C u r ren t A p p ro a c h

to Hepatocellular
C a rc i n o m a
Peter Abrams, MD, J. Wallis Marsh, MD, MBA*

KEYWORDS
 Hepatocellular carcinoma  Partial hepatectomy
 Liver transplantation  Locoregional therapy
 Transarterial chemoembolization  Radiofrequency ablation

Hepatocellular carcinoma (HCC), an epithelial tumor derived from hepatocytes,

accounts for 80% of all primary liver cancers and ranks globally as the fourth leading
cause of cancer-related deaths. Annual mortality rates of HCC remain comparable to
its yearly incidence, making it one of the most lethal varieties of solid-organ cancer.1 A
retrospective study using the population-based registries of the Surveillance, Epide-
miology, and End Results (SEER) program found that 11,547 cases of HCC were diag-
nosed in the United States between 1975 and 1998. Attributed at least in part to the
hepatitis C (HCV) epidemic beginning in the 1960s, the overall age-adjusted incidence
rates of HCC in the United States have steadily increased over the past 2 decades,
from 1.3 per 100,000 persons from 1981 to 1983, to 3.0 per 100,000 persons from
1996 to 1998, increasing again to 4.1 per 100,000 persons from 1998 to 2000.24
Well-established risk factors for the development of HCC include hepatitis B carrier
state, chronic hepatitis C infection, hereditary hemochromatosis, and cirrhosis of any
etiology, as well as certain environmental toxins. Men are more prone to develop HCC,
especially in high-incidence regions such as sub-Saharan Africa and Southeast Asia,
with a mean male-to-female ratio of 3.7 to 1.0. Although not completely understood,
the disparity in gender distribution is thought to be related to variations in hepatitis
carrier states, exposure to environmental toxins, and the trophic effect of androgens.5
Most cases occur in patients with chronic liver disease or cirrhosis, affecting older
persons disproportionately.

DIAGNOSIS

The diagnosis of HCC commonly involves radiology, biopsy, and alpha fetoprotein
(AFP) serology testing. Individual evaluations are guided by the context of the patient

Department of Surgery, Thomas East Starzl Transplantation Institute, Montefiore Hospital,

University of Pittsburgh School of Medicine, N755.8, 3459 Fifth Avenue, Pittsburgh, PA
15215, USA
* Corresponding author.
E-mail address: marshw@upmc.edu

Surg Clin N Am 90 (2010) 803816

doi:10.1016/j.suc.2010.04.010 surgical.theclinics.com
0039-6109/10/$ see front matter 2010 Elsevier Inc. All rights reserved.
804 Abrams & Marsh

presentation. In almost every instance, some form of high-resolution imaging, usually

