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 extra-hepatic bile duct epithelium [1]. Historically, it was first described byDurand-Fardel in 1840 [2]. It was not until 1911 that primary liver neopla-sias were distinguished based on their cellular origin into ‘‘hepatomas’’ and‘‘cholangiomas’’ or ‘‘hepatocellular carcinomas’’ and ‘‘cholangiocarcino-mas’’ [3,4]. Hilar cholangiocarcinoma as a specific entity was first describedby Klatskin in 1965, and cholangiocarcinomas arising at this anatomic siteare often referred to as Klatskin tumors [5]. Cholangiocarcinomas may beconsidered rare tumors comprising only 3% of gastrointestinal tumors;however, they are the second most common primary hepatic tumors, andtheir incidence is increasing. Surgical resection or liver transplantation isthe only potentially curative therapeutic option. Photodynamic therapycan be palliative for unresectable but localized cancer. In the future, targetedtherapies have the potential to extend life for patients with advanced meta-static disease.

Clin Liver Dis 12 (2008) 131–150

Classification

Cholangiocarcinomas are classified according to their anatomic locationas intrahepatic and extrahepatic (Fig. 1A). The extrahepatic type includingcancers involving the confluence of the right and left hepatic ducts accountsfor 80% to 90% and the intrahepatic type for 5% to 10% of all cholangio-carcinomas. The anatomic margins for distinguishing intra- and extrahe-patic cholangiocarcinomas are the second order bile ducts. Extrahepaticcholangiocarcinomas can further be subdivided according to the Bismuthclassification 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

Fig. 1. Anatomic classification of cholangiocarcinoma. (A) The anatomic classification of chol-

angiocarcinoma in intrahepatic, hilar, and distal ductal cholangiocarcinoma is depicted. Extra-

hepatic 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 � 1999, Massachusetts Medical Society.)

132 BLECHACZ & GORES

duct distal to the biliary confluence; type II, tumor involves the biliary con-fluence; type IIIa, tumor involves the biliary confluence plus the righthepatic duct; type IIIb, tumor involves the biliary confluence plus the lefthepatic duct; type IV, multifocal or tumor involves the confluence andboth the right and left hepatic ducts) (Fig. 1B). Further subclassificationof extra- and intrahepatic cholangiocarcinomas has been defined based ontheir macroscopic appearance. Extrahepatic cholangiocarcinomas displaya sclerosing, nodular, and papillary phenotype of which the sclerosing orperiductal infiltrating type is the most common. It is characterized by annu-lar bile duct thickening due to infiltration and fibrosis of periductal tissues.Intrahepatic cholangiocarcinomas are subclassified into mass forming, peri-ductal infiltrating, mass forming plus periductal infiltrating, and intraductal;this classification has been shown to correlate with prognosis [6]. Histolog-ically, adenocarcinoma is the most common pathologic form, comprising90% of cases. Other histologic types include papillary adenocarcinoma,intestinal type adenocarcinoma, clear cell adenocarcinoma, signet-ring cellcarcinoma, adenosquamous carcinoma, squamous cell carcinoma, and oatcell carcinoma [7].

Epidemiology

Cholangiocarcinoma accounts for less than 2% of all human malignan-cies [8]; however, it is the second most common primary hepatic malignancy

133CHOLANGIOCARCINOMA

after hepatocellular carcinoma, accounting for 10% to 15% of primaryhepatic malignancies. Its prevalence is geographically heterogeneous, withthe highest rates in Asia, especially Southeast Asia [9]. In Western Europeand the Unites States, the incidence and mortality have increased over thelast 4 decades.

Incidence

In the United States, the age-adjusted incidence of intrahepatic cholan-giocarcinoma has increased by 165% from 0.32/100,000 in 1975 to 1979to 0.85/100,000 in 1995 to 1999; between 1985 and 1993, the incidencerate increased dramatically [10,11]. An increasing incidence has also beenobserved in other regions around the globe. Estimated incidence rates inCrete, Greece, have increased from 0.998/100,000 in 1992 to 1994 to3.327/100,000 in 1998 to 2000 [12]. In Japan, the frequency of intrahepaticcholangiocarcinoma diagnosed at autopsy increased from 0.31% to 0.58%between 1976 to 1977 and 1996 to 1997 [13]. Although it was reportedthat the incidence rates for extrahepatic cholangiocarcinoma decreased by14% from 1.08/100,000 to 0.82/100,000 in 1998 [9], these numbers are notaccurate because the majority of the epidemiologic studies misclassified hilarcholangiocarcinoma as intrahepatic cholangiocarcinoma. This systematicmistake was due to a misclassification of these tumors in the ICD-O codingsystem derived data form for the Surveillance, Epidemiology, and EndResults program. Welzel and colleagues [14] addressed this issue and reeval-uated incidence rates of intra- and extrahepatic cholangiocarcinoma aftercorrection of this misclassification. They reported that 91% of hilar tumorswere misclassified as intrahepatic, resulting in an overestimation of intrahe-patic cholangiocarcinoma by 13% and an underestimation of extrahepaticcholangiocarcinoma by 15%. Nevertheless, reevaluation of incidence ratesin the United States between 1978 and 2000 still identified a significantincrease of intrahepatic cholangiocarcinomas, while no significant changein the incidence of extrahepatic cholangiocarcinomas was noted. The causeof the global increase in the incidence rates for intrahepatic cholangiocarci-nomas is unclear. The etiopathogenesis for most patients with cholangiocar-cinoma remains obscure.

Gender, age, and other factors

Worldwide, the average age at presentation is 50 years. In Westernnations, most instances of cholangiocarcinomas are diagnosed at 65 yearsof age or older and only rarely before the age of 40 years [9]. In the generalpopulation, 52% to 54% of cholangiocarcinomas are observed in malepatients; however, mortality data show a higher estimated annual percent-age change (EAPC) in females when compared with males, with an EAPCof 6.9 � 1.5 for males and 5.1 � 1.0 for females [15]. Differences in theprevalence of cholangiocarcinoma have been reported globally as well as

134 BLECHACZ & GORES

between different racial and ethnic groups [16]. Globally, the highest preva-lence has been described in Southeast Asia. Within the United States,a comparison of the 10-year prevalence between 1990 and 2000 showeda high age-adjusted prevalence of 1.22/100,000 for intrahepatic cholangio-carcinomas in Hispanics. Interestingly, within this group, the prevalencewas higher in females. The lowest prevalence was described in AfricanAmericans, with a prevalence of 0.5/100,000 for males and 0.17/100,000for females. Asian Pacific Islanders and Caucasians had prevalence ratesranging between these two groups.

