Diagnosis and Staging of Hepatocellular Carcinoma

JAYANT A. TALWALKAR and GREGORY J. GORES

William J. von Liebig Transplantation Center, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine,
Rochester, Minnesota
The diagnosis of hepatocellular carcinoma (HCC) includes
detection of the index lesion, staging of the lesion within
the liver, and assessment for extrahepatic metastasis. HCC
is a highly vascular neoplasm usually arising in a cirrhotic
liver. Based on this concept, consensus criteria have been
developed for the radiographic diagnosis of HCC. These
include: (1) identication of a mass >2 cm in diameter in
a cirrhotic liver in 2 imaging modalities, and (2) contrast
enhancement on computed tomography, magnetic reso-
nance, or angiography. A mass lesion within a cirrhotic
liver in the presence of a serum -fetoprotein level >400
ng/mL also is diagnostic. For lesions <2 cm in diameter,
histological conrmation is required. Serum markers for
the diagnosis of early HCC (<2 cm in diameter) have not
been established. Staging HCC for metastases is insensi-
tive and is based on conventional criteria (eg, pulmonary
nodules, skeletal metastases, and lymphadenopathy). Ad-
ditional diagnostic techniques based on cytological ad-
vances, genomics, and proteomics are needed for the
diagnosis and staging of this highly malignant neoplasm.
H
epatocellular carcinoma (HCC) is the third leading
cause of cancer-related death worldwide. Recent ob-
servations indicate that the incidence of HCC is increasing
in western countries, including the United States. In the
majority of cases, cirrhosis is the major underlying risk
factor. Despite advances in surgical and ablative therapies
for HCC, a number of controversial issues associated with
the accurate diagnosis and staging of HCC remain. This
article reviews current standards for the clinical diagnosis of
HCC. In particular, attention focuses on the 3 questions of
most interest to the clinician: (1) Does the lesion represent
HCC and is a biopsy needed to conrm the diagnosis? (2)
Are there other lesions in the liver and is there vascular
invasion? (3) Are extrahepatic metastases present? Investi-
gative opportunities for more accurate diagnosis and staging
also are discussed. Evidence-based recommendations are
highlighted when deemed appropriate.
Diagnosis of Hepatocellular
Carcinoma
The diagnosis of HCC is of considerable interest
to clinicians evaluating patients with liver cirrhosis.
1,2
Based on the growing availability of potential curative
therapies that may improve survival in selected patients,
3
a consensus statement from the European Association for
the Study of the Liver (EASL) has been formulated to
standardize diagnostic approaches in patients with
HCC.
4
This statement recognizes both histological and
radiological criteria as sufcient evidence for identifying
HCC in patients with cirrhosis. Recommendations were
categorized based on size of the primary lesion when
detected by conventional imaging modalities.
Hepatocellular Carcinoma Lesions >2 cm
in Diameter
The accurate diagnosis of HCC lesions 2 cm in
diameter can be made noninvasively, based on radio-
graphic criteria in patients with cirrhosis. The ability to
diagnose these tumors noninvasively is based on the high
prevalence of HCC in patients with cirrhosis, the neo-
vascularity of HCC (a biological hallmark of neoplasia),
and the ability to equate neovascularity with contrast
enhancement on rapid-sequence cross-sectional imaging
studies (Figure 1). Consensus diagnostic criteria have
been developed and widely accepted (Table 1). Require-
ments for establishing a radiologic diagnosis of HCC
include the presence of a focal lesion 2 cm in diameter,
identied by using 2 imaging modalities and showing
arterial hypervascularization in at least 1 of the imaging
modalities. Contrast-enhanced computed tomography
(CT), magnetic resonance (MR) imaging (MRI), and
angiography are used most commonly to identify these
features in clinical practice. If the lesion is identied in
only a single imaging modality, the presence of a serum
-fetoprotein (AFP) level 400 ng/mL also is considered
diagnostic of HCC in the setting of cirrhosis.
4
Given the
superb diagnostic accuracy of these criteria,
48
percuta-
Abbreviations used in this paper: AFP, -fetoprotein; CT, computed
tomography; DCP, des-carboxyprothrombin; EASL, European Associa-
tion for the Study of the Liver; FISH, uorescent in situ hybridization;
HCC, hepatocellular carcinoma; MR, magnetic resonance; MRI, mag-
netic resonance imaging.
