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GASTROINTESTINAL NEOPLASMS 1653

Hepatocellular Carcinoma: Illustrated

Guide to Systematic Radiologic Di-
agnosis and Staging According to
Guidelines of the American Associa-
tion for the Study of Liver Diseases1
Sinead H. McEvoy, MBBCh, FFRRCSI • Colin J. McCarthy, MBBCh,
SA-CME
FFRRCSI • Lisa P. Lavelle, MBBCh • Deirdre E. Moran, MBBCh,
See www.rsna
.org/education
FFRRCSI • Colin P. Cantwell, MBBCh, FFRRCSI • Stephen J. Skehan,
/search/RG MBBCh, FFRRCSI • Robert G. Gibney, MBBCh, FFRRCSI • Dermot E.
Malone, MD, FFRRCSI
LEARNING
OBJECTIVES Hepatocellular carcinoma is a malignancy that predominantly occurs in the
FOR TEST 6 setting of cirrhosis. Its incidence is rising worldwide. Hepatocellular carci­
After completing this noma differs from most malignancies because it is commonly diagnosed on
journal-based SA-
CME activity, partic-
the basis of imaging features alone, without histologic confirmation. The
ipants will be able to: guidelines from the American Association for the Study of Liver Diseases
■■Describe the ap­ (AASLD) are a leading statement for the diagnosis and staging of hepato­
propriate steps for
investigation of focal
cellular carcinoma, and they have recently been updated, incorporating
liver nodules identi­ several important changes. AASLD advocates the use of the Barcelona
fied during cirrhosis Clinic Liver Cancer (BCLC) staging system, which combines validated im­
surveillance.
■■Recognize the
aging and clinical predictors of survival to determine stage and which links
characteristic dy­ staging with treatment options. Each stage of the BCLC system is outlined
namic perfusion pat­ clearly, with emphasis on case examples. Focal liver lesions identified at
tern of hepatocellu­
lar carcinoma. ultrasonographic surveillance in patients with cirrhosis require further
■■Assign a BCLC investigation. Lesions larger than 1 cm should be assessed with multipha­
stage to a lesion sic computed tomography or magnetic resonance imaging. Use of proper
that satisfies the
noninvasive imaging equipment and protocols is essential. Lesions larger than 1 cm can be
criteria for hepato­ diagnosed as hepatocellular carcinoma from a single study if the character­
cellular carcinoma.
istic dynamic perfusion pattern of arterial hyperenhancement and venous
INVITED or delayed phase washout is demonstrated. If the imaging characteristics
COMMENTARY of hepatocellular carcinoma are not met, the alternate modality should be
See discussion on performed. Biopsy should be used if neither modality is diagnostic of hepa­
this article by Ros tocellular carcinoma. Once the diagnosis has been made, the cancer should
(pp 1668–1671).
be assigned a BCLC stage, which will help determine suitable treatment
options. Radiologists require a systematic approach to diagnose and stage
hepatocellular carcinoma with appropriate accuracy and precision.
©
RSNA, 2013 • radiographics.rsna.org

Abbreviations: AASLD = American Association for the Study of Liver Diseases, AFP = a-fetoprotein, BCLC = Barcelona Clinic Liver Cancer,
CTP = Child-Turcotte-Pugh, EASL = European Association for the Study of the Liver, ECOG = Eastern Cooperative Oncology Group, LI-RADS =
Liver Imaging Reporting and Data System, NCCN = National Comprehensive Cancer Network, TACE = transcatheter arterial chemoembolization

RadioGraphics 2013; 33:1653–1668 • Published online 10.1148/rg.336125104 • Content Codes:

1
From the Department of Radiology, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Presented as an education exhibit at the 2011
RSNA Annual Meeting. Received May 10, 2012; revision requested July 6; final revision received February 24, 2013; accepted April 11. For this
journal-based SA-CME activity, the authors, editor, and reviewers have no financial relationships to disclose. Address correspondence to S.H.M.
(e-mail: [email protected]).
©
RSNA, 2013
1654 October Special Issue 2013 radiographics.rsna.org

Introduction
Hepatocellular carcinoma is the fifth most com­
mon cancer worldwide, and its incidence is rising
in many countries, including the United States
(1). The major risk factor for development of
hepatocellular carcinoma is cirrhosis, particularly
cirrhosis related to chronic viral hepatitis, alco­
holic cirrhosis, cirrhosis caused by hemochro­
matosis, and primary biliary cirrhosis (2). For
patients with an established diagnosis of cirrhosis,
surveillance by means of ultrasonography (US)
and measuring serum a-fetoprotein (AFP) levels
has been shown to reduce hepatocellular carci­
noma–related mortality by 37% (3).
Unlike other tumors that develop within a Figure 1. Diagram illustrates the sequence of hepa­
background of normal tissue, hepatocellular car­ tocarcinogenesis and neovascularization in cirrhosis.
cinoma occurs as part of a hepatic field change, HCC = hepatocellular carcinoma.
characterized by replacement of liver parenchyma
with fibrosis, scarring, and nodular regeneration.
Hepatocarcinogenesis is a sequence of dedifferen­ for hepatocellular carcinoma. Measurement
tiation from regenerative nodule, through dysplas­ of the serum levels of AFP is used as an aid to
tic nodule, to hepatocellular carcinoma. Hepato­ diagnosis and in screening. A rise in the serum
carcinogenesis should be considered a continuum, level of AFP in a patient with cirrhosis should
rather than a series of discrete states. Changes raise concern that hepatocellular carcinoma has
to feeding vessels and neovascularization occur developed. However, an elevated level of AFP
during the process (Fig 1). Overt hepatocellular is not specific for hepatocellular carcinoma; in
carcinoma does not have a portal blood supply; it particular, AFP may be elevated in flares of viral
is supplied solely by abnormal, unpaired hepatic hepatitis. Furthermore, when a cutoff value of
arteries. This results in a characteristic vascular 20 mg/L is used, measurement of serum AFP
enhancement pattern that can be used to make a level has a sensitivity of only 60% (6,7).
definitive radiologic diagnosis. In 2005, the American Association for the
Hepatocellular carcinoma differs from most Study of Liver Diseases (AASLD) published
malignancies because it is commonly diag­ practice guidelines for the diagnosis and manage­
nosed on the basis of imaging features alone, ment of hepatocellular carcinoma in Hepatology
without histologic confirmation. Multiplicity (8). In 2011, the guidelines were updated, with
of nodules, small size of nodules, and “nod­ changes made to the diagnostic criteria on the
ules within nodules” each represent part of the basis of new evidence (9). AASLD advocates
disease spectrum and make routine biopsy of the use of the Barcelona Clinic Liver Cancer
cirrhotic nodules impossible. Also, biopsy of he­ (BCLC) staging system, which links cancer stag­
patocellular carcinoma carries a theoretical risk ing with treatment options.
of seeding cancer cells along the needle tract, Because imaging is the primary means for
which may lead to tumor recurrence after liver diagnosis and staging of hepatocellular carci­
transplantation. This risk is small. Meta-analysis noma, radiologists require a systematic approach
has shown that the prevalence of tumor seeding to perform this task with appropriate accuracy
after biopsy is 2.7% (4). Use of trocars dur­ and precision. The purpose of this article is to
ing biopsy has not been associated with tumor illustrate the use of the AASLD radiologic diag­
seeding (4,5). There is no reliable tumor marker nostic criteria and BCLC staging system in the
detection, diagnosis, and staging of hepatocellular
carcinoma in patients with cirrhosis.
RG • Volume 33 Number 6 McEvoy et al 1655

