AJR 2003; 180:1015-1022
© American Roentgen Ray Society
Hepatocellular Carcinoma: Imaging and Imaging-Guided Intervention
Kelvin H. Y. Lee1,
Martin E. O'Malley1,2,
John R. Kachura1,
Masoom Haider1 and
Anthony Hanbidge1
1 Department of Medical Imaging, University Health Network and Mount Sinai
Hospital, University of Toronto, Toronto, Ontario, M5G 2C4 Canada.
2 Department of Medical Imaging, Toronto General Hospital, ES 1-401a, 200
Elizabeth St., Toronto Ontario, M5G 2C4 Canada.
Received July 16, 2002;
accepted after revision August 28, 2002.
Address correspondence to M. E. O'Malley.
Presented at the annual meeting of the American Roentgen Ray Society,
Atlanta, April–May 2002.
Introduction
Hepatocellular carcinoma is relatively uncommon in North America, with
incidence rates varying between one and three cases per 100,000 person-years
[1]. However, the incidence has
increased over the past several years, mainly because of rising rates of
hepatitis C virus infection
[1]. Imaging plays a central
role in the management of hepatocellular carcinoma, including screening
populations at risk, confirming the diagnosis, planning treatment, guiding
therapy, and following up after treatment. The purpose of this pictorial essay
is to describe the role of imaging and imaging-guided therapy in patients with
hepatocellular carcinoma.
Risk Factors and Screening
Most cases of hepatocellular carcinoma arise in cirrhotic livers. Common
causes of cirrhosis include chronic hepatitis B infection, chronic hepatitis C
infection, and chronic ethanol abuse. The regular screening of populations at
risk for hepatocellular carcinoma using serum 
-fetoprotein measurements
and sonography affords the best opportunity for early diagnosis and improved
survival. However, mildly elevated levels of -fetoprotein (<500
ng/mL) are relatively nonspecific and can be seen in up to 20% of patients
with chronic hepatitis and 40% of those with cirrhosis
[2]. Using a threshold of 500
ng/mL for the -fetoprotein value yields a specificity of 90% and a
sensitivity of 50% for the detection of hepatocellular carcinoma
[2]. Sonography is similarly
nonspecific, and any solid lesion detected in a cirrhotic liver needs to be
further evaluated with CT or MR imaging.
Role of CT and MR Imaging
CT performed with a triphasic liver protocol can be used to characterize
focal lesions detected on sonography and to evaluate patients with negative
findings on a screening sonogram but a significantly elevated
-fetoprotein value. CT is also used for staging hepatocellular
carcinoma and for follow-up of patients who have been treated with resection,
radiofrequency ablation, or percutaneous ethanol injection. MR imaging is used
primarily to evaluate liver lesions with indeterminate findings on CT and to
image patients with a contraindication to iodinated contrast material.
Liver Lesions in Patients with Cirrhosis
In most patients with end-stage liver disease, changes in the liver,
including hepatic nodularity and lobar redistribution, are visible on imaging.
The transformation of regenerative nodules, present in all cirrhotic livers,
to dysplastic nodules to hepatocellular carcinoma is well documented
[3]. Regenerative nodules
correspond to areas of parenchymal enlargement surrounded by fibrous septa and
occur in response to necrosis or altered circulation.
Regenerative nodules are visible on unenhanced CT in approximately 25% of
patients and appear as hyperattenuating nodules
[4]. On contrast-enhanced CT,
these nodules are typically isointense and therefore indistinguishable from
the surrounding liver parenchyma. On T1-weighted MR images, regenerative
nodules have variable signal intensity but are usually isointense to the
surrounding liver parenchyma. On T2-weighted MR images, regenerative nodules
are of low signal intensity (Fig.
1A,
1B,
1C).
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Fig. 1A. —59-year-old man with hepatitis B. T2-weighted MR image shows
mildly hyperintense hepatocellular carcinoma nodule (arrow) in
segments VIII and IVA of liver on background of hypointense regenerative
nodules (asterisks) scattered throughout liver.