2004 by the American Gastroenterological Association
0016-5085/04/$30.00
doi:10.1053/j.gastro.2004.09.026
GASTROENTEROLOGY 2004;127:S126S132
neous biopsy for histological conrmation is not manda-
tory. Among 160 patients with 225 focal liver lesions
evaluated by means of sequential radiological imaging
studies in preparation for planned surgical therapy,
5
the
preoperative diagnostic accuracy rate without histologi-
cal conrmation was reported to be 98.2%. For patients
with HCC, sensitivity, specicity, and accuracy of diag-
nosis by means of radiological criteria were 100%,
98.8%, and 99.1%, respectively.
Other cited advantages for using noninvasive criteria
to diagnose HCC in lesions 2 cm in diameter include
avoidance of a 10%20% false-negative rate from histo-
logical sampling.
911
This phenomenon has been ob-
served even when cytological analysis is combined with
ne-needle biopsy.
10
In clinical practice, because of this
high false-negative rate, a negative biopsy result in the
setting of cirrhosis does not conclusively exclude the
possibility of HCC.
4
Moreover, tumor seeding from an
invasive biopsy has been well described,
1113
with prev-
alence rates between 1.5% and 5%. Of note, the majority
of lesions in which needle-track seeding was reported
were 2 cm in size.
13
The reported incidence of tumor
seeding from an invasive biopsy is based solely on the
presence of needle-track seeding, which may underesti-
mate this problem. All biopsies disrupt the tumor-vas-
cular integrity and may promote more widely dissemi-
nated seeding. Thus, many experienced medical centers
contemplating curative therapeutic approaches use the
consensus criteria and do not routinely subject patients
to needle biopsies. In the case of indeterminate radiolog-
ical ndings (ie, a lesion identied on only 1 imaging
modality with no contrast enhancement) and lesions that
are obviously advanced and require systemic therapies, an
image-guided biopsy of suspicious lesions 2 cm in size
is reasonable.
11,13
Limitations associated with noninvasive diagnostic
criteria include the misclassication of dysplastic nod-
ules
14,15
as malignant. Consequences of this misdiagnosis
are unclear. Less than 20% of patients with high-grade
dysplastic nodules remain cancer free during 3 years.
16
Perhaps these lesions should be treated aggressively;
however, the decision is more complex when contem-
plating liver transplantation compared with surgical re-
section or ablative therapies. Additionally, other malig-
nant hepatic lesions, such as non-Hodgkins lymphoma,
recently described in association with hepatitis C
induced cirrhosis, could be missed without histological
conrmation and result in misguided therapy.
17
How-
ever, in the United States, intrahepatic hepatitis C
associated lymphoma appears to be rare.
Hepatocellular Carcinoma Lesions <2 cm
in Diameter
Criteria for the diagnosis of HCC are less well
dened for nodules 2 cm in diameter. As a result, a
number of recall procedures have been outlined by the
EASL consensus statement to initiate follow-up. How-
ever, evidence to support the clinical effectiveness and
widespread use of these recommendations is lacking.
4
Focal hepatic lesions 1 cm in diameter carry a
50% risk for harboring malignancy.
1,2,18
To exclude
interval growth, serial abdominal ultrasound examina-
tions every 3 months are recommended until the lesion
exceeds 1 cm in size. For nodules between 1 and 2 cm in
size, the use of ne-needle aspiration with biopsy is
recommended for diagnosis, according to EASL consen-
sus guidelines. This is based on evidence suggesting that
the sensitivity and diagnostic accuracy with existing
imaging techniques is reduced for lesions 2 cm.
