1. health and fitness
2. disease

JBR–BTR, 2007, 90: 475-481.
HOW TO DIFFERENTIATE LIVER LESIONS IN CIRRHOSIS
C. Bartolozzi, L. Crocetti, M.C. Della Pina1
The diagnosis of hepatocellular carcinoma is based on imaging examinations in combination with clinical and laboratory findings. Despite technological advances, imaging cirrhotic patients remains a challenging issue, since preneoplastic hepatocellular lesions, such as dysplastic nodules, mimic a small hepatocellular carcinoma. One of the
key pathologic factors for differential diagnosis that is reflected in imaging appearances is the vascular supply to the
lesion. It is accepted that imaging techniques may establish the diagnosis of hepatocellular carcinoma in nodules
larger than 1 cm showing arterial hypervascularization and venous wash-out. In lesions that do not show a typical
pattern, biopsy is still recommended. Contrast-enhanced ultrasound, spiral computed tomography or dynamic magnetic resonance imaging are required for characterization of lesions in cirrhotic liver. However, during the development of hepatocellular carcinoma, significant histological changes are present with or without an evident arterial
supply of the nodule. Due to the ability of magnetic resonance to investigate differences in soft tissues and to exploit
the properties of tissue-specific contrast agents, this imaging modality is particularly useful in the demonstration of
the pathologic changes that take place at the histological level and at the level of the biliary and reticuloendothelial
systems during carcinogenetic process in liver cirrhosis.
Key-words: Liver, cirrhosis – Liver neoplasms.
Hepatocellular carcinoma (HCC)
is the fifth most frequent cancer in
the world and the third most common cause of cancer mortality.
HCCs mostly develop in patients
with chronic liver disease caused by
viral hepatitis, alcohol abuse and
inborn metabolic errors. Eighty percent of all HCCs worldwide occur
when the underlying chronic liver
disease has reached the cirrhotic
stage (1). The carcinogenesis in liver
cirrhosis, i.e. the development and
progression of a HCC in a chronically diseased liver, is a multistep and
longterm process characterized by
the progressive accumulation and
interplay of genetic alterations and
associated with the presence of distinct nodular lesions in the liver (2).
These nodular lesions are associated with and can precede the growth
and progression of well-differentiated HCCs (2).
The availability of different imaging modalities help to investigate
three parallel processes that take
place during the carcinogenetic
pathway towards dysplasia and full
malignancy: the progressive capillarization of the sinusoids together
with an increase in number of muscularized unpaired arterioles, the
progressive loss of biliary polarization of the hepatocyte and the
derangement of the microscopic
secretory structure, and the progressive nodular depletion of
Kupffer cells (3) .
Purpose of this review is to
provide information on the role that
different imaging modalities have in
the diagnosis of HCC in cirrhosis,
investigating the vascular supply of
the nodules and the pathologic
changes that take place at the histological level and at the level of the
biliary and reticuloendothelial systems.
Assessment of blood supply to
nodular lesions in cirrhosis
The carcinogenesis in liver cirrhosis is morphologically associated
with the presence of distinct nodular
lesions in the liver (2). These hepatocellular nodules include hyperplastic lesions such as large regenerative nodules (LRNs) and neoplastic
lesions such as low-grade dysplastic
nodules (LGDNs) and high-grade
dysplastic nodules (HGDNs) (4,5).
While LRNs are thought to carry a
malignant potential not greater than
that of the adjacent cirrhosis, neoplastic nodules (LGDNs and HGDNs)
are considered precancerous (6).
Clinical follow-up studies have
revealed that a considerable proportion of HGDNs progress to a HCC
within a few years (7). A recent
detailed study on this subject
showed that the risk of developing
HCC is four-fold higher in patients
having a HGDN; in contrast, the risk
of malignant transformation of a
LGDN is much lower (8).
An LGDN is characterized by preserved hepatic architecture and lowgrade cytological atypias. Portal
areas are present (3) and sometimes
From: 1. Division of Diagnostic and Interventional Radiology, Department of Oncology,
Transplants and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy.
Address for correspondence: Prof. C. Bartolozzi, M.D., Division of Diagnostic and
Interventional Radiology, Pisa University Hospital, Via Roma 67, I-56125 Pisa, Italy.