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Fig. 1B. —59-year-old man with hepatitis B. T1-weighted MR image shows
hepatocellular carcinoma nodule (arrow). Nodule is heterogeneous with
hypointense capsule on background of multiple hypointense siderotic
regenerative nodules (asterisk).
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Fig. 1C. —59-year-old man with hepatitis B. Arterial phase
gadolinium-enhanced fat-suppressed T1-weighted MR image shows marked
enhancement of hepatocellular carcinoma nodule (arrow) compared with
background regenerative nodules (asterisk), which are not
hypervascular.
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Dysplastic nodules are regenerative nodules that have cellular atypia
without frank malignant change. Most dysplastic nodules cannot be visualized
on CT or MR imaging; however when visible on CT, these nodules may appear
slightly hyperattenuating on unenhanced images
[3], and when visible on MR
imaging, they are typically bright on T1-weighted images, dark on T2-weighted
images, and isointense on contrast-enhanced images (Fig.
2A,
2B).
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Fig. 2B. —51-year-old man with hepatitis B. T2-weighted MR image shows
dysplastic nodule (arrow) to be dark. Second dysplastic nodule seen
in A is located more superiorly and is not visible on this image.
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Hepatocellular Carcinoma
Hepatocellular carcinoma has three growth patterns: a solitary lesion,
multifocal lesions (Fig. 3), or
diffuse hepatic infiltration. Larger masses tend to be heterogeneous and to
have a central area of necrosis and abnormal internal vessels. On sonography,
hepatocellular carcinoma has a variable appearance, but most small lesions are
hypoechoic. Arterial hypervascularity is the hallmark of hepatocellular
carcinoma on contrast-enhanced CT and MR imaging, with washout of
intralesional contrast on portal venous and delayed phase images. On MR
imaging, hepatocellular carcinoma has a variable signal intensity on
T1-weighted images (Fig. 4A,
4B,
4C,
4D), whereas most
hepatocellular carcinomas are mildly hyperintense on T2-weighted images.
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Fig. 3. —69-year-old man with autoimmune hepatitis. Arterial phase
contrast-enhanced CT scan shows dominant hepatocellular carcinoma in
peripheral right lobe (arrow). Multifocal enhancing tumor
(asterisk) can be seen throughout remainder of liver.
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Fig. 4B. —51-year-old man with chronic hepatitis B and C. In-phase
(B) and out-of-phase (C) T1-weighted MR images show fat within
hepatocellular carcinoma (arrow), which has lower signal on
out-of-phase image than on in-phase image.
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Fig. 4C. —51-year-old man with chronic hepatitis B and C. In-phase
(B) and out-of-phase (C) T1-weighted MR images show fat within
hepatocellular carcinoma (arrow), which has lower signal on
out-of-phase image than on in-phase image.
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Fig. 4D. —51-year-old man with chronic hepatitis B and C. Arterial
phase gadolinium-enhanced fat-suppressed T1-weighted MR image shows
hepatocellular carcinoma (arrow) to be brightly enhancing.
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Hepatocellular carcinoma tends to invade the portal and hepatic veins,
producing tumor thrombus (Fig.
5A,
5B,
5C). Uncommonly,
hepatocellular carcinoma may invade the biliary tree, causing obstructive
jaundice (Fig. 6A,
6B). The most common locations
of metastatic spread are to the lungs and to the regional lymph nodes, with
osseous (Fig. 7), adrenal, and
peritoneal metastases being less common
[5].
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Fig. 5A. —57-year-old woman with hepatitis C. Arterial phase
contrast-enhanced CT scan shows large hypervascular hepatocellular carcinoma
(asterisk) with tumor thrombus (arrow) extending into right
hepatic vein and inferior vena cava. Tumor thrombus can be distinguished from
bland thrombus by enhancing abnormal vessels within clot itself.
