GASTROENTEROLOGY 2013;145:1215–1229

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REVIEWS IN BASIC AND CLINICAL

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GASTROENTEROLOGY AND HEPATOLOGY
Robert F. Schwabe and John W. Wiley, Section Editors

Pathogenesis, Diagnosis, and Management of Cholangiocarcinoma

SUMERA RIZVI and GREGORY J. GORES
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota

Cholangiocarcinomas (CCAs) are hepatobiliary can- encasement.3 pCCA is the most common type of CCA. In a
cers with features of cholangiocyte differentiation; large series of patients with bile duct cancer, 8% had iCCA,
they can be classified anatomically as intrahepatic 50% had pCCA, and 42% had distal CCA.4 CCA has a poor
CCA (iCCA), perihilar CCA (pCCA), or distal CCA. prognosis; patients have a median survival of 24 months
These subtypes differ not only in their anatomic after diagnosis. The only curative treatment option is sur-
location, but in epidemiology, origin, etiology, path- gery, for early stage disease.5
ogenesis, and treatment. The incidence and mortality
of iCCA has been increasing over the past 3 decades,
Epidemiology
and only a low percentage of patients survive until 5
years after diagnosis. Geographic variations in the inci- Cholangiocarcinoma accounts for 3% of all gastro-
dence of CCA are related to variations in risk factors. intestinal tumors. Over the past 3 decades, the overall
Changes in oncogene and inflammatory signaling path- incidence of CCA appears to have increased.6 The percent-
ways, as well as genetic and epigenetic alterations and age of patients who survive 5 years after diagnosis has not
chromosome aberrations, have been shown to contribute increased during this time period, remaining at 10%.7,8
to the development of CCA. Furthermore, CCAs are In the United States, Hispanics and Asians have the
surrounded by a dense stroma that contains many highest incidence of CCA (2.8 per 100,000 and 3.3 per
cancer-associated fibroblasts, which promotes their 100,000, respectively), whereas African Americans have the
progression. We have gained a better understanding of lowest incidence of CCA (2.1 per 100,000). African Amer-
the imaging characteristics of iCCAs and have developed icans also have lower age-adjusted mortality rates
advanced cytologic techniques to detect pCCAs. Patients compared with whites (1.4 per 100,000 vs 1.7 per 100,000).
with iCCAs usually are treated surgically, whereas liver Men have a slightly higher incidence of CCA and mortality
transplantation after neoadjuvant chemoradiation is an from cancer than women.7 With the exception of patients
option for a subset of patients with pCCAs. We review with primary sclerosing cholangitis (PSC), a diagnosis of
recent developments in our understanding of the epide- CCA is uncommon before age 40 years.
miology and pathogenesis of CCA, along with advances
in classification, diagnosis, and treatment. Abbreviations used in this paper: a-SMA, a-smooth muscle actin;
CA19-9, carbohydrate antigen 19-9; CAF, cancer-associated fibroblast;
Keywords: Cancer-Associated Fibroblasts; Distal Chol- CCA, cholangiocarcinoma; CT, computed tomography; CXCR4, chemo-
angiocarcinoma; Intrahepatic Cholangiocarcinoma; kine (C-X-C motif) receptor 4; dCCA, distal cholangiocarcinoma; ECM,
Molecular Pathogenesis. extracellular matrix; EGFP, enhanced green fluorescent protein; EGFR,
epidermal growth factor–receptor; EMT, epithelial–mesenchymal tran-
sition; ERBB2, v-erb-b2 avian erythroblastic leukemia viral oncogene
homolog 2; ERC, endoscopic retrograde cholangiography; ERK, extra-

C holangiocarcinoma (CCA) is the most common

biliary malignancy and the second most common
hepatic malignancy after hepatocellular carcinoma (HCC).1
cellular signal regulated kinase; FGFR, fibroblast growth factor receptor;
FISH, fluorescence in situ hybridization; HGF, hepatocyte growth factor;
HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C
CCAs are epithelial tumors with features of cholangiocyte virus; iCCA, intrahepatic cholangiocarcinoma; IDH, isocitrate dehydro-
differentiation. Intrahepatic cholangiocarcinomas (iCCAs) genase; IL 6, interleukin 6; KRAS, Kirsten rat sarcoma viral oncogene
homolog; MAPK, mitogen-activated protein kinase; miR, microRNA;
are located within the hepatic parenchyma. The second- MCL1, myeloid cell leukemia sequence 1; MET, met proto-oncogene;
order bile ducts serve as the point of separation between MMP, matrix metalloproteinase; MRI, magnetic resonance imaging; OR,
iCCAs and perihilar CCAs (pCCAs) or distal CCAs odds ratio; pCCA, perihilar cholangiocarcinoma; PDGF, platelet-derived
(dCCAs)—the cystic duct is the anatomic boundary between growth factor; PI, phosphatidyl inositol; PI3K, phosphatidylinositol-4,5-
these latter 2 subtypes (Figure 1A).2 The Bismuth–Corlette bisphosphate 3-kinase; PSC, primary sclerosing cholangitis; STAT, signal
transducer and activator of transcription; TP53, tumor protein 53.
classification stratifies perihilar tumors on the basis of © 2013 by the AGA Institute
biliary involvement. This classification recently was 0016-5085/$36.00
extended to also take into account arterial and venous http://dx.doi.org/10.1053/j.gastro.2013.10.013
 1216 RIZVI AND GORES GASTROENTEROLOGY Vol. 145, No. 6

Globally, hepatobiliary malignancies account for 13% of In the West, PSC is the most common predisposing
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cancer-related deaths; 10%–20% of these are attributable to condition for CCA. Among patients with PSC, the annual
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CCA. The mean age at diagnosis of CCA is 50 years. The risk of development of CCA is 0.5%–1.5%, with a lifetime
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global incidence of iCCA varies widely, from rates of 113 prevalence of 5%–10%17; CCA is diagnosed within 2 years
per 100,000 in Thailand to 0.1 per 100,000 in Australia.9,10 of PSC in most of these patients. A number of potential
Differences in the prevalence of genetic and other risk risk factors for CCA in patients with PSC have been
factors presumably account for this extensive variation. studied, including smoking and alcohol, although defin-
Epidemiologic studies have indicated that the age-adjusted itive data are lacking.8
mortality rate for iCCA is increasing, whereas the mortality Hepatitis B virus (HBV) or hepatitis C virus (HCV) infec-
rate from pCCA and dCCA could be decreasing.9–14 A study tion and cirrhosis have been proposed as potential etiologies
of a World Health Organization database reported a sub- of iCCA.23–25 A recent meta-analysis of 11 studies found that
stantial global increase in iCCA mortality, with a decreasing cirrhosis, HBV, and HCV were major risk factors for iCCA,
trend in mortality from pCCA plus dCCA.15 Although this with odds ratios (ORs) of 22.92, 5.1, and 4.8, respectively.26 A
observed increase in the incidence of CCA over the past 30 case-control study from Korea found a significant associa-
years has been recorded as an increase in iCCA, it could result tion between HBV (OR, 2.3) and CCA, but not HCV and
from misclassification of perihilar tumors as iCCAs.16 Ac- CCA. Cirrhosis also was found to be a significant risk factor
cording to the US Surveillance, Epidemiology, and End Re- for CCA, with an OR of 13.6. HCV and cirrhosis were asso-
sults database, the age-adjusted incidence rate for iCCA ciated with iCCA in a US case-control study. Compared with
increased from 0.59 per 100,000 in 1990 to 0.91 per 100,000 controls, patients with iCCA had a higher prevalence of
in 2001. It subsequently decreased to 0.6 per 100,000 by 2007. anti-HCV antibodies, with an OR of 7.9.24
Conversely, the incidence rate for pCCA plus dCCA remained CCA development has been associated with other risk
around 0.8 per 100,000 until 2001, and then gradually factors, including inflammatory bowel disease indepen-
increased to 0.97 per 100,000 by 2007. Perihilar tumors were dent of PSC, alcohol, smoking, fatty liver disease, diabetes,
coded as iCCAs before 2001 and subsequently were coded as cholelithiasis, and choledocholithiasis.8,27–29 Additional
pCCAs after implementation of the third edition of the In- studies have associated variants of genes that regulate
ternational Classification of Disease for Oncology. This up- DNA repair, inflammation, and carcinogen metabolism
date likely influenced the aforementioned changes in with CCA development.8 Further studies are necessary to
incidence rates of both CCA subtypes. Similar trends in the verify these potential associations.
incidence of CCA subtypes were noted in the United
Kingdom after the change to the third edition of the Inter-
national Classification of Disease for Oncology in 2008.6,16 Cells of Origin
iCCA is a histologically diverse hepatobiliary ma-
lignancy considered to develop from biliary epithelial cells
Risk Factors or hepatic progenitor cells (Figure 1B). A recently pro-
There are several established risk factors for CCA, posed classification of iCCAs subdivided these tumors
and most cases are sporadic.6,8,17 Geographic variations in into the conventional, bile ductular, or intraductal
incidence rates of CCA are related in part to variations in neoplasm type, or rare variants (combined hepatocellular
risk factors. For example, in Southeast Asia, which has one CCA, undifferentiated type, squamous/adenosquamous
of the highest incidence rates of CCA, infection with the type). The conventional type includes small-duct or pe-
hepatobiliary flukes Opisthorchis viverrini and Clonorchis ripheral type and large-duct or perihilar type.30 Neural cell
sinensis has been associated with the development of CCA. adhesion molecule, a marker of hepatic progenitor cells,
Both parasites cause chronic inflammation and are has been detected in the bile ductular and combined he-
considered carcinogens.8,18 Hepatolithiasis is another risk patocellular CCA types, so these might have originated
factor for CCA (mainly iCCA) in Asian countries.8 Chronic from hepatic progenitor cells.30–32
biliary inflammation secondary to calculi has been pro- Distal and pCCA have been proposed to arise from the
posed to increase the risk of malignancy. Moreover, biliary epithelium and peribiliary glands.33 Extrahepatic
infestation with hepatobiliary flukes has been shown to be bile ducts and large intrahepatic bile ducts are lined by
more common in patients with hepatolithiasis.8,19 The mucin-producing cuboidal cholangiocytes. A recent study
incidence and prevalence of CCA in patients with bile duct showed that mucin-producing iCCAs and hilar CCAs had
(choledochal) cysts are also higher in Asian than in gene expression and immunohistochemical profiles similar
Western countries.20,21 Choledochal cystic diseases, to those of the cylindric, mucin-producing cholangiocytes
including Caroli’s disease, are rare congenital abnormal- that line hilar and intrahepatic large bile ducts.34
ities of the pancreatic and biliary ducts. Choledochal cysts A model in which iCCAs arise from transdifferentiation
can be intrahepatic or extrahepatic, and are diagnosed in and subsequent neoplastic conversion of normal hepato-
patients at an average age of 32 years old.8,17 Thorotrast, a cytes into malignant cholangiocytes has been proposed.
previously used contrast agent that is now banned, was Fan et al35 showed in mice that overexpression of Notch1
found to increase risk for CCA by 300-fold in a Japanese and AKT resulted in the development of invasive cys-
study.22 tadenocarcinomas via conversion of hepatocytes into
December 2013 CHOLANGIOCARCINOMA 1217