2
How-
ever, limitations of invasive biopsy include a 30%40%
false-negative diagnostic rate
12
and the risk for tumor
seeding, as described. Given the inadequate test perfor-
mance of an invasive biopsy and serum AFP level (dis-
cussed next), novel strategies are required to improve the
diagnosis of HCC in lesions 2 cm. Better cytological
techniques may enhance the utility of ne-needle aspirate
specimens in making the diagnosis of HCC. For example,
gains of chromosome 1 and 8 are common features of
HCC and are diagnostic of aneuploidy,
19
a diagnostic
feature of neoplasia, when present. Fluorescent in situ
Table 1. Noninvasive Diagnostic Criteria for Hepatocellular
Carcinoma
Mass in a cirrhotic liver, 2 cm, identied by means of 2
coincident imaging techniques (ultrasonography, spiral computed
tomography, magnetic resonance imaging, angiography)
One imaging study showing contrast enhancement
Figure 1. Computed tomographic scan of the liver in a patient with
cirrhosis attributable to hepatitis Crelated disease shows a contrast-
enhanced lesion typical of hepatocellular carcinoma (arrow).
November Supplement 2004 HCC DIAGNOSIS S127
hybridization (FISH) techniques using probes for the
centromeres of these 2 chromosomes have been developed
for HCC.
20
In other hepatobiliary neoplasia, namely
cholangiocarcinoma, FISH techniques are clinically
available to aid in the cytological diagnosis of cancer.
21
The role of FISH in the diagnosis of small HCC needs to
be explored and represents a high priority investigative
opportunity.
Serum Markers for Hepatocellular
Carcinoma: -Fetoprotein and
Des-Carboxyprothrombin Serum Levels
Selection of a serum AFP cutoff level 400
ng/mL as a complementary method for the diagnosis of
HCC is based on experience from patients with viral-
induced cirrhosis.
2225
However, serum AFP levels 400
ng/mL also may be observed in patients with active viral
replication without evidence for HCC.
25
Furthermore,
serum AFP levels often are normal (20 ng/mL) with
lesions between 1 and 2 cm and do not help clarify the
status of most indeterminate nodules.
24
Finally, a recent
systematic review conrmed the poor diagnostic ability
of serum AFP level for detecting HCC at any level of
pretest risk.
25
However, as a conrmatory test in patients
with a mass on imaging studies, AFP determination
remains clinically useful
24
despite the less than optimal
correlation of serum AFP level with HCC. It should be
emphasized that the reported poor performance of serum
AFP determinations for HCC pertains to patient popu-
lations with primarily viral liver diseases. The utility of
serum AFP determinations in patients with cholestatic
liver diseases, alcohol and nonalcohol steatohepatitis syn-
dromes, hemochromatosis, cryptogenic cirrhosis, and
1
-
antitrypsin deciency has not been established.
The des-carboxyprothrombin (DCP) test has been
available for a couple of decades, but interest in its
performance as an HCC biomarker has resurfaced. A
recent study suggests it has a high specicity for differ-
entiating malignant from benign liver disease.
26
Its abil-
ity to specically identify early HCC 2 cm is unknown
and currently the subject of investigation.
Individual Cross-Sectional Imaging
Techniques for the Diagnosis of
Hepatocellular Carcinoma
Earlier studies attempting to document the diag-
nostic accuracy of imaging techniques were limited by
retrospective study design and problems related to veri-
cation bias. However, more recent studies have used
explant histological evaluation as a comparative gold
standard.
2731
Abdominal ultrasonography is associated
with a sensitivity and specicity of 20%51% and 92%
96% for detecting lesions consistent with HCC in pa-
tients with cirrhosis, respectively.
2729
Further reduc-
tions in test performance result when additional lesions
are sought with this modality.
27
Detection rates for
lesions between 2 and 3 cm and 1 and 2 cm with
ultrasonography are estimated at 20% and 13%, respec-
tively.
28
However, the high specicity with ultrasound
implies that any recognized lesion in patients with cir-
rhosis requires additional evaluation to exclude malig-
nancy.
29
Computed tomographic imaging was associated
with similar test performance characteristics from earlier
liver explant comparative studies.
30,31
However, recent
investigations documented sensitivity and specicity
rates of 71%80% and 80%96% for contrast-enhanced
CT compared with explant histological evaluation, re-
spectively.
3234
This probably is related to an increased
proportion of larger tumors among patients referred for
possible liver transplantation.
33
However, Lipiodol
(Guerbet Andre, Aulnay-Sous-Bois, France)-enhanced
techniques are less accurate.
