N u c l e a r M e d i c i n e a n d M o l e c u l a r I m a g i n g • R ev i ew

Sacks et al.
PET/CT in Primary Hepatobiliary Tumors CME Value of PET/CT
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SAM
Nuclear Medicine and Molecular Imaging
Review

Value of PET/CT in the

FOCUS ON:

Management of Primary
Hepatobiliary Tumors, Part 2
Ari Sacks1 OBJECTIVE. Primary hepatobiliary malignancies consist of hepatocellular carcinoma,
Patrick J. Peller 2 cholangiocarcinoma, and gallbladder cancer. Benign hepatic lesions include hepatic cysts,
Devaki S. Surasi 3 hemagiomas, adenomas, and focal nodular hyperplasias. The utility of PET/CT in imaging
Luke Chatburn1 primary hepatobiliary lesions varies according to the type and location of the lesion.
Gustavo Mercier 3 CONCLUSION. There is a consistent benefit to the use of PET/CT for detection and
staging, and it ultimately helps to establish the best course of treatment and to determine
Rathan M. Subramaniam 3
prognosis. In addition, PET/CT is very useful in local ablative and systemic therapy
Sacks A, Peller PJ, Surasi DS, Chatburn L, Mercier assessment and surveillance for hepatobiliary malignancies.
G, Subramaniam RM

Keywords: hepatobiliary tumors, PET/CT
DOI:10.2214/AJR.11.6995
Received April 1, 2011; accepted without revision
April 7, 2011.
1
Boston University School of Medicine, Boston, MA.
2
Department of Radiology, Boston Medical Center and
Boston University School of Medicine, Boston, MA.
3
Department of Radiology, Boston Medical Center and
Boston University School of Medicine, 820 Harrison Ave,
FGH Bldg, Level 3, Boston, MA 02118. Address
correspondence to R. M. Subramaniam
(rathan.subramaniam@bmc.org).
CME/SAM
This article is available for CME/SAM credit.
See www.arrs.org for more information.
WEB
This is a Web exclusive article.
AJR 2011; 197:W260–W265
0361–803X/11/1972–W260
© American Roentgen Ray Society
P
rimary hepatobiliary malignan-
cies include liver tumors, cholan-
giocarcinoma, and gallbladder
cancer. Primary hepatic tumors,
malignant or benign, are infrequent [1] and
include hepatocellular carcinomas (HCCs),
hemagiomas, adenomas, and focal nodular
hyperplasias. There is increased incidence of
HCC in patients with chronic liver diseases,
such as hepatitis [2], alcoholic cirrhosis [3],
and systemic immune diseases, especially
HIV [4]. Biliary tree and gallbladder primary
tumors are rare (< 2% of cancer prevalence)
and are difficult to diagnose at an operable
stage. The epidemiology of gallbladder cancer
varies globally, correlating strongly with cho-
lelithiasis and Salmonella infection rates [5].
PET and PET/CT may play a significant role
in the diagnosis, staging, or follow-up of each
of these malignancies.
Newer hepatic MRI techniques have vastly
improved the ability of MRI to differentiate
between benign and malignant focal hepatic
lesions. For example, diffusion-weighted im-
aging has been shown by Koike et al. [6] to
differentiate malignant from benign lesions
by having a lower apparent diffusion coeffi-
cient and higher relative contrast ratio when
compared with surrounding liver parenchy-
ma. Furthermore, the development of spe-
cific MRI hepatobiliary contrast agents im-
proves lesion detection and characterization
[7]. Such state-of-the-art hepatic MRI tech-
niques may play a role in better characteriza-
tion of hepatic lesions in the future.
This article provides an overview of the
current role of PET and PET/CT in primary
hepatobiliary tumors.
Hepatocellular Carcinoma
The liver is the major producer of nondi-
etary glucose, at a rate of 2.0 mg/kg/min,
which helps maintain glucose homeostasis
[8]. Studies have shown that there are a va-
riety of different levels of glucose-6-phos-
phatase activity and glucose transporters in
HCC, leading to variable 18F-FDG uptake
[9–12]. Torizuka et al. [9] showed that FDG
uptake of HCC lesions correlates with the de-
gree of differentiation of the HCC; high-grade
HCCs have increased FDG uptake (mean [±
SD] standardized uptake value [SUV], 6.89 ±
3.39) compared with low-grade HCCs (mean
SUV, 3.21 ± 0.58) (p < 0.005).
Because of this variability, it is likely that
FDG PET scans have an increased ability to
detect higher grade HCCs and, alternatively,
have a decreased ability to detect low-grade
HCCs, as a result of decreased FDG uptake.
The overall sensitivity of FDG PET/CT in
detecting HCC suffers, with a reported range
of 50–65% [12–16]. For this reason, FDG
PET has been determined [14] to be insuf-
ficiently sensitive to diagnose primary HCC.

