American Journal of Transplantation 2009; 9: 592600

Wiley Periodicals Inc.

C
2009 The Authors
Journal compilation
C
2009 The American Society of
Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2008.02516.x
18
F-FDG-Uptake of Hepatocellular Carcinoma
on PET Predicts Microvascular Tumor Invasion
in Liver Transplant Patients
A. Kornberg
a,
, M. Freesmeyer
b
, E. B arthel
a
,
K. Jandt
a
, K. Katenkamp
c
, J. Steenbeck
b
,
A. Sappler
a
, O. Habrecht
a
and D. Gottschild
b
a
Department of General, Visceral and Vascular Surgery
b
Department of Nuclear Medicine
c
Institute of Pathology,
Friedrich-Schiller-University, Jena, Germany

Corresponding author: Arno Kornberg,

Arno.Kornberg@med.uni-jena.de
Vascular invasion of hepatocellular carcinoma (HCC) is
a major risk factor for poor outcome after liver trans-
plantation (LT). The aim of this retrospective analysis
was to assess the value of preoperative positron emis-
sion tomography (PET) using
18
F-uorodeoxyglucose
(
18
F-FDG) in liver transplant candidates with HCC for
predicting microvascular tumor invasion (MVI) and
posttransplant tumor recurrence.
Forty-two patients underwent LT for HCC after PET
evaluation. Sixteen patients had an increased
18
F-FDG
tumor uptake on preoperative PET scans (PET +), while
26 recipients revealed negative PET ndings (PET)
pre-LT. PET recipients demonstrated a signicantly
better 3-year recurrence-free survival (93%) than PET +
patients (35%, p <0.001). HCCrecurrence rate was 50%
in the PET + group, and 3.8% in the PETpopulation
(p < 0.001). PET + status was identied as indepen-
dent predictor of MVI [hazard ratio: 13.4]. Patients with
advanced PET negative tumors and patients with HCC
meeting the Milan criteria had a comparable 3-year-
recurrence-free survival (80% vs. 94%, p = 0.6).
Increased
18
F-FDG uptake on PET is predictive for MVI
and tumor recurrence after LT for HCC. Its application
may identify eligible liver transplant candidates with
tumors beyond the Milan criteria.
Key words: Hepatocellular carcinoma, liver transplan-
tation, microvascular invasion, Milan criteria, positron
emission tomography, tumor biology
Received 08 July 2008, revised 30 October 2008 and
accepted for publication 07 November 2008
Introduction
Hepatocellular carcinoma (HCC) in liver cirrhosis has be-
come a major indication for liver transplantation (LT) in the
last two decades (1). Early results of LT for HCC were asso-
ciated with recurrence rates from 60% to 70%, and 5-year
survival rates of less than 30% (24). More recently, trans-
plant groups from Milan and Barcelona reported about a
4-year survival rate of 75% after LT in HCC patients. These
extraordinary outcome data were a result of careful se-
lection of patients with specic morphological tumor crite-
ria. Only patients with HCC in cirrhosis who had a maxi-
mumof three tumor nodules that were 3 cmin maximum
diameter, or a single tumor with a maximum diameter of
5 cm, both without macrovascular tumor invasion, were
considered as being eligible for LT (5,6). The adoption of
the so-called Milan criteria resulted in survival rates after
LT that are similar to those after resection in noncirrhotic
lesions with comparable tumor stage (1).
In recent years there is, however, an increasing concern
that strict allocation of liver allografts based on these new
morphological criteria may exclude a signicant number of
patients with HCC from potentially curative LT (710). Sev-
eral groups have shown that parameters of tumor biology,
such as tumor grade and vascular tumor invasion, may sig-
nicantly inuence outcome after LT (1116). An accurate
pretransplant prediction of these histopathological tumor
features might lead to a reasonable expansion of the se-
lection criteria, with regard to acceptable size and numbers
of HCC nodules (1720).
