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Clin Liver Dis 12 (2008) 131–150
Cholangiocarcinoma
Boris R.A. Blechacz, MD, PhD,
Gregory J. Gores, MD*
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center
for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW,
Rochester, MN 55905, USA
Cholangiocarcinoma is a neoplasm originating from the intra- or extrahepatic bile duct epithelium [1]. Historically, it was ﬁrst described by
Durand-Fardel in 1840 [2]. It was not until 1911 that primary liver neoplasias were distinguished based on their cellular origin into ‘‘hepatomas’’ and
‘‘cholangiomas’’ or ‘‘hepatocellular carcinomas’’ and ‘‘cholangiocarcinomas’’ [3,4]. Hilar cholangiocarcinoma as a speciﬁc entity was ﬁrst described
by Klatskin in 1965, and cholangiocarcinomas arising at this anatomic site
are often referred to as Klatskin tumors [5]. Cholangiocarcinomas may be
considered rare tumors comprising only 3% of gastrointestinal tumors;
however, they are the second most common primary hepatic tumors, and
their incidence is increasing. Surgical resection or liver transplantation is
the only potentially curative therapeutic option. Photodynamic therapy
can be palliative for unresectable but localized cancer. In the future, targeted
therapies have the potential to extend life for patients with advanced metastatic disease.
Classiﬁcation
Cholangiocarcinomas are classiﬁed according to their anatomic location
as intrahepatic and extrahepatic (Fig. 1A). The extrahepatic type including
cancers involving the conﬂuence of the right and left hepatic ducts accounts
for 80% to 90% and the intrahepatic type for 5% to 10% of all cholangiocarcinomas. The anatomic margins for distinguishing intra- and extrahepatic cholangiocarcinomas are the second order bile ducts. Extrahepatic
cholangiocarcinomas can further be subdivided according to the Bismuth
classiﬁcation into types I to IV (type I, tumor involves the common hepatic
* Corresponding author.
E-mail address: [email protected] (G.J. Gores).
1089-3261/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cld.2007.11.003
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Fig. 1. Anatomic classiﬁcation of cholangiocarcinoma. (A) The anatomic classiﬁcation of cholangiocarcinoma in intrahepatic, hilar, and distal ductal cholangiocarcinoma is depicted. Extrahepatic cholangiocarcinoma includes hilar and distal ductal cancers. (B) The Bismuth
classiﬁcation of hilar cholangiocarcinoma into type I to IV stages is illustrated. Yellow areas
represent tumor and green areas normal bile duct. (Modiﬁed from de Groen PC, Gores GJ,
LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341:1369; with permission.
Copyright Ó 1999, Massachusetts Medical Society.)
duct distal to the biliary conﬂuence; type II, tumor involves the biliary conﬂuence; type IIIa, tumor involves the biliary conﬂuence plus the right
hepatic duct; type IIIb, tumor involves the biliary conﬂuence plus the left
hepatic duct; type IV, multifocal or tumor involves the conﬂuence and
both the right and left hepatic ducts) (Fig. 1B). Further subclassiﬁcation
of extra- and intrahepatic cholangiocarcinomas has been deﬁned based on
their macroscopic appearance. Extrahepatic cholangiocarcinomas display
a sclerosing, nodular, and papillary phenotype of which the sclerosing or
periductal inﬁltrating type is the most common. It is characterized by annular bile duct thickening due to inﬁltration and ﬁbrosis of periductal tissues.
Intrahepatic cholangiocarcinomas are subclassiﬁed into mass forming, periductal inﬁltrating, mass forming plus periductal inﬁltrating, and intraductal;
this classiﬁcation has been shown to correlate with prognosis [6]. Histologically, adenocarcinoma is the most common pathologic form, comprising
90% of cases. Other histologic types include papillary adenocarcinoma,
intestinal type adenocarcinoma, clear cell adenocarcinoma, signet-ring cell
carcinoma, adenosquamous carcinoma, squamous cell carcinoma, and oat
cell carcinoma [7].
Epidemiology
Cholangiocarcinoma accounts for less than 2% of all human malignancies [8]; however, it is the second most common primary hepatic malignancy
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after hepatocellular carcinoma, accounting for 10% to 15% of primary
hepatic malignancies. Its prevalence is geographically heterogeneous, with
the highest rates in Asia, especially Southeast Asia [9]. In Western Europe
and the Unites States, the incidence and mortality have increased over the
last 4 decades.