Etiology

In most patients, cholangiocarcinoma has developed without an identifi-able etiology; however, certain risk factors for cholangiocarcinoma havebeen established. One of the most commonly recognized risk factors isprimary sclerosing cholangitis. The prevalence of cholangiocarcinoma inpatients who have primary sclerosing cholangitis is 5% to 15% [17]. Theannual incidence rate for cholangiocarcinoma in the setting of primary scle-rosing cholangitis is 0.6% to 1.5% [17,18]. In most patients, cholangiocarci-nomas are diagnosed within the first 2.5 years after the diagnosis of primarysclerosing cholangitis, and prospective studies have reported that 37% ofpatients developing cholangiocarcinoma will do so within the first yearfollowing the diagnosis of primary sclerosing cholangitis [17,18]. Hepatobili-ary flukes are another risk factor for cholangiocarcinomas. A strong associ-ation has been shown with the species Opisthorchis viverrini and Clonorchissinensis and the development of cholangiocarcinoma [19]. Especially in EastAsia, one of the regions with the highest prevalence of cholangiocarcinoma,these flukes are endemic. They are ingested with undercooked fish and infestthe bile ducts and occasionally the gallbladder. Increased incidence rates ofcholangiocarcinomas in liver fluke–infected patients have been shown in sev-eral case-control studies, and the correlation has been confirmed in animalmodels [20–22]. Another risk factor for cholangiocarcinoma that is morecommon in Asian than Western countries is hepatolithiasis. Cholangiocar-cinoma incidence rates of 10% in patients who have hepatolithiasis havebeen reported [23–25]. Additional risk factors for cholangiocarcinomainclude Caroli’s syndrome, congenital hepatic fibrosis, and choledochalcysts, all of which carry a 10% to 15% risk for cholangiocarcinoma [26–28].

Pathophysiology

The previously described etiologic factors create an environment ofchronic inflammation predisposing biliary epithelium to malignant transfor-mation. Chronic inflammation and cholestasis have been linked to carcino-genesis in cholangiocarcinoma. Together, both conditions can promote the

135CHOLANGIOCARCINOMA

four major cancer phenotypes: (1) autonomous cell proliferation; (2) inva-sion/metastases; (3) escape from senescence; and (4) evasion of cell death[29,30]. A variety of molecular alterations have been described in thesecarcinogenic phenotypes [29–32]. Chronic inflammation results in theexpression of multiple cytokines and chemokines by cholangiocytes andinflammatory cells [29,33]. One of the key cytokines in cholangiocarcinomacarcinogenesis is interleukin-6 (IL-6) [29,34–36]. It mediates cholangiocarci-noma cell survival by up-regulation of the potent anti-apoptotic proteinMcl-1 [37–39]. Cellular Mcl-1 protein levels are further enhanced by bileacid–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 oxidesynthase (iNOS) in inflammatory cells and epithelial bile duct cells.Increased iNOS expression has been observed in cholangiocytes in primarysclerosing cholangitis and cholangiocarcinoma, and elevated serum nitrateconcentrations have been identified in patients with liver fluke infection[43]. Increased expression of iNOS results in increased generation of nitricoxide which inhibits DNA repair proteins and apoptosis by nitrosylationof base excision repair enzymes (eg, OGG1) and caspase-9, respectively[43,44]. Several additional molecular alterations have been reported, result-ing in the activation of growth factors and proto-oncogenes as well asinhibition of tumor suppressor genes [29,45]. In addition, alterations ingenes coding for adhesion molecules and anti-angiogenic factors havebeen described, mediating tumor invasion and spread [29,45].

Diagnosis

The diagnosis and staging of cholangiocarcinoma require a multimodalityapproach involving laboratory, radiologic, endoscopic, and pathologic anal-ysis. Despite the variety of techniques used, determining the extent of dis-ease still poses a challenge and is often underestimated. The diagnosticmodalities described in the following sections, in combination and in theappropriate clinical context, are useful to help achieve diagnostic accuracy.

Clinical, endoscopic, and radiologic diagnosis

Extrahepatic and intrahepatic cholangiocarcinomas present with distinctclinical 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 dom-inated by the anatomic location of the tumor. The predominant clinical fea-ture of extrahepatic cholangiocarcinoma is biliary obstruction resulting inpainless jaundice, with which 90% of patients initially present [7,46].

136 BLECHACZ & GORES

Intrahepatic cholangiocarcinoma presents in most cases as an intrahepaticmass causing right upper abdominal quadrant pain and other tumor-relatedsymptoms such as cachexia and malaise. Approximately 10% of patientspresent with cholangitis [7].

Ultrasonography

Ultrasound is one of the first-line imaging modalities chosen for the eval-

uation of cholestasis or liver dysfunction. For the identification of cholan-giocarcinoma, it has only limited value [46]. Findings include unspecificsigns such as intrahepatic bile duct dilatation with an abrupt change inbile duct caliber in cases of extrahepatic and hilar cholangiocarcinoma.Extrahepatic cholangiocarcinoma tumor masses are seldom identified byultrasound [47,48]. Intrahepatic cholangiocarcinomas are identified as a non-specific intrahepatic mass. Doppler ultrasonography can be helpful fordetecting compression and tumor encasement of the portal vein or hepaticartery. Overall, the sensitivity and specificity of ultrasound is poor in thediagnosis of cholangiocarcinoma, and staging generally relies on otherimaging modalities [49,50].

Computed tomography

CT can be helpful in the staging, preoperative planning, and evaluation

of vascular encasement. Intrahepatic cholangiocarcinoma can present asan irregular shaped mass with delayed and peripheral enhancement duringthe portovenous phase of the study. Hilar and extrahepatic cholangiocarci-nomas may present as a mass, ductal thickening, or nonunion of the rightand left hepatic duct with or without ductal thickening. As is true for ultra-sound, hilar tumor masses are difficult to visualize by CT. Intrahepatic bileduct dilatation in a single small lobe and hypertrophy of the contralaterallobe signify the atrophy-hypertrophy complex seen with lobar duct obstruc-tion frequently plus ipsilateral portal vein encasement [51]. Evaluation ofintraductal spread and detection of lymph node and peritoneal metastasesby CT are also suboptimal. The sensitivity for N2 metastases detection byCT has been reported to be 50% and the overall accuracy in the assessmentof resectability 60% to 75%.

Magnetic resonance imaging and magnetic resonancecholangiopancreatography

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 hepaticparenchymal anatomy, and intrahepatic metastases. Cholangiocarcinomais characterized on MRI as a hypointense structure on T1-weighted imagesand a hyperintense structure on T2-weighted images (Fig. 2). Centralhypointensity on T2-weighted MRI corresponds to central fibrosis. In dy-namic contrast-enhanced MRI, cholangiocarcinoma is usually recognized

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).