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Fig. 5B. —57-year-old woman with hepatitis C. Arterial phase
contrast-enhanced CT scan obtained at more superior level than A shows
hepatocellular carcinoma (asterisk) with tumor thrombus
(arrow) extending into right atrium.
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Fig. 6A. —81-year-old man with hepatitis B. Transverse sonogram
obtained through left lobe of liver shows poorly defined hepatocellular
carcinoma (asterisk). Note intraductal extension with tumor
incompletely filling segment II bile duct (black arrow). Segment III
bile duct (white arrow) is completely obliterated by tumor.
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Fig. 6B. —81-year-old man with hepatitis B. Arterial phase
contrast-enhanced CT scan that corresponds to A shows similar findings
of hepatocellular carcinoma (asterisk) growing into and obstructing
segment II bile duct (arrow).
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Fig. 7. —58-year-old woman with hepatitis B. Arterial phase
gadolinium-enhanced fat-suppressed T1-weighted MR image shows hypervascular
metastasis (arrow) to spine. Hepatocellular carcinoma (not shown) was
located in dome of right lobe of liver.
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Treatment
Sonography, CT, and MR imaging are complementary in assessing surgical
resect-ability. Any extrahepatic disease is a contraindication for surgery
(Fig. 8A,
8B). Tumors should have at
least a 1-cm margin from the adjacent vessels for segmentectomy or lobectomy.
Because satellite nodules and portal vein tumor thrombus are predictors for
radiologically occult disease elsewhere in the liver, these findings generally
exclude a patient from being considered for treatment with surgical resection
[6]. Given that most patients
with hepatocellular carcinoma have underlying cirrhosis, the risk that the
remaining liver will not function sufficiently after resection is significant.
Surgery can be considered in patients with Child-Pugh class A cirrhosis or
with indocyanine green clearance levels of 5 mL/min/kg of body weight or
higher [7]. Preoperative
percutaneous transhepatic portal vein embolization of hepatic segments to be
resected has been used to induce compensatory hypertrophy of non-embolized
liver (Fig. 9A,
9B,
9C). When performed several
weeks before surgery, this treatment may optimize hepatic reserve in patients
undergoing partial hepatectomy.
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Fig. 8A. —77-year-old woman with hepatitis C and unresectable
hepatocellular carcinoma. Arterial phase contrast-enhanced CT scan shows
subcapsular hepatocellular carcinoma (thick arrow). Extrahepatic
tumor extension (thin arrow) beyond liver capsule precludes surgical
resection and transplantation.
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Fig. 8B. —77-year-old woman with hepatitis C and unresectable
hepatocellular carcinoma. Oblique subcostal sonogram of hypoechoic
hepatocellular carcinoma (thick arrow) shows irregular tendrils
(thin arrow) of extracapsular tumor extension more clearly than CT
scan (A).
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Fig. 9A. —53-year-old woman who underwent preoperative portal vein
embolization in anticipation of surgical resection for borderline liver
function. Portal venogram obtained using carbon dioxide confirms patency of
portal venous system before embolization.
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Fig. 9B. —53-year-old woman who underwent preoperative portal vein
embolization in anticipation of surgical resection for borderline liver
function. Portal venogram obtained after embolization with trisacryl gelatin
microspheres (Embosphere Microspheres; Biosphere Medical, Rockland, MA) shows
truncation of right (white arrows) and medial left (black
arrows) portal vein branches.
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Fig. 9C. —53-year-old woman who underwent preoperative portal vein
embolization in anticipation of surgical resection for borderline liver
function. Portal venous phase contrast-enhanced CT scan obtained after
trisegmentectomy shows marked compensatory hypertrophy of remaining left
lateral lobe.
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Liver transplantation is considered the definitive treatment for
hepatocellular carcinoma because this procedure removes the risk of
hepatocellular carcinoma developing from occult disease left behind or new
tumors arising from dysplastic nodules in the remaining cirrhotic liver. Any
extrahepatic disease is a contraindication to transplantation, and the maximal
tumor burden should be a single lesion smaller than 5 cm or fewer than three
lesions with each lesion being smaller than 3 cm
[8].