Incidence
In the United States, the age-adjusted incidence of intrahepatic cholangiocarcinoma has increased by 165% from 0.32/100,000 in 1975 to 1979
to 0.85/100,000 in 1995 to 1999; between 1985 and 1993, the incidence
rate increased dramatically [10,11]. An increasing incidence has also been
observed in other regions around the globe. Estimated incidence rates in
Crete, Greece, have increased from 0.998/100,000 in 1992 to 1994 to
3.327/100,000 in 1998 to 2000 [12]. In Japan, the frequency of intrahepatic
cholangiocarcinoma diagnosed at autopsy increased from 0.31% to 0.58%
between 1976 to 1977 and 1996 to 1997 [13]. Although it was reported
that the incidence rates for extrahepatic cholangiocarcinoma decreased by
14% from 1.08/100,000 to 0.82/100,000 in 1998 [9], these numbers are not
accurate because the majority of the epidemiologic studies misclassiﬁed hilar
cholangiocarcinoma as intrahepatic cholangiocarcinoma. This systematic
mistake was due to a misclassiﬁcation of these tumors in the ICD-O coding
system derived data form for the Surveillance, Epidemiology, and End
Results program. Welzel and colleagues [14] addressed this issue and reevaluated incidence rates of intra- and extrahepatic cholangiocarcinoma after
correction of this misclassiﬁcation. They reported that 91% of hilar tumors
were misclassiﬁed as intrahepatic, resulting in an overestimation of intrahepatic cholangiocarcinoma by 13% and an underestimation of extrahepatic
cholangiocarcinoma by 15%. Nevertheless, reevaluation of incidence rates
in the United States between 1978 and 2000 still identiﬁed a signiﬁcant
increase of intrahepatic cholangiocarcinomas, while no signiﬁcant change
in the incidence of extrahepatic cholangiocarcinomas was noted. The cause
of the global increase in the incidence rates for intrahepatic cholangiocarcinomas is unclear. The etiopathogenesis for most patients with cholangiocarcinoma remains obscure.
Gender, age, and other factors
Worldwide, the average age at presentation is 50 years. In Western
nations, most instances of cholangiocarcinomas are diagnosed at 65 years
of age or older and only rarely before the age of 40 years [9]. In the general
population, 52% to 54% of cholangiocarcinomas are observed in male
patients; however, mortality data show a higher estimated annual percentage change (EAPC) in females when compared with males, with an EAPC
of 6.9 1.5 for males and 5.1 1.0 for females [15]. Diﬀerences in the
prevalence of cholangiocarcinoma have been reported globally as well as
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between diﬀerent racial and ethnic groups [16]. Globally, the highest prevalence has been described in Southeast Asia. Within the United States,
a comparison of the 10-year prevalence between 1990 and 2000 showed
a high age-adjusted prevalence of 1.22/100,000 for intrahepatic cholangiocarcinomas in Hispanics. Interestingly, within this group, the prevalence
was higher in females. The lowest prevalence was described in African
Americans, with a prevalence of 0.5/100,000 for males and 0.17/100,000
for females. Asian Paciﬁc Islanders and Caucasians had prevalence rates
ranging between these two groups.
Etiology
In most patients, cholangiocarcinoma has developed without an identiﬁable etiology; however, certain risk factors for cholangiocarcinoma have
been established. One of the most commonly recognized risk factors is
primary sclerosing cholangitis. The prevalence of cholangiocarcinoma in
patients who have primary sclerosing cholangitis is 5% to 15% [17]. The
annual incidence rate for cholangiocarcinoma in the setting of primary sclerosing cholangitis is 0.6% to 1.5% [17,18]. In most patients, cholangiocarcinomas are diagnosed within the ﬁrst 2.5 years after the diagnosis of primary
sclerosing cholangitis, and prospective studies have reported that 37% of
patients developing cholangiocarcinoma will do so within the ﬁrst year
following the diagnosis of primary sclerosing cholangitis [17,18]. Hepatobiliary ﬂukes are another risk factor for cholangiocarcinomas. A strong association has been shown with the species Opisthorchis viverrini and Clonorchis
sinensis and the development of cholangiocarcinoma [19]. Especially in East
Asia, one of the regions with the highest prevalence of cholangiocarcinoma,
these ﬂukes are endemic. They are ingested with undercooked ﬁsh and infest
the bile ducts and occasionally the gallbladder. Increased incidence rates of
cholangiocarcinomas in liver ﬂuke–infected patients have been shown in several case-control studies, and the correlation has been conﬁrmed in animal
models [20–22]. Another risk factor for cholangiocarcinoma that is more
common in Asian than Western countries is hepatolithiasis. Cholangiocarcinoma incidence rates of 10% in patients who have hepatolithiasis have
been reported [23–25]. Additional risk factors for cholangiocarcinoma
include Caroli’s syndrome, congenital hepatic ﬁbrosis, and choledochal
cysts, all of which carry a 10% to 15% risk for cholangiocarcinoma [26–28].