E-mail: bartolozzi@med.unipi.it
an increase in the number of
unpaired arterioles can be detected
(4,5). An HGDN is a neoplastic lesion
with incipient malignancy. A number of architectural abnormalities
can be documented and portal areas
may be present or absent in the
nodule. An increased number of
unpaired
arteries
is
usually
detectable (9, 10). Therefore HGDNs
have a vascular profile that partially
overlaps with that of HCCs and distinction from well-differentiated
HCC may be very difficult (9, 10). In
well-differentiated HCC architectural
abnormalities are associated with
an abnormally high number of
capillarized vessels, muscularized
unpaired arterioles, and infiltration
of portal tract / fibrous septa / veins
by single hepatocytes (11).
Sinusoidal capillarization and
increase in number of non-triadal
arteries give to the HCC nodules the
typical arterial hypervascularization
that is traditionally depicted by different imaging modalities (contrast
enhanced computed tomography
(CT), dynamic magnetic resonance
imaging (MRI), contrast enhanced
ultrasound (US)) and that is presently considered a fundamental noninvasive radiological criterion for the
diagnosis of HCC in cirrhosis (12, 13).
In the setting of a patient with cirrhosis a mass found incidentally or
on screening US has a high likelihood of being HCC. The sequence of
tests used to diagnose HCC depends
on the size of the lesion (12)
(Table I). Nodules found on US surveillance that are smaller than 1 cm
should be followed with US at intervals from 3-6 months. Nodules
between 1-2 cm should be investigated further with two dynamic
studies, either CT scan, contrast-
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JBR–BTR, 2007, 90 (6)
isoechoic or hypoechoic appearance
in the portal venous and delayed
phases (Fig. 1) (18, 19). In contrast,
LRN and DN usually does not show
any early contrast uptake, and
resemble the enhancement pattern
of liver parenchyma in particular in
the portal-venous and delayed phases. In two recent series, selective
arterial enhancement at contrast US
was observed in 91-96% of HCC
lesions, confirming that contrast US
may be a tool to show arterial
neoangiogenesis of HCC (17, 18).
Assuming findings at spiral CT as
the gold standard, the sensitivity of
contrast US in the detection of arterial hypervascularity was 97% in
lesions larger than 3 cm, 92% in
lesions ranging from 2 to 3 cm, 87%
in lesions ranging from 1 to 2 cm,
and 67% in lesions smaller than 1
cm (18). The vascular pattern of
some nodules may be different from
that at spiral CT with more nodules
being positive only at contrastenhanced US. The proportion of
these nodules may reach 19%, as
reported in one study (19). This discrepancy may be because of the different vascular distribution of the
US and CT contrast agents (being
the first purely blood-pool contrast
agents, and the latter intravascularinterstitial), the capacity of perfusional US, by working in continuous
real-time, to detect hypervascularity
lasting for only a short time or
occurring very early, or both (19).
Even at spiral CT typical HCC
lesions shows clear-cut enhancement in the arterial phase and rapid
wash-out in the portal venous and
delayed phases (Fig. 2). In contrast,
Table I. — Diagnostic criteria for HCC according to American Association
for the Study of Liver Diseases (AASLD) and the European Association for
the Study of Liver (EASL) (12).
DIAGNOSTIC CRITERIA FOR HCC
• Cyto-histological criteria
• Non-invasive criteria (cirrhotic patients)
1. One imaging technique *
Focal lesion > 2 cm with arterial hypervascularization
and venous wash-out
2. Two coincident imaging techniques *
Focal lesion 1-2 cm with arterial hypervascularization
and venous wash-out
* Three techniques considered: contrast US, CT, and dynamic MR imaging
enhanced US or MRI with contrast.
If the appearances are typical of
HCC (i.e., hypervascular with
washout in the portal/venous phase)
in two techniques the lesion should
be treated as an HCC. If the nodule
is larger than 2 cm at initial diagnosis and has the typical features of
HCC on a dynamic imaging technique, biopsy is not necessary for
the diagnosis of HCC. Alternatively,
if the AFP is > 200 ng/mL biopsy is
also not required (12) (Table I).
US is the imaging technique most
commonly used worldwide for early
detection of HCC in surveillance programs (12). The introduction of
microbubble contrast agents and
the development of contrast-specific
scanning techniques have opened
new prospects in liver US (14).
Contrast-specific techniques produce images based on nonlinear
acoustic effects of microbubbles
A
and display enhancement in grayscale, with high contrast and spatial
resolution. The advent of secondgeneration agents and low mechanical index real-time scanning techniques has been instrumental in
improving the easiness and the
reproducibility of the examination (14-19) and has prompted the
American Association for the Study
of Liver Diseases (AASLD) and the
European Association for the Study
of Liver (EASL) to introduce contrast-enhanced US in the diagnostic
flow chart, as one of the imaging
modalities useful to demonstrate
the vascular pattern of nodules
higher than 1 cm in diameter (12)
(Table I).
