GASTROENTEROLOGY 2008;134:17521763
Diagnosis and Treatment of Hepatocellular Carcinoma
Hashem B. ElSerag* Jorge A. Marrero
*Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas; Division of Gastroenterology, University of Michigan, Ann Arbor,
Michigan; and Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, Pennsylvania and Institute of Molecular Medicine and Max-
Planck-Research Group on Stem Cell Aging, University of Ulm, Ulm, Germany
The diagnosis and treatment of hepatocellular carci-
noma (HCC) have witnessed major changes over the
past decade. Until the early 1990s, HCC was a rela-
tively rare malignancy, typically diagnosed at an ad-
vanced stage in a symptomatic patient, and there were
no known effective palliative or therapeutic options.
However, the rising incidence of HCC in several re-
gions around the world coupled with emerging evi-
dence for efficacy of screening in high-risk patients,
liver transplantation as a curative option in select
patients, ability to make definitive diagnosis using
high-resolution imaging of the liver, less dependency
on obtaining tissue diagnosis, and proven efficacy of
transarterial chemoembolization and sorafenib as
palliative therapy have improved the outlook for
HCC patients. In this article, we present a summary of
the most recent information on screening, diagnosis,
staging, and different treatment modalities of HCC,
as well as our recommended management approach.
Diagnosis of Hepatocellular Carcinoma
C irrhosis is the strongest and the most common
known risk factor for hepatocellular carcinoma
(HCC), particularly cirrhosis related to hepatitis C virus
(HCV) and hepatitis B virus (HBV) infections.13 In addi-
tion, HBV acquired in the perinatal period and early
childhood is associated with increased risk of HCC even
in the absence of cirrhosis.
Clinical Features
Patients with HCC present with one or more of
several clinical features including right upper quadrant
pain, weight loss, and/or worsening liver enzymes in a
patient known to have cirrhosis. Rare presenting features
include acute abdominal catastrophe from rupture of
HCC with intraabdominal bleeding or extra hepatic man-
ifestations (eg, hypercalcemia, hypoglycemia, thyrotoxi-
cosis).4,5 Anemia is present in more than half of cases,
Lenhard Rudolph K. Rajender Reddy
although rarely erythrocytosis can be seen because of
extrarenal synthesis of erythropoeitin.6 In addition to
signs of cirrhosis (eg, jaundice, palmar erythema, gyneco-
mastia) and portal hypertension (eg, ascites, varices), a
hepatic bruit could be detected in 10%20% of patients
with HCC.7 With the increased awareness of HCC, more
asymptomatic patients are being diagnosed as part of
active surveillance. Unfortunately, the majority of pa-
tients still presents with signs and symptoms suggestive
of liver decompensation and/or tumor spread.
HCC Screening
HCC screening is recommended in high-risk pa-
tients (Table 1). In a randomized controlled trial of nearly
19,000 HBV-infected patients in China, it was shown that
HCC surveillance with testing of serum -fetoprotein
(AFP) and performance of abdominal ultrasound (US) at
repeated 6-month intervals improves survival.8,9 Al-
though adherence to surveillance was relatively low
(60%), a 37% reduction in HCC-related mortality was
reported. A similar, randomized clinical trial study in
China, however, reported that surveillance for HCC is not
beneficial in the absence of curative therapies after the
cancer was diagnosed.10 In addition, several nonrandom-
ized trials, as well as observational studies, have observed
a survival benefit in those identified with small and early
tumors.11
AFP and liver US are the most widely used tools for
HCC surveillance. Based on the estimated HCC doubling
time, the recommended surveillance interval is 6 months,
Abbreviations used in this paper: AFP, -fetoprotein; HCC, hepato-
cellular carcinoma; BCLC, Barcelona-Clinic Liver Cancer; CTP, Child-
Turcotte-Pugh; LDLT, living donor liver transplantation; OTL, orthotopic
liver transplantation; PEI, percutaneous ethanol injection; RFA, radio-
frequency ablation; TACE, transarterial chemoembolization; UNOS,
United Network for Organ Sharing; US, ultrasound.
2008 by the AGA Institute
0016-5085/08/$34.00
doi:10.1053/j.gastro.2008.02.090
May 2008
Table 1. Groups in Whom HCC Screening and Surveillance
Is Recommended
Hepatitis B carriers (HBsAg positive)
Asian males 40 y
Asian females 50 y
All cirrhotic hepatitis B carriers
Family history of HCC
Africans over age 20 y
Nonhepatitis B cirrhosis
Hepatitis C
Alcoholic cirrhosis
Genetic hemochromatosis
Primary biliary cirrhosis
Possibly: 1-antitrypsin deficiency, nonalcoholic steatohepatitis,
autoimmune hepatitis
although a 1-year interval may be equally effective.8,12,13
The performance of US depends on the experience of the
examiner, the technology used, the body habitus, the
presence of cirrhosis, and the size of the tumor. Recent