137CHOLANGIOCARCINOMA

by delayed moderate peripheral enhancement. Involved bile ducts are iden-tified by irregular ductal narrowing with proximal dilatation [52]. The imag-ing quality of cholangiocarcinoma can be enhanced significantly by the useof 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 evaluatethe proximal and distal intraductal extent of the tumor. Cholangiographycan be done by performing endoscopic retrograde cholangiopancreatogra-phy (ERCP), MRCP, or transcutaneous cholangiography (PTC). MRCPhas the advantage of being noninvasive and the possibility of obtainingadditional information about other intra- and extrahepatic anatomic struc-tures, whereas ERCP and PTC have the advantage of allowing bile ductsampling for diagnostic analysis as well as the possibility of relieving biliaryobstruction by the insertion of stents. The choice of the imaging modalitydepends also on location of the tumor; distal extrahepatic cholangiocarci-noma is optimally evaluated by ERCP. At times, hilar cholangiocarcinomascan 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 addi-tion, it allows ultrasound-guided, fine-needle aspiration of lymph nodetissue for pathologic analysis. The use of this technique for obtaining tissue

138 BLECHACZ & GORES

from a suspicious hilar lesion is not advised because it can result in tumorspread 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 becausethey have been shown not to accumulate FDG [49]. In a recent studywith a limited number of patients, a sensitivity of 92% and specificity of93% for detecting the primary lesion were described [56]; however, the sen-sitivity for detecting distant metastases and regional lymph node metastaseswas only 67% and 13%, respectively. In addition, false-positive results canbe generated in the setting of chronic inflammation, and negative results donot exclude malignancy [57]. In a larger number of patients, CT/PET scan-ning of cholangiocarcinoma was associated with a lower sensitivity, espe-cially for extrahepatic cancer [58].

Other imaging modalities

Other imaging techniques include intraductal ultrasound, endoscopic/

percutaneous flexible cholangioscopy, and radiolabeled imaging. Thesetechniques are not part of the routinely performed diagnostic work-up.

Laboratory analysis

Laboratory-based analysis for the diagnosis of cholangiocarcinoma isrestricted to serum, bile, bile duct brush cytology, and lymph node pathol-ogy. Percutaneous biopsy of the primary tumor is not advised due to anincreased 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 antigen125 (CA-125). CEA and CA-125 are unspecific and can be elevated in thesetting of other gastrointestinal or gynecologic malignancies or other bileduct pathology such as cholangitis and hepatolithiasis [59]. CA 19-9 wasfirst described in 1979 and is currently the most commonly used tumormarker for cholangiocarcinoma [60,61]. Nevertheless, CA 19-9 has certainlimitations which need to be considered when using it as a tumor marker.First, CA 19-9 serum concentrations depend on the Lewis phenotype. Asmany 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 alsobe elevated in other gastrointestinal or gynecologic malignancies and inthe setting of bacterial cholangitis [64–66]. The use of a CA 19-9 level cutoffvalue 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 timeprovided a sensitivity of 90% and specificity of 98% [67].

139CHOLANGIOCARCINOMA

Cytologic analysis

A tissue diagnosis is usually obtained by brush cytology or bile duct

biopsy during ERCP. In the setting of primary sclerosing cholangitis, inter-pretation of cytology can be challenging due to reactive changes by inflam-mation [68]. The sensitivity and specificity for conventional brush cytologyare reported to be 37% to 63% and 89% to 100%, respectively [69–71]. Thelimitations of conventional cytology relate to the typically desmoplasticstructure of this cancer and limited access to the biliary system. To improvediagnostic accuracy for the diagnosis of cholangiocarcinoma, new advancedcytologic techniques have been introduced, including digital image analysisand fluorescence in situ hybridization (FISH). Both techniques identifyaneuploidy. In digital image analysis, DNA content relative to normalploidy is quantitated. A comparison of digital image analysis with cytologyin patients with suspicious biliary strictures demonstrated a sensitivity of39.3% with digital image analysis compared with 17.9% by cytology. Thespecificity was 77.3% with digital image analysis compared with 97.7%with cytology [72]. Evaluation of digital image analysis in patients whohad primary sclerosing cholangitis, 20% of whom had cholangiocarcino-mas, demonstrated a sensitivity and specificity of 43% and 87%, respec-tively. In patients who had primary sclerosing cholangitis with negativecytology, a sensitivity and specificity of 14% and 88% were described[73]. FISH allows the detection of chromosomal amplifications by fluores-cence and is interpreted as positive if five or more cells display gains oftwo or more chromosomes (polysomy) [73]. In patients who had primarysclerosing cholangitis, polysomy detected by FISH had a sensitivity of47%, a specificity of 100%, a positive predictive value of 100%, and a neg-ative predictive value of 88% in the detection of cholangiocarcinomas. Inthe setting of neither positive nor suspicious cytology, the sensitivity was20% and the specificity 100%; the positive predictive value was reportedto be 100% and the negative predictive value 88% [74]. FISH remarkablyincreases the yield of brush cytology for the diagnosis of cholangiocarci-noma without compromising specificity.

Therapy

Surgery

ResectionSurgical resection with curative intent is the treatment of choice for extra-

hepatic cholangiocarcinoma. Although the rate of resectability has beenreported to be as high as 65%, curative resection or margin-free resection(R0) rates are less than 50% [75]. Criteria for unresectability of cholangio-carcinomas include bilateral involvement of the hepatic ducts to the level ofthe secondary biliary radicals, atrophy of one liver lobe with encasement ofthe contralateral portal vein branch, or atrophy of one liver lobe with

140 BLECHACZ & GORES

contralateral secondary biliary radical involvement [76,77]. Bilateral portalvein branch encasement or involvement of the major portal vein is alsoa classic contraindication to surgical resection. Likewise, bilateral hepaticartery encasement would be a contraindication. Intrahepatic metastasesare associated with such a poor outcome that most surgeons consider thesepatients unresectable. Lymph node involvement is more controversial. Theoutcome has not been reported to be influenced by local lymph nodeinvolvement [78]; therefore, many surgeons will pursue resection despitelocal lymph node metastases. Distant lymph node metastases are a contrain-dication to surgery. Comorbidities including significant liver disease, cirrho-sis, and cardiovascular or other systemic diseases as well as the patient’sperformance status have to be taken into consideration in the decision toproceed with surgery. Solitary intrahepatic cholangiocarcinomas areresected by hepatic lobectomy or segmentectomy. This strategy has reportedto 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 cholangiocarci-nomas have been reported [78,81–85]. Mortality rates of resection are 5%to 10% in major referral centers and mostly due to infections; liver failureis unusual as a cause for postoperative mortality [78]. The perioperativemorbidity rate is between 31% and 85% [86–88].

The goal of neoadjuvant treatment options is to increase resectabilityrates and decrease recurrence rates after resection. Neoadjuvant strategiesinclude chemotherapy, radiation, combined radiochemotherapy, and photo-dynamic therapy. Studies evaluating the treatment effects have demonstratedonly limited effects, have been nonrandomized, have been conducted in onlylimited numbers of patients, and report only short-term follow-up [89,90].Currently, no adjuvant therapy can be recommended. Preoperative portalvein embolization before extended complex hepatectomy with the goal ofdecreasing postoperative liver dysfunction was first described by Makuuchiand colleagues [91]. Liver resection is restricted to a postsurgical remnantliver volume of 25% to 30% [92]. The rationale behind portal vein emboli-zation is a compensatory hypertrophy of the nonembolized hepatic seg-ments, thereby allowing extended hepatectomy with minimal postoperativeliver dysfunction. Increased resectability after portal vein embolization wasshown in a subset of patients who otherwise would have been marginal can-didates for resection due to low remnant liver volumes [93]. A recent study in150 patients undergoing extended hepatectomy for cholangiocarcinomafailed to show a significant difference in 5-year survival [94].