Pathophysiology
The previously described etiologic factors create an environment of
chronic inﬂammation predisposing biliary epithelium to malignant transformation. Chronic inﬂammation and cholestasis have been linked to carcinogenesis in cholangiocarcinoma. Together, both conditions can promote the
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four major cancer phenotypes: (1) autonomous cell proliferation; (2) invasion/metastases; (3) escape from senescence; and (4) evasion of cell death
[29,30]. A variety of molecular alterations have been described in these
carcinogenic phenotypes [29–32]. Chronic inﬂammation results in the
expression of multiple cytokines and chemokines by cholangiocytes and
inﬂammatory cells [29,33]. One of the key cytokines in cholangiocarcinoma
carcinogenesis is interleukin-6 (IL-6) [29,34–36]. It mediates cholangiocarcinoma cell survival by up-regulation of the potent anti-apoptotic protein
Mcl-1 [37–39]. Cellular Mcl-1 protein levels are further enhanced by bile
acid–induced epidermal-derived growth factor receptor activation [40,41].
IL-6 mediates escape from senescence by the induction of telomerase [42].
Further damage is mediated by cytokine induction of inducible nitric oxide
synthase (iNOS) in inﬂammatory cells and epithelial bile duct cells.
Increased iNOS expression has been observed in cholangiocytes in primary
sclerosing cholangitis and cholangiocarcinoma, and elevated serum nitrate
concentrations have been identiﬁed in patients with liver ﬂuke infection
[43]. Increased expression of iNOS results in increased generation of nitric
oxide which inhibits DNA repair proteins and apoptosis by nitrosylation
of base excision repair enzymes (eg, OGG1) and caspase-9, respectively
[43,44]. Several additional molecular alterations have been reported, resulting in the activation of growth factors and proto-oncogenes as well as
inhibition of tumor suppressor genes [29,45]. In addition, alterations in
genes coding for adhesion molecules and anti-angiogenic factors have
been described, mediating tumor invasion and spread [29,45].
Diagnosis
The diagnosis and staging of cholangiocarcinoma require a multimodality
approach involving laboratory, radiologic, endoscopic, and pathologic analysis. Despite the variety of techniques used, determining the extent of disease still poses a challenge and is often underestimated. The diagnostic
modalities described in the following sections, in combination and in the
appropriate clinical context, are useful to help achieve diagnostic accuracy.
Clinical, endoscopic, and radiologic diagnosis
Extrahepatic and intrahepatic cholangiocarcinomas present with distinct
clinical signs that translate into their clinical and radiologic presentation.
Clinical presentation
Most cholangiocarcinomas remain clinically silent until the advanced
stages. Once patients become symptomatic, the clinical presentation is dominated by the anatomic location of the tumor. The predominant clinical feature of extrahepatic cholangiocarcinoma is biliary obstruction resulting in
painless jaundice, with which 90% of patients initially present [7,46].
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Intrahepatic cholangiocarcinoma presents in most cases as an intrahepatic
mass causing right upper abdominal quadrant pain and other tumor-related
symptoms such as cachexia and malaise. Approximately 10% of patients
present with cholangitis [7].
Ultrasonography
Ultrasound is one of the ﬁrst-line imaging modalities chosen for the evaluation of cholestasis or liver dysfunction. For the identiﬁcation of cholangiocarcinoma, it has only limited value [46]. Findings include unspeciﬁc
signs such as intrahepatic bile duct dilatation with an abrupt change in
bile duct caliber in cases of extrahepatic and hilar cholangiocarcinoma.
Extrahepatic cholangiocarcinoma tumor masses are seldom identiﬁed by
ultrasound [47,48]. Intrahepatic cholangiocarcinomas are identiﬁed as a nonspeciﬁc intrahepatic mass. Doppler ultrasonography can be helpful for
detecting compression and tumor encasement of the portal vein or hepatic
artery. Overall, the sensitivity and speciﬁcity of ultrasound is poor in the
diagnosis of cholangiocarcinoma, and staging generally relies on other
imaging modalities [49,50].