Imaging-Guided Therapy
Both radiofrequency ablation and percutaneous ethanol injection using
sonographic guidance result in local tumor ablation and are suitable in
patients who are not candidates for surgery or transplantation. Patients with
multiple lesions or a single lesion that is too large for percutaneous
ablation may be considered for transarterial chemoembolization.
Transarterial chemoembolization combines the administration of chemotherapy
directly into the hepatic artery, thereby avoiding the first-pass effect and
systemic toxicity, with embolization to prolong the duration that the tumor
retains the agent (Fig. 10A,
10B,
10C,
10D). Transarterial
chemoembolization can be used as an adjunctive or temporizing measure in
patients with borderline tumor burden who are awaiting liver transplantation
or in palliative patients who are not candidates for radiofrequency ablation
or percutaneous ethanol injection.
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Fig. 10A. —63-year-old woman who underwent transarterial
chemoembolization for hepatocellular carcinoma. Hepatic arteriograms from
early arterial phase (A) and capillary phase (B) show mass
effect (arrow, A) and tumor blush (arrow, B)
of hypervascular hepatocellular carcinoma.
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Fig. 10B. —63-year-old woman who underwent transarterial
chemoembolization for hepatocellular carcinoma. Hepatic arteriograms from
early arterial phase (A) and capillary phase (B) show mass
effect (arrow, A) and tumor blush (arrow, B)
of hypervascular hepatocellular carcinoma.
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Fig. 10C. —63-year-old woman who underwent transarterial
chemoembolization for hepatocellular carcinoma. Arterial phase
contrast-enhanced CT images obtained before (C) and after (D)
transarterial chemoembolization with doxorubicin and ethiodized oil (Lipiodol
UltraFluid; E-Z-EM Canada, Montreal, Quebec, Canada) show hypervascular
hepatocellular carcinoma (arrow, C) and ethiodized oil
localizing to vascular portions of hepatocellular carcinoma (arrow,
D).
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Fig. 10D. —63-year-old woman who underwent transarterial
chemoembolization for hepatocellular carcinoma. Arterial phase
contrast-enhanced CT images obtained before (C) and after (D)
transarterial chemoembolization with doxorubicin and ethiodized oil (Lipiodol
UltraFluid; E-Z-EM Canada, Montreal, Quebec, Canada) show hypervascular
hepatocellular carcinoma (arrow, C) and ethiodized oil
localizing to vascular portions of hepatocellular carcinoma (arrow,
D).
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Follow-Up After Treatment
Patients undergo routine monitoring after treatment: -fetoprotein
levels are measured, and cross-sectional imaging is performed. CT is ideally
suited for following up patients who have undergone radiofrequency ablation or
percutaneous ethanol injection because any nodular areas of enhancement are
suggestive of residual or recurrent tumor (Fig.
11A,
11B). In patients who have
undergone surgery, resection margins should be carefully evaluated on imaging
studies for recurrent tumor (Fig.
12A,
12B).
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Fig. 11B. —64-year-old man with chronic hepatitis B and C. Arterial
phase contrast-enhanced CT scan obtained 1 day after radiofrequency ablation
shows residual tumor (arrow) as persistent area of nodular
enhancement within radiofrequency ablation defect.
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Fig. 12A. —59-year-old man with chronic hepatitis B. Arterial phase
contrast-enhanced CT scan shows predominantly hypoattenuating hepatocellular
carcinoma (arrow) in right lobe. Note surrounding transient perfusion
abnormality peripheral to tumor.
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Conclusion
The management of hepatocellular carcinoma requires a multidisciplinary
approach among hepatologists, surgeons, and radiologists. Our overall approach
to the management of hepatocellular carcinoma is presented in the flowchart
shown in Figure 13.
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Introduction
Risk Factors and Screening