studies generally indicate a 60% sensitivity, and 90%
specificity.14 The sensitivity of US to detect tumor nod-
ules in cirrhotic livers is particularly low.1517 The serum
AFP level of 20 ng/mL commonly used as the upper limit
of normal18,19 has low sensitivity (25% to 65%) for detect-
ing HCC and is therefore considered inadequate as the
sole screening test. Patients with chronic liver disease,
especially those with a high degree of hepatocyte regen-
eration (eg, HCV), can express elevated serum AFP in the
absence of malignancy.20,21 Other tests such as des-
carboxy prothrombin and lectin-bound AFP (AFP-L3) are
available, but there are no reliable prospective data on
their effectiveness in HCC screening.
The cost-effectiveness of HCC surveillance strategies
using both AFP and US have been evaluated in retrospec-
tive studies as well as mathematical models,1,8 10,14 and
generally reported surveillance for HCC in patients with
compensated cirrhosis might be associated with a modest
gain in quality adjusted life years at acceptable costs. One
study also reported that the effectiveness of surveillance
depends mostly on the outcomes and costs of HCC
treatments.22 In patients undergoing HCC screening
while awaiting liver transplantation, screening with com-
puterized tomography (CT) is associated with the great-
est gain in life expectancy and is possibly cost-effective in
this setting.23
Therefore, current guidelines advocate the use of US at
6 12 months frequency to screen for HCC in high-risk
patients. The use of AFP alone is strongly discouraged,
and its use in addition to US is controversial. High-risk
patients include virtually all patients with cirrhosis and
some HBV-infected patients irrespective of cirrhosis (40
years in men and 50 years in women).8
Diagnostic Imaging
Once a screening test is abnormal or there is a
clinical suspicion that a patient may have HCC, imaging
DIAGNOSIS AND TREATMENT OF HCC 1753
is very important for the diagnosis and staging of this
tumor. The most reliable diagnostic tests are triple-phase
helical CT and triple-phase dynamic contrast enhanced
magnetic resonance imaging (MRI),24,25 whereas hepatic
angiography has fallen out of favor in most practice
settings. HCC derives its blood supply predominantly
from the hepatic artery, whereas the remainder of the
nontumorous liver receives both arterial and portal
blood. The hallmark of HCC during CT scan or MRI is
the presence of arterial enhancement followed by delayed
hypointensity of the tumor in the portal venous and
delayed phases, ie, washout26 (Figure 1). The presence of
arterial enhancement followed by washout has a sensitiv-
ity and specificity of 90% and 95%, respectively. However,
71% of patients with HCC will have arterial enhancement
and washout on more than one test, whereas the rest do
not have these features and, therefore, will require liver
biopsy for the diagnosis of HCC. There have been at least
4 studies that have compared the accuracy of CT and
MRI for HCC diagnosis, using the explanted liver as the
gold standard.2730 These show that MRI is slightly better
in the characterization and diagnosis of HCC when com-
pared with CT scan (Table 2). The performance of CT
and MRI is affected by the size of the lesions. For exam-
ple, in tumors larger than 2 cm, MRI is reported to have
an accuracy 90%; however, in tumors smaller than 2 cm,
this level is reduced to 33%.31
Currently, AFP serum levels above 200 ng/mL are
highly specific for HCC diagnosis in patients with cirrho-
sis and coinciding radiologic evidence of focal hepatic
lesions.8 However, the sensitivity of AFP is much lower
because it has been reported that only one third of
patients with HCC have AFP levels higher than 100
ng/mL.32,33
Diagnostic Approach to HCC
A diagnostic approach to HCC has been devel-
oped based on the literature and expert consensus and
incorporates serology, cytohistology, and radiologic char-
acteristics.8,34 Diagnosis of HCC can be confidently es-
tablished if (1) a focal hepatic mass 2 cm is identified
on one imaging technique wherein characteristic contrast
enhancement features on the arterial phase with venous
washout on an MRI or CT can be demonstrated; (2) a
focal hepatic mass with atypical imaging findings (no
arterial enhancement with washout), or a focal hepatic
mass detected in a noncirrhotic liver, should undergo a
biopsy.
Noninvasive diagnosis of HCC is best limited to patients
with cirrhosis and to patients with a focal hepatic mass 2
cm. On the other hand, the recommended diagnostic ap-
proach for tumors 2 cm or tumors that do not meet
above criteria8 is such that (1), when nodules within 12 cm
on screening of a cirrhotic liver are typical of HCC (hyper-
vascular with washout) on 2 imaging modalities, the lesion
should be treated as HCC. In an atypical lesion where the
1754 ELSERAG ET AL GASTROENTEROLOGY Vol. 134, No. 6