Figure 2. Algorithm for the

investigation of liver nodules
found at US surveillance of
patients with cirrhosis. HCC =
hepatocellular carcinoma,
MDCT = multidetector CT.
(Reprinted, with permission,
from reference 9.)

Detection of Focal Lesions AASLD Criteria

in Cirrhosis with Surveillance US for Diagnosis of Hepato-
The AASLD recommends that US surveillance cellular Carcinoma in Cirrhosis
be performed at 6-month intervals in patients The radiologic diagnosis of hepatocellular carci­
with cirrhosis. The detection of a focal liver nod­ noma can be made at either CT or MR imaging,
ule during imaging surveillance should always provided that a multiphasic contrast material–en­
suggest the possibility of hepatocellular carci­ hanced study is used. Characteristically, hepatocel­
noma, although, practically speaking, many such lular carcinoma enhances during the arterial phase
nodules will be regenerative nodules. It is not because of its blood supply from abnormal hepatic
possible to distinguish between these two entities arteries. Contrast medium in the surrounding liver
with US alone. parenchyma is diluted during this phase because
Hepatocellular carcinoma does not have a the parenchymal blood supply arises mostly from
characteristic appearance at US. The lesions the portal veins, which are not yet opacified. In
are typically hypoechoic, but they can be hyper­ the portal venous phase, the surrounding liver
echoic or have mixed echogenicity. The majority parenchyma becomes relatively hyperattenuated
of nodules that measure less than 1 cm are not and the lesion is perceived to be hypoattenuated
hepatocellular carcinoma (8). Detected nodules because of its lack of portal venous supply. This
that measure less than 1 cm should be rescanned appearance is the so-called washout effect. Occa­
at a 3-month interval with the modality by which sionally, washout is evident only during a delayed
the lesions were first identified. If the nodules re­ phase sequence. Thus, a four-phase imaging study
main stable for a 2-year period, regular 6-month
follow-up examinations can be resumed for
routine surveillance (Fig 2). The nodules that are
suspicious for hepatocellular carcinoma are new
nodules that measure more than 1 cm or nodules
that enlarge over a time interval. These suspicious
nodules require immediate further investigation
with multiphasic computed tomography (CT) or
magnetic resonance (MR) imaging.
1656 October Special Issue 2013 radiographics.rsna.org

Figure 3. Hepatocellular carcinoma in a 45-year-old man with hemophilia and hepatitis C cirrhosis. (a) Surveillance
US scan shows a focal 2.6-cm hypoechoic exophytic nodule (calipers) in a coarse liver, as well as ascites. (b) Axial arterial
phase CT scan from a multiphasic study shows hyperenhancement of the exophytic mass (arrow). (c) Delayed phase CT
scan shows washout of contrast agent within the mass (arrow). The patient underwent orthotopic liver transplantation.
(d) Hepatocellular carcinoma (arrow) is clearly evident in the excised specimen, as shown in the photograph.

is required: non–contrast-enhanced phase, arterial

phase, portal venous phase, and delayed phase. If
the lesion demonstrates characteristic features of
hepatocellular carcinoma—that is, arterial phase
hyperenhancement and portal venous or delayed
phase washout—with a single modality, the diag­
nosis can be made and no further investigation is
required (Fig 3). If both of these features are not
seen and if the imaging findings are not consistent
with a benign process (eg, hemangioma), a second subset of these tumors has been classified as early
imaging study should be performed with an alter­ hepatocellular carcinoma, which has been defined
nate modality. as a histologically distinct, well-differentiated, and
Much diagnostic dilemma surrounds the con­ vaguely nodular hepatocellular carcinoma (10).
cept of hypovascular small hepatocellular carci­ Early hepatocellular carcinoma has been dem­
noma. A small hepatocellular carcinoma is one onstrated histologically to have fewer unpaired
that measures less than 2 cm in diameter. A minor arteries and, therefore, radiologically appears hy­
povascular (10–12). Yoon et al (13) evaluated the
multidetector CT enhancement pattern of hepato­
RG • Volume 33 Number 6 McEvoy et al 1657

Table 1
Pathologic Findings Seen in the Diagnosis of Hepatocellular Carcinoma, Including Useful Immunohis-
tochemical Markers