Specically, microvascular tumor invasion (MVI) has re-
cently been demonstrated to be a very strong predictor
of tumor recurrence and poor survival after LT and liver
resection for HCC (12,14,21,22). While gross vascular tu-
mor invasion can be diagnosed pre-LT by high resolution
imaging techniques (23), MVI cannot be determined pre-
operatively, since it is a histopathological parameter. It is,
therefore, of great importance to identify clinical surrogate
markers that are able to reliably indicate the presence of
MVI already prior to LT.
Positron emission tomography (PET) using
18
F-uoro-
deoxyglucose (
18
F-FDG) has become a standard procedure
within oncology during recent years. It is an important
592
18
F-FDG-Uptake of Hepatocellular Carcinoma
prognostic marker in various cancers, such as nonsmall
lung cancer, pancreatic adenocarcinoma and neck cancers
(24,25). Moreover, PET imaging has been established as
a useful diagnostic tool for evaluating metastatic liver tu-
mors (26,27). Preoperative
18
F-FDG-PET has recently been
shown to predict tumor differentiation and outcome af-
ter liver resection in patients with HCC (28,29). There is,
however, only limited data about the value of
18
F-FDG-PET
as prognostic marker of biological behavior of HCC in the
transplantation setting.
PET assessment has been implemented in our evaluation
program for liver transplant candidates with liver malig-
nancy in 1999.
We performed a retrospective analysis to determine the
prognostic value of preoperative
18
F-FDG-PET in liver trans-
plant candidates with HCC, with special focus on its power
for predicting aggressive tumor biology, such as MVI and
posttransplant tumor recurrence.
Patients and Methods
Patient population
Between April 1999 and December 2007, a total of 42 patients with HCC in
liver cirrhosis underwent LT at our center. There were 35 male and 7 female
recipients. Patients age was ranging between 38 and 68 years (median: 61
years).
Thirty-one patients received a full size transplant, while 11 patients under-
went living-donor liver transplantation (n = 10) or received a left split liver
graft (n = 1) (Table 1).
Pretransplant diagnosis of HCC was based on two abdominal imaging
studies, including ultrasound and computed tomography (CT) or magnetic
resonance imaging (MRI), showing consistent results. The course of -
fetoprotein-levels (AFP) was used for supporting suspected HCC diagnosis.
AFP-levels within normal range, however, did not rule out the diagnosis. We
did not perform preoperative tumor biopsy by protocol. Our inclusion crite-
ria for LT in patients with unresectable HCC in liver cirrhosis was based on
the Milan criteria, consisting of a 5 cm maximum tumor size for one single
HCC nodule, or a maximum of three tumors each up to 3 cm, both with-
out clinical evidence of vascular tumor invasion (5). Since January 1999,
we used transarterial chemoembolization (TACE) as interventional bridg-
ing to LT in patients with HCC (30). Clinically relevant portal hypertension,
as indicated by treatment-refractory ascites, low albumin level (<25 g/L),
increased bilirubin level (>3 mg/dL) and severe coagulopathy, was a con-
traindication for TACE. If chemoembolization could not be realized due to
technical problems, the possibility of percutaneous radiofrequency ablation
of the tumor was investigated in recent years (30). Failure of HCC down-
staging, however, was not used as a biological exclusion criterion for LT, as
has been proposed by others (31,32).
PET study
Since January 1999, all liver transplant candidates with an intrahepatic
malignancy underwent whole-body
18
F-FDG-PET scanning during evalua-
tion for LT. Currently, a total of 42 patients with HCC underwent LT after
preoperative PET assessment.
