Mixed Hepatocellular Cholangiocarcinoma and
Intrahepatic Cholangiocarcinoma in Patients
Undergoing Transplantation for Hepatocellular
Gonzalo Sapisochin,1,4Nicholas Fidelman,2John P. Roberts,1and Francis Y. Yao1,3
Department of1Surgery,2Radiology, and3Medicine, University of California San Francisco, San Francisco,
CA; and4Department of Hepatobiliary and Pancreatic Surgery and Transplantation, Vall d’Hebron
University Hospital, Universidad Autonoma of Barcelona, Barcelona, Spain
Mixed hepatocellular cholangiocarcinoma (HCC-CC) and intrahepatic cholangiocarcinoma (I-CC) are increasingly being
reported in patients with cirrhosis. The aims of this study were (1) to evaluate the incidence, imaging features, and posttrans-
plant outcomes for patients who underwent transplantation for hepatocellular carcinoma (HCC) and were found to have HCC-
CC or I-CC in the explant and (2) to compare the outcomes of these patients with those of controls with HCC who were
matched (1:3) by the tumor size and the number of nodules in the explant. In the explant specimens of 10 of 302 patients
(3.3%) who underwent liver transplantation (LT) for HCC, mixed HCC-CC or I-CC was identified. There were 4 additional inci-
dental cases of HCC-CC. After a median follow-up period of 32 months, 8 of the 14 patients (57%) suffered from tumor recur-
rence, and the median disease-free survival time was 8 months. The cumulative risk of tumor recurrence was 40% and 70%
at 1 and 5 years, respectively, for these 14 patients. When the 4 incidental cases were excluded, the study group with HCC-
CC or I-CC (n ¼ 10) had a significantly lower incidence of well-differentiated tumors (11.1% versus 43.3%, P < 0.02) and a
higher rate of recurrence (60% versus 16.7%, P ¼ 0.008) in comparison with the control group of patients with HCC (n ¼ 30).
The 1- and 5-year cumulative risks of tumor recurrence were 42% and 65%, respectively, in the study group and 10% and
17%, respectively, in the control group (P < 0.002). The actuarial 1- and 5-year patient survival rates without recurrence were
also significantly lower in the study group (79% and 32% in the study group and 90% and 62% in the control group, P < 0.03).
Dynamic contrast-enhanced computed tomography or magnetic resonance imaging showed progressive contrast enhance-
ment throughout the arterial and portal venous phases without washout in 8 of the 10 patients. In conclusion, HCC-CC and I-
CC are associated with a poor prognosis and a high rate of tumor recurrence after LT, and both tumors exhibit radiographic
features that are distinct from those observed with HCC. Liver Transpl 17:934-942, 2011. V
C 2011 AASLD.
Received December 23, 2010; accepted March 8, 2011.
Hepatocellular carcinoma (HCC) is the most common
primary malignancy of the liver and accounts for 20%
of all liver transplantation (LT) procedures performed
in the United States.1Mixed hepatocellular cholangio-
carcinoma (HCC-CC) is a rare tumor with histological
characteristics of both HCC and cholangiocarcinoma
(CC).2,3Poor survival after HCC-CC resection has
been reported,2,4,5but data on outcomes after LT for
Abbreviations: CC, cholangiocarcinoma; CK, cytokeratin; CT, computed tomography; HCC, hepatocellular carcinoma; HCC-CC,
hepatocellular cholangiocarcinoma; I-CC, intrahepatic cholangiocarcinoma; LT, liver transplantation; MELD, Model for End-Stage
Liver Disease; MRI, magnetic resonance imaging; PSC, primary sclerosing cholangitis; RFA, radio frequency ablation; TACE,
transarterial chemoembolization; TNM, tumor-node-metastasis; UNOS, United Network for Organ Sharing.
This study was reported in part in an oral presentation at the 61st Annual Meeting of the American Association for the Study of
Liver Diseases, Boston, MA, October 31, 2010.
Gonzalo Sapisochin was supported by a scholarship grant from the Fundacio ´n Mutua Madrilen ˜a.
Address reprint requests to Francis Y. Yao, M.D., University of California San Francisco, 513 Parnassus Avenue, Room S-357, San Francisco,
CA 94143-0538. Telephone: 415-514-0332; FAX: 415-476-0659; E-mail: email@example.com
View this article online at wileyonlinelibrary.com.
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
LIVER TRANSPLANTATION 17:934-942, 2011
C 2011 American Association for the Study of Liver Diseases.
HCC-CC are very limited.6,7CC tumors are divided
into hilar/perihilar and intrahepatic subtypes. Intra-
hepatic cholangiocarcinoma (I-CC) is rare in patients
with cirrhosis with etiologies other than primary scle-
rosing cholangitis (PSC).8Successful outcomes have
been reported after LT for select patients with hilar
CC and PSC who have been treated with a neoadju-
vant protocol,9whereas I-CC is generally considered a
contraindication to LT because of the high rate of
posttransplant tumor recurrence.10-12
HCC-CC and I-CC were classified into 3 types by
Allen and Lisa13in 1949: type A for separate nodules of
HCC and I-CC, type B for contiguous masses that may
mingle, and type C for individual masses with HCC-CC.
