diagnosis. multifactorial pathogenesis of hcc normal liver hepatitiscirrhosishcc cell death...

Diagnosis

Multifactorial pathogenesis of HCC

Normal liver

Hepatitis Cirrhosis HCCCell death

Regeneration

Persistent/chronic hepatitis

Fibrosis

• HBV• HCV• Alcohol• Metabolic disorders

– NASH– hemochromatosis

Increasing risk

HBV = hepatitis B virus; HCC = hepatocellular carcinoma; HCV = hepatitis C virus; NASH = non-alcoholic steatohepatitis.

1. Adapted from Rivenbark AG, et al. Clin Cancer Res. 2007;13:2309-12. 2. Marotta F, et al. Clin Ther. 2004;155:187-99.

3. Thorgeirsson S, et al. Nat Genet. 2002;31:339-46. 4. Wang XW, et al. Toxicology. 2002;181-182:43-47.

5. Koike K. Hepatol Res. 2005;33:145-50.

Diagnostic challenges in HCC

HCC has a multifactorial pathogenesis, is accompanied by liver disease, and, as a result, is complex to diagnose

Challenges in diagnosis include: • atypically enhancing HCCs on CT/ MRI

– HCCs not showing “arterial enhancement”

– HCCs not showing “washout” sign

• characterization of borderline lesions – distinguishing between early HCC and HGDN

• differentiation between HCC and other mimickers– arterially enhancing pseudolesions

– arterially enhancing focal liver lesions

International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.Bruix J, Sherman M. Hepatology. 2011;53:1020-2

AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf

CT = computed tomography;MRI = magnetic resonance imaging;HDGN = high-grade dysplastic nodules.

Diagnosis of HCC

Laboratory tests • AFP serology

Imaging studies• Ultrasound

• Spiral CT

• MRI with gadolinium

Biopsy

Required to determine the extent of the disease

The lesions could be find incidentally or on screeening ultrasound

The sequence of tests used to diagnose HCC depends on the sizeof the lesion

AFP: alphafetoprotein

Bruix J, Sherman M. Hepatology. 2011;53:1020-2AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf

Clinical performance: dynamic MRI and CEUS vs biopsy

Prospective study of 89 cirrhosis patients with a mass < 2 cm detected using US

Patients assessed using MRI, CEUS, and FNAB at baseline Final diagnoses: HCC (n = 60), cholangiocarcinoma (n = 1), and

benign lesions (n = 28)

Diagnosis of HCC < 2 cm can be made if MRI and CEUS are conclusive• associated with low sensitivity • absence of conclusive pattern does not rule out HCC

Other non-dynamic imaging methods are needed to make a non-invasive early diagnosis of small HCCs

Sensitivity Specificity PPV NPV

MRI 61.7% 96.6% 97.4% 54.9%

CEUS 51.7% 93.1% 93.9% 50.9%

CEUS + MRI 33.3% 100% 100% 42%

Forner A, et al. Hepatology. 2008;47:97-104.CEUS = contrast -enhanced ultrasound; NPV = negative predictive value; PPV = positive predictive value.

With gadoxetic acid a complete and comprehensive liver assessment can be performed in a single examination within only 20-30 minutes

Gadoxetic acid combines the advantages of dynamic MR imaging with the advantages of hepatocyte-specific imaging > rapid liver-specific uptake of 50% of administered dose by hepatocytes

The three phases of dynamic liver imaging ,,. With gadoxetic acid two additional phases – (4) a delayed phase and (5) a hepatocyte-specific late phase – are added.