W260 AJR:197, August 2011


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A study by Khan et al. [13] found that the
sensitivity of FDG PET in the diagnosis of
HCC was 55%, compared with 90% for con-
trast-enhanced CT. Another report, by Wu-
del et al. [15], involving one of the largest se-
ries of FDG PET for HCC (n = 91), reported
that the sensitivity of FDG PET for detection
of HCC was 64%.
Although the sensitivity of FDG PET scans
has been shown to be lower than that of oth-
er imaging modalities for HCC, it still plays
an important role in prognosis. Because FDG
uptake acts as a marker of differentiation,
SUVs can give insight into the histopatho-
logic nature of the tumor. Shiomi et al. [17]
showed that the SUV ratios (SUV ratio of tu-
mor to nontumor in liver) of HCC tumors cor-
relate with tumor volume-doubling time (r =
−0.582; p = 0.006). That study also found that
cumulative survival rate can be predicted on
the basis of the SUV ratio. The patients were
divided into two groups of similar size: group
A (n = 24) had SUV ratios (as defined as the
hepatic tumor-to-nontumor ratio of SUV) of
1.5 or less, and group B (n = 24) had SUV ra-
tios greater than 1.5. The authors showed that
the cumulative survival rate was significantly
lower in group B than in group A (p = 0.026).
Similarly, Kong et al. [18] showed that pa-
tients with HCC who had mean SUVs of 7 or
higher had a significantly (p = 0.0003) lower
median survival time (4 vs 15 months).
Although FDG PET can help to differentiate
tumors, it may also be useful in the staging of
HCC as a complementary modality to CT by
detecting unsuspected regional and distant
metastases [13]. In a study by Yoon et al. [19],
pretreatment FDG PET examinations were
performed on 87 patients with HCC who un-
derwent MRI or CT studies, to assess whether
there were any extrahepatic metastases present
in those patients. Extrahepatic metastases were
identified in 24 of 87 patients. All of the extra-
hepatic metastases were detected by FDG PET.
In addition, FDG PET identified four lymph
node metastases and six bone metastases that
had not been found using MRI or CT. TNM
stage based on the conventional staging work-
up was changed in four cases after FDG PET. It
has been proposed by Ho et al. [20] that poorly
differentiated HCCs, which are more likely to
metastasize, also tend to be FDG avid; there-
fore, metastases from HCCs in general are
more likely to be detected with FDG PET.
Wudel et al. [15] found that, although only
64% of HCCs accumulated FDG, FDG PET
had a clinically significant impact in 26 of 91
patients (28%) with HCC. This impact was
AJR:197, August 2011
PET/CT in Primary Hepatobiliary Tumors
achieved via guiding the biopsy of a large ne-
crotic tumor (n = 1), identifying distant me-
tastases (n = 5), monitoring the response to
treatment with regional therapy (n = 12), and
detecting recurrence (n = 2). The authors
concluded that FDG PET should be consid-
ered as part of the staging and management
of selected patients with HCC.
Fusions of FDG PET and CT images have
been shown to provide improvement of le-
sion detection, localization, and differentia-
tion between physiologic versus patholog-
ic uptake on both CT and FDG PET images
alone [21]. The addition of CT images can
also be very useful for detecting HCC in cas-
es when the lesion is not FDG avid, because
70% of HCCs are visible on unenhanced CT
as hypodense lesions, and an additional 20%
are visible as hyperdense lesions [22].
FDG PET/CT has been shown to be ben-
eficial in detecting extrahepatic disease in
patients with primary HCC (Fig. 1). Kawa-
oka et al. [23] found FDG PET/CT to have
a higher sensitivity for the detection of bone
metastases from primary HCC, compared
with MDCT and bone scintigraphy. In that
study, the mean sensitivity and specificity for
