AJR 2005; 184:1157-1162
© American Roentgen Ray Society
Detection of Combined Hepatocellular and Cholangiocarcinomas on Enhanced CT: Comparison with Histologic Findings
Akihiro Nishie1,
Kengo Yoshimitsu1,
Yoshiki Asayama1,
Hiroyuki Irie1,
Hitoshi Aibe1,
Tsuyoshi Tajima1,
Kenji Shinozaki1,
Tomohiro Nakayama1,
Daisuke Kakihara1,
Mitsuo Shimada2,
Shin-ichi Aishima3,
Kisaku Yoshida4 and
Hiroshi Honda1
1 Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu
University, 3-1-1, Maidashi, Higashi-ku Fukuoka 812-8582, Japan.
2 Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu
University, Higashi-ku Fukuoka 812-8582, Japan.
3 Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu
University, Higashi-ku Fukuoka 812-8582, Japan.
4 Department of Radiology, Fukuoka City Hospital, Yoshizukahonmachi, Hikata-ku
Fukuoka 812-0046, Japan.
Received November 22, 2003;
accepted after revision July 14, 2004.
Address correspondence to A. Nishie
(anishie{at}radiol.med.kyushuu.ac.jp).
Abstract
OBJECTIVE. The purpose of this study was to evaluate the performance
of enhanced CT in making a diagnosis of combined hepatocellular and
cholangiocarcinomas (HCC-CCs) by comparing CT findings with histologic
findings.
CONCLUSION. One third (nine of 27 cases) of the combined HCC-CCs
were correctly diagnosed on enhanced CT by detailed analysis of the enhancing
pattern around or within the mass. Various factors such as an atypical
enhancing pattern, the size of each component, and the presence of a mass
composed of intermediate tumor cells—that is, cells with intermediate
characteristics between HCC and CC—were found to be the causes of
misdiagnosis of combined HCC-CC on enhanced CT.
Introduction
Primary liver cancers are divided into two histologic categories:
hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Combined
hepatocellular and cholangiocarcinomas (HCC-CCs) are a rare (1.0-3.3%) form of
primary liver tumor presenting histologic evidence of both hepatocellular and
biliary epithelial differentiation
[1,
2]. Allen and Lisa
[3] defined three types of
combined HCC-CC. The first type is termed "double cancer" and
represents cases in which HCC and CC exist separately. The second type, which
is called the combined type, is defined as cases in which HCC and CC exist
contiguously but independently. The third type, which is referred to as the
mixed type, occurs when HCC and CC components intermingle within a mass.
We rarely encounter this type of liver tumor and are distressed at the
difficulty in making a preoperative diagnosis of this entity. Because the
frequency of lymph node metastases in combined HCC-CCs has been reported to be
as high as that in CCs [1],
systemic nodal resection is mandatory for curative surgery; therefore, it is
important to diagnose combined HCC-CCs preoperatively.
Although a few reports describe CT findings of combined HCC-CCs
[2,
4,
5], a prospective diagnosis of
this entity on enhanced CT remains difficult. In our study, we examined the
ability of abdominal enhanced CT to allow the diagnosis of combined HCC-CCs by
comparing CT findings with histologic findings.
Materials and Methods
In a review of medical radiologic records at our hospital and its
affiliated hospital between July 1990 and November 2000, we identified 27
patients with histopathologically proven combined HCC-CCs by surgical
resection. All the patients were men, and they ranged in age from 37 to 73
years, with a mean of 60 years. Hepatitis B surface antigen was present in
seven patients and hepatitis C virus antibody in 11 patients.
All histologic specimens were evaluated by one experienced pathologist. The
microscopic histologic definition of combined HCC-CC on H and E staining was
based on several criteria [6,
7]. The component was defined
as HCC if any of the following findings were present: trabecular growth, bile
production, eosinophilic cytoplasm, prominent nucleoli, or hyaline body.
Conversely, the component was identified as CC if a small glandular formation
composed of small cuboidal cells with round nuclei was present. Cases with
mucin production confirmed by either alcian blue or mucicarmine stain in
CC-like areas were defined as combined HCC-CC. Furthermore, tumors composed of
intermediate cells with hybrid or polymorphic cytologic features straddling
malignant hepatocytes and glandular cells were also defined as combined
HCC-CC. The pathologist identified all areas of each cell type and
subclassified combined HCC-CCs according to the criteria of Allen and Lisa
[3]. The areas of each cell
type were also selected by the pathologist for the comparison with CT
findings.