Table 1: Baseline characteristics of the study population (n = 42)
Sex (f/m) 7/35
Median age recipient (yr, range) 61 (3868)
Median age donor (yr, range) 49 (1680)
Mean AFP level pre-LT (ng/mL, range) 1663 (1.546 930)
Etiology of liver disease (n)
Hepatitis B/C 8
Alcohol 27
Autoimmun 1
Other 6
ChildPugh Score (n)
A 22
B 10
C 10
Treatment pre-LT (n)
TACE 21
RFA 2
Mean cold ischemia time (min, range) 339 (340707)
Mean warm ischemia time (min, range) 48 (2574)
Transplant procedure (n)
DLT 31
LDLT 10
Split (left) 1
Immunosuppression (n)
CsA/Tac 9 / 33
AZA/MMF 3 / 39
ATG/IL2-Rab 7 / 35
TACE = transarterial chemoembolization; RFA = radiofrequency
ablation; DLT = deceased donor liver transplantation; LDLT =
living donor liver transplantation; CsA = cyclosprine A; Tac =
tacrolimus; AZA = azathioprine; MMF = mycophenolat mofetil;
ATG = anti-T-lymphocyte globulin; IL2-Rab = interleukin-2-
receptor antibody; AFP = -fetoprotein.
PET was performed using an EACT EXACT 47 (Siemens, Erlangen,
Germany) with the whole-body mode implemented as standard software.
Patients were fasted for at least 8 h before undergoing PET and the plasma
glucose concentration was measured before scanning. Static emission
scanning was performed 6090 min after injection of approximately 360
MBq
18
F-FDG from the neck to the knee level in 2D mode. Images were
reconstructed using an iterative reconstruction algorithm. The PET scans
were compared with the corresponding CT or MRI for accurate tumor lo-
calization. The coronal, sagittal and axial images were evaluated visually to
assess whether the
18
F-FDG uptake in the tumor was (PET + status) or
was not (PETstatus) signicantly higher (Figure 1) than in the surrounding
noncancerous hepatic tissue (33). If PET identied an extrahepatic region
of increased
18
F-FDG uptake, HCC metastases or other malignant tissue
had to be excluded by additional imaging studies or tissue biopsy.
Histopathological study
The number of tumors, maximal tumor diameter and their total diameter
in patients with multiple tumor nodules were determined. The histological
grade according to the modied Edmondson criteria was assessed, with
the nal classication based on the area showing the poorest differentiation
(34). MVI was dened as the presence of tumor emboli within the central
vein, the portal vein or large capsular veins or involvement of the lobar or
segmental branches of the portal vein or the hepatic veins (3). Pathological
tumor staging was assigned by co-operation of the surgical and pathology
staff based on clinical and pathological data according to the 5th edition of
the Tumor, Node, Metastasis/International Union Against Cancer criteria of
American Journal of Transplantation 2009; 9: 592600 593
Kornberg et al.
Figure 1: PET scan of a liver transplant candidate with multi-
focal HCC, revealing two regions of increased
18
F-FDG tumor
uptake.
1997 (36). In addition, tumors were classied as Milan In versus Milan
Out according to the pathomorphological staging on explant livers.
Posttransplant management and follow-up surveillance
Immunosuppressive therapy after LT consisted of a quadruple induction reg-
imen, cyclosporin A- or tacrolimus-based, augmented with mycophenolat
mofetil or azathioprine, and prednisone (Table 1). Steroids were completely
withdrawn 6 months from LT the latest, except for patients presenting with
autoimmune hepatitis.
Our posttransplant tumor surveillance program consisted of abdominal ul-
trasound and AFP level measurement every 3 months during the entire
follow-up period. In addition, CT scans (or MRI) of the chest and abdomen
were performed every 6 months for the rst posttransplant year, and min-
imum once yearly thereafter. Increasing AFP-levels alone without radio-
graphic evidence of new tumor masses did not indicate HCC recurrence
until becoming manifest in imaging studies. Patients with rising AFP lev-
els and inconclusive imaging studies underwent additional whole body
18
F-FDG-PET scanning.
Statistical analysis
Statistical analysis was performed using SPSS version 12.0 for Windows
(SPSS Inc., Chicago, IL).