Pathologic Analysis Findings Comments

Macroscopy Varying from discrete nodular (single vs Small HCC (<2 cm) is a distinct entity,
multiple) to infiltrative tumor subcategorized as early (vaguely nodu­
lar) or progressed (distinctly nodular)
HCC
Microscopy Elevated nuclear to cytoplasmic ratio, Degree of cellular atypia allows grading
nuclear polymorphism, multinucleation of tumor
or trabecular architecture
Stromal invasion Presence of tumor in peritumoral portal Especially helpful in biopsy material
tracts or fibrous septa
Silver staining Absent, decreased, or abnormal stain pat­ Distinguishes benign liver lesions from
tern of reticulin malignant lesions; occasional normal
staining has been described in HCC
Immunohistochemical Positive staining for HepPar1 or poly­ Establishes origin of cell as being from
markers: HepPar1, clonal CEA the liver; does not help distinguish
polyclonal CEA benign from malignant liver disease;
may stain negative if tumor is poorly
differentiated
Immunohistochemical Positive staining for CD34 Stains sinusoidal vascular endothelium;
marker: CD34 may stain negative in early HCC
Immunohistochemical Used in combination: a finding of two Emerging tumor markers; generally re­
markers: glypican 3, positive markers out of three is relatively served for problem solving in cases of
heat shock protein 7, sensitive and highly specific for HCC small or atypical HCC
glutamine synthase
Note.—CEA = carcinoembryonic antigen, HCC = hepatocellular carcinoma, HepPar1 = hepatocyte paraffin antigen.

cellular carcinomas smaller than 3 cm in diameter the United States. It has recently been shown that
in patients with cirrhosis. They found that the clas­ intrahepatic cholangiocarcinoma in patients with
sic enhancement pattern was present in 24% of cirrhosis may exhibit a vascular enhancement pat­
tumors less than 1 cm in diameter, 28% of tumors tern similar to that of hepatocellular carcinoma at
that were 1–2 cm, and 47% of tumors that were contrast-enhanced US; for this reason, contrast-
greater than 2 cm. Occasionally, large hepatocel­ enhanced US is excluded from the updated
lular carcinoma may be hypovascular. In cases in AASLD guidelines as an accepted alternative diag­
which imaging features are equivocal, that is, the nostic modality (14).
perfusion pattern specific for hepatocellular car­ In the original 2005 guidelines, use of both
cinoma is not evident with both MR imaging and CT and MR imaging was required to evaluate
CT, the AASLD recommends that targeted biopsy lesions measuring 1–2 cm because of concern
be performed. Pathologic analysis of hepatocellu­ about whether the specific vascular pattern in
lar carcinoma includes macroscopic, microscopic, these smaller nodules could be recognized with a
and immunohistochemical evaluation (Table 1). single modality. More recent studies report that
At our institution, typical microscopic morphology application of a single contrast-enhanced imag­
and reticulin pattern, along with the presence of ing technique has sensitivity similar to that of two
CD34 and hepatocyte paraffin antigen markers, contrast-enhanced imaging techniques in the as­
are considered to be essential components in es­ sessment of 1–2-cm lesions (15). Therefore, the
tablishing a diagnosis of hepatocellular carcinoma. revised AASLD guidelines state that the diagnosis
In Europe, Canada, and Asia, contrast- of hepatocellular carcinoma can be made on the
enhanced US has been used as a third imaging basis of a single study that shows the typical con­
modality to demonstrate the enhancement pattern trast enhancement pattern of hepatocellular carci­
that is diagnostic of hepatocellular carcinoma. The noma in any lesion over 1 cm in diameter.
microbubble contrast agent employed in contrast-
enhanced US is not currently approved for use in
1658 October Special Issue 2013 radiographics.rsna.org

Figure 4. BCLC
staging system and
treatment allocation
algorithm. HCC =
hepatocellular carci­
noma, PS = perfor­
mance status, RFA =
radiofrequency ab­
lation, TACE =
transcatheter arterial
chemoembolization.
(Reprinted, with
permission, from
reference 9.)

Dynamic Enhanced CT and Contrast-enhanced US studies have shown that

MR Imaging Techniques for De- approximately 90% of hepatocellular carcinomas
tection of Hepatocellular Carcinoma demonstrate washout by 5 minutes after injection
Use of state-of-the-art equipment and protocols of the microbubble contrast agent (19). Use of
is important to ensure accurate characterization a 5-minute delay may be the practical choice for
of focal liver lesions in cirrhotic livers. Detailed the timing of the delayed phase.
acceptable CT and MR imaging techniques have MR imaging should be performed with a
previously been published (16,17). In addition multichannel phased-array body coil and at a
on the basis of a consensus of experts, the Organ magnetic field strength of 1.5 T or greater. A
Procurement and Transplantation Network has mechanical injector should be used to admin­
proposed minimum technical requirements for ister the gadolinium-based contrast agent at a
scanner hardware and protocols for the diagnosis rate of 2–3 mL/sec. Bolus tracking is recom­
of hepatocellular carcinoma (18). mended. Precontrast and dynamic postcontrast
CT should be performed with a multi–detec­ T1-weighted three-dimensional fat-suppressed
tor array scanner with a minimum of eight detec­ gradient-echo sequences are required, in addi­
tor rows. The minimum reconstructed section tion to T2 (with and without fat saturation) and
thickness is 5 mm, although thinner sections are T1 in-phase and opposed-phase imaging. Tim­
preferred. Use of a mechanical injector and a sa­ ing of the dynamic contrast-enhanced sequences
line flush is advised to administer contrast mate­ is the same as that used for the CT examination.
rial to achieve a minimum injection rate of 3 mL/ Emphasis on precise breath-holding is extremely
sec for a total of 370 mg/mL of contrast medium. important.
Bolus tracking software that monitors passage of Systematic review has shown that MR imaging
contrast material through the descending aorta is is more sensitive than CT in the diagnosis of he­
recommended. Images should be acquired in four patocellular carcinoma (81% vs 68%) (20).The
phases: non–contrast-enhanced phase (before the disadvantages of MR imaging are its high cost,
injection of contrast material), late arterial phase length of time required for image acquisition, and
(about 20 seconds after the injection), portal long duration of breath holds. Accessibility is also
venous phase (50 seconds after the injection), an issue in some healthcare centers. The main
and delayed phase (>120 seconds after the injec­ disadvantage of CT is that patients incur a radia­
tion). The optimal timing for image acquisition in tion dose. Use of iodinated and MR imaging con­
the delayed phase is debated, varying between 2 trast media should be in line with the recommen­
and 15 minutes after contrast material injection. dations of the American College of Radiology
manual on contrast media. Caution is advised in
patients with renal failure.
RG • Volume 33 Number 6 McEvoy et al 1659

Table 2
Child-Turcotte-Pugh Score for Assessment of Liver Function

Clinical or Biochemical Parameter One Point Two Points Three Points

Bilirubin (mg/dL) <2 2–3 >3
Serum albumin (g/dL) >3.5 2.8–3.5 <2.8
International normalized ratio <1.7 1.7–2.3 >2.3
Ascites None Mild Moderate to severe
Encephalopathy None Grade I–II Grade III–IV
Source.—Reprinted, with permission, from reference 25.
Note.—Severity of liver disease is graded as CTP A–C, on the basis of a patient’s total score: A =
5–6, B = 7–9, and C = 10–15.