Transplantation

Initial results with liver transplantation for extrahepatic cholangiocarci-

nomas were disappointing, with 5-year survival rates of 23% to 26% and re-currence rates of 51% to 59% [95–97]. Based on the observed outcomes, livertransplantation was discouraged as a therapeutic option for extrahepatic

141CHOLANGIOCARCINOMA

cholangiocarcinomas. Promising results were achieved with a new neoadju-vant strategy including external beam radiation concomitant with fluoroura-cil (5-FU) followed by brachytherapy and then venous infusion of 5-FUbefore liver transplantation for extrahepatic cholangiocarcinomas [98]. Fur-ther evaluation of this strategy with a modification of the chemotherapy reg-imen resulted in significantly improved outcomes after liver transplantationin patients with perihilar cholangiocarcinomas [99]. Pretransplant treatmentconsisted of external beam radiation with 4500 cGy in 30 fractions with con-comitant chemotherapy with 500 mg/m2/d of 5-FU for the first 3 days ofradiation. Chemoradiotherapy was followed by brachytherapy with 2000to 3000 cGy of iridium 192. Upon completion, patients were treated with2000 mg/m2/d of capecitabine 2 of every 3 weeks until transplantation.Patients with surgically confirmed stage I or II disease were approved forliver transplantation. Five-year recurrence rates were 12%, and the overall5-year survival rate in intention-to-treat analysis was 58% and 81% inpatients who underwent liver transplantation. The results were comparedwith retrospective data from patients who had undergone potentially cura-tive resection at the same institution between 1993 and 2004. The 5-year sur-vival rate in the resection group was 21% and the 5-year recurrence rate 58%.Risk factors for tumor recurrence in patients treated with this neoadjuvantchemoradiotherapy approach followed by transplantation in a Cox regres-sion analysis were older age, a level of CA 19-9 greater than 100 U/mL onthe day of transplantation, prior cholecystectomy, a mass on cross-sectionalimaging, residual tumor greater than 2 cm in explant, tumor grade, and peri-neural invasion in explant [100].

A similar protocol involving brachytherapy with 6000 cGy of iridium 192and chemotherapy of 300 mg/m2/d of 5-FU but no external beam radiationwas evaluated at the University of Nebraska [101]. Long-term disease-freesurvival was reported in 45% of transplanted patients; however, histopath-ologic analysis of explants showed the inclusion of stage III tumors in 46%of transplanted patients. The results of these studies show the importance ofcareful patient selection based on thorough surgical staging as well as thefeasibility of a neoadjuvant chemoradiotherapeutic strategy (Box 1). If theserequirements are met, excellent results can be achieved in patients withunresectable, localized, and regional lymph node–negative perihilar cholan-giocarcinomas [102]. In contrast to the excellent outcomes with livertransplantation for extrahepatic perihilar cholangiocarcinomas, liver trans-plantation for intrahepatic cholangiocarcinomas is still fraught with diseaserecurrence 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

Box 1. Criteria for liver transplantation

Diagnostic criteriaPositive (transluminal) biopsyPositive conventional cytology on brush cytologyStricture plus FISH polysomyMass lesion on cross-sectional imagingMalignant appearing stricture and persistent CA 19-9 >100 U/mL

in the absence of cholangitis

Exclusion criteriaPrior radiation or chemotherapyUncontrolled infectionIntrahepatic metastasesExtrahepatic or distal lymph node metastasesOther malignancy within 5 years of cholangiocarcinoma

diagnosisAge <18 or >65 yearsComorbidities forbidding chemo- or radiotherapy or liver

transplantationHilar mass on cross-sectional imaging with a radial diameter

of >3 cm

142 BLECHACZ & GORES

absorption spectrum of the photosensitizer. Illumination initiates a type IIphotochemical reaction resulting in the generation of reactive oxygen species[103]. The antiproliferative effect is mediated by cell death induced by reac-tive oxygen species as well as thromboses within the tumor-supplying ves-sels, with ischemia as well as tumor-specific immune reactions [104–106].The most commonly used compound is porfimer, a hematoporphyrin deriv-ative that is activated at a wavelength of 630 nm and shown to cause celldeath at a tissue depth of 4 to 6 mm [107]. Several studies have evaluatedthe effects of photodynamic therapy in patients with unresectable cholangio-carcinomas [108–110]. The results of these studies indicate a reduction intumor 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 neoadju-vant or adjuvant treatment [90,116]; however, neither one was a controlledstudy. A recent study evaluating photodynamic therapy in patients withmostly Bismuth type III and IV cholangiocarcinoma found on multivariateanalysis that a visible mass on imaging, low serum albumin levels, and a pro-longed time between diagnosis and photodynamic therapy were predictorsof poorer survival [117]. Photodynamic therapy is a reasonable approachfor palliation in cholangiocarcinomas [118]. Its role as a neoadjuvant oradjuvant treatment requires further study.

143CHOLANGIOCARCINOMA

Radiotherapy

Other techniques for local ablation include radiotherapy, radiofrequency

ablation, and transcatheter ablation. There are two main administrationmodes for radiotherapy for cholangiocarcinomasdexternal beam radiother-apy and intraluminal iridium 192 brachytherapy. Several uncontrolled stud-ies have evaluated radiotherapy in the adjuvant, neoadjuvant, and palliativesetting [119–121]. In the palliative setting, survival benefits in a subset ofpatients without metastases were described [122]; however, the studieswere uncontrolled, the results mixed, and the radiation had significant mor-bidity including gastrointestinal bleeding, strictures, small bowel obstruc-tion, and even hepatic decompensation [123]. The authors do not employpostoperative external beam radiotherapy as an adjuvant strategy at theircenter.

Systemic therapy

There are no randomized controlled studies evaluating the effect ofchemotherapy in cholangiocarcinoma. Existing data are derived from casereports or small clinical studies with insufficient statistical power to allowdefinitive conclusions. Several different chemotherapeutic drugs have beenevaluated. In general, tumor response to these drugs was poor. The mostcommonly studied chemotherapeutic drugs include 5-FU and gemcitabine.5-FU has been studied extensively as a monotherapeutic agent as well asin 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 ofpatients studied, nonrandomized, and noncontrolled, and were not able todemonstrate significant tumor responses or significant prolongation oflife. More recent studies have focused on gemcitabine, which was approvedin 2002 by the US Food and Drug Administration for cholangiocarcinoma[134]. Studies evaluating gemcitabine as a monotherapeutic agent or in com-bination with other chemotherapeutic agents such as cisplatin, oxaliplatin,docetaxel, mitomycin C, and 5-FU/leukovorin reported up to 60% responserates [135,136]. Nevertheless, there are no randomized controlled studiesevaluating gemcitabine in cholangiocarcinoma; therefore, its impact on sur-vival is unclear.