Figure 1. MRI features of HCC.

The left top panel shows an arte-
rial phase MRI examination of
the liver and an enhancing mass
in the right lobe, which further in-
tensifies in the left bottom panels
indicated by the arrowheads.
The right top panel shows a
2-minute delayed MRI examina-
tion that shows the mass in the
right lobe, but this is hypointense
compared with the rest of the
liver as well as when compared
with the arterial phase. This is the
phenomenon of washout of con-
trast. The right lower panel
shows a 5-minute examination
that highlights washout of con-
trast in the delayed phase com-
pared with the arterial phase
examination.

vascular profile is not consistent among techniques, a bi-
opsy of the lesion should be considered. (2) Nodules smaller
than 1 cm should be followed with US at 3- to 6-month
intervals. If, over a period of 2 years, growth has not been
observed, a return to routine surveillance at 6-month inter-
vals is suggested.35
Percutaneous liver biopsy under radiologic guidance
have sensitivities and specificities of 90% and 91% for US
and 92% and 98% for CT scan guidance, respectively.36 A
negative biopsy result, although highlight suggestive,
does not completely rule out malignant disease, and the
nodule should be further studied at 3- to 6-month inter-
vals until the nodule disappears, enlarges, or displays
diagnostic characteristics of HCC. If the lesion enlarges
but remains atypical for HCC, a repeat biopsy is recom-
mended.36
Treatment of HCC
The management of HCC involves multiple disci-
plines including hepatology, surgery, diagnostic and inter-
ventional radiology, oncology, and pathology. One has to
consider several patient and tumor factors including the
severity of underlying liver disease, tumor bulk, and associ-
ated comorbidities as well as several practice-setting factors
including availability and expertise in surgical resection,
transplantation, and ablative therapies.
Staging of HCC
A precise staging of the disease may help decide
on prognosis as well as choice of therapy with the great-
est survival potential. There are several prognostic scor-
ing systems including Barcelona-Clinic Liver Cancer
(BCLC), Cancer of the Liver Italian Program, the Chinese
University Prognostic Index and Japanese Integrated
Staging. They use different permutations of variables
related to the severity of liver disease, number and size of
tumor nodules, and cancer spread (Table 3). Although
there is no one universally accepted HCC staging system,
many have adopted the BCLC groups proposal of 5
stages, further validated in a large North American expe-

Table 2. Summary of Several Studies That Compared the Accuracy of CT Scan and MRI Scan in HCC
CT scan MRI
Author Gold standard No. patients No. nodules HCC (n) Sens Sp Sens Sp
De Ledinghen et al28 Explanted liver 34 88 54 51 61
84 93
Rode et al30 Explanted liver 43 69 13 53 77
92 58
Burrel et al27 Explanted liver 50 127 76 61 76
66 75
Libbrecht et al29 Explanted liver 49 136 77 50 70
79 82

Sens, sensitivity (%); Sp, specificity (%).

May 2008 DIAGNOSIS AND TREATMENT OF HCC 1755

Table 3. Several Commonly Used Staging Systems for HCC

Okuda Staginga

Negative: Positive: Stage:

Tumor size 50% of liver 50% of liver I: No positive factors
Ascites Absent Present II: 12 positive factors
Bilirubin 3 mg/dL 3 mg/dL III: 34 positive factors
Serum albumin 3 g/dL 3 g/dL

ChildTurcottePugh (CTP)

1 Point: 2 Points: 3 Points: Class:

Encephalopathy None Grade III Grade IIIIV A 56 pts
Bilirubin (mg/dL) 2 23 3 B 79 pts
PT/INR 1.7 1.712.20 2.20 C 1015 pts
Ascites None Controlled Refractory
Albumin (g/L) 35 2835 28

BCLC Staging and correlation with Okuda Staging

Stage: PS: Tumor stage: Okuda: pH: Bilirubin: Classification:

A1 0 Single I No Normal Very early
A2 0 Single I Yes Normal Early
A3 0 Single I Yes Altered
A4 0 3 3 cm III Yes Altered
B 0 5 cm or multinodular III Intermediate
C 12 Vascular invasion III Advanced
D 34 Any stage III Terminal

CLIP Stagingb

Portal vein
Points: CTP: Tumor morphology: AFP: thrombosis:
0 A Uninodular 50% of liver 400 ng/dL No
1 B Multinodular 50% of liver 400 ng/dL Yes
2 C Massive 50% of liver

CLIP, Cancer of the Liver Italian Program; PH, portal hypertension; PS, performance status; PT, prothrombin time; INR, international normalized
ratio.
aMedian survival without therapy: Stage I: 8.3 years, Stage II: 2 years, Stage III: 0.7 years.
bThe median survival is 36, 22, 9, 7, and 3 months for total CLIP points of 0, 1, 2, 3, and 4 to 6, respectively.