cytokines activate inducible nitric oxide synthase, leading

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to excess nitric oxide with resultant single-stranded, dou-

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ble-stranded, and oxidative DNA lesions, as well as inhi-

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bition of DNA repair enzymes.38 Interleukin (IL)-6, an
inflammatory mediator secreted by CCA and stromal in-
flammatory cells, can function in an autocrine or para-
crine manner to promote cell survival and provide
mitogenic signals.39,40 Myeloid cell leukemia sequence 1
(MCL1) is an anti-apoptotic BCL2 family member that
mediates tumor necrosis factor–related resistance to
apoptosis-inducing ligands in CCAs.41 IL-6 increases the
expression of MCL1 via constitutive activation of signal
transducer and activator of transcription (STAT) signaling
and protein kinase B (Akt).40,42 MCL1 transcription is
activated by IL-6 via a p38 mitogen-activated protein ki-
nase (MAPK)-dependent pathway.43 IL-6 binds to the
gp130 receptor, leading to its subsequent dimerization
and activation of the gp130-associated janus kinases,
including janus kinase 1 and janus kinase 2, which leads
to STAT3 activation.44,45 Epigenetic silencing of suppressor
of cytokine signaling 3 results in sustained IL-6 signaling via
STAT3.46 Inflammatory signaling pathways therefore
appear to promote the development of CCA by causing
DNA damage and blocking the apoptosis normally
induced by the DNA damage response. These cytokines
also promote cell proliferation. The combination of DNA
damage, evasion of apoptosis, and cell proliferation are all
components of cell transformation.
Epidermal growth factor–receptor (EGFR) signaling
also contributes to cholangiocarcinogenesis and CCA
progression. Activation of EGFR leads to activation of
extracellular-signal regulated kinases (ERKs) 1 and 2 (also
Figure 1. Anatomic localization of CCA and cells of origin in CCA. (A) known as p44/42 MAPK). EGFR inhibitors decrease
Anatomic localization of CCA. CCA is divided into 3 subtypes, based expression of cyclooxygenase-2 by CCA cells.47 V-erb-b2
on anatomic location. Modified with permission from Elsevier and
avian erythroblastic leukemia viral oncogene homolog 2
Razumilava et al.17 (B) Cells of origin in CCA.
(ERBB2) is another member of the EGFR family that
cholangiocyte precursors of iCCA.35 Sekiya and Suzuki36 contributes to CCA development. In mice, overexpression
also showed that in mice, Notch-mediated conversion of of ERBB2 led to formation of tumors along the biliary
hepatocytes into biliary cells leads to macronodular epithelium.48 Hepatocyte growth factor (hepapoietin A;
cirrhosis and iCCAs. Therefore, iCCAs may not have a scatter factor) (HGF) is a stromal paracrine mediator that
single lineage, but instead derive from different cells of regulates tumor invasiveness and metastasis.49–51 Activa-
origin. In support of this theory, a recent study showed tion of MET, the receptor for HGF, up-regulates several
that transformed hepatocytes, hepatoblasts, and hepatic signaling pathways, including those involving phosphati-
progenitor cells can give rise to a broad spectrum of liver dylinositol-4,5-bisphosphate 3-kinase (PI3K)–AKT,
tumors, ranging from CCA to HCC.37 These studies STAT3, and MAPK.52 CCAs express higher levels of MET
indicate that multiple cell types, rather than only chol- and HGF than nontumor tissues.53,54 MET overexpression
angiocytes, transform and develop into CCAs. Additional was associated with activation of members of the EGFR
animal models of CCA and lineage tracing studies are family, particularly of ERBB2.54,55
necessary to help identify the cells of origin for CCA. Cholestasis also contributes to the development of
CCA, and bile acids have important roles in this process,
activating growth factors that mediate proliferation. Bile
Inflammation acids activate EGFR and increase expression of
CCAs frequently arises under conditions of cyclooxygenase-2 via a MAPK cascade.56 In addition to bile
inflammation, which is believed to contribute to patho- acids, cyclooxygenase-2 overexpression is induced by oxy-
genesis. A variety of cytokines, growth factors, tyrosine sterols and inducible nitric oxide synthase.57 Oxysterols
kinases, and bile acids can contribute to alterations in are overlooked in the pathogenesis of CCA.58 These
proliferation, apoptosis, senescence, and cell-cycle regula- oxidative degradation products of cholesterol are abun-
tion required for cholangiocarcinogenesis.5 Inflammatory dant in bile. They are endogenous ligands for the
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hedgehog signaling pathway59—a developmental pathway compared with 17% in iCCAs.71 In a transcriptome profile
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implicated in CCA progression.60 analysis of 104 CCAs and 59 matched nontumor samples
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(controls), patients could be categorized based on overall

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survival time, early recurrence, and presence or absence of

Genetics KRAS mutations; a detailed class comparison identified 4
A few studies have assessed the roles of genetic factors, subclasses of patients. Those with CCAs with altered
such as chromosome aberrations or genetic and epigenetic expression of genes that regulate proteasome activity; with
alterations in tumor suppressor genes and oncogenes, in the dysregulation of ERBB2; and with overexpression of EGFR,
pathogenesis of human CCA. However, these studies have MET, and Ki67 had the worst outcomes.71
produced no definitive results because they analyzed a limited Inactivation of TP53, which regulates the cell cycle, is
number of genes in combined CCA specimens, without one of the most common genetic abnormalities in cancer
separate analyses of different subtypes.61 A comparative ge- cells and also has been detected during chol-
nomics hybridization analysis of 32 CCA samples from pa- angiocarcinogenesis. A review of 10 studies, comprising
tients (7 iCCA, 13 pCCA, and 12 dCCA) showed that they all 229 patients with CCA from Europe, Asia, and the United
contained gains at 16q, 17p, 17q, 19p, and 19q, which States, reported TP53 mutations in 21% of CCAs.73 Mu-
included regions encoding ERBB2, mitogen-activated pro- tations in other genes, including EGFR, neuroblastoma
tein kinase kinase 2 (MEK2), and platelet-derived growth RAS viral (v-ras) oncogene homolog (NRAS), PI3K, and
factor- beta (PDGFB).62 A meta-analysis of 5 studies that used APC, have been less frequently described.44
comparative genomics hybridization to analyze 98 iCCAs There has been growing interest in the effects of somatic
found copy number losses at 1p, 4q, 8p, 9p, 17p, and 18q, and mutations in genes encoding isocitrate dehydrogenases
gains at 1q, 5p, 7p, 8q, 17q, and 20q.61 In this meta-analysis, (IDH) 1 and 2. IDH1 and IDH2 mutations frequently have
there was considerable variation among the 4 studies that been detected in gliomas, but rarely have been observed in
were performed in Asia63–66 and the 1 study from Europe.67 other solid tumors. IDH mutations were detected in 22% of
This variation could have resulted from differences in CCA specimens—more frequently in iCCAs (28%) than
ethnicity and etiologic associations among the studies. pCCAs and dCCAs (7%).74 Recurrent mutations in IDH1
Whole-exome sequencing analyses of 8 liver fluke-related were observed in a subset of biliary tract tumor samples in a
CCAs identified 206 somatic mutations in 187 genes.68 The recent broad-based mutation profile analysis of gastroin-
frequency of these mutations was validated in an addi- testinal tumors.75 A subsequent analysis of 62 CCAs
tional 46 liver fluke-related CCAs. Mutations frequently detected IDH1 mutations in only iCCAs.75 IDH1 and IDH2
were detected in oncogenes and tumor suppressor genes mutations were associated significantly with increased
such as those encoding tumor protein 53 (TP53) (muta- levels of p53 and DNA hypermethylation.76 Epigenetic
tions in 44.4% of CCAs), Kirsten rat sarcoma viral oncogene changes associated with IDH mutations likely mediate their
homolog (KRAS) (16.7%), and SMAD family member 4 oncogenic effects. The product of the enzymatic activity of
(16.7%). Mutations also were found in myeloid/lymphoid mutant IDH1 and IDH2 is 2-hydroxyglutarate (Figure 2A).
or mixed-lineage leukemia 3 (MLL3) (14.8% of cases), ring This metabolite therefore might serve as a biomarker for
finger protein 43 (RNF43) (9.3%), paternally expressed 3 IDH1 and IDH2 mutations, and for a subset of patients who
(PEG3) (5.6%), and roundabout, axon guidance receptor, might be treated with IDH inhibitors77–79 (Figure 2B).
homolog 2 (ROBO2) (9.3%). These genes are involved in A number of epigenetic alterations, such as promoter
deactivation of histone modifiers, activation of G-proteins, hypermethylation and microRNA dysregulation, have
and loss of genomic stability.68 This study, performed in been associated with the development of CCA. However,
Asia, has been the only whole-exome sequence analysis of whole-epigenome analysis has not been conducted and
CCAs. Further whole-genome sequencing studies are microRNA (miR) profiling is possible with only small
needed to evaluate CCAs from Western patients. numbers of tumor samples.80,81 Promoter hyper-
A recent study comprising single-nucleotide poly- methylation has been reported to silence tumor suppres-
morphism array, gene expression profile, and mutation sor genes including CDKN2 (observed in 17%–83% of
analyses of 149 iCCAs identified inflammation and prolif- CCAs), suppressor of cytokine signaling 3 (in 62%46), Ras as-
eration classes of this tumor.45 Several copy number alter- sociation (RalGDS/AF-6) domain family member 1
ations were identified, including losses at 3p, 4q, 6q, 9p, 9q, (RASSF1A) (in 31%–69%), and APC (in 27%–47%).45,61
13q, 14q, 8p, 17p, and 21q, and gains at 1q and 7p.45 Fea- Gene fusions, such as the BCR-ABL gene in chronic
tures of the inflammation class included activation of in- myeloid leukemia, are driver mutations in cancer, which play
flammatory pathways, overexpression of cytokines, and a role in certain cancers.82 Fibroblast growth factor receptor
activation of STAT3. The proliferation class was character- (FGFR) fusions are active kinases. A recent study identified
ized by activation of oncogene signaling pathways involving novel FGFR2 gene fusions in CCA.82 Cells with these FGFR
RAS, MAPK, and MET. Activating mutations in KRAS have fusions were susceptible to FGFR inhibitors, signifying that
been detected frequently in CCAs.69–71 At least 2 studies FGFR kinase inhibition may be a valid therapeutic strategy
have reported a higher incidence of activating mutations in in CCA patients harboring these gene fusions.82
KRAS in pCCAs compared with iCCAs.71,72 In one cohort, miRs are noncoding RNAs that function in post-
the incidence of these mutations was 53% in pCCAs transcriptional regulation of gene expression. A cluster
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Figure 2. IDH mutations. (A)
Function of wild-type and
mutant IDH (mIDH). Wild-type
enzymes catalyze a reaction
that converts isocitrate to
a-ketoglutarate and reduces
NADP to NADPH. The mutant
enzymes acquire a neomorphic
activity that converts the normal
metabolite a-KG to 2-HG, and
consumption rather than pro-
duction of NADPH. 2-HG leads to
inhibition of certain dioxygenases,
which has been postulated to
result in cancer-promoting
events. (B) Potential of personal-
ized medicine for CCA, using
mIDH inhibitors, as an example.
a-KG, a-ketoglutarate; 2-HG,
2-hydroxyglutarate; NADPH,
nicotinamide adenine dinucleo-
tide phosphate.