Targeted chemotherapy

We are rapidly entering the era of targeted chemotherapy for solid malig-nancies. For example, antiangiogenic therapies and targeted inhibition ofreceptor tyrosine kinases are now approved for several malignancies. Suchtherapies have not yet been thoroughly exploited for the treatment of chol-angiocarcinoma. Targeted inhibition of the epidermal growth factor recep-tor has been reported with a suggestion of benefit [137,138]. Potentialtherapies in the future may include targeted inhibition of IL-6, blockade

144 BLECHACZ & GORES

of Mcl-1 expression/function, and employment of the death ligand agonist,tumor necrosis factordrelated, apoptosis-inducing ligand (TRAIL). It ishoped that such trials can be developed for cholangiocarcinomas.

Palliation of cholestasis

The main cause of morbidity in cholangiocarcinoma is cholestasis and itscomplications including cholangitis and pruritus. Several treatment optionsfor restoration of biliary drainage exist, including endoscopic treatment viaERCP, surgical, or percutaneous approaches. Surgical drainage is achievedby choledochojejunostomy or hepaticojejunostomy and radiologic treat-ment by PTC with stent placement. A comparison of endoscopic stent place-ment with surgical biliary bypass showed similar efficiency in the treatmentof malignant cholestasis but lower mortality, treatment-related early compli-cations, 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 beunavoidable. A comparison between unilateral and bilateral hepatic ductdrainage showed that unilateral stent placement achieved similar rates ofsuccessful drainage as bilateral stenting [142]. Plastic stents require exchangein 2- to 3-month intervals because they tend to become occluded by a biofilmof bacteria and proteinacious material, but they are preferred in patientswith expected survival of less than 6 months or those awaiting planned sur-gery [143]. Metal stents are superior in stent patency and more cost effectivein patients with anticipated survival of greater than 6 months [144].

Summary

Cholangiocarcinoma is a highly malignant tumor and the second mostcommon form of primary hepatic carcinoma. Its incidence has increasedwithin the last 3 decades without clear etiologic explanations for theincrease. Its prognosis is devastating, and the only curative therapy is surgi-cal; however, significant progress has been achieved in our understanding ofthe etiology and molecular pathogenesis of this malignancy. Also, progresshas occurred in diagnosis and therapy. With the increasing arsenal of diag-nostic modalities, patients can potentially be diagnosed at earlier stages,thereby making them amenable to curative therapies. With the increase inaggressive surgical management, the results of resection have improved asreflected in better overall outcomes. For patients with unresectable perihilarcholangiocarcinomas, impressive 5-year survival rates can be achieved withliver transplantation combined with neoadjuvant chemoradiotherapy inhighly selected patients. With the increasing knowledge of the molecularpathogenesis of this disease, there is hope for nonsurgical alternatives inthe future, especially targeted therapies.

145CHOLANGIOCARCINOMA

References

[1] de Groen PC, Gores GJ, LaRusso NF, et al. Biliary tract cancers. N Engl J Med 1999;341:

1368–78.

[2] Renshaw K. Malignant neoplasms of the extrahepatic biliary ducts. Ann Surg 1922;76:

205–21.

[3] Goldzieher M, von Bokay Z. Der primaere Leberkrebs. Virchows Arch 1911;203:75–131.

[4] Yamagiwa K. Kenntnis des primaren parenchy: matosen Leberkarzinoms (‘‘Hepatoma’’).

Virchows Arch 1911;206:437–67.

[5] KlatskinG. Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis:

an unusual tumor with distinctive clinical and pathological features. Am J Med 1965;38:

241–56.

[6] Hirohashi K, Venishi T, Kubo S, et al. Macroscopic types of intrahepatic cholangiocarci-

noma: clinicopathologic features and surgical outcomes. Hepatogastroenterology 2002;49:

326–9.

[7] Olnes MJ, Erlich R. A review and update on cholangiocarcinoma. Oncology 2004;66:

167–79.

[8] Parker SL, Tong T, Bolden S, et al. Cancer statistics, 1996. CA Cancer J Clin 1996;46:

5–27.

[9] ShaibY, El-SeragHB. The epidemiology of cholangiocarcinoma. Semin Liver Dis 2004;24:

115–25.

[10] Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in

the United States. Hepatology 2001;33:1353–7.

[11] Shaib YH, Davila JA, McGlynn K, et al. Rising incidence of intrahepatic cholangiocarci-

noma in the United States: a true increase? J Hepatol 2004;40:472–7.

[12] Mouzas IA, et al. Increasing incidence of cholangiocarcinoma inCrete 1992-2000. Antican-

cer Res 2002;22:3637–41.

[13] Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 1.

Epidemiology and etiology. J Gastroenterol Hepatol 2002;17:1049–55.

[14] Welzel TM,McGlynn KA, Hsing AW, et al. Impact of classification of hilar cholangiocar-

cinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma

in the United States. J Natl Cancer Inst 2006;98:873–5.

[15] Patel T. Worldwide trends in mortality from biliary tract malignancies. BMCCancer 2002;

2:1–5.

[16] McLean L, Patel T. Racial and ethnic variations in the epidemiology of intrahepatic

cholangiocarcinoma in the United States. Liver Int 2006;26:1047–53.

[17] Burak K, et al. Incidence and risk factors for cholangiocarcinoma in primary sclerosing

cholangitis. Am J Gastroenterol 2004;99:523–6.

[18] Bergquist A, et al. Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.

J Hepatol 2002;36:321–7.

[19] Watanapa P, Watanapa WB. Liver fluke-associated cholangiocarcinoma. Br J Surg 2002;

89:962–70.

[20] Kurathong S, et al.Opisthorchis viverrini infection and cholangiocarcinoma: a prospective,

case-controlled study. Gastroenterology 1985;89:151–6.

[21] Tesana S, et al. Ultrastructural and immunohistochemical analysis of cholangiocarcinoma

in immunized Syrian golden hamsters infected withOpisthorchis viverrini and administered

with dimethylnitrosamine. Parasitol Int 2000;49:239–51.

[22] Parkin DM, et al. Liver cancer in Thailand. I. A case-control study of cholangiocarcinoma.

Int J Cancer 1991;48:323–8.

[23] Kubo S, Kinoshita H, Hirohashi K, et al. Hepatolithiasis associated with cholangiocarci-

noma. World J Surg 1995;19:637–41.

[24] Lesurtel M, et al. Intrahepatic cholangiocarcinoma and hepatolithiasis: an unusual

association in Western countries. Eur J Gastroenterol Hepatol 2002;14:1025–7.

146 BLECHACZ & GORES

[25] Su CH, Shyr YM, LuiWY, et al. Hepatolithiasis associated with cholangiocarcinoma. Br J

Surg 1997;84:969–73.

[26] Chapman RW. Risk factors for biliary tract carcinogenesis. Ann Oncol 1999;10(Suppl 4):

308–11.

[27] Lipsett PA, Pitt HA, Colombani PM, et al. Choledochal cyst disease: a changing pattern of

presentation. Ann Surg 1994;220:644–52.