A typical HCC shows strong intratumoral enhancement in the arterial
phase (i.e., within 25-35 seconds
after the start of contrast injection)
followed by rapid wash-out with
B
C
Fig. 1. — HCC at contrast-enhanced US. The HCC nodule, with inhomogeneous hypo-hyperechoic appearance at baseline (A,
arrow) shows strong intratumoral enhancement in the arterial phase (B, arrow) followed by rapid wash-out with slightly hypoechoic
appearance in the delayed phase (C, arrow).
LIVER LESIONS IN CIRRHOSIS — BARTOLOZZI et al
A
B
477
C
D
Fig. 2. — HCC at contrast-enhanced spiral CT. The HCC lesion in segment IV is barely visible at baseline scan (A), shows clear-cut
enhancement in the arterial phase (B, arrow) and rapid wash-out in the portal venous (C, arrow) and delayed phases (D, arrow).
A
B
C
D
Fig. 3. — HCC at dynamic MR imaging. The HCC lesion in segment II is hyperintense in T2-weighted image (A, arrow), hypointense
in T1-weighted image (B, arrow), shows enhancement in Gadolinium-enhanced arterial phase (C, arrow) and results hypointense in
the portal venous phase (D, arrow).
LRN and DN usually fail to exhibit
this feature and appear isoattenuating or hypoattenuating to surrounding liver parenchyma (20, 21).
Identification of morphological features of HCC may support the diagnosis of HCC in questionable cases.
Tumor capsule appears as a peripheral rim, which is hypoattenuating
on unenhanced and arterial-phase
images and hyperattenuating on
delayed phase images. The CT
detection rate of the capsule is
strongly dependent on lesion size,
and is low in small tumors because
the capsule itself is thin and poorly
developed (22). Internal mosaic
architecture, with components
showing various attenuation indexes on CT images, is another typical
feature of HCC that, however, is usually detected in large nodular
lesions. Invasion of portal vein
branches, with partial or complete
neoplastic thrombosis, is quite frequent in advanced tumors and is
best shown on portal venous phase
images. Neoplastic thrombi, however, may enhance in the arterial
phase, like the main tumor (23).
In a recent meta-analysis evaluating the accuracy of different imaging modalities in the diagnosis of
HCC, spiral CT resulted to have a
sensitivity of 67.5% (95% CI 55%-
80%) and a specificity of 92.5%
(95%CI 89%-96%), abstracting and
pooling the data coming form
10 studies using histopathology of
the explanted liver as standard of
reference (24). The variability of
these results indicate the presence
of a heterogeneity that is probably
related to differences in technical
details (e.g., variations in collimation and the contrast media infusion
rate) and image interpretation,
although no pertinent data were
available. In five series that reported
careful lesion-by-lesion imagingpathologic correlation in explanted
livers, the sensitivity of spiral CT in
detection of HCC lesions ranged 5279% (25-29). Interestingly, 92-100%
of HCC lesions greater than 2 cm
were diagnosed while only 10-43%
of lesions smaller than 1 cm and 4465% of lesions of 1-2 cm were identified. In a recent series in which
multidetector spiral CT was used,
the sensitivity in diagnosing HCC of
1-2 cm was of 76% (29). False positive interpretations are usually
caused by small lesions or pseudolesions (29-32). It is well known that
hyperattenuating nodules may
correspond to preneoplastic hepatocellular lesions, such as lLGDN and
HGDNs (28, 30). Moreover small
(less than 1.5 cm) flash-filling
hemangiomas, which may enhance
homogeneously in the arterial
phase (30), can be misinterpreted as
small HCC. However, these lesions
usually do not exhibit contrast
wash-out and show attenuation
equivalent to that of the aorta during portal venous and delayed
phase CT imaging (32). Nontumorous arterioportal shunts can
also be a cause of pseudolesions,
although in most cases they have
the typical wedge-shaped and
homogeneous appearance (with or
without internal linear branching
structures representing early opacification of portal veins during the
arterial phase) and are isoattenuating or slightly hyperattenuating
during the portal venous phase (33).