triphasic CT scan or MRI with gadolinium injection, is indicated to measure the extent
of disease. Percutaneous fine-needle biopsy (2%3% rate of needle tract seeding)
may be indicated in the setting of inconclusive imaging.6,7 At diagnosis, 20% to 60%
of small lesions are found to be multifocal and, despite adequate preoperative assess-
ment, up to 30% of tumors in patients with cirrhosis are understaged.810 In the setting
of a patient presenting with significant risk factors, the detection of a liver mass requires
a high index of suspicion for HCC. The sequence and type of tests used to diagnose
HCC depend mainly on the radiologic characteristics and dimensions of the liver mass.
Lesions measuring smaller than 1 cm, particularly in the context of cirrhosis, have
a low likelihood of being HCC. If these subcentimeter lesions do not enhance on
contrast imaging, their likelihood of being HCC is further diminished.11 This low likeli-
hood of malignancy, however, is tempered by the ability over time to transform into
HCC.12 Therefore, these lesions must undergo surveillance over the first 1 to 2 years
to confirm lack of growth and, by implication, the absence of HCC. The current
consensus guidelines regarding surveillance of subcentimeter liver lesions is to perform
ultrasound follow-up at intervals from 3 to 6 months over the first 24 months, followed by
routine surveillance after documenting no interval growth.13 Alternative imaging to ultra-
sound, CT, and/or MRI (such as lipiodol angiography) is not recommended as stand-
alone surveillance in this subset of patients owing to lower sensitivity for small lesions.
Lesions measuring 1 to 2 cm in a cirrhotic liver have been shown to have a significant
likelihood of HCC. Many investigators have argued that this size range in the context of
chronic liver disease requires biopsy.14,15 Although obtaining reliable biopsy speci-
mens from these small lesions can be challenging, adequate characterization of
lesions smaller than 2 cm by imaging techniques alone appears similarly burdened
by likelihood of error. The characteristic arterial-phase enhancement and venous-
phase wash-out of HCC lesions are more difficult to identify with certainty in nodules
smaller than 2 cm. Other non-HCC lesions smaller than 2 cm (eg, dysplastic nodules)
may demonstrate similar characteristics to HCC, such as arterial enhancement
without venous washout. In cirrhotic livers, it has been estimated that up to 25% of
lesions smaller than 2 cm in diameter with arterial uptake but without venous washout
will either not increase in size or regress over time and thus do not represent HCC
disease.13,1618 Biopsy, therefore, remains a critical tool in identifying HCC with suffi-
cient confidence in 1- to 2-cm lesions.
Any liver lesion measuring larger than 2 cm in a cirrhotic liver is HCC until proven
otherwise. In the setting of a larger than 2-cm lesion demonstrating characteristic
HCC findings on high-resolution, contrast-enhanced imaging along with an AFP higher
than 200 ng/ml, the diagnosis of HCC is made with sufficient confidence that biopsy
confirmation is rarely indicated.15,16 Lesions larger than 2 cm with incongruous
imaging characteristics in a cirrhotic liver or with classic HCC characteristics in a non-
cirrhotic liver may require biopsy to achieve sufficient diagnostic confidence.13
Current consensus guidelines reiterate the lack of necessity for biopsy in patients
with cirrhosis with a lesion larger than 2 cm with characteristic HCC findings on 2
high-resolution, contrast-enhanced imaging studies, irrespective of AFP level, as
the positive predictive value of the combination of clinical context and imaging find-
ings exceeds 95%.13,14

STAGING

The staging of HCC is complicated twofoldby a lack of global consensus on any

given HCC staging system and the significant impact of underlying liver function on
 Current Approach to Hepatocellular Carcinoma 805

prognosis. Most US physicians and surgeons use the modified TNM staging system
(Table 1); however, this system fails as a robust predictor of tumor-free survival after
transplantation in patients with HCC.13,19,20 The United Network for Organ Sharing
(UNOS) uses an alternative staging system based on the American Liver Tumor Study
Group (ALTSG), allowing certain patients with HCC to be prioritized on the transplant
candidate waiting list (Table 2).21 Like the modified TNM system, the ALTSG classifi-
cation system does not take into consideration the extent of underlying liver disease or
tumor biology.

INDICATIONS FOR PARTIAL HEPATECTOMY

Partial hepatectomy (PH) is the standard treatment for resectable HCC in patients
without cirrhosis, irrespective of extent of liver fibrosis; however, these criteria are
met in only 5% of cases in Western countries, but in up to 40% in Asia. Earlier diag-
nosis, better patient selection, and advances in operative and postoperative
management have increased the long-term survival of patients undergoing PH for
HCC, with reported 1- and 5-year survival rates of 55% to 90% and 10% to 50%,
respectively.22,23 Operative mortality rates in patients with cirrhosis and without

Table 1
TNM staging system for hepatocellular carcinoma

T Primary Tumor
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Solitary, %2 cm, no vascular invasion
T2 Solitary, %2 cm, vascular invasion
Multiple, one lobe %2 cm, no vascular invasion
Solitary, >2 cm, no vascular invasion
T3 Solitary, >2 cm, vascular invasion
Multiple, one lobe, <2 cm, vascular invasion
Multiple, one lobe, >2 cm, with/without vascular invasion
T4 Multiple, more than one lobe
Invasion of major branch of portal or hepatic vein
Invasion of adjacent organs other than gallbladder
Perforation of visceral peritoneum
N Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases
M Distant metastasis
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage grouping
Stage I T1N0M0
Stage II T2N0M0
Stage IIIA T3N0M0
Stage IIIB T1N1M0, T2N1M0, T3N1M0
Stage IVA T4, any N, M0
Stage IVB Any T, any N, M1
806 Abrams & Marsh