[28] Scott J, Shousha S, Thomas HC, et al. Bile duct carcinoma: a late complication of congen-

ital hepatic fibrosis. Case report and review of literature. Am J Gastroenterol 1980;73:

113–9.

[29] Gores GJ. Cholangiocarcinoma: current concepts and insights. Hepatology 2003;37:

961–9.

[30] Malhi H, Gores GJ. Cholangiocarcinoma: modern advances in understanding a deadly old

disease. J Hepatol 2006;45:856–67.

[31] BerthiaumeEP,Wands J. Themolecular pathogenesis of cholangiocarcinoma. Semin Liver

Dis 2004;24:127–37.

[32] Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress. Part 2.

Molecular pathology and treatment. J Gastroenterol Hepatol 2002;17:1056–63.

[33] Moss SF, Blaser MJ. Mechanisms of disease: inflammation and the origins of cancer. Nat

Clin Pract Oncol 2005;2:90–7, quiz 1 p following 113.

[34] OkadaK, ShimizuY,Nambu S, et al. Interleukin-6 functions as an autocrine growth factor

in a cholangiocarcinoma cell line. J Gastroenterol Hepatol 1994;9:462–7.

[35] SugawaraH, et al. Relationship between interleukin-6 and proliferation and differentiation

in cholangiocarcinoma. Histopathology 1998;33:145–53.

[36] Park J, Tadlock L, Gores GJ, et al. Inhibition of interleukin 6-mediated mitogen-activated

protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology

1999;30:1128–33.

[37] Isomoto H, et al. Interleukin 6 upregulates myeloid cell leukemia-1 expression through

a STAT3 pathway in cholangiocarcinoma cells. Hepatology 2005;42:1329–38.

[38] Kobayashi S, Werneburg NW, Bronk SF, et al. Interleukin-6 contributes to Mcl-1 up-

regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma

cells. Gastroenterology 2005;128:2054–65.

[39] Isomoto H, et al. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to

SOCS-3 epigenetic silencing. Gastroenterology 2007;132:384–96.

[40] Yoon JH, et al. Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor

receptor/Raf-1-dependent mechanism. Cancer Res 2002;62:6500–5.

[41] Werneburg NW, Yoon JH, Higuchi H, et al. Bile acids activate EGF receptor via a TGF-

alpha-dependent mechanism in human cholangiocyte cell lines. Am J Physiol Gastrointest

Liver Physiol 2003;285:G31–6.

[42] YamagiwaY,MengF, Patel T. Interleukin-6 decreases senescence and increases telomerase

activity in malignant human cholangiocytes. Life Sci 2006;78:2494–502.

[43] Jaiswal M, LaRusso NF, Burgart LJ, et al. Inflammatory cytokines induce DNA damage

and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide–dependent

mechanism. Cancer Res 2000;60:184–90.

[44] Torok NJ, Higuchi H, Bronk S, et al. Nitric oxide inhibits apoptosis downstream of

cytochrome C release by nitrosylating caspase 9. Cancer Res 2002;62:1648–53.

[45] Malhi H, Gores GJ. Review article: the modern diagnosis and therapy of cholangiocarci-

noma. Aliment Pharmacol Ther 2006;23:1287–96.

[46] Khan SA, et al. Guidelines for the diagnosis and treatment of cholangiocarcinoma:

consensus document. Gut 2002;51(Suppl 6):VI1–9.

[47] Robledo R, Muro A, Prieto ML. Extrahepatic bile duct carcinoma: US characteristics and

accuracy in demonstration of tumors. Radiology 1996;198:869–73.

[48] Hann LE, Greatrex KV, Bach AM, et al. Cholangiocarcinoma at the hepatic hilus:

sonographic findings. AJR Am J Roentgenol 1997;168:985–9.

147CHOLANGIOCARCINOMA

[49] Slattery JM, Sahani DV. What is the current state-of-the-art imaging for detection and

staging of cholangiocarcinoma? Oncologist 2006;11:913–22.

[50] Foley WD, Quiroz FA. The role of sonography in imaging of the biliary tract. Ultrasound

Q 2007;23:123–35.

[51] Hann LE, et al. Hepatic lobar atrophy: association with ipsilateral portal vein obstruction.

AJR Am J Roentgenol 1996;167:1017–21.

[52] Manfredi R, Barbaro B, Masselli G, et al. Magnetic resonance imaging of cholangiocarci-

noma. Semin Liver Dis 2004;24:155–64.

[53] BragaHJ, ImamK, BluemkeDA.MR imaging of intrahepatic cholangiocarcinoma: use of

ferumoxides for lesion localization and extension. AJR Am J Roentgenol 2001;177:111–4.

[54] Raman SS, et al. Hepatic MR imaging using ferumoxides: prospective evaluation with

surgical and intraoperative sonographic confirmation in 25 cases. AJR Am J Roentgenol

2001;177:807–12.

[55] Gores GJ. Early detection and treatment of cholangiocarcinoma. Liver Transpl 2000;6:

S30–4.

[56] Kluge R, et al. Positron emission tomography with [(18)F]fluoro-2-deoxy-D-glucose for

diagnosis and staging of bile duct cancer. Hepatology 2001;33:1029–35.

[57] Fritscher-Ravens A, et al. FDG PET in the diagnosis of hilar cholangiocarcinoma. Nucl

Med Commun 2001;22:1277–85.

[58] Petrowsky H, et al. Impact of integrated positron emission tomography and computed

tomography on staging and management of gallbladder cancer and cholangiocarcinoma.

J Hepatol 2006;45:43–50.

[59] Chen CY, Shiesh SC, Tsao HC, et al. The assessment of biliary CA 125, CA 19-9 and CEA

in diagnosing cholangiocarcinoma: the influence of sampling time and hepatolithiasis.

Hepatogastroenterology 2002;49:616–20.

[60] Koprowski H, et al. Colorectal carcinoma antigens detected by hybridoma antibodies.

Somatic Cell Genet 1979;5:957–71.

[61] Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin

Liver Dis 2004;24:139–54.

[62] Narimatsu H, et al. Lewis and secretor gene dosages affect CA 19-9 and DU-PAN-2 serum

levels in normal individuals and colorectal cancer patients. Cancer Res 1998;58:512–8.

[63] Vestergaard EM, et al. Reference values and biological variation for tumormarkerCA 19-9

in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis

genotyping in a Caucasian population. Clin Chem 1999;45:54–61.

[64] Kim HJ, et al. A new strategy for the application of CA 19-9 in the differentiation of

pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J

Gastroenterol 1999;94:1941–6.

[65] AkdoganM, et al. Extraordinarily elevated CA 19-9 in benign conditions: a case report and

review of the literature. Tumori 2001;87:337–9.

[66] Albert MB, Steinberg WM, Henry JP. Elevated serum levels of tumor marker CA 19-9 in

acute cholangitis. Dig Dis Sci 1988;33:1223–5.

[67] Levy C, et al. The value of serum CA 19-9 in predicting cholangiocarcinomas in patients

with primary sclerosing cholangitis. Dig Dis Sci 2005;50:1734–40.