diagnosis of bone metastasis were 41.6% and
94.5% for MDCT, 83.3% and 86.1% for FDG
PET/CT, and 52.7% and 83.3% for bone
scintigraphy, respectively. FDG PET/CT is
also very useful for assessing chemoemboli-
zation therapy for HCC (Fig. 2).
Because FDG PET has been shown to have
limited sensitivity for the detection of some
HCC tumors because of their variable FDG up-
take, 11C-acetate-PET has been used to com-
plement FDG PET in a dual-tracer PET scan.
Ho et al. [20] found that well-differentiated
HCCs preferentially accumulate 11C-acetate,
whereas poorly differentiated tumors tend to
preferentially accumulate FDG. Delbeke et al.
[24] suggest that different uptake or tracers by
lesions can narrow down a differential diagno-
sis. When a tumor accumulates both tracers, or
only 11C-acetate, HCC is high on the differen-
tial. Lesions that accumulate only FDG suggest
a non-HCC malignancy. The remaining le-
sions, which accumulate neither tracer, imply a
benign pathologic abnormality. On the basis of
tracer avidity to different types of HCC lesions,
dual-tracer PET could lead to increased sensi-
tivity in detecting all HCC. Ho et al. [20] found
that none of 23 HCC lesions in their study pop-
ulation were negative for both tracers (100%
sensitivity using both tracers). HCC tumors
with no evident FDG uptake were detected by
11C-acetate uptake, and vice versa.
In an assessment of dual-tracer (11C-acetate
and FDG) PET/CT, Park et al. [25] prospec-
tively evaluated the value of PET/CT using
FDG and 11C-acetate tracers for the detection
of primary and metastatic HCC. The overall
sensitivities of FDG, 11C-acetate, and dual-
tracer PET/CT in the detection of 110 lesions
in 90 patients with primary HCC were 60.9%,
75.4%, and 82.7%, respectively. The sensitivi-
ties according to tumor size (1–2, 2–5, and ≥
5 cm) were 27.2%, 47.8%, and 92.8%, respec-
tively, for FDG and 31.8%, 78.2%, and 95.2%,
respectively, for 11C-acetate [25]. In that same
study, FDG was found to be more sensitive
than 11C-acetate in detection of extrahepatic
metastases (85.7% vs 77%). The addition of
11C-acetate to FDG PET/CT increases the
overall sensitivity for the detection of primary
HCC, but not for the detection of extrahepatic
metastases. This may be the result of in-
creased FDG PET sensitivity in the detection
of poorly differentiated HCC tumors, which
are often more likely to be more aggressive,
and thus associated with metastases [20].
Overall, for identification and staging of HCC
metastasis, Ho et al. [20] found dual-tracer
PET/CT to have a sensitivity of 98%, a speci-
ficity of 86%, a positive predictive value
(PPV) of 97%, a negative predictive value
(NPV) of 90%, and an accuracy of 96%.
These values, as expected, are all significantly
improved to either imaging modality alone.
In summary, because of the variable glucose
metabolism of HCCs, FDG PET has shown
mixed utility in the detection of HCCs, with
sensitivities of 55–64% and with larger tumors
visualized better than smaller tumors. FDG
PET appears to provide insight into the meta-
bolic activity of the tumor, with higher FDG
uptake correlating with higher grade cancers
and predicting prognosis. FDG PET has also
been shown to be helpful in the detection of
regional and extrahepatic metastases, with a
disproportionate number of metastatic HCCs
being FDG avid; FDG PET/CT is the most
sensitive examination for detecting HCC extra-
hepatic metastases. Finally, 11C-acetate tracer
used in conjunction with FDG was shown in
one study to vastly increase the detection rate
of HCC with PET.
Benign Liver Tumors
The most common benign hepatic tumors
are hemangiomas, focal nodular hyperpla-
sia (FNH), and hepatocellular adenomas.
All of these benign tumors have been shown
to take up FDG at a similar rate as normal
liver tissue.
W261