rience.37,38 The BCLC staging and prognostic system ac-
counts for variables related to tumor stage, physical and
liver functional status, and cancer-related symptoms and
also provides a link to a treatment algorithm. Patients in
stage A can undergo resection, transplantation, or abla-
tion. ChildTurcottePugh (CTP) class, which provides
an assessment of the synthetic function, may serve com-
plementary to the BCLC staging in providing a more
refined treatment algorithm.39 The Okuda classification
takes into account radiologic tumor size and liver func-
tion (ascites, total serum bilirubin, and serum albumin)
is helpful in identifying patients with advanced HCC but
may be less adequate for staging patients with early or
intermediate stage disease. Another commonly used stag-
ing system is the Cancer of the Liver Italian Program,21,40
which uses a mathematical score based on the CTP,
tumor morphology, AFP, and presence of vascular inva-
sion; however, it does not adequately assess populations
undergoing radical therapies, such as resection or trans-
plantation.
Despite some degree of overlap, several stages of HCC
can be identified, and each has different clinical features
as well as treatment and prognosis (Figure 2). Very early
HCC is currently very difficult to diagnose, presenting
with a single HCC lesion 2 cm. Affected patients have
CTP class A, display no signs or symptoms, and the
tumor displays no vascular invasion. Resection and ra-
diofrequency ablation (RFA) likely offer similar 5-year
survival rates. The choice of therapy depends on the
tumor location, degree of portal hypertension, and pres-
ence of medical comorbidities.
Patients presenting as early stage HCC exhibit preserved
liver function (CTP A and B) with a solitary HCC or up
to 3 nodules, each 3 cm in size. These patients can be
effectively treated by resection, liver transplantation (or-
thotopic liver transplantation [OLT]), or ablation with
the possibility of long-term cure, with 5-year survival
figures up to 75%. The choice of therapy is dictated by the
severity of the liver function, portal hypertension, and
medical comorbidities.
1756 ELSERAG ET AL
Patients with compensated cirrhosis and without
HCC-related symptoms or vascular invasion that are out-
side of the criteria of very early or early stage correspond to
the intermediate stage HCC. In this group, transarterial
chemoembolization (TACE) leads to a 23% improvement
in the 2-year survival compared with conservative ther-
apy.
Patients with mild cancer-related symptoms and/or
vascular invasion or extrahepatic spread are considered as
advanced stage (BCLC stage C). TACE may increase sur-
vival in well-selected candidates. However, a recently com-
pleted randomized trial showed that soranefib improved
the overall survival for patients at the BCLC stage C
compared with placebo. This therapy is likely to become
the main option for patients at this stage.
Patients with advanced stage present with cancer
symptoms, related to progressed liver failure, tumor
growth with vascular involvement, extrahepatic spread,
or physical impairment (performance status 2).41 Trials
of tamoxifen,42 44 octreotide,45 interferon,46 or antian-
drogenic therapy47 have shown no clear benefit for these
agents.
Unfortunately, patients who present with or have pro-
gressed into terminal stage have a 1-year survival less than
10%. This group does not benefit from treatments men-
tioned above. Therefore, to prevent unnecessary suffering,
the patient should receive symptomatic treatment.
Treatment Modalities
A summary of the main treatment modalities,
their indications, and reported outcomes is shown in
Table 4.
Surgical resection. Hepatic resection is the treat-
ment of choice for HCC in noncirrhotic patients because
of the fact that the residual liver has well-preserved he-
patic reserve. This group, however, accounts for less than
GASTROENTEROLOGY Vol. 134, No. 6
Figure 2. A proposed algo-
rithm for treatment of HCC
(adapted from BCLC algo-
rithm)103 PS, performance sta-
tus; OLT, orthotopic liver trans-
plantation; PEI, percutaneous
ethanol injection; RFA, radiofre-
quency ablation.
5% of patients in Western countries but nearly 40% in
HBV-endemic Asian countries.14 HBV has several cancer-
promoting actions including insertional mutagenesis
and p53 inhibition that explain its potential to induce
HCC in noncirrhotic liver.48 Patients with HCC and con-
comitant cirrhosis are not suitable for resection because
of the potential for hepatic decompensation after surgi-
cal resection. Hepatic resection for HCC in patients with
cirrhosis, therefore, requires careful selection. A funda-
mental problem is not only the stage of cirrhosis but also
the diminished regenerative reserve at the cirrhosis stage.
Hepatocyte regeneration decreases at the cirrhosis stage,
which has been linked to telomere shortening, senes-
cence, and DNA damage checkpoint activation.49 The
development of molecular markers indicating the regen-
erative reserve of hepatocytes may help to better select
HCC patients with underlying cirrhosis for surgical re-
section in the future.
Historically, the selection of candidates was based on
the CTP classification; however, this often does not ac-
count for some of the symptoms of advanced liver dis-
ease. A normal bilirubin concentration and the absence
of significant portal hypertension are probably the best
predictors of excellent short- and long-term outcomes.50
Significant portal hypertension can be inferred from
signs of esophageal varices and platelet counts below
100,000/mm3 related to splenomegaly or can be deter-
mined by indirect portal pressure measurements (hepatic