Table 2
American liver tumor study group modified TNM staging classification

T0, N0, M0 Not Found

T1 1 nodule <1.9 cm
T2 1 nodule 2.05.0 cm
23 nodules, all <3.0 cm
T3 1 nodule >5.0 cm
23 nodules, at least 1>3.0 cm
T4a R4, any size
T4b T2, T3, or T4a plus gross intrahepatic portal or hepatic vein involvement
as indicated by CT, MRI, or US
N1 Regional (portal hepatitis) nodes involved
M1 Metastatic disease, including extrahepatic portal or hepatic vein involvement
Stage I T1
Stage II T2
Stage III T3
Stage IVA1 T4a
Stage IVA2 T4b
Stage IVB Any N1, any M1

Abbreviation: US, ultrasound.

cirrhosis are 7% to 25% and less than 3%, respectively.8 Recorded deaths after the
perioperative period are most frequently associated with tumor recurrence. Patients
without cirrhosis but demonstrating compromised hepatic function must be carefully
selected for PH to avoid postoperative liver failure and its accompanying high
mortality.
A clear departure has occurred from the historical use of the Child-Pugh classifica-
tion as a predictor of postresection liver function, and most US liver surgeons today
use clinical and diagnostic imaging to screen for portal hypertension to determine
whether PH is a safe option. Multiple studies have demonstrated that a normal serum
bilirubin level and the absence of clinically significant portal hypertension (ie, hepatic
vein pressure gradient <10 mm Hg) are the best available indicators of acceptably low
risk of postoperative liver failure after PH.24,25 In the absence of an elevated serum bili-
rubin and portal hypertension, survival after PH can exceed 70% at 5 years.24 In
patients with an elevated serum bilirubin and significant portal hypertension, survival
after PH drops to less than 30% at 5 years, regardless of Child-Pugh score. Survival
after PH in patients with significant portal hypertension alone decreases to less than
50% at 5 years.24 Direct measurement of portal pressure is not necessary in patients
with clinical signs of severe portal hypertension, including esophageal varices, ascites,
or splenomegaly associated with a platelet count less than 100,000/mL.
Experienced liver centers are now performing advanced laparoscopic liver resec-
tions, including right hepatectomy, left hepatectomy, and even extended right and
left hepatectomy. A recent review of the international experience with laparoscopic
liver resection found that 3- and 5-year survival rates for select patients were compa-
rable with open PH.26 Reported advantages of laparoscopic liver resection include
less analgesic requirements, smaller incisions with preservation of the abdominal
wall, shorter inpatient stays, fewer transfusion requirements, accelerated postopera-
tive recovery, and fewer postoperative adhesions. Potential limitations and disadvan-
tages of laparoscopic liver resection include a significant learning curve, delayed
 Current Approach to Hepatocellular Carcinoma 807

control of major bleeding, insufficient assessment of the liver for additional lesions,
and increased risk for gas embolism.26 As liver surgeons become more proficient
with laparoscopic liver surgery as a component of the overall approach to HCC in
patients without cirrhosis, we anticipate an increasing number of resections will be
performed in a minimally invasive fashion. Similar to transitions occurring in the prac-
tice of vascular surgery, expertise in performing large open resections will likely
contract and eventually be limited to a relatively small number of experienced liver
centers.
Exclusion from PH for multiple HCC lesions is a common but not universal practice
among US liver surgeons. Notwithstanding evidence that increasing diameter does
increase the likelihood of vascular invasion, increased size (>5 cm) of HCC tumors
is not an absolute contraindication for PH. A wealth of anecdotal evidence demon-
strates that some tumors may grow into very large, single lesions without vascular
invasion, and thus represent no increased risk of recurrence after resection as
compared with smaller lesions.25,27
Despite the many advances in patient selection and management leading to
increased rates of long-term survival, the 5-year recurrence rates of HCC following
PH range from 60% to 100%.28 The great majority (>80%) of recurrences are intrahe-
patic. Multivariate statistical analyses demonstrate the presence of microvascular
invasion and multifocal disease as the strongest predictors of recurrence.25,27,29
These risk factors imply that dissemination, rather than de novo lesions, accounts
for most recurrences.30 Undetected dissemination as the predominant mechanism
of early recurrence also explains the preponderance of recurrences occurring within
the first 3 years of follow-up.31 There have been no reports of neoadjuvant or adjuvant
therapy causing significant reductions in recurrence rates after PH.32
Treatment of recurrence after PH remains an individualized practice with little in the
way of outcomes data to support a more or less aggressive approach. Repeat resec-
tion may be indicated in the setting of a solitary recurrence. However, as dissemination
appears to be the predominant cause of early recurrence, one might reasonably
remain skeptical that a single lesion detected on high-resolution imaging does truly
represent a solitary recurrence.33 Nonetheless, repeat resection in selected cases is
warranted.