[68] Rabinovitz M, et al. Diagnostic value of brush cytology in the diagnosis of bile duct

carcinoma: a study in 65 patients with bile duct strictures. Hepatology 1990;12:747–52.

[69] Ponsioen CY, et al. Value of brush cytology for dominant strictures in primary sclerosing

cholangitis. Endoscopy 1999;31:305–9.

[70] Lee JG, Leung JW, Baillie J, et al. Benign, dysplastic, or malignant: making sense of

endoscopic bile duct brush cytology. Results in 149 consecutive patients. Am J Gastroen-

terol 1995;90:722–6.

[71] Furmanczyk PS, Grieco VS, Agoff SN. Biliary brush cytology and the detection of cholan-

giocarcinoma in primary sclerosing cholangitis: evaluation of specific cytomorphologic

features and CA 19-9 levels. Am J Clin Pathol 2005;124:355–60.

148 BLECHACZ & GORES

[72] Baron TH, et al. A prospective comparison of digital image analysis and routine cytology

for the identification of malignancy in biliary tract strictures. Clin Gastroenterol Hepatol

2004;2:214–9.

[73] Moreno Luna LE, Gores GJ. Advances in the diagnosis of cholangiocarcinoma in patients

with primary sclerosing cholangitis. Liver Transpl 2006;12:S15–9.

[74] Moreno Luna LE, et al. Advanced cytologic techniques for the detection of malignant

pancreatobiliary strictures. Gastroenterology 2006;131:1064–72.

[75] Nagorney DM, Kendrick ML. Hepatic resection in the treatment of hilar cholangiocarci-

noma. Adv Surg 2006;40:159–71.

[76] Patel T. Cholangiocarcinoma. Nat Clin Pract Gastroenterol Hepatol 2006;3:33–42.

[77] Jarnagin WR, Shoup M. Surgical management of cholangiocarcinoma. Semin Liver Dis

2004;24:189–99.

[78] Jarnagin WR, et al. Staging, resectability, and outcome in 225 patients with hilar

cholangiocarcinoma. Ann Surg 2001;234:507–17 [discussion: 517–9].

[79] Yeh CN, Jan YY, Yeh TS, et al. Hepatic resection of the intraductal papillary type of

peripheral cholangiocarcinoma. Ann Surg Oncol 2004;11:606–11.

[80] Ohtsuka M, et al. Results of surgical treatment for intrahepatic cholangiocarcinoma and

clinicopathological factors influencing survival. Br J Surg 2002;89:1525–31.

[81] DeOliveiraML, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at

a single institution. Ann Surg 2007;245:755–62.

[82] Neuhaus P, et al. Extended resections for hilar cholangiocarcinoma. Ann Surg 1999;230:

808–18 [discussion: 819].

[83] Silva MA, et al. Surgery for hilar cholangiocarcinoma: a 10 year experience of a tertiary

referral centre in the UK. Eur J Surg Oncol 2005;31:533–9.

[84] Pichlmayr R, et al. Surgical treatment in proximal bile duct cancer: a single-center

experience. Ann Surg 1996;224:628–38.

[85] Weber SM, et al. Intrahepatic cholangiocarcinoma: resectability, recurrence pattern, and

outcomes. J Am Coll Surg 2001;193:384–91.

[86] Kawarada Y, Das BC, Naganuma T, et al. Surgical treatment of hilar bile duct carcinoma:

experience with 25 consecutive hepatectomies. J Gastrointest Surg 2002;6:617–24.

[87] HemmingAW,ReedAI, Fujita S, et al. Surgical management of hilar cholangiocarcinoma.

Ann Surg 2005;241:693–9 [discussion: 699–702].

[88] Gazzaniga GM, Filauro M, Bagarolo C, et al. Surgery for hilar cholangiocarcinoma: an

Italian experience. J Hepatobiliary Pancreat Surg 2000;7:122–7.

[89] McMasters KM, et al. Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma.

Am J Surg 1997;174:605–8 [discussion: 608–9].

[90] Wiedmann M, et al. Neoadjuvant photodynamic therapy as a new approach to treating

hilar cholangiocarcinoma: a phase II pilot study. Cancer 2003;97:2783–90.

[91] Makuuchi M, et al. Preoperative portal embolization to increase safety of major

hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 1990;

107:521–7.

[92] Vauthey JN, et al. Standardized measurement of the future liver remnant prior to extended

liver resection: methodology and clinical associations. Surgery 2000;127:512–9.

[93] Abdalla EK, Barnett CC, Doherty D, et al. Extended hepatectomy in patients with

hepatobiliary malignancies with and without preoperative portal vein embolization. Arch

Surg 2002;137:675–80 [discussion: 680–1].

[94] NaginoM, et al. Two hundred forty consecutive portal vein embolizations before extended

hepatectomy for biliary cancer: surgical outcome and long-term follow-up. Ann Surg 2006;

243:364–72.

[95] Meyer CG, Penn I, James L. Liver transplantation for cholangiocarcinoma: results in 207

patients. Transplantation 2000;69:1633–7.

[96] Casavilla FA, et al. Hepatic resection and transplantation for peripheral cholangiocarci-

noma. J Am Coll Surg 1997;185:429–36.

149CHOLANGIOCARCINOMA

[97] Iwatsuki S, et al. Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic

resection or transplantation. J Am Coll Surg 1998;187:358–64.

[98] De Vreede I, et al. Prolonged disease-free survival after orthotopic liver transplantation

plus adjuvant chemoirradiation for cholangiocarcinoma. Liver Transpl 2000;6:309–16.

[99] Rea DJ, et al. Liver transplantation with neoadjuvant chemoradiation is more effective

than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451–8 [discussion:

458–61].

[100] Heimbach JK, et al. Predictors of disease recurrence following neoadjuvant chemoradio-

therapy and liver transplantation for unresectable perihilar cholangiocarcinoma.

Transplantation 2006;82:1703–7.

[101] Sudan D, et al. Radiochemotherapy and transplantation allow long-term survival for

nonresectable hilar cholangiocarcinoma. Am J Transplant 2002;2:774–9.

[102] Heimbach JK, et al. Liver transplantation for unresectable perihilar cholangiocarcinoma.

Semin Liver Dis 2004;24:201–7.

[103] OrtnerMA,DortaG. Technology insight: photodynamic therapy for cholangiocarcinoma.

Nat Clin Pract Gastroenterol Hepatol 2006;3:459–67.

[104] Abels C. Targeting of the vascular system of solid tumours by photodynamic therapy

(PDT). Photochem Photobiol Sci 2004;3:765–71.

[105] Krammer B. Vascular effects of photodynamic therapy. Anticancer Res 2001;21:4271–7.

[106] Korbelik M, Dougherty GJ. Photodynamic therapy-mediated immune response against

subcutaneous mouse tumors. Cancer Res 1999;59:1941–6.

[107] Dougherty TJ, Mang TS. Characterization of intra-tumoral porphyrin following injection

of hematoporphyrin derivative or its purified component. Photochem Photobiol 1987;46:

67–70.