venous pressure gradient 10 mm Hg). The 5-year sur-
vival is less than 30% in patients with elevated bilirubin
(1 mg/dL) and portal hypertension.
In patients with cirrhosis, 5-year recurrence rates fol-
lowing resection exceed 50%.14,34 Utilization of tools such
as comparative genomic hybridization, integration pat-
tern of HBV, DNA fingerprinting using loss of heterozy-
May 2008
Table 4. Summary of Therapeutic Modalities for HCC and Their Outcomes
Treatment Survival
Surgical resection 1 y: 97%
3 y: 84%
5 y: 26%57%
Transplantation (LT) 1 y: 91%
2 y: 75%
5 y (MILAN): 70%
5 y (extended): 50%
Radiofrequency ablation (RFA) 1 y: 90%
3 y: 74%
5 y: 40%50%
Percutaneous ethanol injection (PEI) 1 y: 85%
3 y: 50%
5 y: 40%50%
Transarterial chemoembolization (TACE) 1 y: 82%
2 y: 63%
NOTE. The 1-year survival rates are reported from different studies and thus may not be used to compare directly the different therapeutic
modalities.
AE, adverse events; OLT, orthotopic liver transplantation.
gosity assays, or DNA microarray has allowed researchers
to determine that 60% to 70% of recurrences correspond
to intrahepatic metastases and that 30% to 40% are de
novo tumors.5153
Several variables affect the risk of recurrence following
resection: these include tumor size, number of tumors,
vascular invasion, and the width of the resection margin.
The recommended upper limit of tumor size for consid-
eration of resection has been argued, noting that there is
a significant difference in the 5-year recurrence rates in
patients with tumors 5 cm that is considerably greater
than those with 5 cm (43% vs 32%, respectively).54
Similarly, multinodular tumors have been determined to
have an increased tendency to recur.55 A large study of
1000 HCC patients reported a 5-year survival after resec-
tion of single tumors to be 57% and 3 or more nodules to
be 26%.56 Resectable tumor-free margins vary on a case-
by-case basis to balance tumor removal to reduce recur-
rence with preservation functioning liver parenchyma to
allow survival. A recent prospective randomized trial
compared wide (2 cm) and narrow (1 cm) resection
margins for solitary HCC.57 Although recurrence rates
remained high in both groups, the overall survival rates
were higher for the wide margin group.
Liver transplantation. Liver transplantation, in
theory, is the optimal therapeutic option for HCC; it
simultaneously removes the tumor and underlying cir-
rhosis thus minimizing the risk of HCC recurrence. Ear-
lier selection criteria for liver transplantation were broad,
leading to poor results with recurrence rates of approxi-
mately 50% and 5-year survival rates of 40%.58,59 The
DIAGNOSIS AND TREATMENT OF HCC 1757
Special issues
Choice of therapy for patients without cirrhosis (low morbidity)
5%15% of HCC patients eligible
Right hepatectomy has higher risk than left hepatectomy
Pre/postresection adjunct therapy not recommended
Curative treatment for chronic disease and HCC
MELD exception points for HCC
Effective corresponding to UNOS criteria (1 tumor 5 cm; up
to 3 tumors 3 cm
Liver donor LT considered for HCC progression outside MILAN
criteria
UCSF criteria not implemented in current MELD exception
allocation policy
Effect is more predictable in all tumor sizes than following PEI
Superior to PEI in larger tumors; equivalent in small tumors
Requires fewer treatment sessions
Early HCC patients not suitable to resection or OLT or RFA not
available or contraindicated
Highly effective for small HCC (2 cm)
Low rate of AEs
Nonsurgical patients with large/multifocal HCC w/o vascular
invasion or extrahepatic spread
currently recommended United Network for Organ Shar-
ing (UNOS) criteria (1 lesion 5 cm or maximum 3
lesions 3 cm in diameter) have shown tremendous
promise, with reported 5-year survival rates of 70% and
recurrence rates of 15%.59 61 The tumor burden criteria
for transplantation for HCC as established by the UNOS
are largely accepted. Expanded selection criteria (a single
lesion of 6.5 cm or up to 3 lesions, none of which are
larger than 4.0 cm, with a maximum combined tumor
bulk of 8.0 cm), have been proposed by University of
California in San Francisco.62 Liver transplantation in
such candidates has been associated with outcomes sim-
ilar to those who are within the UNOS criteria. However,
given the large number of HCC cases considered for liver
transplantation, the struggle is to keep a balance between
HCC and non-HCC recipients.
The UNOS oversees liver allocation in the United
States. Based on the radiologic diagnosis of the number
and size of lesions, Model for End-Stage Liver Disease
(MELD) exception points are awarded for HCC, with the
expectation that liver transplantation is accomplished in
a reasonable period of time. The exception points for
HCC are based on the 3-month pretransplantation mor-
tality rates. For solitary lesions 2 cm and 5 cm, as well
as up to 3 lesions, each 3 cm, patients currently receive
a MELD score of 22, unless their calculated MELD score
is otherwise greater. For each 3-month interval that they
remain on the wait list, a greater number of exception
points are awarded based on an expected increase of 10%
for the 3-month pretransplantation mortality rate (eg,
extension No. 1: 25 points for 25% mortality; extension
1758 ELSERAG ET AL
No. 2: 28 points for 35% mortality, . . .). The challenges
encountered in HCC pertain to the degree of MELD
exception points that should be assigned to HCC pa-
tients so that the number of transplantations done for
HCC patients are reasonable relative to other indications,
that there is an acceptable and comparable mortality