Comparison of categorial and continuous variables was performed using chi-
square test and MannWhitney U-test, respectively. All data were reported
as median with range, mean SD, as appropriate. Overall and recurrence-
free survival was analyzed by the KaplanMeier method. Patient survival
in different groups was compared using the log-rank test. Parameters be-
ing predictive for the presence of MVI and posttransplant HCC recurrence
were assessed in a univariate analysis. All variables with a p-value less than
0.05 were then included in a multivariate analysis applying the Cox multi-
ple backward stepwise model to identify parameters being independently
predictive for MVI (p < 0.05).
Results
PET scans were performed between 2 and 15.5 months
(median: 6.75 months) pretransplantation and before initi-
ating interventional therapy, where feasible. In one patient
of this series (2.4%), a relevant extrahepatic
18
F-FDG up-
take in the submandibular region was assessed in preoper-
ative PET imaging. Surgical resection of the affected tissue
yielded an unspecic inammatory lymph node specimen.
18
F-FDG-PET ndings and associated tumor factors
Tumor characteristics of the study group according to ex-
plant histopathology are summarized in Table 2.
Sixteen patients had positive preoperative PET scans
(38.1%), while 26 recipients (61.9%) had no increased
18
F-FDG uptake. Of 6 patients with poor tumor grade, 5
(83.3%) demonstrated a PET + status and of 17 recipients
with MVI, 14 patients (82.3%) had a PET + nding. More-
over, PET + status was signicantly associated with size,
number and stage of tumors, as well as the pathomorpho-
logical Milan criteria (Table 3).
18
F-FDG-PET ndings and risk of HCC recurrence
Current overall posttransplantation follow-up ranges from
4 to 108 months (median: 26 months). Calculated over-
all and recurrence-free 1- and 3-year survival rates were
93% and 79%, as well as 84.5% and 73%, respectively.
Nine liver recipients (21.4%) developed HCC recurrence
between 4 and 48 months (median: 12 months) post-LT.
Of 16 patients with PET + status, 8 developed posttrans-
plant HCC recurrence (50%), compared to 1 of 26 PET
patients (3.8%; p < 0.001). The positive and negative pre-
dictive values of positive PET ndings for HCC recurrence
were 50% and 96.2%, respectively. In univariate analysis,
none of the clinical variables, but several pathomorphologi-
cal variables and PET ndings were signicantly correlated
594 American Journal of Transplantation 2009; 9: 592600
18
F-FDG-Uptake of Hepatocellular Carcinoma
Table 2: Histopathological tumor characteristics (explant livers)
Number
Variable of patients
Size of largest tumor nodule
5 cm 29
> 5 cm 13
Number of tumor nodules
3 29
> 3 13
Tumor grade
Well (G1) 8
Moderate (G2) 28
Poor (G3) 6
Microvascular invasion
No 25
Yes 17
Lymphatic invasion
No 37
Yes 5
Tumor stage
1 4
2 15
3 10
4 13
Milan classication (pathomorphological)
In 20
Out 22
with an increased risk of posttransplant HCC recurrence
(Table 4). The 3-year recurrence-free survival rate of PET
patients was 93%, compared to 35% in the PET + popu-
lation (Figure 2).
18
F-FDG-PET ndings and Milan criteria
Patients with HCC meeting the Milan criteria had a sig-
nicantly better 3-year recurrence-free survival rate (94%),
compared to those with HCC beyond the Milan criteria
(63%; p = 0.008).
None of 17 Milan In recipients with PET status have yet
developed HCC recurrence (0%), compared to 1 of 3 Milan
In patients with pre-LT PET + scans (33.3%, p = 0.004).
Of 9 PETMilan Out-patients, only 1 was suffering fromtu-
mor recurrence (11.1%), compared to 7 of 13 Milan Out re-
cipients with PET + status (53,8%, chi square, p = 0.004).
In consequence, Milan Out recipients with negative pre-
operative PET ndings (n = 9) demonstrated a 3-year
recurrence-free survival (80%) that was comparable to Mi-
lan In patients (n = 20; 94%; p = 0.6) and signicantly
better than in Milan Out recipients with positive pretrans-
plant PET scans (n = 13; 29%) (Figure 3).