of 38 miRs was expressed differentially in 27 iCCA sam- Developmental Pathways

ples, compared with nontumor tissues. miR21 is overex- The Notch signaling pathway regulates embryonic
pressed in CCAs and could have oncogenic effects, partly development and proliferation of the biliary tree.85 Not
by inhibiting programmed cell death 4 and tissue inhibi- surprisingly, therefore, Notch dysregulation also has
tor of matrix metalloproteinase (MMP)3.83 miR21 also been implicated in cholangiocarcinogenesis. Two recent
was found to regulate phosphatase and tensin homolog studies in mice have shown that Notch activation is
deleted on chromosome ten–dependent activation of PI3K required for conversion of normal adult hepatocytes to
signaling in CCAs, to affect chemosensitivity.84 miR200C biliary cells that are precursors of iCCA.35,36 Over-
prevents the epithelial–mesenchymal transition (EMT); expression of intracellular domain of the Notch 1 re-
changes in its level might be used as a prognostic factor.80 ceptor in liver cells of mice resulted in formation of
Further studies are needed to determine how alterations in iCCAs.86 In this model, an inhibitor of g-secretase, an
miRs contribute to the development of CCA, and how enzyme necessary for Notch signaling, suppressed tumor
these changes might be used to determine patients’ formation.
prognoses.
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Another evolutionary conserved, developmental insulin-like growth factor binding proteins.92 PDGF-
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pathway is the Hedgehog signaling pathway. Hedgehog mediated interactions between CAFs and tumor cells
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signaling is deregulated in many types of tumors, have been observed, such as recruitment of CAFs by
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including CCAs. Inhibition of hedgehog signaling with PDGF-D secreted by CCA cells.60,100,101 PDGF-D stimu-
cyclopamine impedes CCA cell migration, proliferation, lates CAF migration via its receptor platelet-derived
and invasion.87,88 Hedgehog signaling also has been growth factor receptor (PDGFR), which is highly
implicated in survival signaling by myofibroblast-derived expressed on CAFs, and activation of small Rho guanosine
CCAs. PDGF-b protects CCA cells and promotes tumor triphosphatases and the JNK signaling pathway.100
survival in mice with CCAs, but cyclopamine reverses these Activated CAFs also secrete paracrine factors that pro-
effects.60 mote initiation and progression of cancer. These include
Wnt signaling also is required for intrahepatic bile duct matricellular proteins, growth factors, chemokines, and
development and proliferation.89 Wnt-inducible signaling ECM proteases. Periostin is a matricellular protein that is
pathway protein 1v is overexpressed in stroma nests overexpressed by CAFs compared with normal fibroblasts;
around CCAs, and levels of Wnt-inducible signaling its presence correlates with shorter survival times of pa-
pathway protein 1v are associated with reduced survival tients. Knockdown of the periostin receptor, the a5 sub-
times of patients. Wnt-inducible signaling pathway pro- unit of integrin, with small interfering RNA, reduced
tein 1v stimulated the invasive activity of CCA cell lines by stimulation of tumor proliferation and invasion by peri-
activating MAPK1 and MAPK3.90 ostin.102 The ECM that surrounds pancreatic tumors also
has been shown to overexpress periostin, which promotes
tumor invasiveness.103 Tenascin-C, another ECM protein
Tumor Microenvironment produced by CAFs, also promotes tumor migration and
Carcinogenesis in CCA includes alterations in the invasiveness.92 In CCA cell lines, HGF promoted inva-
stroma, recruitment of fibroblasts, remodeling of the siveness and motility by inducing phosphorylation of Akt
extracellular matrix (ECM), changing patterns of immune and ERK 1/2.104 Similarly, stromal cell–derived factor-1,
cell migration, and promotion of angiogenesis through activation of its receptor chemokine (C-X-C
(Figure 3A).91 iCCAs and pCCAs are characterized by a motif) receptor 4 (CXCR4), induced CCA cell invasion via
dense and reactive desmoplastic stroma (Figure 3B) that ERK 1/2 and Akt.105,106 This process was disrupted by the
contains many a-smooth muscle actin (a-SMA)–positive CXCR4 inhibitor AMD3100.106
myofibroblasts, also known as cancer-associated fibro- ECM degradation and remodeling is required for tumor
blasts (CAFs). The tumor stroma surrounds the malignant progression. MMPs degrade and remodel the ECM during
ducts and glands and comprises most of the tumor fibrogenesis and carcinogenesis. MMP1, MMP2, MMP3,
mass.92,93 The stroma promotes tumor progression via and MMP9 are strongly expressed in CCAs and are asso-
reciprocal communication between the stromal cells and ciated with invasive tumors.107,108 Fibroblast activation
cancer cells.92 protein is a stromal protein; its high expression by CAFs
The precise origin of CAFs is unclear, although several has been associated with tumors with an aggressive
cell types, including hepatic stellate cells, portal fibro- phenotype.109
blasts, and bone marrow–derived precursor cells, have The exact mechanisms by which tumor and stroma
been proposed as candidates.92,94–96 The EMT also has communicate are not clear. However, the importance of
been proposed to produce CAFs.93 During tumorigen- the desmoplastic stroma in CCA progression indicates
esis, the EMT is characterized by the presence of tumor that it could be a new therapeutic target, perhaps via se-
cells that express mesenchymal markers such as vimen- lective targeting of CAFs.110
tin, tenascin, fibronectin, and the zinc finger protein
Snail.92 Immunohistochemical studies have shown the
expression of these markers by human CCA cell Animal Models
lines.97–99 In mice, xenograft tumors grown from Animal models are essential for the development of
enhanced green fluorescent protein (EGFP)-expressing new therapeutic strategies and diagnostic tools.111 Animal
human CCA cells were found to be surrounded and models of CCA (Table 1) include mice with xenograft
infiltrated by a-SMA–expressing CAFs. Interestingly, tumors,43,112–119 mice with genetic changes that lead to
EGFP was not co-expressed with a-SMA, indicating that CCA formation,86,120–124 rats with orthotopic tu-
the EMT does not produce CAFs in CCAs.100 Based on mors,125,126 and animals that develop CCAs after exposure
combined evidence, a-SMA–expressing CAFs appear to to carcinogens.55,127–129 Although these models offer an
be a heterogeneous population of cells that originate opportunity to bridge the chasm between in vitro findings
from several cell lineages, but not from epithelial cancer and clinical applicability, they have limitations. The tumor
cells. microenvironment is an important feature in CCA devel-
CAFs produce factors that stimulate ECM production, opment. It sometimes can be a challenge to study in-
leading to a fibrogenic response (Figure 3C).92 Factors teractions between cancer cells and the stroma in mice
produced by CAFs include transforming growth factor-b, with xenograft tumors because the tumor is not growing
PDGF isomers, connective tissue growth factor, and in the same microenvironment as it does in human beings.
December 2013 CHOLANGIOCARCINOMA 1221