35
MRI-angiography appears
to have greater sensitivity (84%) compared with CT for
the detection of nodules between 1 and 2 cm. However,
lesions 1 cm continued to be missed in 70% of cases
with both imaging techniques.
36
Furthermore, in the
absence of a mass lesion on T2 MR images, only 30% of
hypervascular lesions 2 cm eventually are diagnosed as
HCC on follow-up, with the remainder disappearing or
remaining stable in size.
37
Positron emission tomography
is not an effective technique for the detection of HCC
lesions 2 cm.
32
Role of Cross-Sectional Imaging for Early
Detection of Hepatocellular Carcinoma
Despite a complete lack of evidence from random-
ized controlled trials, many centers around the world
have implemented early HCC detection surveillance pro-
grams for patients with cirrhosis. Diagnostic test perfor-
mance characteristics of imaging techniques have been
extrapolated to justify the effectiveness of surveillance
without evidence-based foundations. Based on its cost
and availability, ultrasonography remains the modality
of choice. Both CT and MRI generally are used as
conrmatory tools for diagnosis, given their increased
cost and limited availability. However, the use of CT for
HCC surveillance had a greater sensitivity (88%) com-
pared with ultrasonography (50%) when compared di-
rectly in a single investigation.
34
Enthusiasm for widespread HCC surveillance is tem-
pered by recognized limitations in diagnosis. Ultrasound
remains unable to reliably distinguish macroregenerative
and low-grade dysplastic nodules, which often are
5 mm and have a low risk for malignant transforma-
S128 TALWALKAR AND GORES GASTROENTEROLOGY Vol. 127, No. 5
tion, from true HCC.
38
High-grade dysplastic nodules,
which are usually 1 cm in size and often missed by
ultrasonography, CT, and MRI, develop into HCC in
30% of cases.
15,38
The ability to exclude multicentric
HCC, which occurs in 20%40% of cases, also severely
limits the effectiveness of ultrasonography for detecting
early-stage disease.
39
Staging of Hepatocellular
Carcinoma
There are 2 components to the staging of HCC:
(1) intrahepatic staging and (2) extrahepatic staging.
Intrahepatic staging requires delineation of the number
and size of lesions and whether vascular invasion is or is
not present. Optimally, if 1 lesion is present, staging
technology would permit the distinction between de
novo lesions and intrahepatic metastases. Extrahepatic
staging is performed to determine whether metastasis
outside the liver is or is not present. Each of these issues
is discussed in further detail.
For critical decision making, the number and location
of all intrahepatic lesions needs to be carefully assessed.
For example, current transplant criteria for HCC include
1 lesion 5 cm in diameter or 3 lesions, all 3 cm.
Precise and accurate staging would determine the accu-
rate size of a lesion and the number of lesions present in
the liver. As best can be determined, no published stud-
ies correlated the actual size of lesions noted in explanted
livers with size estimated from preoperative imaging
studies. There also is a tendency to simply measure the
largest diameter of a lesion. Volumetric studies should be
possible and likely would be more reective of tumor
burden.
Genetic studies are necessary to distinguish between
synchronous primary lesions and intrahepatic metastases.
Comparative genomic hybridization and allelotyping
with determination of loss of heterozygosity can be used
for this purpose. Fractional allelic loss (quantitation of
loss of heterozygosity) has been reported to make this
distinction.
40
Furthermore, fractional allelic loss corre-
lates with biological aggressiveness and outcome; high-
frequency fractional allelic loss is associated with reduced
disease-free survival after orthotopic liver transplanta-
tion.
41
Diagnosis of recurrent disease, metachronous vs
metastatic, also has been accomplished by means of com-
parative genomic hybridization.
40
In this study, approx-
imately one third of lesions were metachronous, one
third were metastatic, and one third were not classiable.
Thus, genetic approaches hold great promise for helping
diagnose and stage HCC.
Extrahepatic staging of HCC currently is based solely
on such imaging studies as cross-sectional imaging of the
chest and abdomen and bone scans. However, despite
negative imaging study results, recurrent disease is com-
mon after resection and liver transplantation for large
tumors.