INDICATIONS FOR LIVER TRANSPLANTATION

Although complete surgical resection or ablation can provide cure for select patients,
most patients with HCC have underlying cirrhosis, which itself behaves as a premalig-
nant condition.34,35 Although PH treats localized HCC, it may fail to treat multifocal
HCC and has no efficacy in preventing de novo HCC occurring in the remnant cirrhotic
liver. Liver transplantation (LT) addresses HCC along with its multifocal potential, and
treats the underlying liver disease itself. The accumulation of outcomes data has
clearly established LT as the gold standard for early-stage HCC in the setting of
cirrhosis. Initially poor outcomes were observed from LT for unresectable HCC in
unselected patients (recurrence rates >60% within 2 years and 5-year survival rates
<20%).3638 Much lower recurrence rates after LT were demonstrated for incidentally
detected HCC in pathologic explants, providing the impetus for evaluating the role of
LT for patients with small HCC.39,40 A provocative report by Bismuth and colleagues39
demonstrated that patients with 3 or fewer tumors each 3 cm or smaller in greatest
diameter had a 3-year, disease-free survival of 83% after LT, compared with 18% after
PH. A seminal retrospective study by Mazzaferro and colleagues10 established that
favorable results could be achieved in patients with cirrhosis with either a solitary
808 Abrams & Marsh

HCC smaller than 5 cm or with up to 3 nodules smaller than 3 cm, criteria that came to
be called the Milano criteria. The 5-year survival of these early-stage patients
exceeded 70%. Recipient age, gender, type of viral infection, or Child-Pugh score
did not affect survival after transplantation.
Liver transplantation demonstrates not only the best survival and recurrence-free
rates, but also provides the longest recurrence-free survival, which in one retrospec-
tive analysis was as high as 77% at 5 years, compared with 20% after PH.41 In a multi-
variate analysis of a single-center experience at the University of Pittsburgh involving
307 patients undergoing LT for HCC between 1981 and 1997, the senior investigator of
this review (J.W.M) found that independent predictors of tumor-free survival included
lymph node status, depth of vascular invasion, greatest tumor dimension, lobar distri-
bution, and tumor number (Table 3).20 There was no direct correlation between the
current modified TNM staging system for HCC and tumor-free survival after LT
(Table 4).
In an effort to prioritize for LT those candidates with the highest short-term risk of
mortality, the model for end-stage liver disease (MELD) scoring system was imple-
mented in 2002. Although numerous studies have demonstrated the systems efficacy
in predicting mortality in the setting of chronic viral and alcoholic liver disease, others
have found that MELD is less robust in predicting mortality related to cholestatic liver
disease and has no predictive power for HCC. To impart more urgent access to LT for
select patients with HCC (eg, those with early-stage disease), additional points within
the scoring system were allotted to patients with HCC to equilibrate their risk of death
in comparison with the mortality of end-stage cirrhosis.42 The original scoring excep-
tion, which included lesions smaller than 2 cm, resulted in the overdistribution of donor

Table 3
Univariate analysis of all variables included in the current pathologic TNM staging system