from all indications while awaiting transplantation, and
that the outcomes are similar after transplantation.
The role of downstaging of tumors that are outside of
conventional UNOS criteria for OLT has been explored.
Downstaging is HCC-directed therapy that aims at re-
ducing the size and/or number of HCC lesions. Studies
have shown that successful tumor downstaging can be
achieved in up to 70% of the patients treated in a proto-
col with one or more therapeutic modalities including
TACE, radiofrequency ablation (RFA), or percutaneous
ethanol injection (PEI). Subsequently, successful liver
transplantation was accomplished in nearly half of these
patients.63,64 Although encouraging, longer follow-up is
needed to assess further the risk of HCC recurrence after
OLT before downstaging can be recommended and
adopted. The role of salvage liver transplantation after
initial resection of HCC is less clear. Overall, suboptimal
outcomes have been observed with this strategy com-
pared with primary liver transplantation for HCC.65
Given the shortage of donors and in attempts to
shorten the waiting time for cadaveric liver transplanta-
tion, living donor liver transplantation (LDLT) has been
shown to be an alternative to cadaveric liver transplanta-
tion, with approximately 3000 cases done worldwide for
all indications. LDLT is a complex procedure that is
associated with a morbidity of 20% 40% and a donor
mortality of 0.3% 0.5%.66,67 With that, consideration of
ethical, societal, and legal issues are vital to successful
implementation of LDLT for HCC treatment. A recent
retrospective analysis of a United States experience noted
that the disease-free survival following LDLT was lower
than that of cadaveric liver transplantation. LDLT recip-
ients had a higher rate of HCC recurrence within 3 years
than deceased donor OLT recipients, 30% vs 0%, respec-
tively. However, there was no difference in mortality or
the combined outcome of mortality or recurrence.68
Thus, the role of LDLT, particularly for those outside of
ideal criteria, needs further evaluation.
Percutaneous ablation. Minimally invasive per-
cutaneous treatments are the best treatment alternatives
for early HCC patients who are not eligible for surgical
resection or transplantation. The most widely utilized
methods to induce tumor necrosis are PEI and RFA.
Other, less utilized methods include the injection of
acetic acid, boiling saline, cryotherapy, microwave ther-
apy, and laser therapy.8,58,69
PEI consists of injecting absolute ethanol directly into
the HCC lesions. PEI performed under US guidance
achieves complete tumor necrosis in 70% 80% of solitary
GASTROENTEROLOGY Vol. 134, No. 6
HCC 3 cm24 and in almost 100% in tumors less than 2
cm. Tumor necrosis is less likely to be achieved in large
tumors; 70% necrosis is reported for tumors between 2
and 3 cm and 50% necrosis for HCC between 3 and 5
cm.70 72 It is a well-tolerated, inexpensive procedure with
few adverse effects. In nonrandomized studies of patients
with small HCC, PEI has been shown to carry the same
overall survival and recurrence-free survival as surgical
resection.73,74 In a large series of 3225 patients with
solitary tumors 3 cm reported by Ryu et al,75 there were
no significant differences in survival between resection
and PEI. The best survival for PEI has been shown for
tumors 3 cm and 3 lesions.75
RFA, which has largely replaced PEI, provides more
complete ablation with fewer sessions than PEI (Figure
3).76,77 The efficacy of RFA in ablating tumors 2 cm is
similar to that of ethanol; however, in tumors 2 cm,
efficacy is better than with ethanol.78
Several recent randomized trials compared RFA and
PEI in treating patients with small HCC 4 cm (Table
5)71,7779 and demonstrated the superior efficacy of RFA
in terms of less operator variability, lower local recur-
rence, and longer overall as well as disease-free survival.
Local tumor control was reported to range between 90%
and 96%, with a mean of 1.12.1 sessions for RFA vs
4.8 6.5 for ethanol injection (Table 5). Local recurrence
rates have ranged between 8% and 14% at 23 years in
patients treated with RFA compared with 22%34% in
those treated with PEI. Overall survival rates for patients
treated with RFA were 100% and 98% for 1 and 2 years,
respectively, compared with 96% and 88%, respectively, in
the PEI trials. Recurrence-free survival rates at 1 and 2
years were 86% and 64% for the RFA group and 77% and
43% for the PEI group, respectively.79 Adverse events were
generally similar for the 2 treatment groups. There has
been a large experience reporting RFA safety even in
those with lesions close to vascular structures.80 These
data indicate that RFA leads to better local tumor and
longer overall survival for patients with very early as well
as early stage HCC. Therefore, RFA is the preferred
method of local ablation for patients with tumors 4
cm. RFA should be considered for patients with very early
stage HCC when resection cannot be applied and also for
patients with early stage HCC who are not candidates for
OLT and possibly for those with long waiting times 3
months.
There are at least 2 prospective, randomized controlled
trials comparing RFA with surgical resection. Both found
no significant differences in overall survival or recur-
rence-free survival and expectedly lower complication
rates and lower hospitalization in patients treated with
RFA.81,82 A recent Italian cohort study of 218 patients
with HCC tumors 2 cm in diameter showed a sustained
response in 97% during a median follow-up of 31 months
and a 5-year survival rate of 68%.83 It seems that these 2
May 2008 DIAGNOSIS AND TREATMENT OF HCC 1759