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Figure 3. Microenvironment of cholangiocarc-

inoma. (A) Components of the tumor microenvi-
ronment in CCA. (B) Micrograph of a stromal
CCA. (C) Factors secreted by cancer-associated
fibroblasts. CTGF, connective tissue growth fac-
tor; SDF-1, stromal cell–derived factor 1; TGF-b,
transforming growth factor-b.
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Table 1. Animal Models of Cholangiocarcinoma

1222 RIZVI AND GORES

Experimental approach Key features Study
Mice with xenograft tumors
Injection of 3  106 Mz-ChA-1 cells Tumor development in 3 weeks Fava et al112
Injection of 5  106 Sk-ChA-1 cells  intratumoral tamoxifen injections Significantly decreased CCA development with intratumoral Pawar et al113
tamoxifen injections
Injection of 2  106 QBC939 cells  magnetic nanoparticle injections via tail vein CCA tumor growth inhibition with magnetic nanoparticles Tang et al114
Injection of IL-6 overexpressed Mz-ChA-1 stable cell line (Mz-ChA-IL6) vs Overexpression of IL-6 increased growth of xenograft tumors Meng et al43
control vector Mz-ChA-1 cell line
Injection of miR26a overexpressed CCLP1 cell line vs scramble control Overexpression of miR26a increased growth of xenograft tumors Zhang et al115
CCLP1 cell line
Injection of miR494 overexpressed stable HuCCT1 cell line vs control vector Overexpression of miR494 increased growth of xenograft tumors Olaru et al116
HuCCT1 cell line
Injection of stable QBC939 cell line transfected with Slug siRNA vs control Slug silencing suppressed growth of xenograft tumors Zhang et al117
vector QBC939 cell line
Injection of CypA silenced stable M139 cell line vs control vector M139 cell line CypA silencing decreased growth of xenograft tumors Obchoei et al118
Injection of stable QBC939 cell line transfected with Beclin-1 siRNA vs Beclin-1 silencing decreased growth of xenograft tumors Hou et al119
control vector QBC939 cell line
Genetically engineered mouse models
Liver-specific inactivation of SMAD4 and PTEN Tumor formation in all animals at 4–7 months of age Xu et al120
Chronic carbon tetrachloride exposure in TP53-deficient mice Development of tumors with dense peritumoral fibrosis and other histologic Farazi et al121
and genetic features of human iCCA
Liver-specific inactivation of macrophage stimulating factor 1 and 2 Tumor development (HCC or CCA) in all mice by 6 months of age Song et al122
Liver-specific ablation of WW45, a homolog of Drosophila Salvador and Development of tumors with mixed histologic features of HCC and CCA Lee et al123
adaptor for the Hippo kinase
Liver-specific activation of KRAS and deletion of TP53 Development of stroma-rich tumors; shortened time to tumor development O’Dell et al124
and increased metastasis with the combination of KRAS activation and TP53 deletion
Overexpression of intracellular domain of Notch1 in livers of transgenic mice Formation of tumors with features characteristic of iCCA Zender et al86
Orthotopic rat models
Inoculation of BDEneu cells into bile duct of isogenic rats Rapid (21–26 days) development of cholangiocarcinoma characterized by biliary Sirica et al125
obstruction and gross peritoneal metastasis; origin of tumor stroma and
tumor tissue from same species (rat)
Three-dimensional organotypic culture model of CCA in rats Stromal microenvironment, gene expression profile, and pathophysiologic Campbell et al126
characteristics that mimic desmoplastic iCCA in vivo
Carcinogen-induced models
Furan-induced cholangiocarcinogenesis in rat liver Formation of mucin-producing CCA tumors; overexpression of C-NEU and MET Radaeva et al55
Fava et al127

GASTROENTEROLOGY Vol. 145, No. 6

Chronic administration of thioacetamide in lean rats and rats with Increased development and growth of CCA tumors in
faulty leptin receptors lean rats treated with thioacetamide
Administration of DEN  LMBDL to induce chronic cholestasis Increased CCA progression in mice with LMBDL given DEN compared with Yang et al128
and CCA development mice without LMBDL given DEN
Inoculation with O viverrini and administration of Development of pus and tumor in liver starting at 20 weeks after O viverrini Plengsuriyakarn
dimethylnitrosamine in hamsters infection/DEN administration; all hamsters in experimental group et al129
were dead by 28 weeks
BDEneu, highly malignant cholangiocarcinoma cell line; CCLP1, cholangiocarcinoma cell line; C-NEU, rat homologue of human ERBB2; CypA, cyclophilin A; DEN, diethylnitrosamine; HuCCT1, cholangiocarcinoma
cell line; KRAS, Kirsten rat sarcoma viral oncogene homolog; LMBDL, left and median bile duct ligation; M139, cholangiocarcinoma cell line; Mz-ChA-1, cholangiocarcinoma cell line; PTEN, phosphatase and
tensin homolog deleted on chromosome ten; QBC939, human hilar bile duct carcinoma cell line; Sk-ChA-1, cholangiocarcinoma cell line; siRNA, small interfering RNA; SMAD4, SMAD family member 4.
December 2013 CHOLANGIOCARCINOMA 1223

A model described by Sirica et al,125 in which rat CCA candidates. After surgical resection, the median time of

PERSPECTIVES
cells were injected into rat biliary trees, is unique in disease-free survival is 26 months; reported rates of recur-

REVIEWS
that the stroma and epithelial cells were derived from the rence are 60%–65%.136,137 Approximately 60% of patients

AND
same species. These animals allow for investigations of survive for 5 years after resection. Factors associated with
tumor–stroma interactions that more closely resemble recurrence and reduced survival time after resection include
those of patients. Although transgenic models do allow vascular invasion, lymph node metastasis, multiple tumors,
for study of the tumor microenvironment, they tend to be and cirrhosis.4,138 Nuclear expression of S100A4, a member
technically challenging and expensive. Animals with ge- of the S100 family of calcium-binding proteins, in
netic alterations that lead to production of CCAs that neoplastic ducts was associated with metastasis and
resemble human tumors are needed. reduced time of survival after surgical resection in a subset
of patients with CCA.139
Liver transplantation as a curative option for iCCA is
Diagnosis and Management highly controversial. iCCA was reported to recur in 70% of
It can be a challenge to diagnose CCA because of patients within 5 years of liver transplantation, and the
its paucicellular nature, anatomic location, and silent median disease-free survival time was 8 months in a series
clinical character. Diagnosis requires a high index of sus- of 14 patients with iCCA or mixed HCC-iCCA.135 Patients
picion and a multidisciplinary approach that involves with very small iCCAs (<2 cm) in the context of cirrhosis,
clinical, laboratory, endoscopic, and radiographic analyses. however, do as well as patients undergoing liver trans-
plantation for HCC. Locoregional therapy, including
iCCA transarterial chemoembolization and radiofrequency
iCCA is divided into mass-forming, periductal ablation, has garnered interest as a therapeutic option for
infiltrating, and intraductal growth types.130 The clinical patients with unresectable iCCA.140 The standard practice
manifestations of iCCA include nonspecific symptoms of care for advanced-stage iCCA is systemic chemotherapy
such as abdominal pain, cachexia, malaise, fatigue, and with gemcitabine and cisplatin.141
night sweats.2 iCCA frequently presents as an intrahepatic
mass lesion; imaging modalities including computed to- pCCA
mography (CT) and magnetic resonance imaging (MRI) pCCAs can have exophytic or intraductal macro-
aid in the diagnosis. The use of contrast enhancement scopic growth patterns. The exophytic or mass-forming
improves the sensitivity of MRI for detection of iCCA type can be of the nodular subtype or the periductal sub-
because these tumors typically have progressive uptake of type (the most common subtype).142 There are also sub-
contrast during the venous phase. HCCs, on the other types of intraductal patterns, including the intraductal
hand, are characterized by rapid contrast uptake during growing type, mucin-producing type, papilloma type, and
the arterial phase, followed by a delayed venous washout cystic type.17 Patients with pCCA can present with
phase.131 CT and MRI have similar utility in the evalua- nonspecific symptoms including abdominal discomfort,
tion of tumor size and detection of satellite lesions. cachexia, weight loss, and malaise. However, their presen-
However, CT may be better for assessment of vascular tation typically is consistent with biliary obstruction pre-
encasement, identification of extrahepatic metastasis, and senting with jaundice, and less commonly cholangitis.17
determination of resectability.17,132 Hypertrophy–atrophy complex, a phenomenon character-
Serum levels of carbohydrate antigen 19-9 (CA19-9), a ized by hypertrophy of the unaffected liver lobe and atro-
tumor biomarker, can aid in diagnosis, but this assay phy of the affected lobe, presents as unilobar palpable
detects iCCA with only 62% sensitivity and 63% speci- prominence on physical examination.2 Laboratory analyses,
ficity.133 Moreover, increased levels of CA19-9 also have including measurements of alkaline phosphatase and bili-
been observed in patients with benign diseases such as rubin levels, do not provide specific information because
bacterial cholangitis or choledocholithiasis.5 Nonetheless, they typically reflect concomitant cholestasis and chol-
very high levels of CA19-9 (1000 U/mL) have been angitis. For the same reason, serum levels of CA19-9 are less
associated with metastatic iCCA, so this assay might be specific in detecting pCCA than iCCA. IgG4 disease can
used in disease staging rather than diagnosis.134 Mixed present in a similar manner, so its presence should be
tumors are characterized by histologic and imaging fea- excluded by evaluation for serum levels of IgG4.2
tures of HCC and iCCA. In these cases, immunohisto- In addition to MRI and CT, magnetic resonance chol-
chemical analysis for cytokeratins 7 and 19 can be angiopancreatography, endoscopic retrograde cholangi-
useful—tumors positive for cytokeratins can be considered ography (ERC), and endoscopic ultrasound are used in the
to be mixed hepatocellular CCA.17,135 A definitive diag- diagnosis of pCCA (Figure 4). Of these, MRI plus mag-
nosis of iCCA requires liver biopsy analysis. According to netic resonance cholangiopancreatography is the preferred
the World Health Organization classification criteria, imaging modality because it can assess resectability and
iCCAs can be adenocarcinomas or mucinous carcinomas.2 tumor extent with an accuracy of up to 95%.2 Endoscopic
The treatment of choice for iCCA is surgical resection. ultrasound aids in evaluation for the presence of regional
Patients should undergo surgery only if they have lymphadenopathy and omental metastasis via fine-needle
potentially resectable tumors and are appropriate surgical aspiration. However, fine-needle aspiration should not
 1224 RIZVI AND GORES GASTROENTEROLOGY Vol. 145, No. 6
PERSPECTIVES