Computed tomography
CT can be helpful in the staging, preoperative planning, and evaluation
of vascular encasement. Intrahepatic cholangiocarcinoma can present as
an irregular shaped mass with delayed and peripheral enhancement during
the portovenous phase of the study. Hilar and extrahepatic cholangiocarcinomas may present as a mass, ductal thickening, or nonunion of the right
and left hepatic duct with or without ductal thickening. As is true for ultrasound, hilar tumor masses are diﬃcult to visualize by CT. Intrahepatic bile
duct dilatation in a single small lobe and hypertrophy of the contralateral
lobe signify the atrophy-hypertrophy complex seen with lobar duct obstruction frequently plus ipsilateral portal vein encasement [51]. Evaluation of
intraductal spread and detection of lymph node and peritoneal metastases
by CT are also suboptimal. The sensitivity for N2 metastases detection by
CT has been reported to be 50% and the overall accuracy in the assessment
of resectability 60% to 75%.
Magnetic resonance imaging and magnetic resonance
cholangiopancreatography
At present, MRI with magnetic resonance cholangiopancreatography
(MRCP) is the best available imaging modality for cholangiocarcinoma
[46]. It provides information regarding tumor extent, biliary and hepatic
parenchymal anatomy, and intrahepatic metastases. Cholangiocarcinoma
is characterized on MRI as a hypointense structure on T1-weighted images
and a hyperintense structure on T2-weighted images (Fig. 2). Central
hypointensity on T2-weighted MRI corresponds to central ﬁbrosis. In dynamic contrast-enhanced MRI, cholangiocarcinoma is usually recognized
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Fig. 2. MRI study of hilar cholangiocarcinoma. Gadolinium-enhanced MRI analysis of the
liver with ferumoxide in a patient with hilar cholangiocarcinoma Bismuth type III-IV. (A)
T2-weighted MRI images. There is a hyperattenuating mass at the conﬂuence of the right
and left biliary ducts and dilatation of the right and left intrahepatic bile duct system (white
arrow). (B) MRCP of the same patient demonstrating a dominant stricture in the area of the
biliary conﬂuence and dilatation of the intrahepatic left and right biliary system (white arrow).
by delayed moderate peripheral enhancement. Involved bile ducts are identiﬁed by irregular ductal narrowing with proximal dilatation [52]. The imaging quality of cholangiocarcinoma can be enhanced signiﬁcantly by the use
of ferumoxide, a routine adjunct for MRI at the authors’ center [53,54].
Cholangiography
Cholangiography is one of the most important tests in the evaluation of
cholangiocarcinoma [46,55]. It allows early diagnosis and can help evaluate
the proximal and distal intraductal extent of the tumor. Cholangiography
can be done by performing endoscopic retrograde cholangiopancreatography (ERCP), MRCP, or transcutaneous cholangiography (PTC). MRCP
has the advantage of being noninvasive and the possibility of obtaining
additional information about other intra- and extrahepatic anatomic structures, whereas ERCP and PTC have the advantage of allowing bile duct
sampling for diagnostic analysis as well as the possibility of relieving biliary
obstruction by the insertion of stents. The choice of the imaging modality
depends also on location of the tumor; distal extrahepatic cholangiocarcinoma is optimally evaluated by ERCP. At times, hilar cholangiocarcinomas
can only be stented by the percutaneous route.
Endosonography with ﬁne-needle aspiration
Endosonography allows further evaluation of regional lymph nodes and
the biliary tree, thereby obtaining further information for staging. In addition, it allows ultrasound-guided, ﬁne-needle aspiration of lymph node
tissue for pathologic analysis. The use of this technique for obtaining tissue
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from a suspicious hilar lesion is not advised because it can result in tumor
spread with peritoneal tumor seeding [45].
Positron emission tomography
As seen in other malignancies, cholangiocarcinoma cells may accumulate
[18F]-2-deoxy-glucose (FDG), thereby depicting cholangiocarcinomas as
‘‘hot spots’’ [46]. Mucinous cholangiocarcinomas are an exception because
they have been shown not to accumulate FDG [49]. In a recent study
with a limited number of patients, a sensitivity of 92% and speciﬁcity of
93% for detecting the primary lesion were described [56]; however, the sensitivity for detecting distant metastases and regional lymph node metastases
was only 67% and 13%, respectively. In addition, false-positive results can
be generated in the setting of chronic inﬂammation, and negative results do
not exclude malignancy [57]. In a larger number of patients, CT/PET scanning of cholangiocarcinoma was associated with a lower sensitivity, especially for extrahepatic cancer [58].