Figure 3. Percutaneous abla-

tion of HCC using radiofrequency.

procedures offer similar efficacy, and the choice of ther-
apy for very early stage HCC should depend on candidacy
for surgery in terms of performance status, severity of
portal hypertension, and feasibility of RFA in terms of
tumor location.
Transarterial embolization/chemoembolization.
TACE may offer palliative benefits for patients with
intermediate stage HCC with 5-year survival rates after
treatment exceeding 50%. TACE has been shown to
improve survival in patients outside of the early stage
criteria, especially in those who have not presented
with cancer-related symptoms or vascular invasion.69
However, its safe and effective use is limited to patients
with preserved liver function, absence of extrahepatic
spread or vascular invasion, and no significant cancer-
related symptoms. A European study revealed that only
12% of the 903 patients evaluated for HCC were suit-
able for TACE.84
The basis of embolization is to induce ischemic tumor
necrosis via acute arterial occlusion. Embolization may
be done alone (transarterial embolization) or combined
with selective intraarterial chemotherapy (TACE) such as
doxorubicin, mitomycin, or cisplatin and a contrast
agent, lipiodol.
TACE induces extensive tumor necrosis in 30% to up
to 50% of those treated patients, but with fewer than 2%
achieving a complete response.84 A meta-analysis of 7
randomized controlled trials comparing in that meta-
analysis, arterial embolization and/or chemoemboliza-
tion as a primary treatment for HCC in comparison with
conservative management and/or suboptimal therapies.85
Arterial embolization improved 2-year survival compared

Table 5. Summary of Several Studies That Compared PEI and RFA for HCC Treatment
Complete Sessions
necrosis rate (%) (average number)

Author N Tumor size PEI RFA PEI RFA Survival difference

Livraghi et al71 86 3 cm 80 90 4.8 1.2 No
Lencioni et al79 102 Milan criteria 82 91 5.4 1.1 Yes
Recurrence free
Lin et al78 157 4 cm 88 96 6.5 1.6 Yes
Shiina et al77 232 Milan criteria NA 6.4 2.1 Yes