All 27 patients underwent dynamic CT (X-Vigor or TCT-900S, Toshiba) within
1 month before hepatectomy. Contiguous axial 1-cm-thick sections were
obtained. Dynamic incremental scanning was performed after 100 mL of iopamidol
(61.2%, 300 mg I/mL) was administered IV at a rate of 2 mL/sec with a power
injector. In the early phase, scanning was begun 45 or 50 sec after
commencement of the injection. Scanning time was 1 sec with a 1- or 1.6-sec
interscan delay to permit table motion between scans. From 12 to 16 scans were
obtained during suspension of respiration for 30-40 sec. In the delayed phase,
scanning was begun 6 min after the contrast medium was administered using the
same technique as that used for the early phase images.
Enhanced CT findings were evaluated by consensus of two abdominal
radiologists. We focused on the enhancing pattern of a part or component of
the lesions. On the basis of findings from previous reports, we defined
components showing high attenuation on the early phase and low attenuation on
the delayed phase (high-low pattern) as an HCC pattern component
[8] and components showing low
attenuation on the early phase and low, iso-, or high attenuation on the
delayed phase (low-low, low-iso, or low-high patterns, respectively) as a CC
pattern component [9].
Furthermore, a CC component showing a low-low pattern was defined as one with
minimal delayed enhancement.
We correlated the radiologically determined components to the histologic
areas of each cell type. When the component detected radiologically and the
histologic finding were in complete concordance in terms of site, size, and
enhancing pattern, we decided as a correct concordance. The concordance rate
of the radiologic HCC-CC pattern component to the histologic findings was
calculated for all areas of each cell type and also for the areas of each cell
type that were more than 1 cm in diameter. The diagnostic rate was defined as
the ratio of the number of patients in whom CT correctly depicted the HCC and
CC pattern components to the total number of patients.
Results
According to the criteria of Allen and Lisa
[3], histologic evaluation
indicated that two, nine, and 16 patients with combined HCC-CC had double
cancer, the combined type, and the mixed type, respectively.
In two patients with double cancer, the diameters of the HCCs were 6 and 4
cm and those of the CCs were 5 and 2 cm, respectively. The HCC and CC in one
patient were located in the medial segment and the lateral segment,
respectively, and those in the second patient were in the anterior segment and
the posterior segment of the right lobe, respectively. Two distinct masses
were described as showing the HCC pattern and CC pattern components in both
patients (Table 1). The
concordance rate and diagnostic rate were both 100% in these cases of double
cancer.
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TABLE 1 Concordance Rate of CT Pattern and Histology in Cases of Double Cancer
Type of Combined Hepatocellular and Cholangiocarcinoma
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The mean diameter of the whole masses in nine patients with the combined
type was 5.4 cm (range, 3.5-10 cm), and the masses were seen in the anterior
segment (n = 5) and the posterior segment (n = 4) of the
right lobe. The mean diameters of histologic HCC (n = 9) and CC
(n = 9) components were 3.14 cm (range, 0.5-6 cm) and 3.38 cm (range,
0.4-10 cm), respectively. The concordance rates of HCC and CC pattern
components and those of more than 1 cm in diameter are described in
Table 2. The diagnostic rate
was 44.4% in the combined type cases. The reasons for discordance included
different enhancing pattern from those as defined earlier and the small size
of each component.
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TABLE 2 Concordance Rate of CT Pattern and Histology in Cases of Combined Type
of Combined Hepatocellular and Cholangiocarcinoma
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Although two different enhancing areas within or around the mass were
detected in two patients, the HCC pattern and CC pattern components on CT were
histologically proven to be CC and HCC, respectively. The CC in one patient
showed the high-low (HCC) pattern on CT and was composed of poorly
differentiated adenocarcinoma cells with a small amount of desmoplastic stroma
(Figs. 1A,
1B, and
1C). The HCC in the other
patient showed the low-low (CC) pattern on CT and was composed of
well-differentiated HCC. Either component was very small (< 1 cm in
diameter) in three patients and could not be detected on CT.
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Fig. 1A. —62-year-old man with combined type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Early phase enhanced CT scan shows tumor,
with diameter of 4.5 cm, is located in right lobe. Left-sided mass shows high
attenuation, and right-sided component shows slightly high attenuation with
irregular margin (arrow). Two components are in close contact.
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Fig. 1B. —62-year-old man with combined type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Delayed phase enhanced CT scan reveals that
left-sided mass shows low attenuation with relatively clear margin and
right-sided component shows slightly low attenuation (arrow); both
components are recognized as HCC pattern components.
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Fig. 1C. —62-year-old man with combined type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Photograph shows macroscopic specimen.
Inner part of tumor is yellowish mass with thin capsule and septum,
representing HCC, and outside part is white and solid mass with necrosis
(arrow), representing CC. In outside part, poorly differentiated
adenocarcinoma cells grew in solid nest and focally glandular pattern with
small amount of desmoplastic stroma.