Other imaging modalities
Other imaging techniques include intraductal ultrasound, endoscopic/
percutaneous ﬂexible cholangioscopy, and radiolabeled imaging. These
techniques are not part of the routinely performed diagnostic work-up.
Laboratory analysis
Laboratory-based analysis for the diagnosis of cholangiocarcinoma is
restricted to serum, bile, bile duct brush cytology, and lymph node pathology. Percutaneous biopsy of the primary tumor is not advised due to an
increased risk of tumor spread.
Tumor markers
The most studied serum tumor markers are the carbohydrate antigen
19-9 (CA 19-9), carcinoembryonic antigen (CEA), and carbohydrate antigen
125 (CA-125). CEA and CA-125 are unspeciﬁc and can be elevated in the
setting of other gastrointestinal or gynecologic malignancies or other bile
duct pathology such as cholangitis and hepatolithiasis [59]. CA 19-9 was
ﬁrst described in 1979 and is currently the most commonly used tumor
marker for cholangiocarcinoma [60,61]. Nevertheless, CA 19-9 has certain
limitations which need to be considered when using it as a tumor marker.
First, CA 19-9 serum concentrations depend on the Lewis phenotype. As
many as 10% of the population have been found to be Lewis negative,
resulting in undetectable CA 19-9 levels [62,63]. Second, CA 19-9 can also
be elevated in other gastrointestinal or gynecologic malignancies and in
the setting of bacterial cholangitis [64–66]. The use of a CA 19-9 level cutoﬀ
value of greater than129 U/mL was shown to result in a sensitivity of 78.6%
and a speciﬁcity of 98.5%, and a change in CA 19-9 of 67.3 U/mL over time
provided a sensitivity of 90% and speciﬁcity of 98% [67].
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Cytologic analysis
A tissue diagnosis is usually obtained by brush cytology or bile duct
biopsy during ERCP. In the setting of primary sclerosing cholangitis, interpretation of cytology can be challenging due to reactive changes by inﬂammation [68]. The sensitivity and speciﬁcity for conventional brush cytology
are reported to be 37% to 63% and 89% to 100%, respectively [69–71]. The
limitations of conventional cytology relate to the typically desmoplastic
structure of this cancer and limited access to the biliary system. To improve
diagnostic accuracy for the diagnosis of cholangiocarcinoma, new advanced
cytologic techniques have been introduced, including digital image analysis
and ﬂuorescence in situ hybridization (FISH). Both techniques identify
aneuploidy. In digital image analysis, DNA content relative to normal
ploidy is quantitated. A comparison of digital image analysis with cytology
in patients with suspicious biliary strictures demonstrated a sensitivity of
39.3% with digital image analysis compared with 17.9% by cytology. The
speciﬁcity was 77.3% with digital image analysis compared with 97.7%
with cytology [72]. Evaluation of digital image analysis in patients who
had primary sclerosing cholangitis, 20% of whom had cholangiocarcinomas, demonstrated a sensitivity and speciﬁcity of 43% and 87%, respectively. In patients who had primary sclerosing cholangitis with negative
cytology, a sensitivity and speciﬁcity of 14% and 88% were described
[73]. FISH allows the detection of chromosomal ampliﬁcations by ﬂuorescence and is interpreted as positive if ﬁve or more cells display gains of
two or more chromosomes (polysomy) [73]. In patients who had primary
sclerosing cholangitis, polysomy detected by FISH had a sensitivity of
47%, a speciﬁcity of 100%, a positive predictive value of 100%, and a negative predictive value of 88% in the detection of cholangiocarcinomas. In
the setting of neither positive nor suspicious cytology, the sensitivity was
20% and the speciﬁcity 100%; the positive predictive value was reported
to be 100% and the negative predictive value 88% [74]. FISH remarkably
increases the yield of brush cytology for the diagnosis of cholangiocarcinoma without compromising speciﬁcity.