Dynamic MRI well demonstrates
the typical vascular features of overt
HCC, that is, arterial phase enhancement with portal-venous and/or
delayed phase wash-out (Fig. 3).
This feature enables differentiation
of frank HCC from LRN or DN, which
usually are not hypervascular (Fig.4)
(13). Nevertheless, as discussed for
CT imaging, non-malignant hepatocellular lesions – especially HGDN –
may show increased arterial blood
supply and be indistinguishable
from a small HCC. In addition, nontumorous arterioportal shunts may
478
JBR–BTR, 2007, 90 (6)
A
B
C
D
E
Fig. 4. — DN at dynamic MR imaging. The nodule in segment IV is hyperintense in T1-weighted image (A, arrow), does not show
significant enhancement in the arterial phase (B, arrow), and results hypointense in the portal venous (C, arrow) and delayed phases (D, arrow). Dynamic subtraction image shows the lack of enhancement throughout the dynamic study (E, arrows).
cause false-positive interpretations
(34). In one study, the majority (93%)
of hepatic arterial phase enhancing
lesions less than 2 cm, that were
occult at T2-weighted and portal
and/or equilibrium phase MRI, had
no correlative pathologic finding,
even in patients with pathologically
proved HCC (35).
In series in which MRI findings
were correlated with histopathologic results after thin-section slicing of
the explanted liver, lesion-by-lesion
analysis revealed a sensitivity of 3378%, with positive predictive values
ranging 54-93% (25-27, 36, 37). In
particular, 100% of HCC lesions
greater that 2 cm were diagnosed
while 4-71% of lesions smaller than
1 cm and 52-89% of lesions of 1-2
cm were identified. The clinical significance of these results is relevant.
The ability to detect tumors larger
than 2 cm with high sensitivity is
significant because this size is the
threshold for scoring additional priority points according to the Model
of End-Stage Disease (38).
State-of-the-art dynamic MRI outperforms single-detector spiral CT
in the detection of small nodules: in
one comparative study with explant
correlation, the sensitivity for the
identification of additional HCC
lesions was significantly higher for
MRI than for spiral CT in the range 12 cm (27).
Assessment of histological changes
in nodular lesions in cirrhosis
During the development of HCC,
significant histological changes are
present with or without an evident
arterial supply of the nodule. Due to
the ability of MR to investigate differences in soft tissues and to
exploit the properties of tissue-specific MR contrast agents, this imaging modality is particularly useful in
the demonstration of the pathologic
changes that take place at the histological level and the level of the
A
biliary and reticuloendothelial systems during carcinogenetic process
in liver cirrhosis.
In fact, HCC shows a variety of
MRI features, that reflect the variable characteristics of this malignancy in tumor architecture, grading, stromal component, as well as
intracellular content of certain substances, such as fat, glycogen, or
metal ions, that greatly affect the
appearance of the lesion on baseline T1-weighted and T2-weighted
MR images (13) (Fig. 5, 6). The signal
intensity
may
range
from
B
Fig. 5. — Well-differentiated HCC at plain MR imaging. The
nodule appears markedly hyperintense in T1-weighted image
(A, arrow) due to the presence of glycoproteins, and isointense
in T2-weighted image (B, arrow).
LIVER LESIONS IN CIRRHOSIS — BARTOLOZZI et al
A
B
Fig. 6. — HCC with fat deposits at plain MR imaging. The nodule appears hyperintense in T1-weighted in-phase image (A,
arrow), and hypointense in T1-weighted out-of-phase image (B,
arrow).
hypointensity to isointensity to
hyperintensity on T1-weighted
images and from isointensity to
hyperintensity on T2-weighted
images. Hyperintensity on T1weighted images and isointensity
on T2-weighted images are typical
features
of
well-differentiated
tumors, while hypointensity on T1weighted images and hyperintensity
on T2-weighted images are usually
associated with moderately or poorly-differentiated tumors (39). The
signal intensity of HCC lesions may
be inhomogeneous, reflecting the
presence of areas with different
degree of differentiation. Lesion signal intensity on baseline T1-weighted and T2-weighted images may
help differentiate HCC from LRN or
DN, although considerable overlap
exists (39).
During the carcinogenetic pathway towards dysplasia and full
malignancy a progressive loss of
biliary polarization of the hepatocyte with the derangement of the
microscopic secretory structure
takes place. While in LGDN the biliary domain of the cells is preserved
and bile ducts are present in portal
areas (3, 11), in HGDN biliary function can be partially impaired and
bile ducts can be missing. In welldifferentiated HCC bile canaliculi are
nearly always present between cells
and bile pigment may be found in
tumor cells or in dilated canaliculi.