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The mean diameter of the whole masses in the patients (n = 16)
with the mixed type was 4.6 cm (range, 1.6-10 cm); masses of the mixed type
were seen in the anterior segment (n = 5) and posterior segment
(n = 2) of the right lobe, the medial segment (n = 4), the
lateral segment (n = 4), and the caudate lobe (n = 1). In
three of these 16 patients, the masses (range in diameter, 2.1-6.5 cm) were
composed of intermediate tumor cells. The masses showed an HCC enhancing
pattern in one patient and a CC enhancing pattern in the other two patients
(Figs. 2A,
2B, and
2C). Two distinct components
cannot be detected in this type of tumor. The mean diameters of histologic HCC
(n = 17) and CC (n = 13) components in the remaining 13
patients were 3.14 cm (range, 0.5-6 cm) and 3.38 cm (range, 0.4-10 cm),
respectively.
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Fig. 2A. —48-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Early phase enhanced CT scan shows tumor is
mainly located in medial segment with diameter of 5 cm. Mass shows entirely
low attenuation of central area with ring enhancement.
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Fig. 2B. —48-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Delayed phase enhanced CT scan shows inner
part of mass was gradually enhanced. Mass is recognized as CC pattern
component.
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Fig. 2C. —48-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Photomicrograph shows microscopic findings.
Tumor is composed of intermediate polygonal cells arranged in solid nest with
fibrous stroma.
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The concordance rates of the HCC and CC pattern components and those of
more than 1 cm in diameter are described in
Table 3. The diagnostic rate
was 18.8% for the mixed type including masses composed of intermediate tumor
cells (Figs. 3A,
3B, and
3C). The reasons for
discordance included different enhancing pattern from those as defined earlier
and small size of each component. In one patient, the CC pattern component on
CT was histologically proven to be HCC. The HCC showed the low-iso (CC)
pattern on CT and was composed of moderately differentiated HCC with abundant
fibrous stroma (Figs. 4A,
4B, and
4C). Either component was very
small (< 1 cm in diameter) in nine patients and could not be detected on
CT. In one of these nine patients, very small HCC components (n = 5)
were sparsely scattered within the mass histologically. The total diagnostic
rate on enhanced CT was 33.3% (9/27) (Table
4).
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TABLE 3 Concordance Rate of CT Pattern and Histology in Cases of Mixed Type of
Combined Hepatocellular and Cholangiocarcinoma
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Fig. 3A. —73-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Early phase enhanced CT scan shows tumor is
located in right lobe with diameter of 3.5 cm. Left-sided main component shows
high attenuation, and right-sided component under hepatic capsule shows low
attenuation (arrow).
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Fig. 3B. —73-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Delayed phase enhanced CT scan reveals
left-sided component shows low attenuation with mild ring enhancement, and
right-sided component shows low attenuation (arrow). These findings
are recognized as HCC pattern component and CC pattern component,
respectively.
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Fig. 3C. —73-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Photograph shows macroscopic findings.
Inner part of tumor is yellowish mass with partial necrosis and capsule,
representing HCC, and outside part is white mass without expansion
(arrow), representing CC. Enhancing patterns of two components were
consistent with histologic findings.
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Fig. 4A. —43-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Early phase enhanced CT scan shows
lobulated tumor is located in lateral segment, with diameter of 6 cm. Mass
shows slightly low attenuation.
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Fig. 4B. —43-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Delayed phase enhanced CT scan reveals mass
shows isoattenuation relative to that of noncancerous liver tissue. This mass
is recognized as CC pattern component.
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Fig. 4C. —43-year-old man with mixed type of combined hepatocellular
and cholangiocarcinomas (HCC-CCs). Photograph shows macroscopic specimen.
Tumor is mainly composed of moderately differentiated HCC with abundant
fibrous stroma. Although CC component, with diameter of 1.3 cm, exists within
mass (arrow), we could not detect CC component on enhanced CT,
probably because its enhancing pattern was similar to that of HCC component
that occupied most of mass.
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TABLE 4 Diagnostic Rate of Enhanced CT for Three Types of Combined
Hepatocellular and Cholangiocarcinoma (HCC-CC)
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Discussion
Combined HCC-CC is one of the important differential diagnoses of primary
liver tumors, although it is rarely encountered clinically. The preoperative
diagnosis of this entity on enhanced CT would contribute to the selection of
the appropriate operative methods, such as the addition of complete resection
of lymph nodes. Although a few reports have described CT findings of combined
HCC-CCs [2,
4,
5], a diagnostic rate for
combined HCC-CCs based on radiologic findings has not been reported yet, to
our knowledge. In this study, we attempted to evaluate the ability to diagnose
combined HCC-CCs on abdominal enhanced CT by detecting different components
with enhancing patterns that we defined.
The reasons for discordance of radiologic HCC or CC component to the
histologic findings were divided into two factors: the different enhancing
patterns from the categorizations defined in the study design and the small
size of each component. In two patients with the combined type, an HCC pattern
component and a CC pattern component on CT were histologically proven to be CC
and HCC, respectively. That is, the CC component in one patient showed the
high-low (HCC) pattern and was proven to be poorly differentiated
adenocarcinoma with a small amount of desmoplastic stroma.