42
Moreover, recurrence in the graft is a common
presentation in this context. These data suggest micro-
metastases are common and often return to the fertile
garden, the liver. Detection of micrometastases is an
important clinical goal and will help dictate which ther-
apies are optimal for a given patient. Attempts to cor-
relate polymerase chain reactionbased detection of AFP
and albumin levels in peripheral-blood samples and pa-
tient outcome were unsuccessful and have been largely
abandoned. In particular, these techniques were sensitive
and detected circulating gene products in a wide variety
of clinical circumstances.
43
However, a recent study re-
ported the detection of circulating tumor cells in the
blood of patients with HCC.
44
The presence of circulat-
ing tumor cells was associated with limited survival
compared with patients who did not have circulating
cells present in peripheral blood. This nding needs to be
veried. It also may be that micrometastases reside in
bone marrow. In patients with breast cancer, detection of
epithelial markers within bone marrow (ie, cytokeratin-
positive cells) is associated with greater recurrence and
lower survival rates in patients with apparent early-stage
disease.
45
Again, this approach needs to be assessed in the
context of HCC. Until the presence and clinical signif-
icance of micrometastases can be determined, it remains
difcult to establish which patients should be considered
for locoregional therapies (eg, surgery, transplantation,
ablation, and chemoembolization).
Prognostic Staging Systems for
Hepatocellular Carcinoma
The natural history of HCC depends on the se-
verity of the underlying cirrhosis, tumor characteristics
(ie, size, multicentricity, presence or absence of vascular
invasion, pathological grade, and extrahepatic metasta-
ses), performance status of the patient, comorbid condi-
tions, and the efcacy of treatment interventions. Four
prognostic classications have been developed for HCC
(Table 2).
4649
None of them is perfect. The Okuda
classication uses a gross assessment of tumor factors and
is not very useful in the clinical evaluation of patients.
The Barcelona Clinic Liver Cancer, Cancer of the Liver
Italian Program, and Groupe dEtude et de Traitement
du Carcinome Hpatocellulaire classications use more
rened assessments. These models cannot provide a pre-
cise prognosis for individual patients, but nevertheless
are helpful as a guide for prognosis and treatment of
November Supplement 2004 HCC DIAGNOSIS S129
patient subgroups. For example, according to the Barce-
lona Clinic Liver Cancer classication, patients with uni-
centric disease, no symptoms, and no evidence of vascular
invasion or extrahepatic spread have a 3-year survival rate
of 50%.
46
Conversely, patients with severe cancer-related
symptoms reected by deteriorated performance status
and marked impairment of their liver function have a
50% survival rate at 3 months, regardless of tumor
characteristics. The information provided by these mod-
els needs to be kept in mind when considering treatment
options for each patient.
Summary
Considerable advances have been made in the
ability to diagnose HCC. These advances relate to the
recognition that patients with cirrhosis are at high risk
for this disease, resulting in the implementation of
screening strategies. Cross-sectional imaging modalities,
including CT and MR, have improved in resolution and
speed, permitting imaging during the arterial phase of
contrast administration. Given that most HCC lesions
are highly vascular, small tumors frequently are identi-
ed by means of contrast enhancement during MRI and
CT. In a cirrhotic liver, the presence of a mass lesion
2 cm in diameter with contrast enhancement is virtu-
ally diagnostic of HCC, and consensus criteria have been
established for the noninvasive diagnosis of HCC. Diag-
nosis of a small HCC nodule 2 cm in diameter is still
challenging and requires advances in imaging modalities
and/or cytological approaches (Table 3). Likewise, greater
effort is required to diagnose micrometastases to aid in
staging and therapeutic selection (Table 3).
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Hepatocellular Carcinoma
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Address requests for reprints to: Gregory J. Gores, MD, Professor of
Medicine, Mayo Medical School, Clinic, and Foundation, 200 First
Street SW, Rochester, Minnesota 55905. e-mail: gores.gregory@
mayo.edu; fax: (507) 284-0762.
Supported in part by grant no. DK41876 from the National Institutes
of Health (to G.J.G.) and the Mayo and Palumbo Foundations.
The excellent secretarial services of Erin Bungum are gratefully
acknowledged.
S132 TALWALKAR AND GORES GASTROENTEROLOGY Vol. 127, No. 5