Tumor-Free Survival in Months

Risk Factor (no.) (mean SE) 95% CI Significancea
Lymph node status
Neg (231) 140.6  6.8 (127.2154.0) P<.00001
Pos (6) 5.3  1.0 (3.37.3)
Vascular invasion
None (133) 178.4  7.5 (163.8192.9) P12<.00001
Micro (67) 112.4  11.2 (90.4134.4) P13<.00001
Macro (37) 15.3  3.5 (8.522.1) P23<.00001
Tumor size (cm)
%2 (101) 123.6  6.8 (110.3137.0) P12<.0001
24 (71) 142.7  11.8 (119.5165.8) P13<.0001
>4 (65) 70.2  9.8 (51.089.5) P23<.0001
Lobar distribution
Unilobar (161) 169.9  7.2 (155.9183.9) P<.0001
Bilobar (76) 49.7  6.2 (37.561.8)
Tumor number
Single (120) 168.8  9.2 (150.9186.8) P<.0001
Multiple (117) 98.2  8.3 (81.9114.4)

Abbreviations: CI, confidence interval; Neg, negative; Pos, positive; SE, standard error; , failed to
reach statistical significance.
a
Pxy expresses the significance between level x and level y.
 Current Approach to Hepatocellular Carcinoma 809

Table 4
Multivariate analysis of all variables included in the current pathologic TNM staging system

Risk Factor Relative Riska 95% CI

Vascular invasion
None J31 5 14.0 6.2331.35
Micro J32 5 3.96 2.676.92
Macro J21 5 3.54 2.334.5
Tumor size (cm)
<2 J31 5 5.37 1.8115.9
24 J32 5 1.55 0.852.81
>4 J21 5 3.46 2.135.66
Lymph node status
Negative J21 5 2.95 0.988.9
Positive
Lobar distribution
Unilobar J21 5 3.1 1.805.60
Bilobar

Abbreviation: CI, confidence interval; , failed to reach statistical significance.

a
Jxy expresses the relative risk of level x to level y.

livers to patients with HCC (with many expected small tumors turning out not to be
HCC on explanted pathology) and was therefore modified by a reduction in allocated
points for Stage II patients and an elimination of the upgrade for Stage I.43 Using the
American Liver Tumor Study Group Modified TNM staging system (see Table 2),
current UNOS guidelines do not allow upgrading of candidates with Stage I disease,
irrespective of biopsy confirmation; only candidates with Stage II HCC disease are
upgraded on the waiting list to a MELD score of 22 (equivalent to a 15% probability
of candidate death within 3 months) with the intent to shorten their waiting time. Owing
to widely varying degrees of benefit from LT, patients with Stage III to IVa are not allo-
cated extra points while on the UNOS waiting list, a blanket policy with which we
disagree. Moreover, we believe that patients with Stage I disease should have the
option of undergoing a biopsy, which, if positive for HCC, should qualify for an imme-
diate MELD upgrade, as patients in Stage I are in their most curable stage.
The strict application of the Milano criteria by UNOS for MELD upgrade allocation
disadvantages patients with HCC with tumor profiles exceeding the criterias maximal
size or multifocal parameters but in whom favorable outcomes after LT have been
demonstrated.20,44,45 There is an ongoing debate within the liver transplantation
community regarding whether and to what extent the indications for LT as primary
therapy for HCC should be expanded.46 For patients with HCC disease beyond stan-
dard listing criteria in whom there is no macroscopic evidence of vascular invasion or
extrahepatic spread, the survival rates after LT are generally comparable with patients
transplanted for disease within the standard listing criteria. Most groups report
a 5-year survival of more than 50% in patients transplanted for extended criteria
HCC,41 which many investigators have argued is the minimum acceptable survival
rate. In 2001, using explant pathologic data, Yao and colleagues44 at the University
of California, San Francisco (UCSF) defined an expanded set of HCC criteria (solitary
tumor %6.5 cm, or %3 nodules with the largest tumor %4.5 cm and total tumor diam-
eter %8 cm) for which 1- and 5-year survival rates after LT were 90% and 75%,
810 Abrams & Marsh

respectively. Retrospectively evaluating post-LT survival for patients with tumors