Yoshida et al. [10] also
reported two cases of small intrahepatic CCs with marked hypervascularity,
composed of a large number of tumor cells and little interstitial fibrous
tissue. Honda et al. [9]
reported that 5% of intrahepatic peripheral CCs showed the high-low pattern.
The HCC component in the other patient showed the low-low (CC) pattern and was
proven to be well-differentiated HCC. Fujita et al.
[11] reported that 17.6% of
well-differentiated HCCs showed the low-low pattern. Furthermore, in one
patient with the mixed type, the HCC component, which occupied most of the
mass, showed the low-iso (CC) pattern. It was composed of moderately
differentiated HCC with abundant fibrous stroma. Although a discrete CC
component of 1.3 cm in diameter existed within the mass, it was not detected
on enhanced CT, probably because the enhancing pattern was similar to that of
the HCC component. The presence of these components with an
"unusual" enhancing pattern, such as CC with a small amount of
fibrous tissue, well-differentiated HCC, or HCC with rich fibrous tissue, made
it difficult to make a correct diagnosis of combined HCC-CCs.
The other reason for discordance was the small size (< 1 cm in diameter)
of each component in three and nine patients with the combined type and mixed
type, respectively. This may be attributable to the resolution of CT used in
this study, because concordance rates for the combined and mixed types
increased when only components of more than 1 cm in diameter were
evaluated.
Another factor related to the diagnosis of combined HCC-CCs is the presence
of tumors composed of intermediate cells
[12]. The development of this
kind of tumor may reflect the common embryologic derivation of hepatocytes and
biliary epithelium and also suggests that combined HCC-CC may develop from a
common stem cell. Two different components are not reasonably detected in this
type of tumor, which is constructed by single tumor cells. In our series,
three patients had the mixed type of tumors that were shown to be totally
composed of intermediate tumor cells, with one tumor showing an HCC pattern
and the other two showing a CC pattern on CT. The two intermediate cell tumors
showing a CC pattern had a large amount of interstitial fibrosis, which is
similar to CC. The third tumor, showing an HCC pattern, was composed of
malignant cells proliferating in a trabecular, solid, and tubular pattern,
some of which reacted with carbohydrate antigen 19-9 and a small amount of
fibrous tissue was seen.
To the best of our knowledge, there is no other report describing
radiologic findings of mixed type tumors composed of intermediate tumor cells.
Considering the results of the present study, we presume that the ratio of
cellular and fibrous tissue within the tumor—rather than the
characteristics of the tumor cells themselves—may contribute to the
enhancing pattern.
The main differential diagnosis of combined HCC-CCs is considered to be HCC
or CC containing various kinds of differentiation. However, it may be
difficult to differentiate them from combined HCC-CCs on only enhanced CT when
HCC or CC components without a typical enhancing pattern are possibly
contained in the tumor. Although another differential diagnosis is early
advanced HCC, combined HCC-CCs may be differentiated from it by delayed
enhancement of a low-attenuation component during the early phase because most
CCs had increased CT values on delayed phase compared with early phase
[9].
One limitation of our study is that all the CT images we evaluated were
obtained with incremental dynamic technique. Because combined HCC-CCs are rare
tumors, cases were recruited over 10 years, and CT images scanned by single-
or MDCT technology were not included among our cases. The arterioportal phase
and the portal-dominant phase are expected to be present together in the early
phase of our CT protocol because of the relatively long scanning time.
Therefore, the attenuation of each component on the early phase may not be
standardized. MDCT technology can improve this limitation and may also depict
components of less than 1 cm in diameter using its high spacial resolution.
The correct diagnostic rate of combined HCC-CCs may increase, especially in
mixed type cases, when they are scanned by MDCT technology.
The other limitation of our study is the lack of other types of hepatic
tumor used for comparison. In our study, consensus—rather than
individual interpretation of the findings—was achieved without an
evaluation of inter-observer variability. We speculate that the real correct
diagnostic rate of combined HCC-CCs may be lower than the diagnostic rate in
our study. Careful interpretation of components with different enhancing
patterns may lead to an increase in sensitivity; however, it may decrease
specificity.
In conclusion, 100%, 44.4%, and 18.8% of double cancer, combined type, and
mixed type tumors, respectively, were correctly diagnosed on the basis of the
enhancing pattern on CT. Overall, a correct diagnosis was made for 33.3% of
the combined HCC-CCs in our study group. Various factors such as an atypical
enhancing pattern, the small size of each component, and the presence of a
tumor composed of intermediate tumor cells were found to be the causes of
misdiagnosis.
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Abstract
Introduction