18
F-FDG-PET ndings and MVI
Of 17 recipients with presence of MVI, 8 patients (47%)
demonstrated posttransplant tumor recurrence, while only
Table 3: Association between PET status and tumor variables
PET PET + p-
Tumor variable (n = 26) (n = 16) Value
Histopathological grade 0.014
Moderate/well 25 11
Poor 1 5
Microvascular invasion <0.001
No 23 2
Yes 3 14
Lymphatic invasion 0.926
No 23 14
Yes 3 2
Pre-LT AFP level 0.658
100 ng/mL 21 12
>100 ng/mL 5 4
Number of tumor nodules 0.036
3 nodules 21 8
>3 nodules 5 8
Size of largest tumor nodule 0.036
5 cm 21 8
>5 cm 5 8
Overall tumor diameter 0.088
10cm 21 9
> 10cm 5 7
Tumor stage 0.003
1 or 2 17 2
3 or 4 9 14
Milan status (pathomorphological) 0.003
Milan In 17 3
Milan Out 9 13

By chi-square test.
1 of 25 patients without MVI (4%) has developed recurrent
HCC (p = 0.001).
Patients without the presence of MVI (n = 25) had a cal-
culated 91% 3-year recurrence-free survival, compared to
28% in those with MVI (n = 17; p < 0.001).
Advanced tumor stage, tumors beyond the Milan cri-
teria, poor tumor grade and pretransplant PET + sta-
tus were univariately associated with the presence of
MVI (Table 5). In multivariate analysis, only preoperative
PET + status was identied as an independent predictor
of MVI (Table 6). The positive and negative predictive values
of positive PET imaging for MVI were 87.5% and 88.5%,
respectively.
18
F-FDG-PET ndings and TACE
Overall 3-year recurrence-free survival posttransplantation
was not different between patients with (n =21, 70%) and
without (n = 19.74%) pre-LT TACE.
In the PET population, 3-year recurrence-free survival af-
ter LT was comparable in patients with (n =12, 100%) and
patients without pretreatment (n = 13.89%), since there
was only one case of HCC recurrence in the nontreated
group.
American Journal of Transplantation 2009; 9: 592600 595
Kornberg et al.
Table 4: Univariate analysis of clinical, morphological and
histopathological variables inuencing risk of HCC recurrence
Variable p-Value
Age recipients (> versus 60 years) 0.658
Age donors (> versus 50 years) 0.914
AFP-level (> versus 100 IU/mL) 0.326
Child classication (A versus B or C) 0.914
Transplant procedure (DDT versus LDLT) 0.496
Cold ischemia time (> versus 300 min.) 0.622
Warm ischemia time (> versus 50 min.) 0.208
Immunosuppression (CsA versus Tac) 0.326
Size of largest tumor nodule (> versus 5 cm) 0.005
Number of tumor nodules (> versus 3) 0.072
Total diameter (> versus 10 cm) 0.043
of tumor nodules
Tumor stage (3/4 versus 1/2) 0.005
Milan status (Milan Out versus 0.013
Milan In)
Tumor grade (Poor versus
moderate/well) <0.001
Microvascular invasion (Yes versus no) 0.001
PET (Pos. versus neg.) 0.001
TACE (No versus yes) 0.734
Lymphatic invasion (Yes versus no) 0.281
In the PET + population, posttransplant 3-year recurrence-
free survival after preoperative TACE (n = 9.33%) was not
superior to that of recipients without neoadjuvant therapy
(n = 6.40%).
In none of the recipients undergoing pre-LT TACE com-
plete tumor necrosis was conrmed at explant pathology.
Recurrence-free survival
PET + patients versus PET - recipients
Months post-LT
0 6 12 18 24 30 36 42 48 54 60 66
C
a
l
c
u
l
a
t
e
d

s
u
r
v
i
v
a
l

(
%
)
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
PET + status
PET - status
Log rank < 0,001
Figure 2: Liver recipients with negative preoperative PET nd-
ings had a signicantly better 3-year recurrence-free survival
than patients with positive pretransplant PET scans.