beyond Milano criteria but within these UCSF expanded criteria by pretransplanta-
tion imaging and explant pathology, the group at the University of California, Los
Angeles (UCLA) confirmed acceptable 1-, 3-, and 5-year survival rates of 82%,
65%, and 52%, respectively.47 Moreover, the difference in 5-year recurrence-free
survival after LT for HCC in the UCLA study did not reach statistical significance
between Milano criteria and UCSF expanded criteria tumor groups (74% vs 65%,
P 5 .09). The Barcelona Clinic Liver Cancer Group4850 has demonstrated 5-year
post-LT survival of greater than 50% using expanded criteria including 1 tumor size
smaller than 7 cm, 3 tumors smaller than 5 cm, 5 tumors smaller than 3 cm, or down-
staging to conventional Milano criteria with pre-LT adjuvant therapies. In the absence
of more precise markers of HCC, biologic behavior that might better predict which
patients with HCC would benefit from LT, it remains to be seen whether the overly
restrictive UNOS tumor size and numberbased criteria for HCC will be expanded
to allow access to LT to carefully selected patients who otherwise face certain death.
The major limitation for LT as therapy for early-stage HCC is the insufficient number
of donor livers. Without a living donor, there is always a waiting period between candi-
date listing and transplantation. If the waiting period extends over a sufficient length of
time, the tumor will grow and eventually manifest absolute contraindications to LT
(eg, macroscopic vascular invasion or extrahepatic spread). In a study by Yao and
colleagues51 of patients with HCC on the waiting list, a 6-month waiting period for
LT was associated with a 7.2% cumulative dropout probability, increasing to 37.8%
and 55.1% at 12 and 18 months, respectively.
Efforts to address the large waiting list of LT candidates and to decrease the
dropout rate have included new strategies such as living donor LT, domino LT, split
LT, the use of extended criteria donors, and donors after cardiac death. Living donor
LT appears to be an effective option for patients with HCC within the Milano criteria,
essentially equivalent in terms of survival to cadaveric LT, and should be especially
considered if the anticipated waiting period is sufficient that tumor progression is
likely. There are few data to support the use of living donor LT for patients with
HCC who exceed the Milano criteria, although its use for this purpose is becoming
increasingly common. We disagree with this practice. Because living donation puts
a healthy individual at risk, it is our opinion that livers donated from living donors
should be reserved for early-stage disease, whereas cadaveric livers should be
used for more advanced but acceptable cases.
Some investigators have suggested that patients with recurrent HCC after PH might
be candidates for salvage transplantation.52 This option continues to lack support
from clinical outcomes data. Alternatively, because the most strongly predictive
factors for recurrence attributable to dissemination (eg, vascular invasion and satellite
lesions) can be identified on pathologic examination, other investigators have
proposed that a pathology-specific subset of patients lacking these findings on
explant pathology be listed for LT immediately after PH, as the results of LT in this pop-
ulation appear favorable.53

INDICATIONS FOR ALTERNATIVE THERAPIES

Local regional therapy (LRT) is indicated for select patients who are not candidates for
either PH or LT. LRT modalities include percutaneous ethanol injection (PEI), transar-
terial chemoembolization (TACE), and radiofrequency ablation (RFA), as well as trans-
arterial radioembolization with Yttrium-90 (TARE-90Y). Although PH remains the
standard for resectable HCC in the patient without cirrhosis, a growing body of clinical
 Current Approach to Hepatocellular Carcinoma 811