Table 3
Eastern Cooperative Oncology Group Scale for Assessment of Patient Performance Status

Grade Description of Performance Status

0 Fully active, able to complete all predisease performance tasks without restriction
1 Restricted in physically strenuous activity but ambulatory and able to complete work of a
light or sedentary nature (eg, light house work, office work)
2 Ambulatory and capable of all self-care but unable to complete any work activities; up and
active for more than 50% of waking hours
3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours
4 Completely disabled; cannot perform any self-care; totally confined to bed or chair
5 Dead
Source. —Reprinted, with permission, from reference 26.

Staging of it the reference staging system, and it is continu­

Hepatocellular Carcinoma ously updated to incorporate emerging changes
Once the diagnosis of hepatocellular carcinoma (22,23). The BCLC system links each tumor
has been made, clinical staging should be per­ stage with appropriate therapeutic interventions
formed to assess prognosis and to guide thera­ in a guideline format (Fig 4).
peutic intervention. Many staging systems have The BCLC system assesses liver function by
been proposed over the years, including the Tu­ using the Child-Turcotte-Pugh (CTP) score,
mor Node Metastasis (TNM) system, the BCLC which grades the severity of liver disease from
system, the Japanese Integrated System (JIS), A to C. A range of biochemical and clinical pa­
Cancer of Liver Italian Program (CLIP), Groupe rameters is assigned point values, which are then
d’Etude de Traitement du Carcinoma Hepato­ totaled to derive a patient’s CTP score for liver
cellulaire (GRETCH), the Chinese University function (24,25) (Table 2). A patient’s perfor­
Prognostic Index (CUPI), and the Okuda staging mance status is assessed by using the Eastern
system; however, there is no worldwide consensus Cooperative Oncology Group (ECOG) scale,
on which system to use. AASLD advocates use of which ranges from 0 to 5 and ranks a patient’s
the BCLC staging system because it is the only abilities to complete activities of daily living (26)
system that encompasses the three factors that (Table 3). Radiologic tumor extent is evaluated
have been shown to be independent predictors on the basis of the maximum length of the lesion,
of survival—radiologic tumor extent, liver func­ the number of lesions, evidence of vascular inva­
tion, and patient’s performance status—and thus sion, and the presence of lymphatic or metastatic
has the best chance of predicting patient survival disease. Because this article is targeted to a radi­
compared with other prognostic systems (21). ology readership, the description of each BCLC
The BCLC system is used in most major trials of
hepatocellular carcinoma interventions, making
1660 October Special Issue 2013 radiographics.rsna.org

Figure 5. BCLC stage 0 hepatocellular carcinoma in a

73-year-old man with hepatitis C cirrhosis. (a) Surveillance
US scan demonstrates a 1.7-cm hyperechoic nodule (arrow)
in the right hepatic lobe. (b) Axial arterial phase MR image
from a multiphasic study shows hyperenhancement of the
mass (arrow). (c) Delayed phase MR image demonstrates
washout within the mass (arrow). The mass was classified
as radiologic BCLC stage 0 because it was a solitary hepa­
tocellular carcinoma and less than 2 cm in size. The patient
underwent radiofrequency ablation. (d, e) Follow-up arterial
phase (d) and delayed phase (e) images from a multiphasic
MR imaging study performed 3 months after therapy dem­
onstrate complete tumor necrosis (arrow).

stage is presented from an imaging viewpoint; or hyperbilirubinemia. If these conditions are

readers should note, however, that a patient’s absent, resection may be a suitable treatment
CTP or ECOG score can upstage each radiologic option for the patient; if these conditions are
stage. Radiologic tumor extent is only an element present, transplantation is the preferred therapy.
of the BCLC stages 0, A, B, and C. If the patient has associated comorbidities, a
Radiologic BCLC stage 0 disease is a solitary minimally invasive treatment option such as ra­
lesion that measures less than 2 cm in diameter diofrequency ablation may be more appropriate.
(Fig 5). Treatment options for a stage 0 lesion Meta-analysis has demonstrated the superiority
depend on the presence of portal hypertension of radiofrequency ablation over percutaneous
ethanol ablation in terms of patient survival and
local tumor recurrence (27).
RG • Volume 33 Number 6 McEvoy et al 1661

Figure 6. BCLC stage A hepatocellular carcinoma in

a 58-year-old man with hepatitis C cirrhosis. (a) Axial
arterial phase CT scan from a multiphasic study shows
hyperenhancement of a solitary 4-cm mass (arrow).
(b) Axial portal venous phase CT scan demonstrates
washout (arrow). (c, d) A similar enhancement pattern
(arrow) is seen in the arterial (c) and portal venous (d)
phases of multiphasic MR imaging. The mass was classi­
fied as radiologic BCLC stage A because it was a solitary
hepatocellular carcinoma and greater than 2 cm in size.
The patient underwent orthotopic liver transplantation.
(e) Hepatocellular carcinoma (arrow) is clearly evident
in the excised specimen, as shown in the photograph.