[108] Rumalla A, et al. Endoscopic application of photodynamic therapy for cholangiocarci-

noma. Gastrointest Endosc 2001;53:500–4.

[109] OrtnerMA, et al. Photodynamic therapy of nonresectable cholangiocarcinoma. Gastroen-

terology 1998;114:536–42.

[110] Berr F, et al. Photodynamic therapy for advanced bile duct cancer: evidence for improved

palliation and extended survival. Hepatology 2000;31:291–8.

[111] OrtnerME, et al. Successful photodynamic therapy for nonresectable cholangiocarcinoma:

a randomized prospective study. Gastroenterology 2003;125:1355–63.

[112] Shim CS, et al. Prospective study of the effectiveness of percutaneous transhepatic

photodynamic therapy for advanced bile duct cancer and the role of intraductal ultrasonog-

raphy in response assessment. Endoscopy 2005;37:425–33.

[113] Harewood GC, et al. Pilot study to assess patient outcomes following endoscopic applica-

tion of photodynamic therapy for advanced cholangiocarcinoma. J Gastroenterol Hepatol

2005;20:415–20.

[114] Dumoulin FL, et al. Phase II study of photodynamic therapy and metal stent as palliative

treatment for nonresectable hilar cholangiocarcinoma. Gastrointest Endosc 2003;57:

860–7.

[115] Zoepf T, Jakobs R, Arnold JC, et al. Palliation of nonresectable bile duct cancer: improved

survival after photodynamic therapy. Am J Gastroenterol 2005;100:2426–30.

[116] NanashimaA, et al. Adjuvant photodynamic therapy for bile duct carcinoma after surgery:

a preliminary study. J Gastroenterol 2004;39:1095–101.

[117] Prasad GA, et al. Factors associated with increased survival after photodynamic therapy

for cholangiocarcinoma. Clin Gastroenterol Hepatol 2007;5:743–8.

[118] Berr F. Photodynamic therapy for cholangiocarcinoma. Semin Liver Dis 2004;24:177–87.

[119] Czito BG, AnscherMS, Willett CG. Radiation therapy in the treatment of cholangiocarci-

noma. Oncology (Williston Park) 2006;20:873–84 [discussion: 886–8, 893–5].

[120] Foo ML, Gunderson LL, Bender CE, et al. External radiation therapy and transcatheter

iridium in the treatment of extrahepatic bile duct carcinoma. Int J Radiat Oncol Biol

Phys 1997;39:929–35.

150 BLECHACZ & GORES

[121] Pitt HA, et al. Perihilar cholangiocarcinoma: postoperative radiotherapy does not improve

survival. Ann Surg 1995;221:788–97 [discussion: 797–8].

[122] Grove MK, Hermann RE, Vogt DP, et al. Role of radiation after operative palliation in

cancer of the proximal bile ducts. Am J Surg 1991;161:454–8.

[123] Cherqui D, et al. Intrahepatic cholangiocarcinoma: results of aggressive surgical manage-

ment. Arch Surg 1995;130:1073–8.

[124] Falkson G, MacIntyre JM, Moertel CG. Eastern cooperative oncology group experience

with chemotherapy for inoperable gallbladder and bile duct cancer. Cancer 1984;54:965–9.

[125] Takada T, et al. Comparison of 5-fluorouracil, doxorubicin and mitomycin C with 5-

fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 1994;51:

396–400.

[126] Choi CW, et al. Effects of 5-fluorouracil and leucovorin in the treatment of pancreatic-

biliary tract adenocarcinomas. Am J Clin Oncol 2000;23:425–8.

[127] PattYZ, et al. Phase II trial of intravenous fluorouracil and subcutaneous interferon alfa-2b

for biliary tract cancer. J Clin Oncol 1996;14:2311–5.

[128] Patt YZ, et al. Phase II trial of cisplatin, interferon alpha-2b, doxorubicin, and

5-fluorouracil for biliary tract cancer. Clin Cancer Res 2001;7:3375–80.

[129] Ducreux M, et al. Effective treatment of advanced biliary tract carcinoma using

5-fluorouracil continuous infusion with cisplatin. Ann Oncol 1998;9:653–6.

[130] LeeMA,WooIS,KangJH,etal.Epirubicin, cisplatin, andprotracted infusionof5-FU(ECF)

in advanced intrahepatic cholangiocarcinoma. J Cancer Res Clin Oncol 2004;130:346–50.

[131] Taieb J, et al. Optimization of 5-fluorouracil (5-FU)/cisplatin combination chemotherapy

with a new schedule of leucovorin, 5-FUand cisplatin (LV5FU2-P regimen) in patientswith

biliary tract carcinoma. Ann Oncol 2002;13:1192–6.

[132] RadererM, et al. Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin

C and of gemcitabine in patients with advanced biliary cancer. Oncology 1999;56:177–80.

[133] Jones DV Jr, Lozano R, Hoque A, et al. Phase II study of paclitaxel therapy for unresect-

able biliary tree carcinomas. J Clin Oncol 1996;14:2306–10.

[134] Alberts SR, et al. Treatment options for hepatobiliary and pancreatic cancer. Mayo Clin

Proc 2007;82:628–37.

[135] Kiba T, et al. Single-agent gemcitabine for biliary tract cancers: study outcomes and

systematic review of the literature. Oncology 2006;70:358–65.

[136] Scheithauer W. Review of gemcitabine in biliary tract carcinoma. Semin Oncol 2002;29:

40–5.

[137] Jimeno A, et al. Epidermal growth factor receptor dynamics influence response to

epidermal growth factor receptor targeted agents. Cancer Res 2005;65:3003–10.

[138] Wiedmann M, et al. Novel targeted approaches to treating biliary tract cancer: the dual

epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is

more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib.

Anticancer Drugs 2006;17:783–95.

[139] Shepherd HA, et al. Endoscopic biliary endoprosthesis in the palliation of malignant

obstruction of the distal common bile duct: a randomized trial. Br J Surg 1988;75:1166–8.

[140] Andersen JR, Sorensen SM,Kruse A, et al. Randomised trial of endoscopic endoprosthesis

versus operative bypass in malignant obstructive jaundice. Gut 1989;30:1132–5.

[141] Smith AC, Dowsett JF, Russell RC, et al. Randomised trial of endoscopic stenting versus

surgical bypass in malignant low bile duct obstruction. Lancet 1994;344:1655–60.

[142] De Palma GD, Galloro G, Siciliano S, et al. Unilateral versus bilateral endoscopic hepatic

duct drainage in patients with malignant hilar biliary obstruction: results of a prospective,

randomized, and controlled study. Gastrointest Endosc 2001;53:547–53.

[143] Abu-Hamda EM, Baron TH. Endoscopic management of cholangiocarcinoma. Semin

Liver Dis 2004;24:165–75.

[144] Kaassis M, et al. Plastic or metal stents for malignant stricture of the common bile duct?

Results of a randomized prospective study. Gastrointest Endosc 2003;57:178–82.