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Kurtaran et al. [26] showed that malignant
liver lesions accumulate more FDG than FNH
lesions (mean, 10.07 ± 3.79 and 2.12 ± 0.38,
respectively). Furthermore, FNH lesions showed
normal or even decreased accumulation of
FDG compared with background liver tissue.
Ho et al. [14] found that FNH lesions can
show mildly increased levels of 11C-acetate
uptake (11C-acetate SUVmax, 3.59, with a lesion-
to-normal liver ratio of 1.25). Hemangiomas
showed poor FDG uptake [27], with an SUV
ratio of less than 2.
To further delineate the imaging role of
PET in evaluating liver masses, Delbeke et
al. [28] were able to show the ability of FDG
PET to differentiate between benign and ma-
lignant hepatic lesions in 110 patients who
were referred for examination of hepatic le-
sions greater than 1 cm at largest diameter.
The authors found that all benign hepatic le-
sions (n = 23), including adenoma and FNH,
had poor uptake and an SUVmax less than
3.5, except for one of three abscesses that
had definite uptake. All 66 liver metastases
and 16 of 23 HCCs had avid FDG uptake.
In summary, benign liver tumors take up
FDG at a similar rate to surrounding tissue,
differentiating them from HCCs or metasta-
ses or both on PET. Hemangiomas take up
the least FDG of the non-HCC liver tumors.
Liver abscesses may be a source of false-pos-
itive findings on FDG PET.
Cholangiocarcinoma
Cholangiocarcinoma is notoriously dif-
ficult to diagnose early and is usually fatal
because of its late clinical presentation and
the lack of effective nonsurgical therapeutic
modalities [29]. Diagnostic imaging of this
type of tumor is usually performed with ul-
trasound, CT, or MR cholangiography. Stud-
ies show that, although FDG PET/CT has no
statistically significant advantage over con-
trast-enhanced CT, MRI, or MR cholangiog-
raphy in the diagnosis of primary biliary tu-
mors [30, 31], it is very valuable in detecting
regional and distant metastases not seen by
conventional imaging.
FDG accumulates in cholangiocarcino-
ma, which appears to be primarily the result
of increased glucose transporter expression
on tumor cells [32]. This increased uptake
is especially prominent in nodular or mass-
forming cholangiocarcinomas, which have
intense FDG uptake due to increased expres-
sion of glucose transporter–1 [11] (Fig. 3).
In assessing the ability of FDG PET to de-
tect and diagnose cholangiocarcinoma, Kluge
W262
Sacks et al.
et al. [33] retrospectively examined the cases
of 20 patients with cholangiocarcinoma and
found that FDG PET had sensitivity, specific-
ity, and diagnostic accuracy of 92.3%, 92.9%
and 92.6%, respectively. A more recent study
investigating FDG PET/CT by Jadvar et al.
[32] found sensitivity and specificity to be 94%
and 100%, respectively. That study included
patients with overt metastatic disease that was
easily detectable by other imaging modalities,
which may have exaggerated the values [32].
In a prospective study, Kim et al. [30] found
overall values for sensitivity, specificity, PPV,
NPV, and accuracy of FDG PET/CT in prima-
ry tumor detection were 84.0%, 79.3%, 92.9%,
60.5%, and 82.9%, respectively.
In 36 patients who underwent imaging for
cholangiocarcinoma, Anderson et al. [34]
found that the sensitivity for detection with
FDG PET was 85% (n = 22) for a nodular
morphology, but only 18% (n = 14) for an in-
filtrating morphology. Periductal infiltrating
cholangiocarcinomas rarely form a focal mass
[35], and FDG uptake is, therefore, streaky.
These data suggest that FDG PET is accurate
in predicting the presence of nodular cholan-
giocarcinoma (mass > 1 cm), but is less effec-
tive for the infiltrating type [32, 34].
The location of the cholangiocarcinoma
also plays a role in the ability of FDG PET
to detect the lesion. The sensitivity of FDG
PET/CT in detecting primary hilar or ex-
trahepatic cholangiocarcinoma tumors was
found to be 18–58.8% [32, 34, 36, 37], sig-
nificantly lower than that of peripheral nod-
ular tumors. One study of 22 patients with
primary sclerosing cholangitis [38] showed
that FDG PET/CT of the liver that was per-
formed after a delay (about 120 minutes af-
ter injection) was able to differentiate benign
strictures from extrahepatic and hilar cho­
langiocarcinomas in all 22 lesions by using
SUVmax greater than 3.6 as a threshold.
Although FDG PET and FDG PET/CT
have not been shown to be highly beneficial
in diagnosing primary cholangiocarcinoma,
they have benefit in the diagnosis of metasta-
ses and staging. Kim et al. [30] found FDG
PET to have improved accuracy in the diag-
nosis of regional lymph nodes metastases
(75.9% vs 60.9%; p = 0.004) and distant me-
tastases (88.3% vs 78.7%; p = 0.004) when