Therapy
Surgery
Resection
Surgical resection with curative intent is the treatment of choice for extrahepatic cholangiocarcinoma. Although the rate of resectability has been
reported to be as high as 65%, curative resection or margin-free resection
(R0) rates are less than 50% [75]. Criteria for unresectability of cholangiocarcinomas include bilateral involvement of the hepatic ducts to the level of
the secondary biliary radicals, atrophy of one liver lobe with encasement of
the contralateral portal vein branch, or atrophy of one liver lobe with
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contralateral secondary biliary radical involvement [76,77]. Bilateral portal
vein branch encasement or involvement of the major portal vein is also
a classic contraindication to surgical resection. Likewise, bilateral hepatic
artery encasement would be a contraindication. Intrahepatic metastases
are associated with such a poor outcome that most surgeons consider these
patients unresectable. Lymph node involvement is more controversial. The
outcome has not been reported to be inﬂuenced by local lymph node
involvement [78]; therefore, many surgeons will pursue resection despite
local lymph node metastases. Distant lymph node metastases are a contraindication to surgery. Comorbidities including signiﬁcant liver disease, cirrhosis, and cardiovascular or other systemic diseases as well as the patient’s
performance status have to be taken into consideration in the decision to
proceed with surgery. Solitary intrahepatic cholangiocarcinomas are
resected by hepatic lobectomy or segmentectomy. This strategy has reported
to achieve 5-year survival rates of 23% to 63% [79–81]. With R0 resection,
overall 5-year survival rates of 30% to 41% for hilar tumors, 31% to 63%
for intrahepatic tumors, and 27% to 37% for extrahepatic cholangiocarcinomas have been reported [78,81–85]. Mortality rates of resection are 5%
to 10% in major referral centers and mostly due to infections; liver failure
is unusual as a cause for postoperative mortality [78]. The perioperative
morbidity rate is between 31% and 85% [86–88].
The goal of neoadjuvant treatment options is to increase resectability
rates and decrease recurrence rates after resection. Neoadjuvant strategies
include chemotherapy, radiation, combined radiochemotherapy, and photodynamic therapy. Studies evaluating the treatment eﬀects have demonstrated
only limited eﬀects, have been nonrandomized, have been conducted in only
limited numbers of patients, and report only short-term follow-up [89,90].
Currently, no adjuvant therapy can be recommended. Preoperative portal
vein embolization before extended complex hepatectomy with the goal of
decreasing postoperative liver dysfunction was ﬁrst described by Makuuchi
and colleagues [91]. Liver resection is restricted to a postsurgical remnant
liver volume of 25% to 30% [92]. The rationale behind portal vein embolization is a compensatory hypertrophy of the nonembolized hepatic segments, thereby allowing extended hepatectomy with minimal postoperative
liver dysfunction. Increased resectability after portal vein embolization was
shown in a subset of patients who otherwise would have been marginal candidates for resection due to low remnant liver volumes [93]. A recent study in
150 patients undergoing extended hepatectomy for cholangiocarcinoma
failed to show a signiﬁcant diﬀerence in 5-year survival [94].
Transplantation
Initial results with liver transplantation for extrahepatic cholangiocarcinomas were disappointing, with 5-year survival rates of 23% to 26% and recurrence rates of 51% to 59% [95–97]. Based on the observed outcomes, liver
transplantation was discouraged as a therapeutic option for extrahepatic
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cholangiocarcinomas. Promising results were achieved with a new neoadjuvant strategy including external beam radiation concomitant with ﬂuorouracil (5-FU) followed by brachytherapy and then venous infusion of 5-FU
before liver transplantation for extrahepatic cholangiocarcinomas [98]. Further evaluation of this strategy with a modiﬁcation of the chemotherapy regimen resulted in signiﬁcantly improved outcomes after liver transplantation
in patients with perihilar cholangiocarcinomas [99]. Pretransplant treatment
consisted of external beam radiation with 4500 cGy in 30 fractions with concomitant chemotherapy with 500 mg/m2/d of 5-FU for the ﬁrst 3 days of
radiation. Chemoradiotherapy was followed by brachytherapy with 2000
to 3000 cGy of iridium 192. Upon completion, patients were treated with
2000 mg/m2/d of capecitabine 2 of every 3 weeks until transplantation.
Patients with surgically conﬁrmed stage I or II disease were approved for
liver transplantation. Five-year recurrence rates were 12%, and the overall
5-year survival rate in intention-to-treat analysis was 58% and 81% in
patients who underwent liver transplantation. The results were compared
with retrospective data from patients who had undergone potentially curative resection at the same institution between 1993 and 2004. The 5-year survival rate in the resection group was 21% and the 5-year recurrence rate 58%.