REVIEWS
AND

Figure 4. Diagnostic modalities

used for cholangiocarcinoma.
(A) MRI of a pCCA mass (out-
lined in circle). (B) CT image of a
pCCA mass with right portal
vein encasement (black arrow).
(C) Magnetic resonance chol-
angiopancreatography image of
common hepatic duct involve-
ment by tumor (white arrow). (D)
ERC image showing excluded
segmental ducts (white arrows)
in a patient with a hilar biliary
stricture extending into the right
main hepatic duct.

be performed on the primary tumor because it can account vascular encasement and parenchymal value of
disseminate the tumor.143 ERC serves a diagnostic and the potential remnant lobe.3 Surgical resection entails
therapeutic purpose—it is used to assess and sample the lobar hepatic and bile duct resection, regional lymphade-
biliary tree via brush cytology and endoscopic biopsy, as nectomy, and Roux-en-Y hepaticojejunostomy. Potential
well as dilatation and stent placement in cases of biliary contraindications to curative surgical resection include
obstruction. contralateral or bilateral vascular encasement and pCCA
Fluorescence in situ hybridization (FISH) analysis in- extension bilaterally to the level of the secondary biliary
creases the sensitivity of cytology in diagnosing pCCA.144 branches. The presence of regional lymphadenopathy does
FISH can detect polysomy or amplification of at least 2
chromosomes: tetrasomy and trisomy 7. Of these, polys-
omy in the presence of a dominant stricture is considered
sufficient for the diagnosis of pCCA, especially if the
polysomy can be confirmed over time.145 Tetrasomy can
be seen during the M phase of mitosis and should be
interpreted with caution.5 Trisomy 7 often is observed
with inflammation of the biliary tree. Detection of polys-
omy by FISH also has been shown to predict the devel-
opment of malignancies in patients with PSC with no
mass and equivocal cytology. In a recent study, patients
with PSC who had polysomy and levels of CA19-9 greater
than 129 U/mL all went on to develop cancer, mainly
within 2 years (Figure 5).146
The only curative options for pCCA are surgical resec-
tion and neoadjuvant chemoradiation followed by liver
transplantation. The Bismuth–Corlette staging classifica-
tion is based on the anatomic location of the CCA within Figure 5. Time to diagnosis of a cholangiocarcinoma based on FISH
the biliary tree and is meant to help guide decision mak- analysis and CA19-9 levels. Reprinted with permission from Wiley
ing. Recently, this classification was expanded to take into InterScience and Barr et al.146
December 2013 CHOLANGIOCARCINOMA 1225

Table 2. Criteria for Liver Transplantation in pCCA Diagnosis is made on the basis of the presence of a

PERSPECTIVES
Diagnosis of cholangiocarcinoma dominant stricture and positive cytology and/or detection

REVIEWS
of polysomy by FISH.2 Surgical treatment of dCCA typi-

AND
Positive transluminal biopsy
Positive biliary brush cytology cally entails a Whipple procedure. Only 27% of patients
Malignant-appearing stricture on ERC with a CA 19-9 level > 100 U/mL survive for 5 years after surgical resection that attains
and/or FISH polysomy
negative margins.4 The role of neoadjuvant chemo-
Mass lesion on cross-sectional imaging and malignant-appearing
stricture on ERC/MRCP radiation is limited. For patients who are not candidates
Tumor size for surgical resection, chemotherapy may be considered.17
Radial tumor diameter of 3 cm
Tumor confined to biliary tree
Absence of intrahepatic or extrahepatic metastasis Future Directions
Unresectability Treatment options for CCA are limited and overall
Unresectable hilar tumor (above the cystic duct)
survival rates are low. Earlier detection of CCA increases
CCA in a PSC patient (owing to skip lesions, the field defect, and
parenchymal liver disease) the chance of having curative treatment options. However,
despite recent advances in diagnosis, such as improved
MRCP, magnetic resonance cholangiopancreatography.
imaging and cytology techniques, including FISH, further
work is necessary to overcome the challenge of diagnosing
not necessarily preclude surgery.147 Occasionally, a tumor CCA at an earlier stage. CCA often still is diagnosed based
may be resectable but the remnant lobe has limited vol- on clinical criteria, such as a malignant-appearing bile
ume. In such cases, resectability can be achieved by pre- duct stricture, increased serum levels of CA19-9, appear-
operative relief of biliary obstruction and portal vein ance of a mass during MRI, normal serum levels of IgG4
embolization of the affected lobe with resultant compen- level, and so forth.
satory hyperplasia of the contralateral unaffected liver There are significant geographic and ethnic variations
lobe.147 Rates of 5-year survival after surgical resection in the incidence of CCA, so genetic factors are likely to
with negative margins range from 11% to 41%.147 contribute to its pathogenesis. Inflammatory and onco-
With the advent of new liver transplantation protocols, genic signaling pathways also are involved in chol-
neoadjuvant chemoradiation followed by transplantation angiocarcinogenesis, and are potential therapeutic targets.
has become an appealing option for patients selected care- Further studies are necessary to elucidate the role of ge-
fully using stringent criteria (Table 2). Sixty-five percent of netic aberrations, particularly in regions encoding key
patients who were treated with neoadjuvant therapy followed components of signaling pathways. In addition, the role of
by liver transplantation at 12 large-volume transplant centers miRs as biomarkers remains to be fully elucidated. CCAs
survived for 5 years.148 Rigorous selection is imperative for are heterogeneous; treatments are likely to be designed
successful outcomes. Eligibility criteria include radial diam- based on features of each individual tumor.150 Potential
eter of tumor of less than 3 cm, absence of intrahepatic or therapeutic targets could include the MET tyrosine re-
extrahepatic metastasis, and, in the case of patients without ceptor kinase, FGFR2, the PI3K–Akt–mTOR pathway, and
PSC, unresectability.149 Because of the presence of paren- IDH mutations. Molecular profiling of tumors, to identify
chymal liver disease, patients with PSC typically require liver their specific mutations, could make it possible to offer
transplantation rather than surgical resection. targeted therapies in personalized treatments (Figure 2B).
For patients who are not candidates for surgical resection Although cancer cells contain many genetic and functional
or liver transplantation, systemic chemotherapy with gem- aberrations, the tumor stroma appears to be more uniform
citabine and cisplatin is recommended. For patients with and has strong potential as a target for new combination
biliary obstruction, adequate drainage is essential to relieve therapies. Further work is needed to highlight the dynamic
cholestasis and increase tolerance to chemotherapy.17 reciprocal communication between tumor and stroma.

dCCA References
Intraductal papillary neoplasm and biliary intra- 1. Welzel TM, McGlynn KA, Hsing AW, et al. Impact of classification of
epithelial neoplasia are the precursor lesions of dCCA.30 hilar cholangiocarcinomas (Klatskin tumors) on the incidence of
dCCA arises from the point of insertion of the cystic intra- and extrahepatic cholangiocarcinoma in the United States.
duct to the ampulla of Vater and therefore can be difficult J Natl Cancer Inst 2006;98:873–875.
to distinguish from early pancreatic cancer.17 Analogous 2. Blechacz B, Komuta M, Roskams T, et al. Clinical diagnosis and
staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol
to pCCA, patients typically present with painless jaundice, 2011;8:512–522.
and laboratory analysis is consistent with biliary obstruc- 3. Deoliveira ML, Schulick RD, Nimura Y, et al. New staging system
tion. Although pCCA and dCCA are distinct with respect and a registry for perihilar cholangiocarcinoma. Hepatology 2011;
to their pathogenesis and treatment, most studies evalu- 53:1363–1371.
ating diagnostic modalities have grouped these as extra- 4. DeOliveira ML, Cunningham SC, Cameron JL, et al. Chol-
angiocarcinoma: thirty-one-year experience with 564 patients at a
hepatic CCAs. Cross-sectional imaging, endoscopic single institution. Ann Surg 2007;245:755–762.
ultrasound, and ERC therefore are used in the same 5. Blechacz BG, Gores, GJ. Tumors of the bile ducts, gallbladder, and
manner in the diagnosis of dCCA as with pCCA. ampulla. In: Feldman, ed. Sleisenger and Fordtran’s
 1226 RIZVI AND GORES GASTROENTEROLOGY Vol. 145, No. 6

gastrointestinal and liver disease. Volume 1. 9th ed. Philadelphia: 30. Nakanuma Y, Sato Y, Harada K, et al. Pathological classification of
PERSPECTIVES

Saunders, 2010:1171–1176. intrahepatic cholangiocarcinoma based on a new concept. World J