Another classification, which was formulated by Good-
man et al.14in 1985, includes type I for HCC and I-CC
in separate nodules in the same liver, type II for HCC-
CC, and type III for the fibrolamellar variant of HCC.
There have been reports describing the imaging fea-
tures of HCC-CC,15,16which might be difficult to differ-
entiate from HCC. Magnetic resonance imaging (MRI)
features of I-CC also have been recently described in
patientswith cirrhosis before
Because mixed HCC-CC and I-CC are relatively rare
malignancies in patients with cirrhosis in comparison
with HCC, mixed HCC-CC and I-CC may be underre-
cognized, misdiagnosed, and treated as if they were
HCC in these patients. The fact that HCC and I-CC can
coexist as separate nodules in the same liver (Goodman
type I) makes the diagnosis even more challenging.
The primary aim of the present study was to evalu-
ate the incidence, imaging features, and posttrans-
plant outcomes of HCC-CC and I-CC discovered in the
explant specimens of patients (excluding those with
PSC) who underwent transplantation for HCC.
resection or LT.17
PATIENTS AND METHODS
Between June 1999 and June 2009, 302 patients
underwent LT for HCC in the setting of cirrhosis with
etiologies other than PSC. According to a retrospective
review of the LT database, 10 of these patients (3.3%)
were found to have either HCC-CC or I-CC according to
Another 4 patients with incidental HCC-CC were identi-
fied among those patients without HCC who underwent
transplantation for other indications during the same
time period. The underlying liver disease in these 4 inci-
dental cases was hepatitis C (3 patients) or autoimmune
hepatitis (1 patient). The overall outcomes for this
cohort of 14 patients with HCC-CC or I-CC were ana-
lyzed. With a matched-control study design (1:3), the
outcomes and clinical and histological characteristics of
the 10 patients (excluding the incidental cases) were
compared with those of a control group of 30 transplant
patients with only HCC in the explant; the study
patients were matched with the control group by the
number of lesions and the size of the largest nodule (68
mm) in the explant. To minimize potential bias in the
comparative analysis of the outcomes of the patients
with HCC-CC or I-CC and the patients with a known di-
agnosis of HCC before LT, only the nonincidental cases
were included in the matched-control study. This study
was approved by the Institutional Review Board of the
University of California, San Francisco.
All pretransplant imaging studies of the 10 patients
with HCC-CC or I-CC and the 30 patients in the control
group [including dynamic contrast-enhanced computed
tomography (CT) or MRI with gadolinium contrast] were
retrospectively reviewed by a radiologist experienced in
the imaging of hepatobiliary malignancies so that he
could identify radiographic features that might be dif-
ferent between the study and control groups. The analy-
sis was focused on the contrast enhancement pattern of
each lesion. The following scoring systems were used:
(0) no enhancement, (1) mild enhancement, and (2) ro-
bust enhancement for arterial phase enhancement and
(0) no washout, (1) mild washout, and (2) robust wash-
out for venous phase washout. We also paid attention to
the lesion size, the number of lesions, capsule retrac-
tion, and the location of hyperenhancement within
lesions (peripheral or central).
For the analysis of tumor characteristics in liver
explants, the tumor size, the number of lesions, the
total tumor diameter, the pathological tumor stage
(pT1-pT4) according to the modified United Network
for Organ Sharing (UNOS) tumor-node-metastasis
the grade of differentiation
according to the Edmonson-Steiner criteria19[(1) well
differentiated, (2) moderately differentiated, and (3)
poorly differentiated], and the presence or absence of
vascular invasion were recorded. Explant tumor stag-
ing was based on the size and number of only viable
tumors as previously reported.20
The histopathological definition of HCC-CC was based
tic criteria included a hepatocellular element showing
lar growth pattern and a cholangiocellular component
showing mucin production or definitive gland formation.
When the diagnosis was difficult, differences between I-
CC and HCC were based on immunohistochemical stud-
ies thatincludedcytokeratin 19(CK19) orCK7 positivity,
as previously reported.22,23The patients were classified
Immunosuppressive Protocol and Postoperative
mycophenolate mofetil, and a steroid (tapered to 5 mg
of prednisone by posttransplant day 42). Rapamycin
was not routinely used in patients undergoing LT for
immunosuppressionconsisted of tacrolimus,
LIVER TRANSPLANTATION, Vol. 17, No. 8, 2011SAPISOCHIN ET AL. 935
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Combined hepatocellular-cholangiocarcinoma: a histo-
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942 SAPISOCHIN ET AL. LIVER TRANSPLANTATION, August 2011