However, the organization of portal
areas is completely lost and bile
ducts are absent, causing the inefficient biliary drainage from the neoplastic tissue. Proliferation of welldifferentiated small HCCs is closely
related to tumor dedifferentiation
and moderately to poorly differentiated HCC tissues gradually replace
the
initial
well-differentiated
HCC (40). Biliary function is lost by
tumoral cells and bile is rarely present in poorly differentiated HCC.
Biliary function of hepatocellular
nodule can be investigated by
means of hepatobiliary or hepatocyte-selective contrast agents,
which are paramagnetic compounds
that are partially taken up by the
hepatocytes and excreted in the biliary tract (41). In the hepatobiliary
phase these agents produce sustained enhancement of liver
parenchyma
on
T1-weighted
images (41).
HCC
demonstrates
variable
uptake of hepatobiliary contrast
479
agents (42-44). This is a result of the
fact that malignant cells of well-differentiated HCC may preserve hepatocellular function and may thus
take up the contrast agent.
Therefore, depending on the
amount of residual hepatobiliary
function of the cells and the degree
of absence of portal areas in the
tumor, the amount of uptake of the
contrast agent can vary. HCC can be
hyperintense,
isointense
or
hypointense after administration of
a hepatobiliary constrast-agent (4244). The HCC nodule is hypointense
when the tumor cells fail to take up
the contrast, while it is hyperintense
when the biliary clearance of the
contrast media is quicker in the surrounding parenchyma than in the
nodule (42) (Fig. 7). Benign hepatocellular lesions, including LRNs and
dysplastic nodules may have homogeneous, hyperintense enhancement simulating that of some HCC,
and it can be difficult to differentiate
these benign/premalignant lesions
from HCC after the administration of
hepatobiliary contrast agents (4345) (Fig. 8).
Considering Kupffer cell population, it has been shown by
histopathological studies that dysplastic lesions in cirrhosis possess
an almost identical or sometimes
slightly increased number of Kupffer
cells when compared to cirrhotic
parenchyma (46). In well differenti-
A
B
C
D
E
F
Fig. 7. — HCC at Gd-EOB-DTPA enhanced MR imaging. The nodule in segment VII is
slightly hyperintense in T2-weighted image (A, arrow), isointense in T1-weighted
image (B, arrow), shows significant enhancement in the arterial phase (C, arrow) and
results hypointense in the portal venous (D, arrow) and delayed (E, arrow) phases. In
the hepatobiliary delayed phase (20 minutes) the nodule appears hypointense
(F, arrow).
480
JBR–BTR, 2007, 90 (6)
10.
11.
A
B
C
12.
13.
D
E
F
14.
Fig. 8. — DNs at Gd-EOB-DTPA enhanced MR imaging. Multiple nodules, (major
located in segment VII , arrows), are slightly hypo- or isointense in T2-weighted image
(A), hyperintense in T1-weighted image (B), do not show significant enhancement in
the arterial phase (C) and result isointense in the portal venous (D) and delayed (E)
phases. In the hepatobiliary delayed phase (20 minutes) the nodules appear iso- or
hyperintense (F).
ated HCC Kupffer cells may be present (46). In fact, in this small
tumors endothelial cells morphologically resemble normal sinusoidal endothelial cells giving an
environment similar to that of normal hepatic parenchyma (46). The
amount of Kupffer cell in cancerous
tissues decreases as tumor size
increases and as grading of the
tumor increases (46). MR reticuloendothelial-system (RES)-targeted
contrast agents are superparamagnetic particles of iron oxide (SPIO)
which produce distortions of local
magnetic field resulting in signal
loss on T2-weighted images. Once
injected intravenously, these agents
are rapidly removed from the circulation by the RES system (47).
Kupffer cells in the liver play a dominant role in this process, taking up
more than 80% of circulating particles. Moderately or poorly differentiated HCCs have usually high signal
intensity and dysplastic nodules
that contain nearly the same number of Kupffer cells as the surrounding cirrhotic hepatic parenchyma
con be not depicted on the post-contrast T2-weighted MR images. There
may be well-differentiated HCCs or
dysplastic nodules that contain the
same number or even more Kupffer
cells than does the surrounding
parenchyma and are depicted as
having a slightly lower signal intensity than does the surrounding liver,
standing out as a nodule (46-49).
15.
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