REVIEWS

6. Khan SA, Davidson BR, Goldin RD, et al. Guidelines for the diag- Hepatol 2010;2:419–427.
AND

nosis and treatment of cholangiocarcinoma: an update. Gut 2012; 31. Komuta M, Spee B, Vander Borght S, et al. Clinicopathological
61:1657–1669. study on cholangiolocellular carcinoma suggesting hepatic pro-
7. Everhart JE, Ruhl CE. Burden of digestive diseases in the United genitor cell origin. Hepatology 2008;47:1544–1556.
States part III: liver, biliary tract, and pancreas. Gastroenterology 32. Tsuchiya A, Kamimura H, Tamura Y, et al. Hepatocellular carcinoma
2009;136:1134–1144. with progenitor cell features distinguishable by the hepatic stem/
8. Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hep- progenitor cell marker NCAM. Cancer Lett 2011;309:95–103.
atology 2011;54:173–184. 33. Cardinale V, Carpino G, Reid L, et al. Multiple cells of origin in
9. Shaib Y, El-Serag HB. The epidemiology of cholangiocarcinoma. cholangiocarcinoma underlie biological, epidemiological and clin-
Semin Liver Dis 2004;24:115–125. ical heterogeneity. World J Gastrointest Oncol 2012;4:94–102.
10. Sripa B, Pairojkul C. Cholangiocarcinoma: lessons from Thailand. 34. Komuta M, Govaere O, Vandecaveye V, et al. Histological diversity in
Curr Opin Gastroenterol 2008;24:349–356. cholangiocellular carcinoma reflects the different cholangiocyte
11. Khan SA, Taylor-Robinson SD, Toledano MB, Beck A, Elliott P, phenotypes. Hepatology 2012;55:1876–1888.
Thomas HC. Changing international trends in mortality rates for 35. Fan B, Malato Y, Calvisi DF, et al. Cholangiocarcinomas can originate
liver, biliary and pancreatic tumours. J Hepatol 2002;37:806–813. from hepatocytes in mice. J Clin Invest 2012;122:2911–2915.
12. Khan SA, Toledano MB, Taylor-Robinson SD. Epidemiology, risk 36. Sekiya S, Suzuki A. Intrahepatic cholangiocarcinoma can arise from
factors, and pathogenesis of cholangiocarcinoma. HPB (Oxford) Notch-mediated conversion of hepatocytes. J Clin Invest 2012;
2008;10:77–82. 122:3914–3918.
13. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the 37. Holczbauer A, Factor VM, Andersen JB, et al. Modeling pathogen-
incidence of hepatocellular carcinoma and intrahepatic chol- esis of primary liver cancer in lineage-specific mouse cell types.
angiocarcinoma in the United States. Cancer Epidemiol Biomarkers Gastroenterology 2013;145:221–231.
Prev 2006;15:1198–1203. 38. Jaiswal M, LaRusso NF, Burgart LJ, et al. Inflammatory cytokines
14. Patel T. Increasing incidence and mortality of primary intrahepatic induce DNA damage and inhibit DNA repair in cholangiocarcinoma
cholangiocarcinoma in the United States. Hepatology 2001; cells by a nitric oxide-dependent mechanism. Cancer Res 2000;
33:1353–1357. 60:184–190.
15. Patel T. Worldwide trends in mortality from biliary tract malig- 39. Park J, Tadlock L, Gores GJ, et al. Inhibition of interleukin
nancies. BMC Cancer 2002;2:10. 6-mediated mitogen-activated protein kinase activation attenuates
16. Khan SA, Emadossadaty S, Ladep NG, et al. Rising trends in growth of a cholangiocarcinoma cell line. Hepatology 1999;
cholangiocarcinoma: is the ICD classification system misleading 30:1128–1133.
us? J Hepatol 2012;56:848–854. 40. Kobayashi S, Werneburg NW, Bronk SF, et al. Interleukin-6 con-
17. Razumilava N, Gores GJ. Classification, diagnosis, and manage- tributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-
ment of cholangiocarcinoma. Clin Gastroenterol Hepatol 2013; signaling pathway in cholangiocarcinoma cells. Gastroenterology
11:13–21 e1; quiz e3–e4. 2005;128:2054–2065.
18. Shin HR, Oh JK, Lim MK, et al. Descriptive epidemiology of chol- 41. Taniai M, Grambihler A, Higuchi H, et al. Mcl-1 mediates tumor ne-
angiocarcinoma and clonorchiasis in Korea. J Korean Med Sci crosis factor-related apoptosis-inducing ligand resistance in human
2010;25:1011–1016. cholangiocarcinoma cells. Cancer Res 2004;64:3517–3524.
19. Huang MH, Chen CH, Yen CM, et al. Relation of hepatolithiasis to 42. Isomoto H, Kobayashi S, Werneburg NW, et al. Interleukin 6 upre-
helminthic infestation. J Gastroenterol Hepatol 2005;20:141–146. gulates myeloid cell leukemia-1 expression through a STAT3
20. Edil BH, Cameron JL, Reddy S, et al. Choledochal cyst disease in pathway in cholangiocarcinoma cells. Hepatology 2005;
children and adults: a 30-year single-institution experience. J Am 42:1329–1338.
Coll Surg 2008;206:1000–1005; discussion 1005–1008. 43. Meng F, Yamagiwa Y, Ueno Y, et al. Over-expression of interleukin-6
21. Mabrut JY, Bozio G, Hubert C, et al. Management of congenital bile enhances cell survival and transformed cell growth in human ma-
duct cysts. Dig Surg 2010;27:12–18. lignant cholangiocytes. J Hepatol 2006;44:1055–1065.
22. Kato I, Kido C. Increased risk of death in thorotrast-exposed patients 44. Sia D, Tovar V, Moeini A, et al. Intrahepatic cholangiocarcinoma:
during the late follow-up period. Jpn J Cancer Res 1987;78:1187–1192. pathogenesis and rationale for molecular therapies. Oncogene
23. Lee TY, Lee SS, Jung SW, et al. Hepatitis B virus infection and 2013;32:4861–4870.
intrahepatic cholangiocarcinoma in Korea: a case-control study. Am 45. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis
J Gastroenterol 2008;103:1716–1720. of intrahepatic cholangiocarcinoma reveals 2 classes that have
24. Shaib YH, El-Serag HB, Nooka AK, et al. Risk factors for intrahepatic different outcomes. Gastroenterology 2013;144:829–840.
and extrahepatic cholangiocarcinoma: a hospital-based case-control 46. Isomoto H, Mott JL, Kobayashi S, et al. Sustained IL-6/STAT-3
study. Am J Gastroenterol 2007;102:1016–1021. signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic
25. Sorensen HT, Friis S, Olsen JH, et al. Risk of liver and other types of silencing. Gastroenterology 2007;132:384–396.
cancer in patients with cirrhosis: a nationwide cohort study in 47. Yoon JH, Gwak GY, Lee HS, et al. Enhanced epidermal growth factor
Denmark. Hepatology 1998;28:921–925. receptor activation in human cholangiocarcinoma cells. J Hepatol
26. Palmer WC, Patel T. Are common factors involved in the patho- 2004;41:808–814.
genesis of primary liver cancers? A meta-analysis of risk factors for 48. Kiguchi K, Carbajal S, Chan K, et al. Constitutive expression of
intrahepatic cholangiocarcinoma. J Hepatol 2012;57:69–76. ErbB-2 in gallbladder epithelium results in development of
27. Shaib YH, El-Serag HB, Davila JA, et al. Risk factors of intrahepatic adenocarcinoma. Cancer Res 2001;61:6971–6976.
cholangiocarcinoma in the United States: a case-control study. 49. Matsumoto K, Nakamura T. Hepatocyte growth factor and the Met
Gastroenterology 2005;128:620–626. system as a mediator of tumor-stromal interactions. Int J Cancer
28. Welzel TM, Graubard BI, El-Serag HB, et al. Risk factors for intra- 2006;119:477–483.
hepatic and extrahepatic cholangiocarcinoma in the United States: 50. Nishimura K, Kitamura M, Miura H, et al. Prostate stromal cell-
a population-based case-control study. Clin Gastroenterol Hepatol derived hepatocyte growth factor induces invasion of prostate
2007;5:1221–1228. cancer cell line DU145 through tumor-stromal interaction. Prostate
29. Welzel TM, Mellemkjaer L, Gloria G, et al. Risk factors for intra- 1999;41:145–153.
hepatic cholangiocarcinoma in a low-risk population: a nationwide 51. Nakamura T, Matsumoto K, Kiritoshi A, et al. Induction of hepato-
case-control study. Int J Cancer 2007;120:638–641. cyte growth factor in fibroblasts by tumor-derived factors affects
December 2013 CHOLANGIOCARCINOMA 1227

invasive growth of tumor cells: in vitro analysis of tumor-stromal 73. Khan SA, Thomas HC, Toledano MB, et al. p53 Mutations in human

PERSPECTIVES
interactions. Cancer Res 1997;57:3305–3313. cholangiocarcinoma: a review. Liver Int 2005;25:704–716.

REVIEWS
52. Comoglio PM, Giordano S, Trusolino L. Drug development of MET 74. Kipp BR, Voss JS, Kerr SE, et al. Isocitrate dehydrogenase 1 and 2