Risk factors for tumor recurrence in patients treated with this neoadjuvant
chemoradiotherapy approach followed by transplantation in a Cox regression analysis were older age, a level of CA 19-9 greater than 100 U/mL on
the day of transplantation, prior cholecystectomy, a mass on cross-sectional
imaging, residual tumor greater than 2 cm in explant, tumor grade, and perineural invasion in explant [100].
A similar protocol involving brachytherapy with 6000 cGy of iridium 192
and chemotherapy of 300 mg/m2/d of 5-FU but no external beam radiation
was evaluated at the University of Nebraska [101]. Long-term disease-free
survival was reported in 45% of transplanted patients; however, histopathologic analysis of explants showed the inclusion of stage III tumors in 46%
of transplanted patients. The results of these studies show the importance of
careful patient selection based on thorough surgical staging as well as the
feasibility of a neoadjuvant chemoradiotherapeutic strategy (Box 1). If these
requirements are met, excellent results can be achieved in patients with
unresectable, localized, and regional lymph node–negative perihilar cholangiocarcinomas [102]. In contrast to the excellent outcomes with liver
transplantation for extrahepatic perihilar cholangiocarcinomas, liver transplantation for intrahepatic cholangiocarcinomas is still fraught with disease
recurrence and cannot be advocated.
Local palliative therapy
Photodynamic therapy
Photodynamic therapy includes the application of a photosensitizing
agent followed by exposure to light at a wavelength corresponding to the
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Box 1. Criteria for liver transplantation
Diagnostic criteria
Positive (transluminal) biopsy
Positive conventional cytology on brush cytology
Stricture plus FISH polysomy
Mass lesion on cross-sectional imaging
Malignant appearing stricture and persistent CA 19-9 >100 U/mL
in the absence of cholangitis
Exclusion criteria
Prior radiation or chemotherapy
Uncontrolled infection
Intrahepatic metastases
Extrahepatic or distal lymph node metastases
Other malignancy within 5 years of cholangiocarcinoma
diagnosis
Age <18 or >65 years
Comorbidities forbidding chemo- or radiotherapy or liver
transplantation
Hilar mass on cross-sectional imaging with a radial diameter
of >3 cm
absorption spectrum of the photosensitizer. Illumination initiates a type II
photochemical reaction resulting in the generation of reactive oxygen species
[103]. The antiproliferative eﬀect is mediated by cell death induced by reactive oxygen species as well as thromboses within the tumor-supplying vessels, with ischemia as well as tumor-speciﬁc immune reactions [104–106].
The most commonly used compound is porﬁmer, a hematoporphyrin derivative that is activated at a wavelength of 630 nm and shown to cause cell
death at a tissue depth of 4 to 6 mm [107]. Several studies have evaluated
the eﬀects of photodynamic therapy in patients with unresectable cholangiocarcinomas [108–110]. The results of these studies indicate a reduction in
tumor thickness and an improvement of cholestasis and life quality
[110,111]. Several studies also show a trend toward improved survival
[111–115]. Two studies also evaluated photodynamic therapy as neoadjuvant or adjuvant treatment [90,116]; however, neither one was a controlled
study. A recent study evaluating photodynamic therapy in patients with
mostly Bismuth type III and IV cholangiocarcinoma found on multivariate
analysis that a visible mass on imaging, low serum albumin levels, and a prolonged time between diagnosis and photodynamic therapy were predictors
of poorer survival [117]. Photodynamic therapy is a reasonable approach
for palliation in cholangiocarcinomas [118]. Its role as a neoadjuvant or
adjuvant treatment requires further study.
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Radiotherapy
Other techniques for local ablation include radiotherapy, radiofrequency
ablation, and transcatheter ablation. There are two main administration
modes for radiotherapy for cholangiocarcinomasdexternal beam radiotherapy and intraluminal iridium 192 brachytherapy. Several uncontrolled studies have evaluated radiotherapy in the adjuvant, neoadjuvant, and palliative
setting [119–121]. In the palliative setting, survival beneﬁts in a subset of
patients without metastases were described [122]; however, the studies
were uncontrolled, the results mixed, and the radiation had signiﬁcant morbidity including gastrointestinal bleeding, strictures, small bowel obstruction, and even hepatic decompensation [123]. The authors do not employ
postoperative external beam radiotherapy as an adjuvant strategy at their
center.