NOTE. The 1-year survival rates are reported from different studies and thus may not be used to compare directly the different therapeutic
modalities.
PEI, percutaneous ethanol injection; RFA, radiofrequency ablation.
1760 ELSERAG ET AL
with that in control subjects (odds ratio, 0.53; 95% CI:
0.32 0.89).
In a large, prospective cohort study of 8510 patients
who received TACE for unresectable HCC, the median
survival was 34 months with 1-, 2-, 3-, 5-, and 7-year
survivals of 82%, 47%, 26%, and 16%, respectively.86 There
is currently little data to guide the choice of the chemo-
therapeutic agent or the retreatment schedule for TACE.
The current evidence does not support the use of transar-
terial embolization without chemotherapeutic agent.
Transarterial embolization/TACE are associated with
adverse events in approximately 10% of treated patients;
these events include ischemic cholecystitis, nausea, vom-
iting, bone marrow depression, and abdominal pain.58 A
postembolization syndrome is reported in 50% of pa-
tients treated with TACE and includes fever, abdominal
pain, and moderate degree of intestinal obstruction.
Treatment-related mortality is less than 5%.
TACE is clearly the first-line therapy for patients at the
intermediate stage who exceed the criteria for liver trans-
plantation (Figure 2). In addition, TACE can be per-
formed in patients at the early stage in whom RFA
cannot be performed because of tumor location (proxim-
ity to a gallbladder, biliary tree, or blood vessel) or med-
ical comorbidities. TACE is also the first-line therapy for
downstaging tumors that exceed the criteria for
transplantation.64
Other options. Radionuclide Yttrium-90, a pure
emitter, is a form of hepatic artery-directed therapy. Mi-
crospheres of approximately 25 m in diameter contain-
ing Yttrium-90 are lodged via a catheter insertion into
the lobar or segmental level of either hepatic artery and
emit local radiation with limited exposure to adjacent
healthy tissue.87 Currently, there are no data to suggest
its superiority over ablative therapies.
Molecular Therapies
There are a growing number of clinical studies
evaluating the efficacy of molecular therapies in HCC,
alone or in combination with classical chemotherapy.
Angiogenesis inhibitors. Several studies (phase I,
II, and III) are underway. Positive results have been ob-
tained for therapies using Bevacizumab (vascular endo-
thelial growth factor inhibitor) in combination with
Gemcitabine and Oxalliplatin.
Growth-receptor signaling. Studies have been
conducted targeting platelet-derived growth factor receptor,
endothelial growth factor receptor, Raf, and other signaling
pathways controlling cell proliferation. Positive results were
reported for the use of Nexavar (Bayer Healthcare AG,
Leverkusen, Germany) (sorafenib), an oral multikinase in-
hibitor, in patients with HCC. A phase III double-blind,
randomized, placebo-controlled trial was designed to eval-
uate Nexavar in patients with advanced HCC (BCLC stage
C) who had no prior systemic therapy. Six hundred two
patients were randomized and enrolled at sites in the Amer-
GASTROENTEROLOGY Vol. 134, No. 6
icas, Europe, and Australia/New Zealand. The overall sur-
vival (46.3 weeks, 95% CI: 40.9 57.9, vs 34.4 weeks, 95% CI:
29.4 39.4, respectively, P .058) and time to symptom
progression (24 weeks, 95% CI: 18 30, vs 12 weeks, 95% CI:
11.717.1, respectively, P .007) were significantly longer in
patients administered Nexavar vs those patients adminis-
tered placebo.88 Approximately 83% of the patients in the
sorafenib trial had portal vein invasion and were classified
as Barcelona stage C, with 20% having extrahepatic metas-
tases. The 17% without portal vein invasion were patients
who did not respond to TACE and were classified as Bar-
celona stage B in the study. Most patients had mild to
moderate performance status. Therefore, it is reasonable to
recommend sorafenib for patients with advanced stage or
intermediate stage HCC with portal vein thrombosis. Prom-
ising results89 on progression-free survival have also been
reported for Erlotinib, an inhibitor of endothelial growth
factor receptor signalling.90
Telomerase inhibition. Telomerase is active in
90% of human HCC, and it appears to be necessary for the
immortal proliferation capacity of HCCs.49 Preclinical stud-
ies show that telomerase inhibition can impair proliferation
of human HCC in nude mice.91 Phase I/II clinical studies
are currently underway in patients with lymphoma. In ad-
dition to the above approaches, antibody treatment against
HCC surface markers have been reported to lower recur-
rence rates after liver transplantation.92
Another important factor to improve future therapies
in HCC is the development of new markers to improve
screening of cirrhosis patients for early lesions,93 selec-
tion of HCC patients that could benefit from surgery or
chemotherapy,94 97 or diagnosis of HCC.98 However, the
utility of these tests remains unproven and will have to be
tested in translational and clinical studies.
HCC Treatment: Effectiveness vs Efficacy
Population-based studies in the United States indi-
cate that the overall 1- and 3-year survival rates for patients
with HCC are approximately 20% and 5%, respectively (me-
dian survival of 8 months).99 These figures accommodate
for a 20% improvement in survival that was observed be-
tween 1987 and 2001. To make a positive impact on the
effectiveness of treating HCC, several steps have to be suc-
cessfully accomplished so that more patients can be diag-
nosed at an early stage and receive timely potentially cura-
tive therapy. However, there seems to be a serious chasm
between efficacy and effectiveness of treatment of HCC.100 A
United States population-based study reported that, in
2963 patients 65 years and older diagnosed between 1992
and 1999 with HCC, only 13% received potentially curative
therapy (transplant, 0.9%; resection, 8.2%; local ablation,
4.1%). Furthermore, only 34% of 513 patients with single
lesions and 34% of 143 patients with lesions 3.0 cm
received potentially curative therapy. There were geographic
variations in the management of HCC that are at least as
significant as clinical and tumor-related features in deter-
May 2008
mining the extent and type of HCC therapy.101 Another
United States population-based study of 1156 patients di-
agnosed between 1998 and 2002 with small nonmetastatic
HCC in the United States found that liver transplantation
yielded excellent overall survival, but only 21% of patients
with localized HCC received a transplant. Marked geo-
graphic and racial variations were seen in the use of trans-
plantation for HCC after controlling for other tumor and
patient-related variables. For example, 25% of white pa-
tients, 21% of Hispanic patients, 17% of Asians patients, and
only 13% of African-American patients received a transplant.
Patients with HCC were 2.2 times less likely to get a trans-
plant in the South and 3.3 times less likely in the Northeast
compared with patients in the Western United States.102
Transplantation patients with nonmetastatic HCC have ex-
cellent long-term survival, and this has been shown in single
center as well as population-based studies.
In summary, the evidence indicates marked underuti-
lization of these interventions. Underutilization seems to
follow some disturbing patterns in relation to ethnicity,
poverty, and gender.
Several steps have to be taken to improve effectiveness of
HCC therapy. These include provider and patient education
on risk factors for HCC and methods of diagnosis, increas-
ing the number of patients diagnosed in early or very early
stage by better implementation of screening programs and
optimizing screened patients for curative therapy (eg, drug
and alcohol rehabilitation), improving access to specialized
multidisciplinary treatment, and utilization of a validated
staging system.
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Received December 19, 2007. Accepted February 25, 2008.
Address requests for reprints to: Hashem B. El-Serag, MD, MPH,
Section of Gastroenterology and Hepatology, Baylor College of Medi-
cine, Houston, Texas 77030. e-mail: hasheme@bcm.tmc.edu; fax:
(713) 748 7359.