Risk-stratified recurrence-free survival
Milan In versus Milan Out/PET - versus Milan Out/PET+
Months post-LT
0 6 12 18 24 30 36 42 48 54 60 66
C
a
l
c
u
l
a
t
e
d

s
u
r
v
i
v
a
l

(
%
)
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Milan In (n=20)
Milan Out (PET -, n=9)
Milan Out (PET +, n=13)
Log rank < 0,001
Figure 3: Patients with HCC beyond the Milan criteria and
negative PET ndings demonstrated a 3-year recurrence-free
survival that was comparable to Milan In patients and sig-
nicantly better than for Milan Out recipients with positive
pre-LT PET scans.
Partial tumor necrosis, however, was achieved in all of them
(50% necrosis n = 15; <50% necrosis n = 6).
Discussion
The results of our trial indicate that pretransplant
18
F-FDG
uptake on PET in liver transplant candidates with HCC is
a useful additional parameter for the evaluation of tumor
biology. This study shows that positive preoperative PET
scans are signicantly associated with an increased risk
of posttransplant HCC recurrence and inferior outcome,
which seems to be triggered by a high correlation of a
PET + status and the presence of MVI in explant tumor
pathology.
Table 5: Univariate analysis of predictive factors for microvascular
tumor invasion
Variable p-Value
Size of largest (> versus 5 cm) 0.063
tumor nodule
Number of (> versus 3) 0.063
tumor nodules
Total diameter (> versus 10 cm) 0.136
of tumor nodules
AFP-level (> versus 100 IU/mL) 0.622
Tumor stage (3/4 versus 1/2) 0.001
Milan status (Milan In versus Milan Out) 0.01
Tumor grade (Poor versus well / moderate) 0.001
PET (Pos. versus neg.) <0.001
TACE (No versus yes) 0.182
Lymphatic invasion (Yes versus no) 0.343
596 American Journal of Transplantation 2009; 9: 592600
18
F-FDG-Uptake of Hepatocellular Carcinoma
Table 6: Multivariate analysis of independent predictive factors
for microvascular tumor invasion
Hazard
ratio CI (95%) p-Value
PET (pos. versus neg.) 13.4 0.0030.126 0.001
The outcome after LT in patients with HCC has markedly
improved over the last two decades (16). This is a result of
implementing strict morphological selection criteria, such
as the Milan criteria by Mazzafero et al. (5) Five-year sur-
vival rates above 70% have since been reported, which
are comparable to survival rates after LT in patients with-
out HCC (5,6).
These promising results encouraged several transplant
groups to carefully expand the selection criteria (711).
Roayaie et al. reported about an overall survival rate of
55% after LT for patients with advanced HCC, when being
enrolled in a multimodal preoperative chemotherapy con-
cept (7). Yao et al. have extended the criteria to a single
tumor 6.5 cm, or 3 tumors with the largest 4.5 cmand
a total tumor burden 8 cm (UCSF criteria) and reported
about a 75%5-year survival rate, when using a neoadjuvant
treatment protocol (13). In addition, the implementation of
living donor liver transplantation was reported to further ex-
tend the selection criteria in HCCpatients (37,38). Although
some of the reported results were quite promising, the tu-
mor recurrence rate per se has been signicantly higher
when the selection criteria were expanded beyond the
Milan criteria (39,40). Moreover, extending number and
size of the tumors was shown to increase the risk of pa-
tients drop out from the transplant waiting list, due to
clinically relevant tumor progression (40). These facts illus-
trate the limitations of using tumor size and number as
ultimate variables for selecting appropriate liver transplant
candidates and point out the need for augmenting current
selection criteria with biological parameters of tumor ag-
gressiveness.