Radiologic BCLC stage A disease is a solitary present, therapeutic options include transplanta­
lesion that measures more than 2 cm in diameter tion and radiofrequency ablation, as with stage 0
or early multifocal disease that consists of up to disease. AASLD does not recommend expanding
three lesions, none of which measure more than transplantation criteria beyond the widely used
3 cm in diameter (Fig 6). As with stage 0 disease, Milan criteria (ie, presence of a solitary hepato­
suitable choices of therapeutic options depend on cellular carcinoma <5 cm, or up to three separate
the presence of portal hypertension or hyperbili­ lesions, each <3 cm).
rubinemia. If these conditions are absent, resec­
tion remains a viable option for treating solitary
BCLC stage A lesions. If portal hypertension is
1662 October Special Issue 2013 radiographics.rsna.org

Figure 7. BCLC stage B hepatocellular carcinoma in a 63-year-old man with alcoholic cirrhosis. (a) Axial
arterial phase MR image from a multiphasic study shows hyperenhancement of a 4.2-cm mass in the
right hepatic lobe (arrowhead). (b) Delayed phase image from the same study demonstrates washout
in the lesion (arrowhead). (c) Arterial phase MR image from the same study, but obtained at a more
cranial level, shows an additional, arterially enhancing mass that measured 1.2 cm (arrow). (d) Delayed
phase MR image demonstrates washout in this mass also (arrow). The disease stage was classified as
radiologic BCLC stage B because the hepatocellular carcinoma was multifocal and one of the nodules
was greater than 3 cm in size. The patient underwent TACE. (e) Selected angiographic image from
the TACE procedure shows these two lesions (arrows), as well as two additional hypervascular lesions
(arrowheads) in the right hepatic lobe.

Hepatocellular carcinoma that is graded as

BCLC stages 0 and A is potentially curable,
whereas the aim of treatment for stages B and C
disease is extension of life expectancy or improved
quality of life. There are many palliative treatment
options available, including transcatheter arterial
chemoembolization (TACE), radioembolization,
external beam radiation therapy, systemic chemo­
therapy, and molecularly targeted therapy. The
only treatment options that are integrated into the
BCLC staging system are those that have been
demonstrated to prolong life in adequately pow­
ered randomized trials: TACE and the molecularly
targeted therapy with sorafenib.
Radiologic BCLC stage B disease is advanced or of more than three lesions regardless of size
multifocal disease that consists of more than one (Fig 7). Stage B disease is managed with TACE.
lesion, with at least one that is larger than 3 cm, Meta-analysis has demonstrated that patients who
undergo TACE experience a statistically significant
survival benefit, compared with those who receive
RG • Volume 33 Number 6 McEvoy et al 1663

Figure 8. Malignant portal vein thrombus in a 65-year-old man with alcoholic cirrhosis and hepatocellular car­
cinoma. (a) Color Doppler US scan shows echogenic material and no flow within the main portal vein, a finding
consistent with thrombus (arrow). (b) Axial arterial phase CT scan from a multiphasic study shows extensive pe­
ripheral enhancement of the main portal vein, a finding consistent with neovascularization (arrow). A large hypo­
vascular mass is present in the right hepatic lobe (*). (c) Axial portal venous phase CT scan from the same study
helps confirm the lack of flow in the main portal vein and washout of the enhancement (arrow) seen in the arterial
phase. The large mass is more clearly seen (*). The mass represents radiologic BCLC stage C disease because of
the presence of malignant portal vein thrombus.

Radiologic BCLC stage C disease is hepatocel­

lular carcinoma with either vascular invasion or
nodal or metastatic disease. In the staging system
algorithm, this stage is linked with sorafenib, a
multikinase inhibitor, which has been shown to
produce a statistically significant survival benefit,
compared with supportive treatment, in cases
of advanced hepatocellular carcinoma (31). The
survival benefit has been demonstrated only in pa­
tients with CTP grade A severity liver disease.
Evidence of vascular invasion (malignant
thrombus) is used as a criterion to exclude liver
transplantation as a treatment option; however,
bland portal vein thrombus can occur in cir­
rhotic liver disease. Therefore, correctly distin­
guishing between benign and malignant portal
vein thrombi is important. The characteristic
imaging pattern of hepatocellular carcinoma—
only supportive care, although survival benefit was arterial hyperenhancement and venous or de­
not universal across all trial selection criteria and layed phase washout—is maintained in tumor
combination agents (28). Even without survival invasion of the portal vein (Fig 8). However,
benefit, however, progression of symptomatic dis­ not all malignant thrombi will demonstrate this
ease (ie, development of portal vein invasion and enhancement pattern (32). The additional ob­
resultant ascites) is reduced by TACE (29). The servation of restricted diffusion at MR imaging
evaluation of tumor response to local therapies supports the diagnosis of malignant thrombus
such as radiofrequency ablation and TACE has (Fig 9). When uncertainty about the nature of
evolved from assessment of morphologic size alone thrombi arises that cannot be resolved with im­
to encompass evaluation of posttreatment enhance­ aging, fine needle aspiration biopsy may be per­
ment. The AASLD recommends use of the modi­ formed (33,34).
fied Response Evaluation Criteria in Solid Tumors
(mRECIST) to assess tumor response (30).
1664 October Special Issue 2013 radiographics.rsna.org

Figure 9. Malignant portal vein thrombus in a 61-year-

old man with alcoholic cirrhosis and hepatocellular car­
cinoma. Multiphasic MR images demonstrate anterior
right segmental portal vein thrombosis that enhances
in the arterial phase (arrowhead in a), washes out in
the portal venous phase (arrow in b), and demonstrates
restricted diffusion during the high b value diffusion-
weighted sequence (arrow in c). On the arterial phase
image (a), parenchymal hypervascularity is seen adjacent
to the segmental thrombosis, a finding that likely repre­
sents transient hepatic arterial compensation (*).