Systemic therapy
There are no randomized controlled studies evaluating the eﬀect of
chemotherapy in cholangiocarcinoma. Existing data are derived from case
reports or small clinical studies with insuﬃcient statistical power to allow
deﬁnitive conclusions. Several diﬀerent chemotherapeutic drugs have been
evaluated. In general, tumor response to these drugs was poor. The most
commonly studied chemotherapeutic drugs include 5-FU and gemcitabine.
5-FU has been studied extensively as a monotherapeutic agent as well as
in combination with other chemotherapeutic agents such as doxorubicin,
epirubicin, cisplatin, lomustine, mitomycin C, paclitaxel, and other drugs
(eg, interferon-a) [124–133]. These studies were limited in the number of
patients studied, nonrandomized, and noncontrolled, and were not able to
demonstrate signiﬁcant tumor responses or signiﬁcant prolongation of
life. More recent studies have focused on gemcitabine, which was approved
in 2002 by the US Food and Drug Administration for cholangiocarcinoma
[134]. Studies evaluating gemcitabine as a monotherapeutic agent or in combination with other chemotherapeutic agents such as cisplatin, oxaliplatin,
docetaxel, mitomycin C, and 5-FU/leukovorin reported up to 60% response
rates [135,136]. Nevertheless, there are no randomized controlled studies
evaluating gemcitabine in cholangiocarcinoma; therefore, its impact on survival is unclear.
Targeted chemotherapy
We are rapidly entering the era of targeted chemotherapy for solid malignancies. For example, antiangiogenic therapies and targeted inhibition of
receptor tyrosine kinases are now approved for several malignancies. Such
therapies have not yet been thoroughly exploited for the treatment of cholangiocarcinoma. Targeted inhibition of the epidermal growth factor receptor has been reported with a suggestion of beneﬁt [137,138]. Potential
therapies in the future may include targeted inhibition of IL-6, blockade
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of Mcl-1 expression/function, and employment of the death ligand agonist,
tumor necrosis factordrelated, apoptosis-inducing ligand (TRAIL). It is
hoped that such trials can be developed for cholangiocarcinomas.
Palliation of cholestasis
The main cause of morbidity in cholangiocarcinoma is cholestasis and its
complications including cholangitis and pruritus. Several treatment options
for restoration of biliary drainage exist, including endoscopic treatment via
ERCP, surgical, or percutaneous approaches. Surgical drainage is achieved
by choledochojejunostomy or hepaticojejunostomy and radiologic treatment by PTC with stent placement. A comparison of endoscopic stent placement with surgical biliary bypass showed similar eﬃciency in the treatment
of malignant cholestasis but lower mortality, treatment-related early complications, and shorter hospital stay with endoscopic treatment [139–141];
therefore, endoscopic restoration of biliary drainage is generally preferred.
In complete biliary obstruction, percutaneous or surgical methods can be
unavoidable. A comparison between unilateral and bilateral hepatic duct
drainage showed that unilateral stent placement achieved similar rates of
successful drainage as bilateral stenting [142]. Plastic stents require exchange
in 2- to 3-month intervals because they tend to become occluded by a bioﬁlm
of bacteria and proteinacious material, but they are preferred in patients
with expected survival of less than 6 months or those awaiting planned surgery [143]. Metal stents are superior in stent patency and more cost eﬀective
in patients with anticipated survival of greater than 6 months [144].
Summary
Cholangiocarcinoma is a highly malignant tumor and the second most
common form of primary hepatic carcinoma. Its incidence has increased
within the last 3 decades without clear etiologic explanations for the
increase. Its prognosis is devastating, and the only curative therapy is surgical; however, signiﬁcant progress has been achieved in our understanding of
the etiology and molecular pathogenesis of this malignancy. Also, progress
has occurred in diagnosis and therapy. With the increasing arsenal of diagnostic modalities, patients can potentially be diagnosed at earlier stages,
thereby making them amenable to curative therapies. With the increase in
aggressive surgical management, the results of resection have improved as
reﬂected in better overall outcomes. For patients with unresectable perihilar
cholangiocarcinomas, impressive 5-year survival rates can be achieved with
liver transplantation combined with neoadjuvant chemoradiotherapy in
highly selected patients. With the increasing knowledge of the molecular
pathogenesis of this disease, there is hope for nonsurgical alternatives in
the future, especially targeted therapies.
CHOLANGIOCARCINOMA
145
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