Posttransplant tumor recurrence is thought to result from
cancer cells spread into the systemic circulation at the
time of total hepatectomy (41,42). In fact, vascular inva-
sion has been identied as the strongest predictor of poor
outcome after LT for HCC (1,12,14,15), which is conrmed
by our own experience (43). In contrast to gross vascular
tumor invasion, which can be very frequently diagnosed
prior to transplantation by complementary imaging tech-
niques, MVI is a histopathological diagnosis that cannot
be made prior to native hepatectomy (14,35,44,45). There-
fore, other pretransplant available clinical surrogate mark-
ers for MVI have to be identied. Esnaola et al. and Pawlik
et al. demonstrated that, apart from poor tumor grade, it
is advanced tumor size that correlates strongly with pres-
ence of MVI at explant pathology (14,19). The unrestricted
exclusion of patients with large and multiple HCC, how-
ever, may withhold a subset of liver transplant candidates
frompotentially curative LT. Vauthey et al. showed that size
and number of tumor nodules have no signicant impact
on survival in the absence of MVI (35). These data are con-
rmed by our own experience, since posttransplant 3-year
recurrence-free survival was not signicantly different be-
tween Milan In recipients (94%) and patients with tumors
beyond Milan criteria but without presence of MVI (75%,
p = 0.64).
The value of pretransplant HCC grading by tumor biopsy
for selecting adequate liver transplant candidates with ad-
vanced tumors is being discussed controversially (4,18).
Pawlik et al. reported about poor diagnostic accuracy of
pretransplant ne needle tumor biopsy to predict tumor
grade in the explant pathology, due to a HCC-related
heterogeneous pattern of differentiation (4). Furthermore,
there seems to be a substantial risk of tumor seeding af-
ter HCC biopsy, which may be particularly relevant for im-
munocompromised liver transplant recipients (46).
Preoperative
18
F-FDG tumor uptake on PET was identi-
ed as the only independent predictor of MVI in our trial
(Table 6). Moreover, positive PET scans together with pa-
rameters of the Milan criteria and biological tumor aggres-
siveness were signicantly associated with posttransplant
tumor recurrence in a univariate analysis (Table 4). This is a
very important result of our trial, since
18
F-FDG-PET might,
therefore, be proposed as an additional noninvasive tool
for assessing biological tumor behavior in liver transplant
candidates with HCC, without altering the tumor itself, as
it may happen in preoperative tumor biopsy (46,47).
Several investigators have reported about a limited sen-
sitivity of
18
F-FDG-PET in the detection of HCC, when
compared to other liver neoplasms (48,49). The difference
in the accumulation of
18
F-FDG in HCC and metastatic
liver tumors is due to different activities of glucose-6-
phosphatase, which is responsible for the conversion of
FDG-6-phosphate to FDG. It is high in normal liver tis-
sue and almost zero in metastatic liver tumors (48,49). In
HCC, however, there is a wide variety of enzyme activities
due to cell differentiation. It has been shown that well-
differentiated HCC cells exhibit an
18
F-FDG metabolism
similar to that of normal liver tissue, whereas poorly differ-
entiated tumor cells do not. Therefore, well-differentiated
HCC regions tend to accumulate an amount of FDG that is
comparable to normal surrounding liver tissue, which may
propose PET for describing tumor aggressiveness rather
than detection of HCC (4851). In a clinical approach, Seo
et al. demonstrated a signicant correlation of high stan-
dardized uptake values (SUV) with high-grade tumor differ-
entiation and poor outcome after liver resection for HCC
(29). Based on the close relationship between MVI and
poor tumor grade (12,1416,28,29,5153), we, therefore,
hypothesized that PET scan patterns may have a clinically
relevant correlation with the presence of MVI.
The results of our trial implicate that PET ndings may
optimize the selection process for LT in patients with HCC.
American Journal of Transplantation 2009; 9: 592600 597
Kornberg et al.
This might be particularly relevant for patients with tumors
beyond the Milan criteria, who are rejected for LT in many
centers. In our series, patients with advanced HCC and
negative preoperative PET scans demonstrated a 3-year
recurrence-free survival (80%) that was comparable with
Milan In recipients (94%), and signicantly better than for
Milan Out patients with PET + status (35%, Figure 3).