The diagnostic techniques would be improved…

Before contrast Arterial phase

Portal phase

Portal phase

Primovist ® Product Characteristic

AASLD PRACTICE GUIDELINE 2011: Surveillance and diagnosis


Arterial hypervascularity AND venous or delayed phase

washout

Other contrast enhanced study (CT or MRI)

Arterial hypervascularity AND venous or delayed phase washout

4-phase MDCT / dynamic contrast enhanced MRI

> 1 cm

Biopsy

No

NoYes

Yes

HCC

Suspected HCC

< 1 cm

Repeat US at 3 months

Investigate according to size

Growing / changing character

Stable

AASLD guidelines: nodules less than 1 cm

Nodules < 1cm should be followed with US at intervals from 3 to 6 months

If there has been no growth over a period of up to 2 years, one can revert to routine surveillance


AASLD guidelines: CT, MRI, and biopsy

Nodules > 1 cm should be investigated further with either 4-phase MDCT or dynamic contrast-enhanced MRI

• if appearances are typical for HCC (i.e. hypervascular in the arterial phase with washout in the portal venous or delayed phase), the lesion should be treated as HCC

• if findings are not characteristic or the vascular profile is not typical, a second contrast enhanced study with the other imaging modality should be performed or the lesion should be biopsied

Biopsies of small lesions should be evaluated by expert pathologists• tissue that is not clearly HCC should be stained with all the available markers including CD34, CK7, glypican

3, HSP-70, and glutamine synthetase to improve diagnostic accuracy

If the biopsy is negative for HCC, the lesion should be followed by imaging at 2- to 6-monthly intervals until the nodule either

• disappears

• enlarges

• displays diagnostic characteristics of HCC

If the lesion enlarges, but remains atypical for HCC a repeat biopsy is recommended


AASLD guidelines:high-grade dysplastic nodules

HGDNs are lesions that enhance less than surrounding tissue during imaging• occurs in nodules < 2 cm diameter

As nodule matures, it acquires typical features of HCC

Biopsy is required to morphologically distinguish HGDNs from HCC:• stromal invasion (a hallmark of HCC) may not be detected

Histological staining should be used to differentiate small lesions:• markers of HCC vs benign tissue include glypican 3, HSP-70, and glutamine synthetase

• CD34 staining of vascular endothelium typically stronger in HCC

• CK7 and CK19 staining typically positive in HCC and negative in benign tissue


Smaller HCC lesions are more difficult to distinguish from malignant or benign nodules

“Very early HCC” are generally hypovascular with ill-defined margins, with vague outline on US and hypovascularity on CT:

• thought to be precursors of typical HCC lesions, but frequency of development to full HCC unknown

“Small” or “progressed HCC” has well-defined margins on US and exhibit characteristics of HCC on CT and histology:

• open show microvascular invasion, suggesting poorer prognosis than for very early HCC

Liver nodules with non-specific vascular profile and negative biopsy should continue enhanced follow-up – repeated biopsy or CT/MRI to detect further growth should be considered

For best outcomes, lesions should be < 2 cm at diagnosis

Important to make diagnosis of HCC as early as possible

AASLD guidelines: dysplasia and early HCC


Pathological diagnosis of early HCC

International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.

Small HCC lesions with malignant potential have only subtle differences from surrounding parenchyma

Refined and up-to-date international consensus on histopathological diagnosis of dysplastic nodules and early HCC allows reproducible assessment of nodular lesions

Patologic Diagnosis of Early HepatocellularCarcinoma> A Report of the International Consensus

Group for Hepatocellular Neoplasia

SPECIAL ARTICLE

Hepatology. 2009;49:658-64

1 Recommend only at available institutions. 2 Hypervascular benign nodules of FNH, adenoma, or angiomyolipoma, etc. Kudo M, Okanoue T. Oncology. 2007;72 Suppl 1:2-15.

Treatment Treatment Follow-up Treatment Follow-up

HCC Hypervascular benign nodule2

BiopsyPseudolesion

A–P shuntHCC

Typical HCC

Uptake (−) Uptake (+)

• SPIO-MRI• Kupffer phase on

Sonazoid CEUS

+Diagnostic

algorithm for hypovascular liver nodules

Hypervascularity in the arterial phase on dynamic CT/MRI in

chronic liver disease

Washout in the portal/venous phase or

corona enhancement

+

−

−

Treatment

HCC

Hypervascular on CTHAHypovascular on CTAP

CTHA/CTAP

+ −

Diagnosis of HCC

1

Diagnostic algorithm for hypervascular nodules

1 When the nodule is hypovascular on dynamic CT or dynamic MRI, sonazoid-enhanced contrast US is recommended to confirm whether it is actually a hypovascular nodule.