Distinguishing between benign and malignant Limitations of AASLD Guidelines

thrombi is not always necessary. For example, Advances in MR imaging have resulted in ancil­
in the setting of main portal vein thrombus in lary options for the assessment of hepatic nod­
association with advanced multinodular hepato­ ules. Hepatocyte-specific contrast media (ga­
cellular carcinoma, differentiating between stage doxetate disodium [Eovist or Primovist], Bayer
B disease (bland thrombus) and stage C disease Healthcare, Berlin, Germany; and gadobenate
(malignant thrombus) is not vital, because occlu­ dimeglumine [Multihance], Bracco Diagnostics,
sion of the main portal vein is a relative contrain­ Princeton, NJ) have an extracellular distribu­
dication to TACE and thus leaves only one treat­ tion, but they are also taken up by hepatocytes
ment option available, that is, molecularly tar­ and excreted in the biliary system. Hepato­
geted therapy with sorafenib. Similarly, if nodal cellular carcinoma may or may not take up
or metastatic disease is present, it is unnecessary hepatocyte-specific contrast media, depending
to determine whether portal vein thrombus is be­ on the volume of functioning hepatocytes within
nign or malignant (Fig 10). the tumor (ie, tumor grade). Diffusion-weighted
BCLC stage D disease is not a radiologic stage. imaging provides information on tissue cellular­
It is determined only on the basis of poor liver ity. Hepatocellular carcinoma typically dem­
function and poor patient performance (CTP = C, onstrates restricted diffusion; it is hyperintense
ECOG > 2). Management should consist of only on higher b value images and correspondingly
supportive therapies. hypointense on apparent diffusion coefficient
maps. Well-differentiated or necrotic hepatocel­
lular carcinoma may not demonstrate restricted
diffusion (35).
RG • Volume 33 Number 6 McEvoy et al 1665

Figure 10. Metastatic hepatocellular carcinoma in two cases. (a) Portal venous phase CT scan of a 63-year-old
man with cirrhosis caused by hemochromatosis shows an abdominal wall metastasis (arrowhead) and a large
mass (*) in the right hepatic lobe. The patient had not undergone percutaneous liver biopsy, so this metastasis
did not result from needle tract seeding. (b–e) Recurrent cancer in a 62-year-old man with nonalcoholic ste­
atohepatitis cirrhosis who had undergone orthotopic liver transplantation for BCLC stage A hepatocellular car­
cinoma 3 years previously. (b) Contrast-enhanced CT scan of thorax demonstrates a large soft-tissue mass (ar­
row) in the right lung. (c) Sagittal short inversion time inversion-recovery image from an MR imaging study
of the whole spine shows high signal and compression of the L3 vertebral body, findings consistent with a me­
tastasis (arrowhead). (d) Axial T2-weighted image from same study, obtained at the level of L3, shows an exten­
sive soft-tissue component that invades the left psoas muscle (arrow). Biopsy of the lung lesion was performed.
(e) Photomicrograph of a histologic specimen demonstrates invasive adenocarcinoma with cytoplasmic positivity
for hepatocyte paraffin antigen stain, findings consistent with metastatic hepatocellular carcinoma.
1666 October Special Issue 2013 radiographics.rsna.org

Currently, these newer techniques are not in diameter. If the new nodule is smaller than 1
included in the AASLD guidelines; diagnosis of cm, AASLD recommends that US be performed
malignancy is made on the basis of perfusion char­ at 3-month intervals for 2 years. If the nodule
acteristics alone. This practice may result in a de­ enlarges during this period, multiphasic imaging
gree of underdiagnosis and understaging (36,37). should be performed immediately. If the nodule is
AASLD recognizes the subgroup of hypovascular stable for the duration of the surveillance period,
hepatocellular carcinoma. It seems likely that the the schedule of routine surveillance examinations
use of diffusion-weighted imaging and hepatocyte- can be resumed. EASL recommends that nodules
specific contrast media will contribute to diagnos­ less than 1 cm should be monitored with US every
tic accuracy in this subgroup (37). However, the 4 months for 1 year, and if they remain stable,
evidence for this is under investigation; it is not routine surveillance should be resumed. NCCN
comprehensive enough to be included in the diag­ recommends that multiphasic CT or MR imaging
nostic guidelines at this time. or contrast-enhanced US should be performed at
The added benefit of diffusion-weighted imag­ 3–6-month intervals for nodules less than 1 cm.
ing in the diagnosis of hepatocellular carcinoma is If the nodules remain stable, the NCCN advises
recognized by the American College of Radiology that 3–6-month follow-up imaging be continued
and is incorporated into its Liver Imaging Report­ with the modality that originally demonstrated the
ing and Data System (LI-RADS). LI-RADS pro­ lesion. The NCCN does not include a recommen­
vides a standardized, clear approach to assessment dation regarding the preferred time to return to
of cirrhotic nodules and allows the radiologist to routine surveillance.
classify nodules according to their probability of 3. Use of contrast-enhanced US for diag-
being hepatocellular carcinoma (38). LI-RADS 1 nosis of hepatocellular carcinoma. AASLD
observations are definitely benign. LI-RADS 2–4 has eliminated use of contrast-enhanced US as a
observations have increasing probability of being diagnostic technique. EASL guidelines state that
hepatocellular carcinoma, and LI-RADS 5 obser­ contrast-enhanced US should be used with cau­
vations are definitely hepatocellular carcinoma. tion. NCCN supports its use when the modality
is available.
Comparison of AASLD 4. Role of biopsy in diagnosis of hepato-
Guidelines with Alternate Guidelines cellular carcinoma. All three guidelines recom­
Alternate guidelines exist for the diagnosis and mend proceeding to biopsy for nodules that are
staging of hepatocellular carcinoma, formulated greater than 1 cm in diameter if the enhancement
by groups including the European Association pattern characteristic of hepatocellular carcinoma
for the Study of the Liver (EASL) and the Na­ is not demonstrated with either multiphasic CT
tional Comprehensive Cancer Network (NCCN) or MR imaging. The NCCN guidelines include
(39,40). There is considerable overlap between the an option of repeating imaging at 3 months if
AASLD system and these additional guidelines. nodules are 1–2 cm.
They rely substantially on the same literature 5. Recommended staging system. AASLD
base, and some eminent specialists are members and EASL advocate the use of the BCLC staging
of both expert panels. Key similarities and differ­ system, whereas NCCN does not use a specific
ences are outlined. staging system in its guidelines.
1. Single versus dual modality for diag-
nosis. All three guidelines have been updated to Conclusions
allow diagnosis of hepatocellular carcinoma on the Hepatocellular carcinoma is increasing in fre­
basis of findings from a single modality, provided quency. It is a malignancy encountered mainly in
that the nodule is larger than 1 cm and that the the setting of cirrhosis; therefore, US surveillance
characteristic enhancement pattern has been dem­ and monitoring of AFP levels are recommended
onstrated. EASL guidelines include the caveat that for patients with cirrhosis. The AASLD has pub­
use of only one imaging modality to diagnose a lished guidelines for the management of focal liver
1–2-cm hepatocellular carcinoma is allowable only lesions in cirrhosis, and they are described and il­
in healthcare centers with sophisticated (state-of- lustrated in this article. The detection of focal liver
the-art) radiologic equipment. lesions larger than 1 cm at routine US surveillance
2. Further investigation of new nodules requires immediate further investigation with mul­
seen at US surveillance. All three guidelines rec­ tiphasic CT or MR imaging. The characteristic
ommend that multiphasic imaging be performed imaging appearance of hepatocellular carcinoma is
immediately if the new nodule is larger than 1 cm its enhancement pattern: arterial phase hyperen­
hancement and venous or delayed phase washout.
The diagnosis of hepatocellular carcinoma can be
RG • Volume 33 Number 6 McEvoy et al 1667

