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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 rst 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 specic entity was rst 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.
Classication
Cholangiocarcinomas are classied according to their anatomic location
as intrahepatic and extrahepatic (Fig. 1A). The extrahepatic type including
cancers involving the conuence 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
classication into types I to IV (type I, tumor involves the common hepatic
* Corresponding author.
E-mail address: gores.gregory@mayo.edu (G.J. Gores).
1089-3261/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.cld.2007.11.003
liver.theclinics.com
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Fig. 1. Anatomic classication of cholangiocarcinoma. (A) The anatomic classication of cholangiocarcinoma in intrahepatic, hilar, and distal ductal cholangiocarcinoma is depicted. Extrahepatic cholangiocarcinoma includes hilar and distal ductal cancers. (B) The Bismuth
classication of hilar cholangiocarcinoma into type I to IV stages is illustrated. Yellow areas
represent tumor and green areas normal bile duct. (Modied from de Groen PC, Gores GJ,
LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341:1369; with permission.
Copyright 1999, Massachusetts Medical Society.)
duct distal to the biliary conuence; type II, tumor involves the biliary conuence; type IIIa, tumor involves the biliary conuence plus the right
hepatic duct; type IIIb, tumor involves the biliary conuence plus the left
hepatic duct; type IV, multifocal or tumor involves the conuence and
both the right and left hepatic ducts) (Fig. 1B). Further subclassication
of extra- and intrahepatic cholangiocarcinomas has been dened based on
their macroscopic appearance. Extrahepatic cholangiocarcinomas display
a sclerosing, nodular, and papillary phenotype of which the sclerosing or
periductal inltrating type is the most common. It is characterized by annular bile duct thickening due to inltration and brosis of periductal tissues.
Intrahepatic cholangiocarcinomas are subclassied into mass forming, periductal inltrating, mass forming plus periductal inltrating, and intraductal;
this classication 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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between dierent 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 Pacic Islanders and Caucasians had prevalence rates
ranging between these two groups.
Etiology
In most patients, cholangiocarcinoma has developed without an identiable 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 rst 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 rst year
following the diagnosis of primary sclerosing cholangitis [17,18]. Hepatobiliary ukes 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 ukes are endemic. They are ingested with undercooked sh and infest
the bile ducts and occasionally the gallbladder. Increased incidence rates of
cholangiocarcinomas in liver ukeinfected patients have been shown in several case-control studies, and the correlation has been conrmed in animal
models [2022]. 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 [2325]. Additional risk factors for cholangiocarcinoma
include Carolis syndrome, congenital hepatic brosis, and choledochal
cysts, all of which carry a 10% to 15% risk for cholangiocarcinoma [2628].
Pathophysiology
The previously described etiologic factors create an environment of
chronic inammation predisposing biliary epithelium to malignant transformation. Chronic inammation 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 [2932]. Chronic inammation results in the
expression of multiple cytokines and chemokines by cholangiocytes and
inammatory cells [29,33]. One of the key cytokines in cholangiocarcinoma
carcinogenesis is interleukin-6 (IL-6) [29,3436]. It mediates cholangiocarcinoma cell survival by up-regulation of the potent anti-apoptotic protein
Mcl-1 [3739]. Cellular Mcl-1 protein levels are further enhanced by bile
acidinduced 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 inammatory 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 identied in patients with liver uke 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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by delayed moderate peripheral enhancement. Involved bile ducts are identied by irregular ductal narrowing with proximal dilatation [52]. The imaging quality of cholangiocarcinoma can be enhanced signicantly 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 ne-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, ne-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 specicity 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 inammation, 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 exible 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 unspecic 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
rst 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 [6466]. The use of a CA 19-9 level cuto
value of greater than129 U/mL was shown to result in a sensitivity of 78.6%
and a specicity of 98.5%, and a change in CA 19-9 of 67.3 U/mL over time
provided a sensitivity of 90% and specicity 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 inammation [68]. The sensitivity and specicity for conventional brush cytology
are reported to be 37% to 63% and 89% to 100%, respectively [6971]. 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 uorescence 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
specicity 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 specicity of 43% and 87%, respectively. In patients who had primary sclerosing cholangitis with negative
cytology, a sensitivity and specicity of 14% and 88% were described
[73]. FISH allows the detection of chromosomal amplications by uorescence and is interpreted as positive if ve 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 specicity 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 specicity 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 specicity.
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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cholangiocarcinomas. Promising results were achieved with a new neoadjuvant strategy including external beam radiation concomitant with uorouracil (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 modication of the chemotherapy regimen resulted in signicantly 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 rst 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 conrmed 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 nodenegative 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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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 [119121]. In the palliative setting, survival benets in a subset of
patients without metastases were described [122]; however, the studies
were uncontrolled, the results mixed, and the radiation had signicant 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 eect of
chemotherapy in cholangiocarcinoma. Existing data are derived from case
reports or small clinical studies with insucient statistical power to allow
denitive conclusions. Several dierent 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) [124133]. These studies were limited in the number of
patients studied, nonrandomized, and noncontrolled, and were not able to
demonstrate signicant tumor responses or signicant 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 benet [137,138]. Potential
therapies in the future may include targeted inhibition of IL-6, blockade
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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, signicant 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
reected 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.
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