compared with CT (n = 123). Seo et al. [39]
also found FDG PET to be a more accurate
and specific detector of lymph node metas-
tases in 35 patients when compared with ei-
ther CT or MRI. Diagnostic accuracies in
that study of FDG PET, CT, and MRI for de-
tection of lymph node metastasis were 86%,
68%, and 57%; the sensitivities were 43%,
43%, and 43%; and the specificities were
100%, 76%, and 64%, respectively.
Several other studies [40–42] have shown
that FDG PET has distinct advantages at de-
tecting occult metastases that were not diag-
nosed by standard imaging. Thus, FDG PET/
CT staging has an important impact on the
selection of adequate therapy [31]. FDG PET
has been shown to change surgical manage-
ment in 17–30% [31, 34, 43] of patients eval-
uated for cholangiocarcinoma, primarily as
a result of detection of unsuspected or un-
known metastases and, thus, upstaging [43].
In summary, the sensitivity of FDG PET
and FDG PET/CT in diagnosing cholangio-
carcinoma appears to be dependent on both
the morphologic characteristics and loca-
tion of the lesion, with nodular forms and pe-
ripherally located lesions being easier to de-
tect than infiltrating and hilar lesions. FDG
PET and FDG PET/CT have been shown to
be very beneficial in detecting regional and
distal metastases from cholangiocarcinoma,
which can affect patient management.
Gallbladder Cancer
Gallbladder cancer is a relatively rare ma-
lignancy that has few specific symptoms or
signs. The clinical presentations of gallstone
disease and gallbladder cancer are often dif-
ficult to distinguish. Therefore, symptoms of
gallbladder cancer are often mistakenly in-
terpreted as biliary colic or chronic chole-
cystitis, hampering a timely formation of a
diagnosis [44]. Radical gallbladder resection
remains the most effective tools in the man-
agement of patients with gallbladder cancer,
in the absence of metastatic disease. Surgery
does not offer any survival benefit in patients
with distant metastasis [45].
FDG PET takes advantage of the high glu-
cose utilization of gallbladder cancer (Fig.
4). There are only a handful of studies as-
sessing the role of FDG PET or FDG PET/
CT in gallbladder cancer, making solid con-
clusions of its role more difficult to establish.
In two small series (n = 16 in each) by Koh
et al. [46] and Rodríguez-Fernández et al.
[47], FDG PET was shown to have sensitiv-
ity of 75–80% and specificity of 82–87.5%
in diagnosing gallbladder cancer. Rodríguez-
Fernández et al. found two false-positive re-
sults because of acute cholecystitis. In anoth-
er study (n = 14) [31], the authors found the
sensitivity of PET/CT detecting gallbladder
cancer to be 100% (14/14).
AJR:197, August 2011
 PET/CT in Primary Hepatobiliary Tumors
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FDG PET appears to have a potential role
in the assessment of gallbladder wall thicken-
ing, as seen on conventional imaging. Oe et
al. [48] found that increased FDG uptake was
able to help distinguish between benign and
malignant gallbladder wall thickening found
on ultrasound, CT, or MRI. In their study, four
of 12 patients with gallbladder wall thicken-
ing on conventional imaging had FDG up-
take. Three of those four patients were found
to have gallbladder cancer, whereas none
of the non-FDG-avid thickened walls were
linked to a diagnosis of gallbladder cancer.
Nishiyama et al. [49] showed that a delayed
(146 ± 14 minutes after injection) FDG PET
scan led to increased FDG uptake of lesions
and increased lesion-to-background contrast,
when compared with early-scan (62 ± 8 min-
utes after injection) FDG PET. Shukla et al.
[45] found that FDG PET/CT had a slightly
better accuracy (91.6% vs 87.5%) than did
MDCT in determining tumor resectability in
patients with incidental gallbladder cancer
and no distant metastases.
It appears that the roles of FDG PET and
FDG PET/CT in gallbladder cancer have not
been studied sufficiently to make conclu-
sive statements about their clinical value. At
this time, however, these modalities seem to
be useful in differentiating malignant wall
thickening and benign wall thickening, and
in the preoperative diagnostic algorithm to
assess proper surgical candidates.
Conclusion
In summary, the utility of PET and PET/
CT in imaging primary hepatobiliary lesions
varies according to the type and location of
the tumor. There is a consistent benefit to the
use of PET for detection and staging, which
ultimately helps to establish the best course
of treatment and to determine prognosis.
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AJR:197, August 2011
 PET/CT in Primary Hepatobiliary Tumors
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Fig. 2—47-year-old man with hepatitis B and C and elevated