AND
inhibitors: targeting oncogene addiction and expedience. Nat Rev mutations in cholangiocarcinoma. Hum Pathol 2012;43:1552–1558.
Drug Discov 2008;7:504–516. 75. Borger DR, Tanabe KK, Fan KC, et al. Frequent mutation of iso-
53. Lai GH, Radaeva S, Nakamura T, et al. Unique epithelial cell pro- citrate dehydrogenase (IDH)1 and IDH2 in cholangiocarcinoma
duction of hepatocyte growth factor/scatter factor by putative identified through broad-based tumor genotyping. Oncologist 2012;
precancerous intestinal metaplasias and associated “intestinal- 17:72–79.
type” biliary cancer chemically induced in rat liver. Hepatology 76. Wang P, Dong Q, Zhang C, et al. Mutations in isocitrate dehydroge-
2000;31:1257–1265. nase 1 and 2 occur frequently in intrahepatic cholangiocarcinomas
54. Miyamoto M, Ojima H, Iwasaki M, et al. Prognostic significance of and share hypermethylation targets with glioblastomas. Oncogene
overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J 2013;32:3091–3100.
Cancer 2011;105:131–138. 77. Reitman ZJ, Parsons DW, Yan H. IDH1 and IDH2: not your typical
55. Radaeva S, Ferreira-Gonzalez A, Sirica AE. Overexpression of C-NEU oncogenes. Cancer Cell 2010;17:215–216.
and C-MET during rat liver cholangiocarcinogenesis: a link between 78. Rohle D, Popovici-Muller J, Palaskas N, et al. An inhibitor of mutant
biliary intestinal metaplasia and mucin-producing cholangiocarcinoma. IDH1 delays growth and promotes differentiation of glioma cells.
Hepatology 1999;29:1453–1462. Science 2013;340:626–630.
56. Yoon JH, Higuchi H, Werneburg NW, et al. Bile acids induce 79. Wang F, Travins J, DeLaBarre B, et al. Targeted inhibition of mutant
cyclooxygenase-2 expression via the epidermal growth factor IDH2 in leukemia cells induces cellular differentiation. Science
receptor in a human cholangiocarcinoma cell line. Gastroenter- 2013;340:622–626.
ology 2002;122:985–993. 80. Oishi N, Kumar MR, Roessler S, et al. Transcriptomic profiling re-
57. Yoon JH, Canbay AE, Werneburg NW, et al. Oxysterols induce veals hepatic stem-like gene signatures and interplay of miR-200c
cyclooxygenase-2 expression in cholangiocytes: implications for and epithelial-mesenchymal transition in intrahepatic chol-
biliary tract carcinogenesis. Hepatology 2004;39:732–738. angiocarcinoma. Hepatology 2012;56:1792–1803.
58. Kuver R. Mechanisms of oxysterol-induced disease: insights from 81. Chen L, Yan HX, Yang W, et al. The role of microRNA expression
the biliary system. Clin Lipidol 2012;7:537–548. pattern in human intrahepatic cholangiocarcinoma. J Hepatol
59. Nachtergaele S, Mydock LK, Krishnan K, et al. Oxysterols are 2009;50:358–369.
allosteric activators of the oncoprotein Smoothened. Nat Chem Biol 82. Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of targetable
2012;8:211–220. FGFR gene fusions in diverse cancers. Cancer Discov 2013;3:636–647.
60. Fingas CD, Bronk SF, Werneburg NW, et al. Myofibroblast-derived 83. Yamanaka S, Olaru AV, An F, et al. MicroRNA-21 inhibits Serpini1, a
PDGF-BB promotes Hedgehog survival signaling in chol- gene with novel tumour suppressive effects in gastric cancer. Dig
angiocarcinoma cells. Hepatology 2011;54:2076–2088. Liver Dis 2012;44:589–596.
61. Andersen JB, Thorgeirsson SS. Genetic profiling of intrahepatic 84. Meng F, Henson R, Lang M, et al. Involvement of human micro-RNA
cholangiocarcinoma. Curr Opin Gastroenterol 2012;28:266–272. in growth and response to chemotherapy in human chol-
62. McKay SC, Unger K, Pericleous S, et al. Array comparative genomic angiocarcinoma cell lines. Gastroenterology 2006;130:2113–2129.
hybridization identifies novel potential therapeutic targets in chol- 85. Hofmann JJ, Zovein AC, Koh H, et al. Jagged1 in the portal vein
angiocarcinoma. HPB (Oxford) 2011;13:309–319. mesenchyme regulates intrahepatic bile duct development: in-
63. Koo SH, Ihm CH, Kwon KC, et al. Genetic alterations in hepato- sights into Alagille syndrome. Development 2010;137:4061–4072.
cellular carcinoma and intrahepatic cholangiocarcinoma. Cancer 86. Zender S, Nickeleit I, Wuestefeld T, et al. A critical role for notch
Genet Cytogenet 2001;130:22–28. signaling in the formation of cholangiocellular carcinomas. Cancer
64. Uhm KO, Park YN, Lee JY, et al. Chromosomal imbalances in Cell 2013;23:784–795.
Korean intrahepatic cholangiocarcinoma by comparative genomic 87. Jinawath A, Akiyama Y, Sripa B, et al. Dual blockade of the
hybridization. Cancer Genet Cytogenet 2005;157:37–41. Hedgehog and ERK1/2 pathways coordinately decreases prolifer-
65. Lee JY, Park YN, Uhm KO, et al. Genetic alterations in intrahepatic ation and survival of cholangiocarcinoma cells. J Cancer Res Clin
cholangiocarcinoma as revealed by degenerate oligonucleotide Oncol 2007;133:271–278.
primed PCR-comparative genomic hybridization. J Korean Med Sci 88. El Khatib M, Kalnytska A, Palagani V, et al. Inhibition of hedgehog
2004;19:682–687. signaling attenuates carcinogenesis in vitro and increases ne-
66. Wong N, Li L, Tsang K, et al. Frequent loss of chromosome 3p and crosis of cholangiocellular carcinoma. Hepatology 2013;
hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 57:1035–1045.
2002;37:633–639. 89. Sirica AE, Nathanson MH, Gores GJ, et al. Pathobiology of biliary
67. Homayounfar K, Gunawan B, Cameron S, et al. Pattern of chro- epithelia and cholangiocarcinoma: proceedings of the Henry M.
mosomal aberrations in primary liver cancers identified by and Lillian Stratton Basic Research Single-Topic Conference. Hep-
comparative genomic hybridization. Hum Pathol 2009; atology 2008;48:2040–2046.
40:834–842. 90. Tanaka S, Sugimachi K, Kameyama T, et al. Human WISP1v, a
68. Ong CK, Subimerb C, Pairojkul C, et al. Exome sequencing of liver fluke- member of the CCN family, is associated with invasive chol-
associated cholangiocarcinoma. Nat Genet 2012;44:690–693. angiocarcinoma. Hepatology 2003;37:1122–1129.
69. Xu RF, Sun JP, Zhang SR, et al. KRAS and PIK3CA but not BRAF 91. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment
genes are frequently mutated in Chinese cholangiocarcinoma pa- heterogeneity on therapeutic response. Nature 2013;501:346–354.
tients. Biomed Pharmacother 2011;65:22–26. 92. Sirica AE. The role of cancer-associated myofibroblasts in intra-
70. Ohashi K, Nakajima Y, Kanehiro H, et al. Ki-ras mutations and p53 hepatic cholangiocarcinoma. Nat Rev Gastroenterol Hepatol 2012;
protein expressions in intrahepatic cholangiocarcinomas: relation to 9:44–54.
gross tumor morphology. Gastroenterology 1995;109:1612–1617. 93. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer 2006;
71. Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic 6:392–401.
characterization of cholangiocarcinoma identifies therapeutic tar- 94. Dranoff JA, Wells RG. Portal fibroblasts: underappreciated media-
gets for tyrosine kinase inhibitors. Gastroenterology 2012; tors of biliary fibrosis. Hepatology 2010;51:1438–1444.
142:1021–1031 e15. 95. Okabe H, Beppu T, Hayashi H, et al. Hepatic stellate cells may relate
72. Tada M, Omata M, Ohto M. High incidence of ras gene mutation in to progression of intrahepatic cholangiocarcinoma. Ann Surg Oncol
intrahepatic cholangiocarcinoma. Cancer 1992;69:1115–1118. 2009;16:2555–2564.
 1228 RIZVI AND GORES GASTROENTEROLOGY Vol. 145, No. 6

96. Quante M, Tu SP, Tomita H, et al. Bone marrow-derived myofibro- targets involved in the G1/S checkpoint. Hepatology 2011;
PERSPECTIVES

blasts contribute to the mesenchymal stem cell niche and promote 54:2089–2098.
REVIEWS

tumor growth. Cancer Cell 2011;19:257–272. 117. Zhang K, Chen D, Wang X, et al. RNA interference targeting slug
AND