evidence demonstrates LRT survival rates, and outcomes after RFA in particular, are
comparable with PH for HCC tumors 3 cm or smaller in diameter.54 Despite its increas-
ingly common use as bridge therapy before LT, it remains to be determined whether
LRT provides a survival benefit to those LT candidates facing a prolonged waiting
time. Multiple LRT modalities have been used with mixed and controversial efficacy
to decrease tumor burden and downstage HCC patients to Stage II disease. In
the United States, RFA has become the predominant LRT for small HCCs, as it can
achieve complete necrosis with fewer treatment sessions compared with PEI.55 The
results of a meta-analysis of published randomized controlled studies indicate that
TACE versus conservative management may provide a significant survival benefit to
select patients with advanced-stage disease.50
In response to improving survival results with LRT, there are many centers outside
the United States that offer local ablation as first-line therapy to select patients with
small HCC.56 To date there are no randomized trials comparing PEI or RFA to PH.
For treatment of small HCC in patients with cirrhosis, a single European cohort study
demonstrated similar overall survival and recurrence rates between PEI and PH.57
Multicenter outcomes data from Japan demonstrate that Childs A patients with
successful tumor necrosis may achieve 50% survival at 5 years, which appears to
compare favorably with PH outcomes in nonoptimal surgical candidates.58
Reported HCC recurrence rates after LRT vary widely, with most long-term studies
involving patients with unresectable disease, but in general are at least as high as for
PH.13,59 Recurrences after ablation occur either from dissemination or the persistence
of microscopic satellite nodules outside the ablation zone. With respect to tumor
puncture by RFA and PEI, concerns over seeding are restricted mainly to either poorly
differentiated HCC or peripheral tumors.60,61 Apart from reasonable concerns about
iatrogenic spread of tumor cells, tumor tract seeding is not synonymous with meta-
static disease and has not been found to affect survival.
LRT remains an attractive modality for its ability to induce tumor necrosis and
provide temporary control of tumor spread.14 Preliminary data from several centers
have suggested a possible benefit of LRT in reducing rates of candidate drop-out
because of tumor progression when the waiting period extends beyond 6
months.51,62,63 Given the risk of tumor progression, it is the practice of many trans-
plant centers to treat HCC with LRT upon listing and before LT. The most common
bridge therapy is TACE, as it has been shown to decrease tumor burden and delay
tumor progression.64
The utility of pretransplant TACE as a means of improving survival after LT remains
controversial. A case-control series reported by Decaens and colleagues65 showed
that pre-LT TACE did not impact 5-year survival (59% TACE vs 59% no TACE, P 5
.7). Olthoff and colleagues66 similarly showed no difference in survival at 3 years
post-LT if patients received pre-LT TACE. However, other centers have studied the
outcomes of pathologic stage-specific patients with HCC undergoing TACE followed
by LT and reported encouraging preliminary results. In a retrospective analysis of
a small number of nonrandomized patients with T2 and T3 HCC within UCSF
expanded criteria, treatment with TACE before LT resulted in a significant survival
benefit versus no treatment, with 5-year recurrence-free survival rates of 85% versus
51% and 96% versus 87% for T3 and T2 HCC, respectively.67
To increase access to LT for patients with HCC, all major modalities of LRT have
been used in an attempt to downstage excess tumor burden to within Milano
criteria.67,68 Some investigators have suggested that the process of downstaging
helps to identify aggressive disease, providing a window into an individual tumors
probability of dissemination, thereby improving patient selection for LT and potentially
812 Abrams & Marsh

post-LT survival.69 In a prospective study of a small number of patients reported by

Yao and colleagues,70 70% of patients with tumor burden outside Milano criteria
were successfully downstaged using multiple LRT modalities. Which modality or
combination of LRT modalities to use and whether downstaging of HCC by any
modality leads to better outcomes after LT remain critical questions to be clarified
by randomized prospective studies.

SUMMARY

The incidence of HCC in the United States and worldwide continues to increase.
Despite many significant advances, most patients continue to face a dismal prog-
nosis, with a median survival after diagnosis of 6 to 20 months. In select patients,
PH remains the best treatment option for HCC in the noncirrhotic liver. LT represents
the gold standard for patients with HCC and cirrhosis in the absence of extrahepatic
spread and macrovascular invasion. The scarcity of liver donors requires that national
guidelines ensure outcomes for HCC remain comparable with results for other LT indi-
cations; nonetheless, favorable outcomes for patients with HCC exceeding the current
national guidelines for LT should motivate expanded access to LT through prospective
studies. The inability to offer LT as an immediate treatment option to patients with HCC
undoubtedly jeopardizes the outcome in many patients. Living donor LT is emerging
as a major strategy to address this dilemma but, in our opinion, should be reserved
for patients with early-stage disease given the substantial risk to the donor. In select
patients with unresectable HCC, the use of TACE may lead to significant survival
benefit. The role of LRT as adjuvant therapy in the setting of LT for HCC continues
to evolve and should be further clarified by prospective studies.

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