracts

Tajima T AJR 2002:178;885

Histopathological pathway of Carcinogenesis

•  Replacement of normal liver cells by abnormal liver malignant cells -↓ OATP8 expression •  Hypointensity – HBP Primovist enhanced MRI

•  Unpaired arteries ↑ + Portal tract ↓ •  Wash in/ Wash out – Dynamic CT and MRI

•  Increased cell density with progressive undifferentiated nodules •  Hyperintensity - DWI

Process of Hepatocarcinogenesis

Kudo M J gastroenterology and hepatology 2010;25:439-452

Diagnostic criteria for typical HCC

Bruix J, Sherman M Hepatology 2011;53:1020-1022

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

↑ Sensitivity - Malignant liver nodules

•  Absence of OATP8 expression / kupffer cells •  Liver specific contrast agents •  Primovist MRI, SPIO-MRI, Sonazoid- CEUS

•  Restricted diffusion •  Diffusion weighted MRI

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

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

Hypervascular nodule Size does not matter!

Hypervascular nodule without washout

Primovist

Negative uptake Positive uptake

HCC Biopsy or Follow up

Kudo M Oncology 2010;78:87-93

Hypovascular nodule

Primovist

Negative uptake Positive uptake

≥1.5cm <1.5cm ≥1.5cm <1.5cm

HCC – 98% LGDN – 2%

Follow up Biopsy or FU

Follow up

HCC LGDN 17% progress to

HCC in 1 year

Hypovascular Nodule- size matters!

PRIMOVIST (GD-EOB-DTPA) GADOXETIC ACID

HCC-Hypointense at 20 min HBP (e)

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

Classic HCC -SI ratio 1.83 for b600 (g)

Small HCC -No lesion seen on T1, T2 or enhanced MRI. SI ratio=1.5 at b600

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

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

COMBINED PRIMOVIST AND DWI

Park MJ et al Radiology 2012:264;761-770

COMBINED PRIMOVIST AND DWI

Park MJ et al Radiology 2012:264;761-770

Typical small HCC

Small hypervascular HCC –DWI b=100, 800

Segment 6 hypervascular HCC < 1.5 CM

Atypical small HCC

Hypervascular HCC- hypointense on HBP but DWI normal

Hypervascular HCC – and DN (DWI and HBP-Normal)

CT hypervascular lesion- Segment 5 pseudolesion

Hypovascular HCC < 1.5 CM Hypointense HBP + Hypertintense DWI

SEGMENT 2/3 HCC Hypo/hypervascular component (HBP+DWI = +ve)

HGDN simulating HCC

Hypovascular DN- hypointense on HBP and DWI hyperintense

Segment 5 HGDN – Hypointense HBP (DWI-Normal)

DN > 1.5CM HBP + DWI = negative

Summary - Current Approach •  Nodule detected on USG •  Dynamic CT

•  Hypervascular with washout (>1cm) •  Atypical features

•  Combined Primovist enhanced MRI and DWI •  Hypervascular without washout, hypointense on HBP phase

•  Hypervascular without washout, isointense on HBP phase + Hyperintense DWI

•  Hypovascular nodules, hypointense on HBP phase + Hyperintensity DWI •  Ancillary features

•  Higher diagnostic accuracy and sensitivity •  Particularly for HCC < 2cm •  False positive for HGDN

Conclusion - Current Approach •  Combined Primovist and DWI •  Higher diagnostic accuracy and sensitivity • Particularly for HCC < 2cm

•  false positive include HGDN •  Combined Primovist enhanced MRI and DWI •  Hypervascular without washout, hypointense on HBP phase •  Hypervascular nodules, isointense on HBP phase +

Hyperintense DWI •  Hypovascular nodules, hypointense on HBP phase +

Hyperintensity DWI

SEG 2/3 HYPERVASCULAR HCC WITH PARADOXICAL UPTAKE (DWI-hyperintense)

SEGMENT 6 HCC WITH NORMAL ARTERIAL, T2W AND DWI

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

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.

PRIMOVIST MRI MOST SENSITIVE TECHNIQUE IN DETECTING EARLY HEPATOCARCINOGENESIS

CONSENSUS STATEMENTS- JAPAN 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.

CONSENSUS STATEMENTS- JAPAN 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.

JAPAN SOCIETY OF HEPATOLOGY

JAPAN SOCIETY OF HEPATOLOGY

2ND INTERNATIONAL FORUM LIVER MRI

PRIMOVIST CONTRAST ENHANCED MRI- PROTOCOL OPTIMIZATION AND

EVALUATION OF HEPATIC NODULES IN LIVER CIRRHOSIS

Dr. Tony Loke Consultant Radiologist

United Christian Hospital

PRIMOVIST - GADOLINIUM-ETHOXYBENZYL-DIETHYLENETRIAMINEPENTAACETIC ACID (GD-EOB-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.

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

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.

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

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 weight-

adjusted 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

PRIMOVIST PROTOCOL - DIFFERENCE WITH CONVENTIONAL GD

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.

UCH PROTOCOL – PRIMOVIST ENHANCED MRI LIVER

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

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

PRIMOVIST UPTAKE BY HEPATOCYTE BY OATP1 EXCRETION TO BILE JUICE REGULATED BY MRP2

Kudo M J gastroenterology and hepatology 2010;25:439-452

Kudo M Oncology 2010;78:87-93

HCC (87 lesions) Hepatobiliary phase

Hypointense 92%

Isointense 6%

Hyperintense 2%

In one study

Another study WDHCC (39 lesions) Hepatobiliary phase

Hypointense 35

Isointense 2

Hyperintense 2

DN (8)

Hypointense 3

Isointense 3

Hyperintense 2

Kudo M J gastroenterology and hepatology 2010;25:439-452

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)

CRITERIA FOR HCC DIAGNOSIS

•  A nodule with increased enhancement on arterial phase and wash-out 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.

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

DN > 1.5CM - POSITIVE UPTAKE

DN > 1.5 CM - POSITIVE UPTAKE

DN - NEGATIVE UPTAKE

SEGMENT 3 HCC – LESION DEMARCATION BETTER

HYPERVASCULAR RECURRENT HCC – OTHER DN +VE UPTAKE

SEG 2/3 HYPERVASCULAR HCC WITH PARADOXICAL UPTAKE

HYPERVASCULAR SEG 7 DN - POSITIVE UPTAKE

HYPOVASCULAR < 1.5 CM HCC – T2/DWI BRIGHT

DN –NOT VISIBLE IN OTHER SEQUENCES EXCEPT HEPATOCYTE PHASE

SEGMENT 6 HCC WITH NORMAL ARTERIAL, T2W AND DWI

CT SEGMENT 6 HYPOENHANCING NODULE - HCC IN HEPATOCYTE PHASE > 1.5 CM

CT HYPERVASCULAR LESIONS – SEG 5 HCC

SEGMENT 6 HCC < 1.5 CM

CT HYPERVASCULAR LESION – SEG 5 PSEUDOLESION

SMALL HYPERVASCULAR HCC

SEGMENT 6 HCC & 2 HEMANGIOMAS

SEGMENT 5 – DN FEATURES ON T1/2

SEGMENT 5 HCC – NEGATIVE UPTAKE

COMBINED PRIMOVIST AND DWI

Park MJ et al Radiology 2012:264;761-770

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

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

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

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