This result indicates that a subset of patients with ad-
vanced HCC may benet from LT, due to the biological
low-aggression behavior of the tumor, and PET imaging
may help with identifying these eligible liver transplant can-
didates. The future clinical follow-up of this special sub-
population of our series, however, has yet to be analyzed
thoroughly.
The value of the Milan criteria for selecting appropriate
liver transplant candidates is clearly conrmed by our trial,
since recurrence-free survival rates for Milan In recipi-
ents were signicantly higher than for Milan Out patients.
Nevertheless, there are several problems associated with
their implementation for patient selection, where pretrans-
plant PET assessment may be helpful in the future.
First, using the same criteria for both, inclusion and ex-
clusion, may result in a high drop-out rate, especially for
patients, who are initially approaching to the upper criteria
limits (54). This might exclude a signicant number of pa-
tients with HCC exceeding the Milan criteria from curative
LT, as proposed by our data and by other trials (711). Simi-
lar to other transplant groups with excellent survival results
(e.g. Barcelona group), we, therefore, followed a policy of
patients exclusion based on major events (macrovascu-
lar tumor invasion, lymph node metastases, tumor-related
symptoms, extrahepatic tumor spread) rather than on the
Milan criteria alone (6). Apart from that, tumor understag-
ing by preoperative radiographic imaging is a well-known
phenomenon in this context, resulting in a large fraction
of patients with advanced tumors at explant pathology
(6,39,55). In 17 patients of our series (40.5%), nal pre-
transplant screening underestimated pathological tumor
staging. Against this background, PET evaluation may be
useful for further rening the decision making about drop-
out of liver transplant candidates with tumor progression
during the waiting period for transplantation. This, how-
ever, has yet to be analyzed by a prospective study.
Apart from being a retrospective analysis, there are some
further limitations of our trial.
First, we did not use a quantitative uptake measurement
in our study, since SUV levels were not available in all pa-
tients. Moreover, we did not perform repeat PET imaging
by protocol during waiting time for transplantation. How-
ever, performing follow-up PET scans might be of special in-
terest for evaluating the impact of interventional therapies
on biological tumor viability. Torizuka et al. demonstrated
that an increased or similar
18
F-FDG uptake postchemoem-
bolization suggested residual viable tumor tissue, whereas
decreased or absent
18
F-FDG uptake indicated more than
90% necrosis (56). These data seem to indicate that ac-
curacy of a single pretransplant PET nding for predicting
biological tumor characteristics in the explant specimen
could be affected by additional TACE achieving complete
tumor obliteration.
In our study population, however, there was no case of
complete tumor necrosis following TACE. MVI was evident
in the remaining viable tumor regions in 7 of 9 PET + pa-
tients undergoing pretransplant TACE (77.8%), and in 6 of
6 nontreated PET + recipients (100%). This result seems
to explain the high accuracy of a single positive PET nding
for predicting MVI in our trial, even though 21 patients un-
derwent TACE pretransplantation. Nevertheless, the value
of repeat PET evaluation for detecting changes in biological
tumor aggressiveness during the waiting time for LT and,
thereby, possibly altered patient prognosis post-LT should
be assessed in a prospective framework.
In conclusion, our data suggest that preoperative
18
F-FDG
uptake on PET is a reliable predictor of MVI and tumor re-
currence after LT for HCC. Patients with tumors beyond
the Milan criteria and negative preoperative PET scans
may achieve a posttransplant 3-year recurrence-free sur-
vival that is comparable to that of patients with tumors
meeting the Milan criteria. In the context of neoadjuvant
therapies, repeat PET evaluations by protocol might be use-
ful for unfolding the full potential of PET to predict MVI.
Thereby,
18
F-FDG-PET imaging could emerge as a useful
diagnostic tool for improved decision making about listing
or exclusion of liver transplant candidates with HCC.
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