97. Li T, Li D, Cheng L, et al. Epithelial-mesenchymal transition induced increases cholangiocarcinoma cell sensitivity to cisplatin via upre-
by hepatitis C virus core protein in cholangiocarcinoma. Ann Surg gulating PUMA. Int J Mol Sci 2011;12:385–400.
Oncol 2010;17:1937–1944. 118. Obchoei S, Weakley SM, Wongkham S, et al. Cyclophilin A en-
98. Sato Y, Harada K, Itatsu K, et al. Epithelial-mesenchymal transition hances cell proliferation and tumor growth of liver fluke-associated
induced by transforming growth factor-{beta}1/Snail activation ag- cholangiocarcinoma. Mol Cancer 2011;10:102.
gravates invasive growth of cholangiocarcinoma. Am J Pathol 2010; 119. Hou YJ, Dong LW, Tan YX, et al. Inhibition of active autophagy in-
177:141–152. duces apoptosis and increases chemosensitivity in chol-
99. Korita PV, Wakai T, Ajioka Y, et al. Aberrant expression of vimentin angiocarcinoma. Lab Invest 2011;91:1146–1157.
correlates with dedifferentiation and poor prognosis in patients 120. Xu X, Kobayashi S, Qiao W, et al. Induction of intrahepatic chol-
with intrahepatic cholangiocarcinoma. Anticancer Res 2010; angiocellular carcinoma by liver-specific disruption of Smad4 and
30:2279–2285. Pten in mice. J Clin Invest 2006;116:1843–1852.
100. Cadamuro M, Nardo G, Indraccolo S, et al. Platelet-derived growth 121. Farazi PA, Zeisberg M, Glickman J, et al. Chronic bile duct injury
factor-D and Rho GTPases regulate recruitment of cancer- associated with fibrotic matrix microenvironment provokes chol-
associated fibroblasts in cholangiocarcinoma. Hepatology 2013; angiocarcinoma in p53-deficient mice. Cancer Res 2006;
58:1042–1053. 66:6622–6627.
101. Fingas CD, Mertens JC, Razumilava N, et al. Targeting PDGFR-beta 122. Song H, Mak KK, Topol L, et al. Mammalian Mst1 and Mst2 ki-
in cholangiocarcinoma. Liver Int 2012;32:400–409. nases play essential roles in organ size control and tumor sup-
102. Utispan K, Thuwajit P, Abiko Y, et al. Gene expression profiling of pression. Proc Natl Acad Sci U S A 2010;107:1431–1436.
cholangiocarcinoma-derived fibroblast reveals alterations related to 123. Lee KP, Lee JH, Kim TS, et al. The Hippo-Salvador pathway restrains
tumor progression and indicates periostin as a poor prognostic hepatic oval cell proliferation, liver size, and liver tumorigenesis.
marker. Mol Cancer 2010;9:13. Proc Natl Acad Sci U S A 2010;107:8248–8253.
103. Baril P, Gangeswaran R, Mahon PC, et al. Periostin promotes 124. O’Dell MR, Huang JL, Whitney-Miller CL, et al. Kras(G12D) and p53
invasiveness and resistance of pancreatic cancer cells to hypoxia- mutation cause primary intrahepatic cholangiocarcinoma. Cancer
induced cell death: role of the beta4 integrin and the PI3k pathway. Res 2012;72:1557–1567.
Oncogene 2007;26:2082–2094. 125. Sirica AE, Zhang Z, Lai GH, et al. A novel “patient-like” model of
104. Menakongka A, Suthiphongchai T. Involvement of PI3K and ERK1/2
cholangiocarcinoma progression based on bile duct inoculation of
pathways in hepatocyte growth factor-induced cholangiocarcinoma tumorigenic rat cholangiocyte cell lines. Hepatology 2008;
cell invasion. World J Gastroenterol 2010;16:713–722. 47:1178–1190.
105. Ohira S, Sasaki M, Harada K, et al. Possible regulation of migration of
126. Campbell DJ, Dumur CI, Lamour NF, et al. Novel organotypic culture
intrahepatic cholangiocarcinoma cells by interaction of CXCR4
model of cholangiocarcinoma progression. Hepatol Res 2012;
expressed in carcinoma cells with tumor necrosis factor-alpha and
42:1119–1130.
stromal-derived factor-1 released in stroma. Am J Pathol 2006;
168:1155–1168. 127. Fava G, Alpini G, Rychlicki C, et al. Leptin enhances chol-
106. Leelawat K, Leelawat S, Narong S, et al. Roles of the MEK1/2 and angiocarcinoma cell growth. Cancer Res 2008;68:6752–6761.
AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell 128. Yang H, Li TW, Peng J, et al. A mouse model of cholestasis-
invasion. World J Gastroenterol 2007;13:1561–1568. associated cholangiocarcinoma and transcription factors involved
107. Terada T, Okada Y, Nakanuma Y. Expression of immunoreactive in progression. Gastroenterology 2011;141:378–388, 388 e1–e4.
matrix metalloproteinases and tissue inhibitors of matrix metal- 129. Plengsuriyakarn T, Eursitthichai V, Labbunruang N, et al.
loproteinases in human normal livers and primary liver tumors. Ultrasonography as a tool for monitoring the development and
Hepatology 1996;23:1341–1344. progression of cholangiocarcinoma in Opisthorchis viverrini/
108. Prakobwong S, Yongvanit P, Hiraku Y, et al. Involvement of MMP-9 in dimethylnitrosamine-induced hamsters. Asian Pac J Cancer Prev
peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent 2012;13:87–90.
DNA damage in a hamster model. Int J Cancer 2010;127:2576–2587. 130. Yamasaki S. Intrahepatic cholangiocarcinoma: macroscopic type
109. Cohen SJ, Alpaugh RK, Palazzo I, et al. Fibroblast activation protein and stage classification. J Hepatobiliary Pancreat Surg 2003;
and its relationship to clinical outcome in pancreatic adenocarci- 10:288–291.
noma. Pancreas 2008;37:154–158. 131. Rimola J, Forner A, Reig M, et al. Cholangiocarcinoma in cirrhosis:
110. Mertens JC, Fingas CD, Christensen JD, et al. Therapeutic effects of absence of contrast washout in delayed phases by magnetic
deleting cancer-associated fibroblasts in cholangiocarcinoma. resonance imaging avoids misdiagnosis of hepatocellular carci-
Cancer Res 2013;73:897–907. noma. Hepatology 2009;50:791–798.
111. Ko KS, Peng J, Yang H. Animal models of cholangiocarcinoma. Curr 132. Vilgrain V. Staging cholangiocarcinoma by imaging studies. HPB
Opin Gastroenterol 2013;29:312–318. (Oxford) 2008;10:106–109.
112. Fava G, Marucci L, Glaser S, et al. gamma-Aminobutyric acid in- 133. Blechacz B, Gores GJ. Cholangiocarcinoma: advances in patho-
hibits cholangiocarcinoma growth by cyclic AMP-dependent regu- genesis, diagnosis, and treatment. Hepatology 2008;
lation of the protein kinase A/extracellular signal-regulated kinase 48:308–321.
1/2 pathway. Cancer Res 2005;65:11437–11446. 134. Patel AH, Harnois DM, Klee GG, et al. The utility of CA 19-9 in the
113. Pawar P, Ma L, Byon CH, et al. Molecular mechanisms of tamoxifen diagnoses of cholangiocarcinoma in patients without primary
therapy for cholangiocarcinoma: role of calmodulin. Clin Cancer sclerosing cholangitis. Am J Gastroenterol 2000;95:204–207.
Res 2009;15:1288–1296. 135. Sapisochin G, Fidelman N, Roberts JP, et al. Mixed hepatocellular
114. Tang T, Zheng JW, Chen B, et al. Effects of targeting magnetic drug cholangiocarcinoma and intrahepatic cholangiocarcinoma in pa-
nanoparticles on human cholangiocarcinoma xenografts in nude tients undergoing transplantation for hepatocellular carcinoma.
mice. Hepatobiliary Pancreat Dis Int 2007;6:303–307. Liver Transpl 2011;17:934–942.
115. Zhang J, Han C, Wu T. MicroRNA-26a promotes chol- 136. Endo I, Gonen M, Yopp AC, et al. Intrahepatic cholangiocarcinoma:
angiocarcinoma growth by activating beta-catenin. Gastroenter- rising frequency, improved survival, and determinants of outcome
ology 2012;143:246–256 e8. after resection. Ann Surg 2008;248:84–96.
116. Olaru AV, Ghiaur G, Yamanaka S, et al. MicroRNA down-regulated in 137. Choi SB, Kim KS, Choi JY, et al. The prognosis and survival outcome
human cholangiocarcinoma control cell cycle through multiple of intrahepatic cholangiocarcinoma following surgical resection:
December 2013 CHOLANGIOCARCINOMA 1229

association of lymph node metastasis and lymph node dissection 148. Darwish Murad S, Kim WR, Harnois DM, et al. Efficacy of neo-

PERSPECTIVES
with survival. Ann Surg Oncol 2009;16:3048–3056. adjuvant chemoradiation, followed by liver transplantation, for

REVIEWS
138. Li YY, Li H, Lv P, et al. Prognostic value of cirrhosis for intrahepatic perihilar cholangiocarcinoma at 12 US centers. Gastroenterology

AND
cholangiocarcinoma after surgical treatment. J Gastrointest Surg 2012;143:88–98 e3; quiz e14.
2011;15:608–613. 149. Hong JC, Jones CM, Duffy JP, et al. Comparative analysis of
139. Fabris L, Cadamuro M, Moserle L, et al. Nuclear expression of resection and liver transplantation for intrahepatic and hilar chol-
S100A4 calcium-binding protein increases cholangiocarcinoma angiocarcinoma: a 24-year experience in a single center. Arch Surg
invasiveness and metastasization. Hepatology 2011;54:890–899. 2011;146:683–689.
140. Kuhlmann JB, Blum HE. Locoregional therapy for chol- 150. Geynisman DM, Catenacci DV. Toward personalized treatment
angiocarcinoma. Curr Opin Gastroenterol 2013;29:324–328. of advanced biliary tract cancers. Discov Med 2012;14:
141. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine 41–57.
versus gemcitabine for biliary tract cancer. N Engl J Med 2010;
362:1273–1281.
142. Yamashita Y, Takahashi M, Kanazawa S, et al. Hilar chol-
angiocarcinoma. An evaluation of subtypes with CT and angiog-
Received August 8, 2013. Accepted October 10, 2013.
raphy. Acta Radiol 1992;33:351–355.
143. Heimbach JK, Sanchez W, Rosen CB, et al. Trans-peritoneal fine Reprint requests
needle aspiration biopsy of hilar cholangiocarcinoma is associated Address requests for reprints to: Gregory J. Gores, MD, Professor of
with disease dissemination. HPB (Oxford) 2011;13:356–360. Medicine and Physiology, Mayo Clinic, 200 First Street SW,
144. Moreno Luna LE, Kipp B, et al. Advanced cytologic techniques for Rochester, Minnesota 55905. e-mail: [email protected];
the detection of malignant pancreatobiliary strictures. Gastroen- fax: (507) 284-0762.
terology 2006;131:1064–1072.
145. Barr Fritcher EG, Kipp BR, Voss JS, et al. Primary sclerosing chol- Acknowledgments
angitis patients with serial polysomy fluorescence in situ hybridi- The authors would like to thank Dr Thomas Smyrk for kindly
zation results are at increased risk of cholangiocarcinoma. Am J providing the stromal cholangiocarcinoma photomicrograph and Ms
Gastroenterol 2011;106:2023–2028. Courtney Hoover for outstanding secretarial support.
146. Barr Fritcher EG, Voss JS, Jenkins SM, et al. Primary sclerosing Conflicts of interest
cholangitis with equivocal cytology: fluorescence in situ hybridiza- The authors disclose no conflicts.
tion and serum CA 19–9 predict risk of malignancy. Cancer Cyto-
pathol 2013. Epub ahead of print. Funding
147. Nagorney DM, Kendrick ML. Hepatic resection in the treatment of This work was supported by National Institutes of Health grants
hilar cholangiocarcinoma. Adv Surg 2006;40:159–171. DK59427 (G.J.G.) and T32 DK007198 (S.R.), and the Mayo Foundation.