α-fetoprotein levels.
A, Axial T1-weighted MRI scan shows lesion (arrow)
measuring 4.5 × 3.5 cm in segment 2 of liver. Patient underwent
chemoembolization of liver lesion. PET/CT performed 20 days later
showed residual hepatic disease with pulmonary metastases.
B, Axial fused PET/CT shows large necrotic 9.9 × 4.7 × 9.9
cm mass (arrow) in left lobe of liver with hypermetabolic rim,
consistent with patient’s history of chemoembolization of
large hepatocellular carcinoma.
C, PET/CT shows hypermetabolic lesion (arrow) in middle lobe
of right lung with maximum standardized uptake value (SUVmax)
of 2.6, consistent with pulmonary metastasis. Patient received
systemic chemotherapy with Sorafenib (Nexavar, Bayer
HealthCare) for 3 months, and follow-up PET/CT revealed
significant worsening of disease in both liver and lung.
D, Axial fused PET/CT shows interval increase in extent and
degree of hypermetabolic activity, with SUVmax of 6.6, surrounding
large centrally photopenic defect (arrow) within left lobe of liver.
E and F, CT in lung window (E) and fused PET/CT (F) show
multiple hypermetabolic pulmonary nodules consistent with
progression of pulmonary metastases.

Fig. 3—65-year-old man with history of ulcerative colitis

requiring colectomy and primary sclerosing cholangitis.
A, CT scan performed during his hospitalization for
coronary artery bypass graft revealed low-attenuation
mass (arrow) in left lobe of liver.
B and C, PET/CT shows intensely FDG-avid 6 × 5 cm mass
(arrow, B and C) with central area of decreased activity
(necrosis). No distant metastases were identified. Biopsy
revealed cholangiocarcinoma, and mass was successfully
resected.

Fig. 4—75-year-old female smoker who presented with

right upper quadrant pain.
A, Contrast-enhanced CT revealed mass (arrow) anterior
to gallbladder, arising from liver or gallbladder. Biopsy
revealed gallbladder cancer.
B and C, PET/CT shows intensely FDG-avid mass (arrow,
B) arising from anterior wall of gallbladder and second
FDG-avid right apical lung mass (arrow, C). With biopsy-
confirmed non-small-cell lung cancer, patient received
palliative therapy for both malignancies.

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