2 Recommended only at available institutions.3 Biopsy is not always necessary in this setting. Kudo M, Okanoue T. Oncology. 2007;72 Suppl 1:2-15.

Diagnosis of HCC

Treatment Treatment Follow-up Treatment Follow-up

DN

Biopsy3

Well-differentiated

HCC

Uptake (−) Uptake (+)

• SPIO-MRI• Kupffer phase on

Sonazold CEUS

Diagnostic algorithm for hypervascular liver nodules

Hypovascularity in the arterial phase on dynamic CT/MRI

HCC

CTHA/CTAP

Sonazold CEUS

Biopsy

Treatment

Biopsy

DN

Arterial flow (+) Portal flow ↓

Arterial flow ↓ Portal flow (+)

Well-differentiated

HCC

HCC

Hypovascular

Arterial hypervascularity

Diagnostic algorithm for hypervascular liver nodules

1

2

Diagnostic algorithm for hypovascular nodules

+ −

Pathological diagnosis of dysplasias and early HCC

A consequence of surveillance programmes is the identification of smaller and smaller HCCs as well as dysplastic nodules

The smaller the nodule, the more difficult it is to distinguish malignant from benign nodules

The classification of dysplastic nodules and early HCC has been recently revised to harmonize the approaches taken by western and Japanese pathologists

Available from: Bruix J, Sherman M. http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf. L ast accessed November 2010.

International Consensus Group of Hepatocellular Neoplasm (ICGHN)

IWP classification LGDN HGDN WD-HCC MD-HCC

Pathological features

Gross appearance Vaguely nodularDistinctly nodular

Stromal invasion (–) (–) +/−+/−

Clinical (imaging)

Arterial supply Iso/hypo Iso/hypoIso/hypo

rarely hyperHyper

Portal supply + + + –

Clinicopathological Premalignant Early HCCProgressed

HCC

= portal tract; = unpaired artery;

Iso = isovascular; Hypo = hypovascular; Hyper = hypervascular. International Consensus Group for Hepatocellular Neoplasia.

Hepatology. 2009;49:658-64.

Pathological features of low-grade dysplastic nodules

Sometimes vaguely nodular

Often distinct from surrounding cirrhotic liver because of presence of peripheral fibrous scar

Show mild increase in cell density with a monotonous pattern

Architectural changes beyond clearly regenerative features are not present

Do not contain pseudoglands or markedly thickened trabeculae

Unpaired arteries are sometimes present in small numbers

Nodule in nodule lesions are not present in LGDNs

LGDNs may have diffuse siderosis or diffusely increased copper retention

International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.LGDN = low-grade dysplastic nodules.

Pathological features of high-grade dysplastic nodules

May be distinctly or vaguely nodular in the background of cirrhosis

Lack a true capsule

More likely to show a vaguely nodular pattern than LGDNs

Defined as having architectural or cytological atypia, but the atypia is insufficient for a diagnosis of HCC

Most often show increased cell density, sometimes > 2 times higher than surrounding non-tumoral liver

Unpaired arteries found in most lesions

Nodule in nodule appearance occasionally found


Pathological features of early HCC (small well-differentiated HCC of vaguely nodular type)

Early HCC tumors are vaguely nodular and are characterized by various combinations of the following major histological features• increased cell density > 2 times that of the surrounding tissue, with an

increased nuclear/cytoplasm ratio and irregular thin-trabecular pattern

• varying numbers of portal tracts within the nodule (intratumoral portal tracts)

• pseudoglandular pattern

• diffuse fatty changes

• varying numbers of unpaired arteries

All of the above features may also be found in HGDNs, therefore it is important to note that stromal invasion remains most helpful in differentiating early HCC from HGDNs

International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.HGDN = high grade dysplastic nodule

Pathological diagnosis of early HCC


A: LGDN B: HGDN

C and D: well-differentiated HCC of vaguely nodular type