made from a single imaging study when the char­ 11. Sano K, Ichikawa T, Motosugi U, et al. Imaging
acteristic enhancement pattern is demonstrated. study of early hepatocellular carcinoma: usefulness
of gadoxetic acid–enhanced MR imaging. Radiology
The BCLC system is the staging system of choice
2011;261(3):834–844.
because it combines validated predictors of sur­ 12. Nakashima Y, Nakashima O, Tanaka M, Okuda K,
vival and links staging with treatment options. Nakashima M, Kojiro M. Portal vein invasion and
Stages are not determined on the basis of radio­ intrahepatic micrometastasis in small hepatocellular
logic findings alone; imaging information is com­ carcinoma by gross type. Hepatol Res 2003;26(2):
142–147.
bined with clinical and biochemical parameters. In
13. Yoon SH, Lee JM, So YH, et al. Multiphasic
the future, as classification systems evolve further, MDCT enhancement pattern of hepatocellular car­
the diagnostic roles of diffusion-weighted imag­ cinoma smaller than 3 cm in diameter: tumor size
ing and hepatocyte-specific MR imaging contrast and cellular differentiation. AJR Am J Roentgenol
media and the therapeutic role of newer interven­ 2009;193(6):W482–W489.
14. Vilana R, Forner A, Bianchi L, et al. Intrahepatic
tional techniques will become better defined.
peripheral cholangiocarcinoma in cirrhosis patients
may display a vascular pattern similar to hepatocel­
Acknowledgments.—We thank Jeffrey W. McCann, lular carcinoma on contrast-enhanced ultrasound.
MBBCh, FFRRCSI, and David P. Brophy, MBBCh, Hepatology 2010;51(6):2020–2029.
FFRRCSI, of St Vincent’s University Hospital, who 15. Sangiovanni A, Manini MA, Iavarone M, et al. The
reviewed the manuscript and provided helpful sug­ diagnostic and economic impact of contrast imaging
gestions for its improvement, and Niamh P. Nolan, techniques in the diagnosis of small hepatocellular
MBBCh, FRCPath, of St Vincent’s University Hos­ carcinoma in cirrhosis. Gut 2010;59(5):638–644.
pital, who kindly advised on the components of the 16. Boll DT, Merkle EM. Diffuse liver disease: strategies
manuscript pertaining to histopathology of hepatocel­ for hepatic CT and MR imaging. RadioGraphics
lular carcinoma. 2009;29(6):1591–1614.
17. Hussain SM, Reinhold C, Mitchell DG. Cirrhosis
References and lesion characterization at MR imaging. Radio­
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, For­ Graphics 2009;29(6):1637–1652.
man D. Global cancer statistics. CA Cancer J Clin 18. Pomfret EA, Washburn K, Wald C, et al. Report of
2011;61(2):69–90. a national conference on liver allocation in patients
2. Llovet JM, Burroughs A, Bruix J. Hepatocellular with hepatocellular carcinoma in the United States.
carcinoma. Lancet 2003;362(9399):1907–1917. Liver Transpl 2010;16(3):262–278.
3. Zhang BH, Yang BH, Tang ZY. Randomized con­ 19. Jang HJ, Kim TK, Burns PN, Wilson SR. Enhance­
trolled trial of screening for hepatocellular carcinoma. ment patterns of hepatocellular carcinoma at
J Cancer Res Clin Oncol 2004;130(7):417–422. contrast-enhanced US: comparison with histologic
4. Silva MA, Hegab B, Hyde C, Guo B, Buckels JAC, differentiation. Radiology 2007;244(3):898–906.
Mirza DF. Needle track seeding following biopsy 20. Colli A, Fraquelli M, Casazza G, et al. Accuracy of
of liver lesions in the diagnosis of hepatocellular ultrasonography, spiral CT, magnetic resonance,
cancer: a systematic review and meta-analysis. Gut and alpha-fetoprotein in diagnosing hepatocellular
2008;57(11):1592–1596. carcinoma: a systematic review. Am J Gastroenterol
5. Maturen KE, Nghiem HV, Marrero JA, et al. Lack 2006;101(3):513–523.
of tumor seeding of hepatocellular carcinoma after 21. Marrero JA, Fontana RJ, Barrat A, et al. Prognosis
percutaneous needle biopsy using coaxial cutting of hepatocellular carcinoma: comparison of 7 stag­
needle technique. AJR Am J Roentgenol 2006;187 ing systems in an American cohort. Hepatology
(5):1184–1187. 2005;41(4):707–716.
6. Trevisani F, D’Intino PE, Morselli-Labate AM, et 22. Llovet JM, Brú C, Bruix J. Prognosis of hepatocel­
al. Serum alpha-fetoprotein for diagnosis of hepa­ lular carcinoma: the BCLC staging classification.
tocellular carcinoma in patients with chronic liver Semin Liver Dis 1999;19(3):329–338.
disease: influence of HBsAg and anti-HCV status. J 23. Forner A, Reig ME, de Lope CR, Bruix J. Current
Hepatol 2001;34(4):570–575. strategy for staging and treatment: the BCLC up­
7. Forner A, Reig M, Bruix J. Alpha-fetoprotein for date and future prospects. Semin Liver Dis 2010;
hepatocellular carcinoma diagnosis: the demise of a 30(1):61–74.
brilliant star. Gastroenterology 2009;137(1):26–29. 24. Child CG, Turcotte JG. Surgery and portal hyper­
8. Bruix J, Sherman M; Practice Guidelines Commit­ tension. Major Probl Clin Surg 1964;1:1–85.
tee, American Association for the Study of Liver 25. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni
Diseases. Management of hepatocellular carcinoma. MC, Williams R. Transection of the oesophagus for
Hepatology 2005;42(5):1208–1236. bleeding oesophageal varices. Br J Surg 1973;60(8):
9. Bruix J, Sherman M; American Association for the 646–649.
Study of Liver Diseases. Management of hepatocel­ 26. Oken MM, Creech RH, Tormey DC, et al. Toxicity
lular carcinoma: an update. Hepatology 2011;53(3): and response criteria of the Eastern Cooperative
1020–1022. Oncology Group. Am J Clin Oncol 1982;5(6):
10. International Consensus Group for Hepatocellular 649–655.
Neoplasia. Pathologic diagnosis of early hepatocel­
lular carcinoma: a report of the International Con­
sensus Group for Hepatocellular Neoplasia. Hepa­
tology 2009;49(2):658–664. [Published correction
appears in Hepatology 2009;49(3):1058.]
1668 October Special Issue 2013 radiographics.rsna.org

