Diagnosis
Multifactorial pathogenesis of HCC
Persistent/chronic hepatitis
Fibrosis
Normal
liver
•
•
•
•
HBV
HCV
Alcohol
Metabolic disorders
– NASH
– hemochromatosis
HBV = hepatitis B virus;
HCC = hepatocellular carcinoma;
HCV = hepatitis C virus;
NASH = non-alcoholic steatohepatitis.
Cell death
Hepatitis
Cirrhosis
HCC
Regeneration
Increasing risk
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
CT = computed tomography;
MRI = magnetic resonance imaging;
HDGN = high-grade dysplastic nodules.
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
Diagnosis of HCC

Laboratory tests
• AFP serology

Imaging studies
• Ultrasound
• Spiral CT
• MRI with gadolinium

Required to determine the extent of the disease
Biopsy
The lesions could be find incidentally or on screeening ultrasound
The sequence of tests used to diagnose HCC depends on the size
of the lesion
AFP: alphafetoprotein
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD 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)
MRI
CEUS
CEUS + MRI

Sensitivity
61.7%
51.7%
33.3%
Specificity
96.6%
93.1%
100%
PPV
97.4%
93.9%
100%
NPV
54.9%
50.9%
42%
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
CEUS = contrast -enhanced ultrasound;
NPV = negative predictive value; PPV = positive predictive value.
Forner A, et al. Hepatology. 2008;47:97-104.
The diagnostic techniques would be improved…
 With gadoxetic acid a complete
and comprehensive liver
assessment can be performed in
a single examination within only
20-30 minutes
Before contrast
 Arterial phase
 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
 Portal phase
Portal phase
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.
Primovist ® Product Characteristic
AASLD PRACTICE GUIDELINE 2011:
Surveillance and diagnosis
Suspected HCC
< 1 cm
> 1 cm
Repeat US at 3 months
4-phase MDCT / dynamic
contrast enhanced MRI
Growing / changing
character
Investigate
according to size
Arterial hypervascularity AND
venous or delayed phase washout
Stable
Yes
Other contrast enhanced
study (CT or MRI)
No
HCC
Arterial hypervascularity AND
venous or delayed phase
washout
Biopsy
Yes
No
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf
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
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf
AASLD guidelines: CT, MRI, and biopsy

Nodules > 1 cm should be investigated further with either 4-phase MDCT
or dynamic contrast-enhanced MRI
•
•

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
•
•
•

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
disappears
enlarges
displays diagnostic characteristics of HCC
If the lesion enlarges, but remains atypical for HCC a repeat biopsy is
recommended
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf
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
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf
AASLD guidelines: dysplasia and early HCC
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
Bruix J, Sherman M. Hepatology. 2011;53:1020-2
AASLD PRACTICE GUIDELINE 2011: http://www.aasld.org/practiceguidelines/Documents/Bookmarked%20Practice%20Guidelines/HCCUpdate2010.pdf
Pathological diagnosis of early HCC
SPECIAL ARTICLE
Patologic Diagnosis of Early Hepatocellular
Carcinoma> A Report of the 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
International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.
Diagnostic algorithm for hypervascular nodules
Hypervascularity in the arterial
phase on dynamic CT/MRI in
chronic liver disease
Diagnostic
algorithm for
hypovascular
liver nodules
−
+
Diagnosis of HCC
Washout in the portal/
venous phase or
corona enhancement
1
Hypervascular on CTHA
Hypovascular on CTAP
−
+
+
• SPIO-MRI
• Kupffer phase on
Sonazoid CEUS
Uptake (−)
Typical
HCC
HCC
Treatment
Uptake (+)
Pseudolesion
A–P shunt
Follow-up
−
HCC
Treatment
Biopsy
HCC
Treatment
CTHA/CTAP
Treatment
1 Recommend only at available institutions.
2 Hypervascular benign nodules of FNH, adenoma, or angiomyolipoma, etc.
Hypervascular benign nodule2
Follow-up
Kudo M, Okanoue T. Oncology. 2007;72 Suppl 1:2-15.
Diagnostic algorithm for hypovascular nodules
Diagnosis of HCC
Hypovascularity in the arterial
phase on dynamic CT/MRI
Diagnostic algorithm for
hypervascular liver nodules
+
−
1
• SPIO-MRI
• Kupffer phase on
Sonazold CEUS
Uptake (−)
Biopsy
HCC
Welldifferentiated
HCC
Treatment
Diagnostic algorithm for
hypervascular liver nodules
2
CTHA/CTAP
Arterial flow (+)
Portal flow ↓
Arterial flow ↓
Portal flow (+)
Biopsy
DN
HCC
Treatment
Arterial hypervascularity
Hypovascular
Uptake (+)
Biopsy3
Sonazold
CEUS
Follow-up
Treatment
Welldifferentiated
HCC
Treatment
DN
Follow-up
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.
Kudo M, Okanoue T. Oncology. 2007;72 Suppl 1:2-15.
3 Biopsy is not always necessary in this setting.
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
Vaguely nodular
Distinctly
nodular
Pathological features
Gross appearance
+/−
(–)
(–)
+/−
Arterial supply
Iso/hypo
Iso/hypo
Iso/hypo
rarely hyper
Hyper
Portal supply
+
+
+
–
Early HCC
Progressed
HCC
Stromal invasion
Clinical (imaging)
Clinicopathological
= portal tract;
Premalignant
= 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
LGDN = low-grade dysplastic nodules.
International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.
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
International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.
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
HGDN = high grade dysplastic nodule
International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.
Pathological diagnosis of early HCC
A: LGDN
B: HGDN
C and D: well-differentiated HCC of vaguely nodular type
International Consensus Group for Hepatocellular Neoplasia. Hepatology. 2009;49:658-64.