27. Orlando A, Leandro G, Olivo M, Andriulli A, Cot­ 34. Vilana R, Bru C, Bruix J, Castells A, Sole M, Rodes
tone M. Radiofrequency thermal ablation vs. per­ J. Fine-needle aspiration biopsy of portal vein
cutaneous ethanol injection for small hepatocellular thrombus: value in detecting malignant thrombosis.
carcinoma in cirrhosis: meta-analysis of randomized AJR Am J Roentgenol 1993;160(6):1285–1287.
controlled trials. Am J Gastroenterol 2009;104(2): 35. Taouli B, Koh DM. Diffusion-weighted MR imag­
514–524. ing of the liver. Radiology 2010;254(1):47–66.
28. Llovet JM, Bruix J. Systematic review of random­ 36. Parente DB, Perez RM, Eiras-Araujo A, et al. MR
ized trials for unresectable hepatocellular carcinoma: imaging of hypervascular lesions in the cirrhotic
chemoembolization improves survival. Hepatology liver: a diagnostic dilemma. RadioGraphics 2012;32
2003;37(2):429–442. (3):767–787.
29. Llovet JM, Real MI, Montaña X, et al. Arterial em­ 37. Kim YK, Lee WJ, Park MJ, Kim SH, Rhim H, Choi
bolisation or chemoembolisation versus symptomatic D. Hypovascular hypointense nodules on hepatobili­
treatment in patients with unresectable hepatocellular ary phase gadoxetic acid–enhanced MR images in
carcinoma: a randomised controlled trial. Lancet patients with cirrhosis: potential of DW imaging in
2002;359(9319):1734–1739. predicting progression to hypervascular HCC. Radi­
30. Lencioni R, Llovet JM. Modified RECIST (mRE­ ology 2012;265(1):104–114.
CIST) assessment for hepatocellular carcinoma. 38. American College of Radiology. Liver Imaging
Semin Liver Dis 2010;30(1):52–60. Re­porting and Data System version 2013.1. http
31. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib ://www.acr.org/Quality-Safety/Resources/LI­
in advanced hepatocellular carcinoma. N Engl J RADS/. Accessed January 8, 2013.
Med 2008;359(4):378–390. 39. European Association for the Study of the Liver;
32. Tublin ME, Dodd GD 3rd, Baron RL. Benign and European Organisation for Research and Treatment
malignant portal vein thrombosis: differentiation of Cancer. EASL-EORTC clinical practice guide­
by CT characteristics. AJR Am J Roentgenol 1997; lines: management of hepatocellular carcinoma. J
168(3):719–723. Hepatol 2012;56(4):908–943.
33. Piscaglia F, Gianstefani A, Ravaioli M, et al. Crite­ 40. Benson A, Abrams T, Ben-Josef E, et al. NCCN
ria for diagnosing benign portal vein thrombosis in clinical practice guidelines in oncology: hepatobili­
the assessment of patients with cirrhosis and hepa­ ary cancers. Version 2.2012. http://www.nccn.org
tocellular carcinoma for liver transplantation. Liver /professionals/physician_gls/pdf/hepatobiliary.pdf.
Transpl 2010;16(5):658–667. Accessed August 14, 2012.

TM
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See www.rsna.org/education/search/RG.
Teaching Points October Special Issue 2013

Hepatocellular Carcinoma: Illustrated Guide to Systematic Radiologic Diag-

nosis and Staging According to Guidelines of the American Association for
the Study of Liver Diseases
Sinead H. McEvoy, MBBCh, FFRRCSI • Colin J. McCarthy, MBBCh, FFRRCSI • Lisa P. Lavelle, MBBCh •
Deirdre E. Moran, MBBCh, FFRRCSI • Colin P. Cantwell, MBBCh, FFRRCSI • Stephen J. Skehan, MBBCh,
FFRRCSI • Robert G. Gibney, MBBCh, FFRRCSI • Dermot E. Malone, MD, FFRRCSI
RadioGraphics 2013; 33:1653–1668 • Published online 10.1148/rg.336125104 • Content Codes:

Page 1655
The nodules that are suspicious for hepatocellular carcinoma are new nodules that measure more than
1 cm or nodules that enlarge over a time interval. These suspicious nodules require immediate further
investigation with multiphasic computed tomography (CT) or magnetic resonance (MR) imaging.

Page 1655
The radiologic diagnosis of hepatocellular carcinoma can be made at either CT or MR imaging, provided
that a multiphasic contrast material–enhanced study is used.

Page 1656
If the lesion demonstrates characteristic features of hepatocellular carcinoma—that is, arterial phase hyper­
enhancement and portal venous or delayed phase washout—with a single modality, the diagnosis can be
made and no further investigation is required.

Page 1659
AASLD advocates use of the BCLC staging system because it is the only system that encompasses the
three factors that have been shown to be independent predictors of survival—radiologic tumor extent,
liver function, and patient’s performance status—and thus has the best chance of predicting patient sur­
vival compared with other prognostic systems.

Page 1663
Therefore, correctly distinguishing between benign and malignant portal vein thrombi is important.